not for publication or presentation · aml (2010/2110), all (2011/2111), mds (2014/2114), jmml...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR SOLID TUMORS Salt Lake City, Utah Friday, February 15, 2013, 2:45 – 4:45 PM

Co-Chair: Michael R. Bishop, MD, University of Chicago

Section of Hematology/Oncology, Chicago, IL Phone: 773-702-4400; Fax: 773-702-3163; E-mail: [email protected]

Co-Chair: Edward Stadtmauer, MD, Hospital of the University of Pennsylvania, Philadelphia, PA Phone: 215-662-7910; Fax: 215-662-4064; E-mail: [email protected]

Statisticians: Michael Hemmer, MS, CIBMTR, Milwaukee, WI Phone : 414-805-4638, Fax : 414-805-0714, E-mail : [email protected] Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee WI Phone: 414-456-7387; Fax: 414-456-6530; E-mail: [email protected]

Scientific Director: Mukta Arora, MD, MS University of Minnesota, Minneapolis, MN Phone: 612-626-4105; Fax: 612-625-6919; E-mail: [email protected]

1. Introduction a. 2012 Tandem Minutes for approval (Attachment 1)

b. Newly appointed chair: Yago Nieto, MD; The University of Texas MD Anderson Cancer

Center; E-mail: [email protected].

2. Accrual summary (Attachment 2)

3. Presentation, published or submitted papers a. ST07-01 Hale GA, Arora M, Ahn KW, He W, Camitta B, Bishop MR, Bitan M, Cairo MS,

Chan K, Childs RW, Copelan E, Davies SM, Diaz Perez MA, Doyle JJ, Gale RP, Vicent MG, Horn BN, Hussein AA, Jodele S, Kamani NR, Kasow KA, Kletzel M, Lazarus HM, Lewis VA, Myers KC, Olsson R, Pulsipher M, Qayed M, Sanders JE, Shaw PJ, Soni S, Stiff PJ, Stadtmauer EA, Ueno NT, Wall DA, Grupp SA. Allogeneic Hematopoietic Cell Transplantation for Neuroblastoma: The CIBMTR Experience. (In press)

4. Studies in progress (Attachment 3)

a. ST00-02 Allogeneic stem cell transplant for renal cell cancer (J Barrett) (Attachment 4)

Data Collection

b. ST09-01 Transplant trends for metastatic solid tumors in North America and Europe (R Childs/D Blaise) (Attachment 5)

Protocol Development

c. ST10-01 The value of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with high risk or metastatic inflammatory breast cancer (YC Cheng/NT Ueno) (Attachment 6)


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Not for publication or presentation

5. Deferred studies ST02-02 Allogeneic stem cell transplantation in colorectal cancer (L Barkholt/O Ringden/ M Aglietta)

6. Proposed studies PROP 1112-02 High dose chemotherapy and autologous stem cell transplantation for germ cell tumors. (M Qayed/T Olson/K Chiang) (Attachment 7)

7. Other business

a. Brain-storming session

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Not for publication or presentation Attachment 1

M I N U T E S CIBMTR WORKING COMMITTEE FOR SOLID TUMORS San Diego, California Wednesday, February 1, 2012, 12:15 pm – 2:15 pm Co-Chair: Michael R. Bishop, MD, Medical College of Wisconsin, Clinical Cancer Center, Milwaukee, WI Phone: 414-805-4688 Fax: 414-805-4606; E-mail: [email protected] Co-Chair: Edward Stadtmauer, MD, Hospital of the University of Pennsylvania, Philadelphia, PA Phone: 215-662-7910; Fax: 215-662-4064; E-mail: [email protected] Statisticians: John Bosco Umejiego, MPH, CIBMTR, Minneapolis, MN Phone: 612-362-3433; Fax: 612-884-8661; E-mail: [email protected] Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee WI Phone: 414-456-7387; Fax: 414-456-6530; E-mail: [email protected] Scientific Director: Mukta Arora, MD, MS University of Minnesota, Minneapolis, MN Phone: 612-626-4105; Fax: 612-625-6919; E-mail: [email protected]

1. Introduction

The meeting was called to order at 12:15pm by Dr. Edward Stadtmauer. Co-chairs, scientific director and statisticians were introduced to the audience.

Dr. Stadtmauer announced the new CIBMTR effort, the Forms Revision Process. All data collection forms are undergoing revision over the next two years, starting with the following: CRID (2804), Pre-TED (2400), Baseline (2000), Infectious Disease Markers (2004), HLA (2005), Infusion (2006), AML (2010/2110), ALL (2011/2111), MDS (2014/2114), JMML (2015/2115), Plasma Cell Disorders (2016/2116), Amyloidosis (2017/2117), Lymphoma (2018/2118) and Waldenstrom's Macroglobulinemia (2019/2119). The revised forms will coincide with the development of the new FormsNet application. Members are encouraged to become a member of the Forms Revision Review Committee in order to capture all the relevant information needed to produce high-quality studies. Suggestions for forms can be forwarded to the working committee leadership or Emilie Meissner at [email protected] Minutes of February, 2011 meeting (Attachment 1) The meeting minutes from the 2011 meeting were approved by the committee without any modification.

2. Accrual summary (Attachment 2)

The accrual summary tables were briefly reviewed. Dr. Bishop led the discussion on the accrual summary and encouraged investigators with interest to participate in the STWC studies. He highlighted two areas that can be potentially focused on for studies. One area is the germ cell tumors. The committee had previously published manuscript on germ cell tumors a few years back, and it would be a great opportunity to keep investigating in this area. Interesting topics included effects of high dose therapy on germ cell tumor HCT survivors, effects of single vs. tandem HCTs and late

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relapse after HCTs. Another area is the neuroblastoma and other related sarcomas. Current study ST07-01 looking at the allogeneic transplantation for neuroblastoma is an example of study in this area.

3. Published or submitted papers

ST06-01 E Stadtmauer. AutoHCT for desmoplastic tumor. Submitted to Bone Marrow Transplantation. Dr. Stadtmauer presented this study. This study has been submitted to BMT and is currently under revision for re-submission. The objective of the study is to describe clinical outcomes of autologous transplant for desmoplastic small round cell tumors. There are 36 patients from 29 centers; 18 patients had additional comprehensive research data. This is the largest series study for desmoplastic small round cell tumors. Males were dominant. Majority patients received transplant between 2002 and 2007. Most of patients did not receive radiation therapy. About two third of patients never achieved complete response with therapy. About 71% of patients had relapsed after transplant and one patient died within 100 days of HCT. The study showed that an important predictor of long time survival was complete remission after HCT, with 57% of these patients alive at 3 years post-transplant.

4. Studies in progress (Attachment 3)

a. ST00-02 Allotx for renal cell cancer (J Barrett) (Attachment 4) Supplemental Form/ Data Collection

Dr. Barret presented this study. The specific aims of the study are to describe the worldwide experience of patients undergoing allogeneic peripheral blood stem cell transplants for renal cell cancer; to evaluate the results of allogeneic peripheral blood stem cell transplantation in renal cell cancer patients; and to identify patient, disease, and transplant-related prognostic factors for outcome after transplantation for renal cell cancer. Two hundred and four patients from 61 centers were identified. The study is at the data collection stage. Sixty two forms have been received from the centers. The meeting agreed to send out reminders to the transplant centers to complete the supplementary forms especially centers with high patient numbers.

b. ST02-02 Allotx for colorectal cancer (O Ringdén) (Attachment 5) Supplemental Form /

Data Collection

Dr. Ringdén presented this study. The specific objectives of the study are to study the overall patient survival at 18 months and assessment of survival as compared to the population of untreated patients; to study the allogeneic tumoral response; to study the treatment related toxicity and infectious complications; study post-transplant immunological reactions; and to study the antitumoral activity against cell lines based on the primary tumor or corresponding tumor cell lines from the voluntary centers. This is a descriptive study and under form development. Up to 2005, only 40 patients registered and 19 patients reported to CIBMTR. Forms will be deployed to FormsNet2 this year. The leadership encouraged the audience to send in the forms.

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c. ST07-01 Allogeneic HCT for Neuroblastoma (S Grupp) Manuscript

preparation Dr. Grupp presented this study. This study is at manuscript preparation stage and was presented in the ASH 2011 poster presentation session. The objectives of this study were to describe outcomes after allogeneic HSCT in a modern treatment era in patients with neuroblastoma and to identify variables associated with improved disease-free survival (DFS). Outcomes to be evaluated include time to neutrophil and platelet engraftment, graft failure, acute and chronic graft-versus-host disease (GVHD), DFS, overall survival (OS), disease relapse, and treatment related mortality. The study period is 1990-2007 and 143 patients were registered with CIBMTR with 66 patients having report forms. The patients were put in two categories; those who received only allogeneic HCT and those with allogeneic salvage therapy after autologous HCT. Dr Grupp observed that the practice in management of these patients is evolving as shown by the data. Patients with no prior autologous transplant had lower relapse rates and improved overall survival rates. Future studies comparing OS after autoHCT and alloHCT for patients in CR1 should be considered.

d. ST09-01 HCT trends for metastatic solid tumors in NA (D Blaise / R Childs) (Attachment 6)


Dr. Bishop presented this study. The main objective the study is to study trends in both autologous and allogeneic transplants for solid tumors in Europe and in North America reported through the CIBMTR and EBMT transplant registries between 1980 and 2008. The specific goals of the study are to characterize the overall number of allogeneic transplants performed for solid tumors, the annual number of autologous transplants for solid tumors and specific histology, types of allogeneic transplantation performed for solid tumors in terms of conditioning regimens and types of GVHD prophylaxis. There are 751 patients who have undergone allogeneic transplantation for solid tumors between 1981 and 2008. There are 32,410 patients who have undergone autologous transplants for solid tumors between 1982 and 2008. Discussion on this study centered on cooperation by EBMT and committee members agreed on a time line for the dataset for Europe to be obtained. This study was voted to move forward this year.

e. ST10-01 High-dose chemo and autotx as adjuvant Rx in BC (N Ueno /

Y Cheng) (Attachment 7)


Dr. Arora presented this proposal. The objectives of this study are to determine the overall outcome of patients with IBC who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with high risk or metastatic disease; to determine the prognostic factors for survival in patients with IBC who benefit from high-dose chemotherapy and autologous hematopoietic stem cell transplantation; to compare outcomes of patients with IBC who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation to patients with non-IBC who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation high risk setting or

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metastatic disease. One thousand one hundred and forty five patients with inflammatory breast cancer and 2152 patients with non-inflammatory breast cancer were identified. This study is under protocol development. The protocol will be circulated to the working committee later this year. This study was voted to move forward this year.

5. Other business

The committee chairs reiterated their strong support for the members to submit new study ideas/proposals to the solid tumor working committee. Junior investigators are particularly welcomed to participate. The meeting adjourned at 2:00 pm.

