A G E N D A CIBMTR WORKING COMMITTEE FOR GRAFT … · 2011-02-01 · GS09-03 Brunstein C, Eapen M, Ahn KW, Appelbaum F, Ballen KK, Champlin RE, Kan F, ... GS06-02 Elucidating the

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION Honolulu, Hawaii Saturday, February 19, 2011, 2:45 pm – 4:45 pm Co-Chair: Richard Champlin, MD, UT MD Anderson Cancer Center, Houston, TX Telephone: 713-792-3618; Fax: 713-792-4346;

E-mail: [email protected] Co-Chair: Mary Laughlin, MD, University of Virginia, Charlottesville, VA Telephone: 434-982-6406; Fax: 434-243-0064; E-mail: [email protected] Co-Chair: Daniel H. Fowler, MD, National Cancer Institute, Bethesda, MD Telephone: 301-480-4354; Fax: 301-480-4354; E-mail: [email protected] Statisticians: Mei-Jie Zhang, PhD, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Fiona Kan, MS, MA, CIBMTR Minneapolis, MN Telephone: 612-884-8612; Fax: 612-884-8661; E-mail: [email protected] Scientific Director: Mary Eapen, MD, MS, Medical College of Wisconsin, Milwaukee, WI 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. Published or submitted papers a. GS08-04 Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang M-J, Arcese W, Sirvent A,

Champlin RE, Chao N, Gee AP, Laughlin MJ, Marks DI, Nabhan S, Ruggeri A, Soiffer R, Horowitz MM, Gluckman E, Wagner JE. Effect of graft source on unrelated donor hematopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncology 11:653-660, 2010.

b. R02-42 Collins NH, Gee AP, Durett AG, Kan F, Zhang M-J, Champlin RE, Confer D, Eapen M, Howard A, King R, Laughlin MJ, Plante RJ, Setterholm M, Spellman S, Keever-Taylor C, Wagner JE, Weisdorf D. The effect of the composition of unrelated donor bone marrow and peripheral blood progenitor cell grafts on transplantation outcomes. Biol Blood Marrow Transplant 16:253-262, 2010.

c. GS05-02 Chu R, Brazauskas R, Kan F, Bashey A, Bredeson C, Camitta B, Chiang KY, Frangoul H, Gale RP, Gee A, George B, Goldman FD, Gross TG, Gupta V, Hale GA, Isola L, Ispizua AU, Lazarus H, Marsh J, Russell J, Sabloff M, Waller EK, Eapen M. Comparison of outcomes after transplantation of G-CSF stimulated bone marrow grafts versus bone marrow or peripheral blood grafts from HLA-matched sibling donors for patients with severe aplastic anemia. Biol Blood Marrow Transplant (In press).

d. GS09-03 Brunstein C, Eapen M, Ahn KW, Appelbaum F, Ballen KK, Champlin RE, Kan F, Laughlin MJ, Soiffer RJ, Weisdorf DJ, Woolfrey A, Horowitz MM and Wagner JE. Reduced Intensity Conditioning (RIC) Transplantation in Acute Leukemia: the Effect of Source of

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Not for publication or presentation

Unrelated Donor Stem Cells on Outcomes. Presented at the American Society of Hematology in Orlando, FL, 2010.

e. GS06-01b Passweg JR, Zhang MJ, Rocha V, Kan F, Eapen M. Donor characteristics affecting graft failure, graft vs. host disease and survival after unrelated donor transplantation with reduced intensity conditioning for hematologic malignancies. Submitted.

f. GS08-03 Soiffer RJ, LeRademacher J, Ho V, Kan F, Artz A, Champlin RE, Devine S, Isola L, Lazarus HM, Marks DI, Porter DL, Waller EK, Horowitz MM, Eapen M. Impact of immune modulation with anti-T cell antibodies on the outcome of reduced intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Submitted.

