Conditions: B-Cell Prolymphocytic Leukemia Hypodiploidy Loss of Chromosome 17p Plasma Cell Leukemia Progression of Multiple Myeloma or Plasma Cell Leukemia Recurrent Adult Hodgkin Lymphoma Recurrent Adult Non-Hodgkin Lymphoma Recurrent Childhood Hodgkin Lymphoma Recurrent Childhood Non-Hodgkin Lymphoma Recurrent Chronic Lymphocytic Leukemia Recurrent Plasma Cell Myeloma Recurrent Small Lymphocytic Lymphoma Refractory Childhood Hodgkin Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Non-Hodgkin Lymphoma Refractory Plasma Cell Myeloma Refractory Small Lymphocytic Lymphoma t(14;16) t(4;14) T-Cell Prolymphocytic Leukemia Waldenstrom Macroglobulinemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
This phase II trial studies autologous peripheral blood stem cell transplant followed by donor bone marrow transplant in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft versus host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses stem cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. Event-free survival (EFS) at 1-year after autograft.

SECONDARY OBJECTIVES:

I. Relapse rates at 1-year after autograft.

II. Overall survival (OS) at 1-year after autograft.

III. Incidence of grades II-IV acute GVHD and chronic extensive GVHD.

IV. Non-relapse mortality (NRM) at 200 days and 1 year after allograft.

V. Donor engraftment at day +84.

VI. Incidence of infections.

OUTLINE:

CONDITIONING REGIMEN 1 (lymphoma, Waldenstrom macroglobulinemia, or chronic lymphocytic leukemia \[CLL\] with no dose limiting radiation or significant comorbidities: Patients receive cyclophosphamide intravenously (IV) on days -6 and -5. Patients undergo high-dose total body irradiation (TBI) twice daily (BID) on days -3 to -1.

CONDITIONING REGIMEN 2 (lymphoma, Waldenstrom Macroglobulinemia, CLL, with prior dose-limiting radiation, or significant comorbidities): Patients receive carmustine IV on day -7, etoposide IV BID on days -6 to -3, cytarabine IV BID on days -6 to -3, and melphalan IV on day -2.

CONDITIONING REGIMEN 3 (multiple myeloma or plasma cell leukemia, with no significant renal insufficiency or other significant comorbidities): Patients receive high-dose melphalan IV on day -2.

CONDITIONING REGIMEN 4 (multiple myeloma or plasma cell leukemia, with significant renal insufficiency or other significant comorbidities): Patients receive lessened dose of melphalan IV on day -2.

PBSC TRANSPLANTATION: All patients undergo autologous PBSC transplantation on day 0.

WAITING INTERVAL: Between 40 and 120 days.

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV once daily (QD) on days -6 to -2 and cyclophosphamide IV QD on days -6 to -5 and day 3. Patients infused with donor's peripheral blood stem cells will additionally receive cyclophosphamide IV on day 4. Patients undergo low-dose TBI on day -1.

ALLOGENEIC BONE MARROW TRANSPLANTATION: Patients undergo donor bone marrow transplantation on day 0.

GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 4, patients receive tacrolimus orally (PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also receive mycophenolate mofetil PO thrice daily (TID) on days 4 - 35.

PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning from day 4 and continue till blood counts recover.

ALLOGENEIC PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) TRANSPLANTATION: Patients undergo donor PBMC transplantation on day 0.

GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 5, patients receive tacrolimus orally (PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also receive mycophenolate mofetil PO thrice daily (TID) on days 5 - 35.

PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim IV or SC beginning from day 5 and continue till blood counts recover.

After completion of study treatment, patients are followed up annually for 5 years.

Arms:
arm 1: See Detailed Description

Interventions: intervention 1: Allogeneic Bone Marrow Transplantation intervention 2: Allogeneic Hematopoietic Stem Cell Transplantation intervention 3: Autologous Hematopoietic Stem Cell Transplantation intervention 4: Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation intervention 5: Carmustine intervention 6: Cyclophosphamide intervention 7: Cytarabine intervention 8: Etoposide intervention 9: Fludarabine Phosphate intervention 10: Laboratory Biomarker Analysis intervention 11: Melphalan intervention 12: Mycophenolate Mofetil intervention 13: Peripheral Blood Stem Cell Transplantation intervention 14: Tacrolimus intervention 15: Total-Body Irradiation
Intervention descriptions: intervention 1: Undergo donor HCT intervention 2: Undergo donor HCT intervention 3: Undergo autologous PBSC transplant intervention 4: Undergo autologous-donor tandem HCT intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV intervention 8: Given IV intervention 9: Given IV intervention 10: Correlative study intervention 11: Given IV intervention 12: Given PO intervention 13: Undergo donor HCT intervention 14: Given IV or PO intervention 15: Undergo TBI

Protocol document:
Prot_SAP_000.pdf: 
FHCRC 2241.00  
FHCRC current version: 10/10/2017 
1
 
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE, 
DEPARTMENT OF MEDICINE, DIVISION OF ONCOLOGY 
 SEATTLE CHILDREN’S 
 
Current Version: 10/10/2017 
Previous Version: 10/06/2017 
 
 
1. Title of protocol: Sequential Autologous HCT / Nonmyeloablative Allogeneic HCT 
using Related, HLA-Haploidentical Donors for Patients with High-Risk lymphoma, 
Multiple Myeloma, or chronic lymphocytic leukemia 
 
Investigators: 
 
Mohamed L. Sorror, MD/MSc  
Associate Member, Clinical Research, FHCRC; Associate Professor of 
Medicine, UW (206-667-6298);   
David G. Maloney, MD/PhD   
Member, FHCRC, Associate Professor of  
Medicine, UW (206-667-5616);   
Brenda M. Sandmaier, MD  
Member, FHCRC, Professor of Medicine, UW (206-667-4961); 
Paul Martin, M.D 
 
 
Member, FHCRC; Professor of Medicine, UW; 
Effie Petersdorf, M.D  
 
Member, FHCRC; Associate Professor of Medicine, UW; 
Ann Woolfrey, MD 
Member, FHCRC; Professor of Pediatrics, UW; 
William Bensinger, MD  
Member, FHCRC, Professor, UW (206-667-4933); 
Leona Holmberg, MD, PhD 
Member, FHCRC, Associate Professor of Medicine, UW  
(206-667-6447); 
Rainer Storb, MD  
Member, FHCRC, Professor of Medicine UW (206-667-4407). 
 
Biostatistician: Barry Storer, Ph.D., Member, FHCRC, (206)-667-6151. 
Radiation Oncologist: Ralph Ermoian, MD (206)-598-4100 
Research staff: 
 
Research Nurse: Michelle Bouvier, RN (206) 667-6993, pager (206) 995-7658 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
2
2. Introduction   
 
Patients with advanced lymphoma, multiple myeloma (MM), or chronic lymphocytic leukemia (CLL) have 
poor curative treatment options. High dose therapy followed by autologous hematopoietic cell transplantation 
(HCT) has been shown to be of benefit for patients with chemotherapy-sensitive relapsed lymphoma and 
multiple myeloma (MM) with 3-year disease-free survival (DFS) in the range of 30-65%.[1-7] Among 
lymphoma patients with chemotherapy-resistant or untested relapse, DFS ranged between 0-13%.[1,8-12] 
Similarly, patients with MM, though had survival prolongation compared with chemotherapy, eventually 
relapsed and died. [13] Limited data are available on the long- term efficacy of autologous HCT for CLL 
patients. [14-16] 
 
Allogeneic HCT after myeloablative conditioning resulted in prolonged remissions and low relapse rates for 
advanced lymphoma, MM, and CLL; but on the expense of relatively high (up to 60%) non-relapse mortality (NRM) 
even among patients younger than 50 years and with good performance status (PS). [16-20] Our nonmyeloablative 
conditioning regimen of 2 Gy total body irradiation (TBI) alone or with 90 mg/kg of fludarabine before allogeneic 
HCT have resulted in lessened NRM among a cohort of patients at least 10 years older than those historically offered 
myeloablative HCT with evidence of control of many hematological malignances. [21-28]  
 
Clinical studies at our institution have shown that nonmyeloablative allografts from HLA-related or unrelated 
donors for MM were most effective when performed in patients with low tumor burden. Cytoreductive 
autografts performed 40-120 days before nonmyeloablative allografts significantly improved CR rates without 
increasing the low NRM rates seen with nonmyeloablative allografts alone. [21,28] A more recent prospective 
study using Mendelian randomization suggested superior overall survival among patients with newly diagnosed 
MM after treatment with one autologous HCT followed by nonmyeloablative allografts from HLA-identical 
sibling donors compared to those given tandem autografts. This approach allowed temporal separation between 
the high dose conditioning and the GVT effects with NRM of 18% [29]. The same approach has been used for 
patients with advanced aggressive B cell malignancies with NRM and OS of 16% and 55% at 3-years, 
respectively (protocol 1409 and unpublished results). 
 
Nevertheless, the chance of the patient’s sibling to be HLA genotypically identical is only 25%. The chances of 
finding suitably phenotypically matched unrelated donors range from 60-70% for Caucasians to <10% for ethnic 
minorities. [30,31] [32] Recently, investigators at John Hopkins Medical School (Protocol #J9966) and FHCRC 
(Protocol #1667.00) have used nonmyeloablative conditioning with 2 Gy TBI and fludarabine, 150 mg/m2, in 
addition to cyclophosphamide administered before and after HLA-haploidentical related HCT to facilitate 
engraftment and delete alloreactive donor T-cell clones presumably involved in GVHD. Sixty-eight patients with 
advanced hematological malignancies have been studied. While NRM was relatively low at 1-year (19%), the rate of 
relapse was 50% at 1-year resulting in overall survival (OS) and DFS rates of 45% and 32%, respectively. [33] 
 
Here, we propose to explore the tandem approach of cytoreductive autologous HCT followed by nonmyeloablative 
HCT from HLA-haploidentical related donors for patients with relapsed/refractory MM, lymphoma, or CLL. We 
hypothesize that the high dose chemotherapy and/or myeloablative TBI preceding the autologous HCT will provide 
powerful cytoreduction and achieve a state of minimal disease. This will be augmented 40-120 days later by GVT 
effects associated with HLA-haploidentical related HCT. We hope to achieve lower relapse rates than noted with the 
single HCT approach while preserving the low NRM associated with nonmyeloablative conditioning resulting in 
improved DFS in patients with advanced lymphoma, MM, or CLL. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
3
3. Background 
A. Conditioning regimens for autologous HCT 
 
1. Lymphoma or CLL patients 
 
Several different conditioning regimens involving chemotherapy +/- TBI have been used before 
autologous HCT of patients with lymphoma or CLL. [34-36] Cy/TBI or BEAM given as proposed in 
this protocol should provide cytoreduction for refractory or relapsed lymphoma or CLL while being well 
tolerated, with rapid recovery allowing patients to the HLA-haploidentical allograft. 
 
 
The Cy/TBI conditioning regimen for autologous HCT has proven effective and resulted in high 
response rates (60-80%) and low NRM (in the range of 1-9%) in patients with refractory and relapsed 
lymphoma. Three-year DFS has ranged from 27 to55% suggesting that relapse remains the greatest 
cause of treatment failure. [5,37,38] Similar to results after Cy/TBI, 100 day NRM after BEAM ranged 
between 2.7 to10%, while 3-year DFS ranged from 40 to 62%.[10-12,39-42] The majority of clinical 
trials with autologous HCT for patients with CLL have investigated CY/TBI conditioning [16,43-46] 
and one trial investigated Cy/TBI and BEAM[47] with similar incidences of NRM to that seen in 
patients with lymphoma (range 0-9%). 
 
To date, however, no comparative randomized trials have been performed comparing regimens In 
general, a transplant center’s choice of regimen is based on experience with the regimens through local 
or national clinical trials. [36] We have elected, based on our experience, to use either 
cyclophosphamide and TBI (Cy/TBI), or BEAM for conditioning before autologous HCT. Use of either 
regimen for each enrolled patient will be decided by the Principal Investigator (PI) with preference for 
BEAM in patients who have previously received dose-limiting radiation or have high comorbidity 
scores.  
 
No randomized trials have compared conditioning with chemotherapy alone to chemotherapy + TBI for 
autologous HCT for relapsed lymphoma or CLL and the optimal approach remains undetermined. In 
general, a transplant center’s choice of regimen is based on experience with the regimens through local 
or national clinical trials. [36] Retrospective reviews showed no differences in outcomes. [48-51] 
However, subset analyses have identified two main limitations for the use of TBI-based conditioning 
regimens, one is the hazard of delivering TBI to patients who have received dose limiting radiation to 
vital organs. [52] The second limitation is the burden of pretransplant comorbidities, as summarized by 
the HCT-specific comorbidity index (HCT-CI) [53], where patients with scores of ≥3 experienced 2-
year NRM of 25% versus 5% after TBI-based versus BEAM regimens, respectively. [54]  
We have elected, based on our experience, to use either cyclophosphamide and TBI (Cy/TBI), or BEAM 
for conditioning before autologous HCT. Use of either regimen for each enrolled patient will be decided 
by attending physician after discussion with the Principal Investigator (PI) with preference for BEAM in 
patients who have previously received dose-limiting radiation [52] or have high comorbidity scores. 
[54]  
 
2. MM patients 
 
High-dose therapy with autologous hematopoietic cell transplantation (HCT) for advanced-stage 
myeloma in patients less than 65 years of age has survival advantages compared with conventional 
therapy. [6,55] In the Intergroupe Francais du Myélome (IFM) 90 trial, not only the CR rate, but the 7-
year DFS of 16% and OS of 43% were higher than those (8% and 25%) with conventional 
chemotherapy, respectively. [6,7] With high response rates and relatively low NRM of less than 10%, 
fewer than 30% of patients remain in remission 3 to 7 years later. [56-62] While a number of 
conditioning regimens have been used, melphalan at 200 mg/m2 has been well tolerated, even in patients 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
4
in their seventh decade of life, [63-65] and has generally been accepted as the current standard. [64] 
Conditioning with melphalan at 140 mg/m2 will be reserved for patients older than 70 years, or those 
with significant renal insufficiency, or high comorbidity scores. 
 
B. Tandem autograft/ nonmyeloablative allograft with HLA-matched donors 
 
Initially, nonmyeloablative allografts from HLA-matched related donors were used to treat 13 patients 
with relapsed/refractory MM. This resulted in relatively low NRM (2 patients), while 54% developed 
progressive disease. In a subsequent MM-specific protocol (#1383), the combination of a cytoreductive 
autograft using 200 mg/m2 melphalan with nonmyeloablative allograft was explored. Fifty four patients 
were enrolled in this tandem approach. [21] Median age was 52 (range 29-71) years, and 48% of 
patients had relapsed or refractory disease at time of HCT. Patients experienced medians of 0 days of 
hospitalization, neutropenia, and thrombocytopenia. With a median follow up of 552 days, OS was 78%. 
Overall response rate was 83% and 57% were in CR. A recent update included 102 patients treated with 
the same approach with median follow up of 5 years. [29] Thirty-four percent of patients had chemo-
refractory disease at time of HCT. Grades II-IV and III-IV acute GVHD were seen in 41% and 8% of 
patients respectively, while 69% had extensive chronic GVHD. Cumulative incidences of NRM at 100 
days, 1-year, and 5-year were 1%, 13%, and 19%, respectively. Overall response rate was 94% (63% 
were in CR). The 5-year rates of OS and PFS were 63% and 35%, respectively. These results suggested 
that the low NRM after either transplant modality could be preserved by the tandem approach. Longer 
follow up is required to determine the durability of the observed high response rates.  
 
Investigators from Italy have shown that planned tandem autografts/ nonmyeloablative allografts from 
HLA-matched related donors were associated with superior outcomes compared to tandem autografts. 
[66] In this trial 162 consecutive patients with newly diagnosed myeloma were enrolled. All patients 
were initially treated with vincristine, doxorubicin, and dexamethasone (VAD), followed by high dose 
melphalan and autologous stem-cell rescue. Patients with HLA-identical siblings then received 
nonmyeloablative HCT, while those without HLA-identical siblings received a second autologous HCT. 
With a median follow-up of 45 months, the median OS and DFS were longer in the 80 patients with 
HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months vs. 54 months, 
P=0.01; and 35 months vs. 29 months, P=0.02, respectively). Among patients who completed their 
assigned treatment protocols, NRM was comparable among recipients of the double-autologous-
transplant group (46 patients) and the autograft-allograft group (58 patients, P=0.09), but disease-related 
mortality was significantly higher in the double-autologous-transplant group (43% vs. 7%, P<0.001). 
The authors concluded that among patients with newly diagnosed myeloma, survival in recipients of a 
tandem autologous/allogeneic HCT from HLA-identical siblings was superior to that of recipients of 
tandem autografts.  
 
The tandem autologous/ nonmyeloablative allogeneic HCT from HLA-matched unrelated donors was 
explored in 13 patients with poor-risk MM and the results were compared to those given only 
nonmyeloablative allogeneic HCT. Patients given the tandem autologous-unrelated HCT versus the 
single unrelated HCT had higher overall response rate (77% compared to 18%, respectively, p=0.01). 
PFS was 51% compared to 11%, respectively (p=0.03). 
 
The tandem autologous-related HCT approach is also being investigated in the setting of lymphoma/CLL. 
To date, 33 patients have received autologous HCT followed after a median of 65 days with 
nonmyeloablative allogeneic HCT from HLA-matched related (n=25) or unrelated donors (n=8). Diagnoses 
were NHL (n=22), HL (n=7), or CLL (n=4). Median patient age was 49 years and number of prior regimens 
was 4 (range 1-12). Thirty-six percent of patients had disease responsive to the last chemotherapy before 
autografting [6% were in complete remission (CR)] while 46% and 18% had refractory and progressive 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
5
disease, respectively. Most patients had aggressive disease (82%). Conditioning for autografts consisted of 
BEAM (48%) or Cy/12 Gy TBI (52%). At allografting, 52% of patients had CR/PR (15%/37%), 12% stable 
disease, 3% relapse, and 33% refractory disease. After allogeneic HCT, 24 patients became neutropenic for 
a median of 13 days and 23 patients had thrombocytopenia (<20,000 cells/ul) for a median of 5 days. All 33 
patients had sustained engraftment. Incidences of grades II, III, and IV acute GVHD were 44%, 19%, and 
0% respectively, and chronic GVHD was 51%. With median follow up of 39 (range 10-87) months, the 
overall response rate was 63% (51% CR). Estimated 2-year rates of non-relapse mortality, relapse, overall, 
and progression-free survivals from the time of autografting were 16%, 38%, 55%, and 47% respectively. 
 
C. John Hopkins and FHCRC experience of nonmyeloablative conditioning and HLA-haploidentical 
HCT 
 
Pre-clinical data from a mouse model of H-2 haploidentical HCT have shown that the addition of 
cyclophosphamide before HCT was synergistic with fludarabine in preventing graft rejection and 
increasing the percent of donor chimerism. [67, 68] In addition, post transplantation Cy attenuated lethal 
and non-lethal GVH reactions. [67] Based on these data, two subsequent clinical trials were initiated for 
treatment of patients with high-risk hematological malignancies with nonmyeloablative HCT from 
related, HLA-haploidentical donors (Protocol J9966, Johns Hopkins and 1667 at FHCRC). Conditioning 
regimen was modified from the regimen developed by Storb and colleagues [69] and is detailed in 
Figure 1. Preliminary results demonstrated that partially HLA-mismatched bone marrow can engraft 
rapidly and stably after nonmyeloablative conditioning that included post-transplantation Cy. [70] 
 
A recent update of the results of these two trials incorporated 68 consecutive patients diagnosed with 
poor risk hematological malignancies except for one patient with paroxysmal nocturnal hemoglobinuria. 
{Luznik, O'Donnell, et al. 2008 34429 /id} Patients were treated on two protocols (Protocol J9966, 
Johns Hopkins and 1667 at FHCRC), which differed by postgrafting immunosuppression. 
Twenty-one patients (31%) had failed at least one autologous HCT: 12 of 13 patients with HL, 4 of 10 
patients with NHL, 3 of 27 patients with acute myeloid leukemia (AML), and one patient each with CLL 
and MM. Twenty-five percent of patients were from ethnic minority groups. Half (33 of 68) of the 
donors were siblings of patients, and about a quarter each were either parents or children (19 of 68 and 
16 of 68, respectively). Donors and recipients were mismatched by a median of 4 HLA loci in both the 
host-versus-graft (HVG) and GVH directions. 
 
Median times to neutrophil and platelet 
recoveries were 15 and 24 days, 
respectively. Graft rejections occurred in 9 
of 66 evaluable patients (13%). All but 1 
patient with graft failure experienced 
recovery of autologous hematopoiesis. 
Among engrafting patients, achievement 
of full donor chimerism was rapid and 
>95% by 2 months after transplantation.  
 
The median number of hospitalizations 
prior to day 60 was 1 (range: 0-4), and the 
median length of stay was 4 days (range: 
0-66). Neutropenic fever accounted for 51% of the admissions, nonneutropenic infections accounted for 
22%, aGVHD accounted for 9%, and other causes were the reason for the remaining 19% of admissions. 
A total of 22 patients (32%) did not require hospitalization within the first 60 days of transplantation. 
 
 
 
 
Figure 1. Nonmyeloablative haploidentical BMT 
conditioning and postgrafting immunosuppressive regimen. 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
6
CMV reactivation was observed in 17 of 45 (38%) high-risk patients with a median time to reactivation 
of 34 days. Acute GVHD was present in 7 patients on or about the time of CMV reactivation. There 
were no cases of CMV pneumonia and there was no CMV-associated mortality. Proved or probable 
invasive mold infections posttransplant, all caused by Aspergillus sp, were observed in 5 of 68 (7%) 
patients. Two patients died from Aspergillus infection: 1 while persistently neutropenic following graft 
failure, and 1 with fungal sinusitis. 
 
The probabilities of 
grades II-IV and 
III-IV acute GVHD 
by day 200 were 
34% and 6%, 
respectively (Figure 
2A). There was no 
statistically 
significant 
difference in the 
probability of acute 
GVHD between 
patients who 
received 1 versus 2 
doses of 
posttransplantation 
Cy. However, 
Figure 2B shows 
that the incidence of 
extensive cGVHD 
at 1 year in the group of patients who received 2 doses of posttransplantation Cy (5%) was suggestively 
lower than the incidence of extensive cGVHD in the group of patients who received 1 dose of 
posttransplantation Cy (25%; hazard ratio [HR] 0.21; 95% confidence interval [CI] 0.04-1.01; P = .05). 
 
 
 
 
Figure 2. Cumulative incidence of aGVHD and cGVHD. (A) Cumulative 
incidence of aGVHD grades II-IV and III-IV. (B) Cumulative incidence of 
extensive cGVHD for patients who received 1 (Seattle) versus 2 (Baltimore). 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
7
The probabilities of 
NRM at 100 days 
and at 1 year after 
transplantation 
were 4% and 15%, 
respectively, and 
the probabilities of 
relapse at 1 and 2 
years after 
transplantation 
were 51% and 58%, 
respectively (3A). 
There was no 
statistically 
significant effect of 
the dose of 
posttransplantation 
Cy on either NRM 
or relapse (data not 
shown). Patients 
with lymphoid malignancies had a significantly lower risk of relapse than patients with myeloid 
malignancies (HR 0.54, 95% CI 0.30-0.97, P = .04), suggesting efficacy of the GVL effect in patients 
with lymphoid malignancies.   
 
At a median follow-up among survivors of 745 days (range: 112-1483 days), the actuarial OS at 1 and at 
2 years was 46% and 36%, respectively (Figure 3B). The actuarial EFS at 1 and at 2 years was 34% and 
26%, respectively (Figure 3B). OS and EFS were not statistically significantly different between groups 
(data not shown). Causes of death included disease progression (n=31), GVHD (n=2), infection (n=4), 
and other causes (n=5). 
 
 Overall, 10 patients diagnosed with indolent or aggressive NHL were enrolled in these trials (O’Donnell 
P, 2007, Personal communications). Median number of prior regimens was 4 and four patients failed 
prior autologous HCT. Nine patients had sensitive disease to last chemotherapy regimen. Five patients 
had grade II acute GVHD and 4 patients had chronic GVHD. Four patients died with NRM at days 68, 
109, 163, and 182, respectively. One patient relapsed at 89 and died from relapse at day 225. Five 
patients are living in remission after 683, 727, 735, and 923, and 1716 days, respectively. 
 
Results from 21 patients diagnosed with HL and given nonmyeloablative HLA-haploidentical HCT were 
recently compared to those from 34 and 24 patients given HLA-matched related and unrelated 
nonmyeloablative HCT, respectively.{Burroughs, O'Donnell, et al. 2008 35218 /id} Fifty-two percent of 
haploidentical recipients had relapsed/refractory disease at time of HCT, which was higher than that 
among related recipients (21%) and comparable to the percentage among unrelated recipients (46%). 
Haploidentical recipients had median age of 31 years and 14% of patients had bulky disease, 62% had 
HCT-CI scores of ≥3, 57% had >5 prior regimens, 90% failed prior autologous HCT, and none of these 
characteristics differ from those among related or unrelated recipients. OS rate at 18-months among 
haploidentical recipients (71%) was comparable to that among unrelated recipients (74%) but superior to 
that among related recipients (47%, p=0.009). This was mainly due to exceptionally low cumulative 
incidences of NRM at 18 months among both haploidentical (5%) and unrelated recipients (8%) 
compared to that among related recipients (25%, p=0.02). Relapse rates were relatively high among the 
 
 
 
Figure 3. Outcomes among nonmyeloablative haploidentical BMT recipients. 
(A) Cumulative incidence of NRM and relapse. (B) OS and EFS. .doses of 
posttransplant Cy. 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
8
three patient groups (39%, 56%, and 55%, respectively), which leaves room for improvement of relapse 
rate among haploidentical recipients by appropriate disease cytoreduction using autologous HCT since 
76% of those patients had active disease at HCT. 
 
