Not for publication or presentation · 2011. 2. 1. · RT08-02 Effect of Splx on engraftment after ablative allo HCT (G Akpek) Manuscript Preparation c. RT09-01 Predictors for primary

Not for publication or presentation

AGENDA CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY / SUPPORTIVE CARE Honolulu, Hawaii Thursday, February 17, 2011, 12:15 pm – 2:15 pm

Co-Chair: Kenneth Cooke, MD, Case Western Reserve University School of Medicine Telephone: 216-368-0481; Fax: 216-368-0741; E-mail: [email protected] Co-Chair: Vincent T. Ho, MD, Dana-Faber Cancer Institute Telephone: 617-632-5938; Fax: 617-632-5168; E-mail: [email protected] Co-Chair: Philip M. McCarthy, MD, Roswell Park Cancer Institute Telephone: 716-845-4074; Fax: 716-845-3272; E-mail: [email protected] Statisticians: Xiaochun Zhu, MS, CIBMTR Medical College of Wisconsin Telephone: 414-805-0649; Fax: 414-805-0714; E-mail: [email protected] Brent Logan, PhD, CIBMTR Medical College of Wisconsin Telephone: 414-456-8849; Fax: 414-456-6513; E-mail: [email protected] CIBMTR Sci. Dir: Marcelo Pasquini, MD, MS, CIBMTR Medical College of Wisconsin Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

Minutes of February, 2010 meeting (Attachment 1)

2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers

a. D98-70 Uberti, JP, Agovi M-A, Tarima S, Haagenson M, Gandham S, Abella E, Anasetti C, Baker S, Bashey A, Bearman S, Bolwell B, Bornhauser M, Chan KW, Copelan E, Davis S, Dudek A, Elkins S, Finke J, Hale G, Kernan N, Kollman C, McCarthy P, Ratanatharathorn, V, Ringden O, Wade J, Weisdorf D, Rizzo JD. Comparative analysis of busulfan and cyclosphosphamide versus cyclosphosphamide and total body irradiation in full intensity unrelated donor transplantation for acute myelogeous leukemia, chronic myelogenous leukemia and myelodysplasia. BMT, [Epub ahead of print] 2010 Apr 19.

b. R02-26/SC03-01 Navarro WH, Agovi M-A, Logan BR, Bacigalupo A, Ballen KK, Bolwell BJ, Frangoul H, Gupta V, Hahn T, Juckett M, Lazarus HM, Litzow MR, Liesveld J, Moreb J, Marks DI, McCarthy PL, Pasquini MC, Rizzo JD. Obesity does not preclude safe and effective myeloablative hematopoietic cell transplantation for acute myeloid leukemia (AML) in adults. Biol Blood Marrow Transplant 16(10):1442-50, 2010.

c. RT05-03 Schriber JR, Agovi M-A, Ballen KK, Bacigalupo A, Hale GA, Gupta V, Lazarus HM, Litzow MR, Marks DI, Giller RH, Maziarz RT, Bornhauser M, Isola LM, Bredeson C, Rizzo JD. Second unrelated donor (URD) transplant as a rescue strategy for 122 patients with primary non engraftment: Results from the CIBMTR. Biol Blood Marrow Transplant 16 (8): 1099-106 2010.

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d. RT05-02 Barker CC, Agovi MA, Logan B, Gupta V, Lazarus HM, Ballen K, Hale G, Frangoul H, Rizzo D, Pasquini MC. Obesity Adversely Affects Survival of Pediatric Patients with Severe Aplastic Anemia after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant [Epub ahead of print], 2010, Sep 1.

e. RT06-02 Horan J, Logan B, Agovi MA, Lazarus H, Bacigalupo A, Ballen K, Martino R, Juckett M, Khoury H, Bredeson C, Gupta V, Smith F, Hale G, Carabasi M, McCarthy P, Rizzo D, Pasquini MC. Reducing the Risk for Transplant Related Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation: How Much Progress Has Been Made? JCO in press.

f. RT08-02 Akpek G, Pasquini MC, Logan B, Agovi MA, Cooke KR, Maziarz RT, Gupta V, Lazarus H, Hale GA, Marks DI, Maharaj D, Popat U, Carabasi M, Bornhaeuser M, Bolwell BJ, Ringden O, Ballen KK, Rizzo D, McCarthy PL and Ho VT. The effect of prior splenectomy or splenic irradiation on myeloid engraftment after myeloablative allogeneic HCT: a CIBMTR analysis. Presented at the American Society of Hematology in Orlando, Florida, 2010.

4. Studies in progress (Attachment 3)

a. RT06-01s TGF-B1 promoter polymorphysms in renal dysfunction with CSA (R Shah)

Manuscript Preparation

b. RT08-02 Effect of Splx on engraftment after ablative allo HCT (G Akpek)

Manuscript Preparation

c. RT09-01 Predictors for primary graft failure (S Chaudhury/R Olsson)

Analysis

d. RT07-01 Comorbidities/Aging impact on HCT (M Sorror) (Attachment 4)

Data File Preparation

e. RT08-01 End-stage renal disease in HCT recipients (Trivedi/Hari) Data File Preparation f. RT09-02 Effects of body mass in children with leukemias

undergoing allogeneic HCT (N Bunin) Data File Preparation

g. RT09-04 Genetic polyporphisms and HCT related mortality RE: pre HCT conditioning in MUD HCT (T Hahn)

Protocol Development

5. Approved studies but not initiated

a. RT09-03 Ablative vs RIC for haplo HCT (S Ciurea) (Attachment 5) Protocol Development b. RT10-01 CRP for predicting non-relapse mortality in allo HCT (A

Artz) (Attachment 6) Protocol Development

c. RT10-02 2nd allo post ablative conditioning for relapsed heme-malignancy (G Akpek) (Attachment 7)


d. RT10-03 Pulmonary complications in a/w A1B8DR3 post haplo allo HCT (P McCarthy/H Liu) (Attachment 8)


e. RT10-04 Pre-HCT risk factors for relapse after RIC (F Baron) (Attachment 9)


6. Future/ Proposed studies

a. PROP 1210-23 Risk factors for the development of idiopathic pneumonitis after autologous stem cell transplantation for lymphoma using BCNU-containing regimens (A Lane/YB Chen) (Attachment 10)

b. PROP 1210-30 Chimerism as predictor of secondary graft failure or relapse following allogeneic hsct using reduced intensity conditioning regimens in acute leukemia (R Olsson) (Attachment 11)

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c. PROP 1210-31 Secondary graft failure after myeloablative allogeneic hsct in the treatment of hematological malignancies (R Olsson) (Attachment 12)

d. PROP 1210-36 Development of a predictive scoring system for acute lung injury afterhematopoietic stem cell transplantation (G Akpek) (Attachment 13)

7. Other Business

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Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY / SUPPORTIVE CARE

Orlando, Florida Wednesday, February 24, 2010, 12:15 pm – 2:15 pm

Co-Chair: Kenneth Cooke, MD, Case Western Reserve University School of Medicine Telephone: 216-368-0481; Fax: 216-368-0741; E-mail: [email protected] Co-Chair: Karen Ballen, MD, Massachusetts General Hospital Telephone: 617-724-1124; Fax: 617-724-1126; E-mail: [email protected] Co-Chair: Vincent T. Ho, MD, Dana-Faber Cancer Institute Telephone: 617-632-5938; Fax: 617-632-5168; E-mail: [email protected] Statisticians: Manza-A. Agovi, MPH, CIBMTR Medical College of Wisconsin Telephone: 414-805-0636; Fax: 414-805-0714; E-mail: [email protected] Brent Logan, PhD, CIBMTR Medical College of Wisconsin Telephone: 414-456-8849; Fax: 414-456-6513; E-mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MS, CIBMTR Medical College of Wisconsin Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected] 1. Introduction

Vincent Ho (VH) started the meeting at 12.21pm. Karen Ballen (KB) introduced Philip McCarthy (PM) as the new incoming chair for the committee replacing KB. Marcelo Pasquini (MCP) acknowledged KB’s contributions as a chair to the RRT committee and presented her with a gift on behalf of the CIBMTR.

Minutes from the 2009 Tandem meeting in Tampa were accepted and approved by the chairs and

committee members. 2. Accrual summary: There was no formal presentation of the accrual summary. 3. Presentations, published or submitted papers

MCP updated the group on studies recently published or presented since the last in person meeting. The RRTWC has 7 studies which are either in press or published, or submitted for publication or currently in manuscript preparation. Marks et al and Baccigalupo et al studies have been published in the BBMT; Schriber et al and Uberti et al are in press in BBMT and BMT respectively; Navarro et al have been submitted to BBMT; Barker and Horan study were each accepted for an oral presentation at the 2009 American Society of Hematology meeting in New Orleans. MP informed that the plan is to submit RT 06-02 (Horan et al) to JAMA and RT 05-02 (Barker et al) to BBMT by June 2010.