4. Studies in progress (Attachment 3) a. HC03-01 Prevalence of microbially contaminated hematopoietic stem

cell products (RE Champlin) Manuscript Preparation

b. GS05-01 An audited matched pair analysis of transplants using red cell depleted vs. plasma depleted umbilical cord blood stem cells (K Ballen)

Data Collection

c. GS06-01a Donor characteristics as risk factors in recipients after transplantation of bone marrow or peripheral blood from HLA-identical sibling donors (J Passweg)

Data Collection

d. GS06-02 Elucidating the role of human leukocyte antigen-c (HLA-C) matching on engraftment in umbilical cord blood transplantation (M Eapen / V Rocha / S Spellman)

Manuscript Preparation

e. GS07-01 Peripheral blood vs. bone marrow for non-myeloablative stem cell transplantation (RE Champlin)

Analysis

f. GS07-03 Bone marrow or peripheral blood stem cells as graft source using unrelated donors to children and adolescents with leukemia (M Eapen / O Ringden / Locatelli / V Rocha)

Data collection

g. GS08-01 Reassessment of impact of donor age on outcome after unrelated donor hematopoietic cell transplantation (HCT) (C Kollman)


h. GS08-02 Should an older-aged patient receive a transplant from his older-aged sibling or a young HLA-matched unrelated donor? (A Alousi / R Champlin / R Saliba)


i. GS08-05/R04-88 Umbilical cord blood transplantation for adults with acute leukemia: impact of single vs double cord blood units on transplantation outcomes (EJ Shpall)


j. GS09-02 Parameters of banked cord blood units that may be associated with graft failure (M Eapen / V Rocha / S Spellman)

Protocol Development

k. GS10-01 A retrospective study of the impact of low cell doses on engraftment outcomes in hematopoietic cell transplants using peripheral blood stem cells or marrow (W Navarro / HJ Khoury / N Kernan)


l. GS10-02 Treatment with granulocyte-colony stimulating factor (G-CSF) after allogeneic umbilical cord blood transplantation (UCBT) in pediatric acute leukemia (MJ Burke / J Wagner / MR Verneris)


m. GS10-03 Outcomes using a cryopreserved donor graft in unrelated allogeneic stem cell transplantation (N Frey / S Goldstein / H Lazarus)


5. Future / proposed studies a. PROP 1110-01 The outcome of myeloablative and reduced intensity unrelated donor cord blood

transplants for acute lymphoblastic leukaemia in CR1 and CR2 in adults. A comparison with unrelated donor marrow and peripheral blood transplantation (D Marks) (Attachment 4)

6. Other business

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Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR GRAFT SOURCES & MANIPULATION Orlando, Florida Friday, February 26, 2010, 2:45pm – 4:45 pm Co-Chair: Adrian Gee, PhD, Baylor College of Medicine, Houston, Texas Telephone: 832-824-4214; Fax: 832-825-4668; E-mail: [email protected] Co-Chair: Richard Champlin, MD, UT MD Anderson Cancer Center, Houston, TX Telephone: 713-792-3618; Fax: 713-792-4346;

E-mail: [email protected] Co-Chair: Mary Laughlin, MD, Case Western Reserve University, Cleveland, OH Telephone: 216-368-5693; Fax: 216-368-1166;

E-mail: [email protected] Statisticians: Mei-Jie Zhang, PhD, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: [email protected] Fiona Kan, MS, MA, CIBMTR Minneapolis, MN Telephone: 612-884-8612; Fax: 612-884-8661; E-mail: [email protected] Scientific Director: Mary Eapen, MD, MS, Medical College of Wisconsin, Milwaukee, WI Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

Drs. Gee, Champlin and Laughlin chaired the meeting. Minutes from the 2009 meeting were approved. Only selected projects were presented in the interest of time. Projects were chosen based on following criteria: — Results of projects not previously presented to the committee — Ongoing / new projects to discuss feasibility, objectives and study design

2. Published or submitted papers

a. R02-12 Lazarus H, Kan F, Tarima S, Champlin RE, Confer D, Frey N, Gee AP, Wagner JE, Horowitz MM, Eapen M. Rapid transport and infusion of hematopoietic stem cells is associated with improved outcome after myeloablative therapy and unrelated donor transplant. Biol Blood Marrow Transplant 2009; 15:589-96.

b. R02-42 Collins NH, Gee AP, Gurett AG, Kan F, Zhang M-J, Champlin RE, Confer D, Eapen M, Howard A, King R, Laughlin MJ, Plante RJ, Setterholm M, Spellman S, Keever-Taylor C, Wagner JE, Weisdorf DJ. The effect of the composition of unrelated donor bone marrow and peripheral blood progenitor cell grafts on transplantation outcomes. Biol Blood Marrow Transplant 2010; 16:253-62.

c. GS06-01b Passweg JR, Zhang MJ, Rocha V, Kan F, Champlin RE, Isola LM, Gee AP, Gibson J, Laughlin MJ, Lazarus HM, Loren A, Marks D, Gratwohl A, Eapen M. Donor characteristics affecting graft failure, graft vs. host disease and survival after unrelated donor transplantation with reduced intensity conditioning for hematologic malignancies. Submitted.

