A Feasibility Study of "Early" Allogeneic Hematopoietic Cell Transplantation for Relapsed or Refractory High-Grade Myeloid Neoplasms
Phase: PHASE2
Conditions: Blasts 10 Percent or More of Bone Marrow Nucleated Cells, Chronic Myelomonocytic Leukemia-2, High Grade Malignant Neoplasm, Myelodysplastic Syndrome, Myelodysplastic Syndrome With Excess Blasts-2, Myeloid Neoplasm, Previously Treated Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Sponsor: University of Washington

Cover Page 
A feasibility study of "early" allogeneic 
hematopoietic cell transplantation for relapsed 
or refractory high-grade myeloid neoplasms 
NCT02756572 
Study Protocol with Statistical Analysis Plan 
Document date: August 25, 2021

FHCRC Protocol # 9567
-1-
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current version: August 13, 2021 
Previous version: June 25, 2019 
Title of Protocol:  
A feasibility study of “early” allogeneic hematopoietic cell transplantation for relapsed or refractory 
high-grade myeloid neoplasms 
Investigators List: 
Principal Investigator Professional Title 
Phone Number 
Mary-Elizabeth 
Percival, MD 
Assistant Professor of Medicine (Hematology), 
UW; Assistant Member, FHCRC 
206.606.1320 
Sub-Investigators 
Eli Estey, MD 
Professor of Medicine (Hematology); Member, 
FHCRC 
206.606.7176 
Stephanie Lee, MD 
Member, 
FHCRC; 
Professor 
of 
Medicine 
(Oncology) UW 
206.667.6190 
Kelda Gardner, PA-
C 
206.606.8307 
Pam Becker, MD, 
PhD 
Professor 
of 
Medicine 
(Hematology), 
UW; 
Member, FHCRC 
206.616.1589 
Roland Walter, MD, 
PhD 
Associate Member, FHCRC; Associate Professor 
of Medicine (Hematology) 
206.667.3599 
Brenda Sandmaier, 
MD 
Member, 
FHCRC; 
Professor 
of 
Medicine 
(Oncology), UW 
206.667.4961 
Bart Scott, MD 
Associate Member, FHCRC; Associate Professor 
of Medicine (Oncology), UW 
206.667.1990 
Biostatistician: 
Megan Othus, PhD 
Research Staff: 
Cody Hammer 
Research Manager 
206.606.1286 
IRO REC'D AUG 16 2021
FHCRC IRB Approval  
AUG 25 2021 
Document Released Date

F H C R C Pr ot o c ol # 9 5 6 7
 
-2-  
 
T A B L E O F C O N T E N T S  
1. I N T R O D U C TI O N  ............................................................................................................................. 4 
2. B A C K G R O U N D  .............................................................................................................................. 4 
2. 1 A p pr o a c h t o r el a p s e d/r efr a ct or y ( R/ R) m y el oi d n e o pl a s m s at U W/ F H C R C  ...................... 4 
2. 2 Eff e cti v e n e s s of H C T i n R/ R A M L  .......................................................................................... 4 
2. 3  F e a si bilit y of H C T a s t h er a p y of R/ R A M L  ........................................................................... 5 
2. 4 E x p eri e n c e wit h e arl y H C T at ot h er c e nt er s  ......................................................................... 6 
2. 5 R ati o n al e f or St u d y D e si g n at U W/ F H C R C  ........................................................................... 9 
3. O B J E C TI V E S  ................................................................................................................................ 1 1  
4. E LI GI BI LI T Y  .................................................................................................................................. 1 1  
4. 1 I n cl u si o n a n d e x cl u si o n crit eri a at t h e ti m e of e nr oll m e nt  ............................................... 1 1  
4. 2 I n cl u si o n a n d e x cl u si o n crit eri a at t h e ti m e of tr a n s pl a nt  ................................................ 1 3  
5. D O N O R S E L E C TI O N  ................................................................................................................... 1 3  
5. 1  
D o n or e v al u ati o n  ................................................................................................................ 1 4  
 H L A -m at c h e d r el at e d or u nr el at e d d o n or. D o n or s m u st b e:  ............................................... 1 4  
 H L A -mi s m at c h e d u nr el at e d d o n or.  ...................................................................................... 1 4  
5. 2 E x p e ct e d ti m eli n e of c h e m ot h er a p y a n d tr a n s pl a nt .......................................................... 1 4  
6. P R O T O C O L R E GI S T R A TI O N  ..................................................................................................... 1 5  
7. T R E A T M E N T P L A N: B RI D G E C H E M O T H E R A P Y WI T H G C L A M  ............................................ 1 5  
7. 1 Bri d g e c h e m ot h er a p y  ............................................................................................................ 1 5  
7. 2 Dr u g I nf or m ati o n o n G -C S F ( Gr a n ul o c yt e c ol o n y -sti m ul ati n g f a ct or)  ............................ 1 6  
7. 3 Dr u g I nf or m ati o n o n Cl a dri bi n e ( 2 -c hl or o -2’ -d e o x y a d e n o si n e, 2 -C d A)  .......................... 1 7  
7. 4 Dr u g I nf or m ati o n o n C yt ar a bi n e ( C yt o si n e ar a bi n o si d e)  .................................................. 1 7  
7. 5 Dr u g I nf or m ati o n o n Mit o x a ntr o n e  ...................................................................................... 1 9  
8. T R E A T M E N T P L A N: C O N DI TI O NI N G A N D A L L O G E N EI C T R A N S P L A N T  ............................ 1 9  
8 . 1 D o n or i d e ntifi c ati o n ............................................................................................................... 2 0  
8. 2 S e p ar at e H C T c o n s e nt  .......................................................................................................... 2 0  
8. 3 Pr e -tr a n s pl a nt e v al u ati o n...................................................................................................... 2 0  
8. 4  
Tr e at m e nt pl a n f or c o n diti o ni n g a n d all o g e n ei c H C T  ................................................... 2 0  
8. 4. 1 D o n or s  ............................................................................................................................... 2 0  
T A B L E 4: T y pi c al m o bili z ati o n f or M at c h e d R el at e d D o n or s  .................................................... 2 1  
8. 4. 2 Tr e at m e nt o pti o n s f or c o n diti o ni n g a n d i m m u n o s u p pr e s si o n o pti o n s f or r e ci pi e nt s  ........ 2 1  
 R E GI M E N 1: Fl u/ M el c o n diti o ni n g o pti o n f or p ati e nt s ≤ 5 5 y e ar s wit h 1 0/ 1 0 m at c h e d d o n or 
(r el at e d or u nr el at e d) .................................................................................................................. 2 1  
 R E GI M E N 2: Fl u/ M el c o n diti o ni n g f or p ati e nt s > 5 5 y e ar s or wit h si g nifi c a nt c o -m or bi diti e s 
wit h 1 0/ 1 0 m at c h e d d o n or (r el at e d or u nr el at e d)  ....................................................................... 2 1  
 R E GI M E N 3: Fl u/ M el c o n diti o ni n g o pti o n f or p ati e nt s ≤ 5 5 y e ar s wit h 9/ 1 0 d o n or  ............ 2 2  
 R E GI M E N 4: Fl u/ M el c o n diti o ni n g f or p ati e nt s > 5 5 y e ar s or wit h si g nifi c a nt c o -m or bi diti e s 
wit h 9/ 1 0 d o n or  ........................................................................................................................... 2 2  
8. 5 C o n diti o ni n g r e gi m e n  ............................................................................................................ 2 3  
8. 6  A c ut e G V H D pr o p h yl a xi s  ..................................................................................................... 2 4  
9. S U P P O R TI V E C A R E  .................................................................................................................... 2 5  
1 0. P A TI E N T R E P O R T E D O U T C O M E S A N D R E S O U R C E U TI LI Z A TI O N  ................................... 2 5  
1 1. G UI D E LI N E S F O R S E RI O U S A D V E R S E E V E N T R E P O R TI N G  ............................................. 2 6  
1 1. 1 E x p e dit e d r e p orti n g r e q uir e m e nt s.  .................................................................................... 2 6  
1 1. 2 D efi niti o n s  ............................................................................................................................. 2 6  
1 2. S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................................... 2 9  

FHCRC Protocol # 9567 
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12.1Sample size calculation ....................................................................................................... 29 
12.2 Endpoint definitions ............................................................................................................ 30 
12.3 Analysis plan ........................................................................................................................ 31 
13. DATA AND SAFETY MONITORING PLAN .............................................................................. 31 
14. REFERENCES ............................................................................................................................ 32 

FHCRC Protocol # 9567 
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1. INTRODUCTION 
Patients with relapsed/refractory (R/R) high-grade myeloid neoplasms remain a very challenging 
population to treat. Though the goal for patients being treated with curative intent is to undergo 
allogeneic hematopoietic cell transplant (HCT), many patients never reach this milestone. 
Chemotherapy alone is highly unlikely to cure R/R patients. The goal of this study is to administer 
bridge chemotherapy (with GCLAM) and then, before response to chemotherapy is known, to 
perform “early” allogeneic hematopoietic cell transplantation with a related or unrelated donor. This 
combination of bridge chemotherapy has been used at other centers in the US and Europe, as 
described in Section 2: Background, and we propose this study to evaluate the feasibility of this 
approach at UW/FHCRC. We also plan to follow patient-reported outcomes and resource utilization 
data for participants. 
 
2. BACKGROUND 
 
 
2.1 Approach to relapsed/refractory (R/R) myeloid neoplasms at UW/FHCRC 
“Resistance” manifested as either failure to enter complete remission (CR) or as relapse from CR is 
the main cause of death in high-grade myeloid neoplasms, the most common of which is acute 
myeloid leukemia (AML).1 The most common approach to resistant AML is use of “salvage” 
chemotherapy to induce remission defined as a marrow with < 5% blasts either accompanied (CR) 
or not (CRp/CRi) by blood count recovery and preferably unaccompanied by measurable residual 
disease (MRD). After remission is achieved, allogeneic HCT is pursued as patients are thought to 
be otherwise very likely incurable.2 Allogeneic HCT is used only infrequently as initial therapy of R/R 
AML. From 2008-2015, 689 UW/FHCRC patients received 1087 induction attempts for R/R AML. 
Only 73 of the 689 patients received involved initial HCT; that is, only 11% of all patients had 
allogeneic HCT as their “first salvage” (initial treatment for R/R AML), the time when treatment, 
including HCT, is presumed mostly likely to be successful. The median OS of this subset was 253 
days, and 10% of the 73 patients had documented survival >5 years with multiple other patients still 
alive without relapse. Ultimately, 227 total R/R AML patients proceeded to undergo HCT as part of 
their salvage treatment. Thus, a very small proportion of patients with R/R AML proceed directly to 
HCT rather than receiving salvage chemotherapy. Although it might be supposed that this 
infrequency reflects lack of suitable donors, data presented below indicate this is not the case. 
 
2.2 Effectiveness of HCT in R/R AML  
 
The relatively infrequent use of HCT as initial therapy of R/R AML contrasts with data suggesting 
HCT is more effective than chemotherapy in this setting. In 1992 Clift et al. reported that 26 (21%) 
of 126 patients (median CR duration about 7 months) receiving myeloablative HCT for untreated first 
relapse of AML were living 2 to 17 years later.3 This result appears better than seen with use of 
chemotherapy as initial treatment of first relapse. For example Breems et al. reported a 5-year 
survival rate of 12% in 270 similar patients (all age < 60 years) whose CR1 duration was 7-18 
months.4 MD Anderson data indicate that, similar to FHCRC, only 10% of patients (n = 285) received 
HCT as initial treatment for refractory AML. Follow-up data were available for the 149 of the 257 who 
initially received chemotherapy rather than HCT, with 15 of the 149 subsequently receiving HCT. 
There was an obvious survival advantage for the HCT approach (see graph below) that persisted 
after accounting for age, cytogenetics and type of AML (de novo vs. secondary).5 Another 
retrospective analysis from MD Anderson attempted to quantify the survival benefit for patients 
receiving HCT not just limited to primary refractory patients. Unadjusted analysis showed 
significantly longer survival in patients who underwent HCT in a 396 patient cohort, both in patients 
who had and hadn’t achieved a CR after salvage.6 Thus, observational data suggest that use of HCT 

FHCRC Protocol # 9567 
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immediately for R/R AML may lead to better survival than the more standard approach of trying to 
induce a CR first, then proceeding to HCT. 
 
