Conditions: Lupus Erythematosus Graft-versus-host Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
The main goal of the study is to determine if bone marrow transplant (BMT) from a less specific pool of donors in combination with high dose cyclophosphamide can induce remission of refractory systemic lupus erythematosus.

Detailed description:
Systemic lupus erythematosus (SLE) is a devastating systemic autoimmune disease that predominantly affects young women, is more common in African-Americans than in whites, and results in poor quality of life. Lupus has no cure, and up to 90% of patients require corticosteroids for disease control. More than half of patients with lupus have permanent organ damage, much of which is either directly due to or increased by corticosteroids. To satisfactorily manage moderate-to-severe SLE, the investigators need effective treatments that will allow corticosteroid-sparing.

High-dose chemotherapy followed by autologous BMT or peripheral blood progenitor transplantation (PBSCT) has been proposed as a novel approach to treat severe autoimmune diseases. Allogeneic BMT is not currently utilized for the routine treatment of SLE because of the significant morbidity (GVHD) and mortality associated with the procedure.

The investigators have recently developed an approach to BMT using post-transplant cyclophosphamide that allows us to safely perform allogeneic BMT from matched, mismatched, unrelated or haploidentical donors. Transplant-related mortality, graft-failure and risk of GVHD have been very low with this approach. Furthermore, this approach allows us to greatly expand the donor pool since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases.

This trial will employ a fludarabine + cyclophosphamide conditioning along with posttransplantation cyclophosphamide on for patients with refractory SLE. The purpose of this trial is to improve the salvage rate for patients with refractory SLE through a reformatting of the immune system.

Arms:
arm 1: Nonmyeloablative conditioning with rabbit antithymocyte globulin, cyclophosphamide, fludarabine, and total body irradiation. Allogeneic bone marrow transplant on Day 0. Graft versus host disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and tacrolimus.

Interventions: intervention 1: Cyclophosphamide intervention 2: Fludarabine intervention 3: Tacrolimus intervention 4: Mycophenolate Mofetil intervention 5: Rabbit antithymocyte globulin intervention 6: Total body irradiation intervention 7: Allogeneic bone marrow transplant
Intervention descriptions: intervention 1: 14.5 mg/kg/day on Days -6 and -5. 50 mg/kg/day on Days 3 and 4. intervention 2: 30 mg/m\^2/day on Days -6 through -2. intervention 3: Starting on Day 5. Dose will be adjusted according to blood levels. intervention 4: 15 mg/kg three times per day from Day 5 to Day 35. intervention 5: 0.5 mg/kg on Day -9. 2 mg/kg/day on Days -8 and -7. intervention 6: 200 centigray on Day -1. intervention 7: Infusion on Day 0.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version Date 7June 2016 
1 
Protocol Title:  
A Phase I/II Study of Nonmyeloablative Conditioning and Transplantation of HLA-matched, Partially HLA-
mismatched, HLA-haploidentical or matched unrelated Bone Marrow for Patients with Refractory Systemic 
Lupus Erythematosus 
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
IND Number:  119,351 
IND Sponsor:  Javier Bolaños Meade, MD 
Principal Investigator: 
Javier Bolaños Meade, MD 
Office: 410-614-6398 
Pager: 410-283-8683 
Email: fbolano2@jhmi.edu 
Co-Principal Investigators: 
Michelle Petri, MD, MPH, and Robert A. Brodsky, MD. 
Co-Investigators: 
Ephraim Fuchs, M.D. 
Amy DeZern, M.D.  
Leo Luznik, M.D. 
Approved to Consent (in addition to the PIs and Co-investigators): 
Rich Ambinder, M.D., Ph.D.  
Ivan M. Borrello, M.D. 
William Matsui, M.D. 
Douglas Gladstone, M.D. 
Lode Swinnen, M.D. 
 
Richard J. Jones, M.D. 
Monthida Fangtham, MD 
Eric Zollars, MD 
Shannon McCurdy 
Carol Ann Huff, M.D. 
Statisticians:  
             Gary Rosner, ScD 
             Marianna Zahurak,  MS           
Research Nurse: 
Donna Dorr, RN 
NCT02080195


Protocol Version Date 7June 2016 
 
2 
TABLE OF CONTENTS 
SCHEMA............................................................................................. 
3 
1.0 
OBJECTIVES......................................................................... 
3 
2.0 
BACKGROUND AND RATIONALE...................................... 
4 
3.0 
DRUG INFORMATION........................................................... 
7 
4.0 
PATIENT SELECTION........................................................... 
9 
5.0 
TREATMENT PLAN............................................................... 
11 
6.0 
DATA MONITORING AND MANAGEMENT......................... 
14 
7.0 
PATIENT MONITORING........................................................ 
16 
8.0 
RISKS AND TOXICITIES....................................................... 
20 
9.0 
STUDY PARAMETERS.......................................................... 
22 
10.0 
STATISTICAL CONSIDERATIONS....................................... 
23 
11.0 
RISKS AND BENEFITS......................................................... 
29 
12.0 
INFORMED CONSENT.......................................................... 
30 
13.0 
APPENDICES......................................................................... 
31 
14.0 
REFERENCES....................................................................... 
48 
 
 
 


Protocol Version Date 7June 2016 
 
3 
TREATMENT SCHEMA 
 
Days -9  Thymoglobulin 0.5 mg/kg IV with pre-meds 
Start steroid taper 
 
Days -8,-7 Thymoglobulin 2 mg/kg IV qd with pre-meds 
 
Days –6, -5 Fludarabine 30 mg/M2 iv qd 
Cyclophosphamide (CTX) 14.5 mg/kg IV qd* 
Begin antibiotic prophylaxis (except antifungals) 
↓ 
Days –4 -2 Fludarabine 30 mg/M2 iv qd 
↓ 
Day –1 TBI 200 cGy ↓ 
Day 0 Infuse marrow 
↓ 
Days 3, 4 CTX 50 mg/kg iv q d 
Mesna 40 mg/kg iv q d** 
(First dose of CTX must be administered 60-72hr after infusion of marrow) 
↓ 
Day 5 Begin FK-506 1mg iv/po bid** and 
MMF 15 mg/kg po tid with maximum daily dose 3 gm/d 
Begin antifungal prophylaxis 
↓ 
Day 30 Assess Chimerism in peripheral blood 
↓ 
Day 35 Discontinue MMF 
↓ 
Day 60 Assess Chimerism in peripheral blood 
↓ 
Day 180 Evaluate disease 
Assess Chimerism in peripheral blood 
↓ 
Day 180 Discontinue FK-506  
Evaluate disease 
Assess Chimerism in peripheral blood 
↓ 
1 yr, 2 yrs Evaluate disease 
Assess Chimerism in peripheral blood 
  
 
1.0 OBJECTIVES 
 
Primary Objectives 
1.1 The primary endpoint of this study will be the feasibility of non-myeloablative conditioning  regimen and 
post transplantation cyclophosphamide in refractory SLE patients with donors having various degrees of 
matching.           
. 
 
 


Protocol Version Date 7June 2016 
 
4 
Secondary Objectives 
1.1 To estimate the improvement in the RIFLE (Responder index in Lupus Erythematosus) score with the goal 
as target organ complete response with no worsening in any other organ at 12 months. 
1.2 Of the patients with an initial SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) of 4 points 
or higher, estimate the proportion of patients that have an improvement of 4 points. 
1.3 Estimate the proportion of patients with an improvement in PGA (Physician’s Global Assessment) to 0.5 or 
less 
1.4 To estimate the overall survival (OS) and event-free survival (EFS) at 1 year. 
1.5 To estimate the cumulative incidence of full donor chimerism by day 60 
1.6 To estimate the cumulative incidence of non–relapse-related mortality following transplant. 
1.7 To estimate the incidences of primary and secondary graft failure following transplant. 
1.8 To estimate the cumulative incidences of grade II-IV and grade III-IV graft versus-host disease (GVHD).  
1.9 To estimate the cumulative incidence of chronic graft versus-host disease (GVHD).  
1.10 Summarize all hematologic and non-hematologic toxicities. 
 
2.0 BACKGROUND AND RATIONALE 
Systemic lupus erythematosus is a devastating systemic autoimmune disease that predominantly affects 
young women, is more common in African-Americans than in whites, and results in poor quality of life.(1) 
Lupus has no cure, and up to 90% of patients require corticosteroids for disease control.  More than half of 
patients with lupus have permanent organ damage, much of which is either directly due to or increased by 
corticosteroids.(2) Mortality is increased in patients with systemic lupus erythematosus, with accelerated 
atherosclerosis the most important contributing factor,  although the risk of cancer is also increased. (3)  
Ultimately, to satisfactorily manage moderate-to-severe SLE, we need effective treatments that will allow 
corticosteroid-sparing.   
Although the precise etiology of SLE remains unclear, genetic predisposition, hormonal, and environmental 
factors play a role in the pathophysiology of SLE. If one member of a pair of identical twins develops SLE, 
there is a 14-60% chance that the other member of the pair will acquire the disease; thus, susceptibility to 
develop SLE involves more than genetics alone(4). SLE has a female to male prevalence of 9:1 and occurs 
more frequently in African-Americans than in whites(5). The highly skewed prevalence in women is felt, in 
part, to be secondary to hormonal factors. For example, in (NZBxNZW) F1 mice (a murine model of SLE) the 
onset of disease is delayed in males compared to females, while castration of males makes the onset of the 
disease similar to that in untreated female mice of the same strain. Similarly, ovariectomy of female 
(NZBxNZW) F1 mice delays the onset of disease making it similar to that in untreated males of this strain(6). 
However, recent studies suggest that hormonal differences alone may not be enough to explain the female 
predominance in SLE. In fact, having two X chromosomes may predispose to SLE. Although one X 
chromosome is randomly inactivated, it is now known that the Lyonized X chromosome is only partly 
inactivated in women; about 10-15% of genes can be expressed by both X chromosomes in female cells(7). To 
directly study the role of the X chromosome in autoimmunity, investigators established mice which had 
different compliments of sex chromosomes (XX or XY) but possess the same gonads (ovaries or testes)(8). 
Gonadectomy of such mice allowed for direct assessment of the role of sex chromosomes in the immune 
response and susceptibility to autoimmune diseases. The authors tested two independent models of induced 
autoimmune disease, EAE and pristine-induced lupus. Possession of an XX, as opposed to an XY sex 


Protocol Version Date 7June 2016 
 
5 
chromosome complement conferred greater disease severity in both models. Moreover, cytokine analysis 
revealed that T cells from the XY mice produced increased amounts of Th2 cytokines such as IL-4, IL-5, IL-
13, than have a protective effect in autoimmunity(9). These data suggest that the X chromosome complement 
may directly contribute to the female bias of autoimmune diseases such as lupus. 
 
High-dose chemotherapy followed by autologous BMT or peripheral blood progenitor transplantation 
(PBSCT) has been proposed as a  novel approach to treat severe autoimmune diseases(10-13).  The stimulus to 
explore this approach emanates from a variety of autoimmune animal models demonstrating marked 
improvement or complete eradication of autoimmune disease following allogeneic or autologous BMT.  SLE is 
considered the paradigm of autoimmune diseases and the murine models are known to be curable by means of  
hematopoietic stem cell transplantation.(14;15)  
  
Allogeneic BMT is not currently utilized for the routine treatment of SLE because of the significant morbidity 
(GVHD) and mortality associated with the procedure.  A 2009 EBMT report on 900 patients with a variety of 
severe autoimmune diseases transplanted from autologous PBSCT  found the 5-year survival was 85% and the 
progression-free survival 43%, although the rates varied widely according to the type of autoimmune 
disease(16).  The most common autoimmune diseases treated, accounting for roughly 50% of the cases, were 
multiple sclerosis and systemic sclerosis. High-dose cyclophosphamide-based, non-myeloablative conditioning 
regimens were used in over 50% of the HSCT cases reported by EBMT/EULAR and the CIBMTR.(17-19). A 
subset analysis between myeloablative and non-myeloablative conditioning regimens demonstrated that 
myeloablative regimens were associated with an increase in treatment-related mortality and no clear advantage 
in terms of remission induction and relapse rate(3,5,9). Hence, most investigators now favor non-
myeloablative, immunosuppressive conditioning regimens (usually high-dose cyclophosphamide +/- other 
non-myeloablative agents such as antithymocyte globulin) for HSCT in patients with autoimmune diseases.   
 
Due to concern of reinfusing autoreactive lymphocytes with the autograft, our group performed an evaluation of 
high dose cyclophosphamide without stem cell support for SLE patients as part of a trial of high dose 
cyclophosphamide versus monthly intravenous cyclophosphamide for patients with SLE.(20)  Of the total 40 
patients treated, 16 had highly refractory disease and were treated on an open-label study; 24 were treated as part 
of a randomized trial comparing high-dose cyclophosphamide to monthly intravenous cyclophosphamide in a 
cohort of patients who were less heavily pretreated. In the randomized study, six of seven patients with 
neurologic manifestations of their SLE had a complete response; in the patients with renal manifestations only 
four of ten patients responded to high-dose cyclophosphamide (2 complete and 2 partial responses). Patients on 
this randomized trial who did not respond to intravenous pulse-dose cyclophosphamide were eligible to cross 
over to the high dose arm. Interestingly, of the six patients who crossed over to high dose cyclophosphamide, 
three achieved a complete response(20).  Our data suggest that high dose cyclophosphamide is not superior to 
monthly pulse dose cyclophosphamide and we do not recommend the use of high dose cyclophosphamide as 
front-line therapy in SLE.    
 