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Accrual Summary for Solid Tumor Working Committee

Characteristic of recipients of autologous BMT for sarcoma and other sarcoma cancer reported to the CIBMTR between 1990 and 2012

Bone Sarcoma Other Sarcoma

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 1359 419 682 227Number of centers 219 107 171 84Disease Bone sarcoma (exc. Ewing) 356 (26) 115 (27) 0 0 Ewing sarcoma 1003 (74) 304 (73) 0 0 Soft tissue sarcoma 0 0 560 (82) 192 (85) Sarcoma unspecified 0 0 122 (18) 35 (15)Year of transplant 1990-1991 79 ( 6) 23 ( 5) 61 ( 9) 12 ( 5) 1992-1993 63 ( 5) 24 ( 6) 49 ( 7) 11 ( 5) 1994-1995 98 ( 7) 36 ( 9) 56 ( 8) 22 (10) 1996-1997 158 (12) 86 (21) 126 (18) 71 (31) 1998-1999 249 (18) 108 (26) 143 (21) 61 (27) 2000-2001 202 (15) 54 (13) 68 (10) 24 (11) 2002-2003 127 ( 9 20 ( 5) 60 ( 9) 7 ( 3) 2004-2005 125 ( 9) 21 ( 5) 41 ( 6) 9 ( 4) 2006-2007 81 ( 6) 18 ( 4) 38 ( 6) 5 ( 2) 2008-2009 92 ( 7) 27 ( 6) 15 ( 2) 5 ( 2) 2010-2011 71 ( 5) 2 (<1) 20 ( 3) 0 2012 14 ( 1) 0 5 (<1) 0Age at transplant, median (range), years 17 (1 - 59) 17 (1 - 59) 16 (1 - 64) 15 (1 - 61)Gender Male 829 (61) 264 (63) 376 (55) 127 (56) Female 522 (38) 155 (37) 306 (45) 100 (44) Missing 8 (<1) 0 0 0Graft source Bone marrow 159 (12) 65 (16) 105 (15) 34 (15) PBSC 1072 (79) 326 (78) 500 (73) 174 (77) Bone marrow + PBSC 77 ( 6) 26 ( 6) 56 ( 8) 19 ( 8) Other/missing 51 ( 4) 2 (<1) 21 ( 3) 0Median follow-up time, median (range), months 32 (<1 - 264) 72 (1 - 244) 33 (<1 - 216) 70 (2 - 216)

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Characteristic of recipients of autologous BMT for Neuroblastoma and Breast Cancer reported to the CIBMTR between 1990 and 2012

Neuroblastoma Breast Cancer

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 4476 1223 24080 8242Number of centers 206 108 289 205Disease Neuroblastoma 4476 1223 0 0 Breast cancer, NOS 0 0 20884 (87) 7281 (88) BC, inflammatory 0 0 521 ( 2) 117 ( 1) BC, non-inflammatory 0 0 2675 (11) 844 (10)Year of transplant 1990-1991 235 ( 5) 79 ( 6) 1539 ( 6) 737 ( 9) 1992-1993 207 ( 5) 77 ( 6) 3067 (13) 1332 (16) 1994-1995 257 ( 6) 127 (10) 5104 (21) 1994 (24) 1996-1997 298 ( 7) 148 (12) 7118 (30) 2425 (29) 1998-1999 449 (10) 193 (16) 6036 (25) 1520 (18) 2000-2001 420 ( 9) 115 ( 9) 923 ( 4 ) 201 ( 2) 2002-2003 473 (11) 67 ( 5) 160 (<1) 25 (<1) 2004-2005 520 (12) 158 (13) 86 (<1) 6 (<1) 2006-2007 415 ( 9) 94 (8) 17 (<1) 0 2008-2009 501 (11) 133 (11) 22 (<1) 2 (<1) 2010-2011 590 (13) 22 ( 2) 8 (<1) 0 2012 111 ( 2) 10 (<1) 0 0Age at transplant, median (range), years 4 (<1 - 62) 4 (1 - 39) 46 (<1 - 73) 46 (1 - 72)Gender Male 2609 (58) 708 (58) 175 (<1) 44 (<1) Female 1838 (41) 513 (42) 23768 (99) 8197 (99) Missing 29 (<1) 2 (<1) 137 (<1) 1 (<1)Graft source Bone marrow 857 (19) 323 (26) 2824 (12) 1300 (16) PBSC 3405 (76) 852 (70) 17373 (72) 5803 (70) Bone marrow + PBSC 80 (2) 43 ( 4) 2576 (11) 1135 (14) Other/missing 134 (3) 5 (<1) 1307 ( 5) 4 (<1)Median follow-up time, median (range), months 31 (<1 - 263) 55 (<1 - 259) 48 (<1 - 270) 75 (<1 - 266)

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Accrual Summary for Solid Tumor Working Committee Characteristic of recipients of autologous BMT for ovarian, testicular and germ cell tumors reported to the

CIBMTR between 1990 and 2012

Ovarian and testicular tumor Germ Cell, Extragonadal

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 4381 1634 1131 178Number of centers 272 169 222 78Disease Ovarian (epithelial) 2032 (46) 815 (50) 0 0 Testicular 2349 (54) 819 (50) 0 0 Germ Cell, extragonadal 0 0 1131 178Year of transplant 1990-1991 415 ( 9) 171 (10) 30 ( 3) 11 ( 6) 1992-1993 310 ( 7) 176 (11) 35 ( 3) 11 ( 6) 1994-1995 500 (11) 293 (18) 54 ( 5) 6 ( 3) 1996-1997 743 (17) 362 (22) 24 ( 2) 8 ( 4) 1998-1999 685 (16) 221 (14) 170 (15) 16 ( 9) 2000-2001 253 ( 6) 95 ( 6) 170 (15) 19 (11) 2002-2003 257 ( 6) 57 ( 3) 125 (11) 12 ( 7) 2004-2005 307 ( 7) 51 ( 3) 138 (12) 20 (11) 2006-2007 234 ( 5) 49 ( 3) 167 (15) 18 (10) 2008-2009 242 ( 6) 139 ( 9) 99 ( 9) 52 (29) 2010-2011 345 ( 8) 15 (<1) 98 ( 9) 5 ( 3) 2012 90 ( 2) 5 (<1) 21 ( 2) 0Age at transplant, median (range), years 40 (2 - 76) 41 (2 - 76) 29 (1 - 69) 29 (2 - 58)Gender Male 2348 (54) 813 (50) 905 (80) 141 (79) Female 2029 (46) 821 (50) 225 (20) 37 (21) Missing 4 (<1) 0 1 (<1) 0Graft source Bone marrow 501 (11) 289 (18) 62 ( 5) 18 (10) PBSC 3359 (77) 1176 (72) 1004 (89) 152 (85) Bone marrow + PBSC 281 ( 6) 147 ( 9) 46 ( 4) 7 ( 4) Other/missing 240 ( 5) 22 ( 1) 19 ( 2) 1 (<1)Median follow-up time, median (range), months 27 (<1 - 268) 48 (<1 - 241) 24 (<1 - 193) 42 (<1 - 193)

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Characteristic of recipients of autologous BMT for Medulloblastoma and Wilm’s Tumor reported to the CIBMTR between 1990 and 2012

Medulloblastoma Wilm’s Tumor

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 1755 464 340 63Number of centers 148 62 111 39Disease Medulloblastoma 1755 464 0 0 Wilm’s Tumor 0 0 340 63Year of transplant 1990-1991 7 (<1) 6 ( 1) 10 ( 3) 0 1992-1993 13 (<1) 11 ( 2) 18 ( 5) 3 ( 5) 1994-1995 12 (<1) 8 ( 2) 31 ( 9) 10 (16) 1996-1997 18 ( 1) 9 ( 2) 34 (10) 6 (10) 1998-1999 158 ( 9) 64 (14) 39 (11) 12 (19) 2000-2001 164 ( 9) 60 (13) 36 (11) 8 (13) 2002-2003 161 ( 9) 33 ( 7) 34 (10) 2 ( 3) 2004-2005 185 (11) 39 ( 8) 44 (13) 9 (14) 2006-2007 366 (21) 73 (16) 31 ( 9) 4 ( 6) 2008-2009 330 (19) 160 (34) 33 (10) 9 (14) 2010-2011 279 (16) 1 (<1) 29 ( 9) 0 2012 62 ( 4) 0 1 (<1) 0Age at transplant, median (range), years 7 (1 - 56) 8 (1 - 49) 7 (1 - 49) 6 (1 - 49)Gender Male 1109 (63) 307 (66) 163 (48) 25 (40) Female 645 (37) 157 (34) 174 (51) 38 (60) Missing 1 (<1) 0 3 (<1) 0Graft source Bone marrow 196 (11) 52 (11) 58 (17) 9 (14) PBSC 1505 (86) 397 (86) 262 (77) 50 (79) Bone marrow + PBSC 29 ( 2) 13 ( 3) 15 ( 4) 4 ( 6) Other/missing 25 ( 1) 2 (<1) 5 ( 1) 0Median follow-up time, median (range), months 25 (<1 - 179) 50 (1 - 179) 49 (1 - 239) 51 (1 - 183)

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Characteristic of recipients of autologous BMT for Lung Cancer and CNS Tumor reported to the CIBMTR between 1990 and 2012

Lung Cancer CNS Tumor

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 260 135 3557 956Number of centers 58 30 189 95Disease Lung, small cell 202 (78) 125 (93) 0 0 Lung, non-small cell 39 (15) 10 ( 7) 0 0 Lung, not specified 19 ( 7) 0 0 0 CNS tumor, including CNS PNET 0 0 3557 956Year of transplant 1990-1991 70 (27) 21 (16) 175 ( 5) 31 ( 3) 1992-1993 40 (15) 30 (22) 124 ( 3) 46 ( 5) 1994-1995 52 (20) 34 (25) 112 ( 3) 49 ( 5) 1996-1997 51 (20) 37 (27) 167 ( 5) 52 ( 5) 1998-1999 28 (11) 11 ( 8) 372 (10) 116 (12) 2000-2001 14 ( 5) 2 ( 1) 322 ( 9) 131 (14) 2002-2003 1 (<1) 0 321 ( 9) 51 ( 5) 2004-2005 2 (<1) 0 326 ( 9) 70 ( 7) 2006-2007 0 0 522 (15) 127 (13) 2008-2009 2 (<1) 0 518 (15) 280 (29) 2010-2011 0 0 469 (13) 3 (<1) 2012 0 0 129 ( 4) 0Age at transplant, median (range), years 49 (1 - 74) 50 (1 - 67) 7 (<1 - 69) 8 (<1 - 62)Gender Male 152 (58) 76 (56) 2135 (60) 565 (59) Female 108 (42) 59 (44) 1416 (40) 391 (41) Missing 0 0 6 (<1) 0Graft source Bone marrow 43 (17) 20 (15) 452 (13) 145 (15) PBSC 137 (53) 69 (51) 2852 (80) 764 (80) Bone marrow + PBSC 53 (20) 46 (34) 131 ( 4) 44 ( 5) Other/missing 27 (10) 0 122 ( 3) 3 (<1)Median follow-up time, median (range), months 37 (<1 - 195) 43 (4 - 138) 25 (<1 - 236) 50 (1 - 218)

Abbreviations: PBSC=peripheral blood stem cells

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Characteristic of recipients of autologous BMT for Neuroblastoma and Breast Cancer reported to the CIBMTR between 1990 and 2012