FIGURE 1: Disparity in overall survival between primary refractory AML patients who receive 
chemotherapy alone or who receive allogeneic transplantation. 
 
2.3  Feasibility of HCT as therapy of R/R AML 
 
The results described above are likely affected by selection bias since patients who receive HCT as 
initial therapy for R/R AML may be, in ways that are difficult to quantify, more likely to do well than 
patients who receive chemotherapy. The only way to eliminate this bias is through randomization 
between early HCT and the more usual (“late”) strategy of HCT once CR after salvage chemotherapy 
is confirmed. The benefit/risk ratios of early and late HCT approaches seem plausibly similar. In 
favor of a late approach are data indicating that relapse rates following HCT increase with blast 
percentage (including MRD), raising the possibility of exposing patients to the mortality/morbidity of 
HCT despite a substantial probability of later relapse. There is also the belief that leukemia must be 
reasonably under control to avoid an early relapse before the graft-versus-leukemia effect has time 
to work, generally thought to be at least 3 months. Conversely, administering chemotherapy and 
awaiting documentation of complete response before HCT, and if not in remission, giving more 
chemotherapy, risks development of complications that would reduce the probability of subsequent 
HCT and, based on the FHCRC data described above has had only a 25% (102/403) chance of 
producing CR without MRD. It is unknown whether salvage chemotherapy itself contributes to better 
outcomes, either as a prognostic test identifying patients with truly refractory disease who should not 
undergo any additional therapy or as a temporizing treatment to reduce disease burden and increase 
the likelihood of transplant success by giving the graft-versus-leukemia effect time to develop. Only 
a randomized trial will provide information about the best treatment option: the current approach of 
salvage chemotherapy, followed by observation of response, then HCT if CR or CRp/CRi vs. the 
proposed approach of administering re-induction chemotherapy followed by conditioning therapy 
and “early” allogeneic HCT as soon as possible without awaiting confirmation of CR. 
 
However before embarking on a relatively large randomized study we felt it advisable to gain some 
confidence that early HCT is feasible at FHCRC. Early HCT will require that donors be identified and 

FHCRC Protocol # 9567 
-6- 
 
be available quickly once R/R AML had been diagnosed. FHCRC data over a 2 year period indicate 
that under standard conditions 70 patients already had available donors when they were found to 
have R/R AML without any additional search requirements, although only 18 of these 70 (26%) 
received HCT. In addition, the related and unrelated donor search coordinators have developed an 
“ultra-rapid search” procedure and are confident they can screen related donors and if necessary, 
identify unrelated donors to allow HCT within 60 days of re-induction chemotherapy. These data 
suggest that lack of available donors would not be rate limiting in a feasibility study of early HCT. 
Also affecting feasibility are the possibilities that patients’ medical conditions may not allow HCT and 
the transplant center infrastructure might not be able to accommodate the greater workload 
accompanying accelerated schedules required for early HCT. Patients, families and physicians 
might not be willing to proceed to early HCT. The ability to perform early HCT might be increased if 
re-induction chemotherapy is allowed with the intent to proceed to transplant as early as possible, 
ideally <60 days after diagnosis, irrespective of the marrow status (CR vs. residual disease vs. 
refractory disease). 
 
2.4 Experience with early HCT at other centers 
 
Experience of early or “pre-emptive” HCT has come largely from Germany, where chemotherapy 
has been used as a bridge to allogeneic transplantation. One of the first groups to describe the 
approach enrolled 103 relapsed/refractory patients with a matched related or unrelated donor 
available; patients received FLAMSA induction chemotherapy (fludarabine, amsacrine, and 
cytarabine) from days -12 to -9 followed immediately by a reduced intensity conditioning regimen 
with 4 Gy total body irradiation day -5, cyclophosphamide on days -4 and -3, and rabbit antithymocyte 
globulin from days -4 to -2. The complete remission rate was 91.2% and the median OS was 16.4 
months, with 32% of patients alive at 4 years of follow-up.7 
 
Stölzel et al. investigated this approach, transplanting 95 patients during chemotherapy-induced 
aplasia.8 Donors were already identified, and median time from diagnosis to HCT was 36 days (29 
days for the 29 patients with sibling donors and 36 days for the 66 patients with unrelated donors.) 
30 of the 95 patients had relapsed AML (57% with CR durations < 1 year) and 65 were newly-
diagnosed but at “high risk” based on inadequate blast clearance after chemotherapy in 47 patients 
and/or cytogenetics/molecular features in 18 patients. 52 of the 95 patients received 1 cycle and 43 
received 2 cycles of induction/salvage chemotherapy prior to HCT in aplasia: the median marrow 
blast count was 6% (0-80%) prior to HCT. 71 of the patients received conditioning using fludarabine 
(30mg/m2 daily day -6 to -2) and melphalan (150mg/m2 day -2). The post-HCT CR rate was 86%. 
Survival (FIGURE 2, panel a) and EFS (Figure 2, panel b) were similar in the 18 high-risk patients 
in first CR and the 47 primary refractory patients but was also 25-30% in the 30 relapsed patients.  
Relapse rates appeared relatively low at 100 days and 2 years (Figure 2, panels c and d), as did 
NRM (Figure 2, panel e at 100 days, panel f at 2 years). AML status at HCT was the principal 
predictor of outcome (TABLE 1).  
 
 
 

FHCRC Protocol # 9567 
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FIGURE 2. Stölzel et al5. Panels: a) survival; b) event-free survival; c) relapse at 100 days; d) 
relapse at 2 years; e) non-relapse mortality at 100 days; f) non-relapse mortality at 2 years. 
 
 
   

FHCRC Protocol # 9567 
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TABLE 1. Univariate analysis demonstrating effects of variables on event-free survival and overall 
survival as demonstrated by Stölzel et al8. The only factor significantly influencing OS is AML 
status at the time of treatment (p = 0.048); notably other factors, including percentage of BM blasts 
prior to HCT, did not significantly affect outcomes. 
 
 
 
 
TABLE 1 
 
Event-free Survival 
Overall Survival 
n 
HR (95% CI) 
p-value 
HR (95% CI) 
p-value 
Age at HCT (years) 
  <40 (reference) 
  40–60 
  >60 
 
23 
52 
20 
 
1 
1.77(0.90–3.48) 
1.08(0.45–2.62) 
 
 
0.10 
0.86 
 
1 
1.82(0.92–3.60) 
1.11(0.46–2.69) 
 
 
0.09 
0.81 
AML Status 
  Non-Relapsed primary refractory (ref) 
  Relapsed 
  Non-Relapsed other 
 
47 
30 
18 
 
1 
1.90(1.05–3.43) 
0.98(0.46–2.11) 
 
 
0.085 
 
1 
1.93(1.06-3.51) 
0.82(0.37-1.82) 
 
 
0.048 
Number of Ara-C cycles 
  ≤2 (reference) 
  >2 
 
84 
11 
 
1 
1.53(0.69–3.39) 
 
 
0.30 
 
1 
1.59(0.72–3.53) 
 
 
0.25 
Cytogenetic risk 
  Standard-risk (reference) 
  High-risk 
 
46 
49 
 
1 
1.19.(0.70–
2.02) 
 
 
0.52 
 
1 
1.27(0.74–2.16) 
 
 
0.39 
FLT3-ITD mutation status 
  FLT3-ITD negative (reference) 
  FLT3-ITD positive 
 
48 
18 
 
1 
1.32(0.63–2.77) 
 
 
0.46 
 
1 
1.34(0.63–2.81) 
 
 
0.45 
Bone marrow blasts prior to HCT 
  <20% (reference) 
  ≥20% 
 
45 
21 
 
1 
0.71(0.33–1.51) 
 
 
0.37 
 
1 
0.76(0.36–1.62) 
 
 
0.48 
HCT-CI 
  HCT-CI 0 (reference) 
  HCT-CI 1–2 
  HCT-CI >2 
 
30 
43 
22 
 
1 
1.29(0.69–2.41) 
1.47(0.70–3.08) 
 
 
0.43 
0.31 
 
1 
1.24(0.66–2.32) 
1.56(0.74–3.29) 
 
 
0.51 
0.24 
Donor type 
  Matched related donor (reference) 
  Matched unrelated donor 
  Partially matched unrelated donor 
 
29 
38 
28 
 
1 
1.80(0.92–3.53) 
1.39(0.67–2.88) 
 
 
0.09 
0.38 
 
1 
1.89(0.95–3.76) 
1.54(0.73–3.27) 
 
 
0.07 
0.26 

FHCRC Protocol # 9567 
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The same authors have recently updated their experience with early HCT in R/R AML by performing 
a larger multicenter trial with a standardized re-induction and conditioning regimen.9 They gave 
clofarabine + ara-C (1 g/m2 daily X 5) to 84 patients, median age 61 (43 relapsed after a median 
CR1 duration of 6 months, 41 refractory to initial therapy) with the intent of proceeding to HCT as 
soon as possible, including in aplasia after a day 15 marrow. 26% of the patients had < 5% blasts 
on day 15. 2/3 of the patients (56/84) received HCT: 53 using blood as stem cell source, 10 with 
HLA identical donors, 30 with well-matched unrelated donors, and 16 with partially matched 
unrelated donors. 39 of the 84 had a donor identified prior to enrollment; 32 of these 39 received 
HCT a median of 29 days after enrollment as did 24 of the 45 without a donor identified at enrollment 
at a median of 37 days. Conditioning was clofarabine (30mg/m2 days minus 6 to minus 3) + 
melphalan (140mg/m2 on day minus 2).  
 
With this early approach to HCT, 60% (50/84) attained CR which included CR, CRi, and CR with > 
95% donor chimerism. With a median follow-up of 25 months, 2-year probabilities were 52% for 
survival, 43% for EFS, 26% for relapse, and 23% for NRM. Survival was poorer in patients age > 55 
(34%) than for younger patients (67%) but did not appear influenced by whether disease was 
relapsed or refractory, or by European Leukemia Network (ELN) risk group at enrollment. Likewise 
EFS was not noted to be affected by donor type or type of CR following HCT but was reported longer 
in patients with < 5% blasts 15 days after beginning induction chemotherapy (48% vs 31%). By day 
100 after HCT 50% of patients had developed acute GVHD, 23% had grade 3-4 acute GVHD; 58% 
developed chronic GVHD, which was severe in 6%. The reported response and survival rate appear 
considerably better than might be expected with a standard approach in which HCT is given only 
after response is established. 
 
