Not for publication or presentation. AGENDA CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Honolulu, Hawaii Friday, February 18, 2011, 12:15 pm 2:15 pm

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1 Not for publication or presentation AGENDA CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Honolulu, Hawaii Friday, February 18, 2011, 12:15 pm 2:15 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Directors: Matt Kalaycio, MD, Cleveland Clinic Foundation, Cleveland, OH Telephone: ; Fax: ; Richard Maziarz, MD, Oregon Health and Science University, Portland, OR Telephone: ; Fax: ; Jorge Cortes, MD, M.D. Anderson Cancer Center, Houston, TX Telephone: ; Xiaochun Zhu, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Mukta Arora, MD, University of Minnesota, Minneapolis, MN Telephone: ; Fax: ; Wael Saber, MD, MS, CIBMTR, Medical College of Wisconsin Milwaukee, WI Telephone: ; Fax: ; 1. Introduction Minutes of February, 2010 meeting (Attachment 1) 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. CK00-02 Ballen KK, Shrestha S, Sobocinski KA, Zhang M-J, Bashey A, Bolwell BJ, Cervantes F, Devine SM, Gale RP, Gupta V, Hahn TE, Hogan WJ, Krцger N, Litzow MR, Marks DI, Maziarz RT, McCarthy PL, Schiller G, Schouten HC, Vivek Roy V, Wiernik PH, Horowitz MM, Giralt SA, Arora M. Outcome of transplantation for Myflofibrosis. Biology of Blood & Marrow Transplantation 16: , b. CK03-01b Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora K, Gupta V, Rizzieri DA, George B, DM, Armand Keating, Gale RP, Marks DI, McCarthy PL, Woolfrey A, Szer J, Giralt SA, Maziarz RT, Cortes J, Horowitz MM, Lee SJ. Impact of Pre-Transplant Imatinib Mesylate on Outcomes of Allogeneic Transplantation in Advanced Phase Chronic Myeloid Leukemia: Analysis from the CIBMTR. Submitted. c. CK03-02 Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M, Horowitz MM, Rizzo JD. Myeloablative Allogeneic Hematopoietic-Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase. Journal of Clinical Oncology 28 (11): ,

2 Not for publication or presentation d. CK06-01 Ballen K, Arora M, Woolfrey A, Agovi M, Zhu X, Kalaycio M, Maziarz RT, Cortes J, Horowitz M, Saber W. Results of allogeneic transplantation for polycythemia vera and essential thrombocythemia. Presented at the American Society of Hematology in Orlando, Florida, e. CK07-02 Kalaycio ME, Kukreja M, Woolfrey AE, Szer J, J Cortes J, Maziarz RT, Bolwell BJ, Buser A, Copelan E. Allogeneic hematopoietic cell transplant for prolymphocytic leukemia. Biology of Blood & Marrow Transplantation 16: , Studies in progress (Attachment 3) a. CK02-03 Matched pair intravenous vs oral Busulfan (M Horowitz/ E Copelan) Manuscript Preparation b. CK06-01 Outcomes after allohct for PV and ET (K Ballen) Manuscript Preparation c. CK02-01 BuCy vs CyTBI for leukemia (E Copelan) (Attachment 4) Data File Preparation d. CK07-01 TBI based vs chemo based regimen for CLL (M Sabloff) (Attachment 5) Data File Preparation e. CK06-03 NST/RIC for CLL/SCLL (J Leis/R Maziarz/ R Sobecks) (Attachment 6) Protocol Development f. CK06-04 Decision analysis/allo vs non-bmt Rx for myelofibrosis (K Ballen) (Attachment 7) Protocol Development g. CK08-01 Outcome of allogeneic stem cell for imitanib resistant CML (J Szer) (Attachment 8) Protocol Development h. CK08-02 Allo HCT for Hairy Cell Leukemia (R Kreitman/ S Pavletic) (Attachment 9) Protocol Development i. CK09-01 Minimal intensity vs RIC conditioning for myelofibrosis (V Gupta) (Attachment 10) Protocol Development j. CK10-01 Update - impact of prior Gleevec on HCT for CML in era of TKIs (R Maziarz) (Attachment 11) Protocol Development k. CK10-02 Impact of 2nd generation TKIs on HCT for CML (R Maziarz) (Attachment 12) Protocol Development 5. Future/ Proposed studies a. PROP Allogeneic hematopoietic stem cell transplantation with or without pretransplant azacitidin in the treatment of myelodysplastic syndrome (R Olsson) (Attachment 13) (Deferred because of small number of patients received Azacitidin, n=41.) b. PROP A decision analysis for performing allogeneic hematopoietic stem cell transplant in patients with chronic lymphocytic leukemia (B Hill) (Attachment 14) c. PROP Donor lymphocyte infusion after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for chronic leukemia and chronic myeloproliferative diseases (R Sobecks) (Attachment 15) d. PROP Development of a prognostic scoring system to predict relapse of chronic lymphocytic leukemia/small lymphocytic lymphoma after allogeneic hematopoietic stem cell transplantation (B Shaffer) (Attachment 16) e. PROP Trends in allogeneic stem cell transplantation for myelodysplastic syndromes over the last decade: Impact of novel agents, predictive models, and reduced conditioning intensity (E Warlick) (Attachment 17) 2

3 Not for publication or presentation f. PROP Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation (B Shaffer) (Attachment 18) g. PROP Allogeneic hematopoietic stem cell transplant for chronic myelomonocytic leukemia (H Duong) (Attachment 19-1) and PROP Outcomes of allogeneic hematopoietic stem cell transplantation for adult chronic myelomonocytic leukemia (M Akhtari) (Attachment 19-2) h. PROP The role of EBMT score in predicting outcome of second allogeneic hematopoietic stem cell transplantation for relapse of hematological malignancies after first allogeneic or autologous transplantation (K Rezvani/R Szydlo) (Attachment 20) 6. Other business 3

4 Not for publication or presentation Attachment 1 MINUTES CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Orlando, Florida Saturday, February 27, 2010, 2:45 pm - 4:45 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Jeffrey Szer, MD, Royal Melbourne Hospital Phone : ; Fax: ; jeff.szer@mh.org.au Richard Maziarz, MD, Oregon Health and Science University Phone: ; Fax: ; maziarzr@ohsu.edu Jorge Cortes, MD, M.D. Anderson Cancer Center, Texas Phone: ; Fax: ; Jcortes@mdanderson.org Xiaochun Zhu, MS, CIBMTR Statistical Center Phone: ; Fax: ; xzhu@mcw.edu Kwang Woo Ahn, PhD, CIBMTR Statistical Center Telephone: ; kwooahn@mcw.edu Mukta Arora, MD, University of Minnesota, Minneapolis, MN Phone: ; Fax: ; arora005@umn.edu 1. Introduction The CIBMTR Working Committee for Chronic Leukemia was held on Saturday, February 27, 2010 at 2:45 pm. Dr. Jorge Cortes introduced all the three co-chairs, scientific director, and the statistician were introduced. Dr. Matt Kalaycio, from the Cleveland Clinic was introduced as newly appointed chair of the working committee and will replace outgoing chair Dr. Jeffrey Szer. A gift from CIBMTR was presented to Dr. Jeffrey Szer by Dr. Richard Maziarz to appreciate Dr. Szer s contribution to Chronic Leukemia Working Committee. Xiaochun Zhu was introduced to Working Committee as a new MS statistician. Dr. Jeffrey Szer, Dr. Jorge Cortes and Dr. Richard Maziarz co-chaired the meeting. The minutes from the 2009 Tandem meeting held in Tampa, Florida, were approved by committee members. Attendees were asked to sign the attendance sheet in order to maintain committee membership and to use paper ballot voting sheets for the new proposals and studies in progress. 2. Accrual Summary Accrual table has been updated. 3. Published or submitted papers a. CK00-02 Ballen KK, Shrestha S, Sobocinski KA, Zhang MJ, Bashey A, Bolwell BJ, Cervantes F, Devine SM, Gale RP, Gupta V, Hahn TE, Hogan WJ, Kröger N, Litzow MR, Marks DI, Maziarz RT, McCarthy PL, Schiller G, Harry CS, Roy V, Wiernik PH, Horowitz MM, Giralt SA, Arora M. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant In press. b. CK03-01b Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora K, Gupta V, Rizzieri DA, George B, DM, Armand Keating, Gale RP, Marks DI, McCarthy PL, Woolfrey A, Szer J, Giralt SA, Maziarz RT, Cortes J, Horowitz MM, Lee SJ. Impact of Pre-Transplant Imatinib Mesylate on 4

