Post ASH - SALZBURG, 2011 – 01 - 14

ASH 2010ASH 2010OORLANDORLANDO

AALLOGENEICLLOGENEIC TTXXNNEWEW CCONCEPTSONCEPTS ? N? NEWEW IINDICATIONS NDICATIONS ??

Dirk STRUNK, MD ReRe

TT

SS

StemCellResearchStemCellResearchGRAZGRAZ

1. Relaps after allo. HCT

2. ABMT Toxicity & Risk Score

3. SAA

4. PRESIDENT: Hal E. Broxmeyer & the CBT Story

5. Plenary Session: New Concepts! New Indications!

6. New Cell Sources (beyond BM/PB/UCB)?

3447 Second Allogeneic Stem Cell Transplantation (allo-SCT) Using Reduced-Intensity Conditioning (RIC) for Acute Myeloid Leukemia (AML) Patients Who Relapsed Following a

First RIC Allo-SCT: a Survey of the Acute Leukemia Working Party of EBMT (Poster III-226)

Mohamad Mohty1, Myriam Labopin, MD2*, Jurgen Finke, MD3, Christoph Schmid4*, H.J. Kolb, M.D.5*, Andrea Bacigalupo, MD6, Didier Blaise, MD7, Jérôme Cornillon8*, Noel Milpied, MD9*, J.R. Cabrera-Marin, M.D.10*, Fabio Ciceri, M.D.11*, Vanderson Rocha12* and Arnon Nagler, M.D.13*

… OS / LFS / NRM / RI in 103 AML patients (46F) ~2nd RIC allo-SCT (RIC2) as a salvage after (RIC1)

(who were reported to the EBMT registry with adequate data).

… median age at RIC2 = 54 (range, 20-69) years … median time from RIC1 to relapse = 184 (range, 28-2377)

days … median time from RIC1 to RIC2 was 307 (range, 44-3165) days, and the median time from relapse to

RIC2 = 84 (range, 7-582) days. (RIC2: 56% MSD & 44% MUD … 80% in relapsed or refractory disease.

At 2 years … OS, LFS, NRM and RI were 19%, 13%, 27%, and 60% respectively …

Interval from RIC1 to relapse (>6 months) was the strongest predictor for improved LFS and lower

RI after RIC2 (P=0.004, HR=1.91, 95%CI, 1.23-2.95; and P=0.0008, HR=0.41, 95%CI, 0.25-0.69,

respectively).

When comparing patients relapsing < or > 6 months after the RIC1, LFS & RI rates were 6% vs. 21% (P=0.002) and 71% vs. 48% (P=0.001), respectively … after the RIC1!

AML patients who relapse >6 mo. after RIC1 are potential candidates for RIC2 with a relatively acceptable rate of NRM.

3456 Allogeneic Stem Cell Tranplantation (allo-SCT) for Adult Patients with Active Refractory/Relapsed Hematological Malignancies: a Survey From the Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC). (Poster III-235)

Patrice Chevallier1*, Noel Milpied, MD2*, Karin Bilger, MD3*, Gérard Socié4, Ibrahim Yakoub-Agha, MD, PhD5, Mauricette Michallet6, Jean-Yves Cahn, MD7, Yves Beguin, MD, PhD8, Jacques-Olivier Bay, MD, PhD9, Didier Blaise, MD10, Francois Guilhot11, Christian Berthou12*, Eric Deconinck13*, Nicole Raus14* and Mohamad Mohty15

Patients with active refractory/relapsed hematological diseases have a very poor outcome. Best supportive care or investigational therapies in phase 1 trials are usually proposed to these patients.

861 patients 2005-9 (F/M=344/517; 323 AML, 43 ALL, 129 MDS, 12 CMML, 110 MPS, 28 CML, 100 NHL, 40 HL, 36 myeloma, 24 CLL, 16 other) treated with allo-SCT for active refractory or relapsed disease. 32% had relapse after auto/allo SCT Median age at transplant was 50y (range, 16-71). 350 (41%) MSD, 59% MUD; 72% PBSC (n=617), 16% BM

(n=139), 12% UCB (n0107). 62% RIC & 38% myeloablative…

Median follow-up of 290d (range, 1-1854), engraftment in 88% … (40%) alive (3355%%==229977 iinn CCRR) Grade II-IV/III-IV aGVHD in 35%/17%; cGVHD 21% (limited=77; extensive=82; missing data=24). 246 patients (28.5%) died of PD, 232 of TRM (NRM: 27%). In patients with lymphoma (n=140), OS at 1 and 2 years were 57% (95%CI, 48-66%) and 49% (95%CI, 40-

58%) versus 36% (95%CI, 32-40%) and 27% (95%CI, 23-31%), respectively, in all other diagnoses (P=0.00004). Multivariate analysis: diagnosis of NHL or Hodgkin was the most significant factor associated with improved survival (RR=1.68; 95%CI, 1.3-2.2; P=0.0001). Data support the use of allo-SCT in adult patients with active refractory/relapsed hematological diseases,

especially in patients with lymphomas.