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3. Studies in progress a. GS08-01 Reassessment of the impact of donor age on recipient outcome after unrelated donor

hematopoietic cell transplantation (C Kollman). Steve Spellman presented this study on behalf of Dr Kollman. In 2001, Kollman analyzed 7,000 unrelated donor transplants facilitated by the NMDP and observed higher overall survival after transplantation of BM grafts from younger donors. The HLA categorization was matching at HLA-A, -B using intermediate/antigen level resolution and allele-level at DRB1. Matching at HLA-C locus was not considered. Recent transplants were donor-recipient matching considered allele-level typing at HLA-A, -B, -C, -DRB1 have failed to shown an effect of donor age or a rather weak association. The donor age issue is being looked at because transplant physicians are now requesting younger donors. Consensus: include all the patients including those in the 2001 report with allele-level HLA typing and include BM and PBPC grafts. Status: Study-file preparation

b. GS08-02 Should an older-aged patient receive a transplant from his older aged sibling or a young HLA-matched unrelated donor? (A Alousi / R Champlin / R Saliba). Dr Alousi presented this study, which is trying to answer the clinical question: should one chose an older sibling donor (aged > 50 years) for an older patient (aged > 50 years) when an 8/8 HLA-matched younger unrelated donor (aged < 50 years) is available. Results: — Risks of acute and chronic GVHD were significantly lower after sibling donor HCT

regardless of donor age compared to URD HCT. — We did not find a significant difference in NRM risks by donor type. — Relapse risks were higher after matched sibling donor HCT when the donor is aged ≥ 67

years and URD HCT compared to matched sibling donor HCT when the donor is aged < 67 years.

— Treatment failure (inverse of LFS) was higher after matched sibling HCT when the donor is aged ≥ 67 years and URD HCT compared to matched sibling donor HCT aged < 67 years. Treatment failure risks were similar after matched sibling aged ≥ 67 years and URD transplants.

— Overall mortality was higher after matched sibling HCT when the donor was aged ≥ 67 years but not URD transplants compared to sibling donor transplants when the donor was aged < 67 years. Mortality risks were similar after matched sibling aged ≥ 67 years and URD transplant.

Stratifying the analysis by patient age did not change the analysis. Patient age correlates with donor age and older patients are more likely to have older donors and the findings may be driven by patient age rather than donor age. The committee suggested re-doing the analysis restricting to good risk patients (acute leukemia in any remission and CML in any chronic phase). Of note, the results presented were adjusted for disease status at transplantation. Status: Manuscript preparation

c. GS08-03 Determining the clinical benefit of in vivo T cell depletion in patients undergoing reduced intensity allogeneic transplantation (RJ Soiffer / V Ho). Dr Soiffer presented this study. The study includes patients aged ≥ 21 years, first allo transplant for acute and chronic leukemia and for non-Hodgkin and Hodgkin lymphoma, patients who received prior auto-transplant were eligible. Reduced intensity regimen was defined as: 1) fludarabine + melphalan ≤ 140 mg/m2; 2) busulfan ≤ 8 mg/kg + fludarabine; 3) cyclophosphamide < 120 mg/kg + fludarabine. HLA-matched sibling donor and 8/8 or 7/8 matched URD transplants are included. Patients who received TBI containing regimens were excluded as there were too few in the ATG and campath groups for meaningful comparison. Information on DLI will be descriptive only. We will describe infections that occurred in the first 3 months after transplantation. Given the heterogeneity of diseases considered some wondered whether the analysis should be stratified by

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disease in addition to examining disease as a co-variate (myeloid vs. lymphoid malignancies). Status: Study-file preparation

d. GS08-05/R04-88 Comparison of outcomes after single and double umbilical cord blood transplants for adults with acute leukemia (EJ Shpall). Dr Shpall presented this study. This study compared outcomes after single and double CB transplants from 2001 to 2007 for adults with acute leukemia. Most patients who received double CB transplants were in 1st or 2nd CR whereas most patients who received single CB transplants were in 2nd CR or relapse. Reduced intensity conditioning regimens were used more frequently with double CB transplants. The median total nucleated cell dose pre-freeze for single CB transplants were 2.7 x 107/kg, and for double CB transplants, 4.4 x 107/kg. An optimal TNC for survival and neutrophil recovery were explored and none identified. There was a significant interaction between year of transplant and transplant type (single vs. double CB transplant). 2005 to 2007: transplant outcomes are similar after singles and double CB transplant. Single CB transplants in 2001-2004 had the worst outcome: higher TRM, treatment failure and overall mortality. The double CB transplants in 2001-2004 had similar outcomes compared to single CB and double CB transplants in the later period except grade 2-4 acute GVHD was higher for double CB transplants in 2001-2004. Suggestion: examine differences in outcome by conditioning regimen: myeloablative vs. reduced intensity and GVHD prophylaxis. And if numbers permit, examine use of Cy + TBI 200 cGy + fludarabine the predominant regimen versus other regimens. Limitation: We need approximately 175 single CB and 175 double CB transplants to detect a 15% difference in survival. Most transplant centers use two units to make the minimum cell dose required so we may never accrue the desired numbers to examine for differences in transplant-outcomes.