Similar to autologous BMT, most patients with SLE relapse within a few years after HiCy therapy. Since no 
autograft is given and the dose of cyclophosphamide with HiCy (50mg/kg/d x 4 days) is equivalent that used 
for autologous BMT, our data suggest that either the conditioning regimen is inadequate to eradicate the 
autoimmunity or, similar to the genetic mouse models of autoimmunity, that allogeneic BMT may be required 
to eradicate disease in lupus.  Interest in improving response rates and decreasing relapse has turned attention 
more toward allogeneic stem cell transplantation.  There are already case reports of patients transplanted for 
other indications whose SLE was cured with allogeneic stem cell transplantation.(21;22)   
 
Despite the improved survival achieved in recent years in these patients suffering from SLE, some of them 
continue to have severe morbidity and mortality from their disease particularly if patients do not respond to 
their therapy and have immunosuppressant refractory disease.(24-28). In fact, patients with SLE with renal or 


Protocol Version Date 7June 2016 
 
6 
hematologic manifestations have a sevenfold increase on mortality and those with heterogeneous clinical 
presentation have a 25% increase in mortality(29). Therefore they are the ideal candidates to proceed with 
experimental therapies. Allogeneic bone marrow transplant is one of them. Allogeneic BMT has not 
historically been used for the treating SLE because of perceived morbidity and mortality and the lack of 
suitable HLA-matched donors. However, recent experience using non-myeloablative BMT in patients with 
non-malignant conditions (sickle cell disease and hemoglobinopathies) has shown that these transplants can be 
done safely, with low incidence of graft versus host disease, low transplant related mortality, and high efficacy 
utilizing both HLA matched or haploidentical donors(30-32). Therefore the traditional toxicities encountered 
with BMT employing high dose chemotherapy are avoided and the procedure becomes safer to patients. 
The possibility of maintaining control of autoimmunity by means of mixed chimerism in these autoimmune 
diseases is quite important as well. (33)  These patients may not need full engraftment to have disease 
modification.   
 
From these results, we concluded the following: 
 
1) Post-transplantation immunosuppression with high dose CY, tacrolimus, and thrice daily MMF was 
associated with an acceptably low incidence of graft rejection, severe acute GVHD, and extensive 
chronic GVHD, while allowing reasonably prompt engraftment. 
 
2) In addition to controlling HLA-haploidentical alloreactivity, there was effective clinical immune 
reconstitution as demonstrated by the low incidence of severe opportunistic infections. 
 
3) Relapse is the major cause of treatment failure in this population of patients with mostly poor risk 
hematologic malignancies. A major potential advantage of employing this approach to non-malignant 
diseases such as systemic lupus erythematosus is that the risk of relapse is exceedingly low. In 
essence, engraftment without significant GVHD cures the disease.  
 
Recently, a 25 yo female patient with SLE who received a non-myeloablative HLA-haploidentical bone 
marrow transplant from her brother for the indication of sickle cell disease(32).  Pretransplant, her anti-DNA 
screen for lupus was positive, her C3 was 53 mg/dl, her C4 was 14mg/dl and her dRVVT was prolonged. She 
is now 3 months post BMT with full donor chimerism from her HLA-haploidentical brother. Currently, her 
anti-DNA screen is negative, her C3 is 141 mg/dl, her C4 is 33 mg/dl, her dRVVT is normal, and her urine 
protein has decreased from 859 mg/dl to 395 mg/dl.   
 
Given our promising results in the nonmyeloablative haploidentical setting, including a low incidence of 
engraftment failure, severe acute GVHD, extensive chronic GVHD, and NRM utilizing post-transplantation 
Cy, and our promising results in the myeloablative matched related and unrelated setting, this trial will employ 
a fludarabine + cyclophosphamide conditioning along with posttransplantation Cy on days +3 and +4 for 
patients with refractory SLE. The purpose of this trial is to improve the salvage rate for patients with refractory 
SLE through a reformatting of the immune system. 
 
Given that there are responses of SLE to immunosuppressive therapy in some form, eligible patients will be 
required to have failed at least one course of immunosuppressive therapy. The priority of donors will be as 
follows: HLA-matched sibling donor > HLA-haploidentical donor > matched unrelated donor.  A priority will 
also be placed on male donors over female donors, when both are available.  The rationale for this comes from 
the knowledge that gender, a genetically controlled factor, plays a role in the incidence of autoimmune disease.  
SLE occurs much more frequently in females than males. (34)  The genetic difference in the donation of a 
male allograft to the SLE recipient could influence the recipient’s chance of cure. 
 
 
 


Protocol Version Date 7June 2016 
 
7 
 
 
3.0 DRUG INFORMATION 
3.1 Cyclophosphamide (Cytoxan®) 
Cyclophosphamide is commercially available. Cyclophosphamide is an alkylating agent which prevents cell 
division primarily by cross-linking DNA strands. Cyclophosphamide is cell cycle nonspecific. 
Cyclophosphamide for injection is 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). 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). Cyclophosphamide 
will be dispensed by the Oncology Pharmacy and is produced by Mead Johnson Pharmaceuticals. 
 
3.2 Mesna (sodium-2-mercapto ethane sulphonate) 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the oxasophosphorines 
(cyclophosphamide and ifosphamide). It has no intrinsic cytotoxicity and no antagonistic effects on 
chemotherapy. Mesna binds with acrolein, the urotoxic metabolite produced by the oxasophosphorines, to 
produce a non-toxic thioether and slows the rate of acrolein formation by combining with 4-hydroxy 
metabolites of oxasophosphorines. Mesna is 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 
or as per institutional standards. 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. 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. Mesna will be dispensed by the Oncology Pharmacy and is produced by Mead 
Johnson Pharmaceuticals. 
 
3.3 Fludarabine 
 Fludarabine phosphate is commercially available.  
Fludarabine phosphate is 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.  
Fludarabine monophosphate, 50 mg/vial, 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.  
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 to 12 hours.  
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.  
Fludarabine will be administered by IV infusion over 30 minutes in a dose of 30 mg/m2/day on days -6 to -2.  
Fludara® will be dispensed by the Oncology Pharmacy and is produced by Berlex Pharmaceuticals.  
 
3.4 Tacrolimus 
Tacrolimus, also known as FK-506, is a macrolide immunosuppressant. It inhibits lymphocytes by forming a 
complex with FKBP-12, calcium, and calmodulin, leading to the decrease in the phosphatase activity of 
calcineurin. This drug is used with corticosteroids for prophylaxis of organ rejection in patients receiving 
allogeneic liver transplants. Its use is also currently being investigated in kidney, bone marrow, cardiac, 


Protocol Version Date 7June 2016 
 
8 
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. Nephrotoxic drugs, antifungals, 
calcium channel blockers, cimetidine, danazol, erythromycin, methylprednisone and metoclopramide increase 
the bioavailabilty of FK-506. In contrast, phenobarbital, phenytoin, rifamycins and carbamazepine decrease 
FK-506 levels. Adverse reactions include tremor, headache, diarrhea, hypertension, nausea, and renal 
dysfunction. 
 
3.5 Mycophenolic Acid Mofetil (Cellcept®) 
Mycophenolate Mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid (MPA). This 
active metabolite is a noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). 
There are no pharmacokinetic interactions with ganciclovir, cotrimoxazole, oral contraceptives and 
cyclosporine. Side effect profiles include diarrhea, leukopenia, sepsis, allergic reactions, and vomiting. There 
is also an increase in certain types of infection mainly from the herpes virus family (CMV, HSV & VZV) and 
candida. 
 
3.6  
Rabbit antithymocyte globulin (ATG) 
Thymoglobulin® [Anti-thymocyte Globulin (Rabbit)] is a purified, pasteurized, gamma immune globulin, 
obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains 
cytotoxic antibodies directed against antigens expressed on human T-lymphocytes. This drug is commonly 
used to treat graft rejection in kidney transplantation. It is also commonly used in bone marrow transplantation 
as part of the conditioning regimen to avoid graft failure and to prevent graft-versus-host disease. 
 
Thymoglobulin is a sterile, freeze-dried product for intravenous administration after reconstitution with Sterile 
Water for Injection, USP (SWFI). Each 10 mL vial contains 25 mg anti-thymocyte globulin (rabbit) as well as 
50 mg glycine, 50 mg mannitol, and 10 mg sodium chloride. After reconstitution with 5 mL SWFI, each vial of 
reconstituted product contains approximately 5 mg/mL of Thymoglobulin, of which >90% is rabbit gamma 
immune globulin (IgG). The reconstituted solution has a pH of 7.0 ± 0.4. Human red blood cells are used in the 
manufacturing process to deplete cross-reactive antibodies to non-T-cell antigens. The manufacturing process 
is validated to remove or inactivate potential exogenous viruses. All human red blood cells are from US 
registered or FDA licensed blood banks. A viral inactivation step (pasteurization, i.e., heat treatment of active 
ingredient at 60°C/10 hr) is performed for each lot. Each Thymoglobulin lot is released following potency 
testing (lymphocytotoxicity and E-rosette inhibition assays), and cross-reactive antibody testing 
(hemagglutination, platelet agglutination, anti-human serum protein antibody, antiglomerular 
 
Adverse side effects include immunodeficiency, infusion related toxicities such as hypertension, chills, rigors, 
tachycardia, capillary leak syndrome, hyperglycemia, cytopenias, transient hepatitis, anaphylaxis, serum 
sickness, myalgias, sensory changes including hearing loss, headaches, renal toxicity, dyspnea and bronchial 
spasm, fevers. The drug is potentially teratogenic and is unknown if it can be passed to children in 
breastfeeding. 
 
Thymoglobulin will be dispensed by the Oncology Pharmacy and is produced by Genzyme. ATG–rabbit must 
be infused through a 0.22 micro filter with premedications: acetaminophen 650 mg orally and 
diphenhydramine 25mg orally as well as a steroid taper (see Section 6.3). The dose to be used is 0.5 mg/kg on 
day -9 and 2 mg/kg/day on days -8 and -7. Note: Keep anaphylaxis kit at bedside during ATG administration. 
ATG should not be administered during the weekend. 
 
 
 
 
4.0 PATIENT SELECTION 
 
4.1 Inclusions Criteria  


Protocol Version Date 7June 2016 
 
9 
All patients with moderate-to-severe SLE will be considered for this trial, including women and minorities.  SLE is 
too rare a disease in children for it to be feasible to include them.  Patients must meet the following criteria to be 
eligible for participation in this clinical trial: 
 
1) Four or more ACR criteria as revised by Hochberg(35)for the classification of SLE or 4 or more of the SLICE 
criteria(36)  
 
2) Involvement of one or more of the following organ systems (renal, neurologic, hematologic, cardiac, 
pulmonary, gastrointestinal) of moderate-to-severe severity as indicated by an “A” or 2 B score on the BILAG, 
a 2 or higher on the Physician Global Assessment, or severe enough to require hospitalization if the organ 
involvement was not “captured” on either the BILAG or SLAM instruments,. 
 
 
 
3) Patients must have failed at least two forms of immunosuppression: 
a) moderate-to-high dose corticosteroids  (0.5-1mg/kg/day*, and/or IV pulse methylprednisolone) 
b) azathioprine, methotrexate, cyclosporine, tacrolimus, belimumab, rituximab, or  mycophenolate mofetil,  
In the case of severe and ongoing hemolytic anemia and/or thrombocytopenia, failure of intravenous   
immunoglobulin treatment will count as the second treatment. 
 
 
4) Patients should be eligible for transplantation according to the BMT Policy Manual. 
 
 
*When cyclophosphamide is the accepted standard of care (renal and neurologic), the maximally 
tolerated dose of prednisone will be sufficient to meet the corticosteroid criterion. 
 
 
4.2 Exclusion Criteria: 
1) Age less than 18 years and over 75 years. 
2) Any risk of pregnancy – ALL female patients must have an effective means of birth control or be 
infertile due to hysterectomy, fallopian tube surgery, or menopause. 
3) Active, life threatening or clinically significant uncontrolled systemic infection, known HIV-
related illness, Hep B or Hep C infection. 
 