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4. Studies in Progress a. RT05-01 Role of Gemtuzumab Ozogamicin in the Development of Hepatic Veno-

occlusive disease (S Smiley) Protocol Development. VH presented the study on behalf of Shannon Smiley. This study, which was originally proposed as a retrospective study to assess the impact of gentuzumab ozogomycin (GO) on the development of hepatic veno-occlusive disease (VOD) has been changed to a prospective study utilizing a form to capture details on the use of GO and refine data collection on VOD, as per discussion at last year’s meeting. The study is currently in protocol and supplemental data form development phase. VH explained that in the last year we had several discussions about this study and the protocol is currently in draft format. The PI has relocated to a non-BMT position but she remains interested in the study. The delay in moving the study forward is related in finalizing a form that can be incorporated in FormsNet. Since this study was initially proposed many years ago, perhaps this question is no longer relevant, it is possible that the pre transplant use of GO and the incidence of VOD have decreased in the last few years as practices change. The plan is to look at the database on both of these numbers and reassess whether it is worth move this study forward in its current form. The committee was asked to vote on the priority of this study for the next year. Also, committee members will be invited to participate in the writing committee, depending on voting results.

b. RT06-01 Evaluation of TGF-β1 promoter and signal peptide polymorphisms as risk factors

for renal dysfunction in hematopoietic transplant patients treated with cyclosporine A (R Shah) Manuscript Preparation. MP updated the group on behalf of the PI. He informed the group that the study has been completed and it is currently in manuscript preparation. The overall message of the study is that there was no association found between TFG-B1 polymorphism and the development of renal insufficiency/failure with cyclosporine exposure. The lack of an effect could be related to the sample size. After typing each individual, the number of patients with homozygous polymorphisms that could be related increase renal toxicity was small. This manuscript is expected to be submitted by June 2010.

c. RT07-02 Interaction between comorbidities and aging and their combined impact on the

hematopoietic cell transplantation Outcomes (M Sorror) Data Collection. Mohammed Sorror (MS) presented the status of his study, which is currently in data collection. The main objective is to validate the HCT-comorbidity index (HCT-CI) using data registered with the CIBMTR. MS reviewed the latest demographic tables. Presently, sufficient data have been collected from the pre-TED forms, however additional follow-up is necessary prior we can initiate the analysis. MS explained that with the current CIBMTR data, the total comorbid score calculated for the cohort does not exceed a score of 6, whereas with the Seattle data on the original publication, there were a number of patients with scores greater than 6. MS highlighted that this discrepancy could be due to incorrect reporting of the comorbidities by centers or underscoring of “other comorbidities” in the other specified field on pre-TED. The plan is to identify the source of this discrepancy, by looking at cases reported by Seattle and comparing with cases at Seattle patient database to assess whether this was a reporting bias or other. This will need to be done while waiting for the data to mature with more follow up. Gorgun Akpek (GA) asked if there was an observed difference among patients who received reduced intensity conditioning (RIC) vs. myeloablative conditioning as one would expect more comorbidities in the RIC group, however this was not reflected in the data shown. Another member questioned the accuracy of regimen intensities groups. MP responded that unlike the old forms, the pre-TED form collects data on the intent of the conditioning regimen at transplant, as such the intensity designations are more accurate. The

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plan is to have a minimal of 1 year follow up of all patients in the data set before moving to analysis.

d. RT08-01 End-stage renal disease in bone marrow transplant recipients (H Trivedi, P Hari, E Cohen) Protocol Development. Parameswaran Hari (PH) presented the study. The main aim of the study is to examine the relative incidence and mortality among patients who developed end stage renal disease after an unrelated donor (URD) transplantation. The study will require matching and merging CIBMTR data with data from the United States Renal Data System (USRDS) before data cleaning and analysis. PH informed the group that a finalized protocol was available and IRB approval has been received for the study. Since there are some costs involved in matching the data from the USRDS, PH mentioned that depending on the costs the study will be delayed in order to secure funds. We now await response from the USRDS before moving to the next step of data file preparation.

e. RT08-02 The effect of prior splenectomy on myeloid engraftment after myeloablative

allogeneic stem cell transplantation: An IBMTR analysis (G Akpek) Data file preparation. GA presented the study. The primary outcomes of the study are to evaluate time to engraftment and 100 day non relapse mortality among patients with or without prior splenectomy. He updated the group on the total patient numbers based on the final selection criteria outlined in the finalized protocol. The final population includes a total of 8,329 patients without splenectomy vs. 1236 patients with splenectomy. With a finalized protocol and an established writing committee, the next step is to clean the data file and move on to analysis. The goal for the study is to finalize the analysis and submit an abstract to ASH. Vikas Gupta (VG) asked if there was any information in the database on reason for performing the splenectomy as 16% of the patients with MDS/RA had received a splenectomy. VH explained that although the reason for splenectomy is not listed, we excluded all patients with lymphoma and those transplanted prior to 1999 to keep the population as homogenous as possible. Stephan Ciurea noted that there could be center effect or a difference in procedure as in some centers physicians prefer to have the spleen removed before transplantation. Christopher Bredeson (CB) asked whether is possible to know the size of the spleen to account this in the analysis. PH asked about patient who received splenic radiation as a possible mechanism to abrogate splenic function and treat splenomegaly in patients that cannot undergo splenectomy. These patients were excluded from the study population. KB suggested that if there is enough interest in patients with splenic radiation that could be proposed as a new study to the committee in the future.

f. RT09-01 Primary graft failure following allogeneic HSCT for treatment of hematological

malignancies (R Olsson, J Schriber, S Chaudhry, O Ringden) protocol development. Richard Olsson (RO) presented the study on behalf of the other study chairs. This study is a combination of three proposals on graft failure accepted by the committee last year. The primary aim is to evaluate risk factors for primary graft failure among patients with hematologic malignancies after allogeneic transplantation with myeloablative conditioning. Primary graft failure is defined as 2nd transplant by or before day 28 and alive but not engrafted (ANC < 500) by day 28. RO informed that with the study is still under protocol development, the plan is to finalize the protocol by June 2010 and to move on to data file preparation and analysis by June 2011. Willis Navarro (WN) asked about the patients who received BM+PB grafts having a high graft failure rate of ~7% compared to patients who received other graft types. VH responded that this might be reflective of the fact that for these patients enough BM stem cells were not collected and so PB cells were used as a supplement. SA asked if CMV match will be included in the list of variables to be analyzed as a recent publication by Spellman et al showed that CMV is a risk factor for graft failure.

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This variable will be included in the model. One member pointed out that some of the 464 patients who were excluded because of missing ANC recovery data could be graft failure cases and suggested that this data should be requested for from teams and not excluded. The group agreed that this data should be requested for and included in the study. PH asked about the patients who received more than five transplants and suggested to check the disease and whether these are donor cellular infusions. This data will be checked with the teams and cleaned during data file preparation. RO is coming to Milwaukee and will be working on data file preparation in the spring 2010.

g. RT09-02 Effects of body mass in children with leukemias (R Aplenc, N Bunin) protocol

development. Nancy Bunin (NB) presented the study. This study was proposed last year and the main aim is to compare leukemia free survival and overall survival after transplantation according to BMI groups in children. The study will also look at the impact of dose adjustment on survival among the different BMI groups. The statistics for the study will be done at the PI’s center. The study is currently in protocol development and the plan is to finalize the protocol by June 2010. One member asked if it would be possible to look at non leukemia pediatric patients who received cy-based regimens. NB responded while this is possible, this has recently been explored and reported in patients with SAA by Barker et al. She also stated that although she can include non leukemia patients, it will increase the heterogeneity of the group as such non malignant diseases have been excluded to keep the population homogenous.

5. Future/Proposed studies

a. PROP 1208-30 Comparison of clinical outcomes between myeloablative and RIC for haploidentical stem cell transplantation (S Ciurea.). SC presented his proposal. The main hypothesis is that haploidentical stem cell transplantation using RIC is associated with less treatment related mortality and at least similar outcomes as MA conditioning. Additionally, the study will assess the role of T-cell depletion (TCD) in the setting of haploidentical donor transplants with overall survival as the primary endpoint of the study. This study was proposed last year and although it was well received by the committee it was deferred due to small sample sizes. SC in the last year communicate with other investigators and will be collaborating with Ephraim Fuchs from Johns Hopkins and add 203 patients who received cyclophosphamide a haploidentical donor transplantation. Additionally there are 507 patients who received myeloablative conditioning (MAC)with T-cell depleted haploidentical grafts (TCD), 180 patients who received MAC without TCD, and 99 patients who received reduced intensity conditioning (RIC) for this study. One member asked if ATG will be considered as T-cell depletion. SC responded that ATG was not considered as a TCD method. One member asked how the differences in non myeloablative (NMA) vs. MA conditioning will be accounted for in the analysis as this might be a potential bias in the study. SC explained that we will be comparing approaches among the three groups rather than the actual regimens received.