1293 Azacytidine (AZA) In Relapsed MDS and AML After Allogeneic Stem Cell

Transplantation (allo-HSCT): Results of the French ATU Program (Poster I-273)

Romain Guièze1*, Anne Jouinot2*, Raphael Itzykson3*, Sylvain Thepot3*, Thierry Guillaume4*, Valérie Coiteux5*, Sébastien Wittnebel6*, Stéphane de Botton6*, Caroline Dartigeas7*, Anne Sirvent8*, Pascal Turlure9*, Didier Bouscary10*, Marie Robin11*, Jean-Paul Vernant12*, Laurent Sutton13*, Francois Dreyfus10*, Jacques-Olivier Bay1, Lionel Ades2 and Pierre Fenaux2

Background: Relapse is the most common cause of treatment failure after allo-HSCT for myeloid malignancies, … very poor prognosis (median survival of 3-4 months without active treatment) (Savani et al., BMT 2009)…

Methods: An AZA compassionate program (ATU) … in France … Dec 2004 - Dec 2008 for higher risk MDS, and for AML not candidates or refractory to intensive chemotherapy… retrospectively … 29 pts (M/F: 14/15; median

age: 53y, range 22-66) ... 14 pts received a myeloablative conditioning and 15 a reduced intensity … relapse …

median of 228 days post allo-HSCT (range: 66-1489) … Treatment was according to FDA-EMEA approved schedule (AZA 75 mg/m2/d X 7 d every 4 weeks) in 24 pts (83%) and … (5d/4w) in 5 pts…

MDS: ORR 4/6 pts (66%; 1 CR, marrow CR in 2) ...

AML: ORR 5/23 pts (22%; 3 CR, CRi in 1 and PR in 1)… Progressive disease was the most common cause of death (14/24 died pts).

Conclusion: … AZA appears as an interesting therapeutic option, especially in pts with <30% marrow blasts at diagnosis. The 5d-schedule may be associated with a better response rate possibly related to a less toxicity,

allowing more prolonged treatment. Further reduction of AZA schedules in this context, already tested by Jabbour et al. (Cancer 2009) should be further explored in relapses after allo-HSCT.

1294 Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) In Patients with

Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Interim-Analysis From the

AZARELA-Trial (NCT-00795548) (Poster I-274)

Thomas Schroeder1*, Akos Gabor Czibere1*, Nicolaus Kröger2*, Uwe Platzbecker3, Gesine Bug4*, Kathrin Rieger5*, Thomas Luft6, Ingmar Bruns7, Fabian Zohren7*, Christine Wolschke, MD8*, Roland Fenk1*, Rainer Haas1* and Guido Kobbe, MD9*

Design/Methods: Evaluate activity & safety of Aza + DLI as first salvage therapy in 30 pts (F/M=15/10) from 6 German centres with AML or MDS relapsing (median of 160 days (range 19-1199)) following HSCT after HSCT

… prospective, multicenter, single-arm phase-II trial … 8 cycles Aza (100 mg/m2/d d1-5, every 28 days) and 3 DLI with increasing dosages (1-5x106 – 1-5x108 cells/kg) after every 2nd Aza treatment cycle. Additional DLI were permitted.

ORR was 64% with 5 pts (20%) achieving a CR or CRi, 3 (12%) a partial remission (PR) and 8 (32%) SD.

After a median follow-up of 100 days (range 25-485) 15 of 25 pts (60%) are currently alive … All pts, who achieved a CR/CRi, remained in ongoing remission for a median time of 229 days. Achieving a CR (CR: not reached vs. no CR: 117 days, p .008) or any type of response (CR/CRi, PR or SD) to the combination of Aza

and DLI (any response: not reached vs. no response: 79 days, p .0001) were associated with a significantly longer overall survival.

Conclusion: The combination of Aza and DLI as salvage treatment for patients with AML or MDS who relapse after allogeneic HSCT seems to be safe and shows significant anti-leukemic activity.