5 Not for publication or presentation Attachment 1 Outcomes of Allogeneic Transplantation in Advanced Phase Chronic Myeloid Leukemia: Analysis from the CIBMTR. Submitted to JCO c. CK03-02 Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M, Horowitz MM, Rizzo JD. Myeloablative Allogeneic Hematopoietic-Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase: Incidence of Relapse and Late Mortality in 5-year Survivors. Journal of Clinical Oncology In press. d. CK07-02 Kalaycio ME, Kukreja M, Woolfrey AE, Szer J, Cortes J, Maziarz RT, Bolwell BJ, Buser A, Copelan E, Gale RP, Gupta V, Maharaj D, Marks DI, Pavletic SZ, Horowitz MM, Arora M. Allogeneic Hematopoietic Cell Transplant for Prolymphocytic Leukemia. Biol Blood Marrow Transplant In press. Dr. Cortes briefly mentioned above publications. 4. Studies in progress a. CK02-01 Comparison of results using BuCy compared to CyTBI as preparation for allotx in in early phase AML and CML (E Copelan) Dr. Cortes briefly mentioned about this study. The TED follow up forms need to be updated this year. The next step is to begin the analysis as soon as the data file is updated with center s follow up information. b. CK02-03 Matched pair analysis of IV vs oral busulfan (Horowitz/Copelan) Dr. Copelan mentioned that this study will only do descriptive analysis. c. CK04-01 Comparison of outcome of allo SCT and Imatinib Mesylate therapy in patients with CML (F Ravandi/J Cortes) Dr. Kebriaei on behalf of Dr. Ravandi presented the characteristic of patients of the study.year of transplantation was from 1995 to Dr. Cortes mentioned that two data sets have been cleaned and will do comparison. d. CK06-01 Outcomes after HSCT for Polycythemia Vera and Essential Thrombocytopenia (K Ballen) Dr. Ballen presented the characteristic of patients in this descriptive study. The current issue is that a small number of patients were available. The goal is to complete abstract by the end of this year. Dr. Arora clarified one inclusion criteria that patient would not be included if patient progressed to AML. e. CK06-03 NST/RIC allogeneic HSCT for CLL/small cell lymphocytic lymphoma (J Leis/R Sobecks) Dr Jose Leis presented this study, and highlighted the potential numbers of cases who underwent HLA-identical sibling or unrelated donor transplant and received myeloablative /non-myeloablative or RIC for CLL/SCLL between 1995 and 2006 and reported to CIBMTR. This protocol was updated after the committee s decision was to not collect additional data on cytogenetics and NCI criterion for remission rate, as that might delay the study because of limited resources and funds. Therefore the updated protocol with tables was presented with main objective of the study being to compare the clinical outcomes (like Overall survival, Progression, TRM, and PFS) between patients undergoing HLA-identical sibling or unrelated donor stem cell transplantation using conventional (N=410) versus reduced intensity/nonmyeloblative (N=525). One of the suggestions from the committee was to add a breakdown of unrelated donor and HLA identical siblings, and also state HLA classification for unrelated donor transplants. The study is in protocol development. The committee has discussed for two years that supplemental form for collecting cytogenetic information was not needed. However, the new version of the form includes this information. So this information will be available for future studies. 5

6 Not for publication or presentation Attachment 1 f. CK06-04 Decision analysis of allogeneic BMT for myelofibrosis (K Ballen) Dr. Ballen presented the study. The objective of the study is to compare overall survival with HCT and with non-transplantation therapies for myelofibrosis. The idea is to use the year between 1989 and 2004 in CIBMTR and Fred Hutchinson cancer center database. The patients will be matched for age and date of diagnosis with non-transplant patients under age 70. The table only included patients from CIBMTR till The idea is to extend year to 2004, which will include more reduced intensity patients and also include patients from Fred Hutchinson. Dr. Ballen will cooperate with Dr. Tefferi who has database for non-transplant patients. Samples for NMDP patients (N=74) may be used for JAK 2 analysis. g. CK07-01 TBI vs chemo based regimen for CLL (M Sabloff) Dr. Sabloff presented the study. The objective is to compare the outcomes of patients from CIBMTR database who had a myeloblative allogeneic hematopoietic stem cell transplant for CLL using either a TBI-based vs. chemotherapy-based conditioning regimen. Missing data is a concern. The outcomes are overall survival and disease free survival. h. CK08-01 Outcomes of Allogeneic HSCT for imatinib (J Szer) Dr. Szer briefly presented the updates on this study. The information of mutation has been included in new CML form. Funding source is being sought for conducting mutation analysis. i. CK08-02 Allogeneic HSCT for Hairy cell leukemia (R Kreitman/S Pavletic) Dr. Pavletic presented the table with characteristic of patients and mentioned that study aims to look at the outcomes of allogeneic HCT in hairy cell leukemia patients. Registry is the way to get the retrospective data on rare disease like this. Currently CIBMTR registration database has 17 patients available from 1980 to Dr. Pavletic mentioned that European center may provide extra two patient s information. One of attendees said he also has information available on two patients. j. CK09-01 A comparison of outcomes of reduced intensity and non-myeloablative conditioning regimen for patients with Myelofibrosis (V Gupta) Dr. Gupta briefly outlined the primary objective of this study, which is to evaluate and compare the clinical outcomes of non-myeloablative and reduced intensity conditioning regimens in patients with myelofibrosis. He summarized the characteristics of all the patients with Myelofibrosis who underwent Non-myeloablative or Reduced intensity allogeneic transplants from related or unrelated donors, reported to the CIBMTR, from 1997 to Total of 175 patients were available: 141 in RIC arm and 34 in non-myeloablative arm. The current database does not include all patients from Fred Hutchison cancer center. Dr. Gupta will ask Dr. Deeg from Fred Hutchinson (FH) cancer center for cooperation. 15 to 18 patients may be available from FH. 5. Future/ Proposed studies: a. PROP An updated assessment of the impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors (TKIs) (R Maziarz) Dr. Maziarz presented this proposal. The specific aims are to determine the overall survival after allogeneic stem cell transplantation for patients with CML in the current era and to determine patient-, disease-, and transplantation-specific variables which may influence the outcome of patients with CML treated with tyrosine kinase inhibitors as primary and subsequent allogeneic stem cell transplantation. Between 2001 and 2007 there were 254 CML patients from 115 centers who only received imatinib from the time of diagnosis reported to CIBMTR. 6

7 Not for publication or presentation Attachment 1 b. PROP The impact of treatment with second-generation tyrosine kinase inhibitors on the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia (R Maziarz) The specific aims are to determine the overall survival after allogeneic transplantation for patients with CML with a history of treatment with second-generation tyrosine kinase inhibitors and to determine patient-, disease-, and transplantation-specific variables which may influence the outcome of patients with CML undergoing allogeneic stem cell transplantation, treated with second generation tyrosine kinase inhibitors either as primary or as salvage therapy. Between 2001 and 2007 there were 60 CML patients from 39 centers who had exposure to secondgeneration tyrosine kinase inhibitor reported to CIBMTR. Dr. Maziarz suggested that supplemental forms were needed for actively collecting data for both studies, and mentioned the possibility of applying for a grant from Novartis for this purpose. 6. Other business: Update on data collection on chronic leukemia forms: Dr Cortes presented chronic leukemia data collection forms. He mentioned that modification of medication in old form has been discussed in last year Tandem meeting. The information of PCR and mutation analysis was not available in old form but now included in new form. The form for CML has been developed but CLL not yet. Comments on the new form can be sent to Dr. Arora. All comments will be combined and passed to committee for new form release. 7. Voting results: Studies in progress Study Voting Rank CK CK CK CK CK CK CK CK CK CK Proposal Proposal Voting Rank Prop Prop

8 Not for publication or presentation Attachment 2 Accrual Summary for Chronic Leukemia Working Committee Characteristics of recipients of allogeneic transplant for CLL reported to the CIBMTR between 1990 and 2010 Characteristics of patients Registration only Research Number of patients Number of centers Age, median (range), years 54 (<1-80) 53 (2-75) Sex Male 1460 (73) 1085 (74) Female 533 (27) 389 (26) Missing 3 (<1) 0 Graft type Bone marrow 319 (16) 420 (28) PBSC 1602 (80) 992 (67) Missing 75 ( 4) 62 ( 4) Donor type Twin 6 (<1) 19 ( 1) HLA-identical sibling 1256 (63) 616 (42) Other relative 119 ( 6) 32 ( 2) Unrelated donor 560 (28) 786 (53) Missing 55 ( 3) 21 ( 1) Year of transplant (<1) 21 ( 1) (<1) 39 ( 3) ( 2) 77 ( 5) ( 3) 109 ( 7) ( 6) 99 ( 7) (12) 134 ( 9) (13) 193 (13) (15) 221 (15) (17) 287 (19) a 353 (18) 280 (19) 2010 a 274 (14) 14 (<1) a Cases continue to be reported in this interval. 8