4. Future / proposed studies

a. PROP 0709-03 Treatment with granulocyte-colony stimulating factor (G-CSF) after allogeneic umbilical cord blood transplantation (UCBT) in pediatric acute leukemia (MJ Burke / J Wagner / MR Verneris) Dr Verneris presented this proposal. There are some reports that suggest G-CSF use may be associated with inferior transplant-outcomes and others, use of G-CSF in the immediate post-transplant period does not affect transplant-outcomes. Timing of neutrophil recovery is crucial after CB transplants and it remains to be proven whether a slightly faster with G-CSF use translates into an early survival advantage for these patients. or this proposal, the endpoints of interest are time to hematopoietic recovery, TRM, acute and chronic GVHD, relapse, leukemia-free and survival. The study population would be limited to patients with acute leukemia who received myeloablative transplant conditioning regimens. We would also consider use of GM-CSF. Patients would have had to receive planned growth factor: beginning day –1 to day +7. Priority ranking #2 (assigned by members of working committee)

b. PROP 1209-14 A retrospective study of the impact of low cell doses on engraftment outcomes in

hematopoietic cell transplants using peripheral blood stem cells or marrow (W Navarro / H Khoury / N Kernan) Dr Navarro presented this proposal. PBPC CD34+ dose > 2 x 106/kg or BM TNC > 2 x 108/kg result in reliable hematopoietic engraftment. When the dose is suboptimal engraftment is likely to be affected. This proposal will explore the lower acceptable TNC for BM and CD34+ for PBPC below which neutrophil recovery (myeloablative regimens) and chimerism (within the first 3 months) for reduced intensity regimens affect engraftment and early mortality (day-100, six-month and 1-year survival). If a lower limit is established, this will avoid delays with procurement of second product. The study population will be limited to recent transplants facilitated by the NMDP and the two graft sources analyzed separately. The proposal will also

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attempt to identify a cell dose threshold above which survival may be impaired as a consequence of higher rates of acute or chronic GVHD. Priority ranking #1 (assigned by members of working committee)

The meeting adjourned at 4:45 pm.

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Accrual Summary for Graft Sources and Manipulation Working Committee

Characteristics of patients reported to the CIBMTR between 1989 and 2010

Characteristics Registration

N (%)Research

N (%) Number of cases 145782 68443 Donor type HLA-identical sibling donor HCT 81787 31683 Bone marrow 45846 (56) 20895 (66) Peripheral blood 34667 (42) 10418 (33) Peripheral blood + bone marrow 765 ( 1) 150 (<1) Umbilical cord blood 509 ( 1) 220 ( 1) Identical twin donor HCT 1355 659 Bone marrow 599 (44) 348 (53) Peripheral blood 739 (55) 307 (47) Peripheral blood + bone marrow 12 ( 1) 2 (<1) Umbilical cord blood 5 (<1) 2 (<1) Other related donor HCT 10243 4195 Bone marrow 5406 (53) 2718 (65) Peripheral blood 4446 (43) 1358 (32) Peripheral blood + bone marrow 270 ( 3) 63 ( 2) Umbilical cord blood 121 ( 1) 56 ( 1) Unrelated donor HCT 52397 31906 Bone marrow 25614 (49) 17596 (55) Peripheral blood 18854 (36) 9566 (30) Peripheral blood + bone marrow 290 ( 1) 181 ( 1) Umbilical cord blood 7639 (15) 4563 (14)