Three patients aged, 56, 71, and 63 years old had diagnosis of MM and were given nonmyeloablative 
HLA-haploidentical HCT. Two post-HCT doses of cytoxan were given to the first two patients and only 
one dose to the third patient. Prior regimens were 3, 4, and 3, respectively. Only the third patient had 
failed prior autologous HCT. The first patient did not develop acute GVHD, while the last two had grade 
II acute GVHD. All three patients died from relapsed disease. 
 
D. Rationale for including patients up to 75 years old 
Until recently, patients over 60 years of age have not been considered eligible for more intensive therapies 
including autologous HCT. This is unfortunate since the median age of patients with NHL, MM, or CLL 
ranges between 60 and 70 years, [71,72] suggesting that the majority of those patients are excluded from 
curative treatment clinical trials. Limited data are available on the feasibility and efficacy of autologous 
HCT in patients above 60 years. Comorbidities are more common in elderly patients where individuals who 
are older than 65 years suffer on average from three different diseases. [73] Similarly, older cancer patients 
presented high levels of comorbidity. Comorbidities could be, in part, responsible for the poor tolerance of 
some elderly cancer patients to intensive therapies and the resultant relatively higher mortality compared to 
younger fit patients. 
 
We have recently evaluated impact of comorbidities on outcomes of 273 patients diagnosed with NHL or 
HL and given autologous HCT. [54] Median age was 49 years with a range from 13 to 76. Comorbidities, as 
summarized by HCT-CI scores of >0, were found among 65% of patients, of whom 26% had scores of 3-4 
and 4% scores ≥5. Several pretransplant risk factors were tested in Univariate and then multivariate analyses 
for their impacts on outcomes. Interestingly, only age ≥60 years and HCT-CI scores of ≥3 were associated 
with increased risk for NRM in Univariate analysis. However, when all factors were entered into a Cox 
regression model, age ≥60 years did not have a statistically significant impact on NRM (p=0.73) or OS 
(p=0.73), while comorbidities significantly impacted NRM (p=0.0009) and OS (p<0.0001). The non-
significant impact of age persisted after resetting the age cut-off to ≥50 years. Patients with scores 3-4 and 
≥5 had NRM of 15% and 42% and OS of 57% and 25%, respectively, compared to NRM of 3% and 8% and 
OS of 80% and 78% among patients with scores of 0 and 1-2, respectively. Of note, 8 patients in this cohort 
were aged >70years with upper limit of 76 years old and HCT-CI scores ranged between 0 and 4. Six of 
those patients received BEAM conditioning regimen, while the other two had radiolabeled monoclonal 
antibody-based therapy. Only one patient relapsed after 84 days and died from relapsed disease 445 days 
after his autologous HCT. Two patients died with NRM at 47 and 667 days post autologous HCT, 
respectively. Five patients are currently alive after a median follow up of 740 (range: 441-1187) days. These 
findings suggest that biological rather than chronological age should be considered for eligibility for 
autologous HCT. 
 
Age per se does not seem to affect progenitor cell yield or success of mobilization in NHL or MM patients. 
[74-76] Several recent reports summarized outcomes of MM or NHL patients aged >60 years and given 
intensive chemo/radiotherapy and autologous HCT (Table 1). For NHL patients, NRM was in the range of 
5-10%.[54] For MM patients, low incidences of NRM have been reported (range of 0-5%) even after 
melphalan of 200 mg/m2. [76] 
 
The use of nonmyeloablative conditioning before allogeneic HCT has extended the eligibility of this 
treatment option to patients above 60 years with relatively low NRM. Therefore, patients will be enrolled up 
to age 75 years and eligibility for HCT will be determined by health status and comorbidities.


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
9
Table 1: Autologous HCT in NHL and MM patients >60 years of age 
Author 
Diagnosis 
No. of patients 
Median age (range), 
years 
Conditioning regimen 
100-day NRM, 
% 
Outcome 
Moreau et al[77] 
NHL 
11 
63 (61-65) 
BEAM 
0 
OS 46%/3.5 years 
DFS 50%/3.5 years 
Leger et al[78] 
NHL 
21 
62 (60-73) 
CBV 
BEAM 
10 
67% alive/19 months 
Jantunen et al[75] 
NHL 
13 
63 (60-70) 
BEAM (9) 
BEAC (4) 
8 
Os 62%/16 months 
Gopal et al[79] 
NHL 
53 
62 (60-67) 
BU-MEL-TT (24) 
TBI-CY-VP16 (16) 
TBI-CY (8) 
9 
OS 33%/4 years 
DFS 24%/4 years 
Zallio et al[80] 
NHL 
13 
67 (61-80) 
MEL80 +/- MITOX 
0 
OS 59%/ 5 years 
Bitran et al[81] 
NHL 
11 
66 (65-78) 
TBI-CY-VP16 (6) 
BEAM (5) 
9 
OS/DFS 44%/ 4 years 
Villela et al[82] 
NHL 
13 
63 (60-71) 
BEAM 
CBV 
0 
Not stated 
Jantunen et al[83] 
NHL 
88 
63 (60-70) 
BEAC (49) 
BEAM (34) 
TBI-CY (4) 
11 
OS 55%/5 years 
DFS 45%/ 5 years 
Bouadi et al[84] 
NHL 
93 
66 (60-76) 
BEAC 29 
5.4 
Median OS 25 months 
DFS 38%/ 4 years 
Palumbo et al[55] 
MM 
71 
71 (55-75) 
MEL100 x 2-3 
0 
CR 47% 
Median: OS = 56+ and DFS = 34 
months 
Sirohi et al[85] 
MM 
17 
67 (65-74) 
MEL200 
17 
CR 35% 
OS 3.6 years 
DFS 2 years 
Badros et al[86] 
MM 
25 
45 
72 (70-82) 
MEL200 
MEL140 
16 
2 
CR 20%, duration 31 months 
CR 28%, duration 15 months 
Overall OS 31% ± 10% 
Overall DFS 20% ± 9% 
Reece et al[87] 
MM 
110 
63 (60-73) 
Heterogeneous 
5 
OS 39 months 
DFS 27 months 
Jantunen et al[76] 
MM 
22 
68 (65-73) 
MEL200 
0 
CR 45% 
OS 57 months 
DFS 23 months 
Abbreviations: BEAC=carmustine-etoposide-cytarabine-cyclophosphamide; CBV=cyclophosphamide-carmustine-etoposide; BU-MEL-TT=busulfan-melphalan-thiotepa; TBI-
CY-VP16=total body irradiation-cyclophosphamide-etoposide; DLBCL=diffuse large B-cell lymphoma; EFS=event-free survival; FCL=follicular lymphoma; MCL=mantle cell 
lymphoma; MEL80=melphalan 80 mg/m2; MITOX=mitoxantrone.


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
10 
4. Objectives 
 
A. Proposal: 
Patients with chemotherapy-resistant or bulky lymphoma, high-risk MM, or fludarabine-refractory CLL 
have limited curative treatment options. The use of GVL effects is one way of eradicating residual and 
chemotherapy-resistant disease.  However, there are two potential problems. One is high NRM following 
conventional, myeloablative allogeneic HCT. The other is the unavailability of HLA-matched related or 
unrelated donors (for about 30% of patients) or the lack of time to identify unrelated donors due to rapid 
disease progression. Allogeneic HCT from HLA-haploidentical related donors following 
nonmyeloablative conditioning with 2 Gy TBI and fludarabine and post-transplantation 
immunosuppression with high dose Cy, tacrolimus, and thrice daily MMF was associated with acceptably 
low incidences of fatal graft rejection (2%), severe opportunistic infections (8%), severe acute GVHD 
(10%), and chronic extensive GVHD (22%) while allowing prompt engraftment (82%). However, relapse 
rates were 50% at 1 year resulting in 1 year EFS of 32%. We hypothesize that by applying a tandem 
approach of autologous high-dose HCT used for cytoreduction followed 40-120 days later by allogeneic 
nonmyeloablative HLA-haploidentical HCT, we can capture the benefits of high-dose autografting and 
HLA- haploidentical allografting (GVL effects). This approach would preserve the low GVHD and NRM 
observed after nonmyeloablative HLA-haploidentical HCT, while lowering the rate of relapse resulting in 
improved EFS. 
 
B. Primary objectives 
1. EFS at 1-year after autograft. 
C. Secondary objectives 
1. Relapse rates at 1-year after autograft. 
2. OS at 1-year after autograft. 
3. Incidence of grades II-IV acute GVHD and chronic extensive GVHD 
4. NRM at 200 days and 1 year after allograft 
5. Donor engraftment at day +84 
6. Incidence of infections 
 
5. Patient Selection 
A. Inclusions: 
1. Must have the capacity to give informed consent. 
2. Detectable tumor prior to mobilization regimen 
3. Age ≤75 years. 
4. Patients with stored autologous stem cells will be allowed.  
5. Stem cells from an identical donor could be used for autologous HCT 
6. Marrow is the preferred source of stem cells from the HLA-haploidentical donor, however peripheral 
      blood mononuclear cells (PBMC) could be used as stem cell source, after clearance with the  
      FHCRC principal investigator, in the case of difficulties or contraindications to bone marrow  
      harvest from the donor.         
7. Cross-over to other tandem autologous-allogeneic research protocol (#1409 or other appropriate 
protocol) will be allowed if a suitable HLA-matched related or unrelated donor is identified before 
receiving the allogeneic transplantation and if the patient meets the eligibility criteria of the 
subsequent study.   
8. Cross-over from other tandem autologous-allogeneic research protocol (#1409 or other appropriate 
protocol) will be allowed if the patient loses the suitable HLA-matched related or unrelated donor 
but has an available HLA-haploidentical donor before receiving the allogeneic transplantation and if 
the patient meets the eligibility criteria of the subsequent study.   
9. The following disease diagnoses: 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
11 
a. Lymphoma: Patients with  
i. Diagnosis of NHL or HL, of any histological grade. 
ii. Refractory or relapsed disease after standard chemotherapy. 
iii. High risk of early relapse following autograft alone. 
 
b. Waldenstrom’s Macroglobulinemia – must have failed 2 courses of therapy  
c. CLL:  
i. Patients with either a 
a) Diagnosis of T-cell CLL or T-cell PLL who have failed initial chemotherapy, 
patients with T cell CLL or PLL or 
b) Diagnosis of B-cell CLL, B-cell small lymphocytic lymphoma, or B-cell CLL that 
progressed to prolymphocytic leukemia (PLL), who either: 
I) Failed to meet NCI Working Group criteria2 (Appendix F) for complete or 
partial response after therapy with a regimen containing fludarabine (or another 
nucleoside analog, e.g. 2-CDA, pentostatin) or experience disease relapse within 12 
months after completing therapy with a regimen containing fludarabine (or another 
nucleoside analog). 
II) Failed any aggressive chemotherapy regimen, such as FCR, at any time point. 
III) Have “17p deletion” cytogenetic abnormality and relapsed at any time point 
after initial chemotherapy. 
ii. Harvesting criteria for autologous HCT: 
 
I) Previously collected PBMC may be used 
 
II) Circulating CLL cells <5000 
iii. Marrow involvement with CLL cells <50% 
d. MM: Patients who 
i. Have received induction therapy for a minimum of 4 cycles. 
ii. In addition, patients must meet at least one of the following criteria I-IX (I-VII: at 
time of diagnosis or pre-autograft): 
I) Any abnormal karyotype by metaphase analysis except for isolated t(11,14) 
II) FISH translocation 4:14 
III) FISH translocation 14:16 
IV) FISH deletion 17p 
V) β2-microglobulin > 5.5 mg/ml 
VI) Cytogenetic hypodiploidy 
VII) Plasmablastic morphology (≥2%) 
VIII) Recurrent or non-responsive (less than PR) MM after at least two different 
lines of conventional chemotherapy. 
IX) Progressive MM after a previous autograft (provided stored autologous CD34 
cells are available) 
e. Plasma cell leukemia: after induction chemotherapy 
 
B. Exclusions: 
1. 
Life expectancy severely limited by disease other than malignancy. 
2. 
Seropositive for the human immunodeficiency virus. 
3. 
Female patients who are pregnant or breastfeeding 
4. 
Fertile men or women unwilling to use contraceptive techniques during and for 12 months 
following treatment. 
5. 
CNS involvement with disease refractory to intrathecal chemotherapy. 
6. 
Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those 
with non-hematological malignancies (except non-melanoma skin cancers) who have been 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
12 
rendered with no evidence of disease, but have a greater than 20% chance of having disease 
recurrence within 5 years. 
  
  This exclusion does not apply to patients with non-hematologic malignancies that do not require  
   
 therapy. 
7.  
Patients with fungal infection and radiological progression after receipt of amphotericin B or active 
triazole for greater than 1 month. 
8.  
Patients with the following organ dysfunction: 
a. Cardiac: Symptomatic coronary artery disease or ejection fraction <40% or other cardiac 
failure requiring therapy (or, if unable to obtain ejection fraction, shortening fraction of < 26%). 
Ejection fraction is required if the patient has a history of anthracyclines or history of 
cardiac disease.  Patients with a shortening fraction < 26% may be enrolled if approved by a 
cardiologist. 
b. Pulmonary:  
i. 
Corrected DLCO <50% of predicted, FEV1 <50% of predicted, and/or receiving 
supplementary continuous oxygen. 
ii. 
The FHCRC PI of the study must approve of enrollment of all patients with 
pulmonary nodules 
c. Liver function abnormalities: Patient with clinical or laboratory evidence of liver disease 
will be evaluated for the cause of liver disease, its clinical severity in terms of liver 
function, bridging fibrosis, and the degree of portal hypertension. The patient will be 
excluded if he/she is found to have fulminant liver failure, cirrhosis of the liver with 
evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of 
bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic 
dysfunction evinced by prolongation of the prothrombin time, ascites related to portal 
hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis 
with total serum bilirubin >3mg/dL, and symptomatic biliary disease. 
d. Karnofsky score <50% (Appendix A) for adult patients. 
e. Lansky Play-Performance score <40 (Appendix B) for pediatric patients. 
f. Patient with poorly controlled hypertension despite multiple antihypertensives. 
 
6. Donor Selection 
 
A. Inclusions: 
1. Related donors who are genotypically identical for one HLA haplotype and who may be mismatched at 
the HLA-A, -B, -C or DRB1 loci of the unshared haplotype with the exception of single HLA-A, -B or –C 
allele mismatches. 
2. Marrow is the preferred source of stem cells from the HLA-haploidentical donor, however PBMC could 
be used as stem cell source, after clearance with the FHCRC principal investigator, in the case of 
difficulties or contraindications to bone marrow harvest from the donor. 
3. In the case that PBMC will be used as stem cell source, ability of donors < 18 years of age to undergo 
apheresis without use of a vascular access device; vein check must be performed and verified by an 
apheresis nurse prior to arrival at the SCCA 
4.  Age ≥ 12 years of age  
 
B. Exclusions: 
1. Donor-recipient pairs in which the HLA-mismatch is only in the HVG direction 
2. Infection with HIV 
3. Weight <20 kg. 
4. A positive anti-donor cytotoxic crossmatch. 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
13 
7. Evaluation and Counseling of Patient and Donor 
 
A conference with the patient and family will be held to discuss this study and alternative treatments available for 
the treatment of lymphoma, MM, or CLL. The conferences will be conducted by the outpatient attending 
physician. All potential risks associated with the use of melphalan, Cy, TBI, BEAM, fludarabine, 
immunosuppressive drugs, and autologous and allogeneic transplantation should be discussed as objectively as 
possible to the patients or, in the case of minors, to the patient's responsible family members. It should be 
explained that patients offered this protocol have high-risk disease. Transplant-related risk of autologous and 
conventional allogeneic HCT for MM, lymphoma, or CLL; and poor disease control seen with non-myeloablative 
HCT without preceding cytoreduction should be described as the rationale for this trial. 
Informed consent from the patient and the donor will be obtained using forms approved by the Institutional 
Review Board of the Fred Hutchinson Cancer Research Center. A summary of the conference will be dictated for 
the medical record detailing what was covered. 
 
8. Protocol Registration 
 
 
A. FHCRC patients: Eligible patients will be identified by the Clinical Coordinators Office who will 
register the patient with the Registration Office (206-667-4728) between 8:30 am and 4:00 pm, Monday 
through Friday. After hours, the Registration Office can be reach by paging (206) 995-7437. 
 
B. Collaborating institutions: Eligible patients will be identified by the principal investigator of the 
collaborating institution who will register the patient with the FHCRC Registration Office. Registration 
will include completion of the eligibility checklist/demographic form (Appendix J). This form and a copy 
of the signed informed consent will be faxed to (206-667-5378). Questions regarding eligibility or 
protocol information should be directed to Michelle Bouvier, R.N., Research Nurse (206-667-6993)  
 
9. Plan of Treatment 
 
A. Conventional Cytoreductive Therapy 
Cytoreduction will be given to select patients with advanced disease prior to HCT to reduce tumor bulk. 
The need for cytoreductive therapy will be determined on clinical grounds by the attending physician and 
the principal investigator. Therapy may be given prior to arriving at the transplant center by the referring 
physician. Cytoreduction can be performed with any appropriate therapy for NHL, HL, Waldenstrom’s 
Macroglobulinemia, CLL, MM, or plasma cell leukemia. The choice of therapy will depend on prior 
regimens and the current disease status and may be selected at the discretion of the attending physician 
and/or the referring physician. In general, cytoreductive therapy should be given to patients with bulky 
disease. 
 
B. CNS prophylaxis 
Patients at high risk for CNS disease will receive a diagnostic lumbar puncture per standard practice 
guidelines. Patients with history of CNS disease or positive lumbar puncture pre-transplant, will have 
instillation of IT MTX 12 mg on 2 occasions prior to transplant (between days -20 to -3) and 4-6 
occasions after engraftment starting approximately day 32 and given every 14 days until completion. If the 
patient has an Ommaya Reservoir, the dose should be 6 mg. The IT MTX schedule can be individualized 
for patients at high risk of developing symptomatic leukoencephalopathy. For other drug information, see 
section# 11. 
 
C. Ursodeoxycholic Acid Prophylaxis  
Patients will receive ursodeoxycholic acid prophylaxis for hepatic complications per standard practice. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
14 
D. Autografting 
 
1. Peripheral Blood Stem Cell (PBSC) mobilization 
Patients may have autologous peripheral blood stem cells (PBSC) mobilized and stored prior to 
enrollment on this protocol. If previously stored PBSC are used on this protocol, patients proceed 
directly to autologous conditioning regimen 1 or 2 to be followed by autologous PBSCT. For 
patients without previously stored stem cells, autologous PBSC may be mobilized and collected 
according to available FHCRC or Outside Institution protocols (i.e. FHCRC 506), or on a 
treatment protocol at the discretion of the attending physician. 
 
2. PBSC collection 
The leukapheresis goal will be > 5x106 CD34+ cells/kg. Transplant will NOT be carried out 
unless > 2.5 x 106 CD34+ cells/kg are obtained. The principle investigator should be consulted for 
recommendations if mobilization is inadequate. 
At FHCRC, PBSC collections will be performed in the leukapheresis unit until the target dose of > 
4x106 CD34+ cells/kg has been collected and cryopreserved. Leukapheresis will begin 24 hours 
after the WBC recovers to 1,000/μl or by peripheral blood CD34 measurement of >10 x 106 CD34+ 
cells/μl. Note that CD34 measurements more accurately correlate with higher CD34+ cell 
collections at the time of leukapheresis than does the WBC and should be used if available. 
Collections will last approximately 2 hours using automated apheresis collection. PBSC will be 
cryopreserved using standard techniques. Follow standard practice guidelines for the platelet count 
prior to initiating leukapheresis. 
 
3. Conditioning regimens 
Conditioning chemotherapy for the autologous PBSC transplant is begun after recovery from 
mobilization/cytoreductive therapy. This should occur no earlier than 30 days following high dose 
mobilization regimens, but may occur earlier upon recovery from standard cytoreductive regimens. 
The conditioning regimen for the autologous PBSCT will consist of the following regimens: 
 
 
 
1. Regimen 1: TBI 1200 cGy and Cyclophosphamide 120 mg/kg IV. 
2. Regimen 2: BCNU 300 mg/m2 IV, Etoposide 800 mg/m2 IV, Ara-C 800 mg/m2 IV, Melphalan 140 mg/m2 
IV. 
 
*Patients with lymphoma, Waldenstrom’s Macroglobulinemia, or CLL and no dose limiting radiation or 
significant comorbidities will receive Regimen 1. Others receive Regimen 2.  Selection of the appropriate 
regimen is the discretion of the attending physician after discussing with the PI. 
 
 
 
  
 3. Regimen 3: Melphalan 200 mg/m2 
 
 
  
 4. Regimen 4: Melphalan 140 mg/m2 
 
*Patients with multiple myeloma or plasma cell leukemia with no significant renal insufficiency or other 
significant comorbidities will receive Regimen 3. Others receive Regimen 4.  Selection of the appropriate 
regimen is at the discretion of the attending physician after discussing with the PI. 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
15 
a. Schedule for regimen 1: Cy/TBI 
Table 2: Schedule for regimen 1: Cy/TBI 
Treatment 
Day 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Allopurinol (300 mg/m2/po/day) 
X 
X 
X 
X 
X 
X 
X 
 
Cyclophosphamide 60mg/kg 
 
X 
X 
 
 
 
 
 
Rest 
 
 
 
X 
 
 
 
 
TBI 2.0 Gy BID 
 
 
 
 
X 
X 
X 
 
PBSC infusion 
 
 
 
 
 
 
 
X 
 
 
 
 
i. Allopurinol: per standard practice guidelines 
 
 
 
 
 
 
ii. Cyclophosphamide 
Dosage: Administered at a dose of 60 mg/kg on two consecutive days, –6 and -5 of 
conditioning regimen, using standard practice guidelines for dosing weight. Total 
dose 120 mg/kg. 
Supportive care: Use standard practice guidelines for supportive care 
 
 
 
 
Mesna is the most effective agent for preventing cyclophosphamide urotoxicity by 
inactivating the alkylating metabolites in the urine. It dimerizes in serum to an 
inactive compound and does not inactivate hydroxycyclophosphamide in plasma. 
The dose will be 100% of cyclophosphamide dose given IV in 4 divided doses. 
Mesna will be given per institutional guidelines. In some cases, Mesna is not 
clinically indicated and patients instead will undergo bladder irrigation per 
institutional guidelines. Continuous bladder irrigation begins 1 hour before the first 
dose of cyclophosphamide and continues for 24 hours after the second dose.  
 
For Other Drug Information, see section# 11. 
 
 
 
 
iii. Total body Irradiation:  
Total body irradiation (TBI), 200 cGy BID x 3 days is delivered from opposing 
Cobalt 60 sources or a linear accelerator at a dose rate of 6-15 cGy/min. 
IV Hydration and Antiemetic Therapy: follow standard practice guidelines 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
16 
 
b. Schedule for regimen 2: BEAM (BCNU, Etoposide, Ara-C, and Mel) 
 
Table 3: Schedule for regimen 2: BEAM 
Treatment 
Day 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Allopurinol (200 mg/m2/po/day) 
X 
X 
X 
X 
X 
X 
X 
X 
 
BCNU 300 mg/m2 IV x 1d 
 
X 
 
 
 
 
 
 
 
Etoposide 100mg/m2 IV BID 
x 4d 
 
 
X 
X 
X 
X 
 
 
 
Ara-C 100 mg/m2 IV BID x 
4d 
 
 
X 
X 
X 
X 
 
 
 
Melphalan 140 mg/m2 IV x 1 
 
 
 
 
 
 
X 
 
 
Rest 
 
 
 
 
 
 
 
X 
 
PBSC infusion 
 
 
 
 
 
 
 
 
X 
i. Allopurinol: per standard practice guidelines 
 
ii. BCNU (Carmustine): 
 
Dosage: Carmustine 300 mg/m2 IV x 1 will be infused over 3 hours on 
autografting day -7. Carmustine should not be infused with solutions or tubing 
containing or previously containing bicarbonate solution. 
 
Administration: Carmustine is available as a sterile powder as 100 mg vials. The 
drug is reconstituted by dissolving the contents of the 100 mg vial in 3ml of sterile 
dehydrated (absolute) alcohol, followed by the addition of 27 mL of sterile water 
for injection. The resultant solution contains 3.3 mL of carmustine per mL of 10% 
alcohol. This solution may be further diluted with 0.9% sodium chloride or 5% 
dextrose injection to a final concentration of 0.2 mg/ml in glass containers. The 
manufacturer recommends that only glass containers be used for administration of 
this drug. Carmustine is rapidly degraded in aqueous solutions at a pH greater than 
6. Carmustine should not be admixed with nor administered through a 
common tubing or site with solutions containing sodium bicarbonate. 
 
Maintenance hydration: Follow standard practice guidelines. 
 
iii. Etoposide (VP-16, Vepesid): 
Dosage: Etoposide 100 mg/m2 IV BID will be administered in 500-1000 cc normal 
saline over 2 hours on autografting days -6, -5, -4, and -3 for a total dose of 800 
mg/m2. Etoposide may not be infused with sodium bicarbonate solutions.  
 
Availability, reconstitution and administration: Etoposide is commercially available 
in 100 mg/5 ml, 150 mg/7.5 ml, 500 mg/25 ml or 1000 mg/50 ml sterile multiple 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
17 
dose vials. VP-16 should be diluted prior to use with either 5% Dextrose Injection, 
USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 
or 0.4 mg/ml. Precipitation may occur at solutions above 0.4 mg/ml concentration. 
It is recommended that VP-16 solution be administered IV over 2 hours. However, 
a longer duration of administration may be used when infusing large volumes of 
fluid. VP-16 should not be infused rapidly.  
 