 
4.3 Criteria for donor eligibility 
4.3.1 
Age >18 yr 
4.3.2 
Donors must meet the selection criteria as defined by the BMT Policy Manual. 
4.3.3 
Donors will be selected to minimize HLA mismatch in the host-versus-graft 
Direction. 
4.3.4 
In case there are two or more donors with an equivalent HLA mismatch in the 
HVG direction, donors will next be selected based on the most favorable 
combination of (i) HLA compatibility in cross-match testing and (ii) ABO 


Protocol Version Date 7June 2016 
 
10 
compatibility: 
 
HLA cross matching (in order of priority) 
1. Mutually compatible (no cross-matching antibodies) 
2. Recipient non-cross-reactive with donor, donor cross-reactive with recipient 
3. Mutually cross-reactive 
 
ABO compatibility (in order of priority) 
1. Compatible 
2. Minor incompatibility 
3. Major incompatibility 
4. Major and minor incompatibility 
 
 
 
 
 
 
 
5.0 TREATMENT PLAN (All patients with refractory systemic lupus erythematosus) 
 
Days -9  Thymoglobulin 0.5 mg/kg IV with pre-meds 
Start steroid taper 
 
Days -8,-7 Thymoglobulin 2 mg/kg IV qd with pre-meds 
 
Days -6, -5 Fludarabine 30 mg/M2 iv qd 
Cyclophosphamide (CTX) 14.5 mg/kg IV qd* 
Begin antibiotic prophylaxis (except antifungals) 
↓ 
Days -4 to -2 Fludarabine 30 mg/M2 iv qd 
↓ 
Day –1 TBI 200 cGy  
↓ 
Day 0 Infuse marrow 
↓ 
Days 3, 4 CTX 50 mg/kg iv q d 
Mesna 40 mg/kg iv q d** 
(First dose of CTX must be administered 60-72hr after infusion of marrow) 
↓ 


Protocol Version Date 7June 2016 
 
11 
Day 5 Begin FK-506 1mg iv/po bid** and 
MMF 15 mg/kg IV or po as tolerated tid with maximum daily dose 3 gm/d 
Begin antifungal prophylaxis 
↓ 
Day 30 Assess Chimerism in peripheral blood 
↓ 
Day 35 Discontinue MMF 
↓ 
Day 60 Assess Chimerism in peripheral blood 
↓ 
Day 180 Evaluate disease 
Assess Chimerism in peripheral blood 
↓ 
Day 180 Discontinue FK-506 
Evaluate disease 
Assess Chimerism in peripheral blood 
↓ 
1 yr, 2 yrs Evaluate disease 
Assess Chimerism in peripheral blood 
 
5.1 Indwelling central venous catheter 
Placement of a double lumen central venous catheter will be required for administration of IV medications and 
transfusion of blood products, as per standard BMT requirements. 
 
5.2 Pre-treatment Evaluation 
All patients will require documentation of a detailed history and physical examination and standard BMT 
evaluation of cardiac, pulmonary, liver and renal function. 
 
All patients will undergo a bone marrow aspirate and biopsy for morphological, cytogenetic and flow 
cytometric evaluation. 
 
5.3 Preparative regimen administration 
Fludarabine will be administered by intravenous infusion over 30 min. on D-6 to D-2. The dose will be  
30 mg/m2.  
 
For decreased creatinine clearance (< 61 ml/min) determined by the Cockcroft Formula:  
CCr = (140 – age) x IBW (kg) x 0.85 (for women)  
PCr x 72   
 
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 
 
 
 
Cyclophosphamide will be administered as an iv infusion over 1- 2 hr, (depending on volume) on D-6 and D-5. 
The dose of pre-transplantation cyclophosphamide is 14.5 mg/kg/day. Dose is calculated based on the adjusted 
ideal body weight. (Refer to Appendix 2.) Body weight and height are measured directly. An approximate 
weight for height would be calculated from a standard table or equations that reflect ideal “values”.  


Protocol Version Date 7June 2016 
 
12 
Note: Mesna will be utilized for the Day 3 and Day 4 post BMT cyclophosphamide doses, not for the pre-BMT 
cyclophosphamide doses.  
 
Total body irradiation: 200   cGy AP/PA with 4MV or 6MV photons at 8-12 cGy/min at the point of 
prescription (average separation of measurements at mediastinum, abdomen, hips) will be administered in a 
single fraction on day -1.  
 
Cyclophosphamide will be given in two blocks. The first one on days -6 and -5 at a dose of 14.5 mg/kg  and 
the second block will be given at a dose of 50 mg/kg/day IV over 1-2 hrs x 2 days on day +3 and day +4.  
Dosing of cyclophosphamide is based on ideal body weight for all subjects.  On occasion, a subject’s actual 
body weight may be less than his/her ideal body weight, in which case cyclophosphamide will be dosed using 
the subject’s actual body weight.  Intravenous hydration with appropriate fluids will be started at least 2 hr 
prior to cyclophosphamide and continued for at least 8 hr post-cyclophosphamide. 
 
Mesna will be given to prevent hemorrhagic cystitis at 10 mg/kg/dose IV 30 min pre- and at 3, 6, and 8 or 9 
hours post-cyclophosphamide.  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.  Urine output over 2 
hr will be checked before administering cyclophosphamide and must be at least 3.0 mL/kg.  Urine output must 
be maintained post cyclophosphamide, as per BMT standards.  Urinalysis will be performed to detect evidence 
of hemorrhagic cystitis, a known complication of high-dose Cy therapy. 
 
A day of rest may be added after the preparative regimen doses and prior to bone marrow infusion depending 
on donor availability, operating room schedules, and as clinically indicated. 
 
5.4 Marrow processing and infusion 
Bone Marrow will be harvested and infused on day 0.   
Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient IBW.  
Major incompatible ABO graft will have red blood cell depleted by buffy coat preparation. Minor 
ABO incompatible graft will have plasma removed.  Guidelines for the infusion of bone marrow 
have been established and are outlined in the ABO compatible/minor mismatched allo BMT or 
the ABO incompatible allo BMT standing orders.   
 
 
Major incompatible ABO graft will have red blood cell depleted by buffy coat preparation. Minor ABO 
incompatible graft will have plasma removed.  Guidelines for the infusion of bone marrow have been 
established and are outlined in the ABO compatible/minor mismatched allo BMT or the ABO incompatible 
allo BMT standing orders.   
 
5.5 Post-transplantation cyclophosphamide 
Cyclophosphamide [50mg/kg (IBW)] will be given on D+3 post-transplant (within 60-72hr of marrow 
infusion) and on D+4 post-transplant. Cyclophosphamide will be given as an iv infusion over 1- 2 hr 
(depending on volume). Patients will follow institutional standards for uroprotection. 
It is crucial that no immunosuppressive agents are given until 24 hours after the completion of the post-
transplant Cy. This includes steroids as antiemetics. 
 
5.6 GVHD prophylaxis 
On Day +5, patients will begin prophylaxis with Tacrolimus and Mycophenolic Mofetil (MMF). Tacrolimus 
will be given at a dose of 1mg IV over 4 hours(adults). Serum trough levels of tacrolimus should be measured 
around Day+7 and the dose should be adjusted based on this level to maintain a level of 5-15 ng/ml. 


Protocol Version Date 7June 2016 
 
13 
Tacrolimus should be converted to oral dosing on Day 14. For adults, the oral dosing is 1mg po bid, or 3 times 
the IV dose. Serum trough levels should be checked again on Day 16, or 2 days after conversion from IV to po. 
Patients may continue on IV dosing if they are not tolerating po. It is not a protocol violation to switch 
tacrolimus from IV to po earlier then Day 14. 
Serum trough levels should be checked weekly thereafter and the dose adjusted accordingly to maintain a level 
of 10-15 ng/ml.  Mycophenolic acid mofetil will be given at a dose of 15 mg/kg IV or  po as tolerated TID 
(based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g TID).MMF 
prophylaxis will be discontinued after the last dose on D35 and tacrolimus prophylaxis will be discontinued 
after the last dose around Day 180. 
 
5.7 Infection prophylaxis and therapy 
All infection prophylaxis and therapy will be administered and discontinued as per institutional standards.  
During pre-transplant evaluation patients will be screened for respiratory syncitial virus, influenza A, B and 
parainfluenza viruses if symptomatic.  Assays of these viruses must be negative for symptomatic patients to be 
admitted for transplant.  Strong consideration should be given to institution of ribavirin or cidofovir therapy if 
positive for adenovirus or nalidixic acid if positive for BK virus.  Oral hygiene will be maintained according to 
institutional standards. Prophylactic antimicrobial therapy will be started during the preparative regimen, per 
institutional guidelines. 
 
An oral antibiotic for gastrointestinal decontamination will be administered according to institutional 
preference at least until the ANC is >500 following BMT.  Antifungal prophylaxis will be administered 
according to institutional preference. The prophylactic anti-fungal drug will be discontinued if the patient is 
started on amphotericin B or other anti-fungal therapy empirically while neutropenic or for treatment of 
documented fungal infection.  Pneumocystis jiroveci pneumonia (PCP) prophylaxis will be administered 
with dapsone and should continue for the first year following BMT. Patients intolerant of dapsone will 
receive either atovaquone, or pentamidine as PCP prophylaxis.  Viral prophylaxis for HSV will be 
administered according to institutional preference.  For adults at SKCCC, viral prophylaxis will consist of 
valacyclovir or acyclovir per institutional protocol.  Although not required, CMV viremia (by PCR) or 
antigenemia (by ELISA) should be documented weekly beginning once the WBC>1000 and until discharge.  
Monitoring of CMV viremia or antigenemia is recommended to continue on a weekly basis until at least day 
60, and preferably weekly until patients are off immunosuppressive therapy.  Patients who are viremic or 
antigenemic will be treated preemptively per institutional guidelines. 
 
5.8 Transfusion support 
Platelet and packed red cell transfusions will be given per current institutional recommendations. 
5.9 Anti-ovulatory treatment 
Menstruating females should be started on an anti-ovulatory agent (recommended agent is Lupron) prior to the 
initiation of the preparative regimen. 
 
5.10 Post-BMT evaluation 
Patients will be followed during (i) the initial post-BMT period (ii) IPOP care and (iii) after discharge to the 
referring physician as per standard practice. 
 
6.0 DATA MONITORING AND MANAGEMENT 
This is a Level II study under the SKCCC CRO Data and Safety Monitoring Program. External data 
monitoring of this protocol by the SKCCC CRO QA Department will occur on a regular basis with the 
frequency dependent on the rate of subject accrual and the progress of the study. Additionally, the protocol will 
be monitored internally by Dr. Brodsky, Dr Petri and Dr. DeZern on a routine basis. Trial monitoring and 
reporting will be done through the Data and Safety Monitoring Committee (DSMC). 
 
6.1 Monitoring review plan 
The protocol will be monitored internally by the co- principal investigators.  The investigators (Dr. Petri, Dr. 
Brodsky and Dr. Bolaños Meade) will review data to assure the validity of data, as well as, the safety of the 


Protocol Version Date 7June 2016 
 
14 
subjects.  They will also monitor the progress of the trial.  The investigators will be responsible for maintaining 
the clinical protocol.  The research nurses will be responsible for reporting adverse events, assuring that 
consent is obtained and documented, reporting of unexpected outcomes, and reporting the status of the trial in 
the annual report submitted to the IRB and to the trial monitoring review group. 
 
Content of the annual report at a minimum should include year-to-date and full trial data on accrual and 
eligibility, protocol compliance, treatment administration, toxicity and ADR reports, response, survival, 
regulatory compliance, compliance with prearranged statistical goals.  The report should be submitted in a 
timely manner according to the schedule defined by the SKCCC Clinical Research Office.  The trial should be 
placed on hold or closed if there is non-compliance with this reporting.  This report serves as the annual report 
for the IRB. 
 
 
6.2 Adverse Event Reporting 
Adverse events that will be reported should include: any mortality within the first 100 days after BMT, any 
graft failures (defined as <5% donor chimerism) associated with failure of neutrophil recovery to >500/mm³ by 
day ~60 after transplantation, and all unexpected events as deemed significant by the PIs. 
 
Unexpected, grade 3-5 adverse events (AE) will be reported via an Adverse Event Report form to the 
investigators.  Unexpected Grade 3 adverse events must be reported within 3 business days of knowledge of 
the event.  Unexpected, grade 4-5 AEs must be reported via an adverse event report form to one of the PIs 
within one working day of discovery or notification of the event. Expected AEs will be reported using NCI’s 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined in the 
patient monitoring section (section 7.0). 
 
Sponsor SAE Reporting to the FDA (for Sponsor/Sponsor-Investigator INDs) - All SAEs are reported to the 
FDA by the trial’s IND Sponsor/Sponsor-Investigator via the IND annual report per 21 CFR 312.33. All SAEs 
deemed unexpected and related to the investigational product qualify for expedited reporting and must be 
submitted to the FDA by the IND Sponsor/Sponsor-Investigator per 21 CFR 312.32 
 
 
Clinical Research Review and Monitoring Committee 
550 North Broadway, Suite 1121 
Baltimore, MD 21205 
Phone: 410-955-8866 
Fax: 410-614-1328 
 
 
6.3 Toxicity Monitoring 
6.3.1 GVHD 
A major toxicity of allogeneic BMT is GVHD.  Acute graft-versus-host disease (GVHD) shall be graded 
clinically according to the Keystone criteria.  Diarrhea and/or hyperbilirubinemia in a patient with 
histologically documented skin GVHD may be assumed to be a manifestation of visceral GVHD and will be 
graded as such.  All patients with histologically documented, clinical grade >2 acute GVHD should receive 
initial treatment according to institutional preference.  If skin GVHD resolves with treatment but suspected 
visceral GVHD does not, biopsy of the affected organ (liver or gastrointestinal tract) should be obtained to rule 
out other causes of hyperbilirubinemia and/or diarrhea.  Steroid refractory acute GVHD will be treated 
according to institutional preferences.  In patients who develop GVHD, the GVHD Questionnaire must be 
completed at the time of onset, weekly until GVHD resolves, and Day 60. GVHD summaries will be taken 
weekly from the standard histories and physicals performed from Day 14 through Day 60.  
The following information shall be collected on all patients with acute GVHD: 
 
 
Date of onset (defined as the date of first biopsy confirming GVHD) 


Protocol Version Date 7June 2016 
 
15 
 
GVHD evaluation form at the time of onset, weekly until GVHD resolves, and Day 60 (see appendix 
5) 
 
Initial overall clinical grade 
 
Maximum overall clinical grade 
 
Date of onset of grade III-IV acute GVHD, if any 
 
Chronic graft-versus-host disease (cGVHD) shall be graded clinically according to the criteria 
developed by the NIH consensus conference on chronic GVHD (Appendix 4). 
 
Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung), with no clinically significant 
functional impairment (maximum of score 1 in all affected organs or sites).  Moderate chronic GVHD involves 
(1) at least 1 organ or site with clinically significant but no major disability (maximum score of 2 in any 
affected organ or site) or (2) 3 or more organs or sites with no clinically significant functional impairment 
(maximum score of 1 in all affected organs or sites).  A lung score of 1 will also be considered moderate 
chronic GVHD. 
 
Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in any organ or site). A 
lung score of 2 or greater will also be considered severe chronic GVHD.  The following information shall be 
collected on all patients with chronic GVHD: 
 
 
Date of onset (defined as the date of first biopsy confirming GVHD, if possible or the first day of onset 
of clinical symptoms if no biopsy is performed) 
 
GVHD evaluation form at the time of onset (see appendix 4), until GVHD resolves 
 
Initial overall clinical score 
 
Maximum overall clinical score 
 
The occurrence and severity of acute and chronic GVHD after Day 60 will be captured at the patients’ six 
month and annual evaluations. 
 
Treatment of GVHD will be the standard of care on the BMT unit at that time. 
 
6.4 Transplant-related mortality (TRM) 
Causes of TRM, i.e., death in the absence of relapse, will be documented as important indicators of procedure-
associated toxicity, particularly as these causes relate directly or indirectly to GVHD.  Analysis will stratify 
mortality with respect to the peri-transplant period (<100 d post-BMT) or later times post-BMT. 
 
6.5 Data Management 
Enrollment data will be maintained in CRMS, and study data will be maintained on paper case report forms 
and appropriate Graft Engineering Laboratory spreadsheets.  The research team will make assessments of 
GVHD. GVHD assessment will be evaluated and scored by the GVHD team, the Research Nurse, the 
attending BMT physician and PI.  Hematopoietic engraftment will be assessed by the BMT attending and the 
investigators.  The investigators will be responsible for evaluation of chimerism data and overall toxicities. 
 
The study team will also compile and maintain a master adverse event log as well as a master protocol 
deviation log in Excel in compliance with the requirements of the JHU SKCCC Safety Monitoring Committee. 
 
7.0 PATIENT MONITORING 
 
The following parameters will be obtained according to this schedule: 
(for details of these evaluations, see text sections 7.1-7.3, or additional sections when indicated)  
 
 
Initial 
Allowable Time 
from consent  
Day <60 
Day 30 
Day 60 
Suspected 


Protocol Version Date 7June 2016 
 
16 
date  
+/-7 
+/-7 
GVHD 
History and Physical 
X 
Within 30 days 
 
 
X 
 
Performance status 
X 
Within 30 days 
 
 
 
 
CBC with Diff 
X 
Within 7 days 
Weekly 
X 
X 
 
Comprehensive 
Metabolic Panel 
X 
Within 7 days 
Weekly 
X 
X 
 
Bone marrow biopsy 
X 
Within 60 days 
 
 
X 
 
CXR 
X 
Within 30 days 
 
 
X 
 
Pregnancy test in women 
of child bearing age 
X 
Within 30 days 
 
 
 
 
Chimerism analysis 
X 
 
 
X 
X 
 
PT/PTT 
X 
Within 30 days 
 
 
 
 
ECG 
X 
Within 30 days 
 
 
 
 
MUGA or ECHO 
X 
Within 30 days 
 
 
 
 
HepB Ag, HBC Ab, HCV 
Ab, HSV IgG, CMV IgG, 
RPR, HIV, VZV IgG (if 
possible) 
X 
Within 30 days 
Within 30 days 
 
 
 
 
Toxicity assessment 
X 
 
 
X 
X 
 
HLA typing 
X 
Must be done at 
JHH 
 
 
 
 
PFTs  
(Spirometry and DLCO) 
X 
Within 30 days 
 
 
 
 
GVHD questionnaire 
X 
Within 30 days 
 
X 
X 
 
Sinus CT 
X 
Within 30 days 
 
 
 
 
Lymphocyte subsets 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Version Date 7June 2016 
 
17 
 
Medical history 
All patients will require documentation of a detailed history and physical examination.  
I. 
Baseline investigations including: 
a) Completion of all activity indices (physician’s global asssessment, SELENA SLEDAI, PGA) and 
responder indices (BILAG, RIFLE – see Appendix); SLICC Damage Index, and SF-36 (health status) 
b) SLE serologies 
i. 
C3, C4 
ii. ANA, anti-dsDNA, antiphospholipid antibodies (anticardiolipin, aCL, and lupus anticoagulant, LA) 
iii.  
c) Hematologic 
i. 
CBC with platelets, differential. 
ii. PT, PTT 
iii. ABO and Rh typing 
iv. ESR 
d) Hepatic  
i. Serum SGOT/AST, SGPT/ALT, Alkaline phosphatase, total and direct bilirubin, 
 
7.1 Pre-transplant Evaluation 
These represent the basic baseline studies required on all patients prior to starting their preparative regimen.  
Additional investigations may be clinically indicated in certain individuals. Other baseline studies may be 
required for the purposes of non-preparative regimen protocols on which the patient is enrolled.  In this case, 
such requirements will be stipulated in the pertinent protocols.  
 
7.1.1 Complete medical history which should include particular attention to the following details:  
a) Previous treatment and response  
b) Previous transfusions and transfusion reactions  
c) Previous serious infections  
d) Episodes of CNS/extramedullary involvement  
e) Allergies  
f) Current medications  
g) Assessment of performance status  
h) Assessment of clinical activity of SLE, to be used in completion of the clinical indices (SELENA SLEDAI 
and SLAM) and responder indices (BILAG and RIFLE). 
 
7.1.2 Thorough general medical evaluation which should include:  
a) A careful physical examination  
b) Evaluation for placement of a central venous access device, if the patient does not already have such a 
catheter.  
 
7.1.3 Baseline investigations including:  
a) Completion of all activity indices (physician’s global assessment, SELENA SLEDAI, PGA see Appendix) 
and responder indices (BILAG, RIFLE – see Appendix); SLICC Damage Index, and SF-36 (health status) 
b) SLE serologies 
i.C3, C4, CH50 
ii.ANA, dsDNA (Crithidia), antiphospholipid antibodies (anticardiolipin, aCL, and lupus anticoagulant, 
LA) 


Protocol Version Date 7June 2016 
 
18 
 
c) Hematologic  
i. CBC with platelets, differential, reticulocyte count  
ii. PT, PTT  
iii. ABO and Rh typing  
iv. Bone marrow aspirate and biopsy  
d) Chemistries  
i. Comprehensive chemistry panel   
e) Renal 
i. 
M6, M12 
ii. 
Routine microscopic urinalysis with C &S 
iii. 
Serum creatinine 
iv. 
24-hour urine for creatinine clearance and total protein, or spot protein/creatinine ratio 
f) Cardiac 
i. EKG  
ii. Echocardiogram or MUGA scan with Left Ventricular Ejection Fraction (LVEF)  
g) Pulmonary  
i. Chest X-ray  
ii. Sinus CT scan  
iii. Pulmonary function tests including at least FEV1 and FVC (pediatric patients under 
the age of 8 are excluded from this test)  
h) Immunologic / Infections  
i. HBsAg, anti-HBC, anti-HCV  
ii. RPR  
iii. HIV antibody  
iv. Serology for CMV and HSV (plus VZV – blood samples permitting)  
v. HLA typing/lymphocytotoxic antibody screen  
i) RFLP studies will be drawn as a baseline for subsequent engraftment studies when the donor and 
patient are the same gender.  
j) Additional tests (if applicable) 
       i 
FSH (females) 
       ii   Testosterone (males) 
      iii   Beta HCG  
 
7.2 Post-transplant Evaluation 
7.2.1 Day 0 through Day 60 (+ 7 days) evaluation.  These represent the minimum required. More frequent 
determinations and additional investigations may be indicated by the clinical condition of the patient.  
a) CBC daily with a WBC differential once the total WBC is greater than 100 until ANC > 500 for three 
days or two consecutive measurements over a three day period. Then, CBC weekly with differential.  
b) Comprehensive metabolic panel once a week.  
c) Patients will have evaluations for infectious complications as clinically indicated.  Surveillance 
cultures according to JHOC BMT program standards are recommended.  
d) Evaluations by history and physical examination for GVHD will be performed as per BMT unit 
standards. For study purposes, weekly GVHD summaries will be taken from these standard 
examinations from Day 14 through Day 60.  
 
7.2.2 Evaluations on Day ~ 30 (+7 days)  
a) History and physical examination.  
b) T cell and unsorted chimaerism or XY FISH for donor chimerism on peripheral blood.  
c) CBC and differential, comprehensive panel.  
d) GVHD questionnaire.  
 
7.2.3 Evaluations on day ~60 (+7 days)  


Protocol Version Date 7June 2016 
 
19 
a) History and physical examination.  
b) T cell and unsorted chimaerism Studies for donor cell chimerism on peripheral blood and bone 
marrow.  
c) CBC and white blood cell differential, reticulocyte count, comprehensive panel, lymphocyte subsets.  
d) GVHD questionnaire.  
 
8.0 RISKS AND TOXICITIES 
 
8.1 Cyclophosphamide after graft infusion 
The major risk of participating in this research protocol is that shifting part of the standard BMT dose of 
cyclophosphamide after the graft infusion may damage the graft.  The consequences of damaging the graft may 
include delayed hematologic recovery, graft failure, or treatment-related malignancy in donor cells.  The risk 
of delayed hematologic recovery does not appear to be severe, because patients who have engrafted with donor 
cells in the setting of a nonmyeloablative preparative regimen incorporating the same post-BMT dose of 
cyclophosphamide experienced only approximately two weeks of neutropenia.  However, the risks of delayed 
hematologic recovery in this study cannot be directly extrapolated from referenced studies due to more intense 
pre-transplant chemotherapy with busulfan and cyclophosphamide in this protocol.  The risk of treatment-
related malignancy in donor cells is difficult to estimate, but is likely to be similar to the 1% risk estimated 
after limited exposure to 
cyclophosphamide. 
 
8.2 Acute and Chronic GVHD 
The second major risk in participating in this research protocol is the risk of developing acute and/or chronic 
GVHD given the use of a myeloablative preparative regimen and haploidentical donors. Modified Keystone 
Criteria (See appendix 3) equal to or greater than Overall Grade 2 acute GVHD is considered clinically 
significant and associated with increased morbidity and non-relapse mortality. The likelihood of surviving 
severe GVHD is to a large part dependent on the age of the patient and the patient’s overall condition.  The 
other risks are the same as for standard BMT for high-risk acute hematologic malignancies, as follows: 
 
8.3 Chemotherapy toxicities  
The agents being used in the study are FDA approved. These agents are used extensively in the Bone Marrow 
Transplant setting and have well defined toxicity profiles. In addition, there are many expected toxicities 
related to a bone marrow transplant. For these reasons, toxicities will be captured and recorded/graded if the 
adverse event interferes with the subject’s daily function and are considered clinically significant. We will 
capture and grade all these events structured around the categories of the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0for the first 60 days post BMT.  
Since this trial is an out-patient trial, the definition of an adverse event ‘interfering with daily function’ and 
‘clinically significant’ will be events that require hospitalization. For example, if a patient has a neutropenic 
fever that requires hospitalization, then ‘neutropenic fever’ will be captured and graded as an adverse event. 
An example of a non-captured event is if a patient has hypotension that is corrected by fluid administration in 
the outpatient setting. This will not be captured as an adverse event unless the patient requires a hospital 
admission for further treatment of the hypotension.  
Once the patient becomes hospitalized, the above definition of ‘requiring hospitalization’ cannot be used to 
capture adverse events. For these already hospitalized patients, events will only be recorded once the event is 
greater than a grade 3 or 4 as stated below.  
The following is a list of categories that will not be recorded unless the event becomes a grade 4 or meets the 
criteria of a SAE, as stated in section 6.  
• Allergy/Immunology  
• Auditory/Hearing  
• Cardiovascular (Arrhythmia)  
• Cardiovascular (General)  
• Coagulation  
• Constitutional symptoms  


Protocol Version Date 7June 2016 
 
20 
• Dermatology/Skin  
• Endocrine  
• Hemorrhage  
• Hepatic  
• Infection/Febrile neutropenia  
• Lymphatics  
• Metabolic/Laboratory 
• Secondary Malignancy  
• Sexual/Reproductive Function  
 
The following categories will be recorded only if the event becomes a grade 3 or grade 4 or meets the criteria 
of a SAE.  
• Gastrointestinal  
• Musculoskeletal  
• Neurology  
• Ocular/Visual  
• Pain  
• Pulmonary  
• Renal/Genitourinary  
 
The Blood/Bone Marrow category is captured as endpoints to the study. Thus for this category, we will not 
record data according to the NCI Common Toxicity Criteria. 
 