b. PROP 0909-01 Survival after second allografting following a myeloablative conditioning in

patients with relapsed hematologic malignancies: A CIBMTR report (G Akpek) GA presented the proposal. The primary hypothesis, which is based on his own clinical experience, is that a second allo transplant is a feasible approach for treatment of post allogeneic transplant relapse. The study proposal will include patients with AML/ALL, who received RIC in first transplant, relapsed and went on to received MAC at second transplant. One member pointed out that it would be important to try to answer the question about the benefits of RIC after 2nd transplant as well. The group agreed to include subsequent

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transplants with RIC. A suggestion was made to exclude patients transplanted prior to 2000 as patients transplanted in that era will not add any knowledge to what is already known in the field and this new proposal should define a modern era in order for the study to be relevant. The group agreed to consider this suggestion.

c. PROP 1009-01 C-reactive Protein (CRP) To Predict Non-relapse Mortality after Allogeneic

Hematopoietic Cell Transplantation (HCT) (A Artz). Arthur Artz (AA) presented his proposal. The main objective is to evaluate the prognostic significance of pre-HCT C-reactive protein (CRP) levels on non relapse mortality and its effects on survival, AGVHD and HCT related toxicity. AA explained that CRP is a readily available biomarker and previous publication of < 100 patients has found CRP to be correlated with post transplant outcome. The study will also attempt to establish an optimal cutpoint for pre-HCT CRP levels that independently predicts NRM. There are currently 497 patient’s ≥18 in the NMDP repository with serum samples that can be tested for CRP presence and included in the study. One member asked why children were not included in the study population. AA explained that although he is open to include children in the study population, he would prefer adults as most CRP data has been generated in adult populations only. One member pointed out that there is sufficient CRP data on pediatric populations outside the transplant field. There was a question on the stability of the tissue samples and the timing of evaluating the samples for CRP when it arrived at the lab. As one member pointed out a delay in evaluating the samples could lead to higher levels CRP released from dying cells, which would interfere with interpretation of the analysis. AA responded that most of published reports that looked at CRP used samples collected in a similar way but this is an interesting consideration. Others suggested looking at other potential biomarkers that are clinically available which would maximize the use of samples collected by the NMDP.

d. PROP 1009-03 Effect of ATG and TBI on outcomes in patients receiving reduced intensity

allogeneic transplants (J Hsu) J Hsu (JH) presented his proposal. This study compares clinical outcomes among four groups of patients according to use of total body irradiation (TBI) and anti-thymocyte globulin as part of their conditioning regimen for an allogeneic transplantation. These groups include recipients of TBI vs. ATG vs. both vs. neither. One member requested that patients who received alemtuzumab be included in the study as well. Another member asked if there were enough numbers to evaluate these four groups.

e. PROP 1209-36 HCT for patients with L-F syndrome (J Schiffman, M Pulshipher). Michael

Pulsipher (MP) presented the study to the committee. The main hypothesis for the study is to describe the outcomes of patients with Li-Fraumeni syndrome (LFS) after transplantation. Patients with LFS have a higher risk of developing second malignancies which might be a significant problem after transplantation. There were a total of 12 patients identified in the CIBMTR database. It was asked if these cases will be confirmed with the teams. MP informed the group that if the study is approved all of the 12 cases will have to be confirmed by reviewing case reports. LFS is not readily collected on the forms and the presence of 17p deletion was extracted from the acute leukemia forms, which will need to be confirmed if these represent a somatic mutation or limited to the malignant clone. Another member was interested in knowing the average time to develop second malignancies among LFS patients and the median follow-up time for the cohort. MP responded that according to scarce reports LFS patients are might develop second malignancies within 3-5 years from transplantation, The average follow-up of survivors as reported in the CIBMTR database is 12 months, with a range of 3-24 months. Jeff Schriber (JS) pointed out that more follow-up is needed in

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order to determine if LFS patients develop second malignancies more rapidly after transplant.

f. PROP 1209-47 Assessment of pulmonary complications post transplant in association with

A1B8DR3 haplotype in allo tx recipients (H Liu, P McCarthy, T Hahn). Hong Liu (HL) presented the proposal. She informed the group that in a study recently presented at ASBMT, patients with A1B8DR3 haplotype were shown to have a decreased disease free survival and overall survival. Additionally, other studies have shown that these patients have a higher incidence of pulmonary complications and bronchitis obliterans. The aim of the proposal is to investigate the incidence of pulmonary complications and its association with the A1B8DR3 haplotype among BM or PB patients with AML, ALL or MDS who received a 10/10 HLA URD match or 6/6 HLA relate donor match between 1999-2007. Patients who received a prior allo tx or auto tx, cord blood and ex vivo t-cell depletion will be excluded from the study. Carolyn Hurley wanted to know what markers will be used to determine which haplotypes carry the three specificities making up A1B8DR3. PM responded that this will be determined using statistics to predict who is likely or unlikely to have A1B8DR3 based on other known haplotypes. Another member asked if there was data on pre-transplant pulmonary toxicity or morbidity. He was informed that the pulmonary toxicity is collected on the CIBMTR form however, that data was not included in the tables for the meeting. Another member raised concern of the linkage of TNF-a polymorphism asked how an independent cause of the haplotype was going to be ruled out of the study.

g. PROP 1209-48 Pre-transplant risk factors for relapse after RIC allo (F Baron) Frederic

Baron (FB) presented his proposal. The study proposes to validate the Kahl scoring system which predicts relapse rates among patients. The patient criteria will include allogeneic patients with malignancies who received NMA or RIC conditioning for a first transplant. MS asked for clarification on the definition of relapse which will be used in the study and inquired if the study will be predicting early progression or late relapse. MS and Kenneth Cooke (KC) pointed out that the proposal may not belong in the RRT committee and that it might be better suited for a committee such as late effects working committee.MCP explained to the group that when proposals are submitted, they are triaged to a particular committee and in this case, it came to RRT because it was related to a reduced intensity question and it was not disease specific. He informed the group that although the study is a relapse question the acute leukemia and lymphoma committee were not interested in the study because of other similar studies in that committee. Depending on the priority score we will bring this to proposal to other committee and perhaps this could be merged with other existing studies.

Deferred Study a. PROP 1208-49 Genetic Polymorphisms and HCT related mortality Re: Pre HCT

conditioning in MUD HCT (T Hahn). This study was not presented however MCP informed the group that Theresa Hahn was awarded with an R01 grant to perform GWAS in unrelated donor samples to predict TRM. The study is a joint study with the RRT working committee and the Immunobiology working committee.

The meeting was adjourned at 2.25pm.

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Voting results for RRT working committee Tandem 2010 PROPOSALS Priority score 0 1 2 Total PROP 1208-30 (S Ciurea) 5 11 16 21 PROP 0909-01 (G Akpek) 4 11 20 27 PROP 1009-01 (A Artz) 4 14 14 24 PROP 1009-03 (J Hsu) 8 13 6 11 PROP 1209-36 (J Schiffman, M Pulshipher) 8 9 12 13 PROP 1209-47 (H Liu, P McCarthy, T Hahn) 4 9 24 29 PROP 1209-48 ( F. Baron) 0 9 30 29 For proposals

0 = not recommended/doable at this time 1= low priority 2= high priority

STUDIES IN PROGRESS Priority score 0 1 2 3 Total RT05-01 Smiley 1 6 12 1 33 RT08-01 Trivedi 3 13 5 44 RT09-02 Bunin 1 11 9 50 Ranking

0 = dropped 1= deffered 2= continue low priority 3=continue high priority

• Based on the voting results the goals for the next fiscal year is as follows:

Study # and – PI

Study status on 02/23/2010

Goal by 06/30/2010

Anticipated Goal 06 /30/2011

Additional notes

Studies in progress D98-70 Uberti Accepted Published N/A RT05-03- Schriber Accepted Published N/A SC03-01/R02-26 Navarro Submitted Published N/A RT05-02- Barker MS prep Published N/A RT06-02 Horan MS prep Published N/A RT06-01 Shah MS prep Published N/A RT07-01 Sorror Data collection Data collection Data file prep

RT05-01 Smiley Protocol development

Protocol development Data collection

pending if Gemtuzamab used has decreased or increased

RT08-01 (Trivedi) Data file prep Data file prep Analysis RT08-02 (Akpek) Data file prep Data file prep MS prep RT09-01 (Olsson, Schriber, Ringden Chaudhry)

Protocol development Data file prep Analysis

RT09-02 (Aplenc Bunin) Protocol development

Data file prep Data file prep

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Proposals PROP 1208-30 (Cuirea)

New proposal N/A Protocol development

** Request draft protocol by 10/01/2010

PROP 0909-01 ( Akpek) New proposal N/A Protocol development


PROP 1009-01 (Artz) New proposal N/A Protocol development


PROP 1209-47 (Lui McCarthy Hahn) New proposal

N/A Protocol development


PROP 1208-49 (Hahn) New proposal N/A Protocol

development ** Request draft protocol by 09/01/2010

PROP 1209-48 (Barron) New proposal N/A Protocol

development ** Request draft protocol by 09/01/201

PROP 1209-36 (Schiffman Pulsipher) New proposal Not accepted

N/A N/A

PROP 1009-03 (Hsu) New proposal Not Accepted N/A N/A

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Accrual Summary for Regimen-Related Toxicity/ Supportive Care Working Committee