Supportive Care: Appropriate anti-emetics and sedatives should be given before the 
infusion begins. Before and 2 hours into the infusion, the patient is to receive 25 mg 
of diphenhydramine, and 100 mg of hydrocortisone to prevent allergic reactions. 
Normal saline plus 20 mEq KCL is to be continued at 2 liters/ m2/day. If necessary, 
diuretics may be given. Since in rare cases metabolic acidosis has been observed 
after high dose VP-16, additional NaHCO3 may be added to hydration, though not 
infused while VP-16 is infusing. 
For Other Drug Information, see section# 11. 
 
iv. Cytarabine(Ara-C): 
Dosage: Cytarabine 100 mg/m2  
IV BID will be infused per standard practice guidelines on 
autografting days -6, -5, -4 and -3.  
 
Availability and administration: Cytarabine is available in a reconstituted form in 
solutions containing 20, 50 and 100 mg of cytarabine per mL. These solutions have 
been reconstituted from a sterile powder with bacteriostatic water containing 
0.945% benzyl alcohol for injection. The manufacturers state that the reconstituted 
solutions with water for injection may be diluted with 0.9% sodium chloride or 5% 
dextrose. The diluted solutions containing 0.5 mg of cytarabine per mL are stable 
for at least 8 days at room temperature.  
 
For Other Drug Information: See section# 11. 
 
v. Melphalan: 
Dosage: Melphalan will be administered at a dose of 140 mg/m2 IV x 1 infused 
 
over 30 minutes on autografting day -2. 
 
Administration: Melphalan is available in 50 mg vials and when reconstituted with 
10 mls sterile water results in a concentration of 5 mg/ml. The reconstituted 
melphalan is diluted in 250 cc normal saline to a concentration not greater than 0.5 
mg/ml. Melphalan is administered per standard practice guidelines, not to exceed 60 
minutes. 
 
For Other Drug Information: See section# 11. 
 
c. Schedule for regimen 3: High-dose melphalan (200 mg/m2 iv) 
High dose Melphalan will be given at least 30 days after using high dose 
cyclophosphamide for PBSC mobilization. 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
18 
 
Table 4: Schedule for regimen 3: High-dose melphalan 
 
 
 
 
 
 
 
 
i. Antiemetics: according to standard practice. 
ii. Allopurinol: according to standard practice. 
iii. Bactrim DS: according to standard practice 
 
iv. Melphalan Administration: 
Dosage: Melphalan will be administered at a dose of 200 mg/m2 (adjust for GFR). 
This will be given in one dose infused on day -2. Dose will be calculated 
according to the institutional standard practice. The following dose 
adjustments will be required in patients with significant renal insufficiency: 
--------------------------------------------------------- 
GFR [mL/min]          
Melphalan dose 
--------------------------------------------------------- 
≥40         
 
 
100% 
<40 or on hemodialysis          70% 
--------------------------------------------------------- 
Administration: High dose Melphalan is administered via a central catheter 
following reconstitution with the provided sterile diluent. High-dose melphalan can 
be administered undiluted as a bolus injection or diluted with sodium chloride and 
infused over 30 minutes. 
 
Maintenance hydration: Per standard practice. 
 
d. Schedule for regimen 4: High-dose melphalan (140 mg/m2 iv) 
Table 5: Schedule for regimen 4: High-dose melphalan 
 
 
 
 
 
 
 
 
i. Antiemetics: according to standard practice. 
ii. Allopurinol: according to standard practice. 
iii. Bactrim DS: according to standard practice 
 
iv. Melphalan Administration: 
Dosage: Melphalan will be administered at a dose of 140 mg/m2. This will be given 
in one dose infused on day -2. Dose will be calculated according to the 
institutional standard practice.  
Treatment 
Days 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Allopurinol (200 mg/m2/po/day) 
 
 
X 
X 
X 
X 
 
Bactrim DS (1 tab po bid) 
X 
X 
X 
X 
X 
 
 
Melphalan (adjust for GFR) 
 
 
 
 
X 
 
 
PBSC infusion 
 
 
 
 
 
 
X 
Treatment 
Days 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Allopurinol (200 mg/m2/po/day) 
 
 
X 
X 
X 
X 
 
Bactrim DS (1 tab po bid) 
X 
X 
X 
X 
X 
 
 
Melphalan (140 mg/m2 iv) 
 
 
 
 
X 
 
 
PBSC infusion 
 
 
 
 
 
 
X 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
19 
Administration: High dose Melphalan is administered via a central catheter 
following reconstitution with the provided sterile diluent. High-dose melphalan can 
be administered undiluted as a bolus injection or diluted with sodium chloride and 
infused over 30 minutes. 
 
Maintenance hydration: Per standard practice. 
 
 
4. PBSC Infusion 
Infuse > 2.5 x 106 CD 34+ cells/kg 36-48 hours after chemotherapy. See infusion guidelines, 
hydration requirements and pre-medication per institutional standard practice guidelines. 
. 
 
5. Radiation Therapy 
No radiation therapy is to be permitted concurrent with administration of melphalan. When blood 
count recovery is adequate (ANC >1000 /uL, platelets > 80,000/uL) after the autologous 
transplant, radiation may be administered for the following indications after consultation with the 
primary investigator and a radiation oncologist: (1) palliation of pain from bone lesions, (2) 
prevention of pathologic fractures, (3) relief of spinal cord compression or nerve root compression, 
(4) progression of solitary plasmacytomas of bone or solitary extramedullary plasmacytomas, or 
(5) bulky disease. A radiation oncology consultant in consultation with the attending physician will 
determine dose and duration of radiation to be administered. Radiation to the liver or lungs should 
be avoided. 
 
 
 
6. Antibiotic Prophylaxis 
 
a. All patients should receive prophylactic antibiotics when their granulocyte count is less 
than 500/mm3. Refer to standard practice in Appendix C. 
 
 
 
b. All patients should receive prophylactic Bactrim, Fluconazole and Acyclovir for 
prophylaxis against pneumocystis carinii pneumonia, systemic fungal infection, VZV and 
HSV, respectively.  Refer to standard practice in Appendix C. 
 
c. Patients shedding CMV will receive prophylactic Ganciclovir per standard practice in 
Appendix C.  
 
 
 
7. Blood Products 
 
Only irradiated blood products should be infused (RBC's and platelets).  DO NOT IRRADIATE 
PERIPHERAL BLOOD STEM CELLS.  CMV negative patients should receive only CMV 
negative or leukoreduced blood products. 
 
E. Nonmyeloablative HLA-haplo-identical HCT 
1. Pre-conditioning: 
Upon recovery from autologous HCT, between 40-120 days post autografting (preferably within 
60 days) patients will proceed to the nonmyeloablative allograft. If the interval exceeds 120 days, 
patients should be presented to PCC for discussion and approval.  
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
20 
“Recovery” from autologous HCT will be defined as follows: 
a. Mucositis and gastrointestinal symptoms have resolved and TPN/ IV-hydration have 
been discontinued; 
b. Steroid treatment for autologous GVHD has been discontinued; 
c. LFTs, pulmonary and cardiac function are within the inclusion criteria for the initial 
autograft; 
d. No evidence of radiological progression of previously documented fungal infections 
following treatment of amphotericin B or active triazole; 
e. No detectable CMV-antigenemia; 
f. Patients who experienced CMV-infection/reactivation following autografting: 
Ganciclovir or Foscarnet therapy has been completed more than two weeks ago and patient 
remains CMV-antigenemia negative (ID should be consulted if CMV-antigenemia 
persists); 
g. Radiotherapy has been completed; 
 
Any patient who does not fulfill these criteria may be discussed with the principle 
investigator for recommendations as to the timing of the allograft. 
 
2. Venous access device:  
A double-lumen central venous catheter will be required. 
 
3. Conditioning regimen: 
Treatment will be initiated in the outpatient department and patients will be admitted as medically 
necessary for control of transplant complications. 
 
a. Outline of treatment plan (Scheduling is shown in Table 6A and 6B): 
Note: Stem cell source will be marrow or PBMC with marrow being the preferred 
source.  
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
21 
 
Table 6A: Conditioning Schema and Immunosuppression Schedule for patients 
receiving marrow as source of stem cells 
Days –6, -5 
 
Fludarabine 30 mg/m2 iv qd 
Cyclophosphamide 14.5 mg/kg iv qd 
Mesna (dosed at 100% cyclophosphamide dose) 
 
Days –4 to –2 
 
Fludarabine 30 mg/m2 iv qd 
Day –1 
 
200 cGy TBI at 6-7 cGy/min 
Day 0 
 
Infuse marrow allograft 
Day +3 
 
Cyclophosphamide 50 mg/kg 
(Must be administered 60-72 hr post-BMT) 
Mesna (100% cyclophosphamide dose) 
 
Day +4 
 
Begin Tacrolimus 1 mg IV and MMF 15 mg/kg po tid 
Begin G-CSF (5 μg/kg/d) IV or SC, continue until 
ANC>1000/mm3 x 3d 
 
Day +28 
 
Assess chimerism in peripheral blood (T-cells and granulocytes) 
Day +35 
 
If no GVHD, discontinue MMF 
 
Day +56 
 
Assess chimerism in peripheral blood 
 
Day +84 
 
Assess disease status; assess chimerism in peripheral blood 
 
Day +86 
 
If no GVHD, start Tacrolimus taper 
 
Days +180 
 
Assess disease status, chimerism in peripheral blood 
If no GVHD, stop Tacrolimus 
 
Days +360 
 
Assess disease status, chimerism in peripheral blood 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
22 
 
 
Table 6B: Conditioning Schema and Immunosuppression Schedule for patients 
receiving PBMC as source of stem cells 
Days –6, -5 
 
Fludarabine 30 mg/m2 iv qd 
Cyclophosphamide 14.5 mg/kg iv qd 
Mesna (dosed at 100% cyclophosphamide dose) 
 
Days –4 to –2 
 
Fludarabine 30 mg/m2 iv qd 
 
Day –1 
 
200 cGy TBI at 6-7 cGy/min 
 
Day 0 
 
Infuse PBMC allograft 
 
Days +3 and +4 
 
Cyclophosphamide 50 mg/kg 
(first dose must be administered between 60-72 hr post-PMBC) 
(second dose administered approximately 24 hours after the first 
dose) 
Mesna (100% cyclophosphamide dose) 
 
Day +5 
 
Begin Tacrolimus 1 mg IV and MMF 15 mg/kg po tid 
Begin G-CSF (5 μg/kg/d) IV or SC, continue until 
ANC>1000/mm3 x 3d 
 
Day +28 
 
Assess chimerism in peripheral blood (T-cells and granulocytes) 
 
Day +35 
 
If no GVHD, discontinue MMF 
 
Day +56 
 
Assess chimerism in peripheral blood 
 
Day +84 
 
Assess disease status; assess chimerism in peripheral blood 
 
Day +86 
 
If no GVHD, start Tacrolimus taper 
 
Days +180 
 
Assess disease status, chimerism in peripheral blood 
If no GVHD, stop Tacrolimus 
 
Days +360 
 
Assess disease status, chimerism in peripheral blood 
 
 
 
 
b. Agent: 
 
Menstruating female patients should be placed on an anti-ovulatory agent prior to initiating 
the conditioning regimen. 
i. Fludarabine will be administered by IV infusion over 30 minutes on day-6 to 
day-2. The dose will be 30 mg/M2 with dose-reduction for decreased creatinine 
clearance*: 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
23 
 
Fludarabine dosage should be reduced as follows: 
 
CCr 46-60 ml/min, fludarabine = 24 mg/m2 
CCr 31-45 ml/min, fludarabine = 22.5 mg/m2 
CCr 21-30 ml/min, fludarabine = 19.5 mg/m2 
CCr <20 ml/min, fludarabine = 15 mg/m2 
 
*For adult patients, creatinine clearance may be estimated by the Cockcroft 
Formula: 
CCr = (140 – age) x IBW (kg) x 0.85 (for women) PCr x 72 
For pediatric patients, a formal measurement of creatinine clearance should be 
performed. 
 
ii. Cyclophosphamide (14.5 mg/kg Adjusted BW*, unless IBW>ABW, then ABW 
per Standard Practice Guidelines) will be administered as an IV infusion over 1 hr 
on day -6 and day -5. Patients will be instructed to increase fluids overnight before 
cyclophosphamide administration. For pediatric patients, hydration will be given 
according to standard practice guidelines. For adult patients, hydration with normal 
saline at 3 cc/kg/hr iv will be started 2 hr prior to cyclophosphamide, then the rate 
will be reduced to 2 cc/kg/hr for 1 hr pre cyclophosphamide and continued for 8 hr 
post-cyclophosphamide. Mesna will be given in divided doses IV 30 min pre- and 
at 3, 6, and 8 hr post-cyclophosphamide. Mesna dose will be based on the 
cyclophosphamide dose being given. The total daily dose of Mesna is equal to 
100% of the total daily dose of cyclophosphamide. Urine output over 2 hr will be 
checked before administering cyclophosphamide and must be at least 3.0 cc/kg. Per 
standard practice guidelines, urine output must be maintained at 120mL over the 
first four hours post cyclophosphamide. Urine testing per institutional guidelines 
will be performed prior to administration of cyclophosphamide and on the day 
following cyclophosphamide to monitor for hematuria. Hemorrhagic cystitis is a 
known complication of high-dose cyclophosphamide therapy. It is crucial that no 
immunosuppressive agents are given until 24 hours after the completion of the 
post-transplant Cy. This includes corticosteroids as anti-emetics. 
 
*Adjusted BW = [(ABW – IBW) 0.25] + IBW 
 
iii. TBI (200 cGy) will be given on day –1 at a rate of 6-7 cGy/min per 
Standard Practice Guidelines. 
 
 
4. Bone marrow infusion 
 
All patients will receive infusion of a mononuclear cell (MNC) preparation of donor marrow on 
day 0. Red blood cell and plasma depletion will be done following the standard practice guidelines. 
Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient 
IBW. The minimum acceptable yield should be 1 x 108 nucleated cells/kg recipient IBW. Yields of 
nucleated cells and MNC are about 25% and 85%, respectively. The CD34 and CD3 composition 
of allografts will be determined by flow cytometry.  
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
24 
5. PBMC infusion 
 
Marrow is the preferred source of stem cells from the HLA-haploidentical donor, however PBMC 
could be used as stem cell source, after clearance with the FHCRC principal investigator, in 
the case of difficulties or contraindications to bone marrow harvest from the donor. 
 
Donors who consent to PBMC donation will receive 5 daily doses of GCSF, 16 μg/kg/day by 
subcutaneous injection commencing on day –5. PBMC’s will be collected in the afternoon of day -
1, stored at 4C overnight, and infused as soon as possible on day 0. If the collection on day –1 
contains less than 5.0 X 106 CD34+ cells per kg recipient weight, a second collection will be 
performed the following morning and transfused on day 0. Quantitation of CD34 and CD3 cells 
will be performed by the Cellular Therapy Lab. For all patients, the target number of CD34 cells 
to be infused should be 5-6 X 106 cells per kg recipient weight. PBSC in excess of 6.0 x 106 CD34 
cells/kg recipient weight may be cryopreserved. 
 
6. Post-transplant immunosuppression 
a. Cyclophosphamide 
 
i. For patients receiving marrow as stem cell graft: A single dose of 
cyclophosphamide [50mg/kg Adjusted BW*, unless IBW>ABW, then ABW per 
Standard Practice Guidelines] will be given on day +3 after transplant (within 60-72 
hr of marrow infusion).  
ii. For patients receiving PBMC as stem cell graft: Two doses of Cyclophosphamide 
[50mg/kg Adjusted BW*, unless IBW>ABW, then ABW per Standard Practice 
Guidelines] will be given on Day 3 post-transplant (between 60 and 72 hours after 
PBMC infusion) and on Day 4 posttransplant (approximately 24 hours after Day 3 
cyclophosphamide).  
 
Cyclophosphamide will be given as an IV infusion over 1 hr with Mesna and 
appropriate hydration as described above in Section 9D-3. Monitoring of urine 
output and for hematuria will be performed similarly. It is crucial that no 
immunosuppressive agents are given until 24 hours after the completion of the 
post-transplant Cy. This includes corticosteroids as anti-emetics. 
 
b. Tacrolimus and MMF 
i. Starting on day +4 (Day +5 for PBMC grafts), tacrolimus will be given at a dose of 0.03 
mg/kg/d (for patients <30 kg) and 1mg/d (for patients >30kg) IV over 1-2 hr and should be 
changed to a PO dosing schedule as tolerated once a therapeutic level (5-15 ng/ml) is 
achieved. Serum levels of tacrolimus should be measured on day +8 and then weekly 
thereafter and the dose adjusted accordingly to maintain a level of 5-15 ng/ml.  
 
Tacrolimus will be tapered after day +86 (adapted dose-reduction to be discontinued by day 
+180) if there is no evidence of GVHD. 
 
ii. Starting on day +4 (day +5 for PBMC grafts), MMF will be given orally at a dose of 15 
mg/kg tid. Doses will be rounded to the nearest 250 mg (capsules are 250 mg). If an 
observed toxicity related to MMF administration occurs in the clinical judgment of the 
investigator, the MMF dose will be adjusted. Based on previous observations in patients 
after nonmyeloablative HSCT, the side effect most likely to occur will be neutropenia due 
to myelosuppression. Severe gastrointestinal toxicity such as gastrointestinal hemorrhage 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
25 
has been very rare after nonmyeloablative HSCT. A thorough evaluation of neutropenia 
should occur including peripheral blood chimerism studies, marrow aspiration and review 
of marrow suppressive medications (e.g. co-trimoxazole). Dose adjustments will not be 
made for neutropenia unless it is severe or persists after day +21. In the rare event of 
gastrointestinal toxicity that requires medical intervention including medication for control 
of persistent vomiting or diarrhea that is considered to be due to MMF, a 20% dose 
reduction will be made or the drug may be given IV at the same dose. For severe toxicity 
related to MMF (grade IV neutropenia refractory to G-CSF, severe refractory diarrhea, or 
overt gastrointestinal bleeding), the MMF may be temporarily stopped. MMF should be 
restarted at 20% reduced dose when the underlying toxicity subsides. The discontinuation 
of MMF at any point should be discussed with the Study PI and should be documented in 
the permanent medical record and all Case Report Forms (CRF). 
 
MMF will be discontinued on day +35 if there is no GVHD. 
 
7. Modification of immunosuppression for early disease progression or relapse 
 
Guidelines provided in this section are for patients who demonstrate either (i) progression of stable 
disease present at the time of transplant or (ii) relapse of their underlying disease before 
discontinuation of immunosuppression has been completed. Significant progression of disease is 
defined in Table 7 below. Relapse is defined by presence of malignant cells in marrow, peripheral 
blood or extramedullary sites detectable by morphologic, flow cytometric, cytogenetic or 
molecular assays not evident at the time of transplant. Patients fulfilling these criteria should 
undergo a reduction in immunosuppression after careful evaluation for GVHD. In the event that 
patients with early disease progression or relapse do not have GVHD, immunosuppression should 
be discontinued. Persistence of stable, underlying disease itself does not mandate accelerated 
reduction of immunosuppression. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
26 
Table 7 Definition of disease progression 
Disease 
 
Signs of Progression 
MM or plasma 
cell leukemia 
• Increasing bone pain or  
• increase in serum/urine monoclonal protein by 25% or 
• Increase in circulating or bone marrow blasts by 25% 
Waldenstrom’s 
Macroglobulin
emia 
• new sites of lymphadenopathy or  
• increase of  25% in lymph node size (assessed by CT scan) or 
• blood or bone marrow involvement with clonal B cells (lymphoma) or 
• increase of  25% bone marrow involvement or 
• increase in serum/urine monoclonal protein by 25% 
 
CLL, NHL,  
HL 
• new sites of lymphadenopathy or  
• increase of  25% in lymph node size (assessed by CT scan) or 
• blood or bone marrow involvement with clonal B cells (lymphoma) or 
• increase of  25% bone marrow involvement or 
• increase of  25% blood involvement (of lymphocyte count > 
50x103/µl) with clonal B-cells (CLL) 
 
 
If there is no disease response 4 weeks after stopping immunosuppression and GVHD has not 
developed, patients may be considered for DLI (which is not part of this protocol) and further 
therapy as per institutional protocols for disease relapse or progression after allogeneic HCT. 
 
Patients deemed to be at high risk for graft rejection based on low donor chimerism may also be 
eligible for DLI (which is not part of this protocol) or a second allogeneic HCT on other protocols. 
In the setting of low donor chimerism without evidence of disease progression, 
immunosuppression should be continued at full dose so that DLI on other protocols can be 
considered. 
 
8. Growth Factor Support 
 
Patients will receive G-CSF at 5 μg/kg/d [rounded to the nearest vial size (300 μg or 480 μg )] IV 
or SC starting at day +4 (Day +5 for PBMC grafts),  and continuing until the ANC >1000/mm3 for 
3 d.  
 
9. Infection prophylaxis and therapy 
Patients will receive prophylaxis and therapy for bacterial, fungal and viral infections according to 
Standard Practice Guidelines. Standard CMV monitoring and prophylaxis should commence at the 
time of transplant and should continue as appropriate. Please see standard practice per Appendix C 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
27 
10. Evaluation 
 
NOTE: Research blood specimens marked by ** should NOT be drawn until AFTER the patient and 
donor have signed the consent forms for protocol 2241. 
 
 
A. HLA-typing of patient and potential donors (pre-transplant evaluation) 
 
1. As broad a range of potential related donors as possible should be typed. Included are parents, 
siblings, eligible children, and cousins. 
2. Serotyping (HLA-A, B, C) and DNA typing (HLA-A, B, C, DRB1, DQB1) of patient and donor 
will be performed. 
3. Leukocyte and/or florescence activated cell sorter cross match between the patient and donor 
will be done. Recipient must have a negative cytotoxic cross-match to donor lymphocytes, 
otherwise an alternative HLA-haploidentical donor must be identified. 
4. KIR genotype will not be used in determining donor selection. 
5. Blood samples for HLA-typing should be sent to: Clinical Immunogenetics Lab for HLA-typing 
(heparinized green top tube, 10 cc), 206-667-7700; SCCA G7-200. 
 
B. Donor: 
Donors will be evaluated according to Standard Practice Guidelines and should include 
  1. Complete history and physical examination. 
 
 
2. Lab and research tests 
a. CBC with differential including platelet count and reticulocytes on day –2 (pre-
marrow harvest or PBMC collection) and day 0 (day of marrow harvest or PBMC 
collection). 
b. Chemistry panel 
c. Hepatitis screen, CMV, syphilis, HIV and HTLV I serology 
d. ABO Rh blood typing. If the donor has antibodies against the red cells of the recipient 
or vice versa, the titers must be determined. Cross-matching between patient and donor 
(Clinical Immunogenetics Lab) will be performed. Appropriate RBC depletion of the 
marrow allograft, in case of presence of donor ant-recipient antibodies, will need to be 
done per standard procedures. 
e. A heparinized blood sample (green top tube, 10 cc) as a donor reference for subsequent 
determination of donor chimerism should be sent to the Cytogenetics Lab if the donor-
recipient pair is sex-mismatched or to the Clinical Immunogenetics Lab if sex-matched.  
Label “Protocol 2241”. 
f. In the case that PBMC will be used as stem cell source, ability of donors < 18 years of 
age to undergo apheresis without use of a vascular access device; vein check must be 
performed and verified by an apheresis nurse prior to arrival at the SCCA.  Please note 
donors ≤12 years of age are not eligible for the study.   
 
C. Patient: 
1.  Pre-mobilization Evaluation-Patients will be evaluated with standard work up and standard 
disease specific staging 
 
2. Autografting Evaluations (This is a recommended evaluation schedule. Tests should be 
done within 30 days of auto graft). 
a. Pre-autografting per Standard Practice or standard practice guidelines of your 
institution. In addition, obtain the following 
i. ECG (if not already done within 30 days of planned autologous transplant) 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
28 
ii. Pulmonary function tests for patients ≥6 with corrected DLCO (Note: for patients 
who show <60% carbon monoxide diffusion capacity, or if otherwise clinically 
indicated, arterial blood gases should be obtained)  
iii. For patients with abnormal cardiac exam, or symptoms suggestive of CHF, or 
history of anthracycline exposure obtain Echocardiogram or MUGA to calculate 
ejection fraction 
iv. Lumbar puncture for patient’s at risk for CNS involvement per Standard Practice, 
see Appendix L 
v. Assessment of patient pretransplant comorbidities and assigning scores using the 
HCT Comorbidity Index (HCT-CI; see Appendix N). 
vi. Additionally, see the following tables (Tables 8 and 9) for disease specific pre-
transplant evaluations.  
 
Table 8: Disease-Specific Pre-Auto and Pre-Allo Evaluations for CLL, HL, NHL 
 
Note: All bone marrow aspirates and biopsies are bilateral pre-auto and we recommend them to be collected within 30 
days of treatment. If Pre-Auto bone marrow is positive for disease involvement, then pre-allo bone marrow should be 
bilateral. See Tables 9 and 10 for post-transplant evaluations and additional lab instructions. 
 
Specimen / Test / Imaging 
Clinical / 
Research 
Comment 
Bone marrow aspirate 
 
Pathology 
Clinical 
 
Flow Cytometry- *see comment 
Clinical 
*No HL 
*Include CD38 expression for CLL 
Cytogenetics 
Clinical 
 
FISH for clonal abnormalities 
Clinical 
*If previously abnormal 
PCR for t(11:14) - *see comment 
Clinical 
*Mantle Cell NHL only and pre-
auto only 
PCR for t(14:18) - *see comment 
Clinical 
*Follicular NHL only, and pre-
auto only 
Bone marrow biopsy 
 
Pathology- *see comment 
Clinical 
*HL – only if history of BM 
involvement 
Peripheral Blood 
 
Storage for chimerism analysis 
Clinical 
 
Quantitative Ig levels 
Clinical 
 
β-2 microglobulin 
Clinical 
 
LDH 
Clinical 
 
ZAP – 70 by flow cytometry- *see comment 
Clinical 
*CLL only– for patients not in CR 
Imaging 
 
CT of chest, abdomen, pelvis (neck if indicated) 
Clinical 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
29 
 
Table 9: Disease-Specific Pre-Auto and Pre-Allo Evaluations for MM, Waldenstrom’s Macroglobulinemia, 
or plasma cell leukemia 
 
Note: All bone marrow aspirates and biopsies are bilateral pre-auto and we recommend them to  be collected within 30 
days of treatment. If pre-auto bone marrow is positive for disease involvement, then pre-allo bone marrow should be 
bilateral.  
See Tables 10 and 11 for post-transplant evaluations and additional lab instructions. 
 