Neuroblastoma Breast Cancer

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 4476 1223 24080 8242Number of centers 206 108 289 205Disease Neuroblastoma 4476 1223 0 0 Breast cancer, NOS 0 0 20884 (87) 7281 (88) BC, inflammatory 0 0 521 ( 2) 117 ( 1) BC, non-inflammatory 0 0 2675 (11) 844 (10)Year of transplant 1990-1991 235 ( 5) 79 ( 6) 1539 ( 6) 737 ( 9) 1992-1993 207 ( 5) 77 ( 6) 3067 (13) 1332 (16) 1994-1995 257 ( 6) 127 (10) 5104 (21) 1994 (24) 1996-1997 298 ( 7) 148 (12) 7118 (30) 2425 (29) 1998-1999 449 (10) 193 (16) 6036 (25) 1520 (18) 2000-2001 420 ( 9) 115 ( 9) 923 ( 4 ) 201 ( 2) 2002-2003 473 (11) 67 ( 5) 160 (<1) 25 (<1) 2004-2005 520 (12) 158 (13) 86 (<1) 6 (<1) 2006-2007 415 ( 9) 94 (8) 17 (<1) 0 2008-2009 501 (11) 133 (11) 22 (<1) 2 (<1) 2010-2011 590 (13) 22 ( 2) 8 (<1) 0 2012 111 ( 2) 10 (<1) 0 0Age at transplant, median (range), years 4 (<1 - 62) 4 (1 - 39) 46 (<1 - 73) 46 (1 - 72)Gender Male 2609 (58) 708 (58) 175 (<1) 44 (<1) Female 1838 (41) 513 (42) 23768 (99) 8197 (99) Missing 29 (<1) 2 (<1) 137 (<1) 1 (<1)Graft source Bone marrow 857 (19) 323 (26) 2824 (12) 1300 (16) PBSC 3405 (76) 852 (70) 17373 (72) 5803 (70) Bone marrow + PBSC 80 (2) 43 ( 4) 2576 (11) 1135 (14) Other/missing 134 (3) 5 (<1) 1307 ( 5) 4 (<1)Median follow-up time, median (range), months 31 (<1 - 263) 55 (<1 - 259) 48 (<1 - 270) 75 (<1 - 266)

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Accrual Summary for Solid Tumor Working Committee Characteristic of recipients of autologous BMT for ovarian, testicular and germ cell tumors reported to the

CIBMTR between 1990 and 2012

Ovarian and testicular tumor Germ Cell, Extragonadal

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 4381 1634 1131 178Number of centers 272 169 222 78Disease Ovarian (epithelial) 2032 (46) 815 (50) 0 0 Testicular 2349 (54) 819 (50) 0 0 Germ Cell, extragonadal 0 0 1131 178Year of transplant 1990-1991 415 ( 9) 171 (10) 30 ( 3) 11 ( 6) 1992-1993 310 ( 7) 176 (11) 35 ( 3) 11 ( 6) 1994-1995 500 (11) 293 (18) 54 ( 5) 6 ( 3) 1996-1997 743 (17) 362 (22) 24 ( 2) 8 ( 4) 1998-1999 685 (16) 221 (14) 170 (15) 16 ( 9) 2000-2001 253 ( 6) 95 ( 6) 170 (15) 19 (11) 2002-2003 257 ( 6) 57 ( 3) 125 (11) 12 ( 7) 2004-2005 307 ( 7) 51 ( 3) 138 (12) 20 (11) 2006-2007 234 ( 5) 49 ( 3) 167 (15) 18 (10) 2008-2009 242 ( 6) 139 ( 9) 99 ( 9) 52 (29) 2010-2011 345 ( 8) 15 (<1) 98 ( 9) 5 ( 3) 2012 90 ( 2) 5 (<1) 21 ( 2) 0Age at transplant, median (range), years 40 (2 - 76) 41 (2 - 76) 29 (1 - 69) 29 (2 - 58)Gender Male 2348 (54) 813 (50) 905 (80) 141 (79) Female 2029 (46) 821 (50) 225 (20) 37 (21) Missing 4 (<1) 0 1 (<1) 0Graft source Bone marrow 501 (11) 289 (18) 62 ( 5) 18 (10) PBSC 3359 (77) 1176 (72) 1004 (89) 152 (85) Bone marrow + PBSC 281 ( 6) 147 ( 9) 46 ( 4) 7 ( 4) Other/missing 240 ( 5) 22 ( 1) 19 ( 2) 1 (<1)Median follow-up time, median (range), months 27 (<1 - 268) 48 (<1 - 241) 24 (<1 - 193) 42 (<1 - 193)

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Characteristic of recipients of autologous BMT for Medulloblastoma and Wilm’s Tumor reported to the CIBMTR between 1990 and 2012

Medulloblastoma Wilm’s Tumor

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 1755 464 340 63Number of centers 148 62 111 39Disease Medulloblastoma 1755 464 0 0 Wilm’s Tumor 0 0 340 63Year of transplant 1990-1991 7 (<1) 6 ( 1) 10 ( 3) 0 1992-1993 13 (<1) 11 ( 2) 18 ( 5) 3 ( 5) 1994-1995 12 (<1) 8 ( 2) 31 ( 9) 10 (16) 1996-1997 18 ( 1) 9 ( 2) 34 (10) 6 (10) 1998-1999 158 ( 9) 64 (14) 39 (11) 12 (19) 2000-2001 164 ( 9) 60 (13) 36 (11) 8 (13) 2002-2003 161 ( 9) 33 ( 7) 34 (10) 2 ( 3) 2004-2005 185 (11) 39 ( 8) 44 (13) 9 (14) 2006-2007 366 (21) 73 (16) 31 ( 9) 4 ( 6) 2008-2009 330 (19) 160 (34) 33 (10) 9 (14) 2010-2011 279 (16) 1 (<1) 29 ( 9) 0 2012 62 ( 4) 0 1 (<1) 0Age at transplant, median (range), years 7 (1 - 56) 8 (1 - 49) 7 (1 - 49) 6 (1 - 49)Gender Male 1109 (63) 307 (66) 163 (48) 25 (40) Female 645 (37) 157 (34) 174 (51) 38 (60) Missing 1 (<1) 0 3 (<1) 0Graft source Bone marrow 196 (11) 52 (11) 58 (17) 9 (14) PBSC 1505 (86) 397 (86) 262 (77) 50 (79) Bone marrow + PBSC 29 ( 2) 13 ( 3) 15 ( 4) 4 ( 6) Other/missing 25 ( 1) 2 (<1) 5 ( 1) 0Median follow-up time, median (range), months 25 (<1 - 179) 50 (1 - 179) 49 (1 - 239) 51 (1 - 183)

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Characteristic of recipients of autologous BMT for Lung Cancer and CNS Tumor reported to the CIBMTR between 1990 and 2012

Lung Cancer CNS Tumor

Characteristics TED

N (%)Research

N (%)TED

N (%) Research

N (%)Number of patients 260 135 3557 956Number of centers 58 30 189 95Disease Lung, small cell 202 (78) 125 (93) 0 0 Lung, non-small cell 39 (15) 10 ( 7) 0 0 Lung, not specified 19 ( 7) 0 0 0 CNS tumor, including CNS PNET 0 0 3557 956Year of transplant 1990-1991 70 (27) 21 (16) 175 ( 5) 31 ( 3) 1992-1993 40 (15) 30 (22) 124 ( 3) 46 ( 5) 1994-1995 52 (20) 34 (25) 112 ( 3) 49 ( 5) 1996-1997 51 (20) 37 (27) 167 ( 5) 52 ( 5) 1998-1999 28 (11) 11 ( 8) 372 (10) 116 (12) 2000-2001 14 ( 5) 2 ( 1) 322 ( 9) 131 (14) 2002-2003 1 (<1) 0 321 ( 9) 51 ( 5) 2004-2005 2 (<1) 0 326 ( 9) 70 ( 7) 2006-2007 0 0 522 (15) 127 (13) 2008-2009 2 (<1) 0 518 (15) 280 (29) 2010-2011 0 0 469 (13) 3 (<1) 2012 0 0 129 ( 4) 0Age at transplant, median (range), years 49 (1 - 74) 50 (1 - 67) 7 (<1 - 69) 8 (<1 - 62)Gender Male 152 (58) 76 (56) 2135 (60) 565 (59) Female 108 (42) 59 (44) 1416 (40) 391 (41) Missing 0 0 6 (<1) 0Graft source Bone marrow 43 (17) 20 (15) 452 (13) 145 (15) PBSC 137 (53) 69 (51) 2852 (80) 764 (80) Bone marrow + PBSC 53 (20) 46 (34) 131 ( 4) 44 ( 5) Other/missing 27 (10) 0 122 ( 3) 3 (<1)Median follow-up time, median (range), months 37 (<1 - 195) 43 (4 - 138) 25 (<1 - 236) 50 (1 - 218)

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Characteristic of recipients of allogeneic BMT reported to the CIBMTR between 1990 and 2012

Characteristics TED

N (%) Research

N (%)Hepatobiliary 30 16Year of transplant 1990-1991 0 0 1992-1993 0 0 1994-1995 0 0 1996-1997 2 ( 7) 2 (13) 1998-1999 3 (10) 3 (19) 2000-2001 6 (20) 5 (31) 2002-2003 10 (33) 3 (19) 2004-2005 5 (17) 2 (13) 2006-2007 3 (10) 0 2008-2009 1 ( 3) 1 ( 6) 2010-2011 0 0 2012 0 0Renal carcinoma/kidney 522 232Year of transplant 1990-1991 0 0 1992-1993 0 0 1994-1995 0 0 1996-1997 1 (<1) 0 1998-1999 22 ( 4) 3 ( 1) 2000-2001 233 (45) 127 (55) 2002-2003 192 (37) 66 (28) 2004-2005 48 ( 9) 22 ( 9) 2006-2007 8 ( 2) 6 ( 3) 2008-2009 12 ( 2) 8 ( 3) 2010-2011 6 ( 1) 0 2012 0 0Ovarian cancer 41 17Year of transplant 1990-1991 1 ( 2) 0 1992-1993 1 ( 2) 1 ( 6) 1994-1995 1 ( 2) 0 1996-1997 0 0 1998-1999 4 (10) 2 (12) 2000-2001 4 (10) 1 ( 6) 2002-2003 8 (20) 2 (12) 2004-2005 20 (49) 11 (65) 2006-2007 0 0

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Characteristics TED

N (%) Research

N (%)Year of transplant (continued) 2008-2009 1 ( 3) 0 2010-2011 0 0 2012 0 0Breast Cancer 273 134Year of transplant 1990-1991 6 ( 2) 3 ( 2) 1992-1993 7 ( 3) 5 ( 4) 1994-1995 18 ( 7) 15 (11) 1996-1997 42 (15) 32 (24) 1998-1999 54 (20) 32 (24) 2000-2001 56 (21) 23 (17) 2002-2003 44 (16) 10 ( 7) 2004-2005 28 (10) 11 ( 8) 2006-2007 14 ( 5) 3 ( 2) 2008-2009 3 ( 1) 0 2010-2011 1 (<1) 0 2012 0 0Other disease 421 152 Other malignant, unknown 144 (34) 56 (37) Head and neck 2 (<1) 1 (<1) Lung cancer, small cell 4 (<1) 2 ( 1) Lung cancer, non-small cell 6 ( 1) 0 Pancreas 13 ( 3) 6 ( 4) Prostate 7 ( 2) 1 (<1) Testis 15 ( 4) 5 ( 3) Cervical 1 (<1) 1 (<1) Sarcoma unspecified 19 ( 5) 7 ( 5) Bone sarcoma (exc. Ewing) 29 ( 7) 10 ( 7) CNS tumors 8 ( 2) 5 ( 3) Wilm’s tumor 8 ( 2) 2 ( 1) Retinoblastoma 3 (<1) 1 (<1)