In the US, Chen et al reported 30 patients with high-risk clinical features who underwent early (within 
4 weeks of reinduction chemotherapy) HCT before count recovery and compared them to 42 patients 
with standard risk features who only proceeded to HCT more than 4 weeks after chemotherapy and 
with count recovery.10 Survival and EFS were similar suggesting that early HCT was no more 
dangerous or less successful than standard HCT (performed after CR is established), despite the 
early transplant group having higher risk clinical features. The authors noted that more patients in 
the high risk group would proceed to potentially curative HCT using their approach.10 
 
2.5 Rationale for Study Design at UW/FHCRC 
Considerable discussion was held among leukemia and transplant physicians at UW/FHCRC and 
Roswell Park in the fall of 2015 regarding multiple aspects of the trial, and the consensus decisions 
and rationale will be described in this next section. The first issue was the study population (see 
section 3 for eligibility criteria and Table 2 for a description of what prior regimens patients may 
have received before entering this study). Patients with relapsed AML and refractory AML are the 
target population, though we will also include patients with high-grade myeloid neoplasms such as 
MDS-EB2 and CMML in our study population (as long as they had ≥10% blasts at initial diagnosis). 
Refractory AML patients will have ≥5% abnormal blasts following one cycle of “7+3” or more 
“intensive” induction chemotherapy, although some do not consider AML refractory unless 
unresponsive to two cycles of induction. SWOG data indicate that the proportion of patients 
achieving CR on a 2nd 7+3 (43%) is similar to the proportion doing so following a first course 
(49%). These data support continuing chemotherapy for patients who do not enter a remission 
after their first course, rather than stopping treatment due to “refractory disease.” However, these 
data do not imply patients should receive a second 7+3 if potentially better therapy is available, for 
example early HCT as intended here. Furthermore, the disparity in CR rates following a first and 
second courses may be greater with higher intensity regimens [894/1468 (61%) first course, 
38/129 (29%) second course, MD Anderson data].11 Data are insufficient to evaluate differences 
between CR rates on a first and second GCLAM but the definition of “refractory” AML may depend 
on intensity of induction regimen. Since patients with relapsed AML or failure to enter a 

FHCRC Protocol # 9567 
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hematologic CR after the first induction cycle are generally referred for allogeneic HCT, the 
consensus was to define “refractory” disease as failure to enter remission after one cycle for the 
purposes of trial eligibility. Please note that patients who meet study eligibility by virtue of this 
criterion will automatically get a cycle of GCLAM prior to HCT. 
 
We also discussed which relapsed patients would be eligible for the study, since there was 
concern that multiple courses of GCLAM would increase toxicity and potentially TRM. We were 
also concerned that in patients with a short duration of CR (< 6 months) following GCLAM , the 
likelihood of response to GCLAM followed by early HCT was so low as to make the potential risk 
greater than the potential benefit.4 Therefore, we chose to exclude patients who had received 2 
GCLAM chemotherapy regimens as part of induction, and had a short duration of first CR (<6 
months; see inclusion/exclusion criteria below).  
 
We also reached consensus regarding the chemotherapy to be used as a bridge prior to subsequent 
transplant conditioning regimen. Although allowing physician discretion for AML chemotherapy and 
HCT conditioning regimen was discussed, it was felt use of only 1 chemotherapy and 1 transplant 
regimen would facilitate interpretation of the data. The bridge chemotherapy regimen will be GCLAM, 
a high-dose cytarabine containing regimen which is the most widely used regimen for patients with 
relapsed/refractory AML at UW/FHCRC. The consensus transplant regimen utilizes fludarabine and 
melphalan, a so-called “reduced intensity” regimen, because higher intensity regimens were found 
to be too toxic in other studies. Although recent results from a randomized trial of myeloablative vs. 
reduced intensity conditioning for AML/MDS found better survival in the group randomized to 
myeloablative conditioning,12 patients had to be in a documented remission and presumably were 
not transplanted early after a reinduction attempt as proposed in this protocol. Additionally, only 20% 
of patients in the reduced-intensity arm received fludarabine/melphalan, the conditioning regimen 
specified in the current protocol, with the majority receiving fludarabine/busulfan conditioning. A 
recent retrospective review suggested that fludarabine/melphalan has a decreased relapse risk 
compared to fludarabine/busulfan conditioning.13 We appreciate that some younger patients, 
particularly those with a low HCT-CI score,14,15 may not be enrolled in this study or may be taken off 
study by their treating physicians, who may feel that the risk of relapse following a reduced intensity 
conditioning approach may be unacceptably high. However, utilizing a reduced intensity regimen 
may also broaden the pool of potentially eligible patients by allowing older patients to be considered 
for transplantation and thus balance the decreased enrollment of younger patients. The consensus 
opinion from FHCRC faculty is that a reduced intensity regimen is necessary to minimize the risk of 
excess TRM when given soon after AML chemotherapy (see Table 4 below for stopping rule based 
on TRM for the proposed study). 
 
Additionally, discussion occurred about whether alternative donor transplants (i.e. cord blood or 
haploidentical donors) should be allowed. For this relatively small feasibility study, we chose to 
include only patients with a matched related or matched unrelated donor available to keep the 
population relatively homogeneous and allow standardization of the conditioning regimen across all 
patients. In the planned larger, randomized trial to follow, we will consider including alternative donor 
transplants, particularly since the time to donor identification can be quite short for cord blood and 
haploidentical donors. Notably, a group from the University of Chicago has performed early HCT for 
a variety of hematologic malignancy primarily used cord blood donors.16 
 
Some physicians believed transplant occurring close to 60 days following the start of GCLAM should 
not be considered “early” transplant. Because of the problems identifying and mobilizing a donor 
within a shorter time period, we feel that 60 days is a reasonable cut point for this feasibility study, 
recognizing that the goal of transplantation is closer to 21-30 days. Data from UW/FHCRC showed 
that among 105 patients who achieved CR after 1st salvage, only about 20% (20 of 105) went to HCT 
within 2 months (with the remaining 80% going to HCT by 6 months after re-induction). Thus, 
proceeding to HCT within 60 days would represent considerable acceleration over current practice. 

FHCRC Protocol # 9567 
-11- 
 
 
We added a secondary endpoint to evaluate the outcomes of patients who ultimately undergo HCT, 
but had been taken off study at some point and would therefore count a “failure” for the purposes of 
this study, because they didn’t receive the prescribed conditioning regimen with a pre-specified 
donor type. However, we will collect information on these patients that will inform treatment plans for 
any future trial. These patients may include: 1) younger, fit patients who may be taken off study to 
receive myeloablative conditioning; 2) patients without a matched related or unrelated donor who 
may undergo an alternative donor transplant; or 3) patients who undergo a transplant outside of the 
60-day window dictated by the study. 
 
Due to the fact that several patients were considered “failures” or not able to enroll on the study at 
all because they only had 9/10 matched donors, we discussed the possibility of adding 9/10 matched 
donors as another potential donor source if a matched sibling donor or matched unrelated donor is 
unavailable. The PI had multiple discussions with the transplant team and with the study-specific 
steering committee about the feasibility and logistics of this change. If immunosuppression is 
prolonged to decrease the risk of GVHD, outcomes are similar for 9/10 donors.17-19 Therefore, 9/10 
donors will be added to the potential donor sources for patients on this trial. 
 
3. OBJECTIVES 
 
Principal objective 
1. To evaluate the feasibility of “early” allogeneic hematopoietic cell transplant (HCT) for 
patients with relapsed or refractory (R/R) high-grade myeloid neoplasms.  The feasibility of 
this trial is defined in Section 12.1. 
 
Secondary objectives 
1. Estimate relapse-free survival (RFS), acute GVHD, TRM, event-free survival (EFS), overall  
survival (OS), and complete remission (with or without measurable disease) among 
patients who receive early HCT. Endpoints applicable to patients who don’t receive early 
transplant (survival endpoints and remission) will be also be estimated for all patients 
enrolled on the study. 
2. Assess factors that distinguish patients who receive early HCT from those who do not 
3. Demonstrate the feasibility of collecting patient-reported outcomes and resource utilization 
data for trial participants 
4. Describe the outcomes of patients enrolled who went on to allogeneic HCT off-study 
 
Exploratory objectives 
1. Compare RFS, EFS, OS, acute GVHD, and TRM between patients in the feasibility study 
and matched patients who were transplanted with standard scheduling 
 
 
4. ELIGIBILITY 
 
4.1 Inclusion and exclusion criteria at the time of enrollment 
Inclusion criteria (enrollment): 
1. Age 18-75 years old (inclusive) 
2. Relapsed or refractory high-grade myeloid neoplasms, defined as having a blast count of 
≥10% blasts at the time of initial diagnosis.  Examples include MDS (EB-2, with ≥10% blasts 
at initial diagnosis), AML, or chronic myelomonocytic leukemia (CMML-2).  Standard 
definitions of relapse will apply (i.e., characterized by ≥5% abnormal blasts or blast 
equivalents as assessed by multiparameter flow cytometry or morphologic examination; 
peripheral blood blasts or blast equivalents; or extramedullary granulocytic sarcoma, per ELN 

FHCRC Protocol # 9567 
-12- 
 
2017 guidelines). Bone marrow aspirate/biopsy will be accepted if performed outside 
UW/FHCRC. Determination of disease status should occur within 30 days of signing informed 
consent.  
a. R/R high-grade myeloid neoplasm following intensive induction chemotherapy.  
Relapsed high-grade myeloid neoplasm: Patients will be classified as relapsed if 
they have ≥5% blasts after being in a CR following treatment for high-grade myeloid 
neoplasm.  Refractory high-grade myeloid neoplasm: Patients may be classified 
as refractory if they have received at least one prior cycle of induction chemotherapy, 
whether with GCLAM or another regimen. 
i. Patients may have received up to two courses of intensive induction 
chemotherapy during initial treatment prior to enrollment on this protocol. For 
example, patients who have received two courses of GCLAM (or similar) 
chemotherapy, 
with 
most 
recent 
high-dose 
cytarabine-containing 
chemotherapy >6 months ago and CR lasting >6 months, will be eligible for 
this protocol. Regimens “similar to GCLAM” would include cytarabine at doses 
of 1g/m2 for at least 5 doses; examples of regimens “similar to GCLAM” would 
be GCLA, FLAG, and FLAG-ida. However, patients who received more than 
two courses of GCLAM (or similar) chemotherapy, or patients who received 
two courses of GCLAM and had CR lasting <6 months, would not be eligible. 
See TABLE 2 for examples of eligible prior treatment by disease status. 
b. R/R high-grade myeloid neoplasm following less intensive induction chemotherapy. 
Patients who have received at least three cycles of treatment with a hypomethylating 
agent (HMA; such as azacitidine or decitabine) and still have ≥10% blasts will be 
eligible for the study (they will be considered refractory).  Similarly, patients who have 
received three or more cycles of HMA therapy who have had a response (e.g., 
achieving CR with <5% blasts), but who then progress using standard definitions of 
relapse, will also be eligible (they will be considered relapsed). 
3. Potentially eligible for reduced intensity conditioning based on known organ function  (formal 
organ function testing may occur after consent) 
4. Caregiver capable of providing post-HCT care 
5. Written informed consent 
 
Exclusion criteria (enrollment): 
1. Prior allogeneic HCT 
2. More than two prior courses of induction chemotherapy 
3. Relapse after MRD-negative CR within 3 months of most recent GCLAM chemotherapy 
4. Low likelihood of being eligible for reduced intensity conditioning HCT based on known 
information 
a. Cardiac ejection fraction<40% or symptomatic coronary artery disease or 
uncontrolled arrhythmia, as assessed by MUGA or TTE within previous 3 months and 
since the most recent anthracycline exposure 
b. DLCOc <40% or FEV1<50% 
c. Estimated GFR < 40 ml/min 
d. Need for supplemental oxygen 
e. Direct bilirubin or ALT >2 x upper limit of normal, unless these abnormalities are 
thought to be related to Gilbert’s disease or leukemic infiltration of hepatic 
parenchyma 
5. Known HIV positivity 
6. Pregnant or nursing (to be confirmed with quantitative HCG testing) 
7. Invasive solid tumor within 5 years. Non-melanoma skin cancer or in situ malignancies are 
allowed. 
8. Evidence of serious uncontrolled infection 
9. ECOG of 3 or 4 

FHCRC Protocol # 9567 
-13- 
 
 
TABLE 2. Sample algorithm to determine eligibility for protocol for R/R high-grade myeloid 
neoplasm patients who received intensive induction chemotherapy. See Inclusion Criteria for 
details about other regimens considered similar to GCLAM. We have some institutional data for 
patients who have received two courses of GCLAM, but essentially no experience giving three 
consecutive courses of GCLAM, so patients who have received more than two courses prior to 
enrollment on this protocol are ineligible. 
 