3314 Sorafenib Monotherapy Is Effective In Relapsed and RefractoryFlt3-ITD Positive

Acute Myeloid Leukemia, Particularly After Allogenic Stem Cell Transplantation Poster III-93

Stephan Metzelder, MD1*, Anemone Finck, MD2*, Martin Fey, MD3*, Sebastian Scholl, MD4*, Matthias Kröger, MD5*, Andreas Reiter, MD6*, Helmut R. Salih, MD7, Katharina Götze, MD8*, Ralf Georg Meyer, MD9*, Aristoteles Giagounidis, MD10, Wolfram Brugger, MD11*, Matthias Vöhringer, MD12*, Lothar Müller, MD13*, Linn Yeh Ching, MD14*, Peter Dreger, MD, PhD15*, Masanori Mori, MD16*, Nadezda Basara, MD17, Kerstin Schaefer-Eckart, MD18*, Beate Schultheis, MD19*, Claudia Baldus, MD20*, Andreas Neubauer, MD21 and Andreas Burchert, MD22

Introduction: The FLT3-ITD is the most frequent genetic aberration in normal karyotype AML and associated with a poor prognosis … Sorafenib is a multikinase inhibitor, which is approved in Europe for the treatment of metastatic renal cell and hepatocellular carcinoma. It inhibits the FLT3 RTK and the mutated FLT3-ITD + Raf, PDGFR & VEGFR … report on clinical response of 39 relapsed or refractory FLT3-ITD positive AML patients treated with sorafenib monotherapy (questionnaire; 26 centers).

Results: … 39 evaluable patients (F/M=19/20): i) 11 primary refractory patients (PR-P); ii) 12 relapsing patients (REL-P) after 1-4 cycles of prior chemotherapy, syngenic, or autologous SCT; iii) 16 patients relapsing after allogenic SCT (SCT-P) receiving 200 - 800mg sorafenib p.o. daily. PR-P: 6 hematological remissions (HR), 4 CR; 6 pt. underwent allo-SCT after responding to sorafenib induction. REL-P: 8 HR, 2 bone marrow responses (which includes a HR) and 1 CRp. SCT-P: 3PR, 2HR, 7 BMR and 4 CMR. Median time to treatment failure (sorafenib resistance) was 119 days for PR-P and REL-P, not reached in SCT-P (p=0.0217).

Conclusion: This analysis … confirms … remarkable clinical activity of sorafenib monotherapy in FLT3-ITD AML.

Validation DataValidation Data NHL / CLL & HCTNHL / CLL & HCT --CI > 1CI > 1

Mortality

In the absence

of an identical

sibling

ATG+CSA

is the

standard

1st line

treatment?

Courtesy: Jakob R Passweg MD MS, Basel

Use of Stem Cell Source within EBMT

0

50

100

150

200

250

300

N°

of S

CT

2001 2002 2003 2004 2005 2006 2007 2008 2009

BMPBSCCB

Courtesy: Jakob R Passweg MD MS, Basel

ATG?

Stimulator

Animal source

Courtesy: Jakob R Passweg MD MS, Basel

LBA-4 A Randomized Trial of Horse Versus Rabbit Antithymocyte Globulin In Severe

Acquired Aplastic Anemia

Ph Scheinberg, CO Wu, P Scheinberg, B Weinstein, O Nunez, EM Sloand, NS Young

Hematology Branch, National Heart, Lung, and Blood Institute, NIH

Late-breaking Abstracts Session: Tuesday, 7:30 AM Hall D

Hematologic response rates at 6 months in evaluable patients

Horse ATG 37/54 (69%) 0.0017 Rabbit ATG 19/54 (35%)

Efficacy of Rabbit Anti-Thymocyte Globulin (ATG) Compared to

Horse ATG In Severe Aplastic Anemia

Bone Marrow Failure: Poster II Sunday

M Afable , M Shaik, Y Sugimoto, M Clemente RV Tiu, SR. Mohan, N Bejanyan,

P Elson, M Kalaycio, A Advani, R Sobecks, AE Lichtin, MA Sekeres, J

Maciejewski

rATG: 22, hATG controls: 67

Response was similar for pts treated with rATG compared to hATG

at

3 months: 41% vs. 52% (p=.15),

6 months: 50% vs. 59% (p=.62)

12 months: 54% vs 59% (p=.66)

1st IST course (131 pts) best responsebest responseOR: 58 % (Thymo: 57,8%; Lympho: 58,5%; p=NS)

PR: 33 % (Thymo: 38,9%; Lympho: 19,5%; p=NS)

CR: 25 % (Thymo: 18,9%; Lympho *: 39%; p=NS)

Comparison between Lymphoglobuline- and Thymoglobuline-based immunosuppressive therapy as first-line treatment for patients with Aplastic Anemia

C Vallejo et al. Pethema-GETH (spanish bone marrow failure study group)

Median follow-up: 24 months

P = NS

Lymphoglobuline

Thymoglobuline

Given all of this information

IS vs BMTLife could be easy if we knew

Who will respond to IS?