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Characteristics TED

N (%) Research

N (%)Other disease (continued) Ewing sarcoma 92 (22) 40 (26) Germ cell tumor 19 ( 5) 4 ( 3) Medulloblastoma 10 ( 2) 4 ( 3) PNET 3 (<1) 1 (<1) Gastric malig 1 (<1) 0 Thymoma 2 (<1) 1 (<1) Rhabdomyasarcoma 27 ( 6) 4 ( 3) Leiomyosarcoma 1 (<1) 0 Fibrosarcoma 3 (<1) 0 Synovial sarcoma 1 (<1) 0

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TO: Solid Tumors Working Committee Members FROM: Mukta Arora, MD, MS Scientific Director Solid Tumors Committee RE: Studies in Progress Summery Studies in progress ST10-01: The value of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with high risk or metastatic inflammatory breast cancer (YC Cheng/NT Ueno) The objectives of this study are to determine the overall outcomes (overall survival, treatment-related mortality, disease-free survival, relapse and progression of disease) of patients with IBC who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with high risk or metastatic disease and to determine the prognostic factors in patients who benefit from such a treatment. A final objective is to compare outcomes of patients who underwent high-dose chemotherapy and autologous transplantation in a high-risk or metastatic setting with IBC to those with non-IBC. The revised protocol is available for review. Studies previously proposed, but not initiated ST00-02: Allogeneic stem cell transplants for renal cell cancer (J Barrett): The objectives of this study are to describe the worldwide experience of patients undergoing allogeneic peripheral blood stem cell transplants for renal cell cancer, to evaluate the results of these transplants and to identify patient-, disease- and transplant-related prognostic factors for the transplant’s outcome. An updated protocol is available for review. ST09-01: Transplant trends for metastatic solid tumors in North America (R Childs): The main objective of this study is to evaluate trends in autologous and allogeneic hematopoietic stem cell transplantation in North America over the past 20 years. After initially limiting the scope of the study to North America transplants only, the Solid Tumor WC chairs decided it would be best to open the study to European transplants as well. An updated protocol is available for review.

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CIBMTR ST00-02

ALLOGENEIC STEM CELL TRANSPLANTS FOR RENAL CELL CANCER

Study Chair: A. John Barrett, MD Hematology Branch National Heart, Lung and Blood Institute National Institutes of Health,

Bldg. 10, Room 7C103 9000 Rockville Pike Bethesda, MD 20892 USA Telephone: 301-496-5093 Fax: 301-496-8396 E-mail: [email protected] Study Co-Chair: Olle Ringdén, MD, PhD Professor of Transplantation Immunology Director, Bone Marrow Transplantation Huddinge University Hospital S-141 86 Huddinge, Sweden Telephone: 46-8-585-826-72 Fax: 46-8-746-68-69 E-mail: [email protected] Study Statistician: Kwang Woo Ahn, PhD, CIBMTR Statistical Center 8701 Watertown Plank Rd Milwaukee WI 53226 USA Phone: 414-456-7387 Fax: 414-456-6530 E-mail: [email protected]

Michael Hemmer, MS CIBMTR Milwaukee

9200 W Wisconsin Ave. Milwaukee, WI 53226 USA Telephone: 414-805-4638 Fax: 414-805-0714 E-mail: [email protected]

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Scientific Director: Mukta Aurora, MD University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street Minneapolis, MN 55455 Telephone: 612-626-4105 Fax: 612-625-6919 Email: [email protected] Working Committee Chairs: Michael R. Bishop, MD University of Chicago Section of Hematology/Oncology 5841 S Maryland Ave. MC2115 Chicago, IL 60637 USA Phone: 773-702-4400 Fax: 773-702-3163 E-mail: [email protected] Edward A. Stadtmauer, MD Abramson Cancer Center University of Pennsylvania 3400 Spruce St. 16 Penn Tower Philadelphia, PA 19104 USA Telephone: 215-662-7910 Fax: 215-662-4064 E-mail: [email protected]

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1.0 HYPOTHESIS:

Allogeneic stem cell transplantation (SCT) has a therapeutic role in the treatment of metastatic renal cell cancer (RCC).

2.0 OBJECTIVES:

2.1 To describe the worldwide experience of patients undergoing allogeneic peripheral blood stem cell transplants for renal cell cancer.

2.2 To evaluate the results of allogeneic peripheral blood stem cell transplantation in renal

cell cancer patients. Outcomes to be assessed from the date of transplant include the following:

2.2.1 Response rates; 2.2.2 Acute and chronic GVHD; 2.2.3 Treatment-related mortality; 2.2.4 Progression/ Relapse; 2.2.5 Renal cell cancer-free survival; 2.2.6 Overall survival; 2.2.7 Causes of death.

2.3 To identify patient-, disease-, and transplant-related prognostic factors for outcome after

transplantation for renal cell cancer.

3.0 BACKGROUND:

Allogeneic SCT can cure hematological malignancies by two mechanisms - (i) cytoreduction from dose-intensive chemoradiotherapy, (ii) a lymphocyte-mediated “graft-versus-malignancy” effect. It is possible that either or both these mechanisms may be effective in the treatment of RCC and other non-hematological malignancies. Recently there have been reports of tumor response in breast cancer, ovarian cancer and RCC recipients of allogeneic -SCT (1-4). In particular, the promising tumor responses and complete remissions seen in metastatic RCC following non-myeloablative stem cell transplants (NST) have created wide interest in further exploring allogeneic SCT in this condition. Renal cell carcinoma is considered relatively insensitive to chemotherapy. Current conventional treatment focuses on enhancement of immunologic control using IFN and/or IL-2. The use of low intensity conditioning regimens to treat metastatic RCC is logical because dose intensification of chemotherapy does not have any advantage in the treatment of this malignancy. NST spares unnecessary toxicity while permitting the establishment of a donor hematopoietic and immune system to exert a graft-versus-tumor (GVT) effect (5). Currently the only published reports of NST in RCC are limited to a single series and several case reports (6-10). Many questions are posed by these initial findings concerning the reproducibility and characteristics of the GVT effect, the impact of different transplant techniques on the GVT effect and the overall probability of success in treating RCC by this technique. With its worldwide access to stem cell transplantation data IBMTR provides a unique opportunity to answer these questions.

It is therefore proposed to use the CIBMTR reporting system to collect data on allogeneic SCT for RCC. We will attempt to identify response rates in RCC, and determine the role of specific transplant approaches and the impact of GVHD on disease response and survival.

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4.0 STUDY POPULATION:

Patient eligibility/selection criteria include: 4.1 Patients undergoing allogeneic peripheral blood stem cell transplants for renal cell cancer

between 1998 and 2002, reported to the CIBMTR.

Potential numbers of subjects are given in Tables 1 and 2. 5.0 OUTCOMES:

4.1 Acute graft-versus-host disease: maximum overall grade, and occurrence of grade II, III and/or IV skin, gastrointestinal or liver abnormalities fulfilling the Glucksberg criteria of acute GVHD.

4.2 Chronic graft-versus-host disease: occurrence of symptoms in any organ system fulfilling

the criteria of chronic GVHD.

4.3 Response rate: complete or partial response measured at 100 days and 1 year as described in Table 3.

4.4 Transplant-related mortality: patients who die in the first 28 days after transplant or deaths in

continuous remission are considered events. Those who survive without relapse or progressive disease are censored at the date of last contact. This event is summarized by the cumulative incidence estimate with progression as the competing risk.

4.5 Progression/ Relapse: progressive disease as described in Table 3 or recurrence of disease

for those in complete remission are events. 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 death without progression as the competing risk.

4.6 Progression-free survival: survival without recurrence or tumor progression. Recurrence or

progression of disease, as described in Table 3, and death from any cause are considered events. Those who survive without recurrence or progression are censored at the date of last contact.

4.7 Overall survival: time to death. Patients are censored at time of last contact.

6.0 VARIABLES TO BE ANALYZED: Patient-related:

- Age: continuous - Gender: male vs female - Karnofsky performance status: 80 vs >80

Disease-related:

- Histology: clear cell vs others - Sites of metastasis: bone vs CNS vs others

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- Extent of disease: residual vs bulky - Surgery: yes/no - Interferon: yes/no - Chemotherapy: yes/no - Radiation: yes/no - Disease status at transplant: to be determined

Transplant-related:

- Time from diagnosis to transplant: continuous - Gender match: to be determined (based on feasibility) - Conditioning regimen: to be determined based on protocol regimens - Donor: HLA-identical sibling vs others - GVHD prophylaxis: to be determined

Post-transplant immune therapy

- Planned DLI (intention to treat): yes/no - DLI for progression: yes/no - Cytokines: yes/no - IL-2 Interferon: yes/no - GM-CSF: yes/no

7.0 DATA COLLECTION:

The first step in this study is to prepare a data collection form capturing the disease-specific variables noted in section 6.0. Patient- and transplant-related variables will be captured using the standard CIBMTR Core Report Form and Graft Inserts. Centers registering eligible patients will be contacted requesting that the comprehensive Report Forms be completed (see Table 1). Centers wishing to participate in this study must report all consecutive transplants for renal cell cancer fulfilling the eligibility criteria noted in section 4.0.

8.0 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. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Probability of progression-free survival and overall survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Values for other endpoints will be generated using cumulative incidence estimates (11). 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 6.0) 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, progression-free survival and overall survival.

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Multivariate analyses for response rate will be performed using binary logistic regression model. The response is partial or complete response. A forward stepwise model building approach will be used to model response.

9.0 REFERENCES:

1. Ueno NT, Rondon G, Mirza NQ, et al. Allogeneic peripheral-blood progenitor-cell transplantation for poor-risk patients with metastatic breast cancer. J Clin Oncol 16:986, 1998.

2. Eibl B, Schwaighofer H, Nachbaur D, et al. Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood 88:1501, 1996.

3. Childs R, Clave E, Plante M, et al. Successful treatment of metastatic renal-cell carcinoma with a non-myeloablative allogeneic peripheral blood progenitor cell transplant: evidence for a graft-versus-tumor effect. J Clin Oncol 1999.

4. Bay JO, Choufi B, Pomel C, et al. Potential allogeneic graft-versus-tumor effect in a patient with ovarian cancer. Bone Marrow Transplant. 2000 Mar;25(6):681-2.

5. Barrett AJ, Childs RC. The benefits of an alloresponse - graft-versus-tumor. J Hematotherapy & Stem Cell Res., 2000, 9:347-54.

6. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal- cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem- cell transplantation. N Engl J Med. 2000 Sep 14; 343(11): 750-8.

7. Rini B, Zimmerman TM, Gajewski TF, et al. Allogeneic peripheral blood stem cell transplantation for metastatic renal cell carcinoma. J Urol 2001 Apr; 165(3):1208-9.

8. Bregni M., Dodero A., Peccatori J. et al. Graft-vs-tumor effect in advanced solid tumors following reduced intensity stem cell allografting. Proceedings of The American Society of Clinical Oncology 2001:20; 45.

9. Makimoto A., Mineishi S., Tanosaki R. et al. Nonmyeloablative stem cell transplantation (NST) for refractory solid tumors. Proceedings of The American Society of Clinical Oncology 2001:20; 44.