Status of disease 
Induction #1 
Induction #2 
Eligible for 
enrollment 
on 9567? 
Refractory 
GCLAM or similar 
GCLAM or similar 
No 
Refractory 
GCLAM or similar 
n/a 
Yes 
Refractory 
7+3 or similar 
GCLAM or similar 
Yes 
Refractory 
7+3 or similar 
7+3 or similar 
Yes 
Relapsed 
GCLAM or similar 
GCLAM or similar 
Possibly* 
Relapsed 
7+3 or similar 
GCLAM or similar 
Yes 
Relapsed 
7+3 or similar 
7+3 or similar 
Yes 
Relapsed 
GCLAM or similar 
n/a 
Yes 
Relapsed 
7+3 or similar 
n/a 
Yes 
*A patient may potentially be eligible if they had received two cycles of GCLAM chemotherapy >6 
months prior to relapse (see Inclusion Criteria 2ai for details). 
 
4.2 Inclusion and exclusion criteria at the time of transplant 
For patients eligible for transplantation, the pre-transplant will be performed per standard practice 
guidelines, and will include the following inclusion/exclusion criteria at a minimum. 
 
Inclusion criteria (transplant): 
1. Identified donor (see DONOR SELECTION below for further details) 
a. Matched related or unrelated (one allele mismatch in HLA-A, B, or C OK) donor 
according to institutional standards 
b. Unrelated volunteer donor who is mismatched with the recipient (i.e. 9/10 match) 
2. Caregiver capable of providing post-HCT care, who will be present once induction therapy 
with GCLAM begins 
3. Written informed consent for transplant 
4. Either bone marrow or peripheral blood is allowed 
 
Exclusion criteria (transplant): 
1. Donor specific antibodies against donor HLA–DQ or –DP 
2. Active bacterial, fungal or viral infections unresponsive to medical therapy 
3. Active leukemia in the CNS 
4. HIV positive 
5. Cardiac ejection fraction<40% or symptomatic coronary artery disease or uncontrolled 
arrhythmia 
6. DLCOc <40% or FEV1<50% 
7. Estimated GFR<40 ml/min  
8. Need for supplemental oxygen 
9. Direct bilirubin or ALT >2 x upper limit of normal, unless these abnormalities are thought to 
be related to Gilbert’s disease or leukemic infiltration of hepatic parenchyma 
 
5. DONOR SELECTION 
 

FHCRC Protocol # 9567 
-14- 
 
5.1 Donor evaluation 
Donor evaluation will be performed per standard practice guidelines. The donor search will be 
initiated as soon as the patient’s HLA-typing is complete, if a donor has not already been identified 
prior to enrollment on the protocol. If an appropriate donor is not identified, patients will not be eligible 
for transplantation on this protocol, though their treating physicians may pursue alternative donor 
transplantation if appropriate. 
 
Identification of an appropriate donor will follow the general guidelines listed below. 
 
 
• 
HLA-matched related or unrelated donor. Donors must be: 
i) 
Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing 
ii) 
Only a single allele disparity will be allowed for HLA-A, B, or C as defined 
by high resolution typing 
 
• 
HLA-mismatched unrelated donor.  
Unrelated volunteer donors who are mismatched with the recipient within one of the 
following limitations will be permitted: 
i. Mismatch for one HLA class I antigen with or without an additional mismatch 
for one HLA-class I allele, but matched for HLA-DRB1 and HLA-DQ, OR 
ii. Mismatched for two HLA class I alleles, but matched for HLA-DRB1 and HLA-
DQ 
iii. HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two 
DRB1 and/or DQB1 antigen/allele mismatch 
HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, -DRB1, 
and -DQ. If the patient is homozygous at the mismatch HLA class I locus or II locus, the donor 
must be heterozygous at that locus and one allele must match the patient (i.e., patient is 
homozygous A*01:01 and donor is heterozygous A*01:01, A*02:01) 
 
 
5.2 Expected timeline of chemotherapy and transplant 
The minimum time between initiation of bridge chemotherapy and initiation of conditioning for HCT 
will be 14 days and is anticipated to be closer to 21-30 days. This is based on a median time from 
initiation of chemotherapy to HCT of 29 days (range 19-74) for both patients with matched sibling 
and matched unrelated donors in the Middeke et al. study6. The donor identification process will 
begin when a patient is determined to have relapsed. 
 
As soon as potential patients are identified for this protocol, the treating physician or the study staff 
will contact the Clinical Coordinator’s Office to determine the patient’s donor status. If a donor has 
not previously been identified, the Clinical Coordinator’s Office will work closely with the treating 
physician to expedite HLA-typing of the patient (if necessary) and donor search (sibling or unrelated). 
Patients without a donor identified prior to enrollment on this study will have a rapid search performed 
to help identify a matched related or matched unrelated donor by an experienced search coordinator 
at UW/FHCRC. Donor may provide either peripheral blood or bone marrow. Patients without a 
suitable matched related or unrelated donor identified (8/8 matched at HLA-A, -B, -C, -DRB1) will be 
taken off study and will count as a “failure” to proceed to early HCT; these patients may be eligible 
to receive an alternative donor transplant if available to them off-study (note that data will still be 
collected on these patients who end up proceeding to HCT).  
 
Additionally, to aid in the feasibility, the treating physician or study staff will look into the status of 
patients’ dental evaluations and, in female patients >50, timing of most recent mammogram.  These 
studies, and some of the other pre-transplant work-up listed in section 8.3 (particularly pulmonary 

FHCRC Protocol # 9567 
-15- 
 
function tests and evaluation of ejection fraction), may be done prior to the patients’ formal arrival to 
the transplant service from the leukemia service. 
 
 
6. PROTOCOL REGISTRATION 
A completed eligibility checklist with source documentation, a signed consent form and a signed 
HIPAA authorization are required for registration. Patients may be enrolled any time between 
diagnosis of R/R high-grade myeloid neoplasm and when re-induction chemotherapy is completed, 
provided that they are receiving GCLAM chemotherapy. For questions, please contact the 
hematology research coordinators at hemeresearch@seattlecca.org or the protocol PI. 
 
7. TREATMENT PLAN: BRIDGE CHEMOTHERAPY WITH GCLAM 
 
7.1 Bridge chemotherapy 
All patients will receive bridge chemotherapy after signing consent, prior to anticipated allogeneic 
HCT. Patients will receive GCLAM chemotherapy (consisting of G-CSF subcutaneously daily on 
days 0-5, mitoxantrone hydrochloride IV over 60 minutes on days 1-3, cladribine IV over 2 hours 
daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5), as this regimen is our current 
standard of care for R/R AML patients.20 When protocol 9567 initially opened for accrual, several 
patients were concurrently enrolled on the R/R arm of protocol 2734 (“A Phase 1/2 Trial of G-CSF, 
Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly 
Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic 
Syndromes (MDS)”), but this protocol has now closed. The chemotherapy plan for GCLAM is listed 
in TABLE 3; the dosing of mitoxantrone will be either 10mg/m2 or 16mg/m2.20,21 Patients may have 
previously received a maximum of two cycles of chemotherapy with GCLAM prior to enrollment on 
this trial. See TABLE 2 for examples to help determine eligibility for chemotherapy and participation 
on this clinical trial. Patients will receive a bone marrow aspirate/biopsy prior to the beginning of HCT 
conditioning, though results will not determine whether or not to proceed to transplant.  
 
The treating physician may also elect to add additional chemotherapy agents to the GCLAM 
backbone at his/her discretion.  Such agents may include a tyrosine kinase inhibitor (such as 
sorafenib) for patients with FLT3-mutated disease or hypomethylating agents such as decitabine or 
azacitidine.  The treating physician must discuss such potential additions to the GCLAM backbone 
with the PI and study staff so that the reason for the addition is clear and so that such patients can 
be clearly noted. 
 
Subjects for whom the treating physician chooses a less intensive therapy than GCLAM at the doses 
described below will be considered a screen failure on this protocol. 
 
The next section describes the drug information for the drugs used in GCLAM, which will 
be the re-induction chemotherapy used as a bridge to allogeneic transplant. GCLAM has 
been administered in different forms (particularly with varying doses of mitoxantrone, as 
studied in protocol FH2734), but TABLE 3 outlines the sample bridge chemotherapy plan. 
 
TABLE 3: Sample GCLAM bridge chemotherapy plan. G-CSF dosing dependent on patient weight 
(300 µg dose for patients <76kg and 480 µg dose for patients ≥76kg). Day 0 and Day 1 doses of 
G-CSF may be omitted if WBC>20,000/µl. Day 0 through day 5 of G-CSF may be omitted at the 
discretion of the treating physician and in consultation with the principal investigator (e.g. to avoid 
additional pain for patients with existing bone pain. In the case of significant bone pain related to 
relapsed/refractory high-grade myeloid neoplasm, consideration may be given to omitting G-CSF 
doses until the bone pain is under control. Once bone pain is controlled, the remaining doses of G-

FHCRC Protocol # 9567 
-16- 
 
CSF should be delivered per the chemotherapy schedule pending discussion). Infusion times are 
approximate. The dosing will be performed using actual body weight.22 
 
Day 
# 
Agent 
Management plan 
0 
G-CSF 
G-CSF 300 or 480 µg subcutaneous 
1 
G-CSF 
Cladribine 
Cytarabine 
Mitoxantrone 
G-CSF 300 or 480 µg subcutaneous 
Cladribine 5 mg/m2 IV over 2 hours 
Cytarabine 2 g/m2 IV over 2 hours 
Mitoxantrone 10 or 16mg/m2 IV over 60 minutes 
2 
G-CSF 
Cladribine 
Cytarabine 
Mitoxantrone 
G-CSF 300 or 480 µg subcutaneous 
Cladribine 5 mg/m2 IV over 2 hours 
Cytarabine 2 g/m2 IV over 2 hours 
Mitoxantrone 10 or 16mg/m2 IV over 60 minutes 
3 
G-CSF 
Cladribine 
Cytarabine 
Mitoxantrone 
 G-CSF 300 or 480 µg subcutaneous 
Cladribine 5 mg/m2 IV over 2 hours 
Cytarabine 2 g/m2 IV over 2 hours 
Mitoxantrone 10 or 16mg/m2 IV over 60 minutes 
4 
G-CSF 
Cladribine 
Cytarabine 
G-CSF 300 or 480 µg subcutaneous 
Cladribine 5 mg/m2 IV over 2 hours 
Cytarabine 2 g/m2 IV over 2 hours 
5 
G-CSF 
Cladribine 
Cytarabine 
G-CSF 300 or 480 µg subcutaneous 
Cladribine 5 mg/m2 IV over 2 hours 
Cytarabine 2 g/m2 IV over 2 hours 
 
7.2 Drug Information on G-CSF (Granulocyte colony-stimulating factor) 
Mechanism of Action: G-CSF is a growth factor that stimulates the production, maturation, and 
activation of neutrophils. Further, it promotes premature release of neutrophils from the bone 
marrow and enhances their phagocytic capacity.  
Pharmacokinetics: Peak G-CSF concentrations after sub-cutaneous dosing occur in 2 to 8 hours, 
though the onset of action is approximately 24 hours, with plateau concentrations in 3-5 days, and 
elimination over an 11-20 day period. G-CSF is cleared by systemic degradation. Notably, as G-
CSF binds neutrophils, plasma levels are controlled in large part by the absolute neutrophil count.  
Adverse Effects (AEs): Common drug-related AEs (occurring in >10% of patients) include fever, 
petechiae, elevated uric acid, splenomegaly, bone pain, and epistaxis. Less common drug-related 
AEs (occurring in 1% -10% of patients) include hyper- or hypotension, arrhythmias, headache, 
nausea, vomiting, leukocytosis, and transfusion reaction. Infrequent drug-related AEs (occurring in 
<1% of patients) include acute respiratory distress syndrome, allergic reactions, alopecia, alveolar 
hemorrhage, arthralgia, bone density decrease, capillary leak syndrome, cerebral hemorrhage, 
vasculitis, dyspnea, edema, erythema nodosum, hematuria, hemoptysis, hepatomegaly, 
hypersensitivity, injection site reaction, pericarditis, proteinuria, psoriasis exacerbation, pulmonary 
infiltrates, renal insufficiency, sickle cell crisis, splenic rupture, Sweet’s syndrome, tachycardia, and 
thrombophlebitis. 
Recommended dose adjustments for organ dysfunction: There is limited or no data examining the 
toxicity of G-CSF in patients with renal or liver dysfunction. Therefore, administration of G-CSF to 
patients with liver or kidney disease must be done with caution. 
 