Characteristics of recipients of allogeneic transplant reported to the CIBMTR between

1990 and 2010 Characteristics of patients Registration N (%) Research N (%)Number of patients 60091 43982Number of centers 488 409 Age, median (range), years 36 (


Accrual Summary for Regimen-Related Toxicity/ Supportive Care Working Committee

Characteristics of recipients of autologous transplant reported to the CIBMTR between

1990 and 2010

Characteristics of patients Registration N (%) Research N (%)Number of patients 82236 19073Number of centers 515 358Age, median (range), years 52 (


TO: Regimen-Related Toxicity Working Committee Members FROM: Marcelo Pasquini, MD, MS, Scientific Director for the Regimen-Related Toxicity WC RE: Studies in Progress Summary

RT06-01s: Evaluation of TGF-β1 promoter and signal peptide polymorphisms as risk factors for renal dysfunction in hematopoietic transplant patients treated with cyclosporine A (R Shah): The objectives of this study are 1) genotype hematopoietic transplant patients treated with CsA for three functional TGF-β1 promoter single nucleotide polymorphisms (SNPs): 1550 AGG insertion, -509C-T and +869T-C; 2) to collect data on serum creatinine and blood urea nitrogen before and after the hematopoietic transplant at predefined time intervals as a measure of renal dysfunction; 3) to evaluate the association(s) of TGF-β1 promoter polymorphisms (SNPs -1550, -509 and +869) on development of renal dysfunction in patients receiving CsA for GVHD prophylaxis. The current status is manuscript preparation.

RT08-02: The effect of prior splenectomy on myeloid engraftment after myeloablative allogeneic stem cell transplantation: a CIBMTR analysis (G Akpek): The objectives are 1) to compare engraftment and 100-day survival between transplant recipients with or without splenectomy prior to stem cell transplantation; 2) to compare the cumulative incidence of acute and chronic GVHD and overall survival at 1 year post transplant. Analysis was completed in 2010 and results were presented at the ASH meeting as poster. The manuscript will be finalized soon.

RT09-01: Primary graft failure following allogeneic HSCT for the treatment of hematological malignancies (R Olsson): The objective is to identify risk factors for primary graft failure following myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematological malignancies, with subset analysis in children. This study will also analyze risk factors for graft failures at day 14 and 21 post transplant. The current status is analysis. Initial risk factor analysis in all the population was accepted for oral presentation at the EBMT 2011 meeting. RT07-01: Interaction between comorbidities and aging and their combined impact on hematopoietic cell transplantation outcomes (M Sorror): This study are 1) to investigate the interaction between comorbidities, aging and the addition of age intervals to the HCT-CI to form composite scores using retrospective data collected from 6 collaborative academic institutions; 2) to validate the comorbidities ± aging scores on HCT outcomes using data from the Center for International Bone Marrow Transplantation Registry (CIBMTR). The study started data collection in November 2007.The current status is data file preparation. In 2010, the protocol was expanded to validate the HCT-CI in allogeneic transplant for nonmalignant diseases. This updated will be presented at the RRTWC meeting in Honolulu. RT08-01: End-stage renal disease in bone marrow transplant recipients (H Trivedi): The objectives of this study are 1) to describe the incidence of ESRD and the time to development in URD HCT recipients; 2) to describe the relative incidence of end-stage renal disease in bone marrow transplant recipients from unrelated donors (URD) as compared to the general population; 3) to describe changes in incidence rates of ESRD after BMT in URD over time; 4) to determine the mortality after ESRD in URD compared to transplant recipients of URD transplants who do not develop ESRD (including subgroup analysis

14


according to modality of renal replacement therapy, dialysis vs. kidney transplantation), and to ESRD patients who have not undergone BMT. Data merge with USRDS database was needed to identify cases on chronic renal replacement therapy. Initial attempt to merge the CIBMTR and USRDS databases lead to few cases and another attempt is underway using more identifiers. The current status is data file preparation. RT09-02: Effects of body mass in children with leukemias undergoing allogeneic bone marrow transplant (N Bunin): The objectives are 1) to compare leukemia free survival and overall survival in children with leukemias who underwent allogeneic HSCT by body mass index (BMI) in under, over, and normal weight patients; 2) to compare transplant related morbidity and mortality in under, over and normal weight patients; 3) to evaluate the impact of chemotherapy dose intensity on survival by BMI. The current status is data file preparation. Plan is to move to analysis by June 2011. RT09-04: Assessment of genetic polymorphisms and transplant-related mortality in relation to conditioning regimen before HLA-matched unrelated donor allogeneic SCT (T Hahn): The objectives are 1) to identify genetic polymorphisms that are associated with transplant related mortality in recipients of unrelated donor transplants; 2) to test for a genetic association with type of transplant-related mortality (infection, GVHD, organ failure) by conditioning regimen. The current status is protocol development. This study is federally funded to run genome-wide association studies with unrelated donor and recipient samples and associate with clinical outcomes. Accepted studies, but not initiated RT09-03: Comparison of clinical outcomes between Myeloablative And Reduced-Intensity Conditioning for Haploidentical Stem Cell Transplantation (S Ciurea): The aims are 1) to describe the outcomes of patients with hematologic malignancies (myeloid and lymphoid) treated with haploidentical stem cell transplantation (≥ 2 antigens mismatch), and identify variables associated with improved survival; 2) to compare the outcomes of patients treated with a T-cell depleted as compared with a T-cell replete haploidentical graft; 3) to determine whether RIC is associated with reduced toxicity and overall at least as effective as MA conditioning for haploidentical stem cell transplantation. RT10-01: C-reactive Protein (CRP) To Predict Non-relapse Mortality after Allogeneic Hematopoietic Cell Transplantation (HCT) (A Artz): The aims are 1) to determine the variability in c-reactive protein (CRP) levels prior to allogeneic hematopoietic cell transplant (HCT) conditioning; 2) to evaluate the prognostic significance of pre-HCT CRP levels on non-relapse mortality (NRM); 3) to quantify the prognostic impact of pre-HCT CRP levels HCT related toxicity and acute GVHD; 4) to assess the influence of pre-HCT CRP levels on overall survival; 5) to establish an optimal cutpoint for pre-HCT CRP levels to independently predict NRM. RT10-02: Survival after second allografting following a myeloablative conditioning in patients with relapsed hematologic malignancies: a CIBMTR report (G Akpek): The objectives are 1) is to evaluate overall survival at day 100 and at one-year after second allogeneic stem cell transplantation following myeloablative conditioning; 2) to include rate of complete remission after second allografting, relapse-free survival, the cumulative incidence of acute and chronic GVHD. RT10-03: Assessment of pulmonary complications post-transplant in association with A1B8DR3 haplotype in allogeneic hematopoietic cell transplant recipients (H Liu): The objectives are 1) to examine the incidence of pulmonary complications and their association with A1B8DR3 haplotype; 2) to include incidence and severity of acute and chronic GvHD, progression-free survival (PFS) and overall survival (OS) and their association with A1B8DR3 haplotype. The study is under protocol development stage.

15


RT10-04: Pre-transplant risk factors for relapse after RIC allo transplantation (F Baron): The aims are 1) to validate the Kahl scoring system in a large cohort of patients given a truly non-myeloablative conditioning (Flu+2 Gy TBI, Flu-Cy, or TLI-ATG) or a more intense reduced-intensity conditioning regimen (Flu-Bu ≤8 mg/kg, Flu-Mel 140, Flu+4 Gy TBI, or Fluda-Thiothepa ≤10 mg/kg); 2) to calculate the relapse rate per patient year (PY) during the first 2 years after transplantation in each disease stage defined in the Kahl study in the whole study group; 3) to adapt the Kahl scoring system according to the relapse-risk of each disease stage calculated in the first secondary endpoint; 4) to validate the new scoring system (if different from the Kahl scoring system); 5) to compare the Kahl and the new scoring system; 6) to compare the impact of conditioning intensity (nonmyeloablative versus RIC) on relapse risk after adjustment with the disease-risk scoring system. The study is under protocol development stage.