10. Rini B., Zimmerman T.M., Gajewski T.F., et al. Allogeneic stem cell transplantation for metastatic renal cell cancer after nonmyeloablative chemotherapy: Engraftment rates, toxicity and initial clinical results. Proceedings of The American Society of Clinical Oncology 2001:20; 719.

11. Cox RD. Regression analysis and life tables. J of Royal Statist Soc 1972; B 34:187-220.

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Table 2. Characteristics of patients who underwent allogeneic bone marrow or peripheral blood stem cell transplants for Renal Cell Cancer registered to the CIBMTR between 1998-2012.

Characteristics of patients: N (%)Number of patients 466Number of centers 117Age at transplant, median (range), years 52 (7 - 75)Age at transplant, years ≤ 29 16 ( 3) 30-39 42 ( 9) 40-49 130 (28) 50-59 200 (43) 60+ 78 (17)Gender Male 356 (76) Female 110 (24)Graft type BM 21 ( 5) PBSC 444 (95) BM + PBSC 1 (<1)Donor HLA-identical sibling 382 (82) Other relative 25 ( 5) Unrelated 57 (12) TBD 2 (<1)Year of transplant 1998 3 (<1) 1999 17 ( 4) 2000 70 (15) 2001 152 (33) 2002 92 (20) 2003 68 (15) 2004 28 ( 6) 2005 12 ( 3) 2006 3 (<1) 2007 5 ( 1) 2008 5 ( 1) 2009 5 ( 1) 2010 5 ( 1) 2011 1 (<1)

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Table 2. Continued. Characteristics of patients: N (%)GVHD Prophylaxis None 14 ( 3) T-Cell depletion 18 ( 4) CsA + MTX ± others 37 ( 8) CsA + MMF ± others 89 (19) CsA ± others 75 (16) FK506 + MTX ± others 41 ( 9) FK506 + MMF ± others 28 ( 6) FK506 ± others 13 ( 3) Other 17 ( 4) Missing 134 (29)a The CIBMTR collects data on two levels. All centers provide Registration data (age, sex, disease, disease stage and duration, graft type, donor type, conditioning regimen, graft treatment, GVHD prophylaxis and posttransplant disease status, survival, second cancers and primary cause of death) for all consecutive transplants. Registration data allow analysis of trends in transplant use and outcome and identification of patients for specific studies. Research data are collected on a subset of registered patients. Research data are collected on Report Forms which capture comprehensive clinical and demographic information. *Supplemental forms were sent out on 3-22-2011 to transplant centers to gather sufficient data on 84 Research patients to proceed with the study. As of 1-11-2013, transplant centers for 72 patients have responded. Of the 12 remaining, it seems realistically impossible to retrieve data for 9 of them.

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Table 3.CIBMTR criteria for definition of complete remission, partial response, stable

disease, mixed response and progressive disease in patients with renal carcinoma. CR = Complete Remission Response

- Disappearance of all target lesions for a period of at least one month CRU = Complete Response with persistent bone scan/X-ray abnormalities of unknown significance PR = Partial Response

- At least 30% decrease in the sum of the longest diameter of measured lesions (target lesions) taking as reference the baseline sum of longest diameters

SD = Stable Disease

- Neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameters since the treatment started

PD = Progressive Disease

- At least a 20% increase in the sum of the longest diameter of measured lesions (target lesions), taking as reference the smallest sum of the longest diameters recorded since the treatment started or the appearance on one or more new lesions

NETD = Not Evaluable, Toxic Death NE = Not Evaluable, specify reason

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CIBMTR ST09-01

TRANSPLANT TRENDS FOR METASTATIC SOLID TUMORS IN NORTH AMERICA AND EUROPE

DRAFT PROTOCOL

Study Chair: Richard Childs, MD National Heart, Lung and Blood Institute 10 Center Drive, Building 10, CRC Rm. 3-5322 Bethesda, MD 20892 Telephone: 301-594-8008 Fax: 301-480-2664 E-mail: [email protected]

Study Co-chair: Didier Blaise, MD Institut Paoli Calmettes Marseille, France Telephone: 33-4-91-223-754 Fax: 33-4-91-223-579 E-mail: [email protected] Statistician: Michael Hemmer, MS CIBMTR Milwaukee 9200 W Wisconsin Ave. Milwaukee, WI 53226 USA Telephone: 414-805-4638 Fax: 414-805-0714 E-mail: [email protected] Kwang Woo Ahn, PhD, CIBMTR Statistical Center 8701 Watertown Plank Rd Milwaukee WI 53226 USA Phone: 414-456-7387 Fax: 414-456-6530 E-mail: [email protected]

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Scientific Director: Mukta Arora, MD Assistant Professor University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 USA Office: 612-626-4105 Fax: 612-625-6919

E-mail: [email protected]

Working Committee Chairs: Michael R. Bishop, MD University of Chicago Section of Hematology/Oncology 5841 S Maryland Ave. MC2115 Chicago, IL 60637 USA Phone: 773-702-4400 Fax: 773-702-3163 E-mail: [email protected] Edward A. Stadtmauer, MD Abramson Cancer Center University of Pennsylvania 3400 Spruce St. 16 Penn Tower Philadelphia, PA 19104 USA Telephone: 215-662-7910 Fax: 215-662-4064 E-mail: [email protected]

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1.0 SPECIFIC AIMS:

The main objective is to study trends in both auto and allo HCT for solid tumors in North America and Europe reported through the CIBMTR transplant registries over the past 20 years. Specific aims of the study are listed below: 1.1 To correlate the impact of published clinical trials on transplant trends and annual

transplant numbers 1.2 To evaluate the impact of negative data on autoHCT for breast cancer on autoHCT

numbers for other types of solid tumors 1.3 To evaluate the impact of recent advances in the treatment of metastaic RCC with agents

such as sorafenib, sunitinib, and temsirolimus, on the number of transplants being performed for RCC over the past 3 years

1.4 Annual numbers of alloHCT performed for all solid tumors as well as tumor-specific transplant numbers

1.5 Annual numbers of autoHCT performed for all solid tumors as well as tumor-specific transplant numbers

1.6 The types of alloHCT being performed for solid tumors in terms of conditioning regimens (reduced intensity vs myeloablative, auto followed by reduced intensity allo, etc), and types of GVHD prophylaxis

1.7 To evaluate the trends comparatively in the US 1.8 Transplant related outcomes including

1.8.1 Overall survival of autologous and allogeneic transplant for solid tumors 1.8.2 Trends over time

2.0 SCIENTIFIC JUSTIFICATION:

The number of autologous hematopoietic stem cell transplants (HCT) for metastatic breast cancer declined dramatically in the late 1990s following reports of randomized trials showing no benefit over conventional chemotherapy. European Bone Marrow Transplant (EBMT) data have shown that these negative trials have led to a reduction in autologous HCT being investigated for other solid tumors. Around this time, case reports of metastatic solid tumors regressing following reduced intensity allogeneic HCT as a consequence of a graft vs tumor (GVT) effect sparked global interest in the initiation of clinical trials exploring the potential of allogeneic immunotherapy to treat tumors of epithelial origin. Several small case series published in the early 2000s provided strong evidence for the existence of a GVT effect against metastatic renal cell carcinoma (RCC), ovarian cancer, breast cancer, and colon cancer. Importantly, some patients achieved durable complete responses raising the possibility that the GVT could in some cases be curative for treatment refractory solid tumors. It is unclear how many transplants for metastatic solid tumors and the type of metastatic solid tumors that allogeneic HCT has been explored. Hundreds of patients with metastatic solid tumors undergoing allogeneic HCT have been reported to both the CIBMTR through registration forms. It appears that allogeneic HCT for solid tumors has been pursued most commonly in patients with metastatic RCC, breast cancer, colon cancer, ovarian cancer, neuroblastoma, and sarcomas. However, data regarding transplant trends specific for different solid tumors over time has not been reported. Furthermore, considerable recent advances in the treatment of metastatic RCC with agents such as sorafenib, sunitinib, and temsirolimus have reduced the number of transplants being performed for RCC over the past 3 years.

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3.0 PATIENT ELIGIBILITY CRITERIA:

All patients transplanted for solid tumors between 1985 and 2012 in North America and Europe and reported to the CIBMTR.

4.0 OUTCOMES:

4.1 Treatment-related mortality: Any death within the first 28 days of transplant or any death occurring after day 28 in the absence of overt disease progression.

4.2 Relapse/Progression: Progressive disease or recurrence of disease is considered an event. Those who survive without recurrence or progressive disease are censored at the date of last contact.

4.3 Progression-free survival (PFS): 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 survival without recurrence or tumor.

4.4 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. Overall survival will be described as a time trend separately for auto or allo HCT for solid tumors.

5.0 VARIABLES TO BE ANALYZED:

Patient-related variables: - Age: continuous - Gender: male vs. female - Karnofsky performance status: < 90% vs. > 90%

Disease-related variables:

- Disease type

Transplant-related variables: - Time from diagnosis to transplant - Year of transplant - Conditioning regimen - Myeloablative regimen and reduced intensity regimen for allogeneic transplants - Allograft source (PBSC vs. BM vs. Cord Blood) - HLA match (matched vs. mismatched) and related vs. unrelated transplant

6.0 STUDY DESIGN:

This will be a descriptive study of patients with auto or allo HCT for solid tumors. Descriptive tables of patients-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Probabilities of overall survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula.

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Table 1. Characteristics of patients who underwent first transplant for solid tumor in North America or Europe between 1985 and 2012, as reported to the CIBMTR.

Characteristics of patients: NA – Allo

N (%)NA – Auto

N (%)Europe – Allo

N (%) Europe – Auto

N (%)Number of patients 789 34577 331 2021Number of centers 140 298 71 70Age at transplant, median (range), years 43 (1 - 82) 42 (<1 - 76) 44 (1 - 77) 36 (1 - 73)Age at transplant, years 0-9 130 (16) 5470 (16) 35 (11) 302 (15) 10-19 70 ( 9) 1803 ( 5) 34 (10) 235 (12) 20-29 50 ( 6) 1903 ( 6) 21 ( 6) 254 (13) 30-39 85 (11) 6236 (18) 52 (16) 401 (20) 40-49 201 (25) 10920 (32) 64 (19) 441 (22) 50-59 191 (24) 6826 (20) 79 (24) 320 (16) 60-69 59 ( 7) 1148 ( 3) 44 (13) 65 ( 3) 70+ 3 (<1) 19 (<1) 2 (<1) 1 (<1) Missing 0 252 (<1) 0 2 (<1)Gender Male 436 (55) 7275 (21) 193 (58) 777 (38) Female 351 (44) 27095 (78) 137 (41) 1239 (61) Missing 2 (<1) 207 (<1) 1 (<1) 5 (<1)Donor Type Autologous 0 34577 0 2021 HLA-identical sibling 508 (64) 0 228 (69) 0 Identical twin 55 ( 7) 0 9 ( 3) 0 Other related 55 ( 7) 0 17 ( 5) 0 Unrelated 98 (12) 0 44 (13) 0 Other 3 (<1) 0 0 0 Missing 70 ( 9) 0 33 (10) 0Time from diagnosis to transplant, months < 6 105 (13) 7382 (21) 39 (12) 749 (37) 6-12 174 (22) 10989 (32) 73 (22) 516 (26) > 12 453 (57) 13766 (40) 214 (65) 731 (36) Missing 57 (7 ) 2440 (7 ) 5 (2 ) 25 (1 )Conditioning regimen TBI ± other 169 (21) 533 ( 2) 88 (27) 57 ( 3) Cy +- BU ± other 26 ( 3) 220 (<1) 3 (<1) 4 (<1) BU ± other 39 ( 5) 856 ( 2) 21 ( 6) 24 ( 1) LPAM ± other 105 (13) 3556 (10) 14 ( 4) 105 ( 5) Other 264 (33) 25736 (74) 75 (23) 900 (45) Missing 186 (24) 3676 (11) 130 (39) 931 (46)

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Table 1. Continued.