8.4 Cyclophosphamide (Cytoxan) 
Cyclophosphamide Toxicities: 
a) Hematologic: Leukopenia, anemia 
b) Dermatologic: Alopecia 
c) Gastrointestinal: Nausea, vomiting, increased AST, ALT, mucositis, diarrhea 
d) Neurologic: Headache, dizziness 
e) Cardiovascular: Cardiac necrosis rarely with high dose cyclophosphamide 
f) Renal: Hemorrhagic cystitis, SIADH 
g) Other: teratogenic, may cause secondary neoplasms, anaphylaxis (rare) 
h) Fluid retention. Cy has anti-diuretic effect usually counteracted by furosemide administration. Careful 
physical examination should be made and accurate weights should be determined to detect fluid 
overload early. 
i) Cardiomyopathy. At doses greater than 200mg/kg, Cy can cause fatal myocardial necrosis with clinical 
heart failure. Non-specific ST changes on EKG are not unusual but a decrease in voltage is significant. 
j) Hemorrhagic cystitis. Hematuria is not uncommon at this dose level, but is usually not symptomatic or 
severe unless there is inadequate diuresis. An occasional patient will get severe cystitis despite 
prophylactic measures. 
 
8.5 Mesna (sodium -2-mercapto ethane sulphonate) 
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. 
 
8.6 Tacrolimus/FK-506 
Adverse reactions include tremor, headache, diarrhea, hypertension, nausea, and renal dysfunction. 
 
8.7 MMF 
Side effect profiles include diarrhea, leukopenia, sepsis, allergic reactions, and vomiting.  There is also an 
increase in certain types of infection mainly from the herpes virus family. The drug has been associated with 
fetal malformations. 


Protocol Version Date 7June 2016 
 
21 
 
8.8 Infection 
Infection is a major cause of morbidity in allo BMT and is a major concern in these patients. 
 
8.9 Aplasia 
Pancytopenia is an expected side effect of allogeneic BMT with the use of myeloablative preparative regimens. 
Given the previous experience with post-transplant cyclophosphamide in other trials, we would expect the 
duration of aplasia to be relatively short. Prolonged aplasia can result from the failure of donor BM to engraft. 
 
9.0 STUDY PARAMETERS 
 
9.1 Donor chimerism 
Donor chimerism will be measured in the peripheral blood around day 30 and again in the peripheral blood and 
bone marrow around day 60.  Patients with any amount of donor chimerism around day 60 will be considered 
as having engrafted.  Chimerism determinations will be made on peripheral blood by a number of different 
methods depending on the specific patient. Methods may include (i) the usual standard of restriction fragment 
length polymorphism (RFLP) if the donor and recipient RFLPs are informative, (ii) fluorescence in-situ 
hybridization (FISH) for Y-chromosome markers on PBMC if the donor is male, (iii) cytogenetic analysis, (iv) 
flow cytometric analysis of HLA-A, B or DR on lymphocytes in the peripheral blood if haploidentical and 
suitable reagents exist or (v) PCR analysis of variable nucleotide tandem repeats (VNTR) in PBMC if 
informative. Mixed donor chimerism will be defined as >0%, but <95%. 
Complete donor chimerism will be defined as >95%. Patients who have relapsed or died prior to day 60 will 
not be evaluable for full donor chimerism, as these are competing risk factors. 
 
9.2 GVHD 
Patients will be followed for development of acute and chronic GVHD using standard criteria. Chronic GVHD 
usually develops beyond the high-risk, peritransplant period (i.e., >100 d post-BMT, but can occur earlier) and 
is assessed according to standard criteria (see appendix 4). Treatment of GVHD will follow the BMT standard 
of care at that particular time. 
 
9.3 Transplant-related mortality 
Transplant-related mortality, which is defined as death in the absence of relapse or progression, will be 
characterized at 100 days and at one year after BMT. 
 
9.4 Hematologic toxicity 
A secondary endpoint of this Pilot Study is time to recovery of circulating neutrophils and platelets (following 
chemotherapy). Neutrophil recovery is defined as the first day of three consecutive lab values on different 
days, after the conditioning regimen-induced nadir of blood counts, that the absolute neutrophil count is > 
500/μL. Platelet recovery is defined as the first day of three consecutive lab values on different days, after the 
conditioning regimen-induced nadir of blood counts, that the platelet count is ≥ 20,000 μL without platelet 
transfusion support in the seven days prior. 
 
9.5 Antibodies developed after HLA mismatched bone marrow transplantation 
Pre- and Post-Transplant Antibody Samples: 
Ideally, in addition to a pre-transplant baseline (the pre-transplant sample is a routine clinical test that is 
performed on all patients being evaluated for HSCT), all participants will have multiple post-transplant 
samples tested for donor-specific antibodies.  Recognizing that this requirement may limit participation, data 
will be accepted on any subject provided there is at least one post-transplant sample analyzed, preferably one 
tested between 2 weeks to 1 month post –transplant. 
 
The following are the time points recommended, considering the transplant date as Day 0: 
Pre-Transplant - 30 to -7 days (30 days to 1 week pre-transplant) 
Post-Transplant 1 +7 to +14 days (1 week to 2 weeks post-transplant) 


Protocol Version Date 7June 2016 
 
22 
Post-Transplant 2 +14 to +30 days (2 weeks to 1 month post-transplant) 
Post-Transplant 3 +2 to +3 months (2 to 3 months post-transplant) 
Post-Transplant 4 +4 to 6 months (4 to 6 months post-transplant) 
 
Antibody analysis will be performed by solid phase assays using soluble HLA molecules bound to microbeads 
as targets. To ensure comparable results, the antibody assays will be performed using flow cytometric or 
luminex platforms. Sera can be screened using multiantigen assays, but specificity should be confirmed with 
single phenotype and/or single antigen assays. 
 
One red top should be drawn and sent with an immunogenetics requisition that is marked  
“Post-Transplant Antibody Assay”. The contact person is: 
 
 
Suraya Berger 
saberger@jhmi.edu 
410-955-3600 
JHU Immunogenetics Laboratory 
2041 E. Monument Street. 
Baltimore, MD  21205 
 
10.0  Statistical Methods 
Overall Study Design 
This study is a single-arm feasibility study of a busulfan/cyclophosphamide conditioning regimen and post transplantation 
cyclophosphamide with matched, partially matched, haplo-identical or unrelated donors in patients with refractory SLE.  
With this trial we seek to expand the donor pool as well as reduce the occurrence of graft versus host disease. 
10.1 Accrual 
We plan to enroll a total of 25 patients.  It is estimated that one year of accrual will be necessary to enroll the targeted 
sample size. Patients will be followed on the study for a minimum of one year after accrual ends. 
10.2 Primary Objective 
The primary endpoint of this study will be the feasibility of this conditioning regimen and post transplantation 
cyclophosphamide in refractory SLE patients with donors having various degrees of matching.           
10.3 Secondary Objectives 
10.3.1 To estimate the improvement in the RIFLE (Responder index in Lupus Erythematosus) score with the goal as      
target organ complete response with no worsening in any other organ at 12 months. 
10.3.2 Estimate the proportion of patients that have an improvement of 4 points on the SLEDAI (Systemic Lupus 
Erythematosus Disease Activity Index). 
10.3.3 Estimate the proportion of patients with an improvement in PGA (Physician’s Global Assessment) to 0.5 or less. 
10.3.4 To estimate the overall survival (OS) and event-free survival (EFS) at 1 year. 
10.3.5 To estimate the cumulative incidence of full donor chimerism by day 60 
10.3.6 To estimate the cumulative incidence of non–relapse-related mortality following transplant. 
10.3.7 To estimate the incidences of primary and secondary graft failure following transplant. 


Protocol Version Date 7June 2016 
 
23 
10.3.8 To estimate the cumulative incidences of grade II-IV and grade III-IV graft versus-host disease (GVHD).  
10.3.9 To estimate the cumulative incidence of chronic graft versus-host disease (GVHD).  
10.3.10 Summarize all hematologic and non-hematologic toxicities. 
10.4 Analysis of Primary Endpoint 
The analysis of the primary endpoint will be descriptive, reporting the overall percentage of patients with full donor 
chimerism by day 60, no treatment related mortality, no primary or secondary graft failures, no relapse and no acute or 
chronic graft versus host disease.  With 25 patients, the width of the exact binomial confidence interval for this proportion 
will be approximately ±0.26.  Similar analyses will be done for each of the histocompatability categories: matched, 
partially matched, haplo-identical or unrelated.  If the stopping rule for safety is not triggered and we see reproducible 
results across categories with varying degrees of matching, we would be interested in pursuing this treatment strategy for 
refractory SLE. 
10.5 Analysis of Secondary Endpoints 
10.5.1 
For each patient’s target organ, the 12 month response will be assessed as: complete, partial, the same, or worse.  
Response category proportions will be reported with exact binomial 95% confidence intervals.   
10.5.2    SLEDA index scores will be assessed pre and post study.  The changes in score will be summarized with a  
              mean and 95% confidence interval.  For patients with an initial SLEDAI of ≥4, the proportion of patients     
              with an improvement of 4 points will be reported with a 95% confidence interval. 
10.5.3    PGA scores will be evaluated pre and post study.  Changes will be summarized descriptively and the  
 
proportion of patients with an improvement to 0.5 on this scale will be reported. 
    
10.5.4 
Overall survival: Standard life table methods will be used to analyze OS.  We will report the one-year OS      
 
with a 95% confidence interval.    
10.5.5 
We will estimate the cumulative incidence function for achieving full donor chimerism, where relapse or death 
prior to full donor chimerism by day 60 will be considered as competing events. The period of time during which 
a transplant recipient is likely to achieve full donor chimerism will be calculated from the date of BMT to the 
date on which full donor chimerism is achieved. Graphs of cumulative incidence vs. time will be produced,   and 
the cumulative incidence of full donor chimerism by day 60 will be estimated along with a 90% confidence 
interval. 
10.5.6 
NRM: To estimate the cumulative incidence of non–relapse-related mortality following transplant, a cumulative 
incidence curve will be produced. Incidence of NRM will be estimated at 60 days, 100 days, six months, and one 
year along with 90% confidence intervals. Disease progression or death related to disease progression will be 
considered as competing events. 
10.5.7 
Graft failure: To estimate the incidence of primary and secondary graft failure following transplant.  Exact 
binomial 95% confidence intervals will be reported. 
10.5.8 
Acute GVHD: To estimate the cumulative incidence of grade II-IV and grade III-IV acute GVHD from day of 
transplant.  The first day of acute GVHD onset for a given grade will be used to estimate the cumulative 
incidence curves.  An overall cumulative incidence will be estimated along with a 90% confidence interval at 
100 days post-transplant with graft failure, disease progression or death prior to occurrence of acute GVHD 
considered as competing events. 
10.5.9 
Chronic GVHD: To estimate the cumulative incidence and severity of extensive chronic GVHD from day of 
transplant, the first day of clinical onset of extensive chronic GVHD will be used to estimate a cumulative 
incidence curve. Incidences of chronic GVHD at one and two years post-transplant will be estimated along with 


Protocol Version Date 7June 2016 
 
24 
90% confidence intervals. Death, disease progression, or graft failure prior to occurrence of chronic GVHD will 
be considered as competing events. 
10.5.10 Additional hematologic and non-hematologic toxicities: These will be recorded using NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined in the patient 
monitoring section (section 7.0). Toxicities will be tabulated by type and appropriate confidence intervals will be 
estimated. 
10.6 Stopping Rule 
A Bayesian monitoring rule for two adverse events, failure to engraft by Day 60 (A1) and grade III-IV acute GVHD (A2), 
will be used to monitor the trial for safety after every 5 patients.  Use of this conditioning regimen would be reconsidered 
if the probability of engraftment failure by day 60 is > 25% or the probability of severe acute GVHD is > 25%.  This 
design is based on the Bayesian posterior probability derived for the bivariate case [Etzioni et al.  The likelihood assumes 
that occurrence of one adverse event precludes that of the other.  In the absence of previous experience with this regimen, 
a bivariate uniform prior distribution is assumed.  The posterior distribution is a product of piecewise beta densities and 
the calculation has been programmed using Mathematica [Mathematica].   
Acceptable safety with this stopping rule is defined such that the posterior probability that the frequency of non-
engraftment by day 60 is greater than 25% or severe acute GVHD is greater than 25% is < 0.80.  In the course of this 
study, if the posterior probability exceeds 0.80, accrual to the trial will be temporarily halted and the DSMB will review 
the data and recommend either modification or termination of the trial. 
Tables 2a-e show the stopping rule for the sample sizes of 5, 10, 15, 20, and 25 patients when the allowed probability of 
non-engraftment by day 60 is 25% and severe acute GVHD is 25%.  The bolded/highlighted cells are combinations of 
non-engraftment and severe acute GVHD events that would temporarily halt the trial using a threshold for the Bayesian 
posterior probability of 80%.  For example, if the current sample size of the study is 5 patients (Table 2a) and 3 patients 
fail to engraft by day 60 and 1 patient experiences severe acute GVHD, the posterior probability that this regimen is not 
acceptable would be 92% and the study would be halted for review.   
Table 2a:  Posterior probabilities of excessive engraftment failure (EF) and severe acute GVHD risk.  
Bolded/highlighted boundary corresponds to numbers of EF or GVHD where the posterior probabilities are high 
(80% or more) that these events’ risks exceed the threshold of 25%.  This table applies to the first five patients.                            
 