9 Not for publication or presentation Attachment 2 Accrual Summary for Chronic Leukemia Working Committee Characteristics of recipients of autologous transplant for CLL reported to the CIBMTR between 1990 and 2010 Characteristics of patients Registration only Research Number of patients Number of centers Age, median (range), years 50 (29-73) 52 (18-81) Sex Male 96 (78) 345 (74) Female 27 (22) 123 (26) Missing 0 1 (<1) Graft type Bone marrow 25 (20) 129 (28) PBSC 94 (76) 296 (63) Missing 4 ( 3) 44 ( 9) Year of transplant (<1) 10 ( 2) (14) 11 ( 2) (10) 28 ( 6) (25) 43 ( 9) (32) 120 (26) ( 4) 127 (27) ( 4) 60 (13) ( 5) 38 ( 8) (<1) 23 ( 5) a 5 ( 4) 3 (<1) 2010 a 1 (<1) 6 ( 1) a Cases continue to be reported in this interval. 9

10 Not for publication or presentation Attachment 2 Accrual Summary for Chronic Leukemia Working Committee Characteristics of recipients of allogeneic transplant for CML reported to the CIBMTR between 1990 and 2010 Characteristics of patients Registration only Research Number of patients Number of centers Age, median (range), years 38 (<1-74) 37 (1-76) Sex Male 7293 (60) 6847 (59) Female 4877 (40) 4690 (41) Missing 74 (<1) 1 (<1) Graft type Bone marrow 7616 (62) 8827 (77) PBSC 3837 (31) 2492 (22) Missing 791 ( 6) 219 ( 2) Donor type Twin 76 (<1) 58 (<1) HLA-identical sibling 8438 (69) 5421 (47) Other relative 354 ( 3) 121 ( 1) Unrelated donor 2583 (21) 5350 (46) Missing 793 ( 6) 588 ( 5) Year of transplant ( 4) 1599 (14) ( 9) 1718 (15) (11) 1610 (14) (16) 1673 (14) (20) 1550 (13) (16) 985 ( 9) (11) 743 ( 6) ( 6) 814 ( 7) ( 4) 402 ( 3) a 256 ( 2) 346 ( 3) 2010 a 208 ( 2) 98 (<1) a Cases continue to be reported in this interval. 10

11 Not for publication or presentation Attachment 2 Accrual Summary for Chronic Leukemia Working Committee Characteristics of recipients of autologous transplant for CML reported to the CIBMTR between 1990 and 2010 Characteristics of patients Registration only Research Number of patients Number of centers Age, median (range), years 47 (2-65) 47 (4-70) Sex Male 162 (66) 239 (57) Female 85 (34) 177 (43) Graft type Bone marrow 117 (47) 87 (21) PBSC 112 (45) 253 (61) Missing 18 ( 7) 76 (18) Year of transplant (10) 30 ( 7) (21) 8 ( 2) (26) 51 (12) (22) 92 (22) (18) 123 (30) ( 2) 83 (20) (<1) 21 ( 5) ( 2) 6 ( 1) (<1) 11

12 Not for publication or presentation Attachment 2 Accrual Summary for Chronic Leukemia Working Committee Characteristics of recipients of allogeneic transplant for MDS reported to the CIBMTR between 1990 and 2010 Characteristics of patients Registration only Research Number of patients * Number of centers Age, median (range), years 49 (<1 81) 46 (<1 78) Sex Male 3165 (59) 2508 (58) Female 2211 (41) 1801 (42) Missing 13 (<1) 3 (<1) Graft type Bone marrow 1759 (33) 1855 (43) PBSC 3288 (61) 2150 (50) Missing 342 ( 6) 307 ( 7) Donor type Twin 37 (<1) 18 (<1) HLA-identical sibling 3116 (58) 1500 (35) Other relative 299 ( 6) 95 ( 2) Unrelated donor 1709 (32) 2588 (60) Missing 228 ( 4) 111 ( 3) FAB claasification MDS, NOS 1352 (25) 452 (10) RA 977 (18) 1026 (24) RAEB 1254 (23) 1267 (29) CMML 482 ( 9) 387 ( 9) RARS 158 ( 3) 159 ( 4) RAEB ( 5) 216 ( 5) RAEB ( 8) 250 ( 6) RCMD 184 ( 3) 142 ( 3) RCMD/RS 26 (<1) 28 (<1) Other MDS 260 ( 5) 385 ( 9) Year of transplant ( 1) 152 ( 4) ( 3) 206 ( 5) ( 5) 250 ( 6) ( 7) 317 ( 7) ( 9) 309 ( 7) (10) 408 ( 9) (12) 459 (11) (13) 590 (14) (13) 623 (14) a 819 (15) 699 (16) 2010 a 706 (13) 299 ( 7) a Cases continue to be reported in this interval. * 3092 cases are reported as having MDS at diagnosis and prior HCT (no transformation to other disease). 12

13 Not for publication or presentation Attachment 2 Accrual Summary for Chronic Leukemia Working Committee Characteristics of recipients of autologous transplant for MDS reported to the CIBMTR between 1990 and 2010 Characteristics of patients Registration only Research Number of patients * Number of centers Age, median (range), years 47 (3-68) 47 (2-70) Sex Male 17 (41) 76 (54) Female 24 (59) 65 (46) Graft type Bone marrow 10 (24) 21 (15) PBSC 26 (63) 61 (43) Missing 5 (12) 59 (42) FAB classification MDS, NOS 3 ( 7) 47 (33) RA 17 (41) 27 (19) RAEB 18 (44) 47 (33) CMML 1 ( 2) 6 ( 4) RARS 1 ( 2) 3 ( 2) RAEB (<1) RCMD 0 1 (<1) Other MDS 1 ( 2) 9 ( 6) Year of transplant ( 7) 5 ( 4) (15) 11 ( 8) (10) 17 (12) (29) 12 ( 9) (22) 30 (21) ( 5) 22 (16) ( 5) 23 (16) ( 5) 15 (11) ( 2) 3 ( 2) a 0 1 (<1) 2010 a 0 2 ( 1) a Cases continue to be reported in this interval. * 12 cases are reported as having MDS at diagnosis and prior HCT (no transformation to other disease). 13

14 Not for publication or presentation Attachment 3 TO: FROM: RE: Chronic Leukemia Working Committee Members Wael Saber, MD, MS, Scientific Director for the Chronic Leukemia WC Mukta Arora, MD, MS, Scientific Director for the Chronic Leukemia WC Studies in Progress Summary CK02-03: Pretransplant conditioning therapy using oral or IV Busulfan in hemopoietic stem cell transplantation (Horowitz/Copelan): This study is to to determine whether patients receiving IV Bu as part of a Busulfan/Cytoxan (BuCy) conditioning regimen have less toxicity than similar patients receiving oral BuCy. The manuscript is under review by chairs with recommendations to restrict to early post transplant outcomes. CK06-01: Outcomes after HSCT for Polycythemia Vera and Essential Thrombocytopenia (K Ballen): This study is to determine overall and disease-free survival, hematopoietic recovery, acute and chronic GVHD, and transplant related mortality after allogeneic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia. The univariate analysis has been completed. A poster was presented at ASH Additional data may be needed from Fred Hutchinson Cancer Center for further analysis. CK02-01: Comparison of results using Busulfan/Cyclophosphamide compared to TBI/Cyclophosphomide as preparation for allogeneic transplantation in chronic myelogenous leukemia and acute myelogenous leukemia (E Copelan): The objectives of this study are 1) to compare transplantrelated mortality, relapse, overall survival and leukemia-free survival in patients receiving preparation with Oral Bu/Cy, IV Bu/Cy, and Cy/TBI; 2) to determine the impact of patient, disease and transplamt specific variables on these outcomes. The current status of the study is data file preparation. The followup completeness was very low. Now CRC has provided some follow-up update. Data cleaning is under way. CK07-01: A comparison of total body irradiation (TBI) - based conditioning vs. chemotherapy-based conditioning in myeloablative allogeneic stem cell transplants for chronic lymphocytic leukemia (CLL) (M Sabloff): This study it to compare the outcomes of patients who had a myeloablative allogeneic hematopoietic stem cell transplant for CLL using either a TBI based or chemotherapy-based conditioning regimen; to evaluate the impact of TBI dose (<=1200 vs. >1200) on endpoints. The status of this study is protocol development. The protocol has been presented at the statistical meeting. Due to the fact that many missing data requests have been sent out to the centers a new version of the protocol will be coming soon. CK06-03: NST/RIC allogeneic HSCT for CLL/small cell lymphocytic lymphoma (J Leis): This study is to compare the clinical outcomes between patients undergoing HLA-identical sibling or unrelated donor stem cell transplantation using conventional versus reduced intensity/nonmyeloablative (RIC/NST) conditioning regimen for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); to determine patient-, disease- and transplant-related variables associated with favorable progression-free and overall survival outcomes; to assess the impact of disease prognostic factors on relapse rate, progression-free survival, and overall survival among patients receiving conventional versus RIC/NST 14