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TO: Graft Sources and Manipulation Working Committee Members FROM: Mary Eapen, MD, MS, Scientific Director for the Graft Sources and Manipulation WC RE: Studies in Progress Summary HC03-01: Prevalence of microbially contaminated hematopoietic stem cell products (R Champlin): This study is to examine the potential of microbially contaminated hematopoietic stem cell products to produce morbidity and mortality in transplant recipients. It is under manuscript preparation. GS05-01: An audited matched pair analysis of transplants using red cell depleted vs. plasma depleted umbilical cord blood stem cells (K Ballen): This study is to establish safety and efficacy of hematopoietic stem cell transplantations (HCT) using non-red cell depleted UCB stem cells that have been depleted of plasma (PD) by auditing and analyzing the clinical outcomes of such PD UCB HSCT. It is also to compare the outcome of HSCT using red cell depleted (RD) versus PD UCB stem cells in a matched pair analysis and to compare the outcome of PD UCB HSCT that employed washing versus direct infusion after thawing and prior to infusion. It is under data collection. GS06-01a: Donor characteristics as risk factors in recipients after transplantation of bone marrow or peripheral blood from HLA-identical sibling donors (J Passweg): This study examines donor characteristics associated with outcome for transplants with HLA-identical sibling donor. Of particular interest were H-Y effects, e.g. more GvHD if female donor for male recipient and more graft failure if male donor for female recipients. The data file preparation is pending for better follow-up. GS06-02: Elucidating the role of human leukocyte antigen-c (HLA-C) matching on engraftment in umbilical cord blood transplantation (M Eapen / V Rocha / S Spellman): Umbilical cord blood (UCB) units are selected on antigen-level HLA typing at A and B and allele-level at DRB1 and the relative importance of matching at HLA-C is not known. This study analyzed patients with hematologic malignancies who received a single UCB unit with myeloablative transplant conditioning regimens. It is under manuscript preparation. GS07-01: Peripheral blood vs. bone marrow for non-myeloablative stem cell transplantation (R Champlin): This study is to address the role of graft source for reduced intensity transplants in adults with acute and chronic leukemia and NHL. It is at analysis stage and is expected to be at the manuscript preparation stage by July 2011. GS07-03: Bone marrow or peripheral blood stem cells as graft source using unrelated donors to children and adolescents with leukemia (M Eapen / O Ringden / Locatelli / V Rocha): This study is to compare peripheral stem cell grafts with bone marrow grafts in children and adolescents receiving cells from either matched or mismatched unrelated donors. The analysis is pending for better follow-up. GS08-01: Reassessment of impact of donor age on outcome after unrelated donor hematopoietic cell transplantation (HCT) (C Kollman): This study is to determine the effect of donor age on risk for mortality, graft-versus-host disease, and relapse after unrelated donor hematopoietic cell transplantation. It is at the manuscript preparation stage.

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GS08-02: Should an older-aged patient receive a transplant from his older-aged sibling or a young HLA-matched unrelated donor? (A Alousi / R Champlin / R Saliba): This study is to compare the incidence of grade II-IV acute GVHD in recipients who received their graft from a matched sibling donor who is 50 years or older to those recipients who received their graft from a matched unrelated donor aged less than 50 years. The draft manuscript is underway. GS08-05/R04-88: Umbilical cord blood transplantation for adults with acute leukemia: impact of single vs. double cord blood units on transplantation outcomes (EJ Shpall): This study is to determine the impact of critical variables on the outcome of cord blood transplant patients. It combines the datasets from the CIBMTR and the New York Blood Center. The draft manuscript is underway. GS09-02: Parameters of banked cord blood units that may be associated with graft failure (M Eapen / V Rocha / S Spellman): This study is to examine the association of graft failure with other parameters of banked cord blood units besides total nucleated cell dose such as CD34, mononuclear cell count (MNC) and CFU (post-thaw). It is at the protocol development stage. GS09-03: Comparison of outcomes of unrelated donor peripheral blood stem cells and umbilical cord blood after reduced-intensity conditioning (C Brunstein): This is to determine the place of unrelated umbilical cord blood (UCB) relative to unrelated adult donor sources when considering reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) for acute leukemia. The draft manuscript is being prepared. GS10-01: A retrospective study of the impact of low cell doses on engraftment outcomes in hematopoietic cell transplants using peripheral blood stem cells or marrow (W Navarro / HJ Khoury / NA Kernan): This study is to examine the extremes of cell doses on outcomes in Hematopoietic Cell Transplants using peripheral blood or marrow. It is at the protocol development stage. GS10-02: Treatment with granulocyte-colony stimulating factor (G-CSF) after allogeneic umbilical cord blood transplantation (UCBT) in pediatric acute leukemia (MJ Burke / J Wagner / MR Verneris): This study is to examine whether patients with the diagnosis of ALL and AML who receive prophylactic treatment using G-CSF after allo-UCBT will have significantly worse transplant outcomes as compared to patients who do not receive G-CSF. A protocol will be available for review. GS10-03: Outcomes using a cryopreserved donor graft in unrelated allogeneic stem cell transplantation (N Frey / S Goldstein /H Lazarus): This study is to determine if recipients of cryopreserved unrelated donor grafts have different outcomes compared with recipients of fresh unrelated donor grafts. A protocol will be available for review.