Specimen / Test / Imaging 
Clinical / 
Research 
Comment 
Bone marrow aspirate 
 
Pathology 
Clinical 
 
Flow Cytometry 
Clinical 
 
Cytogenetics 
Clinical 
 
FISH for clonal abnormalities 
Clinical 
 
Bone marrow biopsy 
 
Pathology 
Clinical 
 
Peripheral Blood 
 
Storage for chimerism analysis 
Clinical 
 
SPEP/IFIX 
Clinical 
 
Quantitative Ig levels 
Clinical 
 
β-2 microglobulin 
Clinical 
 
LDH 
Clinical 
 
Cryoglobulins, c-reactive protein, serum viscosity - 
*see comment 
Clinical 
*Serum viscosity only for patients with 
>3gm/dL IgM monoclonal protein or 
>4gm/dL IgA or IgG protein 
Urine 
 
UPEP/IFIX 
Clinical 
 
Protein / creatinine clearance and serum creatinine 
on day of creatinine clearance) 
Clinical 
 
Bence Jones quantification and serum free light 
chain assay - *see comment 
Clinical 
*FLC for patients with light chain 
disease only 
Imaging 
 
MRI –  *see comment 
Clinical 
*MM or plasma cell leukemia only, and 
only Pre-Auto 
Skeletal survey –  *see comment 
Clinical 
*MM or plasma cell leukemia only 
CT of chest, abdomen, pelvis (neck if indicated) –  
*see comment 
Clinical 
*Waldenstrom’s Macroglobulinemia only 
 
 
3. Post-Autograft Evaluation 
Post-autografting workup is to be performed according to institutional Standard Practice 
guidelines. If 90 days passed after the auto-graft, the patient should undergo all evaluation 
guidelines detailed under the Pre-Allograft Evaluation (next section). 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
30 
4.  Pre-Allograft Evaluation 
 
The routine pre-allografting workup is to be performed according to institutional Standard Practice 
and is to include the following: 
 
i. History: A complete history with full details of the patient’s prior treatment and 
response. 
ii. Careful physical exam with determination of Karnofsky score (Appendix A) or Lansky 
Play score (Appendix B) and findings related to underlying malignancy. 
iii. Assessment of patient pretransplant comorbidities and assigning scores using the HCT 
Comorbidity Index (HCT-CI; see Appendix N). 
iv. Chest X-ray (PA and lateral views). 
v. In preparation of posttransplant chimerism analysis, heparinized peripheral blood from 
patient and donor will be drawn and sent to: Clinical Immunogenetics Lab (For FHCRC 
patients send to G-7107) for VNTR-based chimerism analysis for sex-matched and sex-
mismatched transplants. Label “Protocol 2241”. Pretransplant samples are to be sent to 
allow storage of DNA for evaluation of post-transplant chimerism. 
vi. Additionally, see above tables 8 and 9 for disease specific pre-transplant 
evaluations. 
 
5. Post-allograft Evaluation 
 
See Table 10 for disease specific post-transplant evaluation on Day +28, 56, 84, etc. This is a 
recommended evaluation schedule. 
 
Additionally, include the following for all diseases: 
i. CBC three times a week, or more often if clinically indicated, from day 0 until day 
+28, and twice weekly until 2 months post-transplant or later if clinically indicated. 
 
ii. Electrolyte panel, renal and hepatic function three times a week until day 28 and 
then once per week until tacrolimus is stopped, unless clinical circumstances 
suggest the need for more frequent evaluations. 
 
iii. Patients should be assessed for the need of bisphosphonates and IVIG monitoring 
and replacement therapy per Institutional Guidelines 
 
Patients with MM: Patients should be assessed for the need of bisphosphonates per 
 
 
 
   Institutional Guidelines”.      
 
Assessment of GVHD: 
i. Patients will be followed closely for signs and symptoms of acute or chronic GVHD 
as outlined in Appendices D and E, respectively.  Skin involvement should be 
assessed by punch biopsy.  The percentage of body surface area involved will be 
recorded.  GI symptoms suspicious for GVHD should be evaluated by endoscopy 
and biopsy as indicated.  Time to onset of GVHD will be recorded. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
31 
ii. First-line therapy will be reinstitution of tacrolimus, if previously discontinued, and 
administration of high-dose corticosteroids with subsequent taper as described in 
the Standard Practice Guidelines.  Patients with GVHD who are steroid-refractory 
may be eligible for treatment protocols for acute or chronic GVHD or conventional 
salvage therapy. 
 
  
 
 
 
 
 
 
Non-relapse mortality: 
i. Every effort will be made to determine the exact cause of death for all patients as 
they occur.  Non-relapse-related mortality, regardless of cause, occurring by day 
+200, will be recorded and reported on CRFs. 
 
 
 
 
 
 
Post-allograft day +84 Evaluation. 
These patients should be followed as standard allograft recipients. The following 
evaluations should be obtained: 
  
 
Chronic GVHD workup (see Appendix E) 
i. 
A complete history with full details of the patient’s prior treatment including 
dates immunosuppression stopped and response. 
ii. 
Physical examination with determination of Karnofsky score and attention 
to presence of GVHD (skin, oral, scalp, and body hair distribution, nails, 
icterus, etc). 
iii. 
Skin biopsy. 
iv. 
Schirmer's Tear test. 
v. 
Pulmonary function test. 
vi. 
PA and Lateral Chest X-ray. 
vii. Dietician departure assessment. 
viii. Gynecological departure assessment (adult female). 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
32
Table 10: Protocol 2241: Post-Allogeneic Transplant Evaluation 
This is a recommended evaluation schedule. See text and additional table for pre-transplant evaluation and lab information 
 
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
CLL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism   
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH for clonal 
abnormalities 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if <50% 
on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside institutions 
x 
 
 
 
 
 
 
Flow cytometry 
Clinical 
*If peripheral blood 
involvement pre-transplant 
AND bone marrow not done 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Quantitative Ig levels 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
β-2 microglobulins 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
 
 
 
 
LDH 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Imaging 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment 
x 
x 
x 
x 
x 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
33
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
HL – No 
history of BM 
involvement 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM aspirate *see biopsy 
                    ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
 
 
x 
 
x 
 
 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
 
*See 
comment 
 
 
FISH 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
 
*See 
comment 
 
 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if <50% 
on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism (NK CD56+) 
Clinical 
Optional for outside institutions 
x 
 
 
 
 
 
 
Quantitative Ig Levels 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
LDH 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Imaging 
 
CT of chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*If abnormal pre-transplant 
 
*See 
comment 
x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
34
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
HL - History 
of BM 
involvement 
 
 
 
 
 
 
 
 
 
 
BM aspirate *see biopsy 
                     ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
BM biopsy 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if <50% 
on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism (NK CD56+) 
Clinical 
Optional for outside institutions 
x 
 
 
 
 
 
 
Quantitative Ig Levels 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
LDH 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Imaging 
 
CT of chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*If abnormal pre-transplant 
 
*See 
comment 
x 
x 
x 
x 
x 
 
GVHD Evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
35
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
NHL – 
No History of 
BM 
involvement  
 
*see separate 
section for 
additional 
PCR on 
Mantle Cell 
and Follicular 
NHLs in 
suspected CR 
 
 
BM aspirate * If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
 
Pathology 
Clinical 
 
 
 
x 
 
x 
 
 
 
Flow cytometry 
Clinical 
 
 
 
x 
 
x 
 
 
 
Cytogenetics 
Clinical 
*If abnormal pre-transplant  
 
 
*See 
comment 
 
*See 
comment 
 
 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if <50% 
on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
 
Chimerism  (NK CD56+) 
Clinical 
Optional for outside institutions 
x 
 
 
 
 
 
 
 
Flow cytometry 
Clinical 
* If peripheral blood 
involvement pre-transplant, if 
bone marrow not obtained 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
β-2 microglobulin 
Clinical 
 
 
 
x 
 
 
 
 
 
LDH 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Imaging 
 
CT chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*Day 56 only if abnormal  pre-
transplant 
 
*See 
comment  
x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
36
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
NHL – 
History of 
BM 
involvement  
 
*see separate 
section for 
additional 
PCR on 
Mantle Cell 
and Follicular 
NHLs in 
suspected CR 
 
 
 
 
 
 
 
 
BM aspirate * If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism  
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if <50% 
on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism (NK CD56+) 
Clinical 
Optional for outside institutions 
x 
 
 
 
 
 
 
Flow cytometry 
Clinical 
*If abnormal pre-transplant 
AND bone marrow not done 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Quantitative Ig Levels 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
LDH 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Imaging 
 
CT of chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*If abnormal pre-transplant 
 
*See 
comment 
x 
x 
x 
x 
x 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
37
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
Mantle Cell 
NHL in 
suspected CR 
BM aspirate *in addition to complete NHL restaging 
                   ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
PCR for t(11:14) 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood *in addition to complete NHL restaging 
 
PCR for t(11:14) 
Clinical 
*If abnormal pre-transplant 
AND bone marrow not done 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Follicular 
Cell NHL in  
suspected CR 
BM aspirate *in addition to complete NHL restaging 
                    ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
PCR for t(14:18) 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood *in addition to complete NHL restaging 
 
PCR for t(14:18) 
Clinical 
*If abnormal pre-transplant 
AND bone marrow not done 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
38
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
MM and 
Plasma Cell 
Leukemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM aspirate * If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if <50% 
on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism (NK CD56+) 
Clinical 
Optional for outside institutions 
x 
 
 
 
 
 
 
Quantitative Ig Levels 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
SPEP and IFIX 
Clinical 
 
 
 
x 
x 
x 
x 
x 
β-2 microglobulins 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Cryoglobulins, c-reactive 
protein, serum viscosity 
Clinical 
 
 
 
x 
x 
x 
 
x 
24 Hour Urine 
 
Creatinine clearance/protein 
excretion 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
x 
*See 
comment 
*See comment 
UPEP and IFIX 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
x 
*See 
comment 
*See comment 
Imaging 
 
Skeletal survey (including 
skull and long bones) 
Clinical 
 
 
 
 
 
x 
 
x 
MRI 
Clinical 
 
 
 
 
 
x 
 
x 
 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
39
Disease 
Specimen/ Test/ Imaging 
Clinical/ 
Research 
Comment 
Days 
Years 
Annual x 
5 years 
28 
56 
84 
180 
1 
1.5 
Waldenstrom’s 
Macro-
globulinemia 
 
BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment 
 
Chimerism 
Clinical 
 
 
 
x 
 
x 
 
 
Pathology 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Flow cytometry 
Clinical 
 
x 
x 
x 
x 
x 
x 
x 
Cytogenetics 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
FISH 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
Peripheral blood 
 
Chimerism (CD3+) 
Clinical 
*Days 56 and 180 only if <50% 
on day 28 
x 
*See 
comment 
x 
*See 
comment 
x 
 
 
Chimerism (CD33+) 
Clinical 
 
 
 
x 
 
 
 
 
Chimerism (NK CD56+) 
Clinical 
Optional for outside institutions 
x 
 
 
 
 
 
 
Quantitative Ig Levels 
Clinical 
*If abnormal pre-transplant 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See 
comment 
*See comment 
SPEP and IFIX 
Clinical 
 
 
 
x 
x 
x 
x 
x 
β-2 microglobulins 
Clinical 
 
 
 
x 
x 
x 
x 
x 
Cryoglobulins, c-reactive 
protein, serum viscosity 
Clinical 
 
 
 
x 
x 
x 
 
x 
24 Hour Urine 
 
Creatinine clearance/protein 
excretion 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
x 
*See 
comment 
*See comment 
UPEP and IFIX 
Clinical 
*If abnormal pre-transplant 
 
 
*See 
comment 
*See 
comment 
x 
*See 
comment 
*See comment 
Imaging 
 
CT of chest, abdomen, pelvis 
(neck if indicated) 
Clinical 
*If abnormal pre-transplant 
 
*See 
comment 
x 
x 
x 
x 
x 
GVHD evaluation 
Clinical 
See text for details 
 
 
x 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
40
 
Table 11: Additional Lab Instructions 
Note: All bone marrow tests are done on aspirate unless specifically identified as biopsy. All instructions apply to both pre- and 
post-transplant evaluations unless identified otherwise. 
 
Off-site providers may use local facilities for the tests.  
Volumes represent desired amounts. 
 
Specimen / 
Test 
Type 
Instructions 
Lab Name 
Contact Information 
Bone marrow 
 
Chimerism  
Clinical 
1-3mL bone marrow in 
green-top tube 
Clinical Immunogenetics 
Lab 
Seattle Cancer Care Alliance 
 (206) 288-7700 
Pathology 
(aspirate) 
Clinical 
2mL bone marrow in 
EDTA/ formalin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
(206) 288-1355 
Pathology (biopsy) 
Clinical 
1cm bone marrow in 
formalin OR mounted in 
paraffin 
SCCA Pathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-1355 
Flow Cytometry 
Clinical 
2mL bone marrow in green-
top tube 
UW Hematopathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-7060 
Cytogenetics 
Clinical 
3mL bone marrow in green-
top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 288-1390 
FISH 
Clinical 
2mL bone marrow in green-
top tube 
SCCA Cytogenetics Lab 
Seattle Cancer Care Alliance 
 (206) 288-1390 
PCR for t(11:14) or 
t(14:18) 
Clinical 
2mL bone marrow in 
lavender-top tube 
UW Molecular 
Hematopathology Lab  
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 288-7060 
Peripheral blood 
 
Chimerism  
(CD3+), (CD33+) 
NK(CD56+) 
Clinical 
10mL blood in green-top 
tube for Flow sorting, then 
to CIL 
UW Hematopathology Lab, 
routed to Clinical 
Immunogenetics Lab 
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 288-7060 
Flow Cytometry 
Clinical 
10mL blood in green-top 
tube 
UW Hematopathology Lab 
Seattle Cancer Care Alliance 
 (206) 288-7060 
SPEP/IFIX 
Clinical 
3mL blood in red-top tube 
UW Department of 
Laboratory Medicine 
University of Washington 
(800) 713-5198 
Quantitative Ig 
Levels 
Clinical 
3mL blood in red-top tube 
SCCA Alliance Lab 
Seattle Cancer Care Alliance 
(206) 288-2057 
β-2 Microglobulin 
Clinical 
3mL blood in red-top tube 
UW Department of 
Laboratory Medicine 
University of Washington 
(800) 713-5198 
LDH 
Clinical 
3mL blood in red-top tube 
SCCA Alliance Lab 
Seattle Cancer Care Alliance 
(206) 288-2057 
PCR for t(11:14) or 
t(14:18) 
Clinical 
5mL blood in lavender-top 
tube 
UW Molecular 
Hematopathology Lab  
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 288-7060 
 
ZAP – 70 by Flow 
cytometry 
(pre-transplant only) 
Clinical 
5mL blood in green-top 
tube 
UW Hematopathology Lab 
Mailstop G7-800 825 Eastlake Ave, 
East Seattle, WA 98109 
(206) 288-7060 
Outside institutions may use VNTR analysis (sex- matched transplants) or sex chromosome FISH-analysis (sex-
mismatched transplants) for chimerism analysis. 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
41
11. Irradiation and Marrow Administration - Toxicities and Complications 
 
A. Total Body Irradiation: TBI will be given in one 2.0 Gy fraction at a rate of 6-7 cGy/min. 
Dosimetry calculations are performed by the radiation therapist. Refer to Standard Practice of the 
institution for information regarding administration, toxicity and complications. 
 
B. Fludarabine: 
 
1.  Description:  Fludarabine monophosphate is a purine antimetabolite that, after administration, 
undergoes rapid conversion in plasma to the nucleoside 2-fluoro ara-A (F-araA). F-araA 
subsequently enters cells where it is phosphorylated to F-araATP and the monophosphate F-
araAMP.  Once activated, F-araATP inhibits DNA polymerase and ribonucleotide reductase. The 
monophosphate F-araAMP, once incorporated into DNA, is an effective DNA chain terminator. 
Following IV administration, the drug is metabolized to 2-F-araA and widely distributed in 
tissues. 2-F-araA is excreted primarily in urine and has a terminal elimination half-life of 7-12 
hr. 
 
2.  Storage and Administration:  Fludarabine monophosphate is commercially available as a 50 
mg/vial which is reconstituted with 2 ml of sterile water, resulting in a 25mg/ml solution. The 
desired dose is further diluted to concentrations of 0.04-1 mg/ml in normal saline or 5% dextrose 
(50-100ml) for injection and will be administered by IV infusion over 30 minutes or longer. 
Fludarabine will be administered by IV infusion over 1 hr in a dose of 30 mg/m2/day on days -6 
to -2. 
 
3.  Side Effects and Toxicity:  Clinical toxicities of fludarabine monophosphate include: 
myelosuppression, primarily lymphopenia and granulocytopenia, alopecia, rash, dermatitis, 
nausea, vomiting, anorexia, stomatitis, diarrhea, somnolence, fatigue, peripheral neuropathy, 
mental status changes, cortical blindness, hepatocellular toxicity with elevation in serum 
transaminases, and interstitial pneumonitis. These effects are reversible when the drug is 
discontinued.  Immunosuppression observed with the use of fludarabine increases the risk of 
infection which can be life-threatening 
 
C. Cyclophosphamide:  
 
1. Description:  Cyclophosphamide is an alkylating agent which prevents cell division primarily 
by cross-linking DNA strands.  Cyclophosphamide is cell cycle non-specific.  
Cyclophosphamide is not stem cell toxic. 
 
2.  Storage and Administration:  Cyclophosphamide for injection is commercially available in 
2000 mg vials which are reconstituted with 100 ml sterile water for injection.  The concentration 
of the reconstituted product is 20 mg/ml.  The calculated dose will be diluted further in 250-500 
ml of Dextrose 5% in water.  Each dose will be infused over 1-2 hr (depending on the total 
volume). It is crucial that no immunosuppressive agents are given until 24 hours after the 
completion of the post-transplant Cy. This includes corticosteroids as anti-emetics. 
 
3.  Side Effects and Toxicity:  Clinical toxicities of cyclophosphamide include alopecia, nausea 
and vomiting, headache and dizziness, hemorrhagic cystitis, cardiotoxicity, immunosuppression, 
myelosuppression, pulmonary fibrosis, increased hepatic enzymes and syndrome of 
inappropriate anti-diuretic hormone (SIADH). 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
42
 
D. Mesna 
 
1. Description:  Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by 
the oxazaphosphorines (cyclophosphamide and ifosfamide).  It has no intrinsic cytotoxicity 
and no antagonistic effects on chemotherapy.  Mesna binds with acrolein, the neurotoxic 
metabolite produced by the oxazaphosphorines, to produce a non-toxic thioether and slows 
the rate of acrolein formation by combining with 4-hydroxy metabolites of 
oxazaphosphorines. 
 
2. Storage and Administration:  Mesna is commercially available in 200 mg, 400 mg and 1000 
mg vials containing a 100 mg/ml solution. Each dose of mesna will be diluted further in 50 
ml of normal saline to be infused over 15 min.  Mesna dose will be based on the 
cyclophosphamide dose being given.  The total daily dose of mesna is equal to 80% of the 
total daily dose of cyclophosphamide.  
 
3. Side Effects and Toxicity:  At the doses used for uroprotection mesna is virtually non-toxic.  
However, adverse effects which may be attributable to mesna include nausea and vomiting, 
diarrhea, abdominal pain, altered taste, rash, urticaria, headache, joint or limb pain, 
hypotension and fatigue. 
 
E. Tacrolimus  
 
1.  Description:  Tacrolimus, also known as FK-506, is a macrolide immunosuppressive agent. 
Tacrolimus inhibits lymphocytes by forming a complex with FKBP-12, calcium, and calmodulin, 
leading to the decrease in the phosphatase activity of calcineurin.  Calcineurin mediates the first 
intracellular signal required for T-cell activation after antigen recognition by the T-cell receptor.  
This drug is used with corticosteroids for prophylaxis of organ rejection in patients receiving 
allogeneic liver transplants and for prophylaxis of GVHD in the setting of HSCT. It is also used 
for immunosuppression after kidney, cardiac, pancreas, pancreatic islet cell and small bowel 
transplantation. This drug is well-absorbed orally. It is metabolized in the liver by unknown 
mechanisms, but demethylation and hydroxylation have been proposed based on in vitro studies. 
The metabolized products are excreted in the urine. 
 
2.  Storage and Administration:  Tacrolimus is commercially available in capsule form (0.5, 1.0 
and 5.0 mg) and as a sterile solution in 1 mL ampules (5 mg/mL) for IV administration. 
 
3.  Side Effects and Toxicity: Adverse reactions include tremor, headache, insomnia, nausea, 
diarrhea, hypertension, and renal dysfunction (hyperkalemia, increased BUN and creatinine). 
 
Drugs that may increase blood levels of tacrolimus include: macrolide antibiotics, antifungals 
(fluconazole and itraconazole), calcium channel blockers, cimetidine, danazol, 
methylprednisolone and metoclopramide.  Drugs that may decrease blood levels of tacrolimus 
include: phenobarbital, phenytoin, carbamazepine, rifamycins and the anti-fungal agent 
caspofungin. 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
43
 
F. Mycophenolate Mofetil   
 
1.  Description:  Mycophenolate Mofetil is the morpholinyl ethyl ester prodrug of the active 
immunosuppressant mycophenolic acid (MPA). This active metabolite is a noncompetitive, 
reversible inhibitor of inosine monophosphate dehydrogenase, particularly the type II isoform 
that is more prominent in activated lymphocytes. As a result of the inhibition of de novo purine 
synthesis, proliferation of T- and B-lymphocytes is blocked and antibody production is inhibited.  
There are no pharmacokinetic interactions with ganciclovir, cotrimoxazole, oral contraceptives 
or cyclosporine. 
 
2.  Storage and Administration: MMF is commercially available in an oral and an intravenous 
formulation. The oral formulation is supplied in 250mg hard gelatin capsules and can be stored at 
room temperature. MMF for i.v. administration is supplied as a lyophilized powder in a glass vial 
containing the equivalent of 500mg. 
  
3.  Side effects and toxicity:  Side effect profiles include diarrhea, leukopenia, sepsis, allergic 
reactions, and vomiting. An increase in certain types of infection mainly from the herpes virus 
family (CMV, HSV & VZV) and candida has been reported.  MMF has been studied extensively 
among patients after nonmyeloablative HCT. Previous clinical studies in patients after allografting 
suggest that the principal adverse reactions associated with the administration of MMF include nausea, 
vomiting, neutropenia, diarrhea, and on one occasion bloody diarrhea. In the setting of marrow 
transplantation, several etiologic factors may contribute to alterations in gastrointestinal and hematologic 
parameters.  MMF has an increased incidence of digestive system adverse events, including GI tract 
ulceration, and hemorrhage (3% of patients receiving MMF). GI tract perforations have rarely been 
observed. Most patients in these studies were also on other drugs known to be associated with these 
complications. Up to 2% of patients receiving MMF for prevention of rejection developed severe 
neutropenia (ANC <500). The development of neutropenia may be related to MMF itself, concomitant 
medications, viral infections or some combination of these causes. MMF dose adjustments will be made if 
clinically indicated if in the opinion of the attending physician, no other cause is thought to be responsible 
for the abnormality.  These adjustments should be discussed with the principal investigator and 
documented in the medical records and the clinical reporting form (CRF). Dose adjustments are described 
in section 9E.6.h.  With the exception of hypophosphatemia there seems to be no difference in side 
effects between i.v. and oral MMF administration and efficacy is the same with both 
administration routes.  
  
 
G. Marrow or PBMC infusion 
 
Refer to Standard Practice Guidelines. 
 
H. Graft-versus-host disease (GVHD) 
 
The major toxicity of T-replete HSCT from related, HLA-haploidentical donors is GVHD. In the Phase 
II trial of cyclophosphamide-induced immunosuppression discussed above in Section 3 (Preliminary 
Results), cumulative incidence of grade II and grades III-IV GVHD were ─ and 10%, respectively. 
Chronic extensive GVHD was observed in 22% of patients. Mortality secondary to complications of 
GVHD therapy was 1/5 patients. Using thrice weekly MMF and prolonging the course of tacrolimus in 
addition to postgrafting cyclophosphamide have resulted in these relatively low rates of the clinically 
significant GVHD. 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
44
 
Diagnosis: Skin involvement will be assessed by biopsy with percentage of body surface area involved 
recorded. GI symptoms suspicious for GVHD will be evaluated by biopsy as indicated. Acute and 
chronic GVHD will be graded according to established criteria (Appendices D and E). 
 
12. Protocol Registration and Special Considerations 
 
Projected Target Accrual 
ETHNIC AND GENDER DISTRIBUTION CHART 
 
 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects 
Ethnic Category 
 
Sex / Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
11 
17 
28 
Ethnic Category Total of All 
12 
18 
30 
Racial Categories 
American Indian / Alaska Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific 
0 
0 
0 
Black or African American 
0 
1 
1 
White 
11 
16 
27 
Racial Categories:  Total of All 
12 
18 
30 
 
 
13.   Guidelines for Serious Adverse Event Reporting 
 
 
A. Monitoring the progress of trials and the safety of participants 
Protocol 2241 will become a multi-institutional clinical trial that is monitored by the principal 
investigator (PI), Dr. Mohamed Sorror, with oversight by a Data Safety and Monitoring Board (DSMB), 
the Data and Safety Monitoring Committee (DSMC) and the Institutional Review Board (IRB). The PI 
reviews outcome data for each individual patient at a minimum of 3 months after HSCT and the updated 
data are presented at Mixed Chimerism Meetings (includes co-investigators).  
 