15 Not for publication or presentation Attachment 3 conditioning regimen for CLL. The current status is protocol development. The protocol has been presented at the stat meeting. Studies previously proposed, but not initiated CK06-04: Decision analysis of allogeneic bone marrow transplantation for myelofibrosis: comparison of allogeneic stem cell transplantation and non transplantation therapies for myelofibrosis (K Ballen): This study is to compare overall survival with hematopoietic cell transplantation (HCT) and with nontransplantation therapies for myelofibrosis; to determine appropriate patient-,disease-, and transplantrelated selection criteria for transplantation in patients with myelofibrosis. A draft protocol is available for review. CK08-01: Evaluation of the outcome of allogeneic stem cell transplantation for chronic myeloid leukemia (CML) in patients with resistance to Imatinib or second generation tyrosine kinase inhibitors (TKIS) either (I) associated with abl kinase domain mutations or (II) not associated with mutations (J Szer): This study is to assess the progression free and overall survival of patients undergoing an allograft for CML who have resistance to imatinib or second generation TKIs, either due to mutations or other mechanisms. The key issue is whether conditioning and/or graft vs. leukemia (GVL) effects are sufficiently powerful to overcome the otherwise poor prognosis of this condition. A draft protocol is available for review. CK08-02: Results of allogenic hematopoietic stem cell transplantation in patients with hairy cell leukemia (R Kreitman): The primary endpoint of this study is to analyze overall and progression-free survival. The secondary endpoint is to analyze engraftment, acute and chronic GVHD, disease response, progression, and non-relapse mortality. A draft protocol is available for review. CK09-01: A comparison of outcomes of minimal intensity and reduced intensity conditioning regimens for patients with myelofibrosis (V Gupta): This study is to evaluate and compare the outcomes of minimal intensity and reduced intensity conditioning regimens in patients with myelofibrosis. The secondary objective is to study the graft-versus-myelofibrosis effect. A draft protocol is available for review. CK10-01: An updated assessment of the impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors (TKIs)(R Maziarz): The objectives of this study are 1) to determine the overall survival after allogeneic stem cell transplantation for patients with CML in the current era; 2) to determine progression free survival, event free survival, relapse rate and non-relapse mortality of patients with CML undergoing allogeneic stem cell transplantation in the current era; 3) to determine patient-, disease-, and transplantation- specific variables which influence the outcome of patients with CML treated with tyrosine kinase inhibitors as primary therapy and subsequent allogeneic stem cell transplantation. A draft protocol is available for review. CK10-02: The impact of treatment with second-generation tyrosine kinase inhibitors on the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia (R Maziaz): The specific aims of this study are: 1) to determine the overall survival after allogeneic stem cell transplantation for patients with CML with a history of treatment with second-generation tyrosine kinase inhibitors 2) to determine progression free survival, event free survival, relapse rate and non-relapse mortality of patients with CML undergoing allogeneic stem cell transplantation with a history of treatment with secondgeneration tyrosine kinase inhibitors 3) to determine patient-, disease-, and transplantation- specific variables which influence the outcome of patients with CML undergoing allogeneic stem cell 15

16 Not for publication or presentation Attachment 3 transplantation, treated with second tyrosine kinase inhibitors either as primary or as salvage therapy. A draft protocol is available for review. 16

17 Not for publication or presentation Attachment 4 CIBMTR CK02-01 COMPARISON OF RESULTS USING BUSULFAN/CYCLOPHOSPHAMIDE COMPARED TO TBI/CYCLOPHOSPHOMIDE AS PREPARATION FOR ALLOGENEIC TRANSPLANTATION IN CHRONIC MYELOGENOUS LEUKEMIA AND ACUTE MYELOCYTIC LEUKEMIA REVISED PROTOCOL Study Chair: Study Statistician: PhD Statistician: Edward Copelan, MD Cleveland Clinic Hematologic Oncology and Blood Disorder 9500 Euclid Ave R-35 Cleveland, Ohio Telephone: Fax: copelae@ccf.org Xiaochun Zhu, MS The Medical College of Wisconsin CIBMTR 9200 West Wisconsin Ave Ste C5500 Milwaukee, WI Telephone: Fax: xzhu@mcw.edu Kwang Woo Ahn, PhD, The Medical College of Wisconsin CIBMTR 8701 Watertown Plank Rd Milwaukee, WI Telephone: Fax: kwooahn@mcw.edu 17

18 Not for publication or presentation Attachment 4 Scientific Director: Mukta Arora, MD University of Minnesota Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN Telephone: Fax: arora005@umn.edu Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave Ste C5500 Milwaukee, WI Telephone: Fax: wsaber@mcw.edu Working Committee Chairs: Matt Kalaycio, MD The Cleveland Clinic Main Campus Mail Code R Euclid Ave Cleveland, OH Telephone: Fax: kalaycm@ccf.org Richard T. Maziarz, MD Oregon Health and Science University 3181 SW Sam Jackson Park Road Portland, OR Telephone: Fax: maziarzr@ohsu.edu Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX Telephone: Fax: Jcortes@mdanderson.org 18

19 Not for publication or presentation Attachment OBJECTIVES: 1.1 Compare estimated rates of transplant-related mortality, relapse, overall survival and leukemia-free survival in patients receiving preparation with Oral Bu/Cy, IV Bu/Cy, and Cy/TBI. 1.2 Determine the prognostic significance of variables such as age, interval from diagnosis to transplant, abnormal pretransplant LFTs, stem cell source, degree of match, and GVHD prevention method. 2.0 SCIENTIFIC JUSTIFICATION: Acute myelogenous leukemia and chronic myelogenous leukemia are diseases for which patients commonly undergo allogeneic hematopoietic stem cell transplantation. Randomized studies comparing Bu/Cy to Cy/TBI have not demonstrated significantly different outcomes, but significantly decreased toxicity (e.g. duration of neutropenia) and relapse rates (as well as increased relapse rates) have been reported with busulfan. It is critical to analyze whether one regimen is associated with better overall results than the other and whether one regimen is better in specific settings, e.g., in older patients. Lastly it is important to determine whether better results are achieved using IV versus oral busulfan. 3.0 STUDY POPULATION: The study population will include all patients who have undergone first allogeneic transplantation with an HLA-identical sibling donor or an unrelated donor from 2000 through 2005 for Ph+ CML in first CP or acute myelocytic leukemia in first CR and who received preparation with Cy/TBI or BuCy. Only patients who received CsA±other, MTX+CsA ±other, FK506+MTX±other or FK506±other for GVHD prophylaxis will be included. Patients with identical twin or cord blood donors will be excluded as will patients who underwent in vitro T cell depletion. 4.0 OUTCOMES: 4.1 Hematopoietic recovery: Time to neutrophils (ANC) > 0.5 x 10 9 /L for three consecutive days will be the primary measure for comparisons of hematopoietic recovery. Time to platelets 30k will also be measured. 4.2 Incidence of acute and chronic GVHD: The number of patients who experience grade II-IV, and III-IV acute GVHD, and limited and extensive chronic GVHD will be assessed. 4.3 Treatment-related mortality: death within the first 100 days and 1st year following transplant for any cause of death while in complete remission of primary disease. 4.4 Relapse: recurrence of disease for those in complete remission are events. Those who survive without recurrence are censored at the date of last contact. This event is summarized by the cumulative incidence estimate with TRM as the competing risk. 4.5 Leukemia-free survival: time to treatment failure (death or relapse). Patients are censored at time of last follow-up. 19

20 Not for publication or presentation Attachment Overall survival: time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up. 4.7 Other outcomes: development of hepatic VOD, duration of neutropenia post transplant, interstitial pneumonia, diffuse alveolar hemorrhage, bronchiolitis, permanent alopecia, cataracts, second malignancies. 5.0 VARIABLES TO BE ANALYZED: Patient-related: - Age at transplant: continous, 1-10 vs vs vs vs vs >50 - Gender: male vs female - Karnofsky performance score at transplant: <90% vs 90% Disease-related: - Disease: AML, CML - Pre transplant LFT ( Bilirubin and SGOT): Abnormal (3 times normal) vs normal vs missing - Time from diagnosis to transplant: continuous Transplant-related: - Donor recipient gender match: M-M vs M-F vs F-M vs F-F - Donor type: HLA identical sibling vs unrelated - Donor-recipient HLA match: match vs mismatch, degree of mismatch - Donor-recipient CMV status: +/+ vs +/- vs -/+ vs -/- - Donor age: continous and 1-10 vs vs vs vs vs >50 - Graft type: bone marrow vs peripheral blood vs BM+PB - TBI dose: non-fractionated, # 1000 cgy vs >1000 cgy; fractionated, # 1200 cgy vs >1200 cgy - Cyclophosphamide dose: continuous - Busulfan dose: continuous - Year of transplant: vs vs GVHD prophylaxis: CsA ±other vs CsA+MTX±other vs. FK506+MTX±other vs. FK506±other - G-CSF or GM-CSF growth factors post transplant: yes vs no Data collected in the CIBMTR Report Forms would be used. No additional data would be needed. 6.0 STUDY DESIGN: 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. These factors will be compared between the three treatment groups (Oral Bu/Cy vs IV Bu/Cy vs Cy/TBI) using the Chi-Square test for categorical variables and the Mann-Whitney test for continuous variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Probability of leukemia-free survival and overall survival will be calculated using the Kaplan- Meier estimator, with the variance estimated by Greenwood s formula. Values for other 20