Who will not suffer from severe GvHD?

Courtesy: Jakob R Passweg MD MS, Basel

BLOOD 2010 115:2136

Cy 4x50mg/kg; RR 71%

Pearson syndrome: Sideroblastic anemia with marrow cellvacuolization and exocrine pancreatic dysfunction

Clinical features: refractory sideroblastic anemia; pancytopenia; exocrine pancreatic insufficiency; hepatic failure; renaltubulopathy [Inheritance: mitochondrial] Question: Why not CBT? (HEB)

- (WASP=restricted to hematopoiesis)- MSD -> SCTx=standard of care (NEJM 2006)

-2006-2009: n=10 gene therapy (ASCT~ no MSD)

pt.3=1°graft failure -> 2°haplo (father)pt.1,2,4-10 = 5-90% TC ~ WASP+

pt.1 d488 Tpt.1 d488 T --ALL ALL --> BFM> BFM--ALL ALL --> > „„ CRCR““ wk4 (=ASH)wk4 (=ASH)

Totipotent Stem Cells: can construct a complete viable organism

Pluripotent Stem Cells: can differentiate in any cells derived from the three germ layers

Multipotent Stem Cells: can differentiate into more than 3 lineages within one germ layer

Unipotent cells: produce only one cell type, their own

Stem Cell PotencyiPS

Induced Pluripotent Stem Cells

Oct4

Nanogc-myc

Klf4 LIN28

Sox2Oct4

Sox2

Nanog

LIN28

Klf4

c-myc

Safety for Regenerative Medicine

Tumorigenicity: Some of the genes that are transfected for iPSgeneration, like c-myc, are also known to act as proto-oncogenes.One of the characteristics of pluripotent cells is spontaneously teratoma formation in vivo. Chimeric mice produced from iPS cells show a high incidence of death from malignant cancer.

Viral transfection:bears potential risks such as malignant transformation and immune responses to viral proteins.

CASE (Agarwal / Daley)- newborn + severe anemia- Vacuol. RBC precursor- Ringsiderobl.- D.m.

- DNA diagn. -> mitoch. DNA mutation

- BM Fb. (MSC) culture (75% heteroplasmy = defect. mitoch.)

- retrov. transf.: Oct4/Sox2/KLF4/Myc -> 3 iPSC colonies/105 MSC

- over 2-3 mo. Culture = LOSS OF HETEROPLASMY (purged iPS)

- culture + hematop. CK -> virtually disease-free blood cells

- 2 more pt. (n=3) with heteroplasmy <75%

- VISION: autologous iPSC therapy by selection culture

223 Unrelated Cord Blood Transplantation: Comparison After Single Unit Cord Blood

Intrabone Injection and Double Unit Cord Blood Transplantation In Patients with Hematological Malignant Disorders. A Eurocord-EBMT Analysis Oral Session: Clinical Results - Alternative Donor Transplantation I

Vanderson Rocha1*, Myriam Labopin, MD2*, Annalisa Ruggeri, MD1*, Marina Podestà3*, Dolores Caballero4*, Francesca Bonifazi, MD5*, Rovira Montserrat6*, Andrea Gallamini, MD7, Franca Fagioli, MD8*, Gérard Socié, MD9, E. Nikiforakis10*, Mauricette Michallet11, Eric Deconinck12*, Mohamad Mohty13, Andrea Bacigalupo, MD3, Eliane Department, CHU de Nantes, Nantes, France

The limited hematopoietic progenitors in UCB grafts and their homing after IV injection, have prompted …

delivering CB grafts directly into the bone marrow (BM) space (IBCBT) or to use double cord blood

transplantation (dUCBT) to improve engraftment.

To evaluate the impact of IBCBT … compared to dUCBT (2006-2010) ... 87 IBCBT and dUCBT 149 patients … after a myeloablative conditioning regimen for malignant disorders.

IBCBT was performed in 8 EBMT centers whereas dUCBT was performed in 56 EBMT centers (majority AL).