Serious adverse events are reported to the trial coordinator, the study nurse or directly to the PI. The trial 
coordinators at collaborating centers or the local PIs will fax an official report of a serious adverse event 
to the coordinating center (FHCRC) within ten days. The serious adverse event report is reviewed by Dr. 
Sorror. If the serious adverse event meets the FHCRC criteria for reporting then an official signed report 
is submitted to the FHCRC Institutional Review Office (IRO). All deaths, regardless of the cause, are 
reported to the IRB. Protocol 2241 has a DSMB responsible for monitoring patient safety on this clinical 
trial. The DSMB meets twice a year and all outcome data is reviewed including all adverse events 
reported to the coordinating center (FHCRC) along with those officially reported to the FHCRC IRO. 
The DSMB confirms that the trial has met not any stopping rules and reviews any patient safety 
problems necessitating discontinuation of the trial. A report from the DSMB is submitted to the FHCRC 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
45
IRB as well as the trial coordinators/local PIs of this protocol. The DSMB will discontinue the review of 
outcomes when this protocol is closed to accrual.  Furthermore, the FHCRC also has a DSMC that 
reviews the progress of the protocol with respect to the monitoring plan at the time of each annual 
renewal. As with initial review, annual IRB review and approval is also required.  
 
With respect to safety, patients are monitored for the development of graft versus host disease (GVHD), 
myelosuppression and infections.  All patients, regardless of diagnosis, will be considered in the safety 
analysis.  Because of the older age profile of the patients, complications of HSCT and donor lymphocyte 
infusions (DLI), primarily GVHD and infections, may be more severe than usually encountered. These 
events will be closely monitored and severity of GVHD graded. Formal stopping rules are provided. 
Transplant-related mortality (TRM), defined as death before day 100 not related to progression of 
disease, will be closely monitored. This endpoint encompasses serious problems associated with the 
potential complications of severe GVHD, infections and rejection. 
 
Flow of information concerning clinical trial participants originates with the clinicians and nurses in the 
clinic or referring clinicians at other institutions and is transmitted to the trial coordinator. At the 
FHCRC, health care providers and rotating attending physicians assess patients and record their 
observations regarding toxicity and response outcomes in the medical record. This documentation is 
extracted by the study nurse within 140 days +/- after HCT via chart review and collection of copies of 
source documents and entered into a hard copy or electronic Case Report Form (CRF).  Thus, multiple 
health care providers provide independent observations and participate in monitoring this trial.  The PI 
may be a clinician for some patients entered on this trial.  However, assessments are the sum total of the 
primary health care provider (fellow or physician assistant), floor or outpatient nurse and the PI or other 
attending clinician involved with the patient averting possible conflict of interest having the PI as the 
attending clinician for protocol patients. If determination of adverse events is controversial, co-
investigators will convene on an ad hoc basis as necessary to review the primary data and render a 
decision.  
 
B. Plans for assuring compliance with requirements regarding the reporting of adverse events 
 
The adverse event reporting in this multi-institution clinical trial will follow an adapted version of the 
FHCRC Guidelines for serious adverse event (SAE) reporting. These guidelines detail the expedited 
reporting requirements, definitions of particular events. All SAEs that meet expedited reporting are 
reported to the IRO within 10 days of the investigator, trial coordinator, or research nurse upon learning 
of the event.  A completed SAE report form, signed by the PI, must be received by the IRO within 10 
calendar days. Only toxicities that meet the criteria for an SAE will be collected and reported.  For 
patients being cared for at the FHCRC, health care providers communicate with the PI, trial coordinator 
or research nurses as events occur triggering subsequent reporting. For patients not being cared for at 
FHCRC the outside facilities communicate with the PI, trial coordinator, or research nurse for these 
reporting purposes. All other deaths and expected serious adverse events are reported to the IRB at the 
time of annual renewal and at the biannual mixed chimerism meeting.  The PI for a study is responsible 
for this reporting and the IRO assures adverse event reporting on an annual basis.  The PI in the annual 
application for grant continuation will summarize reports of toxicities.  Furthermore, an additional 
safeguard for adverse event analysis and reporting in this protocol is provided by stopping rules and 
interim analysis. All collaborating PIs have fulfilled all NIH requirements for training in human subjects 
protection. 
                               
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
46
 
C. Plans for assuring that any action resulting in a temporary or permanent suspension of an NCI-
funded clinical trial is reported to the NCI grant program director responsible for the grant 
 
This clinical research trial uses commercial agents and there is no associated Investigational New Drug 
(IND) or Investigational Device Exemption (IDE). Any temporary or permanent suspension, as 
determined by the PI, IRB, or DSMC, of this clinical research trial will be reported to the NCI grant 
program director by the PI.  
 
 
 
D. Plans for assuring data accuracy and protocol compliance 
 
 
 
Collaborating sites send signed consents, eligibility forms, and CRFs with source documents 
demonstrating eligibility, treatment, and serious adverse events (if applicable) to the study staff. These 
are reviewed for eligibility, adherence to the protocol, accuracy, and completeness by the study staff. 
Queries are sent to the collaborating investigators if CRFs are inaccurate or incomplete. 
 
The study is monitored under the FHCRC Monitoring Plan. The FHCRC Data and Safety Monitoring 
Plan detail the full scope and extent of monitoring and provides for immediate action in the event of the 
discovery of major deviations. 
 
 
14. Records 
Clinical Statistics maintains a patient database at FHCRC to allow storage and retrieval of patient data collected 
from a wide variety of sources. The investigator will ensure that data collected conform to all established 
guidelines for coding collection, key entry and verification. Any publication or presentation will refer to 
patients by this number and not by name. The licensed medical records department, affiliated with the 
institution where the patient receives medical care, maintains all original inpatient and outpatient chart 
documents. Patient research files are kept in a locked room. They are maintained by the FHCRC data collection 
staff which is supervised by an A.R.T.  Access is restricted to personnel authorized by the Division of Clinical 
Research. 
 
Standard data collection procedures have been developed and agreed upon by the research physicians at 
FHCRC and all collaborating study centers for previous protocols. Ongoing data collection will be monitored 
by the coordinating center to ensure data completeness and uniformity across study centers. Follow-up once the 
patient leaves the research center will be primarily through the patient’s physician and through annual clinic 
visits at the transplant research center. 
 
Collection of Survival and Disease Response Data 
Centers enrolling patients will complete case report forms within 120 days of HCT that detail events occurring 
within the 100 days after HCT (Appendix K).  The case report form provides detailed descriptions of the 
transplantation procedure, disease response, and complications. Detailed treatment-related adverse events will 
be reported using the NCI Common Toxicity Criteria (Appendix M).  The coordinating center will contact 
subjects when they return to the HCT center for routine HCT follow-up at 3, 6, 12, 18 and 24 months and then 
annually time five years, to ascertain the patient’s disease status and survival. Referring physicians are required 
to report the date and cause of death within 48 hours of occurrence. Supporting medical records must be 
available upon request to substantiate data on the case report forms. Death information including date and cause 
will be reviewed from these medical records, and will be confirmed by death certificate. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
47
15. Statistical Considerations and Termination of the Study 
 
This phase II trial will enroll 30 patients with high-risk multiple myeloma, lymphoma, or CLL.  Patients will 
receive an autologous HCT, followed by nonmyeloablative conditioning and allogeneic HCT from a HLA-
haploidentical related donor. We anticipate average annual accrual of 4 patients per year from SCCA with an 
average duration of 12 years to complete the study. 
 
In case of a cross-over from this protocol to another tandem autologous-allogeneic research protocol (#1409 or 
other appropriate protocol) or vice versa, enrollment will be counted on the crossed-over protocol if the patient 
receives the allogeneic transplantation on that protocol. If the patient is crossed-over but does not receive the 
allogeneic transplantation, enrollment will be counted on the initial protocol.  
 
The primary objective of this study is to examine the potential efficacy of this treatment plan in terms of 
progression free survival (PFS). PFS will be calculated for all patients from the date of autologous transplant 
until the time of death. Nonmyeloablative conditioning and HCT from HLA- haploidentical related donors 
resulted in 1-year PFS of 32% among patients with high-risk hematological malignancies. Our hypothesis is that 
the addition of planned autologous HCT will improve PFS by reducing the rates of relapse. Given the relatively 
poor prognostic characteristics of patients eligible for this study, an observed 1-year PFS of ≥50% would be 
considered efficacious and worthy of further study. With 30 patients, the width of an 80% binomial confidence 
interval for the PFS probability would be +/- 10 percentage points; the width of the 95% confidence interval 
would be +/- 18 percentage points. With 30 patients, the probability of observing 1-year PFS of 0.50 or greater 
is 57% if the true rate is 0.50, 77% if the true rate is 0.55, and 90% if the true rate is 0.60. 
 
The secondary objectives of this study are to assess rates of relapse at 1 year, early NRM and incidence/severity 
of acute and chronic GVHD, and immune reconstitution after allografting. 
 
Reconstitution of lymphocyte subsets in peripheral blood at is a secondary endpoint.  Absolute counts of B-cells 
(CD19+ ), T-cell subsets (determined by differential expression of CD4, CD8 or CD45 isoforms on CD3+ cells) 
and NK cells (CD16+/CD56+ ) in peripheral blood determined on day +84 should be compared to pre-transplant 
lymphocyte counts on day –6. 
 
NRM after nonmyeloablative HLA-haploidentical HCT was 15% at 1-year. Therefore, we will choose a NRM 
at 200 days after allograft of 30% as a threshold for a safety stopping rule. This allows for some increase in 
NRM due to additional patients being exposed to the risk of NRM if we are successful in reducing the rate of 
relapse/progression. It also allows for a small amount of NRM after the autograft. Early NRM will be monitored 
in a sequential fashion. A stopping rule will be implemented for: 
 
• NRM within 200 days of the allograft exceeds 30%. 
 
Reasonable evidence will be taken to mean that the lower bound of a one-sided 80% confidence interval for the 
true rate of NRM is above 0.30. Operationally, these limits would be realized if any of the failure rates below 
are observed: 
 
• NRM within 200 days of allograft (30% threshold): 5/10, 9/20, 12/30 
 
These stopping rules will be evaluated at least every 10 patients. Patients may continue to be enrolled pending 
evaluation of the safety endpoints in each cohort of 10 patients; however, the outcome of subsequent patients 
cannot be used to override a stopping rule triggered in the earlier cohort.  The operating characteristics of these 
stopping rules are summarized in the table below. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
48
Table 12: Operating Characteristics of Stopping Rules 
 
True rate of 
day 200 NRM 
Probability of 
early stopping* 
Average n 
at stopping* 
0.35 
45% 
24 
0.40 
66% 
21 
0.45 
81% 
19 
* based on 10,000 Monte Carlo simulations 
 
Since there is limited experience treating patients with lymphoma, Waldenstrom’s Macroglobulinemia, CLL, 
MM, or plasma cell leukemia with the treatment plan proposed in the current study, this trial will be carefully 
monitored for potential complications that could render this proposal a failure relative to more conventional 
treatment plans for eligible patients.  In addition to the above outcomes, secondary endpoints to be examined 
include overall survival, relapse rate, and engraftment. Overall survival will be estimated by the method of 
Kaplan and Meier, and relapse rate will be summarized using cumulative incidence estimates. Confidence 
intervals for all these outcomes will be also be estimated.  Engraftment will be monitored in a sequential 
fashion. Given the preliminary experience with nonablative HCT in patients with lymphoma, Waldenstrom’s 
Macroglobulinemia, CLL, MM, or plasma cell leukemia, we do not expect engraftment failure or rejection to be 
a problem in this population undergoing reduced-intensity allografting, but we will be concerned should the 
observed rejection- or engraftment-failure rate exceed 20%. Should this occur, the study would be suspended 
pending review by the DSMB.  
 
As stated above, should the results of this study indicate that the current treatment plan is potentially 
efficacious, a more definitive analysis of efficacy will be undertaken in a subsequent Phase II study. This future 
study would be designed to show a statistically significant difference in PFS compared to a predetermined fixed 
target rate. 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
49
16. References  
 
Reference List 
 
 
 1.   Bierman P, Anderson J, Vose J, Freeman M, Bishop M, Kessinger A, Armitage J.  High-dose 
chemotherapy with autologous hematopoietic rescue for Hodgkin's disease (HD) following first 
relapse after chemotherapy.  Proc ASCO  12: 366, 1993.(Abstract) 
 
 
 2.   Chopra R, McMillan AK, Linch DC, Yuklea S, Taghipour G, Pearce R, Patterson KG, Goldstone AH.  
The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk 
Hodgkin's disease. A single-center eight-year study of 155 patients.  Blood 81: 1137-1145, 1993. 
 
 
 3.   Sureda A, Arranz R, Iriondo A, Carreras E, Lahuerta JJ, Garcia-Conde J, Jarque I, Caballero MD, Ferra 
C, Lopez A, Garcia-Larana J, Cabrera R, Carrera D, Ruiz-Romero MD, Leon A, Rifon J, Diaz-
Mediavilla J, Mataix R, Morey M, Moraleda JM, Altes A, Lopez-Guillermo A, de la SJ, 
Fernandez-Ranada JM, Sierra J, Conde E.  Autologous stem-cell transplantation for Hodgkin's 
disease: results and prognostic factors in 494 patients from the Grupo Espanol de 
Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group.  J Clin Oncol 19: 
1395-1404, 2001. 
 
 
 4.   Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht, 
Cahn J-Y, Harousseau J-L, Coiffier B, Biron P, Mandell F, Chauvin F.  Autologous bone 
marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-
sensitive non-Hodgkin's lymphoma.  N Engl J Med 333: 1540-1545, 1995. 
 
 
 5.   Freedman AS, Anderson KC, Mauch P, Rabinowe SN, Blake K, Yeap B, Soiffer R, Coral F, Heflin L, 
Ritz J, Nadler LM.  Autologous bone marrow transplantation in B-cell non-Hodgkin's 
lymphoma: Very low treatment-related mortality in 100 patients in sensitive relapse.  J Clin 
Oncol 8: 784-791, 1990. 
 
 
 6.   Attal M, Harousseau J-L, Stoppa A-M, Sotto J-J, Fuzibet J-G, Rossi J-F, Casassus P, Maisonneuve H, 
Facon T, Ifrah N, Payen C, Bataille R, for the Intergroupe Français Du Myélome.  A prospective, 
randomized trial of autologous bone marrow transplantation and chemotherapy in multiple 
myeloma.  N Engl J Med 335: 91-97, 1996. 
 
 
 7.   Attal M, Harousseau JL.  Randomized trial experience of the Intergroupe Francophone du Myelome 
(Review).  Semin Hematol 38: 226-230, 2001. 
 
 
 8.   Lazarus HM, Rowlings PA, Zhang MJ, Vose JM, Armitage JO, Bierman PJ, Gajewski JL, Gale RP, 
Keating A, Klein JP, Miller CB, Phillips GL, Reece DE, Sobocinski KA, van Besien K, 
Horowitz MM.  Autotransplants for Hodgkin's disease in patients never achieving remission: a 
report from the Autologous Blood and Marrow Transplant Registry.  J Clin Oncol 17: 534-545, 
1999. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
50
 
 9.   Constans M, Sureda A, Terol MJ, Arranz R, Caballero MD, Iriondo A, Jarque I, Carreras E, Moraleda 
JM, Carrera D, Leon A, Lopez A, Albo C, Diaz-Mediavilla J, Fernandez-Abellan P, Garcia-Ruiz 
JC, Hernandez-Navarro F, Mataix R, Petit J, Pascual MJ, Rifon J, Garcia-Conde J, Fernandez-
Ranada JM, Mateos MV, Sierra J, Conde E, GEL/TAMO Cooperative Group.  Autologous stem 
cell transplantation for primary refractory Hodgkin's disease: results and clinical variables 
affecting outcome.  Ann Oncol 14: 745-751, 2003. 
 
  10.   Caballero MD, Rubio V, Rifon J, Heras I, Garcia-Sanz R, Vazquez L, Vidriales B, del Canizo MC, 
Corral M, Gonzalez M, Leon A, Jean-Paul E, Rocha E, Moraleda JM, San Miguel JF.  BEAM 
chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of 
efficacy, toxicity and prognostic factors.  Bone Marrow Transplant 20: 451-458, 1997. 
  
  11.   Geisler CH, Hansen MM, Andersen NS, Brown P, Christensen LD, Dickmeiss E, Ersboll J, Myhre J, 
Hansen M, Juhl BR, Mortensen BT, Pedersen-Bjergaard J.  BEAM+autologous stem cell 
transplantation in malignant lymphoma: 100 consecutive transplants in a single centre. Efficacy, 
toxicity and engraftment in relation to stem-cell source and previous treatment.  Eur J Haematol 
61: 173-182, 1998. 
 
  12.   Mills W, Chopra R, McMillan A, Pearce R, Linch DC, Goldstone AH.  BEAM chemotherapy and 
autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's 
lymphoma.  J Clin Oncol 13: 588-595, 1995. 
 
  13.   Stewart AK, Vescio R, Schiller G, Ballester O, Noga S, Rugo H, Freytes C, Stadtmauer E, Tarantolo S, 
Sahebi F, Stiff P, Meharchard J, Schlossman R, Brown R, Tully H, Benyunes M, Jacobs C, 
Berenson R, White M, DiPersio J, Anderson KC, Berenson J.  Purging of autologous peripheral-
blood stem cells using CD34 selection does not improve overall or progression-free survival 
after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized 
controlled trial.  J Clin Oncol 19: 3771-3779, 2001. 
 
  14.   Ritgen M, Lange A, Stilgenbauer S, Dohner H, Bretscher C, Bosse H, Stuhr A, Kneba M, Dreger P.  
Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic 
factor after autologous stem cell transplantation for chronic lymphocytic leukemia.  Blood 101: 
2049-2053, 2003. 
 
  15.   Dreger P, Stilgenbauer S, Benner A, Ritgen M, Krober A, Kneba M, Schmitz N, Dohner H.  The 
prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic 
leukemia: a risk-matched analysis based on the VH gene mutational status.  Blood 103: 2850-
2858, 2004. 
 
  16.   Gribben JG, Zahrieh D, Stephans K, Bartlett-Pandite L, Alyea EP, Fisher DC, Freedman AS, Mauch P, 
Schlossman R, Sequist LV, Soiffer RJ, Marshall B, Neuberg D, Ritz J, Nadler LM.  Autologous 
and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia.  Blood 
106: 4389-4396, 2005. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
51
  17.   Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M, Facon T, Gratwohl A, Hagenbeek A, 
Jacobs P, De Laurenzi A, Van Lint M, Michallet M, Nikoskelainen J, Reiffers J, Samson D, 
Verdonck L, de Witte T, Volin L.  Prognostic factors in allogeneic bone marrow transplantation 
for multiple myeloma.  J Clin Oncol 13: 1312-1322, 1995. 
 
  18.   Michallet M, Archimbaud E, Bandini G, Rowlings PA, Deeg HJ, Gahrton G, Montserrat E, Rozman C, 
Gratwohl A, Gale RP.  HLA-identical sibling bone marrow transplantation in younger patients 
with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and 
the International Bone Marrow Transplant Registry.  Ann Intern Med 124: 311-315, 1996. 
 
  19.   Akpek G, Ambinder RF, Piantadosi S, Abrams RA, Brodsky RA, Vogelsang GB, Zahurak ML, Fuller 
D, Miller CB, Noga SJ, Fuchs E, Flinn IW, O'Donnell P, Seifter EJ, Mann RB, Jones RJ.  Long-
term results of blood and marrow transplantation for Hodgkin's lymphoma.  J Clin Oncol 19: 
4314-4321, 2001. 
 
  20.   de Lima M, van Besien KW, Giralt SA, Khouri IF, Mehra R, Andersson BS, Przepiorka D, Gajewski JL, 
Korbling M, Champlin RE.  Bone marrow transplantation after failure of autologous transplant 
for non-Hodgkin's lymphoma.  Bone Marrow Transplant 19: 121-127, 1997. 
 
  21.   Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W, Storer B, 
Hegenbart U, Somlo G, Chauncey T, Bruno B, Appelbaum FR, Blume KG, Forman SJ, 
McSweeney P, Storb R.  Allografting with nonmyeloablative conditioning following 
cytoreductive autografts for the treatment of patients with multiple myeloma.  Blood 102: 3447-
3454, 2003. 
 
  22.   Maloney DG, Gahrton G.  Allogeneic hematopoietic cell transplantation for multiple myeloma. In: 
Blume KG, Forman SJ, Appelbaum FR (eds):  Thomas' Hematopoietic Cell Transplantation.  
Oxford, UK:  Blackwell Publishing Ltd., p. 1096-1104, 2004. 
 
  23.   Maris MB, Sandmaier BM, Storer BE, Chauncey T, Stuart MJ, Maziarz RT, Agura E, Langston AA, 
Pulsipher M, Storb R, Maloney DG.  Allogeneic hematopoietic cell transplantation after 
fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma.  
Blood 104: 3535-3542, 2004. 
 
  24.   Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, 
Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, 
Al-Ali H, Blume KG, Storb R, Maloney DG.  Hematopoietic cell transplantation after 
nonmyeloablative conditioning for advanced chronic lymphocytic leukemia.  J Clin Oncol 23: 
3819-3829, 2005. 
 
  25.   Norasetthada L, Maris MB, Sandmaier BM, Gooley T, Forman S, Agura E, Maziarz RT, Shizuru J, 
Niederwieser D, Storb R, Maloney DG.  HLA-matched related (MRD) or unrelated donor (URD) 
non-myeloablative hematopoietic cell tranpslantation (HCT) for patients (pts) with refractory and 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
52
relapsed aggressive non Hodgkin lymphoma.  Blood  104 (Part 1): 634a-635a, #2307, 
2004.(Abstract) 
 
  26.   Burroughs LM, Maris MB, Sandmaier BM, Leisenring W, Jain Stuart M, Niederwieser D, McSweeney 
PA, Chauncey T, Maziarz R, Agura E, Little M-T, Blume KG, Storb R, Maloney DG.  HLA-
matched related (MRD) or unrelated donor (URD) non-myeloablative conditioning and 
hematopoietic cell transplant (HCT) for patients with advanced Hodgkin disease (HD).  Biol 
Blood Marrow Transplant  10 (Suppl. 1): 73-74, #197, 2004.(Abstract) 
 
  27.   Rezvani AR, Sandmaier BM, Storer B, Maris M, Agura E, Maziarz R, Wade JC, Chauncey T, Forman 
SJ, Niederwieser DW, Shizuru J, Langston A, Pulsipher M, Storb RF, Maloney DG.  Outcomes 
of allogeneic hematopoietic stem cell transplantation (HCT) after non-myeloablative conditining 
in relapsed, refractory, or transformed indolent non-Hodgkin lymphoma (NHL).  Blood  108 
(Part 1): 891a, #3124, 2006.(Abstract) 
 
  28.   Georges GE, Maris MB, Maloney DG, Sandmaier BM, Sorror ML, Shizuru JA, Lange T, Agura ED, 
Bruno B, McSweeney PA, Pulsipher MA, Chauncey TR, Mielcarek M, Storer BE, Storb R.  
Nonmyeloablative unrelated donor hematopoietic cell transplantation to treat patients with poor-
risk, relapsed, or refractory multiple myeloma.  Biol Blood Marrow Transplant 13: 423-432, 
2007. 
 
  29.   Rotta M, Storer B, Sahebi F, Shizuru JA, Benedetto B, Lange T, McSweeney PA, Pulsipher MA, Hari P, 
Maziarz RT, Agura ED, Chauncey T, Appelbaum FR, Sorror ML, Bensinger W, Sandmaier BM, 
Storb RF, Maloney DG.  Long-term outcome of autologous followed by nonmyeloablative 
allografting from HLA-identical sibling for multiple myeloma (MM).  Blood  110 (Part 1):  
889a, #3029, 2007.(Abstract) 
 
  30.   Beatty PG, Mori M, Milford E.  Impact of racial genetic polymorphism on the probability of finding an 
HLA-matched donor.  Transplantation 60: 778-783, 1995. 
 
  31.   Hansen JA, Petersdorf E, Martin PJ, Anasetti C.  Hematopoietic stem cell transplants from unrelated 
donors.  Immunol Rev 157: 141-151, 1997. 
 
  32.   Howe CWS, Radde-Stepaniak T.  Hematopoietic cell donor registries. In: Thomas ED, Blume KG, 
Forman SJ (eds):  Hematopoietic Cell Transplantation.  Boston, MA:  Blackwell Science, p. 503-
512, 1999. 
 
  33.   Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, 
Kaup M, Ambinder RF, Huff CA, Matsui W, Bolaños-Meade J, Borrello I, Powell JD, 
Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs 
EJ.  HLA-haploidentical bone marrow transplantation for hematologic malignancies using 
nonmyeloablative conditioning and high-dose, post-transplantation cyclophosphamide.  Biol 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
53
Blood Marrow Transplant 14: 641-650, 2008. 
 
  34.   Kharfan-Dabaja MA, Kumar A, Behera M, Djulbegovic B.  Systematic review of high dose 
chemotherapy and autologous haematopoietic stem cell transplantation for chronic lymphocytic 
leukaemia: what is the published evidence? (Review).  Br J Haematol 139: 234-242, 2007. 
 
  35.   Seftel M, Rubinger M.  The role of hematopoietic stem cell transplantation in advanced Hodgkin 
lymphoma (Review).  Transfusion & Apheresis Science 37: 49-56, 2007. 
 
  36.   Fernandez HF, Escalon MP, Pereira D, Lazarus HM.  Autotransplant conditioning regimens for 
aggressive lymphoma: are we on the right road? (Review).  Bone Marrow Transplant 40: 505-
513, 2007. 
 
  37.   Freedman AS, Ritz J, Neuberg D, Anderson KC, Rabinowe SN, Mauch P, Takvorian T, Soiffer R, Blake 
K, Yeap B.  Autologous bone marrow transplantation in 69 patients with a history of low-grade 
B-cell non-Hodgkin's lymphoma.  Blood 77: 2524-2529, 1991. 
 
  38.   Rohatiner AZ, Freedman A, Nadler L, Lim J, Lister TA.  Myeloablative therapy with autologous bone 
marrow transplantation as consolidation therapy for follicular lymphoma.  Ann Oncol 5 (Suppl. 
2): 143-146, 1994. 
 