FHCRC Protocol # 9567 
-17- 
 
7.3 Drug Information on Cladribine (2-chloro-2’-deoxyadenosine, 2-CdA) 
Mechanism of Action: Cladribine is a prodrug that is converted to an adenosine deaminase-
resistant triphosphate derivative (2-CdATP). This molecule is then activated by deoxycytidine 
kinase to a 5’-triphosphate derivative (2-CdAMP), which is incorporated into DNA where it acts as 
a transcription regulator. In addition to its cytotoxic properties in dividing cells, cladribine induces 
death in quiescent cells of lymphoid origin through an unknown mechanism.  
Pharmacokinetics: Cladribine is renally excreted, with 18-35% as unchanged drug. It is able to 
penetrate the CSF, where it achieves 25% of plasma concentrations. It is 20% protein-bound. The 
half-life for elimination after a 2-hour infusion is 6.7±2.5 hours in patients with normal renal 
function.   
Adverse Effects: Common adverse effects (occurring in >10% of patients) include fever, fatigue, 
headache, rash, nausea, anorexia, vomiting, myelosuppression (including grade 3/4 
neutropenia/thrombocytopenia), injection site reaction, and infection. Less common adverse 
effects (occurring in 1 to 10% of patients) include edema, tachycardia, thrombosis, chills, 
dizziness, insomnia, malaise, diarrhea or constipation, weakness, myalgias and arthralgias, cough, 
dyspnea, epistaxis, and diaphoresis. Rare adverse effects (occurring in <1% of patients) include 
aplastic anemia, bacteremia, opportunistic infections, lymphocytopenia, altered mental status, 
hemolytic anemia, hypersensitivity, myelodysplastic syndrome, quadriparesis, and renal 
dysfunction/failure. 
Reconstitution: Cladribine is supplied as a sterile, preservative-free, isotonic solution containing 10 
mg of cladribine (1 mg/mL) in 10 mL single-use vials. Cladribine should be passed through a sterile 
0.22μm filter prior to introduction into the infusion bag containing 0.9% Sodium Chloride Injection, 
USP. 
Administration and Compatibility: The use of 5% dextrose is not recommended as a diluent 
because of increased degradation of cladribine. The infusion solution is stable for 24 hours at room 
temperature. 
Storage and Stability: Store refrigerated 2° to 8°C (36° to 46°F). Protect from light during storage. 
Recommended Dose Adjustments for Organ Dysfunction: Specific guidelines for cladribine dosing 
in patients with hepatic/renal dysfunction or hypoalbuminemia are not clearly defined. Because of 
the potential for compensatory elimination of cladribine in patients with hepatic and/or renal 
dysfunction, specific guidelines for dosing are difficult to define. Thus, when deciding whether to 
adjust cladribine doses for renal dysfunction, the risks for potential toxicities (e.g., 
myelosuppression, neurotoxicity) against the benefits and goals of treatment must be considered. 
 
7.4 Drug Information on Cytarabine (Cytosine arabinoside) 
Mechanism of Action: Cytarabine is a synthetic pyrimidine analog, in which the sugar moiety 
(normally a ribose or deoxyribose) has been replaced with arabinose. Although its mechanism of 
action is not completely understood, the active form of cytarabine is probably incorporated into the 
DNA and interferes with DNA synthesis. As such, cytarabine has been found to primarily effect 
dividing cells, blocking their progression from G1 to S phase.  
Pharmacokinetics: Cytarabine is metabolized by deoxycytidine kinase and other kinases into its 
most active form (aracytidine triphosphate). Aracytidine triphosphate is converted to nontoxic uracil 
derivatives by pyrimidine nucleoside deaminases. This balance between the levels of kinases and 
deaminases is critical for regulating the sensitivity/resistance of cells to the drug. The plasma 
clearance of cytarabine is biphasic, with an initial rapid phase and more prolonged second 
clearance phase. The rapid clearance phase has a relatively short half-life (t1/2α = 10 minutes), 
while the half- life of the second clearance phase is slightly longer (t1/2β = 1 – 3 hours). The 

FHCRC Protocol # 9567 
-18- 
 
nontoxic metabolites from the drug are excreted in the urine, and within 24 hours after the infusion, 
approximately 80% of these nontoxic metabolites can be recovered from the urine.  
Adverse Effects: The dose-limiting toxicity for cytarabine is myelosuppression. Adverse Events 
Associated with Standard Dose Cytarabine: Frequent AEs (not definitely quantified) include the 
following: myelosuppression (leucopenia, anemia, neutropenia, thrombocytopenia), pyrexia, rash, 
anorexia, diarrhea, nausea, vomiting, mucositis, anal inflammation or ulceration, hepatic 
dysfunction or increased liver enzymes, and local thrombophlebitis. Less frequent AEs (not 
definitely quantified) include chest pain, pericarditis, dyspnea dizziness, headache, neural toxicity, 
neuritis, alopecia, pruritus, skin freckling, skin ulceration, urticaria, abdominal pain, bowel necrosis, 
esophageal ulceration, esophagitis, pancreatitis, sore throat, urinary retention, 
jaundice/hyperbilirubinemia, local site cellulites, renal dysfunction, allergic edema or anaphylaxis, 
sepsis, and sudden respiratory distress syndrome. Infrequent AEs (not definitely quantified) 
include aseptic meningitis, cardiopulmonary arrest, cerebral dysfunction, cytarabine syndrome 
(bone pain, chest pain, conjunctivitis, fever, maculopapular rash, malaise, myalgia), 
exanthematous pustulosis, hyperuricemia, intestinal pneumonitis, increased lipase, paralysis with 
intrathecal and IV combination therapy, rhabdomyolysis, veno-occlusive disorder, and death. 
Adverse Events Associated with High Dose Cytarabine include cardiomegaly and cardiomyopathy, 
coma, severe neurotoxicity, personality change, somnolence, total body alopecia, severe rash or 
skin desquamation, gastrointestinal ulceration, peritonitis, intestinal pneumatosis, necrotizing 
colitis, liver abscess or damage, peripheral neuropathy, corneal toxicity, hemorrhagic conjunctivitis, 
pulmonary edema, sudden respiratory distress syndrome, and sepsis.  
Reconstitution: Cytarabine should be reconstituted in sterile water and can be further diluted using 
either 5% dextrose or sodium chloride solutions into appropriate concentrations for infusion.  
Administration and Compatibility:  The diluted cytarabine solution should be inspected for 
particulate matter, discoloration, and haze prior to infusion.  If there is evidence of particulate 
matter, discoloration, or haze the solution should not be infused. Patients should be medicated 
with standard anti-emetic therapy. Cytarabine is not compatible (1) during Y-site administration 
with allopurinol, amphotericin B, ganciclovir; (2) in syringe with metoclopropamide; or (3) admixed 
with fluorouracil, heparin, insulin (regular), nafcillin, oxacillin, penicillin G. Cytarabine may have 
variable compatibility when admixed with gentamycin, hydrocortisone, and methylpredinsone. 
Storage and Stability: Vials of non-reconstituted cytarabine should be stored at room temperature 
15°C - 30°C (59°F - 86°F). The diluted cytarabine solution may be stable for up to 48 hours if 
stored at room temperature.  
Drug-Drug Interaction: Reversible decreases in the plasma steady-state concentration for digoxin 
and cardiac glycosides may occur. Cytarabine may diminish the therapeutic effect of flucytosine. 
There is ex vivo data suggesting that cytarabine may reduce the effectiveness gentamycin for 
killing K. pneumoniae.  
Warnings and Precautions: Ex vivo and in vivo studies have found that cytarabine causes 
extensive chromosomal damage and potential malignant transformation.  Although there have 
been some case reports describing cytarabine use in pregnant humans, these cases reports are 
few. Thus, cytarabine is considered Pregnancy Category D. Women should be advised not to 
become pregnant while receiving cytarabine, and men should be advised not to father a child while 
receiving cytarabine and for at least 3 months after completing the therapy. It is not known whether 
cytarabine or its metabolites are excreted in breast milk; thus, it is not recommended for lactating 
females who are breast-feeding. As with any highly immunosuppressive medication, cytarabine 
may diminish the effectiveness of dead and live vaccines and enhance the toxic/adverse effect of 
live vaccines. One should avoid use of live vaccines while receiving it. A small percentage of 
patients will have a hypersensitivity reaction to cytarabine, and these individuals should not receive 
the drug again. 

FHCRC Protocol # 9567 
-19- 
 
Recommended Dose Adjustments for Organ Dysfunction: Guidelines for adjusting cytarabine dose 
due to renal or liver dysfunction are not standardized, but many clinicians will adjust the dose 
based upon the function of these organs.   
 