Number of Grade III-IV aGVHD 
Number of EF 
0 
1 
2 
3 
4 
5 
0 
0.03 
0.10 
0.29 
0.68 
0.95 
1  
1 
0.11 
0.24 
0.57 
0.90 
0.99 
1 
2 
0.34 
0.59 
0.88 
0.99 
1 
1 
3 
0.75 
0.92 
0.99 
1 
1 
1 
4 
0.97 
1 
1 
1 
1 
1 
5 
1 
1 
1 
1 
1 
1 
 
Table 2b:  Posterior probabilities and stopping boundaries for the first 10 patients. 
 
Number of Grade III-IV aGVHD 
Number of EF 
0 
1 
2 
3 
4 
5 
6 
7 
0 
0.01 
0.02 
0.06 
0.15 
0.35 
0.66 
0.90 
0.98 
1 
0.02 
0.04 
0.10 
0.23 
0.50 
0.81 
0.96 
1 
2 
0.06 
0.10 
0.19 
0.40 
0.71 
0.92 
0.99 
1 
3 
0.16 
0.23 
0.40 
0.66 
0.89 
0.98 
1 
1 
4 
0.38 
0.50 
0.70 
0.89 
0.98 
1 
1 
1 
5 
0.70 
0.80 
0.92 
0.98 
1 
1 
1 
1 


Protocol Version Date 7June 2016 
 
25 
6 
0.92 
0.96 
0.99 
1 
1 
1 
1 
1 
7 
0.99 
1 
1 
1 
1 
1 
1 
1 
 
Table 2c:  Posterior probabilities and stopping boundaries for the first 15 patients.   
Number 
of EF 
Number of Grade III-IV aGVHD 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
0 
0 
0.01 
0.02 
0.04 
0.1 
0.22 
0.44 
0.71 
0.9 
0.98 
1 
0.01 
0.01 
0.03 
0.06 
0.14 
0.29 
0.54 
0.8 
0.94 
0.99 
2 
0.02 
0.03 
0.05 
0.1 
0.2 
0.4 
0.68 
0.89 
0.97 
1 
3 
0.05 
0.06 
0.09 
0.17 
0.32 
0.57 
0.82 
0.95 
0.99 
1 
4 
0.11 
0.13 
0.19 
0.31 
0.52 
0.76 
0.93 
0.98 
1 
1 
5 
0.23 
0.27 
0.37 
0.54 
0.75 
0.91 
0.98 
1 
1 
1 
6 
0.45 
0.51 
0.63 
0.79 
0.91 
0.98 
1 
1 
1 
1 
7 
0.72 
0.78 
0.86 
0.94 
0.98 
1 
1 
1 
1 
1 
8 
0.91 
0.93 
0.97 
0.99 
1 
1 
1 
1 
1 
1 
9 
0.98 
0.99 
0.99 
1 
1 
1 
1 
1 
1 
1 
Table 2d: Posterior probabilities and stopping boundaries for the first 20 patients.    
Number 
of EF 
Number of Grade III-IV aGVHD 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
0 
0 
0 
0.01 
0.02 
0.04 
0.08 
0.16 
0.31 
0.53 
0.76 
0.91 
0.98 
0.99 
1 
0 
0 
0.01 
0.02 
0.05 
0.1 
0.2 
0.38 
0.61 
0.83 
0.94 
0.99 
1 
2 
0.01 
0.01 
0.01 
0.03 
0.06 
0.13 
0.26 
0.46 
0.71 
0.89 
0.97 
0.99 
1 
3 
0.02 
0.02 
0.03 
0.05 
0.09 
0.18 
0.35 
0.58 
0.81 
0.94 
0.99 
1 
1 
4 
0.04 
0.04 
0.06 
0.09 
0.15 
0.28 
0.48 
0.72 
0.89 
0.97 
0.99 
1 
1 
5 
0.08 
0.09 
0.11 
0.16 
0.26 
0.43 
0.65 
0.85 
0.95 
0.99 
1 
1 
1 
6 
0.16 
0.18 
0.21 
0.29 
0.43 
0.63 
0.82 
0.94 
0.98 
1 
1 
1 
1 
7 
0.31 
0.34 
0.39 
0.5 
0.66 
0.82 
0.93 
0.98 
1 
1 
1 
1 
1 
8 
0.53 
0.56 
0.63 
0.74 
0.85 
0.94 
0.98 
1 
1 
1 
1 
1 
1 
9 
0.77 
0.79 
0.84 
0.9 
0.95 
0.98 
1 
1 
1 
1 
1 
1 
1 
10 
0.92 
0.93 
0.95 
0.97 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
11 
0.98 
0.98 
0.99 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
1 
12 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
 
Table 2e:  Posterior probabilities and stopping boundaries for 25 patients.    
Number 
of EF 
Number of Grade III-IV aGVHD 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
0 
0 
0 
0 
0.01 
0.01 
0.03 
0.07 
0.13 
0.23 
0.4 
0.62 
0.81 
0.93 
0.98 
0.99 
1 
0 
0 
0 
0.01 
0.02 
0.04 
0.08 
0.15 
0.28 
0.47 
0.69 
0.86 
0.95 
0.99 
1 
2 
0 
0 
0 
0.01 
0.02 
0.05 
0.1 
0.18 
0.33 
0.54 
0.76 
0.9 
0.97 
0.99 
1 
3 
0.01 
0.01 
0.01 
0.02 
0.03 
0.07 
0.12 
0.23 
0.41 
0.63 
0.83 
0.94 
0.98 
1 
1 
4 
0.01 
0.02 
0.02 
0.03 
0.05 
0.09 
0.17 
0.31 
0.51 
0.73 
0.89 
0.97 
0.99 
1 
1 
5 
0.03 
0.03 
0.04 
0.05 
0.08 
0.14 
0.25 
0.41 
0.63 
0.83 
0.94 
0.98 
1 
1 
1 
6 
0.07 
0.07 
0.08 
0.1 
0.14 
0.23 
0.37 
0.56 
0.77 
0.91 
0.97 
0.99 
1 
1 
1 
7 
0.13 
0.13 
0.15 
0.18 
0.25 
0.36 
0.53 
0.73 
0.88 
0.96 
0.99 
1 
1 
1 
1 
8 
0.23 
0.24 
0.27 
0.32 
0.41 
0.55 
0.72 
0.87 
0.95 
0.99 
1 
1 
1 
1 
1 
9 
0.4 
0.41 
0.45 
0.52 
0.62 
0.75 
0.87 
0.95 
0.98 
1 
1 
1 
1 
1 
1 
10 
0.62 
0.63 
0.67 
0.73 
0.82 
0.9 
0.95 
0.98 
1 
1 
1 
1 
1 
1 
1 
11 
0.81 
0.82 
0.85 
0.89 
0.93 
0.97 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
12 
0.93 
0.93 
0.95 
0.96 
0.98 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
1 


Protocol Version Date 7June 2016 
 
26 
13 
0.98 
0.98 
0.98 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
14 
0.99 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
  
 
Operating characteristics of stopping rule: 
The probability of stopping the study early under three different scenarios, three thresholds, and fixed looks after every 5 
patients is shown in Table 3.  The maximum allowed risk of engraftment failure (EF) by day 60 is 25% and of severe acute 
GVHD (aGVHD) is 25%.  The following table shows the frequency of stopping under several scenarios corresponding to 
different actual risks of these events.  The probability of stopping early was calculated from 5000 simulated trials for sample 
sizes of 25 with 3 different posterior probability thresholds: 0.60, 0.70 and 0.80.  This trial is using 0.80 for the posterior 
threshold.  The average sample size of the simulated studies is given in parentheses.      
 
Table 3:  Probability of stopping early under three scenarios with average sample size in parentheses. 
 
 
 
“True” Risks in the 
Simulations 
 
Posterior 
Threshold 
Planned 
Sample size 
EF risk = 25% & 
aGVHD risk = 25% 
EF risk =35% & 
aGVHD risk =.40% 
EF risk =.25 & 
aGVHD risk = 45% 
0.60 
25 
.42  (18.7) 
.88  (10.1) 
.83  (10.9) 
0.70 
25 
.36  (19.9) 
.81  (11.2) 
.76  (12.2) 
0.80 
25 
.27  (21.2) 
.74  (12.3) 
.71  (12.9) 
 
 
11.0 RISKS AND BENEFITS 
 
11.1 Risks and toxicity 
The major toxicity of using bone marrow from HLA-mismatched, related donors is GVHD. The incidence of 
severe aGVHD (Grades III-IV)) on the phase I nonmyeloablative haploidentical BMT trial utilizing 2 doses of 
post-transplantation Cy, MMF and tacrolimus was approximately 10%. We would not expect a rate of severe 
GVHD greater than 15%.  Another significant risk is failure-to-engraft due to rejection by host lymphocytes.  
Infection is a major cause of morbidity and mortality in the peritransplant period (#100d post-BMT). However, 
given current supportive care and the intensive infection prophylaxis of this protocol, we expect the risk to be 
acceptable. Prolonged neutropenia may increase this risk in the case of graft rejection. 
 
 
11.2 Benefits 
This is a Pilot Study  of toxicity in the setting of a nonmyeloablative BMT using post-transplantation Cy to 
maximize engraftment and minimize GVHD.  The potential benefit of this trial is a durable recovery from 
systemic lupus erythematosus. 
 
12.0 INFORMED CONSENT 
 
Patients eligible for marrow grafting are completely evaluated and presented at group conference.  The group's 
recommendations are discussed with the patient. If the patient is approved for BMT, the marrow processing 
procedure itself, the risks of the preparative regimen, risks of BMT complications including infection and 
GVHD and alternate forms of therapy are presented as objectively as possible. Informed consent is obtained 
from the recipient using the forms approved by the JCCI IRB. 
 
12.1 On-study date 


Protocol Version Date 7June 2016 
 
27 
Date of consent signing. 
 
 
12.2 Off-study date 
Upon completion of “Day 360” evaluations, patients have completed their treatment except for Patient follow-
up beyond day 360 will consist of collecting information regarding ongoing engraftment, disease status, late 
effects of this protocol, acute and chronic graft vs- host disease, immune reconstitution, additional therapies, 
and survival as per standard BMT long-term follow-up. Patients will go off study early in the event of: 
1. Death 
2. Patient decision (or decision by a parent or guardian on behalf of a minor) 
3. Unacceptable toxicity associated with protocol therapy, as determined by the treating physicians in 
consultation with the investigators. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 1 
 
ECOG PERFORMANCE STATUS SCALE GRADE DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease activities without restriction. 
1 
Restricted in physically strenuous activities and able to carry out work of a light or sedentary nature, 
e.g. light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 


Protocol Version Date 7June 2016 
 
28 
5 
Dead. 
 
LANSKY PERFORMANCE STATUS SCALE 
 
100 
Fully active, normal 
90 
Minor restrictions in strenuous physical activity 
80 
Active, but tired more quickly 
70 
Greater restriction of play and less time spent in play activity 
60 
Up and around, but active play minimal; keeps busy by being involved in quieter activities 
50 
Lying around much of the day, but gets dressed; no active playing participates in all quiet play and 
activities 
40 
Mainly in bed; participates in quiet activities 
30 
Bedbound; needing assistance even for quiet play 
20 
Sleeping often; play entirely limited to very passive activities 
10 
Doesn't play; does not get out of bed 
0 
Unresponsive 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
100 
Normal no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
Able to carry on normal activity and to work; no special care needed. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self; unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his personal needs. Unable to work; 
able to live at home and care for most personal needs; varying amount ofassistance needed. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although death not imminent. 
20 
Very sick; hospital admission necessary; active supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be progressing rapidly. 