Characteristics of patients: NA – Allo

N (%)NA – Auto

N (%)Europe – Allo

N (%) Europe – Auto

N (%)Graft type BM 210 (27) 4828 (14) 76 (23) 119 ( 6) PBSC 536 (68) 27467 (79) 241 (73) 1774 (88) UCB 30 ( 4) 4 (<1) 3 (<1) 0 Other 1 (<1) 7 (<1) 0 5 (<1) Missing 12 ( 2) 2271 ( 7) 11 ( 3) 123 ( 6)Disease Renal carcinoma/kidney 298 (38) 19 (<1) 118 (36) 8 (<1) Neuroblastoma 114 (14) 3617 (10) 30 ( 9) 189 ( 9) Breast cancer 131 (17) 22090 (64) 31 ( 9) 726 (36) Ovarian cancer 15 ( 2) 1624 ( 5) 4 ( 1) 82 ( 4) Testis 3 (<1) 1529 ( 4) 0 87 ( 4) Soft tissue sarcoma 17 ( 2) 377 ( 1) 18 (5 ) 69 ( 3) Bone sarcoma (exc Ewing) 1 (<1) 181 (<1) 3 (<1) 102 ( 5) Central Nervous System tumors 2 (<1) 1173 ( 3) 0 138 ( 7) Wilm's tumor 7 (<1) 303 (<1) 0 20 (<1) Ewing sarcoma 40 ( 5) 586 ( 2) 21 ( 6) 114 ( 6) Germ cell tumor 4 (<1) 619 ( 2) 3 (<1) 154 ( 8) Medulloblastoma 5 (<1) 944 ( 3) 1 (<1) 55 ( 3) Other 152 (19) 1515 ( 4) 102 (31) 277 (14)Year of transplant 1985-89 54 ( 7) 614 ( 2) 30 ( 9) 7 (<1) 1990-94 52 ( 7) 7791 (23) 28 ( 8) 262 (13) 1995-99 162 (21) 18195 (53) 34 (10) 1086 (54) 2000-04 407 (52) 3634 (11) 213 (64) 526 (26) 2005-09 93 (12) 2772 ( 8) 23 ( 7) 98 ( 5) 2010-12 21 ( 3) 1571 ( 5) 3 (<1) 42 ( 2)Abbreviations: NA=North America, BM=Bone Marrow, PB=Peripheral Blood Stem Cell, UCB=Umbilical Cord Blood.

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CIBMTR ST10-01

THE VALUE OF HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH HIGH RISK OR METASTATIC

INFLAMMATORY BREAST CANCER

DRAFT PROTOCOL

Study Chair: Yee Chung Cheng, MD Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 USA Telephone: 414-805-8924

Fax: 414-805-4606 E-mail: [email protected]

Study Co-chair: Naoto T. Ueno, MD, PhD The University of Texas MD Anderson Cancer Center

Telephone: 713-792-8754 Fax: 713-794-4385 E-mail: [email protected]

Statistician: Kwang Woo Ahn, PhD, CIBMTR Statistical Center 8701 Watertown Plank Rd Milwaukee WI 53226 USA Phone: 414-456-7387 Fax: 414-456-6530 E-mail: [email protected] Michael Hemmer, MS CIBMTR Milwaukee 9200 W Wisconsin Ave. Milwaukee, WI 53226 USA Telephone: 414-805-4638 Fax: 414-805-0714 E-mail: [email protected]

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Scientific Director: Mukta Arora, MD Assistant Professor University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 USA Office: 612-626-4105 Fax: 612-625-6919 E-mail: [email protected]

Working Committee Chairs: Michael R. Bishop, MD University of Chicago Section of Hematology/Oncology 5841 S Maryland Ave. MC211 Chicago, IL 60637 USA Phone: 773-702-4400 Fax: 773-702-3163 E-mail: [email protected] Edward A. Stadtmauer, MD Abramson Cancer Center University of Pennsylvania 3400 Spruce St. 16 Penn Tower Philadelphia, PA 19104 USA Telephone: 215-662-7910 Fax: 215-662-4064 E-mail: [email protected]

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1.0 SPECIFIC AIMS: 1.1 To determine the overall outcomes of patients with IBC who underwent high-dose

chemotherapy and autologous hematopoietic stem cell transplantation in non metastatic setting or metastatic setting (stage III or IV disease).

1.2 To determine the prognostic factors that select patients with IBC who benefit from high-dose chemotherapy and autologous hematopoietic stem cell transplantation in non-metastatic setting or metastatic setting.

1.3 To compare the overall outcomes of patients with IBC who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation in non-metastatic setting or metastatic setting and that of patients with non-IBC who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation for stage III or IV disease.

2.0 SCIENTIFIC JUSTIFICATION:

Inflammatory breast cancer (IBC) is a distinct form of locally advanced breast cancer that progresses rapidly with a high propensity for early metastasis. It only accounts for 1-5% of all breast cancer cases. The median survival of IBS was much lower than the median survival of non inflammatory locally advanced breast cancer (2.9 years versus 6.4 years) 1. The standard of care for newly diagnosed IBC is a combined modality approach which includes systemic chemotherapy, surgery and radiation therapy. Long term disease-free survival with combined modality approach is about 30%. For patient with high risk of recurrence after standard of care or patient with metastatic IBC, systemic chemotherapy remains the major treatment modality. Multiple phase III randomized trials of high-dose chemotherapy and autologous hematopoietic stem cell transplantation have been conducted in the setting of high risk primary breast cancer and metastatic breast cancer. The exact role is still under investigation at this moment. Currently there is no phase III randomized trial of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in IBC conducted. However, multiple phase II studies (Table 1) suggested a survival benefit of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in this aggressive locally advanced breast cancer compared to historical data of non-transplant approach. In 2003, Pedrazzoli et al reported the data of European Group for Blood and Marrow Transplantation (EBMT) registry 1990-1999 2. With a total of 921 patients with IBC who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation, 5 years PFS was reported as 42%.

3.0 PATIENT ELIGIBILITY CRITERIA:

3.1 Patients with the diagnosis of IBC (III or IV) or non-IBC (III or IV) disease at the time of original diagnosis.

3.2 Patient underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation 1990-2003 (no cases beyond 2003).

4.0 OUTCOMES:

Primary outcomes: Overall survival: This event is defined as death from any cause. The event will be summarized by a survival curve. Patients will be analyzed at time of last follow-up or date last form was due to the CIBMTR. There are no competing risks.

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Treatment-related mortality (TRM): this event is defined as death in continuous remission. The event is summarized by the cumulative incidence estimate with relapse as a competing risk. Progression-free survival: This event is defined as death or relapse. This event is summarized by a survival curve or the sum of the cumulative incidence estimates. Relapse / Disease Progression: This event is defined as the recurrence (of patients in CR) or progression of disease (of patients not in CR). This event is summarized by the cumulative incidence estimate with TRM as a competing risk.

5.0 VARIABLES TO BE DESCRIBED:

Patient-related variables: - Age - Gender - Karnofsky performance status - Menopausal status Disease-related variables: - Tumor histology - Stage of Breast cancer - Location at diagnosis - Disease status pre conditioning - Estrogen receptor status - Progesterone receptor status - Neoadjuvant treatment given - Neoadjuvant treatment - Type of chemotherapy - Response to neoadjuvant therapy - Surgery as initial management - Treatment post-surgery - Type of treatment post-surgery Transplant-related variables: - Time from diagnosis to transplant in months - Graft source: Bone marrow vs. PBSC - Conditioning regimen at transplant - Planned post-transplant therapy - Year of transplant

6.0 VARIABLES TO BE ANALYZED: Patient-related variables: - Age: continuous - Karnofsky performance status: < 90% vs. ≥ 90% - Menopausal status: Menopausal vs. Non-menopausal vs. Male

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Disease-related variables: - Tumor histology: inflammatory versus non-inflammatory. - Stage: III vs. IV - Disease status pre conditioning: Complete + complete response with exception of bone scan

abnormalities of unknown significance vs. partial response vs. stable vs. progressive disease vs. missing

- Estrogen receptor status: positive vs. negative vs. borderline vs. missing - Progesterone receptor status: positive vs. negative vs. borderline vs. missing - Neoadjuvant treatment: chemotherapy only vs. all others vs. none - Response to neoadjuvant therapy: Complete response vs. Partial response vs. Stable ±

Progressive - Surgery as initial management: Yes vs. No - Treatment post-surgery: Yes vs. No Transplant-related variables: - Time from diagnosis to transplant - Graft source: Bone marrow vs. Peripheral blood stem cells - Conditioning regimen before transplant - Planned post-transplant therapy: Yes vs. No - Planned post transplant therapy: Hormone therapy alone vs. Radiation therapy alone vs. vs.

radiation ± hormonal ± immuno vs. all others vs. missing - Year of transplant: 1990-2003

7.0 STUDY DESIGN:

7.1 Review of initial diagnostic criteria of IBC and stage.

According to AJCC Cancer Staging Manual 7th edition, 2010 by American Joint Committee on Cancer, the diagnosis of IBC is primarily a clinical diagnosis. Therefore we will review the initial histology together with the information available of each patient to confirm the diagnosis of IBC.

The initial clinical stage of each patient is also reviewed according to the AJCC Cancer Staging Manual 7th edition, 2010 by American Joint Committee on Cancer.

7.2 Statistical Design

Descriptive tables of patient, disease and transplant characteristics will be created. Continuous variables will be reported as medians with ranges, while categorical variables will be reported as absolute numbers and percent of total patients. Standard descriptive statistics is used in treatment-related toxicity and treatment-related mortality. Survival curves for overall survival, relapse-free survival and progression-free survival will be calculated for all patients using the Kaplan-Meier estimator. To determine different prognostic factors which may be related to the outcome in those patients transplanted for IBC, stepwise multivariate analysis using proportional hazards modeling will be performed. The proportional hazard assumption will be checked. If violated, time dependent covariates will be used in the Cox model. The interaction between the main effect of IBC/non-IBC and significant covariates will be examined, especially the interaction between the main effect and stage of breast cancer will be checked as to whether stage of breast cancer is significant or not.