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Study Proposal 1110-01 Study Title: The outcome of myeloablative and reduced intensity unrelated donor cord blood transplants for acute lymphoblastic leukaemia in CR1 and CR2 in adults: a comparison with unrelated donor marrow and peripheral blood transplantation. David I. Marks, MD, PhD, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, England, UK Specific Aims: 1. To determine the outcome of myeloablative and reduced intensity unrelated donor cord blood

transplants for acute lymphoblastic leukaemia in CR1 and CR2 in adults and to compare this with the outcome in patients who received marrow or peripheral stem cell transplants from unrelated donors.

2. To examine the prognostic factors that determine outcome including the effect of the match of the cord unit(s) and the effect of using 2 cord units on outcome.

Scientific Justification: Allogeneic SCT has an established role in the management of adults with ALL in CR1 and CR2. Recent large prospective donor vs. no donor analyses show matched sibling allografting to produce superior outcomes to chemotherapy and its use is unquestioned in the highest risk, Ph+ cohort (Goldstone et al., 2008). Investigators have explored the use of allografting with unrelated donors (URD) for patients with Philadelphia negative ALL in CR1 at high risk of relapse (Marks et al., 2008). Allogeneic SCT is the treatment of choice for adults with ALL in CR2 with sibling allografts achieving DFS of 25-40%. The outcome of unrelated donor SCT for ALL in CR2 may be less good with the UKALLXII study reporting 16% survival (Fielding et al., 2007). Most conditioning regimens involve the use of TBI with there being some evidence for using doses exceeding 13 Gy (Marks et al., 2006) but more recently there have been some reports of the results of RIC regimens; this is the subject of CIBMTR study LK08-03. Allogeneic SCT is the most effective antileukaemic therapy in ALL but results are compromised by relatively high TRM (Goldstone et al., 2008), especially in the over 35 year age group. The role of alternative donor transplantation in adults with ALL is increasing but there are few data to inform transplanters and patients. Unrelated donor transplants produce 40% 5 year survival in a high risk group (Marks et al., 2008) but about 30% of candidate patients do not have a suitably matched unrelated donor and this figure is higher in certain non-Caucasian ethnic groups. Two large registry based studies published 5 years ago in the New England Journal suggest that overall outcome in adults receiving unrelated donor cord blood transplants for acute leukaemia is the same as for patients receiving 1 antigen mismatched unrelated donor marrow or peripheral blood transplants3,4. Alternative donor stem cell sources for adults with acute leukaemia have been recently compared by Marks, Aversa and Lazarus (2006). There are numerous reasons to do a more up to date focussed study. First, there are no studies looking specifically at adult ALL where the graft versus leukaemia effect may be quite different to other leukaemias. Secondly, there have been major changes in cord blood transplantation technique including the use of double cord blood units (Barker et al., 2005), other graft sources to enhance engraftment (Fernandez et al., 2003) and more recently attempts at ex vivo stem cell expansion (de Lima, 2008). Thirdly, transplant practice and patient selection are rapidly evolving and adult ALL patients with poor risk features and persistent minimal residual disease after chemotherapy are increasingly being transplanted with alternative donor stem cell sources as it is realised that chemotherapy alone is unlikely to cure these patients. Fourthly, although there are limited numbers and relatively short follow up, reduced intensity conditioning is having an increasing role in this disease. Preliminary results are described by Mohty and colleagues from the EBMT (and other small studies) and are being examined in CIBMTR study LK08-03, but this study does not include patients