7.5 Drug Information on Mitoxantrone 
Mechanism of Action: Mitoxantrone (dihydroxyanthracenedione) is an anthracenedione derivative 
that intercalates with DNA, resulting in inhibition of nucleic acid synthesis.  
Pharmacokinetics: Mitoxantrone is 78% bound to plasma proteins. A three-compartment model 
was described after a single intravenous dose of mitoxantrone. The mean alpha half-life is 6 to 12 
minutes, the mean beta half-life is 1.1 to 3.1 hours, and the mean terminal (gamma) or elimination 
half-life is 23 to 215 hours (median 75 hours). Mitoxantrone has extensive distribution into body 
tissues and is metabolized in the liver to two main inactive metabolites (monocarboxylic acid 
derivative and dicarboxylic acid derivative). The major route of excretion for mitoxantrone appears 
to be biliary into the feces; approximately 11% of the dose is recovered in the urine within 5 days of 
drug administration, with 65% of this being unchanged drug. 
Adverse Effects: Common adverse effects (occurring in >10% of patients) include edema, fever, 
fatigue, headache, alopecia, nausea/vomiting, diarrhea, mucositis/stomatitis, myelosuppression, 
weakness, dyspnea, cough, and infection. Less common adverse effects (occurring in 1 to 10% of 
patients) include congestive heart failure, decreased left ventricular ejection fraction (LVEF), 
hypertension, chills, anxiety, cutaneous mycosis, hypocalcemia, hypokalemia, hyponatremia, 
menorrhagia, jaundice, myalgia, arthralgia, renal failure, proteinuria, rhinitis, diaphoresis, and 
infection.  
Mitoxantrone may cause cardiac toxicity with prolonged administration and doses exceeding 80 to 
100 mg/m2; Appendix D provides an overview of the cardiotoxicity index of individual 
anthracyclines as well as mitoxantrone. When used after doxorubicin, cardiotoxicity is more 
frequent; an analysis by the Southwest Oncology Group revealed a risk of 6% at 134 mg/m2 prior 
doxorubicin and 60 mg/m2 mitoxantrone, rising to a 15% risk at 120 mg/m2 mitoxantrone. Cardiac 
events reported included arrhythmias, decreased left ventricular function, chronic heart failure, 
tachycardia, ECG changes, and, infrequently, myocardial infarction. Bradycardia has been rarely 
reported. Patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with 
preexisting cardiovascular disease may have more frequent occurrences of cardiac toxicity. 
Reconstitution: Mitoxantrone must be diluted prior to use. The dose of mitoxantrone should be to at 
least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). 
Mitoxantrone may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with 
Normal Saline and used immediately.  
Administration and Compatibility: Care in the administration of mitoxantrone will reduce the chance 
of extravasation. Mitoxantrone should be administered into the tubing of a freely running 
intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.  Care 
should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone 
with the skin, mucous membranes, or eyes. If any signs or symptoms of extravasation have 
occurred, including burning, pain, pruritus, erythema, swelling, blue discoloration, or ulceration, the 
injection or infusion should be immediately terminated and restarted in another vein. 
 
Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. 
Storage and Stability: Mitoxantrone should be stored between 15°C - 25°C (59°F - 77°F). 
 
8. TREATMENT PLAN: CONDITIONING AND ALLOGENEIC TRANSPLANT 
Once patients have completed GCLAM conditioning, it is expected that they will move on to 
allogeneic HCT with a suitable related or unrelated donor. Patients will receive a bone marrow 

FHCRC Protocol # 9567 
-20- 
 
aspirate/biopsy prior to the beginning of HCT conditioning, though results will not determine whether 
or not to proceed to transplant. The details of the allogeneic HCT are described below. 
 
8.1 Donor identification 
This topic is discussed in section 5. 
8.2 Separate HCT consent 
Because many patients will not have an identified donor nor have been formally evaluated for 
transplant eligibility and attained insurance approval for transplantation when they enroll in this study, 
they will need to sign a separate consent for transplantation. Participants will undergo standard 
transplant consultation, medical evaluation and financial clearance. If a donor is identified and the 
patient’s medical condition is appropriate for transplantation, they will sign a separate consent for 
transplantation. Note that if donor availability or patient medical condition necessitates a different 
transplant approach, the treating physician may elect to pursue the alternative treatment. 
 
8.3 Pre-transplant evaluation 
Patients who have received bridge chemotherapy with GCLAM will be assessed for the eligibility 
criteria for allogeneic transplant described above, and will sign the separate transplant consent. For 
patients who are candidates for allogeneic transplant, they will undergo pre-transplant evaluation 
per standard practice, to include but not limited to:  
 
1) Comprehensive History and Physical Examination including full details of the patient’s diagnosis, 
prior treatment and response, and Karnofsky score (> 16 years)  
2) Two view chest x-ray (PA and lateral).  
3) EKG  
4) MUGA or ECHO for EF evaluation.  
5) Baseline pulmonary function studies, (or for pediatric patients, unable to perform pulmonary 
function tests, then O2 saturation on room air).  
6) Lumbar Puncture and CSF analysis for high risk patients per standard practice.  
7) Nutritional assessment including height, weight and body surface area  
8) Bone marrow aspiration for pathology, flow cytometry, cytogenetic and research studies, within 
30 days of planned donor cell infusion  
9) CBC with differential and reticulocyte count  
10) Serum chemistries including: electrolytes, creatinine, glucose, Ca, Mg, Phos, BUN, uric acid, 
total protein, total bilirubin and direct/indirect fractions, LDH, AST, ALT, GGT, alk phos, albumin, 
fasting triglyceride and cholesterol levels  
11) ABO and Rh typing and direct Coombs  
12) HSV, CMV, VZV and HIV serologies  
13) Infectious hepatitis panel  
14) Urinalysis  
15) HCG (quantitative pregnancy)[PG] (must be obtained on every female patient who is past 
menarche and pre-menopause  
16) Confirmatory HLA typing of recipient and donor 
 
 
8.4 Treatment plan for conditioning and allogeneic HCT 
8.4.1 Donors 
Collection of hematopoietic stem cells for unrelated donors:  HCT scheduling and collection is 
arranged through unrelated donor registries.  The schedule of G-CSF administration and collection 
of PBSC is determined as per NMDP or NMDP Cooperative Registry protocol.  The physician 
responsible for HSC collection will obtain informed consent from the donor. 
 

FHCRC Protocol # 9567 
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Collection of hematopoietic stem cells for related donors: 
 
TABLE 4: Typical mobilization for Matched Related Donors 
Day 
# 
Agent 
Management plan 
-5 
G-CSF 
16 µg/kg subcutaneously 
-4 
G-CSF 
16 µg/kg subcutaneously 
-3 
G-CSF 
16 µg/kg subcutaneously 
-2 
G-CSF 
16 µg/kg subcutaneously 
-1 
G-CSF 
16 µg/kg subcutaneously 
Collection of PBSC* 
0 
 
If collection on Day -1 contains less than 5.0x106 CD34+ cells per kg 
of recipient weight, another PBSC collection will occur 
   *PBSCs will be collected in the afternoon of day -1, stored at 4ºC overnight, and infused as soon 
as possible on day 0. 
 
8.4.2 Treatment options for conditioning and immunosuppression options for recipients 
Recipients will receive one of two different chemotherapy dosing regimens for conditioning based 
on their age and other significant co-morbidities as assessed by the treating transplant physician. 
Two conditioning regimens exist for treatment which vary in their doses of fludarabine and 
melphalan. There are also two variations for immunosuppression based on whether the patient has 
a 10/10 donor or a 9/10 donor. The two conditioning regimens and two concurrent 
immunosuppression options are detailed below in Tables 5 through 8. 
 
• 
REGIMEN 1: Flu/Mel conditioning option for patients ≤ 55 years with 10/10 matched 
donor (related or unrelated) 
 
TABLE 5: Flu/Mel conditioning for patients ≤ 55 years 
Day 
# 
Agent 
Management plan 
-6 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-5 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-4 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-3 
Fludarabine 
Melphalan 
Cyclosporine 
Sirolimus* 
Fludarabine 25 mg/m2 iv over 30 minutes 
Melphalan 70 mg/m2 iv  
Start cyclosporine 5 mg/kg PO bid 
Start sirolimus 2 mg PO bid (target 3-12 ng/ml) 
-2 
Fludarabine 
Melphalan 
Fludarabine 25 mg/m2 iv over 30 minutes 
Melphalan 70 mg/m2 iv 
0 
Graft infusion 
Mycophenylate 
mofetil 
Infuse donor bone marrow or peripheral blood 
Start mycophenylate mofetil (MMF) 15 mg/kg PO tid 
+30 
MMF 
Change MMF to 15 mg/kg PO bid 
+40 
MMF 
Stop MMF 
+96 
Cyclosporine 
Taper cyclosporine until day +150 
+150 
Sirolimus* 
Taper sirolimus until day +180 
 
 
 
• 
REGIMEN 2: Flu/Mel conditioning for patients > 55 years or with significant co-
morbidities with 10/10 matched donor (related or unrelated) 
 

FHCRC Protocol # 9567 
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TABLE 6: Flu/Mel/TBI conditioning for patients > 55 years or with significant co-morbidities 
Day 
# 
Agent 
Management plan 
-6 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-5 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-4 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-3 
Fludarabine 
Cyclosporine 
Sirolimus* 
Fludarabine 25 mg/m2 iv over 30 minutes 
Start cyclosporine 5 mg/kg PO bid 
Start sirolimus 2 mg PO bid (target 3-12 ng/ml) 
-2 
Fludarabine 
Melphalan 
Fludarabine 25 mg/m2 iv over 30 minutes 
Melphalan 100 mg/m2 iv 
-1 or 
0 
Total body 
irradiation 
2 or 3 Gy TBI 
0 
Graft infusion 
Mycophenylate 
mofetil 
Infuse donor bone marrow or peripheral blood 
Start mycophenylate mofetil (MMF) 15 mg/kg PO tid 
+30 
MMF 
Change MMF to 15 mg/kg PO bid 
+40 
MMF 
Stop MMF 
+96 
Cyclosporine 
Taper cyclosporine until day +150 
+150 
Sirolimus* 
Taper sirolimus until day +180 
 
* Note regarding sirolimus: This drug will only be added in for “triple” immunosuppression for patients 
who have matched unrelated donors. Patients with matched sibling donors will receive MMF and 
cyclosporine alone. 
 
 
• 
REGIMEN 3: Flu/Mel conditioning option for patients ≤ 55 years with 9/10 donor 
 
TABLE 7: Flu/Mel conditioning for patients ≤ 55 years 
Day 
# 
Agent 
Management plan 
-6 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-5 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-4 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-3 
Fludarabine 
Melphalan 
Cyclosporine 
Sirolimus 
Fludarabine 25 mg/m2 iv over 30 minutes 
Melphalan 70 mg/m2 iv  
Start cyclosporine 5 mg/kg PO bid 
Start sirolimus 2 mg PO bid (target 3-12 ng/ml) 
-2 
Fludarabine 
Melphalan 
Fludarabine 25 mg/m2 iv over 30 minutes 
Melphalan 70 mg/m2 iv 
0 
Graft infusion 
Mycophenylate 
mofetil 
Infuse donor bone marrow or peripheral blood 
Start mycophenylate mofetil (MMF) 15 mg/kg PO tid 
+30 
MMF 
Change MMF to 15 mg/kg PO bid 
+100 
MMF 
Taper MMF until day +150 
+150 
Cyclosporine 
Taper cyclosporine until day +180 
+180 
Sirolimus 
Taper sirolimus until day +365 
 
 
• 
REGIMEN 4: Flu/Mel conditioning for patients > 55 years or with significant co-
morbidities with 9/10 donor 
 

FHCRC Protocol # 9567 
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TABLE 8: Flu/Mel/TBI conditioning for patients > 55 years or with significant co-morbidities 
Day 
# 
Agent 
Management plan 
-6 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-5 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-4 
Fludarabine 
Fludarabine 25 mg/m2 iv over 30 minutes 
-3 
Fludarabine 
Cyclosporine 
Sirolimus 
Fludarabine 25 mg/m2 iv over 30 minutes 
Start cyclosporine 5 mg/kg PO bid 
Start sirolimus 2 mg PO bid (target 3-12 ng/ml) 
-2 
Fludarabine 
Melphalan 
Fludarabine 25 mg/m2 iv over 30 minutes 
Melphalan 100 mg/m2 iv 
-1 or 
0 
Total body 
irradiation 
2 or 3 Gy TBI 
0 
Graft infusion 
Mycophenylate 
mofetil 
Infuse donor bone marrow or peripheral blood 
Start mycophenylate mofetil (MMF) 15 mg/kg PO tid 
+30 
MMF 
Change MMF to 15 mg/kg PO bid 
+100 
MMF 
Taper MMF until day +150 
+150 
Cyclosporine 
Taper cyclosporine until day +180 
+180 
Sirolimus 
Taper sirolimus until day +365 
 
 
 
8.5 Conditioning regimen 
8.5.1 Donors 
Matched related donors will typically receive G-CSF conditioning beginning at Day -5.  G-CSF will 
be administered per transplant standard practice, which is 16 µg/kg/day, subcutaneously.  On Day 
-1, peripheral blood stem cells (PBSC) will be collected from the donor and stored at -4ºC 
overnight.  If there are fewer than 5x106 CD34+ cells per kg of recipient weight in the Day -1 
collection, a second collection of PBSC will occur on Day 0, and both collections will be transfused 
on day 0. 
 