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Table 1. Phase II studies that have demonstrated a survival benefit of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in advanced breast cancer: Study # patients Outcome Somlo et al. 1997 3 22 Median follow up 46 months and 45% DFS Ayash et al. 1998 4 46 Median follow up 30 months and 64% DFS Cagnoni et al. 1998 5 30 Median follow up 19 months and 73% DFS Viens et al. 1998 6 17 Median follow up 36 months and 59% DFS Adkin et al. 1999 7 47 Median follow up 30 months and 58% DFS Arun et al. 1999 8 24 Median follow up 19 months and 71% DFS Viens et al. 1999 9 95 Pathologic complete response of 32% Schwartzberg et al. 1999 10 56 Median follow up 44 months and 53% EFS Dazzi et al. 2001 11 21 Pathologic complete response of 21% Yalamendhili et al. 2008 12 28 Median PFS of 40 months Sportes et al. 2009 13 21 Median follow up 8 years and 67% PFS

REFERENCES: 1. Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and

end results program at the National Cancer Institute. Hance KW; Anderson WF; Devesa SS; Young HA; Levine PH. J Natl Cancer Inst 2005 Jul 6; 97(13):966-75

2. Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990-1999. Pedrazzoli P, Ferrante P, Kulekci A, Schiavo R, De Giorgi U, Carminati O, Marangolo M, Demirer T, Siena S, Rosti G; European Group for Blood and Marrow Transplantation (EBMT), Solid Tumors Working Party. Bone Marrow Transplant. 2003 Sep; 32(5):489-94

3. High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival. Somlo G, Doroshow JH, Forman SJ, Odom-Maryon T, Lee J, Chow W, Hamasaki V, Leong L, Morgan R Jr, Margolin K, Raschko J, Shibata S, Tetef M, Yen Y, Simpson J, Molina A. J Clin Oncol. 1997 Aug; 15(8):2882-93

4. High-dose multimodality therapy with autologous stem-cell support for stage IIIB breast carcinoma. Ayash LJ, Elias A, Ibrahim J, Schwartz G, Wheeler C, Reich E, Lynch C, Warren D, Shapiro C, Richardson P, Hurd D, Schnipper L, Frei E 3rd, Antman K. J Clin Oncol. 1998 Mar; 16(3):1000-7

5. High-dose chemotherapy with autologous hematopoietic progenitor-cell support as part of combined modality therapy in patients with inflammatory breast cancer. Cagnoni PJ, Nieto Y, Shpall EJ, Bearman SI, Barón AE, Ross M, Matthes S, Dunbar SE, Jones RB. J Clin Oncol. 1998 May; 16(5):1661-8

6. High-dose chemotherapy and haematopoietic stem cell transplantation for inflammatory breast cancer: pathologic response and outcome. Viens P, Penault-Llorca F, Jacquemier J, Gravis G, Cowen D, Bertucci F, Houvenaeghel G, Blaise D, Maraninchi D. Bone Marrow Transplant. 1998 Feb; 21(3):249-54

7. Outcomes of high-dose chemotherapy and autologous stem-cell transplantation in stage IIIB inflammatory breast cancer. Adkins D, Brown R, Trinkaus K, Maziarz R, Luedke S, Freytes C, Needles B, Wienski D, Fracasso P, Pluard T, Moriconi W, Ryan T, Hoelzer K, Safdar S, Rearden T, Rodriguez G, Khoury H, Vij R, DiPersio J. J Clin Oncol. 1999 Jul; 17(7):2006-14

8. Survival after autologous hematopoietic stem cell transplantation for patients with inflammatory breast carcinoma. Arun B, Slack R, Gehan E, Spitzer T, Meehan KR. Cancer. 1999 Jan 1; 85(1):93-9

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9. First-line high-dose sequential chemotherapy with rG-CSF and repeated blood stem cell transplantation in untreated inflammatory breast cancer: toxicity and response (PEGASE 02 trial). Viens P, Palangié T, Janvier M, Fabbro M, Roché H, Delozier T, Labat JP, Linassier C, Audhuy B, Feuilhade F, Costa B, Delva R, Cure H, Rousseau F, Guillot A, Mousseau M, Ferrero JM, Bardou VJ, Jacquemier J, Pouillart P. Br J Cancer. 1999 Oct; 81(3):449-56

10. High-dose chemotherapy with peripheral blood stem cell support for stage IIIB inflammatory carcinoma of the breast. Schwartzberg L, Weaver C, Lewkow L, McAneny B, Zhen B, Birch R, West W, Tauer K, Buckner C. Bone Marrow Transplant. 1999 Nov; 24(9):981-7.

11. Neoadjuvant high dose chemotherapy plus peripheral blood progenitor cells in inflammatory breast cancer: a multicenter phase II pilot study. Dazzi C, Cariello A, Rosti G, Tienghi A, Molino A, Sabbatini R, Aieta M, Frassineti GL, Vertogen B, Giovanis P, Marangolo M. Haematologica. 2001 May; 86(5):523-9

12. High-dose chemotherapy with autologous stem cell rescue in stage IIIB inflammatory breast cancer. Yalamanchili K, Lalmuanpuii J, Waheed F, Farjami S, Kancherla R, Qureshi Z, Hoang A, Khaled Y, Lake D, Puccio C, Chun HG, Seiter K, Ahmed T. Anticancer Res. 2008 Sep-Oct; 28(5B):3139-42

13. Strategies to improve long-term outcome in stage IIIB inflammatory breast cancer: multimodality treatment including dose-intensive induction and high-dose chemotherapy. Sportès C, Steinberg SM, Liewehr DJ, Gea-Banacloche J, Danforth DN, Avila DN, Bryant KE, Krumlauf MC, Fowler DH, Pavletic S, Hardy NM, Bishop MR, Gress RE. Biol Blood Marrow Transplant. 2009 Aug; 15(8):963-7

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Table 2. Characteristics of adult patients who underwent first autologous transplant for stage III-IV IBC and non-IBC from 1990-2003.

Characteristics of patients: IBC, Stage III IBC, Stage IVNon-IBC,

Stage III Non-IBC, Stage IV

Patient-related Number of patients 849 63 1041 665Number of centers 136 38 143 128Age at transplant, median (range), years 47 (20 - 68) 46 (27 - 66) 46 (21 - 70) 46 (24 - 69)Age at transplant, years 20-29 17 ( 2) 3 ( 5) 28 ( 3) 11 ( 2) 30-39 173 (20) 11 (17) 247 (24) 137 (21) 40-49 345 (41) 28 (44) 448 (43) 303 (46) 50-59 258 (30) 17 (27) 271 (26) 182 (27) 60+ 56 ( 7) 4 ( 6) 47 ( 5) 32 ( 5)Menopausal status Male patient 3 (<1) 0 5 (<1) 6 (<1) Premenopausal 486 (57) 37 (59) 677 (65) 404 (61) Postmenopausal 278 (33) 22 (35) 270 (26) 179 (27) Missing 82 (10) 4 ( 6) 89 ( 9) 76 (11)Gender Male 3 (<1) 0 5 (<1) 6 (<1) Female 0 63 0 659 (99)Race Caucasian 724 (85) 53 (84) 886 (85) 571 (86) African-American 68 ( 8) 5 ( 8) 82 ( 8) 45 ( 7) Other 37 ( 4) 4 ( 6) 48 ( 5) 30 ( 7) Missing 20 ( 2) 1 ( 2) 25 ( 2) 19 ( 3)Karnofsky score prior to transplant <90% 117 (14) 12 (19) 146 (14) 151 (23) ≥90% 724 (85) 49 (78) 879 (84) 508 (76) Missing 8 (<1) 2 ( 3) 16 ( 2) 6 (<1)

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Table 2. Continued



Disease-related Location of breast cancer at time of diagnosis

Right breast 407 (48) 33 (52) 505 (49) 301 (45) Left breast 410 (48) 27 (43) 505 (49) 324 (49) Bilateral 25 ( 3) 3 ( 5) 25 ( 2) 28 ( 4) Missing 7 (<1) 0 6 (<1) 12 ( 2)Disease status at time of transplant CR + CR w/exception of bone scan abnormalities of unknown significance

668 (79) 31 (49) 818 (79) 274 (41)

Partial response 111 (13) 24 (38) 125 (12) 278 (42) Stable 49 ( 6) 7 (11) 73 ( 7) 86 (13) Progressive disease 21 ( 2) 1 ( 2) 25 ( 2) 27 ( 4)Estrogen receptor status Estrogen receptor assays not done 40 ( 5) 8 (13) 22 ( 2) 28 ( 4) Positive 334 (39) 16 (25) 544 (52) 347 (52) Negative 360 (42) 28 (44) 404 (39) 218 (33) Borderline 14 ( 2) 0 15 ( 1) 15 ( 2) Missing 101 (12) 11 (17) 56 ( 5) 57 ( 9)Progesterone receptor status Progesterone receptor assays not done 36 ( 4) 8 (13) 29 ( 3) 36 ( 5) Positive 295 (35) 13 (21) 487 (47) 309 (46) Negative 378 (45) 32 (51) 433 (42) 247 (37) Borderline 19 ( 2) 0 22 (2 ) 11 ( 2) Missing 121 (14) 10 (16) 70 (7 ) 62 ( 9)Treatment-related Neoadjuvant treatment given Yes 543 (64) 45 (71) 230 (22) 190 (29) No 287 (34) 18 (29) 808 (78) 471 (71) Missing 19 ( 2) 0 3 (<1) 4 (<1)Type of neoadjuvant treatment Number Evaluable 543 45 230 190 Chemotherapy only 493 (91) 41 (91) 207 (90) 138 (73) Chemo + Hormonal + Radiation 4 ( 1) 0 1 (<1) 10 ( 5) Hormonal only 0 0 1 (<1) 1 ( 1) Hormonal + Chemo 27 ( 5) 2 ( 4) 12 ( 5) 19 ( 1) Hormonal + Radiaton 0 0 1 (<1) 0 Radiation only 0 0 1 (<1) 2 ( 1) Radiation + Chemo 16 ( 3) 2 ( 4) 5 ( 2) 15 ( 8) Missing 3 ( 1) 0 2 ( 1) 5 ( 3)

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Table 2. Continued



Response to neoadjuvant treatment Number Evaluable 543 45 230 190 Complete response 100 (18) 8 (18) 44 (19) 29 (15) Partial response 327 (60) 27 (60) 126 (55) 98 (52) Stable and/or Progressive disease 63 (12) 5 (11) 30 (13) 19 (10) Not evaluable 4 ( 1) 1 ( 2) 1 (<1) 4 ( 2) Missing 49 ( 9) 4 ( 9) 29 (13) 40 (21)Conditioning regimen CARB + CY + THIO alone 379 (42) 30 (34) 397 (37) 333 (39) CARB + CY + THIO +-others 53 ( 6) 5 ( 6) 60 ( 6) 29 ( 3) CARB + CY +-others 80 ( 9) 15 (17) 81 ( 8) 85 (10) CARB +-others 56 ( 6) 8 ( 9) 66 ( 6) 62 ( 7) CISP +-others 64 ( 7) 10 (11) 94 ( 9) 64 ( 7) CY +-others 242 (27) 18 (20) 316 (30) 204 (24) LPAM +-others 29 ( 3) 2 ( 2) 41 ( 4) 46 ( 5) Other 10 ( 1) 0 12 ( 1) 34 ( 4)Graft source BM 76 ( 9) 6 (10) 83 ( 8) 43 (6 ) PBSC 708 (83) 51 (81) 851 (82) 575 (86) PBSC + BM 65 ( 8) 6 (10) 107 (10) 47 ( 7)Initial Management-related Surgery part of initial management Yes 797 (94) 41 (65) 1015 (98) 533 (80) No 48 ( 6) 22 (35) 19 ( 2) 126 (19) Missing 4 (<1) 0 7 (<1) 6 (<1)Adjuvant treatment post-surgery Yes 616 (73) 38 (60) 919 (88) 503 (76) No 211 (25) 25 (40) 117 (11) 157 (24) Missing 22 ( 3) 0 5 (<1) 5 (<1)Type of adjuvant treatment therapy given Number Evaluable 616 38 919 503 Chemotherapy only 433 (70) 24 (63) 678 (74) 316 (63) Chemo + Hormonal + Radiation 38 ( 6) 2 ( 5) 72 ( 8) 42 ( 8) Hormonal only 7 ( 1) 2 ( 5) 7 ( 1) 15 ( 3) Hormonal + Chemo 20 ( 3) 1 ( 3) 65 ( 7) 57 (11) Hormonal + Radiation 8 ( 1) 0 2 (<1) 10 ( 2) Radiation only 22 ( 4) 2 ( 5) 6 ( 1) 9 ( 2) Radiation + Chemo 86 (14) 7 (18) 88 (10) 52 (10) Missing 2 (<1) 0 1 (<1) 2 (<1)Time from diagnosis to transplant, median (range), months