16


CIBMTR RT07-01

PROSPECTIVE VALIDATION OF THE IMPACTS OF THE HEMATOPIETIC CELL TRANSPLANTATION COMORBIDITY INDEX, ALONE AND COMBINED WITH AGING ON

HEMATOPOIETIC CELL TRANSPLANTATION OUTCOMES

DRAFT PROTOCOL Study Chair: Mohamed L. Sorror, MD, MSc

Fred Hutchinson Cancer Research Center University of Washington, Department of Oncology

1100 Fairview Ave. North, D1-107 PO Box 19024 Seattle, WA 98109 USA Telephone: 206-667-2765 Fax: 206-667-6124 E-mail: [email protected]

Study Statistician: Xiaochun Zhu, MS

Medical College of Wisconsin CIBMTR 9200 West Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected]

PhD Statistician: Brent Logan, PhD Medical College of Wisconsin CIBMTR

8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-8849 Fax: 414-456-6513 E-mail: [email protected]

17

Not for presentation or publication Attachment 4

Scientific Director: Marcelo Pasquini, MD, MS

Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected]

Working Committee Chairs: Kenneth R. Cooke, MD Director, Pediatric BMT Program Case Western Reserve University School of Medicine Department of Pediatrics Wolstein Research Building 6th Floor, Room 6524 2103 Cornell Road Cleveland, OH 44106-7288 Telephone: 216-368-0481 Fax: 216-368-0741 E-mail: [email protected] Vincent T. Ho, MD Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Telephone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected]

Philip McCarthy, MD Medical Director, Bone Marrow Transplant Program Roswell Park Cancer Institute Elm and Carlton Street Buffalo, NY 14263 Telephone: 716-845-4074

Fax: 716-84503272 E-mail: [email protected]

18


1.0 OBJECTIVES:

1.1 Validate the prognostic impacts of the HCT-CI on the HCT outcomes among patients diagnosed with various hematological diseases. 1.1.1 Allogeneic HCT for malignant disease 1.1.2 Allogeneic HCT for non-malignant diseases 1.1.3 Autologous HCT for all diseases

1.2 Validate the prognostic impacts of the HCT-CI + aging scores on HCT outcomes and

compare its predictive capacity to that of the HCT-CI alone. 1.3 Stratify outcomes of recipients of nonmyeloablative and myeloablative with hematologic

malignancies allogeneic HCT using the HCT-CI ± aging scoring systems. 2.0 SCIENTIFIC JUSTIFICATION:

Comorbidities have been reported to affect chemotherapy dosing, treatment toxicity, survival, and quality of life of patients with cancer. [1,2] The use of comorbidity indices has facilitated the incorporation of comorbidities into decision-making for treatment and clinical trial design.(Reviewed in[3]) The Charlson comorbidity index (CCI) [4] has been the most widely used comorbidity index to predict mortality risks in various diseases and solid malignancies. [5] Allogeneic conventional HCT is considered potentially curative for many patients with hematological malignancies but has been limited to patients without significant comorbidities and who were less than 50 to 65 years of age. [6-13] With the advent of minimally toxic conditioning regimens, the HCT choices have been expanded to include older patients and those with comorbidities. We developed a nonablative regimen, which consists of 2 Gy total body irradiation (TBI) either alone or in combination with fludarabine. [14,15] The regimen largely relies on graft-versus-leukemia effects for tumor cell kill. This nonablative regimen has expanded allogeneic HCT to include elderly and comorbid patients with various hematological malignancies. [16-18] There are continued efforts to evaluate novel approaches in the laboratory to further reduce the intensity of conditioning regimen thereby further minimizing its side effects. As these novel approaches will be introduced in the clinic in the future, it has become important to comprehensively study the comorbidity differences between patient groups, investigate the interactions between comorbidities and aging and their impacts on HCT outcomes and quality of life to help standardize comorbidity assessment for future clinical trials. Several investigators have studied single organ comorbidities as predictors for HCT outcomes. [19-26] None of these has taken into account the impact of different comorbidities or their interaction with age. We began systematic analyses of the roles of comorbidities on HCT outcomes using the CCI as a non-transplantation specific comorbidity index. We applied the CCI to the settings of myeloablative and nonmyeloablative allogeneic HCT in patients with hematological malignancies. We found that an adapted form of the CCI successfully predicted the risks of 1-year NRM in patients given HCT from unrelated [27] or related donors [28]. In a further analysis, we found that the CCI detected comorbidities among only 35% of all HCT patients (12% among myeloablative patients [27]). Therefore, we developed a new index that more specifically addressed comorbidities in HCT patients.

We refined comorbidity definitions, added newly identified comorbidities, and, evaluated each comorbidity category by Cox regression hazard models in a training set of patients. The HCT-CI was then tested in a randomly-selected validation set of Seattle patients, where 62% of patients had HCT-CI scores of >0 compared with 12% by the original CCI. [29] Overall, the HCT-CI was

19


better able to capture comorbidities and to predict NRM than the CCI among HCT recipients. Results were further retrospectively validated among a different patient population diagnosed with a single disease entity, AML in first remission, and transplanted in MD Anderson Cancer Center. [30] The HCT-CI could also be used to efficiently compare the risk-benefit ratios among nonmyeloablative versus myeloablative patients diagnosed with either myeloid[31] or lymphoid malignancies. [32] Our ongoing studies are aimed at understanding the correlation between comorbidities and another important pretransplant factor, age and investigating their joint importance for outcomes. To this purpose, retrospective data are being collected from six academic institutions within the Seattle Consortium, and comorbidities are assessed by a single investigator. The data is being used to develop a new HCT-CI + ageing scoring system, which should further refine risk assessment among transplanted patients with different HCT strategies. The effectiveness of HCT-CI in prediction of HCT outcomes specifically for non-malignant diseases has not been extensively studied. Patients receiving allografts for non-malignant conditions have the potential of having distinct comorbidity profiles specific to their diseases that may or may not affect outcomes in the same manner as malignant patients. The initial HCT-CI study included only 3% of patients with non-malignant diseases[29] and, likewise, other studies evaluating comorbidities and HCT outcomes of non-malignant patients suffered from relatively small sample of patients.[33] Other complexities when studying non-malignant diseases include the wide spectrum of diseases, ranging from marrow failure syndromes to immunodeficiencies and metabolic diseases, and the bias of having a cohort of younger patients at time of transplant. It is of extreme importance to validate these findings in a large cohort of patients, who are prospectively treated and assessed by multiple local investigators. Although combining malignant and non-malignant patients when performing a prospective analysis would increase numbers, the challenges in disease presentations and defining outcomes make it critical to analyze both groups separately. A prospective study of both malignant and non-malignant diseases would ensure the accuracy and the universal application of the HCT-CI ± aging scoring systems in comparing clinical trial outcomes with given treatment modalities obtained at given academic centers to those achieved at others and in assessing the risk-benefit ratios for planned treatments.

3.0 STUDY POPULATION: The study population will include all patients who received an autologous or allogeneic HCT for a hematological malignant or non malignant disease of any stage, reported to the CIBMTR within a duration of 12 month starting roughly from January 2008. No restrictions for age, degree of host-donor HLA-matching, or type of conditioning regimen, however, patients receiving a cord blood transplant will be excluded. Potential numbers of subjects are given in Table 1.

4.0 OUTCOMES: Primary Outcomes: 4.1 Impacts of HCT-CI scores on post-HCT outcomes: We will analyze predictive capacity

of the HCT-CI for non-relapse mortality (NRM) and overall survival separately among recipients of allogeneic and autologous HCT for treatment of malignant diseases. For patients with non-malignant diseases, we will analyze the impact of HCT-CI on overall survival. Stratification by the individual HCT-CI scores as well as the collapsed risk

20


groups will be investigated. Events will be summarized by a cumulative incidence and Kaplan Meier survival curves, respectively. The competing risk for non-relapse mortality is relapse for malignant diseases Patients alive (or alive and without relapse) at last observation are considered censored for this event. The independent impacts of the HCT-CI on NRM and overall survival will be tested in multivariate models, after adjustment for other pre-transplant variables, among all patient population. Separate analyses for patients with myeloid and lymphoid malignancies and nonmalignant diseases will be performed. The prognostic ability of these models will be examined at four time points: Day 100, Day 180, Day 365, and Day 730.

4.2 Effect of the comorbidity-age composite scores on HCT outcomes: We will compare the

discriminative capacity of the HCT-CI + age composite scores and HCT-CI scores for predicting the previously mentioned HCT outcomes. Assess whether specific outcomes might be better predicted by the composite scoring system.

Secondary outcomes: 4.3 Comparison of the HCT outcomes between recipients of nonmyeloablative and

myeloablative allogeneic HCT: The most successful measure from the analysis of the primary outcomes will be used to risk-stratify and compare the outcomes of patients given nonmyeloablative versus myeloablative regimens and separately for the myeloid and lymphoid malignancies.

5.0 DATA COLLECTION:

Comorbidity data and HCT-CI scores will be collected prospectively from patients transplanted within one year duration (roughly between January and December 2008) using the new CIBMTR SCTOD forms. Requested data will also include all demographic and pre-transplant data collected on the CIBMTR data collection forms. Follow up data will be collected starting from day 100 (roughly in April 2009) and to be continued at days 180, 365, and 730.