Protocol Version Date 7June 2016 
 
29 
0 
Dead 
 
APPENDIX 2 
 
NCI COMMON TOXICITY CRITERIA 
The NCI common toxicity criteria can be accessed and downloaded via the website: 
http://ctep.cancer.gov/reporting 
 
 
 
 
 
 
APPENDIX 3 
 
NIH Consensus Scoring/Evaluation Forms for Chronic GVHD48 
Organ scoring of chronic GVHD. *AP may be elevated in growing children, and not reflective of liver 
dysfunction. 
+ Pulmonary scoring should be performed using both the symptom and pulmonary function testing (PFT) scale 
whenever possible. When discrepancy exists between pulmonary symptom or PFT scores the higher value 
should be used for final scoring. Scoring using the Lung Function (LFS) is preferred, but if DLCO is not 
available, grading using FEV1 should be used. The LFS is a global assessment of lung function after the 
diagnosis of bronchiolits obliterans has already been established. The percent predicted FEV1 and DLCO 
(adjusted for hematocrit but not alveolar volume) should be converted to a numeric score as follows: >80% = 
1, 70-79& = 2; 60-69% = 3; 50-59% =4, 40-49% =5, <40% = 6. The LFS = FEV1 score + DLCO score, with a 
possible range of 2-12. GVHD= graft versus host disease, ECOG=Eastern Cooperative Group, KPS-= 
Karnofsky Performance Scale; LPS= Lansky Performance Status; BSA= body surface area; ADL=activities of 
daily living; LFTs = liver function tests; AP= alkaline phosphatase; ALT=alanine aminotransferase; AST= 
aspartate aminotransferase; ULN=upper limit of normal 
 
 


Protocol Version Date 7June 2016 
 
30 
Appendix 4 
Acute GVHD Evaluation Form 
Acute GVHD Evaluation Note – v6.2001 
 
Date of Evaluation __________________________ 
 
Is this patient’s initial GVHD evaluation?      No  
Yes:  
GVHD Prophylaxis:_________________________ 
SUBJECTIVE 
_________________________________________________________ 
_________________________________________________________ 
_________________________________________________________ 
____________________________________ 
PHYSICAL EXAM 
 
SKIN Rash: ________________% 
N Y Erythroderma 
N Y Bullae 
N Y Raised skin 
N Y Blanching 
N Y Edema 
N Y Hyperpigmentation 
N Y Hypopigmentation 
N Y Abnormal Nails 
 
LIVER T Bili: _______________ 
N Y Jaundice 
N Y Hepatomegaly 
N Y Hepatic tenderness 
N Y Ascites 
N Y Weight gain 
DB LDH _______________ 
ALT AST_______________ 
AlkPhos ________ 
 
GUT Avg Stool Output:_________cc 
N Y Nausea 
N Y Vomiting 
N Y Cramping 
N Y Tender to Palpitation 
N Y Ileus 
S/O from past 3 days: 
D-1: ________ D-2_________ D-3_________ 
 
 
HEMATOLOGY 
N Y Upper GI Bleeding 
N Y Lower GI Bleeding 
N Y GU Bleeding 
N Y Pulmonary Bleeding 
N Y CNS Bleeding 
N Y Oral Bleeding 
N Y ENT Bleeding 
 
OPTHALMOLOGICAL 
N Y Conjunctival Erythema 
N Y Conjunctival Ulceration 
N Y Dry Eyes 
 
ORAL 
N Y Leucoplacia 
N Y Thrush 
N Y Erythema 
N Y Ulceration 
N Y Xerostra 
Comments: 
____________________________ 
____________________________________ 
____________________________________ 
 
Is there evidence of Chronic GVHD?  
• No • 
 Yes:  
 
 
 
 
 
 
 
 
 
Complete Chronic GVHD Evaluation 


Protocol Version Date 7June 2016 
 
31 
BIOPSIES SINCE LAST EVALUATION  
• None 
Site: ____________  
• Consistent with GVHD • Not Diagnostic of GVHD Date: ____/_____/_____ 
 
Site: ____________  
• Consistent with GVHD • Not Diagnostic of GVHD Date: ____/_____/_____ 
 
ACUTE GRAFT VERSUS HOST DISEASE STAGING (Please circle stage for each organ) 
 
STAGE SKIN LIVER GUT (adults) GUT (children) 
0 No evidence of GVHD Bili <2.0mg/dL < 500 mL diarrhea per day < 10 ml/kg/day 
1 <25% 2.0 –3.0 mg/dL > 500 mL /day, or persistent nausea with histologic evidence 10-15 ml/kg 
2 25-50% 3.1 – 6.0 mg/dL > 1,000 mL diarrhea per day 16-20 ml/kg 
3 >50% 6.1 – 15.0 mg/dL > 1,500 mL diarrhea per day 21-25 ml/kg 
4 W/ bullous formation >15.0 mg/dL Severe abdominal pain w-w/o ileus >26 ml/kg 
 
OVERALL GRADE (Please circle current overall grade) 
 • Cannot be determined 
GRADE SKIN LIVER GUT 
0 None None None 
1 Stage 1-2 None None 
2 Stage 3, OR Stage 1, OR Stage 1 
3 ---------- Stage 2 – 3, OR Stage 2 - 4 
4 Stage 4, OR Stage 4 ---------- 
 
CURRENT GVHD TREATMENT: 
Therapy Name & Dose Start date Stop date Most recent level 
 
 
 
 
 
 
 
 
 
 
OVERALL GVHD ASSESSMENT 
� No current evidence of GVHD � Symptoms resolved � Symptoms improved 
� No Changes � Mixed response � Symptoms progressing 
� Symptoms questionable for GVHD � Symptoms suggestive of GVHD 
RECOMMENDATIONS 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
_______________________________ ____________ _____________ ________ 
Signature ID# Pager # Date 
 
 
 
 
 


Protocol Version Date 7June 2016 
 
32 
Appendix 5: RIFLE 
 
 
 
 
 
 
Visit Date:  ___________________ 
 
 
 
 
 
 
Patient Study Code:  _________________ 
 
 
 
 
 
 
Patient History Number:  ______________ 
 
 
 
 
 
 
Patient Name:  _______________________ 
 
 
 
 
 
 
MD Initials:  ______________________ 
 
RESPONDER INDEX FOR SYSTEMIC LUPUS ERYTHEMATOSUS 
(RIFLE) 
 
 
PREPARED SEPTEMBER 14, 1998 AT IDEC MEETING by: 
Michelle Petri, Ken Kalunian, Joan Merrill, David Wofsy, Ellen Ginzler, John Davis, Jill Buyon                                                   
 
GUIDELINE FOR USE: At each physician encounter, score RIFLE as a comparison to the previous encounter 
except at the last visit compare to both the first (baseline) encounter and the final encounter.   All must be 
attributable to SLE. 
 
A. 
ORGAN SYSTEMS 
 
1. 
Neurological  
 
 
DEFINITIONS 
 
a) 
CNS 
 
psychosis 
 
not present 
 
worsening  
  
 
new or progressive as per SLEDAI glossary   
 
present, no change 
 
partial response   
signs of improvement with no increase in anti-psychotic meds  
 
resolution  
  
 
no psychosis but can be on stable medication   
 
seizures (any type) 
 
not present 
 
worsening  
  
 
new or increase in frequency 
 
present, no change 
 
partial response   
a 50% decrease in frequency (over 1 month) without increase in seizure meds 
 
resolution  
  
 
no seizures for 3 months but can be on stable medications   
 
impairment of cognitive function  
 
not present 
 
worsening  
  
 
new or progressive as per SLEDAI glossary (worsening mini mental exam) 
 
present, no change  
 
partial response   
improvement in mini-mental exam but not return to normalcy 
 
resolution 
 
normal mini-mental exam 
 
TIA/stroke 
 
not present 
 
worsening  
  
 
new TIA or CVA due to lupus including secondary aPS 
 
present, no change 
 
partial response   
decreased frequency of TIAs over three months 
 
resolution    
 
no TIAs over three months, can be on stable therapeutic anticoagulation  
 
 
 
 
 
 
 
 
 
 
 


Protocol Version Date 7June 2016 
 
33 
Rifle Cont. 
Visit Date:  ___________________ 
 
 
 
 
 
 
Patient Study Code:  _________________ 
 
 
 
 
 
 
Patient History Number:  ______________ 
 
 
 
 
 
 
Patient Name:  _______________________ 
 
 
 
 
 
 
MD Initials:  ______________________ 
meningitis (requires LP)   
 
not present 
 
worsening   
 
 
new meningitis by LP (culture negative), for pre-existing meningitis new 
physical findings, new obtundation, new papilledema  
 
present, no change 
 
partial response   
reduction in headache and meningeal signs, improvement in level of 
consciousness 
 
resolution  
  
 
no meningeal signs, normal level of consciousness, no papilledema 
 
pseudotumor cerebri (requires CT or MRI) 
 
not present 
 
worsening    
 
new pseudotumor cerebri by LP, CAT, or MRI, if present worsening headache 
and visual symptoms 
 
present, no change 
 
partial response  
improvement in signs (as in meningitis) without new treatment  
 
 
 
 
 
 
(i.e., remains on stable treatments) 
 
 
resolution  
  
 
asymptomatic and normal fundoscopic exam 
 
scleritis and episcleritis 
 
not present 
 
worsening  
 
 
new scleritis or episcleritis 
 
present, no change 
 
partial response   
50% improvement by ophthalmologic exam 
 
resolution   
 
 
normal ophthalmologic exam and on no medications  
 
optic neuritis 
 
not present 
 
worsening  
 
 
new optic neuritis 
 
present, no change 
 
partial response   
50% improvement by ophthalmologic exam and/or visual acuity 
 
resolution   
 
 
normal ophthalmologic exam and/or visual acuity on no medications  
 
uveitis 
 
not present 
 
worsening  
 
 
new uveitis 
 
present, no change 
 
partial response   
50% improvement by ophthalmologic exam  
 
resolution   
 
 normal ophthalmologic exam   
 
retinitis 
 
not present 
 
worsening  
 
 
new retinitis 
 
present, no change 
 
partial response   
50% improvement by ophthalmologic exam  
 
resolution   
 
 normal ophthalmologic exam   
 
 
 
 
 
 
 
 
 
 


Protocol Version Date 7June 2016 
 
34 
Rifle Cont. 
 
Visit Date:  ___________________ 
 
 
 
 
 
 
Patient Study Code:  _________________ 
 
 
 
 
 
 
Patient History Number:  ______________ 
 
 
 
 
 
 
Patient Name:  _______________________ 
 
 
 
 
 
 
MD Initials:  ______________________ 
 
chorea 
 
not present 
 
worsening  
 
 
new or worsening chorea  
 
present, no change 
 
partial response   
50% improvement  
 
resolution   
 
 not present 
 
ataxia   
 
not present 
 
worsening  
 
 
new or worsening ataxia  
 
present, no change 
 
partial response   
50% improvement  
 
resolution   
 
 not present 
 
encephalopathy 
 
not present 
 
worsening  
 
 
new coma or deteriorating level of consciousness  
 
present, no change 
 
partial response   
50% improvement  
 
resolution   
 
 not present 
 
cord (transverse myelitis) 
 
not present 
 
worsening  
  
 new or worsening sensory and/or motor symptoms or signs 
 
present, no change 
 
partial response 
 any improvement in sensory and/or motor symptoms 
 
resolution  
  
 complete resolution, normal neurologic exam  
 
b) 
Peripheral  
 
cranial neuropathy 
 
not present 
 
worsening   
 
 
new one and/or worsening of an existing one 
 
present, no change 
 
partial response   
decrease in total number of cranial nerves involved if originally more than one 
and/or improvement in a single cranial nerve if only one is involved (e.g., ptosis 
less marked if III, improved sensation if V, improved motor strength if VII) 
 
resolution    
 
absence of any cranial neuropathy   
 
mononeuritis multiplex 
 
not present 
 
worsening  
  
 
new mononeuropathy or progression of existing mononeuropathy 
 
present, no change 
 
partial response  
improvement in sensory, motor, or reflexes, but not to normal in 3 months 
 
resolution  
 
 
normal motor, sensory, and reflex exam 
 
 
 


Protocol Version Date 7June 2016 
 
35 
 
Visit Date:  ___________________ 
Rifle Cont. 
 
 
 
 
 
Patient Study Code:  _________________ 
 
 
 
 
 
 
Patient History Number:  ______________ 
 
 
 
 
 
 
Patient Name:  _______________________ 
 
 
 
 
 
 
MD Initials:  ______________________ 
 
neuropathy (sensory or motor)  
 
not present 
 
worsening  
  
new sensory or motor neuropathy or progression of existing sensory neuropathy 
 
present, no change 
 
partial response   
improvement in sensory or motor symptoms but not to normal 
 
resolution  
 
normal sensory exam 
                                                                                                                      
 
2. 
Renal 
 
proteinuria 
 
not present   
 
worsening   
 
    a) if baseline proteinuria <500 mg/24 h then increase of 500 mg/24 h 
 
 
 
 
 
    b) if baseline proteinuria 500 mg/24 h then 100% increase  
 
no change 
 
partial response   
        improvement by 50% but not to normal value <500 mg/24 hr, do not count if 
reduction in proteinuria is considered due to reduction in GFR or the addition 
of ACE inhibitors  
 
resolution  
 
 
<500 mg/24 h, do not count if reduction in proteinuria is due to reduction in 
GFR or the addition of ACE inhibitors   
 
RBC 
 
not present 
 
worsening  
  
    a) if baseline 5-10, increase to >20   
 
 
 
 
 
    b) if baseline >10, increase by 200% 
 
present, no change 
 
partial response   
   50% reduction from baseline  
 
resolution    
 
  decrease to <5 RBC/hpf 
 
RBC casts 
 
not present 
 
worsening   
 
 
any new cast, or 
 
 
 
 
 
 
a) if baseline 1-10, increase to 20 or greater 
 
 
 
 
 
 
b) if baseline >10, 100% increase 
 
present, no change if baseline 1-10, no change means remains at 1-19     
 
partial response  
 
a) if baseline >10 must be 50% reduction 
 
resolution 
 
 
no RBC casts 
 
abnormal creatinine  
 
not present 
 
worsening   
 
 
a) increase >0.3 if baseline 1.5  
 
 
 
 
 
 
b) increase >0.5 if baseline >1.5  
 
no change 
 
partial response 
 
a) decrease of 0.5 if baseline 2.5  
 
 
 
 
 
 
b) decrease of 1.0 if baseline >2.5  
 
resolution  
 
 
<1.0 mg/dl 
 
 
 
 
Rifle Cont. 