8.5.2 Recipients 
The reduced-intensity conditioning regimen will consist of fludarabine and melphalan. Because 
of increased toxicity noted with the Flu/Mel conditioning regimen recently noted at UW/FHCRC, the 
dose of melphalan will be decreased to a one-time dose of 100mg/m2 for patients >55 years of age, 
or with significant co-morbidities (at investigators’ discretion). The dosing schedule is described in 
TABLES 5 and 6 above.23 Fludarabine and melphalan are commercially available.  Infusion times 
are approximate. These medications should be stored and mixed according to the manufacturer’s 
recommendations. Calculation of m2 will be per Standard Practice Guidelines. 
 
Fludarabine: Fludarabine will be administered once daily intravenously according to pharmacy 
standards. Fludarabine may cause bone marrow suppression, nausea, vomiting, diarrhea, 
stomatitis, rash, pneumonitis and neurotoxicity. 
 
Melphalan: Melphalan will be infused once daily intravenously according to pharmacy standards. 
Melphalan can cause bone marrow suppression, nausea, vomiting, anorexia, stomatitis, hair loss, 
and weakness. 
 
TBI: On day -1 or 0 (dependent on scheduling), 2 or 3 Gy of total body irradiation will be administered 
at 6-7 cGy/min from a linear accelerator. Regardless of the actual time of TBI administration on Day 

FHCRC Protocol # 9567 
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0, immunosuppression should be given per schedule and prior to the infusion of stem cells. 
Dosimetry calculations are performed by the radiation therapist.  
 
Criteria for 3 Gy TBI:  Patients need to fulfill one or more of the following criteria for 3 Gy TBI: 
a. Patients not previously treated with myelosuppressive chemotherapy prior to starting G-
CLAM (e.g., patients who have received hypomethylating therapy alone) 
b. Patients who have not had myelosuppressive chemotherapy prior to starting G-CLAM within 
3-6 months of HCT may be at higher risk of rejection depending on treatment history and 
underlying diagnosis.  Confirm TBI dose (200 vs 300 cGy) with PI. 
c. Patients with AML or MDS with any measurable residual disease (by multiparameter flow 
cytometry) prior to HCT 
 
Please refer to Standard Practice Guidelines for information about administration, toxicity and 
complications. 
 
8.6  Acute GVHD prophylaxis 
Triple immunosuppressive therapy per FH2448 (MMF, cyclosporine, and sirolimus) will be used for 
patients with matched unrelated donors; details follow and are available in TABLES 5 and 6 above. 
Double immunosuppressive therapy (MMF and cyclosporine) will be used for patients with matched 
sibling donors, with the same schedule but without sirolimus. 
 
Protocol FH2448 used triple therapy with mycophenylate mofetil (MMF), cyclosporine, and sirolimus 
in a reduced-intensity conditioning protocol with fludarabine and TBI for matched unrelated donor 
transplants. The regimen will include MMF given at a dose of 15 mg/kg PO tid starting day 0 until 
day +30, then bid until day +40; cyclosporine given at a dose of 5 mg/kg PO bid starting day -3 until 
day +96, with a taper until day +150 (therapeutic target prior to taper as per table 9 below); and 
sirolimus, given at a dose of 2 mg PO daily, starting day – 3 until day +150, with a taper until day 
+180 (therapeutic target prior to taper 3-12 ng/ml). This regimen has been shown to be superior to 
an arm containing only MMF and cyclosporine in a randomized phase 3 study (FH2448). Patients 
with matched related donors will receive only MMF and cyclosporine. 
 
Mycophenolate mofetil, cyclosporine, and sirolimus are commercially available.  These 
medications should be stored and mixed according to the manufacturer’s recommendations. 
Calculation of m2 will be per Standard Practice Guidelines. 
 
Mycophenolate mofetil (MMF): MMF will be given at a dose of 15 mg/kg PO tid based on 
adjusted body weight starting day 0 until day +30, then bid. The first dose will be given on day 0 in 
the evening after HCT (i.e., approximately 4-6 hours after HCT). Doses will be rounded to the 
nearest 250mg. If there is nausea and vomiting at any time preventing the oral administration of 
MMF, MMF should be administered IV based on adjusted body weight at 15 mg/kg q8hr. . If in the 
clinical judgment of the investigator the observed toxicity is related to MMF administration, a dose 
adjustment may occur. If severe refractory diarrhea, overt gastrointestinal bleeding, or neutropenia 
occurs, MMF may be temporarily stopped. The MMF should be restarted at 20% reduced dose 
when the underlying toxicity subsides. MMF will be stopped without taper per the schedules above 
unless GVHD or disease relapse/progression occurs. 
 
Cyclosporine: Cyclosporine will be given at a dose of 5 mg/kg PO q12 hours from day -3, based 
on adjusted body weight. If there is nausea and vomiting at any time during cyclosporine 
treatment, the drug should be given IV at the appropriate dose that was used to obtain a 
therapeutic level. In the absence of acute or chronic GVHD, cyclosporine is tapered per the 
schedules above. 
 

FHCRC Protocol # 9567 
-25- 
 
Blood pressure, renal function (Cr, BUN), electrolytes and magnesium will be followed at least 
three times per week during the first month, twice weekly until day +100, then once per week until 
cyclosporine is stopped. Whole blood trough levels of cyclosporine will be evaluated start on day 0 
and twice weekly post-transplant during the first 28 days. After taper, dose levels will be measured 
weekly if stable. 
 
Dose reductions should only be made if cyclosporine toxicity is present or levels exceed upper 
limits of target by 20%, in the absence of toxicity. 
 
Cyclosporine side effects are generally reversible, and may include renal insufficiency, 
hypomagnesemia, paresthesias, tremor, seizures, visual disturbances, paresis, disorientation, 
depression, confusion, somnolence, coma, nausea, hypertension, hemolytic-uremic syndrome, 
hyperglycemia, gynecomastia, and hypertrichosis. 
 
TABLE 9: Cyclosporine target trough levels and recommended dose adjustments. 
 
 
Cyclosporine target level 
Day 0 to day +28 
350 ng/ml 
After day +28 
120-300 ng/ml 
Levels exceeding upper limits of target by 
>20% 
• 
With or without cyclosporine toxicity 
• 
Decrease in GVHD ≥ 50% 
• 
Increase in creatinine 2x baseline 
due to cyclosporine 
25% dose reduction 
 
Sirolimus Sirolimus should be given at least 4 hours after an oral dose of cyclosporine as 
concurrent administration leads to elevation of sirolimus levels. Sirolimus will be started on day -3 
at 2mg every day orally through day +150. In the absence of GVHD, sirolimus should be tapered at 
day 150 by 25% per week for 4 weeks and discontinued on day +180. In the presence of GVHD or 
if the patient is receiving glucocorticoid therapy, continuation of sirolimus will be at the discretion of 
the attending physician. To minimize variability of exposure to sirolimus, the drug should be taken 
consistently with or without food. Grapefruit juice reduced CYP3A4-mediated metabolism of 
sirolimus and should not be administered with sirolimus or used for dilution. 
 
Dosing will be adjusted to maintain a target blood level of 3-12 ng/ml. Dose adjustments are based 
on clinical toxicity, blood levels, and GVHD. The dosage should be adjusted if the patient vomits 
within 15 minutes of taking a dose. Premedication with antiemetics is acceptable if vomiting 
occurs. Taper will occur as per the schedules above. 
 
Refer to the Standard Practice Guidelines for additional information regarding the use of MMF, 
cyclosporine, and sirolimus for GVHD prophylaxis.   
 
9. SUPPORTIVE CARE 
Patients will receive transfusions, infection prophylaxis, and therapy according to standard practice 
guidelines. Supportive care will be determined by the physicians from the leukemia and transplant 
teams caring for the patient. 
 
10. PATIENT REPORTED OUTCOMES AND RESOURCE UTILIZATION 
Patient-reported outcomes and resource utilization – If we proceed to a randomized trial, we will 
incorporate measurement of patient-reported outcomes and resource utilization. Hence, we wish to 
pilot collection of these data in this trial. Patient-reported outcomes (PROs) will include: 

FHCRC Protocol # 9567 
-26- 
 
1) the 27 item FACT-G comprised of physical, emotional, social and function well-being 
subscales  
2) FACT-Leuk (which includes the FACT-G, as well as the Leukemia subscale with 17 items) 
3) the FACT-BMT subscale, composed of 10 scored items in the BMT subscale 
4) the MD Anderson Symptom Inventory 
5) the EuroQOL-5D – 5 items that allow calculation of utility, a factor used for cost-utility 
(effectiveness) analysis. 
 
Patient-reported outcomes will be collected at enrollment (including sociodemographics, information 
about their caregiver situation, and patient-defined goals of care), then after completion of re-
induction chemotherapy (day 10 +/- 3 days). For patients who undergo HCT regardless of timing, 
PROs will be collected just prior to HCT conditioning and at 6 and 12 months after HCT (if possible). 
These questionnaires are expected to take 10-15 minutes to complete. Many patients live outside 
the Seattle area, so study staff will mail questionnaires to patients up to two times before declaring 
that the patient has not responded; lack of response will be documented and will not count as a 
deviation from study procedures. Resource utilization for the 12 months after enrollment will be 
obtained from the administrative systems at the Seattle Cancer Care Alliance and University of 
Washington Hospitals. Certain costs will not be captured such as professional fees, outpatient 
pharmacy, and care delivered outside the study site. 
 
 
11. GUIDELINES FOR SERIOUS ADVERSE EVENT REPORTING 
 
11.1 Expedited reporting requirements. 
In accordance with FHCRC/UW Cancer Consortium IRB policy, all adverse events (AEs; whether 
occurring on-site or off-site), which in the opinion of the principal investigator are (1) unexpected, 
and (2) related or possibly related to the research, and (3) serious or suggests that the research 
places research participants or others at a greater risk of physical or psychological harm than was 
previously known or recognized, will be submitted to the IRB within ten (10) calendar days of learning 
of the problem. Both the “Expedited Reporting Form for Unanticipated Problems or Noncompliance” 
and the “Adverse Event Reporting Form”, or equivalent forms, will be completed for this reporting. 
 
11.2 Definitions 
Adverse Event (AE): Any harm or untoward medical occurrence in a research participant 
administered a medical product, medical treatment or procedure even if it does not necessarily 
have a causal relationship with the product, treatment, or procedure. An adverse event can be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medical product, medical treatment, 
or procedure whether or not considered to be related. Mechanisms of obtaining information on AE 
include monthly transcripts, assessment forms obtained after each clinic visit, and hospital 
progress and discharge notes. Grade ≥3 adverse events other than hematologic toxicities will be 
recorded, graded, and reported as appropriate.  
 
Related or Possibly Related AE: An AE is “related or possibly related to the research procedures” if 
in the opinion of the principal investigator, it was more likely than not caused by the research 
procedures. AEs that are solely caused by an underlying disease, disorder or condition of the subject 
or by other circumstances unrelated to either the research or any underlying disease, disorder or 
condition of the subject are not “related or possibly related”. If there is any question whether or not 
an AE is related or possibly related, the AE should be reported. 
 