6.0 VARIABLES TO BE ANALYZED:

Patient-related variables

– Age at transplant – Gender: Male vs. female – Race of patient – Karnofsky/Lanksy score at transplant – Pre-transplant comorbidities and HCT-CI score

Disease-related variables – Disease – Disease status prior to transplant(where applicable) – Interval between diagnosis and HCT – Donor/Recipient CMV sero-status – Cytogenetics (if applicable)

Transplant-related variables

– Year of transplant – Type of transplant

21


– Conditioning regimen – Type of preparative regimen: ablative vs. non-ablative – Planned sequential transplant or not. – Source of stem cells – Graft manipulation – Number of CD34+ and CD3+ cells – Type of Donor (where applicable) – Donor sex – HLA match status – GVHD prophylaxis

7.0 STUDY DESIGN:

Data from the CIBMTR will be used for validation of the impacts of comorbidities ± aging scores on HCT outcomes. Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Inter-rater reliability rates will be evaluated and reported as part of the study. This evaluation will compare a sample of patients whose HCT-CI were calculated using data reported to the CIBMTR and compared to an independent review of each patient by a physician. The reviewer will be blinded to the score assigned using the CIBMTR data. One hundred patients from at least two transplant centers will be randomly selected for this comparison. The degree of agreement between evaluations will be analyzed using kappa statistics. Cumulative incidence or Kaplan-Meier curves will be calculated for incidences of NRM and overall survival. Analyses of survival and NRM incidences will be done using the Cox regression model. Relapse will be treated as a competing risk for NRM, and vice versa. The relationship between comorbidity scores and HCT outcomes will be examined using Cox regression. The prognostic discriminatory capacity of the HCT-CI as compared to a composite score incorporating age will be assessed by comparing the Brier scores [29] of the two models at each of the four time points of interest.

8.0 REFERENCES:

1. Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chron Dis 23: 455-468, 1970.

2. Van Spronsen DJ, Janssen-Heijnen ML, Breed WP, Coebergh JW. Prevalence of co-morbidity and its relationship to treatment among unselected patients with Hodgkin's disease and non-Hodgkin's lymphoma, 1993-1996. Ann Hematol 78: 315-319, 1999.

3. Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 35: 181-200, 2000.

4. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40: 373-383, 1987.

5. Di Iorio B, Cillo N, Cirillo M, De Santo NG. Charlson Comorbidity Index is a predictor of outcomes in incident hemodialysis patients and correlates with phase angle and hospitalization. Int J Artif Organs 27: 330-336, 2004.

6. Goldstein LB, Samsa GP, Matchar DB, Horner RD. Charlson Index comorbidity adjustment for ischemic stroke outcome studies. Stroke 35: 1941-1945, 2004.

22


7. Hemmelgarn BR, Manns BJ, Quan H, Ghali WA. Adapting the Charlson Comorbidity

Index for use in patients with ESRD. American Journal of Kidney Diseases 42: 125-132, 2003.

8. Sachdev M, Sun JL, Tsiatis AA, Nelson CL, Mark DB, Jollis JG. The prognostic importance of comorbidity for mortality in patients with stable coronary artery disease. J Am Coll Cardiol 43: 576-582, 2004.

9. Lubke T, Monig SP, Schneider PM, Holscher AH, Bollschweiler E. Does Charlson-comorbidity index correlate with short-term outcome in patients with gastric cancer? [German]. Zentralblatt fur Chirurgie 128: 970-976, 2003.

10. Firat S, Byhardt RW, Gore E. Comorbidity and Karnofksy performance score are independent prognostic factors in stage III non-small-cell lung cancer: an institutional analysis of patients treated on four RTOG studies. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 54: 357-364, 2002.

11. Sabin SL, Rosenfeld RM, Sundaram K, Har-el G, Lucente FE. The impact of comorbidity and age on survival with laryngeal cancer. Ear, Nose, & Throat Journal 78: 578-4, 1999.

12. Singh B, Bhaya M, Stern J, Roland JT, Zimbler M, Rosenfeld RM, Har-el G, Lucente FE. Validation of the Charlson comorbidity index in patients with head and neck cancer: a multi-institutional study. Laryngoscope 107: 1469-1475, 1997. Extermann M. Measuring comorbidity in older cancer patients (Review). Eur J Cancer 36: 453-471, 2000.

13 McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger WI, Bryant E, Flowers MED, Georges GE, Grumet FC, Kiem H-P, Torok-Storb B, Yu C, Blume KG, Storb RF. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97: 3390-3400, 2001.

13. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, Petersdorf E, McSweeney P, Pulsipher M, Woolfrey A, Chauncey T, Agura E, Heimfeld S, Slattery J, Hegenbart U, Anasetti C, Blume K, Storb R. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102: 2021-2030, 2003.

14. Maris MB, Sandmaier BM, Storer BE, Chauncey T, Stuart MJ, Maziarz RT, Agura E, Langston AA, Pulsipher M, Storb R, Maloney DG. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood 104: 3535-3542, 2004.

15. Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 23: 3819-3829, 2005.

16. Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W, Storer B, Hegenbart U, Somlo G, Chauncey T, Bruno B, Appelbaum FR, Blume KG, Forman SJ, McSweeney P, Storb R. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102: 3447-3454, 2003.

17. Bearman SI, Petersen FB, Schor RA, Denney JD, Fisher LD, Appelbaum FR, Buckner CD. Radionuclide ejection fractions in the evaluation of patients being considered for bone marrow transplantation: Risk for cardiac toxicity. Bone Marrow Transplant 5: 173-177, 1990.

23


18. Hertenstein B, Stefanic M, Schmeiser T, Scholz M, Göller V, Clausen M, Bunjes D,

Wiesneth M, Novotny J, Kochs M, Adam W-E, Heimpel H, Arnold R. Cardiac toxicity of bone marrow transplantation: Predictive value of cardiologic evaluation before transplant. J Clin Oncol 12: 998-1004, 1994.

19. Fujimaki K, Maruta A, Yoshida M, Sakai R, Tanabe J, Koharazawa H, Kodama F, Asahina S, Minamizawa M, Matsuzaki M, Fujisawa S, Kanamori H, Ishigatsubo Y. Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction. Bone Marrow Transplant 27: 307-310, 2001.

20. Goldberg SL, Klumpp TR, Magdalinski AJ, Mangan KF. Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem-cell and bone marrow transplant recipients. J Clin Oncol 16: 3796-3802, 1998.

21. Crawford SW, Fisher L. Predictive value of pulmonary function tests before marrow transplantation. Chest 101: 1257-1264, 1992.

22. Chien JW, Maris MB, Sandmaier BM, Maloney DG, Storb RF, Clark JG. Comparison of lung function after myeloablative and 2 Gy of total body irradiation-based regimens for hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11: 288-296, 2005.

23. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118: 255-267, 1993.

24. Rozman C, Carreras E, Qian C, Gale RP, Bortin MM, Rowlings PA, Ash RC, Champlin RE, Henslee-Downey PJ, Herzig RH, Hinterberger W, Klein JP, Prentice HG, Reiffers J, Zwaan FE, Horowitz MM. Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. Bone Marrow Transplant 17: 75-80, 1996.

25. Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG, Storb R. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplant comorbidities. Blood 104: 961-968, 2004.

26. Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R. Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 104: 1550-1558, 2004.

27. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106: 2912-2919, 2005.

28. Graf E, Schmoor C, Sauerbrei W, and Schumacher M. Assessment and comparison of prognostic classification schemes for survival analysis. Statistics in Medicine 18: 2529-2545, 1999.

29. Sorror ML, Giralt S, Sandmaier BM, de Lima M, Shahjahan M, Maloney DG, Deeg HJ, Appelbaum FR, Storer B, Storb R. Hematopoietic cell transplantation-specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: Combined FHCRC and MDACC experiences. Blood 110: 4608-4613, 2007. Reference ID: 33146

30. Sorror ML, Sandmaier BM, Storer BE, Maris MB, Baron F, Maloney DG, Scott BL, Deeg HJ, Appelbaum FR, Storb R. Comorbidity and disease status-based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25: 4246-4254, 2007. Reference ID: 32391

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31. Sorror ML, Storer BE, Maloney DG, Sandmaier BM, Martin PJ, Storb R. Outcomes after

allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood 111: 446-452, 2008. Reference ID: 33209

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Table 1: Characteristics of US patients who received an allogeneic HCT for malignant diseases

between 2007 and 2009, registered with the CIBMTR

Characteristics of patients NST/RIC MyeloablativeNumber of patients 2604 6081Number of centers 122 155Age, median (range), years 59 (


Table 1. Continued. Characteristics of patients NST/RIC Myeloablative

ATG +TLI 86 ( 3) 2 (


Table 1. Continued. Characteristics of patients NST/RIC Myeloablative

10 3 (


Table 1. Continued. Characteristics of patients NST/RIC Myeloablativesolid tumor prior

No 2377 (91) 5742 (94)yes 227 ( 9) 339 ( 6)

heart valve disease No 2572 (99) 6050 (99)yes 32 ( 1) 31 (


Table 2: Characteristics of US patients who received an allogeneic HCT for non-malignant

diseases between 2007 and 2009, registered with the CIBMTR.