Protocol Version Date 7June 2016 
 
36 
Visit Date:  ___________________ 
 
 
 
 
 
 
Patient Study Code:  _________________ 
 
 
 
 
 
 
Patient History Number:  ______________ 
 
 
 
 
 
 
Patient Name:  _______________________ 
 
 
 
 
 
 
MD Initials:  ______________________ 
 
abnormal Cr clearance 
 
not present 
 
worsening  
  
 
30% worsening  
 
present, no change 
 
partial response  
 
30% improvement  
 
resolution  
  
 
normal for body mass  
     
 
 
                                                                                                                  
 
3. 
Mucocutaneous 
 
photosensitivity 
 
not present 
 
worsening  
  
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution  
  
 
no lesions in 3 months 
 
malar rash 
 
not present 
 
worsening  
  
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution   
 
 
no lesions in 3 months 
 
discoid/follicular plugging  
 
not present 
 
worsening  
  
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution  
  
 
no lesions in 3 months 
 
bullous 
 
not present 
 
worsening  
  
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution   
 
no lesions in 3 months 
 
vasculitis 
 
not present 
 
worsening   
 
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution  
 
 
no lesions in 3 months 
 
 
Rifle cont. 


Protocol Version Date 7June 2016 
 
37 
Visit Date:  ___________________ 
 
 
 
 
 
 
Patient Study Code:  _________________ 
 
 
 
 
 
 
Patient History Number:  ______________ 
 
 
 
 
 
 
Patient Name:  _______________________ 
 
 
 
 
 
 
MD Initials:  ______________________ 
 
mucocutaneous ulcers 
 
not present 
 
worsening  
  
 
new or more frequent (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution  
  
 
no lesions in 3 months 
 
alopecia 
 
not present 
 
worsening  
  
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution  
  
 
no lesions in 3 months 
 
panniculitis 
 
not present 
 
worsening  
  
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution  
  
 
no lesions in 3 months 
 
angioedema/urticaria 
 
not present 
 
worsening  
  
 
new lesions or worsening (number, frequency, or distribution)  
 
present, no change 
 
partial response   
decrease by 50% (number, frequency, or distribution) 
 
resolution  
  
 
no lesions in 3 months 
                                                                                                                               
 
 
 
 
 
4. 
Musculoskeletal 
 
arthritis 
 
not present 
 
worsening  
 
 any new tender or swollen joint (even if synovitis in previous joints had 
improved)   
 
no change 
 
partial response  
50% reduction in tender and swollen joints 
 
resolution  
 
 no tender or swollen joints 
 
 
 
 
 
 
 
 


Protocol Version Date 7June 2016 
 
38 
Rifle Cont. 
                                                                                     Visit Date:  ___________________                        
 
 
 
 
        Patient Study Code:  ______________ 
 
Patient History Number:  ______________ 
Patient Name:  _______________________                      
                                                                                           MD Initials:  ______________________ 
 
myositis 
 
not present 
 
worsening  
  
 new myositis or increasing weakness in 2 muscle groups or increase of 50% 
in CPK and/or aldolase 
 
no change 
 
partial response  
50% improvement in CPK and/or aldolase and muscle strength within 3 
months 
 
resolution   
 
normal CPK and aldolase, normal strength 
 
 
tendinitis 
 
not present 
 
worsening  
  
 new tendinitis (even if previous tendinitis improved) or worsening of existing 
tendinitis.  Must be distinguished from the tender points of fibromyalgia. 
 
no change 
 
partial response  
50% improvement  
 
resolution   
 
no tendinitis 
                                                                                                                               
 
5. 
Cardiac 
 
pericarditis 
 
no change 
 
worsening  
 
 new pericarditis, worsening by echo of pre-existing pericarditis, or signs of 
cardiac tamponade (pulsus paradoxicus) 
 
no change 
 
partial response  
any improvement in symptoms 
 
resolution  
 
 no evidence of pericardial disease 
 
myocarditis 
 
not present 
 
worsening  
 
 new or worsening by echo and/or clinical symptoms or signs 
 
no change 
 
partial response  
improved symptoms and/or improved echo but not normal 
 
resolution  
 
 no symptoms, echo returns to baseline, enzymes normal 
 
valvular abnormalities 
 
not present 
 
worsening  
 
 
new murmur confirmed by echo or worsening valvular function by echo  
 
no change 
 
partial response   
reduction in valvular vegetations or valvular dysfunction by echo 
 
resolution  
  
 normal valvular function and integrity by echo 
 
pulmonary hypertension 
 
not present 
 
worsening  
 
 new onset, or increase of >20 mm Hg in PA pressure by either echo or 
arteriogram 
 
no change 
 
partial response  
decrease of 20 mm Hg in PA pressure by either echo or arteriogram 
 
resolution  
 
 normalization to <25 mm Hg in PA pressure by either echo or arteriogram  
 


Protocol Version Date 7June 2016 
 
39 
 
Rifle Cont.                                                                            Visit Date:  ________________________                        
 
 
 
 
        Patient Study Code:  _________________ 
 
Patient History Number:  ______________ 
Patient Name:  _______________________                      
                                                                                           MD Initials:  ______________________ 
                                                                                                                           
6. 
Pulmonary  
 
pleuritis 
 
not present 
 
worsening  
 
 new symptoms or any increase in frequency or severity of symptoms, or 
increase in pleural effusions 
 
no change 
 
partial response  
any improvement in symptoms and/or reduction in pleural effusions 
 
resolution  
 
 no signs or symptoms and nl CXR  
 
 
pneumonitis 
 
not present 
 
worsening  
  
 any new pneumonitis or any worsening in any pulmonary function tests or CXR 
or CT 
 
no change 
 
partial response  
any improvement in symptoms, PFTS, or CXR/CT 
 
resolution  
  
 no signs or symptoms and nl PFTs and CXR/CT 
 
hemorrhage 
 
not present 
 
worsening  
 
 any new hemorrhage or worsening of hemorrhage as assessed by symptoms or 
signs 
 
no change 
 
partial response   
improvement by symptoms or signs (e.g., CXR) 
 
resolution  
 
 asymptomatic and CXR returns to baseline 
                                                                                                                              
7. 
Gastrointestinal 
 
vasculitis 
 
not present 
 
worsening  
 
 new or worsening 
 
no change 
 
partial response   
any improvement by colonoscopy 
 
resolution  
 
 asymptomatic, guaiac neg, normal colonoscopy  
 
colitis  
 
not present 
 
worsening  
 
 any new or worsening symptoms 
 
no change 
 
partial response   
50% improvement in bowel movements and or decreased abdominal pain or 
blood loss 
 
resolution  
 
 asymptomatic, guaiac neg, normal colonoscopy  
 
 
serositis (peritonitis)  
 
not present 
 
worsening  
 
 any new symptoms; worsening of symptoms or increasing ascites by ultrasound   
 
no change 
 
partial response  
any improvement in symptoms, reduction of ascites by ultrasound 
 
resolution  
 
 asymptomatic and no ascites by ultrasound 
 
 
 
Rifle Cont. 


Protocol Version Date 7June 2016 
 
40 
 
pancreatitis 
 
not present 
    worsening  
any new symptoms; worsening of symptoms or increase of amylase or lipase        
    no change 
 
partial response  
any improvement in symptoms or amylase or lipase  
 
resolution  
 
 asymptomatic and normal amylase and lipase  
 
 
hepatitis 
 
not present 
 
worsening  
 
 any new or worsening of liver transaminases    
 
no change 
 
partial response  
any improvement in symptoms or liver transaminases  
 
resolution  
 
 asymptomatic and normal liver transaminases  
  
protein losing enteropathy 
 
not present 
 
worsening  
 
 any new or increasing symptoms or decreasing serum albumin (x2) 
 
no change 
 
partial response  
any improvement in serum albumin and decrease in frequency of bowel 
movements 
 
resolution  
 
 asymptomatic and normal serum albumin  
                                                                                                                                                                                                                
 
8. 
Hematologic 
 
splenomegaly 
 
not present 
 
worsening  
 
 any new or increase in size of spleen by physical exam or ultrasound   
 
no change 
 
partial response  
any reduction in size by physical exam or ultrasound 
 
resolution  
 
 asymptomatic and normal size by exam or ultrasound 
 
hemolytic anemia 
 
not present 
 
worsening  
 
 new hemolysis or decrease in HCT by 20% and lab confirmation of hemolysis 
 
no change 
 
partial response  
any improvement in HCT and decrease in reticulocyte count   
 
resolution  
 
 return to baseline HCT and nl retic count  
  
TTP 
 
not present 
 
worsening  
 
 any new or worsening features of TTP 
 
no change 
 
partial response  
improvement in smear, HCT, plt count, fever or neurologic status,  improvement 
in renal status 
 
resolution  
 
 normal HCT, normal plt, normal renal function, normal neurologic status, no 
fever 
 
leukopenia 
 
not present 
 
worsening  
 
 new to <3,000 or decrease of >25% from pre-existing leukopenic value  
 
no change 
 
partial response  
50% improvement  
 
resolution  
  
 >3,000  
  
Rifle Cont. 


Protocol Version Date 7June 2016 
 
41 
 
lymphopenia 
 
not present 
 
worse  
 
 
 new to <1,000 or 25% decrease from pre-existing lymphopenic value 
 
no change 
 
partial response  
50% improvement  
 
resolution  
 
 >1,000  
 
neutropenia 
 
not present 
 
worse  
 
 
 new to <1,800 or 25% decrease from pre-existing neutropenic value 
 
no change 
 
partial response  
50% improvement  
 
resolution  
 
 >1,800  
 
thrombocytopenia 
 
not present 
 
worsening  
 
 new to <100k or 25% decrease from pre-existing thrombocytopenia 
 
no change 
 
partial response   
50% improvement  
 
resolution  
 
 150k  
 
9. 
Constitutional 
 
fever 
 
not present 
 
worsening  
 
 new temperature to 38C 
 
present, no change 
 
partial improvement 
improvement with or without antipyretics for 1 wk   
 
resolution   
 
 
<38C on no antipyretics  
 
 
weight loss 
 
not present 
 
worsening  
 
 new involuntary loss of 5% in 1 month 
 
present, no change 
 
partial improvement 
weight gain but not to baseline or desired weight  
 
resolution   
 
 
no involuntary weight loss and either return to baseline or desired weight  
 
lymphadenopathy (palpable, >1 cm diameter) 
 
not present 
 
worsening  
 
 any new or increase in size and distribution of pre-existing lymphadenopathy 
not due to infection 
 
present, no change 
 
partial improvement 
any decrease in size and distribution  
 
resolution  
  
 no lymphadenopathy  
                                                                                                                                                                                                   
B. 
IMMUNE SYSTEM 
 
1. 
Autoantibodies 
 
anti-dsDNA 
 
not present 
 
worsening  
 
 
newly positive by any assay, or doubling of abnormal titer 
 
present, no change 
 
partial improvement 
50% reduction in titer  
 
resolution  
  
 absence of detectable anti-dsDNA abs by any assay  
 
Rifle Cont. 


Protocol Version Date 7June 2016 
 
42 
 
aPL 
 
not present  
 
worsening  
 
 newly positive by ELISA or new dRVVT (LAC), or doubling of previously 
abnormal ELISA value 
 
present, no change 
 
partial improvement 
50% reduction in titer of any isotype without increase in any other isotype 
 
resolution  
 
 dRVVT normal (no LAC), aCL IgG and IgM in normal range, anti-β2GP1 in 
normal range 
 
2. 
Abnormal complement 
 
not present 
 
worsening  
 
 a) reduction of 25% in C4 to an abnormal range  
 
 
 
 
 
 b) reduction of 25% in C3 to an abnormal range 
 
present, no change 
 
partial improvement 
50% improvement in either C3 or C4  
 
resolution  
 
a) normal C4 (unless C4 deficient) 
 
 
 
 
 
 b) normal C3 
 
                                                                                                                                                                                
Guidelines for interpretation of RIFLE 
 
 
In any given parameter: 
 
 
yes = 
partial response or complete response 
 
no = 
no change or worsening 
 
Outcomes: 
 
A. 
By patient 
 
 
Favorable: 
1. partial or complete resolution in at least one organ 
 
(winner) 
 
and 
 
 
2. no worsening in any organ 
 
 
Unfavorable: 
1. worsening in any organ 
 
(loser) 
 
B. 
By organ/category 
 
 
Favorable: 
1. partial or complete resolution 
 
 
Unfavorable: 
1. no change or worsening 
 
 
Additional data for outcome measure: 
 
 
Physician must rank organ systems he/she feels would be most important to respond favorably, e.g.: 
 
 
 
1. primary 
 
 
 
2. secondary 
 
 
 
a) 
 
 
 
b) 


Protocol Version Date 7June 2016 
 
43 
Appendix 6: SLEDAI  


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Protocol Version Date 7June 2016 
 
45 
Reference List 
 
 
(1)  Barr SG, Zonana-Nacach A, Magder LS, Petri M. Patterns of disease activity in systemic lupus 
erythematosus. Arthritis Rheum 1999 Dec;42(12):2682-8. 
 
(2)  Zonana-Nacach A, Barr SG, Magder LS, Petri M. Damage in systemic lupus erythematosus and its 
association with corticosteroids. Arthritis Rheum 2000 Aug;43(8):1801-8. 
 
(3)  Bernatsky S, Ramsey-Goldman R, Clarke AE. Revisiting the issue of malignancy risk in systemic 
lupus erythematosus. Curr Rheumatol Rep 2005 Dec;7(6):476-81. 
 
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