21 Not for publication or presentation Attachment 4 endpoints included in section 4.0 will be generated using cumulative incidence estimates to account for competing risks. Comparison of survival curves will be done using the log-rank test. Multivariate analyses will be performed using proportional hazards models. These analyses will fit models to determine which risk factors (Sec 5.0) may be related to a given outcome. All variables will first be examined to assure that they comply with the proportional hazards assumption. Factors found to have non-proportional hazards will be adjusted for in subsequent analyses. A stepwise model building approach will then be used to develop models for relapse, treatment-related mortality, leukemia-free survival and overall survival. 7.0 REFERENCES: 1. Cox RD. Regression analysis and life tables. J of Royal Statist Soc 1972; B 34:

22 Not for publication or presentation Attachment 4 Table 1. Characteristics of patients who underwent first allogeneic transplantation with an HLAidentical sibling donor or an unrelated donor for CR1 AML and CP1 Ph+ CML and received preparation with Cy/TBI, oral or IV Bu/Cy, reported to CIBMTR from 2000 to 2005 a. Cy TBI Oral BuCy IV BuCy N eval N (%) N eval N (%) N eval N (%) P-value b Variable Patient-related Number of patients Number of centers Age, median (range), years (1-63) (1-63) (1-65) <0.001 Age at transplant, years < ( 5) 57 ( 8) 30 (10) (11) 110 (15) 45 (15) (19) 146 (20) 44 (14) (27) 169 (24) 43 (14) (25) 156 (22) 86 (28) > (13) 81 (11) 60 (19) Male sex (56) (57) (52) Karnofsky score at transplant <0.001 <90% 146 (18) 65 ( 9) 60 (20) 90% 664 (82) 634 (91) 237 (80) Disease-related Disease <0.001 AML 529 (62) 376 (52) 204 (66) CML 326 (38) 343 (48) 104 (34) Pretransplant LFT Normal 778 (91) 640 (89) 287 (93) Abnormal (3 times 62 ( 7) 70 (10) 16 ( 5) normal) Missing 15 ( 2) 9 ( 1) 5 ( 2) Time from diagnosis to transplant, median (range), months (1-170) (2-107) (1-68)

23 Not for publication or presentation Attachment 4 Table 1. Continued. Cy TBI Oral BuCy IV BuCy N eval N (%) N eval N (%) N eval N (%) P-value b Variable Transplant-related Donor/recipient gender match M-M 308 (36) 250 (35) 106 (34) M-F 200 (23) 168 (24) 89 (29) F-M 166 (20) 158 (22) 55 (18) F-F 178 (21) 137 (19) 58 (19) Donor <0.001 HLA-identical sibling 267 (31) 527 (73) 127 (41) Unrelated 588 (69) 192 (27) 181 (59) Donor-recipient HLA match <0.001 Match 771 (90) 691 (96) 280 (91) Mismatch 84 (10) 28 ( 4) 28 ( 9) Donor-recipient CMV status < /+ 222 (28) 364 (53) 106 (37) +/- 102 (13) 48 ( 7) 35 (12) -/+ 212 (27) 121 (18) 71 (24) -/- 255 (32) 155 (22) 79 (27) Donor age < ( 1) 45 ( 6) 14 ( 5) ( 3) 107 (15) 17 ( 6) (26) 166 (24) 68 (23) (33) 191 (27) 98 (32) (27) 137 (19) 77 (25) >50 82 (10) 60 ( 9) 28 ( 9) Donor age, median (range), years (1-66) (1-70) (2-64) <0.001 Graft type BM 474 (55) 364 (51) 141 (46) PB 381 (45) 355 (49) 167 (54) Bu dose, median (range),mg/kg NA (4-35) (3-27) 23

24 Not for publication or presentation Attachment 4 Table 1. Continued. Variable Cy dose, median (range),mg/kg Cy TBI Oral BuCy IV BuCy N N N eval N (%) eval N (%) eval N (%) P-value b (33-201) (40-232) (14-222) TBI dose 849 NA NA Non-fractionated 1000cGy 67 ( 8) Non-fractionated>1000cGy 3 ( 1) Fractionated 1200 cgy 504 (59) Fractionated > 1200 cgy 275 (32) Year of transplant < (44) 298 (42) 38 (12) (27) 239 (33) 71 (23) (29) 182 (25) 199 (65) GVHD prophylaxis <0.001 MTX+CsA ± others 498 (58) 604 (84) 149 (48) FK506+MTX ± others 246 (29) 56 ( 8) 113 (37) CsA ± others 79 ( 9) 48 ( 7) 22 ( 7) FK506 ± others 32 ( 4) 11 ( 1) 24 ( 8) Growth factors post transplant: G-CSF or GM- CSF <0.001 Yes 279 (33) 218 (30) 156 (51) No 576 (67) 501 (70) 152 (49) Median follow-up of survivors, months (3-78) (3-79) (3-62) Abbreviations: CML = chronic myelogenous leukemia; AML= acute myelogenous leukemia; GVHD = graft versus host disease; MTX = methotrexate; CsA = cyclosporine; FK506 = tacrolimus; BM = bone marrow; PB = peripheral blood; CMV = cytomegalovirus; LFT= Liver function test; TBI=Total body irradiation; Bu=Busulfan; Cy=cyclophosphamide; GM-CSF=granulocyte macrophage colony stimulating factor; G-CSF= granulocyte colony stimulating factor; CP1=chronic phase 1; CR1= first complete remission. a Selection criterion: - First allogeneic transplant with HLA identical siblings and unrelated donor from 2000 to Ph+ CML in first chronic phase and AML in first CR who received preparation with Cy/TBI or Bu/Cy - Only patients who received CsA+/-other, MTX+CsA+/-other, FK506+MTX ± others or FK506 ± others as GVHD prophylaxis included - Patients with twin transplant and graftype cord blood excluded - IBMTR cases (n=1223) and NMDP (n=659) b The chi-square test is used for discrete covariates; the Kruskal-Wallis test is used for continuous covariates. Follow up completeness index=83% One year of complete follow-up [Cy/TBI (95%); Oral Bu/Cy (96%); IV Bu/Cy (87%)] Three year of complete follow-up [Cy/TBI (87%); Oral Bu/Cy (83%); IV Bu/Cy (67%)] Five year of complete follow-up [Cy/TBI (78%); Oral Bu/Cy (59%); IV Bu/Cy (69%)] 24

25 Not for publication or presentation Attachment 5 CIBMTR CK07-01 A COMPARISON OF TOTAL BODY IRRADIATION (TBI) - BASED CONDITIONING VS. CHEMOTHERAPY-BASED CONDITIONING IN MYELOABLATIVE ALLOGENEIC STEM CELL TRANSPLANTS FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DRAFT PROTOCOL Study Chair: Study Statisticians: Mitchell Sabloff, MD The Ottawa Hospital, Ottawa, Ontario, Canada, K1H 8L6 Telephone: ext Fax: msabloff@ottawahospital.on.ca Wael Saber, MD, MS CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI Telephone: Fax: wsaber@mcw.edu Kwang Woo Ahn, PhD CIBMTR The Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, WI Telephone: Fax: kwooahn@mcw.edu 25

26 Not for publication or presentation Attachment 5 Scientific Director: Working Committee Chairs: Mukta Arora, MD University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN Telephone: Fax: arora005@umn.edu Matt Kalaycio, MD The Cleveland Clinic Main Campus Mail Code R Euclid Ave Cleveland, OH Telephone: Fax: kalaycm@ccf.org Richard T. Maziarz, MD Oregon Health and Science University 3181 SW Sam Jackson Park Road Portland, OR Telephone: Fax: maziarzr@ohsu.edu Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX Telephone: Fax: Jcortes@mdanderson.org 26