Characteristics of patients Non-malignant N(%)Number of patients 868Number of centers 188Age, median (range), years 13 (


Table 2. Continued. Characteristics of patients Non-malignant N(%)Donor type

HLA-identical sibling 402 (46)Other related 74 ( 9)Unrelated donor 387 (45)twin 5 (


Table 3: Characteristics of US patients who received an autologous HCT between 2007 and 2009,

registered with the CIBMTR

Characteristics of patients N %Number of patients 13424Number of centers 177Age, median (range), years 56 (=70 796 ( 6)Missing 2 (


Table 3. Continued. Characteristics of patients N %

Other 449 ( 3)BU + FLUD +-other 12 (


Table 3. Continued. Characteristics of patients N %Cerebrovascular disease

No 13275 (99)yes 149 ( 1)

psychiatric disturbance No 11964 (89)yes 1460 (11)

mild chronic hepatitis No 13191 (98)yes 233 ( 2)

Obesity BMI > 35kg/m2 No 12473 (93)yes 951 ( 7)

Infection No 13187 (98)yes 237 ( 2)

Rheumatoid arthritis No 13280 (99)yes 144 ( 1)

Peptic Ulcer No 13244 (99)yes 180 ( 1)

Renal moderate/severe No 12961 (97)yes 463 ( 3)

Pulmonary moderate No 11737 (87)yes 1687 (13)

solid tumor prior No 12660 (94)yes 764 ( 6)

heart valve disease No 13351 (99)yes 73 (


Table 3. Continued. Characteristics of patients N %Research or Ted track patient?

Ted (registration) patient 10499 (78)CRF (research) patient 2861 (21)Missing 64 (


CIBMTR RT09-03

COMPARISON OF CLINICAL OUTCOMES BETWEEN MYELOABLATIVE AND REDUCED-INTENSITY CONDITIONING FOR HAPLOIDENTICAL STEM CELL TRANSPLANTATION.

DRAFT PROTOCOL

Study Chairs: Stefan O. Ciurea, MD M.D. Anderson Cancer Center 1515 Holcombe Blvd. Houston, TX 77030 Telephone: 713-792-6161 Fax: 713-794-4747 E-mail: [email protected] Marcos de Lima, MD M.D. Anderson Cancer Center 1515 Holcombe Blvd. Houston, TX 77030 Telephone: 713-792-4179 Fax: 713-794-4902 E-mail: [email protected] Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Brent Logan, PhD The Medical College of Wisconsin CIBMTR 8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-8849 Fax: 414-456-6513 E-mail: [email protected]

36


Scientific Director: Marcelo Pasquini, MD, MS Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected]

Working Committee Chairs: Kenneth R. Cooke, MD

Case Western Reserve University School of Medicine Wolstein Research Building 2103 Cornell Road Cleveland, OH 44106-7288 Telephone: 216-368-0481 Fax: 216-368-0741 E-mail: [email protected] Vincent T. Ho, MD Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Telephone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected] Philip McCarthy, MD Medical Director, BMT program Roswell Park Cancer Institute Elm and Carlton Street Buffalo, NY 14263 Telephone: 716-845-4074 Fax: 716-845-3272 E-mail: [email protected]

37


1.0 HYPOTHESIS: Haploidentical stem cell transplantation using reduced-intensity conditioning (RIC) is associated with less treatment-related mortality (TRM) and at least similar outcomes as myeloablative (MA) conditioning.

2.0 SPECIFIC AIMS:

2.1 To describe the outcomes of patients with hematologic malignancies (myeloid and

lymphoid) treated with haploidentical stem cell transplantation (≥ 2 antigens mismatch), and identify variables associated with improved survival. Outcomes to be evaluated include: transplant-related mortality (TRM), relapse rate (RR), disease-free survival (DFS) and overall survival (OS).

2.2 To compare the outcomes of patients treated with a T-cell depleted as compared with a T-cell replete haploidentical graft.

2.3 To determine whether RIC is associated with reduced toxicity and overall at least as effective as MA conditioning for haploidentical stem cell transplantation.

2.4 Assess the impact of the number of HLA mismatches on outcomes (Engraftment, TRM, RR, DFS, OS)

2.5 Evaluate outcomes (TRM, RR, OS, DFS) based on predictive NK cell alloreactivity 2.6 Compare the outcomes for patients who received peripheral blood vs. bone marrow 2.7 Assess the impact of lymphocyte recovery (ALC to 1000/µL) on outcomes (TRM, RR,

OS, DFS) 3.0 BACKGROUND:

Hematopoietic stem cell transplantation is an effective treatment for advanced hematologic malignancies, both myeloid and lymphoid. An HLA-identical donor is preferred; however a matched sibling or unrelated donor is unavailable for many patients. Mismatched relatives represent a potential donor source of stem cells for such patients, and virtually all patients will have an available haploidentical donor. Historically, haploidentical stem cell transplantation has been limited by the high rates of graft rejection and acute graft-versus-host disease (aGVHD). T-cell depletion decreased the rate of GVHD at the expense of a higher risk of rejection and, in some settings, a reduced graft-versus-leukemia effect with an increased relapse rate and severe infections. Reisner and colleagues reported that “megadoses” of purified CD34+ cells administered with a T-cell depleted graft can overcome major HLA incompatibility and achieve an acceptable rate of engraftment. Aversa et al. demonstrated the feasibility of using high doses of CD34+ cells in patients undergoing myeloablative HaploSCT and concluded that the optimal composition of the haploidentical graft should contain more than 10x106 CD34+ cells/kg and less than 5x104 CD3+ cells/kg body weight. T-cell replete haploidentical transplantation with the use of post transplant high-dose cyclophosphamide for GVHD prophylaxis has been explored by researchers from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Early clinical studies form this group and the group from Fred Hutchinson Cancer Research Center, indicate favorable outcomes at least for patients with lymphoma. Most studies have used a myeloablative, total body irradiation-based preparative regimens for haploidentical transplants. We and others were concerned about the severe toxicity in this setting with a high rate of transplant-related mortality, particularly in adult patients. A recent review identified median non-relapse mortality (NRM) of approximately 50% in haploidentical stem cell

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transplant patients treated with myeloablative conditioning. For the purpose of this study MA conditioning is defined as TBI > 6 Gy, Busulfan > 8mg/kg or Melphalan > 140mg/m2. Reduced-intensity preparative regimens have been developed to decrease regimen-related toxicities and allow treatment of older or patients with concurrent medical conditions. The experience with such regimens for haploidentical transplantation, where a more profound immune suppression is required to prevent rejection, has been limited. The purpose of this study is to evaluate the outcomes of RIC preparative regimens for haploidentical stem cell transplantation and to compare these with outcomes of patients treated with MA conditioning in this setting.

4.0 SIGNIFICANCE:

This proposal relates to the Bone Marrow Transplantation Cancer Center Program Area goal of improving the efficacy and safety of marrow and stem cell transplantation. This study aims to improve the outcome of patients receiving haploidentical transplants by utilizing data collected by the IBMTR. The large database of the IBMTR will allow estimation of transplant outcomes in these patients with much greater precision than currently available. Additionally, transplant-related complications contributing to morbidity and mortality, commoner in this group of patients, will be identified. Analysis of prognostic factors will likely identify patients most likely to benefit from different types of haploidentical transplantation. The ability to compare diverse transplant strategies should identify those regimens with the highest likelihood of success for certain diseases.

5.0 ANALYSIS PLAN:

Eligibility Criteria: This study will include patients with hematologic malignancies who received a haploidentical stem cell transplant from a related donor with ≥ 2 antigen mismatch and reported to the IBMTR. Study period: January 1st 1990 to December 31st 2007.

6.0 ENDPOINTS:

The primary endpoints of these analyses are:

– Hematopoietic recovery:

– Time to neutrophil engraftment - ANC > 0.5 x 109/L for three consecutive days will be the primary measure for comparisons of hematopoietic recovery.

– Time to platelet engraftment - platelet count ≥ 20 x 109/L – Time to platelet count ≥ 100 x 109/L

– Incidence of acute and chronic GVHD: grade II-IV acute GVHD and limited and extensive chronic GVHD.

– Treatment-related mortality: time to death without evidence of disease recurrence. Patients are censored at time of relapse or at last follow-up.

– Disease recurrence: time to onset of disease relapse. Patients will be censored at death in continuous CR or, for patients surviving in continuous complete remission, at the last contact.

– Disease free survival: time to treatment failure (death or relapse). Patients are censored at time of last follow-up.

– Overall survival: time to death. Patients are censored at time of last follow-up.