  39.   Brice P, Marolleau JP, Dombret H, Lepage E, Baruchel A, Adam M, Miclea JM, Sitthy X, Gisselbrecht 
C.  Autologous peripheral blood stem cell transplantation after high dose therapy in patients with 
advanced lymphomas.  Bone Marrow Transplant 9: 337-342, 1992. 
 
  40.   Linch DC, Hancock B, Winfield D, McMillan A, Hudson GV, Goldstone AH, Chopra R, Moir D, 
Milligan D.  Dose intensification with autologous bone-marrow transplantation in relapsed and 
resistant Hodgkin's disease: results of a BNLI randomised trial.  Lancet 341: 1051-1054, 1993. 
 
  41.   Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Muller P, 
Kirchner H, Lohri A, Decker S, Koch B, Hasenclever D, Goldstone AH, Diehl V, German 
Hodgkin's Lymphoma Study Group, Lymphoma Working Party of the European Group for 
Blood and Marrow Transplantation.  Aggressive conventional chemotherapy compared with 
high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed 
chemosensitive Hodgkin's disease: a randomised trial.  Lancet 359: 2065-2071, 2002. 
 
  42.   Stamatoullas A, Fruchart C, Khalfallah S, Buchonnet G, Contentin N, Bastit D, Tilly H.  Peripheral 
blood stem cell transplantation for relapsed or refractory aggressive lymphoma in patients over 
60 years of age.  Bone Marrow Transplant 19: 31-35, 1997. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
54
  43.   Rabinowe SN, Soiffer RJ, Gribben JG, Daley H, Freedman AS, Daley J, Pesek K, Neuberg D, Pinkus G, 
Leavitt PR, Spector NA, Grossbard ML, Anderson K, Robertson MJ, Mauch P, Chayt-Marcus K, 
Ritz J, Nadler LM.  Autologous and allogeneic bone marrow transplantation for poor prognosis 
patients with B-cell chronic lymphocytic leukemia.  Blood 82: 1366-1376, 1993. 
 
  44.   Khouri IF, Keating MJ, Vriesendorp HM, Reading CL, Przepiorka D, Huh YO, Andersson BS, van 
Besien KW, Mehra RC, Giralt SA, Ippoliti C, Marshall M, Thomas MW, O'Brien S, Robertson 
LE, Deisseroth AB, Champlin RE.  Autologous and allogeniec bone marrow transplantation for 
chronic lymphocytic leukemia: preliminary results.  J Clin Oncol 12: 748-758, 1994. 
 
  45.   Pavletic ZS, Bierman PJ, Vose JM, Bishop MR, Wu CD, Pierson JL, Kollath JP, Weisenburger DD, 
Kessinger A, Armitage JO.  High incidence of relapse after autologous stem-cell transplantation 
for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.  Ann Oncol 9: 1023-
1026, 1998. 
 
  46.   Sutton L, Maloum K, Gonzalez H, Zouabi H, Azar N, Boccaccio C, Charlotte F, Cosset JM, Gabarre J, 
Leblond V, Merle-Beral H, Binet JL.  Autologous hematopoietic stem cell transplantation as 
salvage treatment for advanced B cell chronic lymphocytic leukemia.  Leukemia 12: 1699-1707, 
1998. 
 
  47.   Milligan DW, Fernandes S, Dasgupta R, Davies FE, Matutes E, Fegan CD, McConkey C, Child JA, 
Cunningham D, Morgan GJ, Catovsky D, National Cancer Research Institute Haematological 
Studies Group.  Results of the MRC pilot study show autografting for younger patients with 
chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses.  
Blood 105: 397-404, 2005. 
 
  48.   Gutierrez-Delgado F, Holmberg L, Hooper H, Petersdorf S, Press O, Maziarz R, Maloney D, Chauncey 
T, Appelbaum F, Bensinger W.  Autologous stem cell transplantation for Hodgkin's disease, 
busulfan, melphalan and thiopeta compared to a radiation-based regimen.  Bone Marrow 
Transplant 32: 279-285, 2003. 
 
  49.   Mounier N, Gisselbrecht C.  Conditioning regimens before transplantation in patients with aggressive 
non-Hodgkin's lymphoma (Review).  Ann Oncol 9 (Suppl. 1): S15-S21,1998. 
 
  50.   Vose JM, Armitage JO.  Role of autologous bone marrow transplantation in non-Hodgkin's lymphoma 
(Review).  Hematology - Oncology Clinics of North America 7: 577-590, 1993. 
 
  51.   Stewart FM.  Indications and relative indications for stem cell transplantation in non-Hodgkin's 
lymphoma (Review).  Leukemia 7: 1091-1094, 1993. 
 
  52.   Appelbaum FR, Sullivan KM, Buckner CD, Clift RA, Deeg HJ, Fefer A, Hill R, Mortimer J, Neiman 
PE, Sanders JE, Singer J, Stewart P, Storb R, Thomas ED.  Treatment of malignant lymphoma in 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
55
100 patients with chemotherapy, total body irradiation, and marrow transplantation.  J Clin 
Oncol 5: 1340-1347, 1987. 
 
  53.   Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B.  Hematopoietic cell 
transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before 
allogeneic HCT.  Blood 106: 2912-2919, 2005. 
 
  54.   Sorror M, Storer B, Gopal A, Holmberg L, Sandmaier BM, Bensinger WI, Maloney DG, Press OW, 
Storb RF.  Comorbidity, lactate dehydrogenase (LDH), and chemosensitivity are independent 
predictors of mortality after autologous hematopoietic cell transplantation (HCT) for patients 
(pts) with lymphoma.  Blood  110 (Part 1): 190a, #616, 2007.(Abstract) 
 
  55.   Palumbo A, Triolo S, Argentino C, Bringhen S, Dominietto A, Rus C, Omede P, Tarella C, Pileri A, 
Boccadoro M.  Dose-intensive melphalan with stem cell support (MEL100) is superior to 
standard treatment in elderly myeloma patients.  Blood 94: 1248-1253, 1999. 
 
  56.   Vesole DH, Barlogie B, Jagannath S, Cheson B, Tricot G, Alexanian R, Crowley J.  High-dose therapy 
for refractory multiple myeloma: improved prognosis with better supportive care and double 
transplants.  Blood 84: 950-956, 1994. 
 
  57.   Barlogie B, Jagannath S, Vesole D, Tricot G.  Autologous and allogeneic transplants for multiple 
myeloma.  Semin Hematol 32: 31-44, 1995. 
 
  58.   Cavo M, Benni M, Gozzetti A, Tura S.  The role of haematopoietic stem cell-supported myeloablative 
therapy for the management of multiple myeloma.  Baillieres Clin Haematol 8: 795-813, 1995. 
 
  59.   Marit G, Faberes C, Pico JL, Boiron JM, Bourhis JH, Brault P, Bernard P, Foures C, Cony-Makhoul P, 
Puntous M, Vezon G, Broustet A, Girault D, Reiffers J.  Autologous peripheral-blood 
progenitor-cell support following high-dose chemotherapy or chemoradiotherapy in patients with 
high-risk multiple myeloma.  J Clin Oncol 14: 1306-1313, 1996. 
 
  60.   Bensinger WI, Rowley SD, Demirer T, Lilleby K, Schiffman K, Clift RA, Appelbaum FR, Fefer A, 
Barnett T, Storb R, Chauncey T, Maziarz RT, Klarnet J, McSweeney P, Holmberg L, Maloney 
DG, Weaver CH, Buckner CD.  High-dose therapy followed by autologous hematopoietic stem-
cell infusion for patients with multiple myeloma.  J Clin Oncol 14: 1447-1456, 1996. 
 
  61.   Mehta J, Singhal S, Desikan K, Munshi N, Badros A, Zangari M, Anaissie E, Lim S, Barlogie B.  High-
dose therapy and stem-cell support in myeloma.  PPO Updates: Principles & Practice of 
Oncology 13: 1-12, 1999. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
56
  62.   Desikan R, Barlogie B, Sawyer J, Ayers D, Tricot G, Badros A, Zangari M, Munshi NC, Anaissie E, 
Spoon D, Siegel D, Jagannath S, Vesole D, Epstein J, Shaughnessy J, Fassas A, Lim S, Roberson 
P, Crowley J.  Results of high-dose therapy for 1000 patients with multiple myeloma: durable 
complete remissions and superior survival in the absence of chromosome 13 abnormalities.  
Blood 95: 4008-4010, 2000. 
 
  63.   Barlogie B, Alexanian R, Smallwood L, Cheson B, Dixon D, Dicke K, Cabanillas F.  Prognostic factors 
with high-dose melphalan for refractory multiple myeloma.  Blood 72: 2015-2019, 1988. 
 
  64.   Cunningham D, Paz-Ares L, Milan S, Powles R, Nicolson M, Hickish T, Selby P, Treleavan J, Viner C, 
Malpas J.  High-dose melphalan and autologous bone marrow transplantation as consolidation in 
previously untreated myeloma.  J Clin Oncol 12: 759-763, 1994. 
 
  65.   Siegel DS, Desikan KR, Mehta J, Singhal S, Fassas A, Munshi N, Anaissie E, Naucke S, Ayers D, 
Spoon D, Vesole D, Tricot G, Barlogie B.  Age is not a prognostic variable with autotransplants 
for multiple myeloma.  Blood 93: 51-54, 1999. 
 
  66.   Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, 
Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo 
A, Storb R, Ciccone G, Boccadoro M.  A comparison of allografting with autografting for newly 
diagnosed myeloma.  N Engl J Med 356: 1110-1120, 2007. 
 
  67.   Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ.  Durable engraftment of major 
histocompatibility complex-incompatible cells after nonmyeloablative conditioning with 
fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide.  Blood 
98: 3456-3464, 2001. 
 
  68.   Petrus MJ, Williams JF, Eckhaus MA, Gress RE, Fowler DH.  An immunoablative regimen of 
fludarabine and cyclophosphamide prevents fully MHC-mismatched murine marrow graft 
rejection independent of GVHD.  Biol Blood Marrow Transplant 6: 182-189, 2000. 
 
  69.   McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, 
Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger 
WI, Bryant E, Flowers MED, Georges GE, Grumet FC, Kiem H-P, Torok-Storb B, Yu C, Blume 
KG, Storb RF.  Hematopoietic cell transplantation in older patients with hematologic 
malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.  Blood 97: 
3390-3400, 2001. 
 
  70.   O'Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M, Rhubart P, Cowan K, 
Piantados S, Fuchs EJ.  Nonmyeloablative bone marrow transplantation from partially HLA-
mismatched related donors using posttransplantation cyclophosphamide.  Biol Blood Marrow 
Transplant 8: 377-386, 2002. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
57
  71.   Molina AJ, Storb RF.  Hematopoietic stem cell transplantation in older adults. In: Rowe JM, Lazarus 
HM, Carella AM (eds):  Handbook of Bone Marrow Transplantation.  London, UK:  Martin 
Dunitz Ltd, p. 111-137, 2000. 
 
  72.   Goss PE.  Non-Hodgkin's lymphomas in elderly patients (Review).  Leuk Lymphoma 10: 147-156, 
1993. 
 
  73.   Fried LP, Bandeen-Roche K, Kasper JD, Guralnik JM.  Association of comorbidity with disability in 
older women: the Women's Health and Aging Study.  Journal of Clinical Epidemiology 52: 27-
37, 1999. 
 
  74.   Kuittinen T, Nousiainen T, Halonen P, Mahlamaki E, Jantunen E.  Prediction of mobilisation failure in 
patients with non-Hodgkin's lymphoma.  Bone Marrow Transplant 33: 907-912, 2004. 
 
  75.   Jantunen E, Mahlamaki E, Nousiainen T.  Feasibility and toxicity of high-dose chemotherapy supported 
by peripheral blood stem cell transplantation in elderly patients (>/=60 years) with non-
Hodgkin's lymphoma: comparison with patients <60 years treated within the same protocol.  
Bone Marrow Transplant 26: 737-741, 2000. 
 
  76.   Jantunen E, Kuittinen T, Penttila K, Lehtonen P, Mahlamaki E, Nousiainen T.  High-dose melphalan 
(200 mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly 
(>or=65 years) myeloma patients: comparison with younger patients treated on the same 
protocol.  Bone Marrow Transplant 37: 917-922, 2006. 
 
  77.   Moreau P, Milpied N, Voillat L, Colombat P, Mahe B, Rapp MJ, Moreau A, Dupas B, Bulabois CE, 
Juge-Morineau N, Harousseau JL.  Peripheral blood stem cell transplantation as front-line 
therapy in patients aged 61 to 65 years: a pilot study.  Bone Marrow Transplant 21: 1193-1196, 
1998. 
 
  78.   Leger CS, Bredeson C, Kearns B, Bence-Bruckler I, Atkins H, Huebsch L.  Autologous blood and 
marrow transplantation in patients 60 years and older.  Biol Blood Marrow Transplant 6: 204-
210, 2000. 
 
  79.   Gopal AK, Gooley TA, Golden JB, Maloney DG, Bensinger WI, Petersdorf SH, Appelbaum FR, Press 
OW.  Efficacy of high-dose therapy and autologous hematopoietic stem cell transplantation for 
non-Hodgkin's lymphoma in adults 60 years of age and older.  Bone Marrow Transplant 27: 593-
599, 2001. 
 
  80.   Zallio F, Cuttica A, Caracciolo D, Gavarotti P, Bergui L, Giaretta F, Bondesan P, Tassi V, Gallo E, 
Pileri A, Tarella C.  Feasibility of peripheral blood progenitor cell mobilization and harvest to 
support chemotherapy intensification in elderly patients with poor prognosis: non-Hodgkin's 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
58
lymphoma.  Ann Hematol 81: 448-453, 2002. 
 
  81.   Bitran JD, Klein L, Link D, Kosirog-Glowacki J, Stewart C, Raack D, Sheahan P, Lisowski J, Rowen J.  
High-dose myeloablative therapy and autologous peripheral blood progenitor cell transplantation 
for elderly patients (greater than 65 years of age) with relapsed large cell lymphoma.  Biol Blood 
Marrow Transplant 9: 383-388, 2003. 
 
  82.   Villela L, Sureda A, Canals C, Sanz MA, Jr., Martino R, Valcarcel D, Altes A, Briones J, Gomez M, 
Brunet S, Sierra J.  Low transplant related mortality in older patients with hematologic 
malignancies undergoing autologous stem cell transplantation.  Haematologica 88: 300-305, 
2003. 
 
  83.   Jantunen E, Itala M, Juvonen E, Leppa S, Keskinen L, Vasala K, Remes K, Wiklund T, Elonen E, 
Nousiainen T.  Autologous stem cell transplantation in elderly (>60 years) patients with non-
Hodgkin's lymphoma: a nation-wide analysis.  Bone Marrow Transplant 37: 367-372, 2006. 
 
  84.   Buadi FK, Micallef IN, Ansell SM, Porrata LF, Dispenzieri A, Elliot MA, Gastineau DA, Gertz MA, 
Lacy MQ, Litzow MR, Tefferi A, Inwards DJ.  Autologous hematopoietic stem cell 
transplantation for older patients with relapsed non-Hodgkin's lymphoma.  Bone Marrow 
Transplant 37: 1017-1022, 2006. 
 
  85.   Sirohi B, Powles R, Mehta J, Rudin C, Kulkarni S, Horton C, Saso R, Singhal S, Treleaven J.  An 
elective single autograft with high-dose melphalan: single-center study of 451 patients.  Bone 
Marrow Transplant 36: 19-24, 2005. 
 
  86.   Badros A, Barlogie B, Siegel E, Morris C, Desikan R, Zangari M, Fassas A, Anaissie E, Munshi N, 
Tricot G.  Autologous stem cell transplantation in elderly multiple myeloma patients over the age 
of 70 years.  Br J Haematol 114: 600-607, 2001. 
 
  87.   Reece DE, Bredeson C, Perez WS, Jagannath S, Zhang MJ, Ballen KK, Elfenbein GJ, Freytes CO, Gale 
RP, Gertz MA, Gibson J, Giralt SA, Keating A, Kyle RA, Maharaj D, Marcellus D, McCarthy 
PL, Milone GA, Nimer SD, Pavlovsky S, To LB, Weisdorf DJ, Wiernik PH, Wingard JR, Vesole 
DH.  Autologous stem cell transplantation in multiple myeloma patients <60 vs >/=60 years of 
age (Review).  Bone Marrow Transplant 32: 1135-1143, 2003. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
59
APPENDICES 
 
 
 
Table of Contents 
APPENDIX A 
THE KARNOFSKY PERFORMANCE STATUS SCALE 
APPENDIX B 
THE LANSKY PLAY-PERFORMANCE SCALE 
APPENDIX C 
INFECTIOUS DISEASE GUIDELINES 
APPENDIX D 
ACUTE GRAFT-VERSUS-HOST DISEASE GRADING 
APPENDIX E 
CHRONIC GRAFT-VERSUS-HOST DISEASE GRADING 
APPENDIX F 
EVALUATION OF DISEASE RESPONSE 
APPENDIX G 
STUDY COORDINATOR’S MANUAL INCLUDING 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
APPENDIX H 
ADVERSE EVENT REPORT 
APPENDIX I 
NOTICE OF DEATH FORM 
APPENDIX J 
PATIENT DEMOGRAPHICS AND REGISTRATION FORM 
APPENDIX K 
CORE CASE REPORT FORM 
APPENDIX L 
INTRATHECAL DIAGNOSTIC STUDY AND THERAPY 
APPENDIX M 
ADAPTED COMMON TOXICITY CRITERIA 
APPENDIX N 
THE HEMATOPOIETIC CELL TRANSPLANT-COMORBIDITY 
INDEX (HCT-CI) 
APPENDIX O 
WEIGHT / ADJUSTED BODY WEIGHT FOR DRUG DOSING 
APPENDIX P 
COORDINATING CENTER FUNCTIONS 
 
APPENDIX Q 
SALMON AND DURIE CRITERIA FOR DIAGNOSIS OF 
MULTIPLE MYELOMA  
APPENDIX R 
RADIOTHERAPY TREATMENT GUIDELINES 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
60
APPENDIX A 
THE KARNOFSKY PERFORMANCE STATUS SCALE 
 
General 
Index 
Specific Criteria 
Able to carry on normal activity; no 
special care needed 
100 
Normal, no complaints, no evidence of 
disease 
 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease 
 
80 
Normal activity with effort, some signs 
or symptoms of disease 
Unable to work, able to live at home and 
care for most personal needs, varying 
amount of assistance needed 
70 
Care for self, unable to carry on normal 
activity or to do work 
 
60 
Requires occasional assistance from 
others but able to care for most needs 
 
50 
Requires considerable assistance from 
others and frequent medical care 
Unable to care for self, requires 
institutional or hospital care or 
equivalent; disease may be rapidly 
progressing 
40 
Disabled; requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated, death not imminent 
 
20 
Very sick, hospitalization 
necessary, active supportive 
treatment necessary 
 
10 
Moribund 
 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
61
APPENDIX B 
THE LANSKY PLAY-PERFORMANCE SCALE 
(FOR USE WITH PERSONS AGES 1 – 16 YEARS) 
  
 
 
 
 
Score (%) 
Description 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both, greater restrictions of, and less time spend in play activities 
60 
Up and around, but minimal active play, keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play; able to 
participate in all quiet play activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
Unresponsive 
0 
Dead 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
62
Appendix C 
INFECTIOUS DISEASE GUIDELINES 
Please note that the content of these PDFs is from the Fred Hutchinson Clinical Research Division Standard 
Practice Manual and does not contain research related procedures. 
 
Herpes Simplex and Varicella Zoster Virus Prevention and Treatment 
hsv-vzv.pdf
 
 
CMV Prevention: Surveillance and Preemptive Therapy 
cmvprevention.pdf
 
CMV Disease: Diagnosis and Treatment 
cmvdiseasetreatmen
t.pdf
 
Antifungal Therapy Guidelines 
antifungal_therapy.p
df
 
Pneumonia / Pneumocystis Jiroveci Prophylaxis 
pneumocystisjiroveci
.pdf
 
Antibiotic Prophylaxis for Encapsulated Bacteria in Allogeneic Patients with Chronic GvHD Requiring 
Immunosuppressive Therapy 
antibioticprophylaxisf
orencapsulatedbacter 
Vaccinations 
 
Foscarnet 
 
foscarnet.pdf
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
63
APPENDIX D 
GRADING OF ACUTE GRAFT-VERSUS-HOST DISEASE 
Severity of Individual Organ Involvement 
Skin 
+1 
a maculopapular eruption involving less than 25% of the body 
surface 
+2 
a maculopapular eruption involving 25-50% of the body surface 
+3 
generalized erythroderma 
+4 
generalized erythroderma with bullous formation and often with 
desquamation 
Liver 
+1 
bilirubin (2.0-3.0 mg/100 ml) 
+2 
bilirubin (3-5.9 mg/100 ml) 
+3 
bilirubin (6-14.9 mg/100 ml) 
+4 
bilirubin > 15 mg/100 ml 
Gut 
Diarrhea is graded +1 to +4 in severity. Nausea and vomiting and/or 
anorexia caused by GVHD is assigned as +1 in severity 
The severity of gut involvement is assigned to the most severe involvement 
noted.  Patients with visible bloody diarrhea are at least stage +2 gut and 
grade +3 overall 
Diarrhea 
+1 
 1000 ml of liquid stool/day* ( 15ml of stool/kg/day)† 
+2 
>1,000 ml of stool/day* (> 15ml of stool/kg/day)† 
+3 
>1,500 ml of stool/day* (> 20ml of stool/kg/day)† 
+4 
2,000 ml of stool/day* ( 25ml of stool/kg/day)† 
*In the absence of infectious/medical cause 
†For pediatric patients 
 
Severity of GVHD 
Grade I 
+1 to +2 skin rash 
No gut or liver involvement 
Grade II 
+1 to +3 skin rash 
+1 gastrointestinal involvement and/or +1 liver involvement 
Grade III 
+2 to +4 gastrointestinal involvement and/or 
+2 to +4 liver involvement with or without a rash 
Grade IV 
Pattern and severity of GVHD similar to grade 3 with extreme 
constitutional symptoms or death 
 
_______________ 
a From “Graft-vs-host disease” Sullivan, Keith M. Hematopoietic Cell Transplantation Ed: D. Thomas, K. Blume, S. Forman, Blackwell Sciences; 
1999, pages 518-519


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
64
APPENDIX E 
CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) 
 
Chronic GVHD in allogeneic transplant recipients resembles autoimmune disorders such as 
scleroderma, Sjogren syndrome, primary biliary cirrhosis, lichen planus, wasting syndrome, 
bronchiolitis obliterans among others manifestations (see below). Approximately 50% of 
patients will develop this complication within 6 months after the transplant despite continued 
treatment with immunosuppressive medications. Close monitoring is recommended during 
the first 2 years after allogeneic stem cell transplantation so that appropriate treatment can be 
instituted promptly in patients who develop chronic GVHD. Debilitation, joint contractures 
and profound immunosuppression resulting in recurrent bacterial infections are prominent 
characteristics of untreated chronic GVHD. 
 
A. Classification of Chronic GVHD 
The purpose of this classification is to identify patients with cGVHD who need long-term 
systemic immunosuppression according to clinical and laboratory findings and risk factors at 
the time of initial diagnosis. In addition, a morbidity scale has been developed to help grade 
the severity of manifestation of chronic GVHD (Appendix D) at the time of diagnosis, when 
changes in treatment are made and when assessing treatment response. 
 
1.  Chronic GVHD not requiring systemic treatment: mild abnormalities involving a single site, 
with platelet count >100,000 and no steroid treatment at the onset of 
chronic GVHD 
a)  Oral abnormalities consistent with cGVHD, a positive skin or lip biopsy, and no other 
manifestations of cGVHD 
b)  Mild liver test abnormalities (alkaline phosphatase ≤2 x upper limit of normal, AST or ALT ≤3 x 
upper limit of normal and total bilirubin ≤1.6) with positive skin or lip biopsy, and no other 
manifestations of cGVHD 
c)  Less than 6 papulosquamous plaques, macular-papular or lichenoid rash involving <20% of body 
surface area (BSA), dyspigmentation involving <20% BSA, or erythema involving <50% BSA, 
positive skin biopsy, and no other manifestations of cGVHD 
d)  Ocular sicca (Schirmer’s test ≤5mm with no more than minimal ocular symptoms), positive skin 
or lip biopsy, and no other manifestations of cGVHD 
e)  Vaginal or vulvar abnormalities with positive biopsy, and no other manifestations of cGVHD 
 
2.  Chronic GVHD requiring systemic treatment: more severe abnormalities or 
involvement of multiple sites, or platelet count <100,000, or steroid treatment 
at the onset of chronic GVHD 
a)  Involvement of two or more organs with symptoms or signs of cGVHD, with biopsy 
documentation of cGVHD in any organ 
b)  ≥15% base line body weight loss not due to other causes, with biopsy documentation of cGVHD 
in any organ 
c)  Skin involvement more extensive than defined for clinical limited cGVHD, confirmed by biopsy 
d)  Scleroderma or morphea 
e)  Onycholysis or onychodystrophy thought to represent cGVHD, with documentation of cGVHD 
in any organ 
f)  Decreased range of motion in wrist or ankle extension due to fasciitis caused by cGVHD 
g)  Contractures thought to represent cGVHD 
h) Oral involvement with functional impairment, refractory to topical treatment 
i)  Vaginal involvement with functional impairment, refractory to topical treatment 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
65
j)  Bronchiolitis obliterans not due to other causes 
k)  Positive liver biopsy; or abnormal liver function tests not due to other causes with 
alkaline phosphatase >2 x upper limit of normal, AST or ALT >3 x upper limit of 
normal, or total bilirubin >1.6, and documentation of cGVHD in any organ 
l)  Positive upper or lower GI biopsy 
m)  Fasciitis or serositis thought to represent cGVHD and not due to other causes 
 
B. Physical manifestations of Chronic GVHD 
Manifestations that are distinctive for chronic GVHD can begin before day 100 after the 
transplant, and manifestations that are typical of acute GVHD can persist long after day 100. 
For this reason, the differential diagnosis between acute and chronic GVHD cannot be made 
solely according to the time interval from transplant. The diagnosis of chronic GVHD 
requires at least one manifestation that is distinctive for chronic GVHD (identified by italic 
print below) as opposed to acute GVHD. In all cases, infection and others causes must be 
ruled out in the differential diagnosis of chronic GVHD. 
 