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with cord blood as a stem cell source. Finally, the results of cord blood transplants are improving and single centres such as Minneapolis are reporting excellent results of CBT for adult ALL. Patient Eligibility Population: Patients aged 16 years and above with ALL in CR1 or CR2 who have had a myeloablative or reduced intensity conditioning single or double unrelated donor cord blood transplant. These patients will be compared with patients who had unrelated donor marrow or PBSC transplants in the same time period. The CBT patients will only include those patients where the cord unit(s) were ≥ 4/6 HLA-A, -B, -DRB1 matched with the recipient and with the other unit if 2 were used. UD BM or PBSC patients will be categorised into well or partially matched or mismatched (Weisdorf criteria). Outcomes: — Incidence of acute and chronic GVHD: grade II-IV, grade III-IV acute GVHD and limited and

extensive chronic GVHD. — Treatment-related mortality: time to death without evidence of leukemia recurrence. Censoring of

patients at relapse or last follow-up. — Leukemia recurrence: time to first leukemia recurrence. Patients will be censored at death in

continuous CR, second transplant or at last contact. — Leukemia free survival: defined as survival in continuous CR. Leukemic relapse and death in CR

are events. Censoring at last contact for survivors. — Overall survival: Events are death from any cause with censoring at last contact. — Engraftment: 0.5 x 109 neutrophils/L for 3 consecutive days before day 42. Variables to be Analyzed: Patient-related: — Age (by decades, or as a continuous variable) — Gender (M vs. F) — Karnofsky PS (< 90% vs. 90% or more) Disease-related: — Cytogenetic abnormalities: t(4;11), t(9;22), hypodiploidy or near triploidy, complex cytogenetics

(> 5 abnormalities) vs. none vs. not known vs. other abnormalities — Lineage (T vs. B vs. not known) — FAB classification (L1-2 or unclassified) — WCC at diagnosis < 25, 25-100, 100-200, > 200 — Time to achieve CR1: < 4 weeks, 4-8 weeks, > 8 weeks — Time from diagnosis to transplant for CR1 patients — Relapse on chemotherapy (yes/no) — Extramedullary disease at diagnosis: CNS (yes/no), testis (yes/no), other (yes/no) Transplant-related: — Time from remission to transplant (CR1 and CR2) — Duration of CR1 for CR2 transplants — For RIC transplants: fludarabine + TBI 2Gy vs. fludarabine and melphalan vs. fludarabine and

busulphan vs. other — Alemtuzamab vs. ATG (dose to be collected) — GVHD prophylaxis for UD transplants: ex vivo T cell depletion vs. CsA + MTX vs. tacrolimus

and methotrexate — GVHD prophylaxis for CBT: ATG vs. none, CsA + MMF vs. other (including tacrolimus +

sirolimus) — Steroids as GVHD prophylaxis (yes/no) — Donor age for unrelated donors (continuous variable) — Gender match (F-M vs. M-F vs. M-M vs. F-F) — CMV status: -/- vs. +/- vs. -/+ vs. +/+ — Year of transplant

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— Matching of unrelated donors: well matched vs. partly matched vs. mismatched (CIBMTR criteria)

— Post-transplant therapy: DLI (yes/no); chemotherapy (yes/no); intrathecal chemotherapy (yes/no) — PBSC vs. BM vs. cord blood — DLI (yes vs. no) UD transplants only — Dose of TBI < 13 Gy vs. > 13 Gy — ? cell dose data Patients to be excluded: — L3 ALL — Second transplants Study Design (Scientific Plan): Patient-, disease- and transplant-related variables will be analysed in all patients, with the Chi-square test for categorical and Mann-Whitney test for continuous variables. Survival and leukemia free survival will be calculated using the Kaplan-Meier method and survival curves will be compared using the log rank test. Data will be analyzed using a proportional hazards model. Analysis for a centre effect for both cord blood and unrelated donor transplants. References:

1. Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation / maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111(4):1827-33.

2. Marks DI, Pérez WS, He W, Zhang MJ, Bishop MR, Bolwell BJ, Bredeson CN, Copelan EA, Gale RP, Gupta V, Hale GA, Isola LM, Jakubowski AA, Keating A, Klumpp TR, Lazarus HM, Liesveld JL, Maziarz RT, McCarthy PL, Sabloff M, Schiller G, Sierra J, Tallman MS, Waller EK, Wiernik PH, Weisdorf DJ. Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission. Blood 2008; 112(2):426-34

3. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow M, Buck G, Durrant IJ, Luger SM, Marks DI, McMillan AK, Tallman MS, Rowe JM and Goldstone AH. Outcome of 609 adults after relapse of acute lymphoblastic leukaemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007; 109(3):944-950.

4. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004; 351(22):2265-75.

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7. Fernandez MN, Regidor C, Cabrera R, et al. Unrelated umbilical cord blood transplants in adults: early recovery of neutrophils by supportive co-transplantation of a low number of highly purified peripheral blood CD34+ cells from an HLA-haploidentical donor. Exp Hematol 2003; 31(6):535-44.

8. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105(3):1343-7.