IBCBT patients were older (p<0.001) and importantly had more advanced disease at transplantation (p=0.04).

Median number of infused (after thawing) NC intrabone was 2.5x107/kg vs. 3.9x107/kg in dUCBT (p<0.001). 72% HLA 4/6 of both groups, GVHD prophylaxis CSA+MMF in 100% of IBCBT and in 62% of dUCBT …

ATG in all IBCBT and 40% of dUCBT. Median follow-up time was 18 months in IBCBT and 17 months in dUCBT.

@ day 30, CI of ANC >500 was 83% after IBCBT and 63% after dUCBT @ day 60, 90% in both groups; median time to ANC>500 = 23 vs. 28 days IBCBT vs. dUCBT (p=0.001)

@ day 180 CI of platelet recovery was 81% after IBCBT and 65% after dUCBT (p<0.001)

@ day 100, CI of aGVHD (II-IV) was 19% and 47% (p<0.001) and cGVHD 34% and 37% respectively (p=NS)

Unadjusted 2 y-DFS estimation was 47% after IBCBT and 37% after dUCBT (p=NS).

In multivariate analysis … recipients of IBCBT had improved DFS (HR: 1.64, p=0.035),

faster platelet recovery (HR:2.13, p<0.001) decreased acute GVHD (HR:0.31; p<0.001)

No cut-off value of number of NC for IBCBT or dUCBT could be associated with outcomes.

CONCLUSION: both strategies have extended the use of CB transplants to adults in need of cord blood transplantation. Therefore, IBCBT is an option to transplant adult patients with single CB units after

myeloablative conditioning regimen and may impact the total costs of cord blood transplantation. Based on

these results, intra-bone technique may disclose new transplant potentialities also with other HSC sources.

Francesco Frassoni = presenting

1295 Outocomes of Second Unrelated Cord Blood Transplant for Relapse After First Allogeneic Transplant In Adult Patients with Progressive Acute Myeloid

Leukimia/Myelodysplastic Syndrome (Poster I-275)

Sachi Tainosho, MD, PhD1*, Kazuhiro Masuoka, MD, PhD2*, Aya Nishida, MD1*, Nobuaki Nakano, MD1*, Kazuya Ishiwata, MD1*, Masanori Tsuji, MD1*, Hisashi Yamamoto, MD1*, Yuki Asano-Mori, MD, PhD1*, Naoyuki Uchida, MD, PhD1, Koji Izutsu, MD, PhD1, Atsushi Wake, MD, PhD1, Shigeyoshi Makino, MD, PhD3*, Akiko Yoneyama, MD, PhD4* and Shuichi Taniguchi, MD, PhD1* Tokyo, Japan

Retrospective analysis of 2nd allo-HSCT using UCB for 34 adult patients with AML/MDS relapsed after 1st HSCT.

130 adult patients with AML/MDS (21/13) & HSCT … 53 relapsed, 34 = 2nd Tx with UCB (19 did not receive 2nd

Tx ~ severe organ dysfunction or uncontrolled active infection or CR by donor lymphocyte infusion). The

median age at 2nd UCBT was 54 years (18-69) and interval between 1st allo-HSCT and 2nd UCBT was 9

months (1-54). All patients at 2nd UCBT were in progressive disease … received a single cord blood unit with

median TNC/CD34 cell dose of 2.8×107/kg (range, 1.4-4.8) and 0.7×105/kg (range, 0.2-2.2), respectively. HLA

disparities were 3/6 match (n=4), 4/6 (n=25), 5/6 (n=4) and 6/6 (n=1). Conditioning regimen consisted of fludarabine and alkylating agent. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (Tac)

alone in 15, Tac plus mycophenolate mofetil in 11, and cyclosporine alone in 8.

10 patients died by day 28 (PD=5; TRM=5)

24 patients survived > 28 days, aGVHD developed in 14, cGVHD in 4.

Estimated 3-year OS, TRM and relapse mortality rate were 16%, 32%, and 52%.

Univariate analysis: worsened survival if early relapse < 100 days after 1st allo-HSCT (0 vs 21%; P=0.01). Eighteen of 19 patients who did not undergo 2nd UCBT died of progressive disease or multiple organ failure.

Conclusion: 3 year-OS of 16% with 2nd UCBT following relapsed AML/ MDS comparable with 2nd BMT or PBCST.

Considering that all patients in this study were in non-remission and in relatively higher age (median age 54

years), 2nd UCBT following relapse of AML/MDS could be a viable therapeutic option.