27 Not for publication or presentation Attachment OBJECTIVES: 1.1 To compare the outcomes of patients extracted from the CIBMTR database that underwent a myeloablative allogeneic hematopoietic stem cell transplant for CLL using either a TBIbased or chemotherapy-based conditioning regimen. Primary endpoint: Disease-free survival (DFS) Secondary endpoints: Hematopoietic recovery Incidence of acute GVHD or chronic GVHD Treatment-related mortality (TRM) Recurrence or progression Overall survival (OS) 1.2 To evaluate the impact of TBI dose (<=1200 vs. >1200) on endpoints. 2.0 SCIENTIFIC JUSTIFICATION: Treatment options for CLL have been evolving, recently, from the standard conservative management to more aggressive approaches. This has been possible due to the identification of novel prognostic markers and the development of more effective treatments. These include such agents as purine analogues, antibodies such as Rituximab and Alemtuzumab, combinations of the above and autologous and allogeneic stem cell transplants 1-4. Intensive treatments such as allogeneic hematopoietic stem cell transplants have demonstrated some promising results; however, the optimal conditions regimen has not been identified yet. Both myeloablative and reduced-intensity hematopoietic stem cell transplants have been performed 5-8. Although the more intense myeloablative transplants appear to be effective on the disease they have been complicated by high treatment related mortality 9. This has been reduced by reduced-intensity transplants but they may be hindered by more frequent relapse and reduced effect on more resistant disease, particularly those who present with bulky adenopathy 10. Radiotherapy, is very effective at treating non-hodgkin s lymphoma, particularly chemotherapy resistant lymphoma There have been examples of even low-dose radiotherapy having a useful effect in treating localized CLL, irrespective of the previous chemotherapy 14;15. Total body irradiation (TBI), which is used routinely in a variety of stem cell transplant for hematological diseases and in autologous stem cell transplants for CLL, is only used in a subset of allogeneic stem cell transplants for CLL 5;16;17. Those receiving reduced intensity regimen transplants have received very low dose or no radiotherapy 7. There have been some recent reports comparing myeloablative radiotherapy-based conditioning regimens and chemotherapy regimens but both were retrospective and very small sample sizes 5;16. In addition, no difference was detected in one of the reports and the other suggested a difference in favor of TBI but it appeared to be more because of a difference in toxicity rather than disease relapse, which may be attributable to oral busulfan. It would be of interest to know if the addition of radiation to the conditioning regimen is important to a relatively radiation naïve but sensitive disease, in order to overcome some of the 27

28 Not for publication or presentation Attachment 5 obstacles of resistance in chemotherapy based conditioning regimens. This might help guide future transplants in terms of adding radiation to the transplant if it is found useful in overcoming these obstacles or continuing with the current trends, employing primarily chemotherapy-based regimens. Such a question would require a large database to draw on such as the CIBMTR. 3.0 STUDY POPULATION: All patients who have been reported to the CIBMTR who received a first myeloablative allogeneic stem cell transplant (per CIBMTR consensus criteria) in the past 10 years for B-CLL, non-transformed, from a related or unrelated donor. Excluded from the population are any transplants with a TBI dose of 500 cgy as a single fraction or 800 cgy, if fractionated, twin transplants, and cord blood transplants. 4.0 OUTCOMES: 4.1 Hematopoietic recovery: The primary measures for hematopoietic recovery will be: Time to neutrophils (ANC) > 0.5 x10 9 /L sustained for three consecutive days within 28 and 100 days posttransplant. This endpoint does not specify whether recovery is engraftment of donor cells or autologous reconstitution. This event is summarized by the cumulative incidence estimate with death as the competing risk Time to achieve a platelet count of (a) >20 x 10 9 /L independent of platelet transfusions for 3 consecutive days, and (b) >50 x 10 9 /L independent of platelet transfusions for 3 consecutive days within 28 and 100 days posttransplant. This event is summarized by the cumulative incidence estimate with death as the competing risk. 4.2 Incidence of acute and chronic GVHD: Occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD and limited and extensive chronic GVHD. This event is summarized by the cumulative incidence estimate with death as the competing risk. 4.3 Treatment-related mortality (TRM): Any death within the first 28 days of transplant or any death occurring after day 28 in the absence of disease progression. This event is summarized by the cumulative incidence estimate with relapse as the competing risk. 4.4 Relapse/Progression: progressive disease or recurrence of disease are events except death occurred within the first 28 days of transplant. Those who survive without recurrence or progressive disease are censored at the date of last contact. This event is summarized by the cumulative incidence estimate with TRM as the competing risk. 4.5 Disease-free survival (DFS): survival without recurrence or tumor progression. Recurrence or progression of disease and death are events. Those who survive without recurrence or progression are censored at last contact. 4.6 Overall survival: time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up. 28

29 Not for publication or presentation Attachment VARIABLES TO BE ANALYZED: 5.1 Patient-related: Age at transplant: in decades Gender: (male vs. female) Karnofsky performance score at transplant: (<90% vs. 90%) 5.2 Disease-related: At diagnosis: Rai stage: (0/I/II vs. III/IV) B-symptoms: (y/n) Between diagnosis and transplant: Number of prior treatments: ( 2 vs. 3) Prior fludarabine therapy: (y/n) Fludarabine-refractory: (y/n) Chemotherapy-refractory: (y/n) Best response after any therapy prior to transplant (molecular CR/continuing CR/CR/Nodular PR/PR vs. Stable disease/progressive disease vs. Not evaluable/not tested) At transplant: Hemoglobin: ( or <110 g/l) Platelets count: ( or < 100 x 10 9 /L) Lymphocytosis: (>50 x 10 9 /L) Splenectomy: (y/n) Rai stage: (0/I/II vs. III/IV) Bulky lymphadenopathy: (< or 5cm) State of disease: (molecular CR/continuing CR/CR/Nodular PR/PR vs. Stable disease/progressive disease vs. not evaluable/not tested) Extramedullary or extra-nodal disease: (y or n) 5.3 Transplant-related: Time from diagnosis to transplant: (continuous) Donor recipient gender match: (M-M vs. M-F vs. F-M vs. F-F) Donor type: (related vs. unrelated) Donor-recipient HLA match Donor-recipient CMV status: (+/+ vs. +/- vs. -/+ vs. -/-) Donor age CD34 stem cell dose: (< or 5 x 10 6 cells/kg) Graft type: BM vs. PB Year of transplant: GVHD prophylaxis ATG (y or n) 29

30 Not for publication or presentation Attachment STUDY DESIGN: From the data collected as described in the study population above the group will be divided into 2 groups: those that received TBI vs. those that did not. Differences between the 2 groups (i.e. TBI containing vs. chemotherapy only) will be identified using chi-squared analysis for categorical variables and the Mann-Whitney test for continuous variables. The Kaplan-Meier product limit method will be used to assess for OS and PFS. The overall follow-up completeness index is 72% 5yrs). Thus, the survival curves after 5 years for OS and PFS should be interpreted with a caution. Values for the other outcomes listed in Section 4.0 will be calculated by cumulative incidence estimate to account for competing risks. Multivariate analyses will be performed using the proportional hazards model. To see whether there is statistical difference between TBI (<=1200) and TBI (>1200), the subgroup analysis will be performed first. If it shows statistically significant difference between the two subgroups, the proportional hazards model with TBI (<=1200) vs. TBI (>1200) vs. chemotherapy only will be employed. If it shows no statistically significant difference between the two, the proportional hazards model with TBI vs. chemotherapy only will be used. The interaction between the main effect and the other covariates will be checked. Factors violating the proportional hazard assumptions will be included in the model as time-dependent covariates. 7.0 REFERENCES: 1. Shanafelt TD, Kay NE. Comprehensive management of the CLL patient: a holistic approach. [Review] [63 refs]. Hematology Tam CS, Khouri I. The role of stem cell transplantation in the management of chronic lymphocytic leukaemia. [Review] [52 refs]. Hematological Oncology 2009;27: Gribben JG. Stem cell transplantation in chronic lymphocytic leukemia. [Review] [30 refs]. Biology of Blood & Marrow Transplantation 2008;15:Suppl Gribben JG. Role of allogeneic hematopoietic stem-cell transplantation in chronic lymphocytic leukemia.[comment]. Journal of Clinical Oncology 2008;26: Toze CL, Galal A, Barnett MJ et al. Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versushost disease. Bone Marrow Transplantation 2005;36: Malhotra P, Hogan WJ, Litzow MR et al. Long-term outcome of allogeneic stem cell transplantation in chronic lymphocytic leukemia: analysis after a minimum follow-up of 5 years.[see comment]. Leukemia & Lymphoma 2008;49: Sorror ML, Storer BE, Sandmaier BM et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.[see comment]. Journal of Clinical Oncology 2008;26: Caballero D, Garcia-Marco JA, Martino R et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clinical Cancer Research 2005;11:

31 Not for publication or presentation Attachment 5 9. Pavletic SZ, Khouri IF, Haagenson M et al. Unrelated donor marrow transplantation for B- cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. Journal of Clinical Oncology 2005;23: Dreger P, Brand R, Milligan D et al. Reduced-intensity conditioning lowers treatmentrelated mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 2005;19: Kahn ST, Flowers CR, Lechowicz MJ, Hollenbach K, Johnstone PA. Refractory or relapsed Hodgkin's disease and non-hodgkin's lymphoma: optimizing involved-field radiotherapy in transplant patients. Cancer Journal 2005;11: Wadhwa PD, Fu P, Koc ON et al. High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: an effective regimen with low morbidity and mortality. Biology of Blood & Marrow Transplantation 2005;11: Girinsky T, Lapusan S, Ribrag V et al. Phase II study of concomitant chemoradiotherapy in bulky refractory or chemoresistant relapsed lymphomas. International Journal of Radiation Oncology, Biology, Physics 2005;61: Johannsson J, Specht L, Mejer J, Jensen BA. Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-hodgkin's lymphoma and chronic lymphocytic leukemia.[see comment]. International Journal of Radiation Oncology, Biology, Physics 2002;54: Sawyer EJ, Timothy AR. Low dose palliative radiotherapy in low grade non-hodgkin's lymphoma. Radiotherapy & Oncology 1997;42: Doney KC, Chauncey T, Appelbaum FR, Seattle Bone Marrow Transplant Team. Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplantation 2002;29: Pavletic ZS, Arrowsmith ER, Bierman PJ et al. Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplantation 2000;25:

32 Not for publication or presentation Attachment 5 Table 1. Characteristics of 396 CLL patients that underwent a myeloablative HCT from and reported to the CIBMTR based on type of conditioning regimen (TBI based vs. chemotherapy based) Variable TBI Chemotherapy P-value* Number of patients Number of centers Age at transplant, median (range), years 48 (24-64) 50 (27-72) 0.007** Age at transplant, years (23) 12 (13) (48) 42 (45) >51 86 (28) 40 (43) Male sex 206 (68) 64 (68) 0.98 Karnofsky score prior to transplant 0.72 <90 91 (30) 30 (32) >= (65) 58 (62) missing 14 ( 5) 6 ( 6) Disease-related: Rai stage at diagnosis 0.31 Early (stages 0, I and II) 144 (48) 37 (39) Late (III and IV) 36 (12) 11 (12) missing 122 (40) 46 (49) Symptoms at diagnosis 0.97 A 126 (42) 40 (43) B 41 (14) 12 (13) missing 135 (45) 42 (45) Prior radiation between diagnosis and tx 0.55 No 157 (52) 44 (47) Yes 16 ( 5) 4 ( 4) missing 129 (43) 46 (49) Number of prior lines of treatments (21) 19 (20) 3 99 (33) 28 (30) missing 140 (46) 47 (50) Fludarabine therapy between diagnosis and transplant 0.04 No 45 (15) 8 ( 9) Yes 152 (50) 41 (44) missing 105 (35) 45 (48) Fludarabine-refractory between diagnosis and transplant 0.96 No 48 (16) 13 (14) Yes 73 (24) 24 (26) Not applicable 172 (57) 54 (57) missing 9 ( 3) 3 ( 3) 32

33 Not for publication or presentation Attachment 5 Table 1. Continued. Variable TBI Chemotherapy P-value* Chemotherapy-refractory between diagnosis and 0.62 transplant No 62 (21) 15 (16) Yes 92 (30) 28 (30) Not applicable 131 (43) 47 (50) missing 17 ( 6) 4 ( 4) Best response after any therapy prior to tx 0.70 continuing CR - CR - nodular PR - PR 127 (42) 35 (37) stable - progressive 28 ( 9) 9 (10) unknown 147 (49) 50 (53) Hemoglobin level at transplant (g/dl) 0.41 hgb > = (26) 26 (28) hgb < (15) 19 (20) missing 178 (59) 49 (52) Platelets at transplant (x10 3 /mm 3 ) 0.38 platelets > = (26) 25 (27) platelets < (17) 21 (22) missing 174 (58) 48 (51) ANC at transplant 0.01 Neutrophils = > 0.5 x 10^9/L at tx 108 (36) 40 (43) Neutrophils < 0.5 x 10^9/L at tx 6 ( 2) 7 ( 7) missing 188 (62) 47 (50) Lymphocyte count at transplant (x 10 9 /L) 0.64 Lymphocyte count < 50 x 10^9/L at tx 110 (36) 39 (41) Lymphocyte count = > 50 x 10^9/L at tx 35 (12) 9 (10) missing 157 (52) 46 (49) Splenectomy 0.91 no 180 (60) 56 (60) yes 19 ( 6) 7 ( 7) missing 103 (34) 31 (33) B symptoms present at transplant 0.01 No 30 (10) 20 (21) Yes 14 ( 5) 4 ( 4) missing 258 (85) 70 (74) Rai stage at transplant 0.72 Early (CR; stages 0, I and II) 121 (40) 34 (36) Late (stages III and IV) 64 (21) 23 (24) missing 117 (39) 37 (39) 33

34 Not for publication or presentation Attachment 5 Table 1. Continued. Variable TBI Chemotherapy P-value* Bulky LAD at transplant: (< or 5cm) 0.59 No 159 (53) 47 (50) Yes 36 (12) 15 (16) missing 107 (35) 32 (34) Extramedullary or extra-nodal disease at transplant 0.59 No 128 (42) 37 (39) Yes 68 (23) 26 (28) missing 106 (35) 31 (33) State of disease at transplant± 0.43 CR/PR at tx 111 (37) 28 (30) Stable/Progressive at tx 82 (27) 30 (32) Unknown/Not evaluable/missing at tx 109 (36) 36 (38) Transplant-related: Time from diagnosis to transplant, median (range), months 43 (2-236) 41 (6-198) 0.47** missing 3 0 Donor age, median (range), years 42 (13-69) 41 (18-67) 0.23** Donor age, years 0.76 <31 55 (18) 20 (21) (27) 26 (28) > (53) 45 (48) missing 6 ( 2) 3 ( 3) Donor recipient gender match 0.79 M-M 118 (39) 41 (44) M-F 58 (19) 19 (20) F-M 88 (29) 23 (24) F-F 38 (13) 11 (12) Donor-recipient CMV status 0.06 Pos-pos 88 (29) 41 (44) Pos-neg 28 ( 9) 8 ( 9) Neg-pos 79 (26) 24 (26) Neg-neg 92 (30) 17 (18) Not tested/inconclusive 15 ( 5) 4 ( 4) Donor-recipient HLA match 0.68 HLA-id sib and Related partially matched 159 (53) 47 (50) Related mismatched and Related matching unknown 15 ( 5) 3 ( 3) URD well-matched and URD partially matched 101 (33) 37 (39) URD mismatched and URD matching unknown and URD matching TBD 27 ( 9) 7 ( 7) 34

35 Not for publication or presentation Attachment 5 Table 1. Continued. Variable TBI Chemotherapy P-value* CD34 stem cell dose: (< or 5 x 10 6 cells/kg) <.0001 <5 71 (24) 39 (41) >5 54 (18) 28 (30) missing 177 (59) 27 (29) Graft type <.0001 Bone marrow 179 (59) 32 (34) Peripheral blood 123 (41) 62 (66) Year of transplant < (16) 6 ( 6) (15) 6 ( 6) (13) 7 ( 7) ( 8) 7 ( 7) (12) 3 ( 3) ( 5) 8 ( 9) ( 4) 2 ( 2) ( 4) 7 ( 7) ( 6) 12 (13) ( 4) 13 (14) ( 6) 7 ( 7) ( 6) 8 ( 9) ( 2) 8 ( 9) Year of transplant (grouped) < (51) 26 (28) (25) 20 (21) (16) 32 (34) ( 8) 16 (17) GVHD prophylaxis 0.01 none and other 5 ( 2) 3 ( 3) T-cell depletion 58 (19) 7 ( 7) FK506+MTX+-oth and FK506+MTX+-oth 82 (27) 38 (40) CsA+MTX+-oth and CsA+-oth 157 (52) 46 (49) ATG at conditioning or as GVHD prophylaxis <.0001 No 284 (94) 67 (71) Yes 18 ( 6) 27 (29) Median (range) follow-up of survivors, m 84(3-159) 43( ) --- *Chi-Square **Wilcoxon two-sample Test The completeness index FU as of is 72%. The completeness index FU at 1, 3, and 5 years is 96%, 88% and 79%, respectively. Additional follow up information is being sought from the centers. Centers will be contacted ±Additional information is being sought to reduce the proportion of missing data. 35