Karnofsky or Lansky Clinical Performance scores <60%, ≥15% weight loss, and recurrent 
infections are usually signs of clinical extensive chronic GVHD. Abnormalities that could 
indicate chronic GVHD are categorized by organ system are listed below (italic print 
identifies manifestation more distinct of chronic GVHD): 
 
Skin 
Erythema, dryness, pruritis, macular-papular or urticarial rash, pigmentary 
changes (i.e., hyperpigmentation, vitiligo), mottling, papulosquamous or 
lichenoid plaques, hyperkeratosis, exfoliation (ichthyosis), nodules, scleroderma, 
morphea (one or several circumscribed, indurated and shiny lesions). The extent 
of skin involvement and the skin thickness score for patients with scleroderma 
needs to be recorded at the time of diagnosis, when changes in treatment are 
made and when assessing treatment response. Medical photos are also useful for 
assessing the extent of skin involvement and response to treatment. 
Nails 
Ridging, onychodystrophy, onycholysis 
Hair 
Premature graying (scalp hair, eyelashes, eyebrows), thinning scalp hair, 
alopecia, decreased body hair 
Mouth 
Dryness, burning, gingivitis, mucositis, striae, dryness, atrophy, erythema, 
lichenoid changes, ulcers, labial atrophy or pigmentary changes, tightness 
around the mouth, sensitivity to acidic, strong flavors, heat or cold, tooth decay 
Eyes 
Dryness, burning, blurring, gritty eyes, photophobia, pain 
Vagina/vulva 
Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or lichenoid 
changes not induced by ovarian failure or other causes 
Liver 
Jaundice and elevated liver function tests not due to other causes (see laboratory 
tests) 
Lung 
Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on 
exertion, history of recurrent bronchitis or sinusitis 
GI 
Anorexia, nausea, vomiting, diarrhea, malabsorption, dysphagia, odynophagia 
Myofascial 
Stiffness and tightness with restriction of movement, occasionally with swelling, 
pain, cramping, erythema and induration, most commonly affecting the forearms, 
wrists and hands, ankles, legs and feet, inability to extend the wrists without 
flexing the fingers or the elbows, contractures 
Muscle 
Proximal muscle weakness, cramping 
Skeletal 
Arthralgia of large proximal girdle joints and sometimes smaller joints 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
66
Serosal 
Unexplained effusions involving the pleural, pericardial, or peritoneal cavities 
not due to venocclusive disease of the liver, cardiac insufficiency, malignancy, 
infection, GM-CSF toxicity or other causes 
 
 
 
C. Laboratory Testing and Diagnostic Indicators of Chronic GVHD 
 
Eye 
Schirmer’s test with a mean value ≤ 5 mm at 5 minutes, or values of 6-10 mm in 
patients who have sicca symptoms, or keratitis detected by slit lamp examination 
Liver 
Elevated liver function tests not due to other causes (alkaline phosphatase ≥2 x 
upper limit, of normal, AST or ALT >3 x upper limit of normal or total serum 
bilirubin ≥1.6) 
Lung 
New obstructive lung defect defined as an FEV1 <80% of predicted with either an 
FEF 25-75 <65% of predicted or RV >120% of predicted, or a decrease of 
FEV1/FVC by >12% within a period of less than 1 year, thought not to be caused 
by an infectious process, asthma or recurrent aspiration from the sinuses or from 
gastroesophageal reflux. In the absence of GVHD in any other organ, the 
diagnosis of bronchiolitis obliterans requires negative microbiological tests from 
bronchoalveolar lavage, evidence of air trapping by high resolution end-
expiratory and end-inspiratory CAT scan of the lungs, or confirmation by 
thoracoscopic biopsy. 
Esophagus 
Esophageal web formation, stricture or dysmotility demonstrated by barium 
swallow, endoscopy or manometry 
Intestine 
Endoscopic findings of mucosal edema and erythema or focal erosions with 
histological changes of apoptotic epithelial cells and crypt cell drop out. Patients 
with unresolved acute GVHD may have more severe intestinal mucosal lesions 
including ulcers and mucosal sloughing. 
Muscle 
Elevated CPK or aldolase, EMG findings consistent with myositis with biopsy 
revealing no other etiological process 
Blood 
Thrombocytopenia (usually 20,000-100,000/l), eosinophilia (> 0.4 x 103/uL), 
hypogammaglobulinemia. Hypergammaglobulinemia and autoantibodies occur in 
some cases. 
 
 
D. Guidelines for Treatment of Chronic GVHD after allogeneic HSCT 
 
We strongly recommend that you consult the LTFU office before beginning treatment for chronic GVHD and 
before making changes in immunosuppressive treatment. Clinical trials should always be considered because 
current standard therapies are associated with high morbidity and decreased survival for patients with high risk 
chronic GVHD 
 
Standard treatment of chronic GVHD usually begins with administration of glucocorticoids (1mg/kg/day) 
followed by taper to eventually reach an alternate-day regimen, with or without daily cyclosporine or tacrolimus 
(FK506). Other medications used for treatment of corticosteroid-resistant chronic GVHD are summarized on 
the next page. Telephone consultation with the LTFU medical team is available to you, seven days a week, to 
discuss appropriate treatment and provide other follow up recommendations. In addition to immunosuppressive 
treatment, antibiotic prophylaxis for encapsulated bacterial infections and PCP must be given to all patients 
being treated for chronic GVHD (see Appendix C). 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
67
The duration of systemic immunosuppressive treatment of chronic GVHD varies but requires at least one year 
of therapy. Approximately 80% of patients require systemic immunosuppressive for 2 years and 40% of them 
requires therapy for at least 4 years. 
 
 
Adapted From: Long-Term Followup After Hematopoietic Stem Cell Transplant General Guidelines For Referring Physicians, Fred 
Hutchinson Cancer Research Center Standard Practice Manual, Section X, Chronic Graft Versus Host Disease (GVHD), Nov/2003 
Version 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
68
Appendix F 
 
Evaluation of Disease Response: 
 
 
A. Multiple Myeloma, Waldenstrom’s macroglobulinemia, or plasma cell leukemia: 
 
Complete remission: 
 
1. Complete disappearance of serum M protein and urine globulins. 
2. Absence of new bone lesions. 
3. Normal bone marrow aspirate and biopsy as defined by less than 5% plasma cells and normal 
histology. 
4. Normal peripheral blood counts. 
5. Normal serum calcium level. 
6. Absence of disease at any other previously involved site (e.g., CNS, extramedullary 
plasmacytomas, etc.). 
 
Partial remission: 
 
1. Greater than 75% reduction in serum M protein. 
2. Greater than 90% decrease in 24 hour urine globulin excretion. 
3. Size and number of lytic bone lesions must not increase. 
 
Patients who do not meet these criteria are considered to be non-responders. 
 
 
 
B. Lymphomas or Waldenstrom’s Macroglobulinemia: 
 
 
 
Complete remission: 
 
Normalization for  1 month of all pretransplant markers of disease as assessed by CT scans and 
by morphologic and flow cytometric examination of bone marrow and peripheral blood.  
 
Complete disappearance of serum M protein and urine globulins (for Waldenstrom’s 
Macroglobulinemia) 
 
 
 
Partial remission: 
 
Fifty percent or greater reduction in all markers of disease as assessed by CT scans and by 
morphologic and flow cytometric examination of bone marrow and peripheral blood, sustained 
for  1 month. 
 
Greater than 75% reduction in serum M protein (for Waldenstrom’s Macroglobulinemia) 
 
Patients who do not meet the criteria for complete or partial remission are considered to be 
non-responders. 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
69
C. CLL 
 
Modified response criteria based on the NCI-Working Group and the International Workshop Group Joint Formal Criteria 
for evaluating disease response for CLL. [1-3] 
 
Complete Remission (CR) 
 
Imaging studies (Xray, CT, MRI)  (nodes, liver, and spleen) 
Normal 
Peripheral blood by flow cytometry 
No clonal lymphocytes 
Bone marrow by flow cytometry 
No clonal lymphocytes 
 
Bone marrow by morphology 
No nodules; or if present, nodules are free from 
CLL cells by immunohistochemistry 
Duration  
≥2 months 
CR with minimal residual disease 
 
Peripheral blood or bone marrow by flow cytometry 
>0 - <1 CLL cells/1000 leukocytes (0.1%) 
Partial Remission (PR):  
 
Both  criteria: 
 
Absolute lymphocyte count in peripheral blood 
≥50% decrease3 
Physical exam/Imaging studies (nodes, liver, and/or spleen) 
≥50% decrease3,4 
Duration  
≥2 months 
Progressive disease: ≥1 of 
 
Physical exam/Imaging studies (nodes, liver, and/or spleen) 
≥50% increase or new 
    Circulating lymphocytes by morphology and/or flow cytometry 
≥50% increase 
Lymph node Biopsy 
Richter’s transformation 
Stable disease 
 
Did not meet any of the above criteria for complete or partial remission or progression. 
Relapsed disease 
 
     Criteria of progression occurring 6 months after achievement of complete or partial remission. 
1 Without granulocyte colony stimulating factor support. 
2 Without red blood cell transfusions or erythropoietin support. 
3 Compared to before starting therapy. 
4 Defined by the sum of the products of up to 6 lymph nodes with no increase in the size of any single lymph node (ie, an increase of <25 percent in a lymph node <2cm 
is not considered significant) and no new enlarged lymph nodes. 
 
  1.   Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR.  National Cancer Institute-sponsored Working 
Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment.  Blood 87: 4990-
4997, 1996. 
  2.   Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, 
Kipps TJ, International Workshop on Chronic Lymphocytic Leukemia.  Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating 
the National Cancer Institute-Working Group 1996 guidelines [Erratum appears in Blood. 2008 Dec 15;112(13):5259].  
Blood 111: 5446-5456, 2008. 
  3.   Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on 
Chronic Lymphocytic Leukemia.  Ann Intern Med 110: 236-238, 1989. 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
70
APPENDIX G 
 
Study Coordinator’s Manual 
 
I.  
Introduction 
 
The mixed chimerism protocols have been opened to multiple sites to increase the referral base and accrual. 
Because of this expansion of collaborators, the data collection procedures are being revised. The procedure 
manual was created to assure consistency of data reporting across the centers and to assure compliance with 
regulations. General expectations of collaborators are that they will comply with appropriate regulatory 
requirements, specified protocol requirements, and provide outcome data. 
 
The manual translates working procedures for study coordination. Its goal is to describe the procedures with 
sufficient clarity to ensure that all study centers will use the same procedures and follow-up schedules for 
participant data management and reporting. Changes to the manual and relevant forms will be made as soon as 
practical and will become effective on receipt of the revised procedures at the study centers, unless otherwise 
noticed. 
 
II. 
Institutional Review Board Review of Protocols and Modifications 
 
All research protocols proposed for use that involves human subjects must be reviewed and approved by the 
Institutional Review Board (IRB) prior to implementation. New protocols will undergo review at the FHCRC 
IRB and then will be distributed to sites that wish to participate for their IRB’s review. For Centers that have a 
Federal Wide Assurance (FWA), formal collaboration includes submission of a form 310 and a copy of the IRB 
approved protocol and consent forms to the FHCRC.  For sites without a FWA, an FWA form needs to be filed. 
Once the paperwork is submitted to the Office for Human Research Protection, the approval process can take up 
to a couple of months, and must be completed before collaboration on a protocol can begin.  
 
In addition, all amendments and/or revisions to on-going, approved activities must be submitted for review and 
approved prior to implementation at an institution.  No revisions may be implemented at outside institutions 
without the prior approval of the FHCRC Principal Investigator.  The FHCRC and the local site’s IRB must 
review all protocol activities at least once annually. This must be done within 365 days of the last review 
regardless of the policies of the institution. A copy of annual renewal approvals must be received for 
collaboration to continue for the next year. 
 
III. 
Registrations 
 
Collaborating Institutions: The principal investigator of the collaborating institution who will register the patient 
with the FHCRC will identify eligible patients. Registration will include completion of the eligibility 
checklist/demographic form. This form will be faxed (206-667-5378) prior to treatment initiation. Patients must 
be registered prior to treatment initiation for valid registration 
 
IV. 
Reporting Adverse Events 
 
The following guidelines are the minimum serious adverse event (SAE) reporting guidelines for Category 1 and 
2 studies conducted at the Fred Hutchinson Cancer Research Center.   


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
71
Expedited Reporting Requirements  
All unexpected and serious adverse events which may be due to study treatment or intervention must be 
reported to the FHCRC Institutional Review Office as soon as possible but within at least 10 calendar 
days of the investigator learning of the event. 
 
Definitions 
 
Adverse Event - Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product, medical treatment or procedure and which does not necessarily have to have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, medical treatment or procedure whether or not considered related to the medicinal 
product.  
 
Life-threatening Adverse Event  – Any adverse event that places the patient or subject, in view of the 
investigator, at immediate risk of death from the reaction.  Study toxicities are graded using the NCI Common 
Toxicity Criteria (where appropriate use the criteria for transplant patients.)  All Grade 4 (life-threatening) 
toxicities in Appendix M occurring between start of conditioning and day 200 that meet expedited reporting 
requirements must be reported as soon as possible but within at least 10 calendar days of the investigator 
learning of the event.  
 
Unexpected Adverse Event – An adverse event, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an unapproved investigational product or 
package insert/summary of product characteristics for an approved product).  If applicable product information 
is not available, such as for studies that do not involve pharmaceutical products or devices, an unexpected 
adverse event is an adverse event that was not described in the study protocol or informed consent. 
 
Serious Adverse Event (SAE) – Any adverse event occurring that results in any of the following outcomes:   
➢ Death – start of conditioning to day 200, regardless of cause,  
➢ a life-threatening adverse event (see above)  
➢ a persistent or significant disability/incapacity,  
➢ a congenital anomaly  
➢ requires intervention to prevent permanent impairment or damage.  
 
Hospitalization, in general, will not be considered a serious adverse event as approximately half of evaluable 
MRD patients AND the majority of evaluable URD patients receiving nonmyeloablative transplants were 
hospitalized.  Hospitalization will be considered a serious adverse event if it fulfills the criteria for a serious and 
unexpected adverse event as described above. 
 
To ensure no confusion or misunderstanding exist of the differences between the terms “serious” and “severe,” which are not synonymous the following note 
of clarification is provided: 
 
The term “severe” is often used to describe the intensity (severity) or a specific event (as in mild, moderate or 
severe myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache).  This is not the same as “serious,” which is based on patient/event outcome or 
action criteria usually associated with events that pose a threat to a patient’s life or functioning.  Seriousness 
(not severity) serves as a guide for defining regulatory obligations. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
72
Attribution - The FHCRC designation for the determination of whether an adverse event is related to a medical 
product, treatment or procedure will be as follows: 
➢ Related – includes adverse events that are definitely, probably, or possibly related to the medical treatment 
or procedure. 
➢ Not Related – includes adverse events are doubtfully related or clearly not related to the medical treatment 
or procedure. 
 
 
The FHCRC Serious Adverse Event (SAE) Report Form should be completed for all adverse events that meet 
the expedited reporting requirements.   All available information should be submitted but it is acceptable to fax 
an incomplete report form at the initial report.  A completed report should be faxed as soon as possible but must 
be received within 10 calendar days. 
 
It is the responsibility of the FHCRC Principal Investigator to notify the sponsor, NIH, FDA or other agencies 
of serious adverse events as required in the protocol. 
 
Serious adverse events that do not meet the requirement for expedited reporting (not related to study treatment 
or expected) will be reported to the IRB as part of the annual renewal of the protocol. 
 
FHCRC is acting as the Coordinating Center for this multi-institutional study, and it is the responsibility of the 
FHCRC Principal Investigator (or designee) to complete the FHCRC Serious Adverse Event Report for all 
serious adverse events that meet the expedited reporting requirements that are received from the participating 
sites.   
 
Procedure for Reporting Serious and Unexpected Adverse Events from Participating Sites 
Regulations defining the responsibilities for reporting serious and unexpected adverse reactions are defined 
above.  Serious and unexpected adverse events must be reported to the FHCRC Investigator within 10 days of 
learning of the event. This includes patient deaths, regardless of cause (serious, unexpected, and related/possibly 
related), occurring start of conditioning - day 200 post-transplant procedure.  The immediate telephone report 
must be followed by faxed comments to the Trial Coordinator at (206) 667-5378. This will be followed by 
detailed written report (See Appendix “H”) within 10 working days.  The report must include the date and time 
of onset, severity and duration of the event, the relationship to the study, the treatment given and eventual 
outcome.  Follow-up information to a SAE report must be submitted as soon as the relevant information is 
available. 
 
Obligation of Investigators 
All grade 3 or 4 adverse events (or highly unusual grade 2 adverse events), which occur between start of 
conditioning and day 100 during the study will be recorded on the Case Report Form (Appendix K).  These 
adverse events which are observed by the Investigator or reported by the patient, whether or not attributed to the 
study, will be reported on the Case Report Form using the modified (for HSCT) NCI Common Toxicity Criteria 
(Appendix M). Attributes will include a description, date of onset, maximum severity, and assessment of 
relationship to the study agent or other suspect agent(s). 
 
Adverse events will be graded accordingly: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening or 
debilitating, and 5 = fatal.   All Grade 4 (life-threatening) or Grade 5 (fatal) events on the Adapted HSCT NCI 
scale meet expedited reporting requirements. 
 
Association or relatedness to the study agent will be graded as follows: 1 = unrelated, 2 = unlikely, 3 = possibly, 
4 = probably, and 5 = definitely related. 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
73
V. 
Case Report Forms 
 
Case report forms must be completed for all patients registered onto the protocols and submitted to the FHCRC 
data coordinating center. The first case report form (day 28) is due on day 50.  For outside centers a Staging Form must 
accompany the form with the patient staging at registration, day 28, day 56, day 84 and day 100. Staging forms should 
also be completed with each Follow Up Form completed on day 180, 1 year, 1.5 years, 2 years, 3 years, and yearly 
thereafter. For Outside Centers, case report forms are expected to be submitted no later than 30 days following the 
scheduled follow up date. A DLI Form must be completed and submitted for every infusion given. 
 
VI. 
Protocol Monitoring 
 
As the coordinating center, FHCRC will monitor accrual at the outside institutions. The guidelines below are 
intended to guide the reviewers in their assessment of items that significantly alter the clinical effectiveness of 
the treatment or the evaluation of its toxicity. 
 
A. Registration/Randomization 
1. Patient was registered prior treatment 
2. Information given at registration represents actual data in medical records (stage, diagnosis, cell type, 
etc.) 
 
B. Informed Consent/IRB Approval Dates 
1. The consent was signed prior to registration 
2. The consent is in language that was approved by the institution’s IRB. IRB approval and reapproval are 
documented including appropriate use of full-board review and proper review of appropriate 
amendments or revisions 
3. IRB approval was obtained prior to the patient signing the consent form and start of treatment. 
 
C. Patient Eligibility 
1. Eligibility criteria and exclusion criteria were met 
2. Treatment/Intervention Administration 
3. Doses were modified according to protocol 
4. Accurate documentation of drug administration 
 
D. Study Tests/Evaluation 
1. Protocol specified laboratory tests or diagnostic studies are available 
2. Appropriate record of protocol intervention is documented. 
 
E. Study Events/Adverse Drug Experience 
 
1. Serious Adverse Evens reported according to protocol specifications 
 
F. Follow-Up 
1. Disease status assessed according to the required protocol guidelines documenting   
      response to treatment. 
2. Accurate determination of cancer progression 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
74
APPENDIX H 
Fred Hutchinson Cancer Research Center 
 
Clinical Research Division 
Institutional Review Office 
SERIOUS ADVERSE EVENT REPORT (SAE) Form IRO-08 
FHCRC IR File Number: 
FHCRC Protocol Number: 
 
FHCRC Unique Patient #  
 FHCRC/SCCA   
  Other 
Gender:  
 Male 
 Female 
Age:   
FHCRC Principal Investigator:  
  
Phone Number: 
Mailstop: 
 
Date of Report: 
 
 
 Initial Report 
 Follow-Up Report #  
 Other 
Date Serious Adverse Event Started: 
Date study staff became aware of event:______________________________ 
Date Ended: 
Or 
 Ongoing (if ongoing – must submit follow up report) 
Adverse Event: 
 
 
Describe the Serious Adverse Event including a summary of all relevant clinical information. 
(Or attach a MedWatch Form or other SAE reporting form if one has been completed.)  Use Page 2, if 
necessary: 
 
Outcomes Attributed to adverse event:  (Check all that apply) 
 Death            /           /     
 Life-Threatening 
 Hospitalization (initial or prolonged) 
 
 Disability 
 Congenital Anomaly 
 Required intervention to prevent permanent      
impairment/damage 
Specify Agent(s) and/or Procedure(s) involved in this protocol: 
 
#1 
Pharmaceutical product/medical 
treatment/procedure 
 
#2 
Pharmaceutical product/medical 
treatment/procedure 
 Not Related (Unrelated, Unlikely) 
 Not Related (Unrelated, Unlikely) 
 Related (Possible, Probable, Definite) 
 Related (Possible, Probable, Definite) 
 
 
 Follow-up Report Required 
 Final Report (PI must sign final report) 
Report Completed by: 
 
Date: 
 
The PI has determined that the consent form must be revised: 
 Yes      
 No 
 
Does this study involve the deliberate transfer of recombinant DNA or DNA or RNA derived from recombinant 
DNA, into human subjects (human gene transfer)? 
 yes  
 no  If yes and the activity involves the SCCA 
outpatient clinic, a copy of this Protocol Modification Form and any supporting documents to be reviewed and 
approved, will be forwarded to the FHCRC’s Institutional Biosafety Committee (IBC) by the Protocol Office 
(Mailstop:  LM-230). 
 
 
Signature of Principal Investigator 
 
 
Date: 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
75
 
Fred Hutchinson Cancer Research Center 
 
Clinical Research Division 
Institutional Review Office 
SERIOUS ADVERSE EVENT REPORT (SAE) Form IRO-08 
 
 
 
FHCRC IR File Number: 
 
FHCRC Protocol Number: 
 
FHCRC Unique Patient #  
Date of Report: 
Describe the Serious Adverse Event including a summary of all relevant clinical information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
76
APPENDIX I 
 
NOTICE OF DEATH 
 
Patient ID:  __________________ 
Date of Death:  ______________ 
 
Place of Event:  ___________________________________________    
 
 
Apparent cause of death (Please be specific.  Attach hospital summary or death summary when possible): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Form completed by:  ________________________________Date:   ______________ 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
77
APPENDIX J 
Protocol 2241 Patient Demographics and Eligibility Form 
Please Fax this completed form to (206)-667-5378 for patient registration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria  
 
 
1. 
 Yes 
 No  Patient signed and dated consent form.   
Date:  ___________ 
       
Date of IRB approval of consent form: ___________ 
IRB file:  __________ 
 
Questions #2-6 must be marked “Yes” Or “NA” for the patient to enroll on 2241. 
 
2. 
 Yes 
 N/A  
Lymphoma: Patients with i) diagnosis of NHL or HL, of any histological grade, ii) 
Refractory or relapsed disease after standard chemotherapy, and iii) High risk of early relapse 
following autograft alone.  
 
3.  
 Yes 
 N/A  
Waldenstrom’s Macroglobulinemia- Must have failed 2 courses of therapy 
 
UPN: _____________ 
Research Subject Name: _______________________________ 
(Last) 
________________________  
(First) 
_____  
(MI) 
Date of Birth: 
_____ / _____ / __________Age:__________ 
 (Mo)    (Day)         (Year) 
Gender (choose one): 
 Male    
 Female   
 Unknown 
Patient Diagnosis: ______________________________________  
Disease Status: _________________________________________  
Planned Day 0: _____/______/_____ 
 
(Mo) 
(Day) 
 (Year) 
Ethnicity (choose one):  Instruct the research subject to select one of the following. 
 Hispanic (A person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture 
or origin, regardless of race.  Term “Spanish Origin” can also be used in addition to “Hispanic” or 
“Latino”.) 
 Not Hispanic or Latino 
 
 Declined to Report 
Race (check all that apply):  Instruct the research subject to select one or more of the following. 
 American Indian/Alaska Native (A person having origins in any of the original peoples of North, 
Central, or South America, and who maintains tribal affiliations or community attachment). 
 Asian (A person having origins in any of the original peoples of the Far East, Southeast, Asia, or the Indian 
subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the 
Philippine Islands, Thailand and Vietnam). 
    Black/African American (A person having origins in any of the black racial groups of Africa). 
 Native Hawaiian/Pacific Islander (A person having origins in any of the original peoples of Hawaii, 
Guam, Samoa or other Pacific Islands). 
 White (A person having origins in any of the original peoples of Europe, the Middle East or North Africa). 
 Research subject does not know race 
 Declined to report 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
78
4.  
 Yes 
 N/A 
CLL:  
i. Patient with 
a) Diagnosis of T-cell CLL or T-cell PLL who have failed initial chemotherapy, patients 
with T cell CLL or PLL OR 
b) Diagnosis of B-cell CLL, B-cell small lymphocytic lymphoma, or B-cell CLL that 
progressed to prolymphocytic leukemia (PLL), who either: 
I)      Failed to meet NCI Working Group criteria2 (Appendix F) for complete 
or partial response after therapy with a regimen containing fludarabine (or 
another nucleoside analog, e.g. 2-CDA, pentostatin) or experience disease 
relapse within 12 months after completing therapy with a regimen 
containing fludarabine (or another nucleoside analog). 
II)     Failed any aggressive chemotherapy regimen, such as FCR, at any time   
point. 
III)   Have “17p deletion” cytogenetic abnormality and relapsed at any time 
point after initial chemotherapy. 
 