7 (1 – 161) 7 (2 – 35) 7 (<1 – 173) 8 (<1 – 192)

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Table 2. Continued


Stage III Non-IBC, Stage

IVTime from diagnosis to transplant, months 3 - 6 282 (33) 17 (27) 391 (38) 180 (27) 6 - 12 414 (49) 33 (52) 396 (38) 296 (45) > 12 144 (17) 10 (16) 248 (24) 182 (27) Missing 9 (1 ) 3 (5 ) 6 (<1) 7 (1 )Year of transplant 1990 2 (<1) 0 0 3 (<1) 1991 10 ( 1) 1 ( 2) 1 (<1) 10 ( 2) 1992 12 ( 1) 5 ( 8) 9 (<1) 12 ( 2) 1993 18 ( 2) 1 ( 2) 20 ( 2) 15 ( 2) 1994 64 ( 8) 2 ( 3) 69 ( 7) 38 ( 6) 1995 137 (16) 8 (13) 166 (16) 98 (15) 1996 163 (19) 15 (24) 213 (20) 168 (25) 1997 198 (23) 7 (11) 239 (23) 128 (19) 1998 153 (18) 15 (24) 209 (20) 126 (19) 1999 49 ( 6) 4 ( 6) 76 ( 7) 48 ( 7) 2000 30 ( 4) 3 ( 5) 24 ( 2) 7 ( 1) 2001 9 ( 1) 1 ( 2) 11 ( 1) 10 ( 2) 2002 3 (<1) 0 1 (<1) 1 (<1) 2003 1 (<1) 1 ( 2) 3 (<1) 1 (<1)Planned Therapy-related Planned post-transplant therapy Yes 849 63 1041 665Planned post-transplant therapy Hormonal therapy alone 285 (34) 23 (37) 363 (35) 350 (53) Radiation therapy alone 540 (64) 30 (48) 628 (60) 239 (36) Radiation +- Hormonal +- Immuno 14 ( 2) 4 ( 6) 30 ( 3) 51 ( 8) Others 10 ( 1) 6 (10) 20 ( 2) 25 ( 4)Abbreviations: CR=Complete Remission, IBC=Inflammatory Breast Cancer, TBD=To Be Determined.

Selection Criteria Exclusion N

First autologous HCT for Inflammatory or Non-inflammatory Breast Cancer from 1990-2003

7604

Stage IIIa, IIIb, IV 4628 2976

Exclude those missing metastatic status 19 2957

Exclude those under 18 years of age 1 2956

Exclude those missing conditioning regimen 5 2951

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CIBMTR Study Proposal: 1112-02 Study Title: High dose chemotherapy and autologous stem cell transplantation for germ cell tumors. Muna Qayed, MD MSc; Emory University, Atlanta, GA; [email protected] Thomas Olson, MD; Emory University, Atlanta, GA; [email protected] Kuang-Yueh Chiang, MD PhD; Emory University, Atlanta, GA; [email protected] Hypothesis: High dose chemotherapy and autologous stem cell transplantation (SCT) has a therapeutic role in the treatment of high risk germ cell tumors (GCT). Specific Aims:

To determine the overall outcomes of patients with testicular and extragonadal GCT (excluding intracranial tumors) who underwent high-dose chemotherapy and autologous SCT.

To identify patient-, disease-, and transplant-related prognostic factors for outcome after high dose chemotherapy and autologous SCT for testicular and extragonadal GCT

Scientific Justification:

Children with extracranial GCTs have overall cure rates that are greater than 80%.1-3

Patients with recurrence after surgery and platinum based chemotherapy continue to have unfavorable outcomes, with

reports regarding salvage treatment being limited by small sample size. 4-6

There are multiple treatment

strategies that have been found to be effective in the treatment of adults with recurrent GCTs7-9

, however, the differences between adults and children in terms of primary GCT site, patterns of relapse and biology

may limit the applicability of these approaches in children.10

The role of high dose chemotherapy and autologous stem cell transplantation (SCT) in adults with germ cell tumors is controversial. Some reports have shown the efficacy of this approach even in multiply11, 12

relapsed patients , while other reports failed to show an effect for single SCT, and advocate the tandem

approach for patients with poor risk features. 13

Several large randomized trials failed to show an advantage to the use of SCT in first-line treatment for GCT in adults, and its use is reserved for salvage therapy in

relapsed disease.14

In children, the use of SCT for treatment for GCTs has been mostly anecdotal. The European Group for Blood and Marrow Transplantation reported their experience in using high dose chemotherapy and autologous SCT for children with relapsed extragonadal GCTs (including intracranial tumors). Of the 23 patients in first to 3rd relapse, 16 had a complete response, and the disease-free survival

was 43% for all patients (including 8/14 patients with extracranial GCTs).15

There is consideration to incorporating SCT for patients with high risk GCTs in the upcoming Children’s Oncology Group GCT trial (personal communication, Thomas Olson). Given the paucity of data on SCT in children with GCTs, we propose a review of data reported to the CIBMTR, to describe outcomes, and identify risk groups that stand to have potential benefits from SCT, as well as risk factors for relapse. Study Population: Patient eligibility/selection criteria include: patients younger than 21 years of age undergoing autologous SCT for testicular and extragonadal germ cell tumors between 2000 and 2010, reported to the CIBMTR. Data Requirements: Data in italics are captured through standard CIBMTR short forms (Forms 2400, 2450), the rest is data captured through long forms 2022 and 2120.

46


Patient-related: Age at diagnosis Sex: male vs. female Performance status

Disease-related:

Histology: Disease site: gonadal vs. extragonadal (site of extragonadal disease) Presence of metastasis Stage Baseline αFP and βHCG Treatment: surgery, chemotherapy, radiation theray (RT) -Best response Relapse (sensitivity to chemotherapy completed for patients with relapse only) Disease staging prior to SCT Response status prior to SCT, labs prior to SCT (αFP, βHCG)\ Treatment planned post-transplant

Transplant-related:

Time from diagnosis to transplant Conditioning regimen Post-transplant therapy given CD34+ cell dose

Outcomes:

Complete response post-transplant, best response post-transplant Transplant related mortality Relapse or progression, progression free survival Sites of progression Planned treatment given post SCT: Surgery, chemotherapy, RT Labs post SCT (AFP, BHCG) Disease status at time of last follow-up Overall survival

Study design: Descriptive analysis of patient, disease, and transplant-related factors will be performed, and will be reported as median and range for continuous variables and percent of total for categorical variables. Probability of progression-free survival and overall survival will be calculated using the Kaplan-Meier method. Comparison of survival curves will be done using the log-rank test. Multivariate analyses will be performed using proportional hazards models, and will be used to evaluate the relationship of risk factors to outcomes (relapse, transplant related mortality, progression-free survival and overall survival).

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References: 1. Mann JR, Raafat F, Robinson K, et al. The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol. Nov 15 2000;18(22):3809-3818. 2. Cushing B, Giller R, Cullen JW, et al. Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study--Pediatric Oncology Group 9049 and Children's Cancer Group 8882. J Clin Oncol. Jul 1 2004;22(13):26912700. 3. Marina N, London WB, Frazier AL, et al. Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric intergroup study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Jun 1 2006;24(16):2544-2548. 4. Gobel U, Schneider DT, Calaminus G, Haas RJ, Schmidt P, Harms D. Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups. Ann Oncol. Mar 2000;11(3):263-271. 5. Schneider DT, Wessalowski R, Calaminus G, et al. Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol. Apr 1 2001;19(7):1951-1960. 6. Wessalowski R, Schneider DT, Mils O, et al. An approach for cure: PEI-chemotherapy and regional deep hyperthermia in children and adolescents with unresectable malignant tumors. Klinische Padiatrie. 2003 Nov-Dec 2003;215(6):303-309. 7. Loehrer PJ, Sr., Gonin R, Nichols CR, Weathers T, Einhorn LH. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1998 Jul 1998;16(7):2500-2504. 8. Motzer RJ, Sheinfeld J, Mazumdar M, et al. Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000 Jun 2000;18(12):2413-2418. 9. Hartmann JT, Einhorn L, Nichols CR, et al. Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis. J Clin Oncol. Mar 15 2001;19(6):1641-1648. 10. Gobel U, Schneider DT, Calaminus G, Haas RJ, Schmidt P, Harms D. Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2000 Mar 2000;11(3):263-271. 11. Motzer RJ, Mazumdar M, Sheinfeld J, et al. Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000 Mar 2000;18(6):1173-1180. 12. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol. Apr 1 2010;28(10):1706-1713. 13. De Giorgi U, Rosti G, Salvioni R, et al. Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features. Urologic oncology. 2011 May-Jun 2011;29(3):284-290. 14. Voss MH, Feldman DR, Motzer RJ. High-dose chemotherapy and stem cell transplantation for advanced testicular cancer. Expert review of anticancer therapy. 2011 Jul 2011;11(7):1091-1103. 15. De Giorgi U, Rosti G, Slavin S, et al. Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. British journal of cancer. 2005 Aug 22 2005;93(4):412-417.

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Characteristics of patients undergoing first autologous transplant in 2003-2010 for testicular cancer or germ cell tumors, as reported to the CIBMTR.

N (%)Number of patients 191Number of centers Age at transplant, median (range), years 18 (1 - 21)Age at transplant, years 0-10 34 (18) 10-17 72 (38) 18-20 85 (45)Gender Male 144 (75) Female 47 (25)Race Caucasian 116 (61) African-American 11 ( 6) Other 48 (25) Unknown/Missing 16 ( 8)Karnofsky score prior to transplant <90% 7 ( 4) ≥90% 14 ( 7) Missing 170 (89)Disease Testicular cancer 72 (38) Germ cell tumor 119 (62)Graft type Bone Marrow 6 ( 3) Peripheral Blood 182 (95) Missing 3 ( 2)Year of transplant 2003 20 (10) 2004 23 (12) 2005 20 (10) 2006 23 (12) 2007 16 ( 8) 2008 15 ( 8) 2009 16 ( 8) 2010 29 (15) 2011 29 (15)Follow-up of survivors, median (range), months 33 (1-100)

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Continued. Completeness Follow-up Index:

Overall Year 1 Year 2 79 100 97

Selection Criteria: Excluded N

First autologous HCT between 2003-2011 for Testicular cancer and Germ Cell Tumors (GCT)

1376

Age < 21 years old 865 191

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not for publication or presentation · aml (2010/2110), all (2011/2111), mds (2014/2114), jmml...

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