36 Not for publication or presentation Attachment 5 Table 1a. Characteristics of 396 CLL patients that underwent a myeloablative HCT from and reported to the CIBMTR based on type of conditioning regimen (TBI based vs. chemotherapy based) and radiation dose intensity (TBI>1200 cgy vs. TBI 1200 cgy) TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value* Number of patients Number of centers Age at transplant, median (range), years 49 (24-64) 44 (27-60) 50 (27-72) <0.0001** Age at transplant, years < (19) 26 (34) 12 (13) (46) 42 (55) 42 (45) >51 78 (35) 8 (11) 40 (43) Male sex 149 (66) 57 (75) 64 (68) 0.34 Karnofsky score prior to transplant 0.94 <90 68 (30) 23 (30) 30 (32) >= (65) 49 (64) 58 (62) missing 10 ( 4) 4 ( 5) 6 ( 6) Disease-related: Rai stage at diagnosis 0.18 Early (stages 0, I and II) 113 (50) 31 (41) 37 (39) Late (III and IV) 29 (13) 7 ( 9) 11 (12) missing 84 (37) 38 (50) 46 (49) Symptoms at diagnosis 0.16 A 103 (46) 23 (30) 40 (43) B 31 (14) 10 (13) 12 (13) missing 92 (41) 43 (57) 42 (45) Prior radiation between diagnosis and tx 0.25 No 125 (55) 32 (42) 44 (47) Yes 12 ( 5) 4 ( 5) 4 ( 4) missing 89 (39) 40 (53) 46 (49) Number of prior lines of treatments (21) 15 (20) 19 (20) 3 83 (37) 16 (21) 28 (30) missing 95 (42) 45 (59) 47 (50) Fludarabine therapy between diagnosis and 0.18 transplant No 33 (15) 12 (16) 8 ( 9) Yes 115 (51) 37 (49) 41 (44) missing 78 (35) 27 (36) 45 (48) 36

37 Not for publication or presentation Attachment 5 Table 1a. Continued. TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value* Fludarabine-refractory between diagnosis 0.60 and transplant No 38 (17) 10 (13) 13 (14) Yes 60 (27) 13 (17) 24 (26) not applicable 122 (54) 50 (66) 54 (57) Missing 6 ( 3) 3 ( 4) 3 ( 3) Chemotherapy-refractory between diagnosis 0.12 and transplant No 50 (22) 12 (16) 15 (16) Yes 76 (34) 16 (21) 28 (30) not applicable 89 (39) 42 (55) 47 (50) missing 11 ( 5) 6 ( 8) 4 ( 4) Best response after any therapy prior to tx 0.05 continuing CR - CR - nodular PR - PR 103 (46) 24 (32) 35 (37) stable - progressive 24 (11) 4 ( 5) 9 (10) unknown 99 (44) 48 (63) 50 (53) Hemoglobin level at transplant (g/dl) 0.17 hgb > = (29) 13 (17) 26 (28) hgb < (15) 11 (14) 19 (20) missing 126 (56) 52 (68) 49 (52) Platelets at transplant (x10 3 /mm 3 ) 0.05 platelets > = (30) 11 (14) 25 (27) platelets < (16) 13 (17) 21 (22) missing 122 (54) 52 (68) 48 (51) ANC at transplant Neutrophils = > 0.5 x 10^9/L at tx 89 (39) 19 (25) 40 (43) Neutrophils < 0.5 x 10^9/L at tx 6 ( 3) 0 7 ( 7) missing 131 (58) 57 (75) 47 (50) Lymphocyte count at transplant (x 10 9 /L) 0.26 Lymphocyte count < 50 x 10^9/L at tx 88 (39) 22 (29) 39 (41) Lymphocyte count = > 50 x 10^9/L at tx 22 (10) 13 (17) 9 (10) missing 116 (51) 41 (54) 46 (49) Splenectomy 0.04 no 144 (64) 36 (47) 56 (60) yes 16 ( 7) 3 ( 4) 7 ( 7) missing 66 (29) 37 (49) 31 (33) B symptoms present at transplant 0.01 No 27 (12) 3 ( 4) 20 (21) Yes 10 ( 4) 4 ( 5) 4 ( 4) missing 189 (84) 69 (91) 70 (74) 37

38 Not for publication or presentation Attachment 5 Table 1a. Continued. TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value* Rai stage at transplant 0.86 Early (CR; stages 0, I and II) 91 (40) 30 (39) 34 (36) Late (stages III and IV) 50 (22) 14 (18) 23 (24) missing 85 (38) 32 (42) 37 (39) Bulky LAD at transplant: (< or 5cm) 0.03 No 124 (55) 35 (46) 47 (50) Yes 32 (14) 4 ( 5) 15 (16) missing 70 (31) 37 (49) 32 (34) Extramedullary or extra-nodal disease at transplant No 103 (46) 25 (33) 37 (39) Yes 57 (25) 11 (14) 26 (28) missing 66 (29) 40 (53) 31 (33) State of disease at transplant± 0.21 CR/PR at tx 78 (35) 33 (43) 28 (30) Stable/Progressive at tx 68 (30) 14 (18) 30 (32) Unknown/Not evaluable/missing at 80 (35) 29 (38) 36 (38) tx Transplant-related: Time from diagnosis to transplant, 45 (4-236) 37 (2-137) 41 (6-198) 0.49** median (range), months Donor age, median (range), years 43 (13-69) 39 (13-66) 41 (18-67) 0.10** Donor age, years 0.50 <31 41 (18) 14 (18) 20 (21) (25) 26 (34) 26 (28) > (54) 36 (47) 45 (48) missing 6 ( 3) 0 3 ( 3) Donor recipient gender match 0.67 M-M 88 (39) 30 (39) 41 (44) M-F 46 (20) 12 (16) 19 (20) F-M 61 (27) 27 (36) 23 (24) F-F 31 (14) 7 ( 9) 11 (12) Donor-recipient CMV status 0.17 Pos-pos 70 (31) 18 (24) 41 (44) Pos-neg 20 ( 9) 8 (11) 8 ( 9) Neg-pos 61 (27) 18 (24) 24 (26) Neg-neg 65 (29) 27 (36) 17 (18) Not tested/inconclusive 10 ( 4) 5 ( 7) 4 ( 4) 38

39 Not for publication or presentation Attachment 5 Table 1a. Continued. TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value* Donor-recipient HLA match 0.16 HLA-id sib and Related partially 129 (57) 30 (39) 47 (50) matched Related mismatched and Related 11 ( 5) 4 ( 5) 3 ( 3) matching unknown URD well-matched and URD 69 (31) 32 (42) 37 (39) partially matched URD mismatched and URD 17 ( 8) 10 (13) 7 ( 7) matching unknown and URD matching TBD CD34 stem cell dose: (< or 5 x 10 6 < cells/kg) <5 53 (23) 18 (24) 39 (41) >5 44 (19) 10 (13) 28 (30) missing 129 (57) 48 (63) 27 (29) Graft type < Bone marrow 127 (56) 52 (68) 32 (34) Peripheral blood 99 (44) 24 (32) 62 (66) Year of transplant < (17) 10 (13) 6 ( 6) (15) 12 (16) 6 ( 6) (14) 7 ( 9) 7 ( 7) ( 6) 9 (12) 7 ( 7) ( 9) 16 (21) 3 ( 3) ( 4) 4 ( 5) 8 ( 9) ( 4) 4 ( 5) 2 ( 2) ( 4) 3 ( 4) 7 ( 7) ( 5) 5 ( 7) 12 (13) ( 5) 2 ( 3) 13 (14) ( 8) 2 ( 3) 7 ( 7) ( 7) 2 ( 3) 8 ( 9) ( 3) 0 8 ( 9) Year of transplant (grouped) < (51) 38 (50) 26 (28) (21) 27 (36) 20 (21) (18) 9 (12) 32 (34) (10) 2 ( 3) 16 (17) 39

40 Not for publication or presentation Attachment 5 Table 1a. Continued. TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value* GVHD prophylaxis 0.03 none and other 4 ( 2) 1 ( 1) 3 ( 3) T-cell depletion 40 (18) 18 (24) 7 ( 7) FK506+MTX+-oth and 66 (29) 16 (21) 38 (40) FK506+MTX+-oth CsA+MTX+-oth and CsA+-oth 116 (51) 41 (54) 46 (49) ATG at conditioning or as GVHD <.0001 prophylaxis No 215 (95) 69 (91) 67 (71) Yes 11 ( 5) 7 ( 9) 27 (29) Median (range) follow-up of survivors, 75( ) 84( ) 43( ) --- m Centers will be contacted. ±Additional information is being sought to reduce the proportion of missing data. 40

41 Not for publication or presentation Attachment 6 CIBMTR CK06-03 COMPARISON OF CONVENTIONAL MYELOABLATIVE VS. NONMYELOABLATIVE OR REDUCED-INTENSITY CONDITIONING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA REVISED PROTOCOL Study Chairs: Jose F. Leis, MD, PhD Adult Blood & Marrow Transplant Program Mayo Clinic 5777 East Mayo Boulevard Phoenix, Arizona Telephone: Fax: leis.jose@mayo.edu Richard T. Maziarz, MD Center for Hematologic Malignancies Oregon Health & Science University 3181 S.W. Sam Jackson Park Road Mail Code: UHN73C Portland, Oregon Telephone: Fax: maziarzr@ohsu.edu Ronald M. Sobecks, MD Taussig Cancer Center The Cleveland Clinic 9500 Euclid Ave. R35 Cleveland, OH Telephone: Fax: sobeckr@ccf.org 41