Serious AE (SAE): An adverse event that results in any of the following outcomes: 

FHCRC Protocol # 9567 
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• Death 
• Life-threatening adverse event (real risk of dying)  
• Prolongation of hospitalization* 
• Persistent or significant disability/incapacity/or change in psychosocial status 
• Congenital anomaly 
• Requirement of intervention to prevent permanent impairment of damage 
*Hospitalization itself will not be considered a serious adverse event if required for 
complications of AML or comorbid conditions. Hospitalization will be considered a SAE if it fulfills 
the criteria for a serious and unexpected adverse event as otherwise described. 
 
Unexpected AE: An AE is “unexpected” when its nature (specificity), severity, or frequency are not 
consistent with (a) the known of foreseeable risk of adverse events associated with the research 
procedures described in the protocol-related documents, such as the IRB-approved research 
protocol, informed consent document, and other relevant sources of information such as product 
labeling and package inserts. 
 
Myelosuppression and associated complications are expected events during leukemia 
chemotherapy and allogeneic transplant; therefore, myelosuppression and associated expected 
complications such as fever, infections, bleeding, and related hospitalizations will be summarized in 
the annual report to the IRB. Therefore, in this study, we expect to monitor closely and report 
promptly on AEs that are serious, related, and unexpected. 
 
AE monitoring will begin on Day 1 of GCLAM therapy or the date of consent, whichever date comes 
first.  AEs will continue to be monitored until the following timepoints: 
• 
For subjects who are “successes,” AEs will be followed up to day 100 after transplant. 
• 
For subjects who are “failures” and do not receive transplant within 60 days, AEs will be 
followed only until the date the subject is off-study. 
 
 

FHCRC Protocol # 9567 
-28- 
 
TABLE 10: Schedule of study assessments 
 
Procedure 
Pre-study 
screening1 
Induction 
Pre-HCT 
HCT 
Post-HCT 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Demographics (age, 
race/ethnicity, gender) 
X 
 
 
 
 
Physical exam, ECOG PS, 
height, weight, vitals 
X 
 
 
 
 
Pregnancy test (quantitative 
HCG)2 
X 
 
 
 
 
GCLAM chemotherapy3 
 
X 
 
 
 
Fludarabine/melphalan 
 
 
 
X 
 
GVHD prophylaxis4 
 
 
 
X 
X 
Bone marrow evaluation 
X5 
 
X6 
 
 
TRM evaluation 
 
 
 
X 
X 
Formal organ function 
testing7 
 
 
X 
 
 
Patient-reported outcomes8 
X 
 
X 
 
X 
Monitoring of SAEs9 
 
X 
X 
X 
X 
 
1 All pre-study screening must be done within 30 days of signing consent unless otherwise specified. 
2 Women of age <60 will be considered for pregnancy testing prior to enrollment. If potential female participants have not had menstrual bleeding in >2 
years prior to enrollment, pregnancy test will not be required. 
3 Please note that GCLAM induction chemotherapy may start prior to consent. Additionally, G-CSF will start 24 hours prior to chemotherapy (i.e., day 0). 
4 The GVHD prophylaxis regimen will be dosed per tables 5, 6, 7, and 8.  
5 Bone marrow evaluation will routinely be done to establish eligibility but does not need to be repeated for the study. 
6 Timing of bone marrow evaluation will be left to the discretion of the treating physician, but should preferably be done within 7 days of beginning HCT 
conditioning. Results of bone marrow evaluation will not affect ability of patient to move on to allogeneic HCT. 
7 See section 3 for full inclusion/exclusion criteria. Patients will have organ function assessed prior to proceeding to HCT: heart (echocardiogram or MUGA), 
lungs (pulmonary function testing), kidneys (GFR), and liver (bilirubin, ALT). 
8 See section 10 for details. Patient-reported outcomes will be collected at enrollment, day 10 after initiation of induction chemotherapy +/- 3 days, prior 
to HCT, and at 6 and 12 months post-HCT. 
9 SAEs will be routinely monitored and reported to the IRB. 

FHCRC Protocol # 9567 
-29- 
 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 Sample size calculation 
 
As noted in Section 2A, only 62/583 (11%) patients presenting with R/R AML over the 7 year period 
2008-2015 received HCT within 60 days of their presentation as initial treatment, i.e. 7 patients per 
year. Our ultimate goal is to launch a study that will randomize patients between early HCT and the 
late approach of HCT only once CR or CRp/CRi +/- MRD has occurred. We anticipate that a 
randomized trial would require at least 40 patients (20/arm, assuming median survival is 6 months 
with the standard approach and is 12 months with early HCT, testing with a one-sided alpha value 
of 10% and 80% power). Before undertaking a randomized trial, we propose this feasibility trial to 
assess the feasibility of accruing to such a study and of transplanting patients quickly enough to 
make a randomized trial feasible. 
 
We would consider this feasibility study a success and plan to launch a randomized trial if: 1) we 
were able to enroll 30 patients per year (1/3 of the anticipated 90 who present with R/R AML), and 
2) we transplant at least 15 of the 30 patients within 60 days of start of induction therapy, and 3) 
among patients who are transplanted the observed 6-month relapse-free survival after transplant is 
40% or higher.  As noted in Background, we anticipate that 35 patients with R/R AML per year will 
have donors already identified when found to have R/R AML at FHCRC, so we believe accrual to 
the trial is feasible. The expected 6-month relapse-free survival rate for patients not undergoing early 
HCT is 10% (personal communication, E. Estey and S. Buckley, based on 246 patients receiving 
GCLAM without early transplant in the last 3 years at the Center).  
 
Early stopping of the accrual to this study will be monitored for relapse-free survival (RFS) and acute 
GVHD (GVHD graded III or IV) at day 100 after transplant. Based on the poor outcomes for this 
patient population without early transplant, we would find an observed day 100 RFS rate of 30% or 
higher acceptable and want to place the study on an enrollment hold to review potential corrective 
actions if the observed day 100 RFS rate is lower than 30%.  Based on aGVHD data from the center 
we would find an observed aGVHD rate of 25% or lower acceptable and would want to place the 
study on an enrollment hold to review potential corrective actions if the observed day 100 aGVHD 
rate exceeds 25%.  Based on these criteria, the stopping rules will be used: 
 
Number of transplanted 
patients 
Number of RFS events for early 
stopping (stop if observe at least 
the number of events below) 
7 
5 
8 
6 
9-10 
7 
11 
8 
12 
9 
13-14 
10 
15 
11 
16-17 
12 
18 
13 
19-20 
14 
21 
15 
22 
16 

FHCRC Protocol # 9567 
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23-24 
17 
25 
18 
26-27 
19 
28 
20 
29-30 
21 
 
 
 
 
 
 
 
Number of transplanted 
patients 
Number of aGVHD events for early 
stopping (stop if observe at least 
the number of events below) 
8-11 
3 
12-15 
4 
16-19 
5 
20-23 
6 
24-27 
7 
28-30 
8 
 
 
RFS and aGVHD will be monitored independently.  If either endpoint has a number of events for 
stopping early, the trial will pause to review potential corrective actions regardless of the outcomes 
with the other endpoint. 
 
All events which qualify toward meeting stopping rules will be reviewed at study steering committee 
meetings as detailed in section 13.0.  All decisions involving enrollment pause or termination, as well 
as implementation of any corrective actions, will be first reviewed by the steering committee. 
 
 
12.2 Endpoint definitions 
- Early transplant – infusion of an allogeneic graft less than 60 days after initiation of re-induction 
chemotherapy 
- Remission - <5% blasts on bone marrow biopsy with hematologic recovery, defined as 
ANC>1000/ul and platelets >100,000/ml 
- CRi – complete remission with insufficient hematologic recovery, defined as ANC < 1000/ul or 
platelets < 100,000/ul 
- CRp – complete remission but platelets < 100,000/ul 
- Minimal residual disease – any detectable disease by flow cytometry, cytogenetics, FISH or PCR 
in a patient otherwise fulfilling remission criteria 
- Relapse – >5% blasts in bone marrow, flow cytometry, or manual differential OR treatment for 
active relapsed disease. Prophylaxis against relapse or treatment for MRD (including donor 
lymphocyte infusion, genetically modified T cells or withdrawal of immunosuppression) will not be 
considered relapse for the purposes of this trial. 
 

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12.3 Analysis plan 
Principal objective:  If the definition of feasibility in met as defined in Section 12.1, the study will be 
considered feasible. 
 
Secondary objectives: as this is a feasibility study, all analyses will be descriptive in nature. 
 
1. Overall survival relapse-free survival and event-free survival will be estimated with the 
Kaplan-Meier method. Cumulative incidence of aGVHD and TRM will be calculated.  
Remission rates will be tabulated.  These endpoints will be estimated for all patients who 
receive early transplant, and all endpoints applicable to the full study cohort (survival 
endpoints and remission rate) will be estimated in the full study cohort.   
2. We will compare patients who receive early HCT to those that don’t using Fisher’s exact test 
for categorical variables (e.g., gender) and the Wilcoxon rank sum test for quantitative 
variables (e.g., age). 
3. Patient-reported outcomes and resource utilization will be summarized descriptively. The 
amount of missing data will be summarized for each type of data using percent collection 
from surviving patients for PRO timepoints and description of days of hospitalization (the 
major driver of costs within the first year) for resource utilization. 
4. The treatment course and outcomes for patients who enrolled and had allogeneic HCT off-
study will be described 
. 
Exploratory objective: We plan to identify one patient not enrolled on this study, transplanted with 
standard scheduling the past 5 years, matched on age (within +/- 5 years), relapse status (refractory, 
relapse with 1 prior CR, relapse with more than 1 prior CR). We will then compare outcomes between 
patients who received transplant on this study with the matched patients.  Log-rank tests and Cox 
regression will be used for survival outcomes.  Cumulative incidence regression will be used to 
compare outcomes subject to competing risks (acute GVHD and TRM). 
 
13. DATA AND SAFETY MONITORING PLAN 
 
The Principal Investigator will carry out ongoing trial oversight. The study team will meet regularly to 
review recently acquired data and adverse events. The data recorded within the research charts and 
protocol database is compared with the actual data that is available from the medical record and/or 
clinical histories. All investigators on the protocol have received formal training in the ethical conduct 
of human research. 
 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the provisions 
of this plan, FHCRC Clinical Research Support coordinates data and compliance monitoring 
conducted by consultants, contract research organizations, or FHCRC employees unaffiliated with 
the conduct of the study.  Independent monitoring visits occur at specified intervals determined by 
the assessed risk level of the study and the findings of previous visits per the institutional DSMP.  
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB).  The review 
committees evaluate accrual, adverse events, stopping rules, and adherence to the applicable data 
and safety monitoring plan for studies actively enrolling or treating patients.  The IRB reviews the 
study progress and safety information to assess continued acceptability of the risk-benefit ratio for 
human subjects.  Approval of committees as applicable is necessary to continue the study. 
 

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The trial will comply with the standard guidelines set forth by these regulatory committees and other 
institutional, state and federal guidelines. 
 
Previous versions of the protocol specified that a Data Safety and Monitoring Board (DSMB) would 
also be assembled. As of June 2017, monitoring of the study will primarily be taken over by the 
bodies described above (DSMC, SRC, and IRB). The previous DSMB will continue to convene as 
a steering committee approximately quarterly to help with study oversight and planning. This 
steering committee will include the Principal Investigator (as a consulting member), research 
coordinator, data manager and three faculty members from within the UW/FHCRC Cancer 
Consortium. These three faculty members must practice outside of the AML Disease Group. The 
steering committee will meet to discuss safety of protocol participants, validity and integrity of the 
data, adherence to protocol (potential or real protocol violations), data completeness, and progress 
of data for secondary objectives.  
 
 
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