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7.0 VARIABLES TO BE ANALYZED:

– Continuous variables – Categorical variables − Patient related:

– Age at transplant (A) – Gender (female vs male) (B) – Karnofsky performance score at transplant (1) for patients with acute leukemia (B) – Number of chemotherapy courses for patients with lymphoid malignancies (A)

– Treatment-related: – Donor age (A) – Donor-recipient gender match (F-M vs M-F vs M-M vs F-F) (B) – Donor type (child/parent/sibling/other) (B) – Donor-recipient HLA-match (# of antigen mismatches) (A) – Donor-recipient CMV status: (-/- vs others) (B) – Conditioning regimen (TBI vs non-TBI) (B) – Conditioning regimen (RIC vs MA) (B) – Conditioning regimen type (A) – Donor-recipient KIR-ligand mismatch (y/n) (B) and direction (HvG or GvH) (B)

(if data available) – Maternal source of mismatched haplotype (yes/no) (B) (if data available) – Infused number of nucleated and CD34+ cells: n/kg recipient weight (A) – Infused number of CD3+ cells: n/kg recipient weight (A) – Source of stem cells: (BM vs PBSC vs both) (B) – Year of transplant (1990-1999 vs 2000-2007) – GVHD prophylaxis (yes/no) (B) – T-cell depletion (yes/no) (B) – Growth factors post transplant: G-CSF or GM-CSF: (yes/no) (B)

– Treatment-related - Second transplant (if applicable): – Second transplant for graft failure? (y/n) (B) – Second transplant - same donor? (y/n) (B) – Disease status at transplant (remission vs not) (B) – Relapse after transplant? (y/n) (B)

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– GVHD present at time of second BMT? (y/n) (B) – Time from relapse post transplant (A) – Time from transplant (A)

8.0 STATISTICAL METHODS: Descriptive tables of patient, disease and transplant characteristics will be created. Continuous variables will be reported as medians with ranges, while categorical variables will be reported as absolute numbers and percent of total patients. Whenever applicable, univariate comparisons will be done using Chi-square test for categorical variables and Wilcoxon test for continuous variables. Survival curves for overall survival and leukemia –free survival will be calculated for all patients using the Kaplan-Meier estimator and the variance estimated by Greenwood’s formula. Cumulative incidence rates for leukemia recurrence and transplant-related mortality will be calculated and plotted. The data will be analyzed using Cox proportional hazards models. This method shall build a single model for the outcome of interest as dependent variable and all the relevant exposure variables as adjusting variables. The main effect term for specific aim shall be forced into each model. This will include a term delineating an appropriate cut-off point for duration of remission after first transplant. The proportional hazards assumption for all the variables will be examined using time-varying covariate and graphical approaches. Constructions of stratified proportional variables are identifies. First order interactions between main effect term and other confounding variables will be explored. If this interaction term is significant, then the final model will have an interaction term between the factor and the main effect term and separate inferences about the effect the comparing groups will be made for each level of the confounding factor. The final model constructed by this technique will include all the factors found prognostic of the outcome plus a term for the main effects of interest. The proportional hazards assumption will again be examined and adjustments made for non-proportional hazards as necessary. Due to a considerable number of confounding variables entered in the model, a p value of < 0.01 would be considered significant for any confounder. Likewise, this p-value would be retained in determining significant interaction between main effect term and a significant confounder found. Due to the multi-center nature of the data, test for significant center differences will be tested using random effects of probability models. Analyses will be performed using the procedure PHREG, SAS statistical software program.

9.0 REFERENCES:

1. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813-

1826. 2. Powles RL, Morgenstern GR, Kay HE, et al. Mismatched family donors for bone marrow

transplantation as treatment for acute leukemia. Lancet. 1983;8325:612-615. 3. Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical

transplants in leukemia. Blood. 1991;78:2120-2130. 4. Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of T-cell-depleted

haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 1994; 84:3948-3955.

5. Giralt S, Estey E, Albitar M, et al. Engraftment of allogneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89:4531-4536.

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6. Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow transplant for leukemia using donors other then HLA-identical sibling. J Clin Oncol. 1997;15:1767-1777.

7. Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA Haplotype. N Eng J Med. 1998;339:1186-1193.

8. Handgrettinger R, Klingebiel T, Lang P, et al. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant. 2001;27:777-283.

9. Aversa F, Terenzi A, Felicini R et al. Haploidentical stem cell transplantation for acute leukemia. Int J Hematol. 2002;76 Suppl(1):165-168.

10. Champlin R, Hesdorffer C, Lowenberg B et al. Haploidentical ‘megadose’ stem cell transplantation in acute leukemia: recommendations for a protocol agreed upon at the Perugia and Chicago meetings. Leukemia. 2002;16:427-428.

11. Kato S, Yabe H, Yasui M, et al. Allogeneic hematopoietic transplantation of CD34+ selected cells from an HLA haploidentical related donor. Along-term follow-up of 135 patients and a comparison of stem cell source between the bone marrow and the peripheral blood. Bone Marrow Transplant. 2000;26:1281-1290.

12. Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98:3456-3464.

13. O'Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2002;8:377-386.

14. Dobyski WR, Klein J, Flomenberg N, et al. Superior survival associated with transplantation of matched unrelated versus on-antigen mismatched unrelated or highly human-leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishinga treatment algorithm for recipients of alternative donor grafts. Blood. 2002;99:806-814.

15. Ruggeri L, Capanni M, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-2100.

16. van Rood JJ, Loberiza Jr. FR, Zhang MJ, et al. Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or and HLA-haploidentical sibling. Blood. 2002;99:1572-1577.

17. Lacerda JF, Martins C, Carmo JA et al. Haploidentical stem cell transplantation with purified CD34+ cells after a chemotherapy-alone conditioning regimen. Biol Blood Marrow Transplant. 2003;9:633-642.

18. Kanda Y, Chiba S, Hirai H, et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991-2000). Blood. 2003;102:1541-1547.

19. Spitzer TR, McAfee SL, Dey BR, et al. Nonmyeloablative haploidentical stem-cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation. 2003;75:1448-1751.

20. Mehta J, Singhal S, Gee AP, et al. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant. 2004; 33:389-396.

21. Aversa F, Terenzi A, Tabilio A ,et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23:3447-3454.

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22. Bethge WA, Haegele M, Faul C, et al. Haploidentical allogeneic stem cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol. 2006;34:1746-1752.

23. Rizzieri DA, Koh LP, Long GD, et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007;25:690-697.

24. Koh, LP, Rizzieri DA, Chao NJ. Allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors. Biol Blood Marrow Transplant. 2007; 13:1249-1267.

25. Handgretinger R, Chen X, Pfeiffer M et al. feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci. 2007;1106:279-289.

26. Ciurea SO, Quareshi SR, Rondon G, et al. Sustained Engraftment Using Fludarabine, Melphalan and Thiotepa Conditioning for Haploidentical Stem Cell Transplantation. Blood. 2007;110;5081a.

27. Ciurea SO, Quareshi SR, Rondon G, et al. Improved outcomes of patients with AML/MDS undergoing haploidentical stem cell transplantation using fludarabine, melphalan and thiotepa (FMT) conditioning chemotherapy. Biol Blood Marrow Transplant. 2008;14:132a.

28. Ciurea SO, de Lima M, Cano P, et al. High Risk of Graft Failure in Patients with Anti-HLA Antibodies Undergoing Haploidentical Stem Cell Transplantation. Submitted for publication.

29. Luznik L, O’Donnell PV, Symons HJ et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008; 14:641-650.

30. Burroughs LM, O’Donnell PV, Sandmaier BM, et al. Comparisson of outcomes of HLA-matched related, unrelated, or HLA-haploidentcila related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed of refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14:1279-1287.

31. Ciceri F, Lobopin M, Aversa F, et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112:3574-3581.

32. Kaplan EL, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc.1958;53:457-481.

33. Prentice RL, Kalbfleisch JD, Peterson AV, Jr. et al. The analysis of failure times in the presence of competing risks. Biometrics 1978;34(4): 541-554.

34. Cox DR. Regression models and life tables [with discussion]. J R Stat Soc B. 1972;34:187-202.

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Table 1. Characteristics of RIC/NMA* vs myeloablative patients with hematologic malignancies who received a haploidentical stem cell transplant from a related donor with ≥ 2 antigen mismatch and reported to the CIBMTR or John Hopkins transplant center between 1990 and 2009

Characteristics of patients MA/TCD MA/Non TCD RIC/NST

N% N % N% Number of patients 507 180 99Age at transplant, median (range), years 22 (1 - 60) 29 (1 - 66) 38 (1 - 77)

0-10 134 (26) 25 (14) 8 ( 8)11-20 107 (21) 38 (21) 12 (12)21-30 82 (16) 30 (17) 14 (14)31-40 86 (17) 33 (18) 19 (19)41-50 59 (12) 27 (15) 19 (19)51-60 34 ( 7) 20 (11) 13 (13)>60 5 (


Table 1. Continued.

Characteristics of patients MA/TCD MA/Non TCD RIC/NST

N% N % N% Campath use?

No 7 ( 1) 2 ( 1) 4 ( 4) Yes 26 ( 5) 10 ( 6) 5 ( 5) Missing 474 (93) 168 (93) 90 (91) Year of transplant

1990-1999 352 (69) 92 (51) 20 (20)2000-2009 155 (31) 88 (49) 79 (80)

Conditioning regimen Cy + TBI ± other 363 (72) 72 (40) 19 (19)Cy + Bu ± other 32 ( 6) 57 (32) 3 ( 3)TBI ± other 63 (12) 17 ( 9) 9 ( 9)Cy ± other 5 (


Table 2. Characteristics of RIC patients wit

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