Describe which inclusion is specific for this patient:__________________________ 
____________________________________________________________________. 
 
 ii. Patient must meet harvesting criteria for autologous HCT:  
a) previously collected PBMC may be used 
b) circulating cells <5000 
 
iii. Marrow involvement with CLL cells <50%  
 
5.  
 Yes 
 N/A 
 MM: Patients who 
i. Have received induction therapy for a minimum of 4 cycles. 
ii. In addition, patients must meet at least one of the following criteria I-IX (I-VII: at 
time of diagnosis or pre-autograft): 
I) Any abnormal karyotype by metaphase analysis except for isolated t(11,14) 
II) FISH translocation 4:14 
III) FISH translocation 14:16 
IV) FISH deletion 17p 
V) β2-microglobulin > 5.5 mg/ml 
VI) Cytogenetic hypodiploidy 
VII) Plasmablastic morphology (≥2%) 
VIII) Recurrent or non-responsive (less than PR) MM after at least two different 
lines of conventional chemotherapy. 
IX) Progressive MM after a previous autograft (provided stored autologous CD34 
cells are available) 
 
Describe which inclusion is specific for this patient:__________________________ 
____________________________________________________________________. 
 
6.  
 Yes 
 N/A 
Plasma cell leukemia: after induction chemotherapy 
 
7.  
 Yes 
 No   
Age ≤75 years. 
 
 
8.  
 Yes 
 No   
Detectable tumor prior to mobilization regimen. 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
79
 
 
Exclusion Criteria  
Each of the following questions must be marked “No” Or “NA” for the patient to enroll on 2241. 
 
1.  
 Yes 
 No   
Life expectancy severely limited by disease other than malignancy. 
 
2.  
 Yes 
 No   
Seropositive for the human immunodeficiency virus 
 
3.  
 Yes 
 No  
 N/A  Female who is Pregnant or Breastfeeding   
 
4.  
 Yes 
 No  
 N/A  Fertile men or women unwilling to use contraceptive techniques during and for the     
12 months following treatment 
 
 
 
5.  
 Yes 
 No     
CNS involvement with disease refractory to intrathecal chemotherapy 
 
6.  
 Yes 
 No     
Patients with active non-hematologic malignancies (except non- melanoma skin 
cancers) or those with non-hematological malignancies (except non-melanoma skin 
cancers) who have been rendered with no evidence of disease, but have a greater than 
20% chance of having disease recurrence within 5 years.  
This exclusion does not apply to patients with non-hematologic malignancies that do not 
require therapy. 
 
7. 
 Yes 
 No  
Patient with fungal infection and radiological progression after receipt of 
amphotericin B or active triazole for greater than 1 month 
 
8. 
 Yes 
 No    
 
Patient with symptomatic coronary artery disease or ejection fraction <40% or other 
cardiac failure requiring therapy (or, if unable to obtain ejection fraction, shortening 
fraction of < 26%). Ejection fraction is required if the patient has a history of 
anthracyclines or history of cardiac disease.   
NOTE: If shortening fraction is <26%, a cardiology consult is required.  The      
PI of the study must approve eligibility 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
PI Signature:  
_______________Date: 
__ 
__ 
 
9. 
 Yes 
 No    
Corrected DLCO < 50% of predicted, FEV1 <50% of predicted, and/or receiving 
supplementary continuous oxygen. 
NOTE: The FHCRC PI of the study must approve of enrollment of all patients 
with pulmonary nodules. 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
PI Signature:  
_______________Date: 
__ 
__ 
 
 
 
 
10. 
 Yes 
 No    
Liver function abnormalities: Patient with clinical or laboratory evidence of 
 
 
liver disease will be evaluated for the cause of liver disease, its clinical severity in 
terms of liver function, bridging fibrosis, and the degree of portal hypertension. The 
patient will be excluded if he/she is found to have fulminant liver failure, cirrhosis of 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
80
the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, 
a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable 
hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, 
ascites related to portal hypertension, bacterial or fungal liver abscess, biliary 
obstruction, chronic viral hepatitis with total serum bilirubin >3mg/dL, or 
symptomatic biliary disease. 
 
 
11. 
 Yes 
 No   
Patient has a Karnofsky score less than 50% Lansky score less than 40% 
 
12. 
 Yes 
 No     
Patients with poorly controlled hypertension despite multiple antihypertensives 
 
*Note – the HCT-Comorbidity score is:  _______________ 
 
Planned donor stem cell source is: 
 
 Bone Marrow 
 
 PBMC 
 
PI Initials:  
_________Date: 
__ 
__ 
 
 
Signature of person completing form: __________________________ 
Date:____________ 
 
Signature of Principal Investigator: __________________________ 
Date:____________ 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
81
APPENDIX K 
Core Case Report Form 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
82
APPENDIX L 
 
Intrathecal Diagnostics and Therapeutics 
 
Please note that the content of this PDF is from the Fred Hutchinson Clinical Research Division Standard Practice Manual 
and does not contain research related procedures. 
intrathecaltherapy-c
ombined.pdf
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
83
Appendix M 
 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
ALLERGY/IMMUNOLOGY 
Adverse Event 
Grade 3 
Grade 4 
Allergic reaction/ hyper-
sensitivity (including drug 
fever) 
Symptomatic bronchospasm, 
requiring parenteral medication(s), 
with or without urticaria; allergy-
related edema/angioedema  
 
Anaphylaxis  
Vasculitis  
Requiring steroids  
Ischemic changes or requiring 
amputation 
 
Allergy/Immunology – Other 
(specify):________________ 
 
Severe 
Life-threatening or disabling  
BLOOD/BONE MARROW 
Adverse Event 
Grade 3 
Grade 4 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis, other) 
Requiring transfusion and/or 
medical intervention (e.g., 
steroids) 
Catastrophic consequences of hemolysis 
(e.g., renal failure, hypotension, 
bronchospasm, emergency 
splenectomy)  
 
For BMT studies, if specified 
in the protocol.   
 
 
 
For pediatric BMT studies, if 
specified in the protocol.   
>4 u pRBC in 24 hours  
 
 
 
 
>30mL/kg in 24 hours 
Hemorrhage or hemolysis associated 
with life-threatening anemia; medical 
intervention required to improve 
hemoglobin  
 
Hemorrhage or hemolysis associated 
with life-threatening anemia; medical 
intervention required to improve 
hemoglobin 
 
CARDIOVASCULAR - ARRHYTHMIA 
Adverse Event 
Grade 3 
Grade 4 
Cardiovascular/Arrhythmia -
Other (specify): __________ 
_______________________ 
Symptomatic, and requiring 
treatment of underlying cause 
Life-threatening (e.g., arrhythmia 
associated with CHF, hypotension, 
syncope, shock) 
 
CARDIOVASCULAR - GENERAL 
Adverse Event 
Grade 3 
Grade 4 
Acute vascular leak syndrome Respiratory compromise or 
requiring fluids 
Life-threatening;  requiring pressor 
support and/or ventilatory/support 
 
Cardiac-ischemia/infarction 
Angina without evidence of 
infarction 
 
Acute myocardial infarction 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
84
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
CARDIOVASCULAR - GENERAL (cont’d) 
Adverse Event 
Grade 3 
Grade 4 
Cardiac left ventricular 
function 
CHF responsive to treatment 
Severe or refractory CHF or requiring 
intubation 
 
Cardiac troponin I (cTnI) 
Levels consistent with unstable 
angina as defined by the 
manufacturer 
Levels consistent with myocardial 
infarction as defined by the 
manufacturer 
 
Cardiac troponin T (cTnT) 
 0.1 - <0.2ng/mL 
 0.2ng/mL 
 
Hypotension 
 
  
Requiring therapy and sustained 
medical attention, but resolves 
without persisting physiologic 
consequences 
 
Shock (associated with acidemia and 
impairing vital organ function due to 
tissue hypoperfusion) 
Myocarditis  
CHF responsive to treatment 
 
Severe or refractory CHF 
Pericardial effusion/ 
pericarditis 
With physiologic consequences 
Tamponade (drainage or pericardial 
window required) 
 
Syncope (fainting) is graded 
in the Neurology category.   
 
- 
- 
Thrombosis/embolism 
Deep vein thrombosis, requiring 
anticoagulant therapy 
Embolic event including pulmonary 
embolism 
 
Vein/artery operative injury is 
graded as Operative injury of 
vein/artery in the 
Cardiovascular (general) 
category. 
 
 
 
Cardiovascular/General – 
Other (specify):___________ 
 
Severe 
Life-threatening or disabling 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
85
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
COAGULATION 
Adverse Event 
Grade 3 
Grade 4 
DIC (disseminated intravascular 
coagulation) 
 
Also consider 
Platelets. 
 
Note:  Must have increased fibrin 
split products or D-dimer in order 
to grade as DIC. 
Laboratory findings present with 
no bleeding 
Laboratory findings and bleeding  
Thrombotic microangiopathy 
(e.g., thrombotic 
thrombocytopenic purpura/TTA or 
hemolytic uremic syndrome/HUS) 
 
 
Also consider  
Hemoglobin, platelets, creatinine.  
 
Note:  Must have micro-
angiopathic changes on blood 
smear (e.g., schistocytes, helmet 
cells, red cell fragments).  
Laboratory findings present 
without clinical consequences  
 
 
 
 
 
Evidence of RBC destruction with 
creatinine (>3 x ULN) not 
requiring dialysis  
Laboratory findings and clinical 
consequences, (e.g., CNS 
hemorrhage/bleeding or 
thrombosis/embolism or renal 
failure) requiring therapeutic 
intervention  
 
Evidence of RBC destruction with 
renal failure requiring dialysis 
and/or encephalopathy. 
 
Coagulation - Other (specify): 
_________________________ 
 
Severe 
Life-threatening or disabling  
CONSTITUTIONAL SYMPTOMS 
Adverse Event 
Grade 3 
Grade 4 
Weight gain associated with 
Veno-Occlusive Disease (VOD) 
for BMT studies, if specified in 
the protocol.  
 
Also consider  
Ascites Edema, Pleural effusion 
(non-malignant). 
 
>10% or as ascites 
>10% or fluid retention resulting in 
pulmonary failure 
DERMATOLOGY/SKIN 
Adverse Event 
Grade 3 
Grade 4 
Erythema multiforme (e.g., 
Stevens-Johnson syndrome, toxic 
epidermal necrolysis) 
Severe or requiring IV fluids (e.g., 
generalized rash or painful 
stomatitis) 
Life-threatening (e.g., exfoliative or 
ulcerating dermatitis or requiring 
enteral or parenteral nutritional 
support) 
Rash/desquamation associated 
with graft versus host disease 
(GVHD) for BMT studies, if 
specified in the protocol. 
Symptomatic generalized 
erythroderma or symptomatic 
macular, papular or vesicular 
eruption, with bullous formation, 
or desquamation covering 50% of 
body surface area. 
Generalized exfoliative dermatitis 
or ulcerative dermatitis or bullous 
formation 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
86
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
GASTROINTESTINAL 
Adverse Event 
Grade 3 
Grade 4 
Ascites (none-malignant) 
Symptomatic, requiring 
therapeutic paracentesis  
 
Life-threatening physiologic 
consequences 
Colitis  
 
 
Also consider  
Hemorrhage/ bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
melena/GI bleeding, rectal 
bleeding/hematochezia, 
hypotension.   
 
Abdominal pain, fever, change in 
bowel habits with ileus or 
peritoneal signs, and radiographic 
or biopsy documentation 
Perforation or requiring surgery or 
toxic megacolon 
Diarrhea associated with graft 
versus host disease (GVHD) for 
BMT studies, if specified in the 
protocol. 
 
For pediatric BMT studies, if 
specified in the protocol. 
 
Also consider  
Hemorrhage/ bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
pain, dehydration, hypotension. 
 
>1500mL of diarrhea/day 
 
 
 
 
>15mL/kg of diarrhea/day 
Severe abdominal pain with or 
without ileus 
 
 
 
 
 
 
 
Duodenal ulcer (requires 
radiographic or endoscopic 
documentation) 
Uncontrolled by outpatient 
medical management; requiring 
hospitalization 
 
Perforation or bleeding, requiring 
emergency surgery 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
87
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
GASTROINTESTINAL (cont’d) 
Adverse Event 
Grade 3 
Grade 4 
Gastric ulcer (requires 
radiographic or endoscopic 
documentation) 
 
Also consider  
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
 
Bleeding without perforation, 
uncontrolled by outpatient medical 
management; requiring 
hospitalization or surgery 
Perforation or bleeding, requiring 
emergency surgery 
Gastritis 
 
Also consider  
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia. 
 
Uncontrolled by out-patient 
medical management; requiring 
hospitalization or surgery 
Life-threatening bleeding, requiring 
emergency surgery 
Pancreatitis 
 
Also consider  
Hypotension. 
 
Note:  Amylase is graded in the 
METABOLIC/LABORATORY 
category. 
 
Abdominal pain with pancreatic 
enzyme elevation 
Complicated by shock (acute 
circulatory failure) 
Mucositis 
 
Note:  Radiation-related mucositis 
is graded as Mucositis due to 
radiation. 
 
Painless erythema, edema, or 
ulcers preventing swallowing or 
requiring hydration or parenteral 
(or enteral) nutritional support 
Severe ulceration requiring 
prophylactic intubation or resulting 
in documented aspiration 
pneumonia 
Typhlitis 
(inflammation of the cecum) 
 
Also consider  
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia, 
hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, 
hypotension, febrile neutropenia.  
 
Abdominal pain, diarrhea, fever, 
and radiographic or biopsy 
documentation 
Perforation, bleeding or necrosis or 
other life-threatening complication 
requiring surgical intervention (e.g., 
colostomy) 
 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
88
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
HEMORRHAGE 
Notes:   
Transfusion in this section refers to pRBC infusion. 
For any bleeding with grade 3 or 4 platelets (<50,000), always grade Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia. Also consider Platelets, Transfusion: pRBCs, and Transfusion: platelets in addition to 
grading severity by grading the site or type of bleeding.   
 
If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: 
NS Hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, 
Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal bleeding/ 
hematochezia, Vaginal bleeding. 
 
Adverse Event 
Grade 3 
Grade 4 
Hemorrhage/bleeding with grade 
3 or 4 thrombocytopenia   
 
Also consider  
Platelets, hemoglobin, transfusion: 
platelets, transfusion: pRBCs, site 
or type of bleeding.  
 
If the site is not listed, grade as 
Hemorrhage – Other (specify 
site):___________ 
 
Note:  This adverse event must be 
graded for any bleeding with 
grade 3 or 4 thrombocytopenia. 
 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia 
 
Also consider  
Platelets, hemoglobin, transfusion: 
platelets, transfusion: pRBCs, 
hemorrhage – Other (specify site): 
___________________ 
 
Note:  Bleeding in the absence of 
grade 3 or 4 thrombocytopenia is 
graded here only if the specific 
site or type of bleeding is not 
listed elsewhere in the 
Hemorrhage category.  Also 
grade as Other in the Hemorrhage 
category.   
 
Requiring transfusion 
Catastrophic bleeding requiring 
major non-elective intervention 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
89
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
HEMORRHAGE (cont’d) 
Adverse Event 
Grade 3 
Grade 4 
CNS hemorrhage/bleeding 
Bleeding noted on CT or other 
scan with no clinical consequences 
Hemorrhagic stroke or hemorrhagic 
vascular event (CVA) with 
neurologic signs and symptoms 
 
Hemoptysis  
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
 
Melena/GI bleeding 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Rectal bleeding/hematochezia 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Vaginal bleeding 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
Hemorrhage – Other (specify 
site): _____________________ 
Requiring transfusion 
Catastrophic bleeding, requiring 
major non-elective intervention 
HEPATIC 
Adverse Event 
Grade 3 
Grade 4 
Bilirubin  
 
Bilirubin associated with graft 
versus host disease (GVHD) for 
BMT studies, if specified in the 
protocol. 
 
>3.0 – 10.0 x ULN 
 
>6 - <15mg/100mL 
>10.0 x ULN 
 
>15mg/100mL 
INFECTION/FEBRILE NEUTROPENIA 
Adverse Event 
Grade 3 
Grade 4 
Febrile neutropenia (fever of 
unknown origin without clinically 
or microbiologically documented 
infection). 
 
Present 
Life-threatening sepsis (e.g., septic 
shock) 
Infection/Febrile Neutropenia – 
Other (specify): ______________ 
 
Severe 
Life-threatening or disabling 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
90
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
NEUROLOGY 
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. 
Adverse Event 
Grade 3 
Grade 4 
CNS cerebrovascular ischemia 
Transient ischemic event or attack 
(TIA) 
Permanent event (e.g., 
cerebral vascular accident) 
 
Leukoencephalopathy associated 
radiological findings 
Severe increase in SAS; severe 
ventriculomegaly; near total white 
matter T2 hyperintensities or 
diffuse low attenuation (CT); focal 
white matter necrosis (cystic) 
Severe increase in SAS; 
severe ventriculomegaly; 
diffuse low attenuation with 
calcification (CT); diffuse 
white matter necrosis (MRI) 
 
Seizure(s) 
Seizure(s) in which consciousness 
is altered  
Seizures of any type which 
are prolonged, repetitive, or 
difficult to control (e.g., 
status epilepticus, intractable 
epilepsy) 
 
PULMONARY 
Adverse Event 
Grade 3 
Grade 4 
Adult Respiratory Distress Syndrome 
(ARDS) 
 
- 
Present 
Apnea 
 
Present 
Requiring intubation 
Carbon monoxide diffusion capacity 
(DLCO) 
 
>25 - <50% of pretreatment or 
normal value 
<25% of pretreatment or 
normal value 
FEV1 
>25 - <50% of pretreatment or 
normal value 
 
<25% of pretreatment or 
normal value 
Hypoxia 
Decreased O2 saturation at rest, 
requiring supplemental oxygen 
Decreased O2 saturation, 
requiring pressure support 
(CPAP) or assisted 
ventilation 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
91
Appendix M (cont’d) 
Adapted from COMMON TOXICITY CRITERIA (CTC) 
 
RENAL/GENITOURINARY  
Adverse Event 
Grade 3 
Grade 4 
Creatinine 
 
Note:  Adjust to age-appropriate 
levels for pediatric patients. 
 
>3.0- 6.0 x ULN 
>6.0 x ULN 
Renal failure 
 
Requiring dialysis, but reversible 
Requiring dialysis and irreversible 
SECONDARY MALIGNANCY 
Adverse Event 
Grade 3 
Grade 4 
Secondary Malignancy – Other 
(specify type): _______________  
 
Excludes metastasis from initial 
primary. 
 
- 
Present 
 
 
 
 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
92
Appendix N 
The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 9/7/10 
 
  
 
 
  
  
Assign scores appropriately if the patient has any of these comorbidities 
 
 
  
 
 
  
  
 
 
UPN______________                                                      Date___                                              __________ 
Comorbidities 
Definitions 
HCT-CI 
scores 
Actual Lab 
Values/Comments 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, and 
ventricular arrhythmias requiring treatment in the patient’s 
past history 
1 
 
Cardiac 
Coronary artery disease†, congestive heart failure, 
myocardial infarction in patient’s past history or EF of 
50% at time of HCT 
1 
 
Inflammatory bowel 
disease 
Crohn’s disease or ulcerative colitis requiring treatment in 
the patient’s past history 
1 
 
Diabetes 
Requiring treatment with insulin or oral hypoglycemic, but 
not diet alone, at time of HCT 
1 
 
Cerebro-vascular 
disease 
Transient ischemic attack or cerebro-vascular accident in 
patient’s past history 
1 
 
Psychiatric disturbance 
Depression/anxiety requiring psychiatric consult or 
treatment at time of HCT 
1 
 
Hepatic – mild 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN at time of HCT 
1 
 
Obesity 
Patients with a BMI of 
>35 for adults or with BMI-for-age percentile of ≥ 95th 
percentile for children at time of HCT 
1 
 
Infection 
Documented infection or fever of unknown etiology 
requiring anti-microbial treatment before, during and after 
the start of conditioning regimen 
1 
 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica in patient’s past history  
2 
 
Peptic ulcer 
Requiring treatment in patient’s past history 
2 
 
Renal 
Serum creatinine >2 mg/dl, on dialysis, or prior renal 
transplantation at time of HCT 
2 
 
Moderate pulmonary 
DLco and/or FEV1 >65%-80% or 
Dyspnea on slight activity at time of HCT 
2 
 
Prior solid tumor 
Treated at any time point in the patient’s past history, 
excluding non-melanoma skin cancer 
3 
 
Heart valve disease 
At time of HCT excluding mitral valve prolapse 
3 
 
Severe pulmonary 
DLco and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen at time of HCT 
3 
 
Moderate/severe 
hepatic 
Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT 
>2.5XULN at time of HCT 
3 
 
Please provide (KPS): 
 
Karnofsky Performance Score = _______% 
Total Score 
=________ 
Signature of 
Provider: 
________________ 
 
†One or more vessel-coronary artery stenosis, requiring medical treatment, stent, or bypass graft. 
 
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythmatosis; RA, rheumatoid arthritis; CTD, connective tissue disease; DLco, 
diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in one second; AST, aspartate aminotransferase; ALT, alanine aminotransferase. 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
93
 
Appendix O 
 
Weight / Adjusted Body Weight for Drug Dosing 
 
weight_for_drug_do
sing.pdf
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
94
APPENDIX P 
 
COORDINATING CENTER FUNCTIONS 
Outside Center – PI Communication in Hematologic Malignancies 
 
I. 
Study Management, data analysis, and Data and Safety Monitoring 
 
a. Study Management: 
i. 
Each local PI is responsible for selection, training and oversight of local study coordinators 
ii. 
The Coordinating Center registers subjects on the study and assigns study IDs 
iii. 
One copy of the research data is retained by the site. Another data set (identified only by 
study IDs) is transmitted to the Coordinating Center to create the master data file. All data 
are kept in locked areas and password protected databases accessible only to study staff 
iv. 
The quality of data is monitored in an ongoing fashion with the study team and corrective 
action plans instituted as necessary  
b. Data Analysis: 
i. 
Study staff review data for completeness as it is submitted by the sites 
ii. 
The study statistician is responsible for data cleaning and the conduct of analyses as outlined 
in the protocol and grant 
c. Data Safety and Monitoring: 
i. 
The trial coordinators at collaborating centers or the local PIs will fax an official report of an 
SAE to the Coordinating Center within ten days 
ii. 
The SAE report is reviewed by the Overall PI. If the SAE meets the FHCRC criteria for 
reporting then an official signed report is submitted to the IRB 
iii. 
An independent DSMB will meet at six-month intervals and all outcome data is reviewed 
including all adverse events and SAEs reported to the Coordinating Center along with those 
officially reported to the IRB 
iv. 
A report from the DSMB is submitted to the IRB as well as the trial coordinators/local PIs 
participating in the protocol 
 
II.  
Protocol and informed consent document management 
a. A master protocol is maintained by the Coordinating Center and distributed to the sites for 
customization and local IRB review 
b. All protocol and consent modifications initiated by the Coordinating Center are sent to the 
Collaborating Sites following approval by the Coordinating Center IRB, for review and approval 
by the local IRB 
c. Changes required by local IRBs are reviewed by the Coordinating Center and approved prior to 
implementation at local sites 
 
III. 
Assurance of local IRB OHRP-approved assurance 
a. Each site provides their OHRP assurance number and evidence of IRB certification 
b. Study staff monitor maintenance of institutional assurance and IRB certification 
 
IV. 
Assurance of local IRB approvals 
a. The Coordinating Center maintains copies of the most current collaborating site Consent Forms 
and IRB approval documentation 
b. No site may enroll subjects until the Coordinating Center has received confirmation of local IRB 
approval 
c. Each site is responsible for preparation and submission of their continuing reviews. Any changes 
to the protocol or consent form will be communicated to the Coordinating Center 
d. Sites are required to have active IRB approvals to participate in any study related activities 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
95
 
V. 
Any substantive modification by the Collaborating Institution related to risks or alternative 
procedures is appropriately justified 
a.   The Coordinating Center reviews any modifications to consent forms to ensure that site consents 
do not delete or change the basic or additional elements or alternatives required in the sample 
consent form 
 
VI. 
Informed consent is obtained from each subject in compliance with HHS regulations 
a. Subjects must provide written informed consent prior to study participation 
b. The Coordinating Center verifies eligibility and signed consent prior to assigning a study ID 
number 
 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
96
APPENDIX Q 
 
Salmon and Durie Criteria for Diagnosis of Multiple Myeloma 
1. Major criteria 
 
i. Plasmacytoma on tissue biopsy. 
ii. Bone marrow plasmacytosis with > 30% plasma cells. 
iii. Monoclonal globulin spike on serum electrophoresis exceeding 3.5 g/dL for IgG peaks or 2.0 g for 
IgA peaks, > 1.0 g/24 h of k or l light chain excretion on urine electrophoresis in the absence of 
amyloidosis. 
 
2. Minor criteria 
 
a. Bone marrow plasmacytosis with 10% to 30% plasma cells. 
b. Monoclonal globulin spike present, but less than the levels defined above. 
c. Lytic bone lesions. 
d. Normal IgM <50 mg, IgA <100 mg, or IgG <600 mg/dL. 
 
 
Diagnosis will be confirmed when any of the following features are documented in 
symptomatic patients with clearly progressive disease. The diagnosis of myeloma requires a minimum of 
one major + one minor criterion or three minor criteria that must include a + b. 
 
1. i + b, i + c, i + d (i + a not sufficient) 
2. ii + b, ii+ c, ii + d. 
3. iii + a, iii + c, iii + d. 
4. a + b + c, a + b + d. 


FHCRC 2241.00  
FHCRC current version: 10/10/2017 
97
APPENDIX R 
 
Radiotherapy Treatment Guidelines 
 
TBI_Pediatric_NON_
Myeloablative.pdf
TBI_Adult_Non_Myel
oablative.pdf