9. Stein A, O’Donnell M, Snyder D et al. Reduced-intensity stem cell transplantation for high-risk acute lymphoblastic leukaemia. Biol Blood Marrow Transplant 2007; 13(2[S1]):134.

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10. Kottaridis P et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 2000; 96:2419-2425.

11. Martino R, Giralt S, Caballero MD, Mackinnon S, Corradini P, Fernández-Avilés F et al. Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukemia: a feasibility study. Haematologica 2003; 88:555-560.

12. Massenkeil G, Nagy M, Neuburger S, Tamm I, Lutz C, et al. Survival after reduced-intensity conditioning is not inferior to standard high-dose conditioning before allogeneic haematopoietic cell transplantation in acute leukemias. Bone Marrow Transplantation 2005; 36:683-689.

13. Hamaki T, Kami M, Kanda Y, Yuji K, Inamoto Y, Kishi Y et al. Reduced intensity stem-cell transplantation for acute lymphoblastic leukemia: a retrospective study of 33 patients. Bone Marrow Transplant 2005; 35:549-556.

14. Mohty M, Labopin M, Tabrizzi R, Theorin N, Fauser AA, Rambaldi A, Maertens J, Slavin S, Majolino I, Nagler A, Blaise D, Rocha V; Acute Leukemia Working Party; European Group for Blood and Marrow Transplantation. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica 2008; 93(2):303-6.

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Characteristics of ALL CR1 and CR2 patients aged ≥ 16 who underwent 1st allogeneic stem cell transplant with unrelated CBU, BM or PBPC from 2002 to 2009 in the US *

BM PBPC CBU Characteristics N (%) N (%) N (%) Number of patients 264 506 87 Age, median (range), years 31 (16 - 66) 36 (16 - 68) 31 (16-68) 16-20 64 (24) 62 (12) 19 (22) 21-30 63 (24) 135 (27) 24 (28) 31-40 55 (21) 102 (20) 16 (18) 41-50 41 (16) 96 (19) 13 (15) 51-60 37 (14) 85 (17) 10 (11) Over 60 4 ( 2) 26 ( 5) 5 ( 6) Recipient CMV at transplant Negative 117 (44) 228 (45) 33 (38) Positive 145 (55) 269 (53) 50 (57) Unknown 2 (<1) 9 ( 2) 4 ( 5) Number of CBUs ----- ----- Single 27 (31) Double 60 (69) Disease status CR1 137 (52) 301 (59) 44 (51) CR2 127 (48) 205 (41) 43 (49) Conditioning regimen Myeloablative 251 (95) 430 (85) 62 (71) Non-myeloablative/RIC** 13 ( 5) 76 (15) 25 (29) ATG or campath use ATG use 63 (24) 88 (17) 28 (32) Campath use 13 ( 5) 16 ( 3) 1 ( 1) No atg or campath 188 (71) 402 (79) 58 (67) GVHD prophylaxis Tacrolimus ± steroids ± other 17 ( 6) 41 ( 8) 4 ( 5) Tacrolimus + Methotrexate ± other 150 (57) 292 (58) 6 ( 7) Tacrolimus + MMF ± other 10 ( 4) 58 (11) 17 (20) CSA ± steroids ± other 6 ( 2) 8 ( 2) 5 ( 6) CSA + Methotrexate ± other 74 (28) 81 (16) 2 ( 2) CSA + MMF ± other 6 ( 2) 21 ( 4) 53 (61) Other*** 1 (<1) 5 ( 1) 0 Year of transplant 2002-2005 166 (63) 252 (50) 13 (15) 2006-2009 98 (37) 254 (50) 74 (85) Median follow-up of patients, month 48 (7 - 98) 39 (3 - 98) 12 (3-62)

Abbreviations: CBU=cord blood unit; CMV=cytomegalovirus; CR=complete remission; RIC=reduced intensity conditioning regimen; CSA=Cyclosporine; MMF=Mycophenolate mofetil. * Numbers of cases were before CAP modelling.

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** Conditioning regimen breakdown for non-myeloablative/RIC transplants: BM PBPC CBU TBI2Gy + fludarabine ± other 1 15 18 Melphalan + fludarabine ± other 6 21 7 Busulfan + fludarabine ± other 4 19 0 Cyclophosphamide + fludarabine ± other 0 8 0 Other 2 13 0

*** Other GVHD prophylaxis were: BM – Methotrexate+/-pentostation (n=1); PBPC – MMF (n=3); Methotrexate+/-pentostation(n=2).

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