Hematopoietic Stem Cell Transplantation: Evolving Strategies That Have Resulted in Improved Outcomes

Hematopoietic Stem Cell Transplantation: Evolving Strategies That Have Resulted in Improved Outcomes Asad Bashey, MD, PhD Blood and Marrow Transplantation Program at Northside Hospital Atlanta, Georgia

Transplant Activity in the U.S. 1980-2011 Transplants Center for International Blood & Marrow Transplant Research

Challenges In Allogeneic HCT in 2015 Lack of donor availability Treatment-related mortality/morbidity Regimen-related toxicity Infections Graft versus host disease (GVHD) Relapse of malignancy Late effects

Only One in 4 Siblings Will Be HLA-Identical

No Donor 40% Matched Sibling Donor 30% Matched Unrelated Donor 30%

7/8 and 8/8 Allele, Available-Match Rates in the Adult Donor Registry - 2010 National Marrow Donor Program 7

Alternative Donor Sources Cord blood (CBT) Rapidly available Low cell dose necessitates double CBT in most adult patients ($$) Delayed immune reconstitution, infection Partially matched related donor (haploidentical) Almost universally available (quickly) Less expensive Post-transplant cyclophosphamide (Cy) has revolutionized its use

Prior Attempts at Haploidentical Donor Transplantation T-cell replete (Seattle 1975-1990) Graft failure >20% Severe acute GVHD >50% Survival <10% Ex vivo T-cell depletion (Perugia 1980-) High rates of graft rejection Abrogated by megadoses of stem cells/intense conditioning Severe post-bmt immunoparesis - high death rate from infections

Anasetti C, et al. Hum Immunol. 1990;29(2):79-91. Reisner Y, et al. Blood. 201;118(23):6006-6017.

Post-Transplantation Cy = Selective Allodepletion Signal 1: Peptide-MHC recognition by TCR Peptide-MHC T-cell activation CD80/CD86 TCR CD28 Signal 3: T-cell growth factors Receptor T-cell proliferation Dendritic Cell CD40 CD40L Signal 2: Co-stimulation

Memory/Effector T con and et reg Are Preserved, but Naïve T con Are Depleted Following Posttransplantation Cyclophosphamide Kanakry CG, et al. Science Translational Medicine. 2013;5(211):211ra157. Ross D, et al. Biol Blood Marrow Transplant. 2013;19(10):1430-1438.

Nonmyeloablative T-Replete Haploidentical Transplant Utilizing Post-Transplant Cyclophosphamide Johns Hopkins University (JHU) Regimen O Donnell PV, et al. Biol Blood Marrow Transplant. 2002;8(7):377-386. Luznik L, et al. Biol Blood Marrow Transplant. 2008;14(6):641-650.

Results of Nonmyeloablative Haplo-BMT at JHU McCurdy SR, et al. Blood. 2015 March 26 [epub ahead of print].

Results of Nonmyeloablative Haplo-BMT at JHU McCurdy SR, et al. Blood. 2015 March 26 [epub ahead of print].

Tony D. 44 years old Oct /2003 Ph-positive ALL Hyper-CVAD A + imatinib -Refractory, 30% Blasts Hyper-CVAD B+ imatinib -CR-1 Completed HCVAD + imatinib (1A through 4B) No matched related donor No 8 of 8 or 7 of 8 matched unrelated donors (MUD) No adequate cord blood unit (CBU) option Maintenance imatinib started May 2004 Jun 2006 hematologic relapse of Ph-positive ALL ME+ imatinib 800 mg/day Aug 2006 <5% blasts, flow negative, cytogenetics normal, PCR + Sept 2006 nonmyeloablative haploidentical BMT Day 30 chimerism 100 donor CD3 and CD33 No GVHD 2014 continued molecular CR, KPS 100, no active GVHD, off all immunosuppression

Myeloablative Transplants With T-Replete Haploidentical Donors and Post Transplant Cy Two consecutive single-institution phase II trials Use of myeloablative conditioning+ G-CSF mobilized PBSC graft NSH 864 (Busulfan based) 1/3/09 through 3/2/11 (n = 20) (Solomon SR, et al. Biol Blood Marrow Transplant. 2012;18(12):1859-1866.) NSH 922 (Total body irradiation [TBI]-based) 5/13/11 through 2/11/14 (n = 35) (Solomon SR, et al. Biol Blood Marrow Transplant. 2015 Mar 19 [epub ahead of print].) NSH, Northside Hospital

NSH 864 i.v. Busulfan 110mg/m 2 /day Cy 14.5mg/ kg/day T cell replete PBSC -7-6 -5-4 -3-2 -1 0 +5 +10 +20 +30 +40 +90 +180 Fludarabine 25 mg/m 2 /d Cy 50mg/ kg/d MMF Tacrolimus NSH 922 TBI 150cGy T cell replete bid/day PBSC (total 1200cGy) -7-6 -5-4 -3-2 -1 0 +5 +10 +20 +30 +40 +90 +180 Fludarabine 30 mg/m 2 /d Cy 50mg/ kg/d MMF Tacrolimus

Results of TBI-Based Myeloablative Haplo Transplants at NSH Solomon SR, et al. Biol Blood Marrow Transplant. 2015 Mar 19 [epub ahead of print].

Incidence and Severity of BK Virus Cystitis After Myeloablative Haploidentical Transplantation TBI-Based vs Busulfan-Based Conditioning Solomon SR, et al. Biol Blood Marrow Transplant. 2015 Mar 19 [epub ahead of print].

Comparison of Myeloablative Haplo vs MUD DFS GVHD Solomon SR, et al. Biol Blood Marrow Transplant. 2015 Mar 19 [epub ahead of print].

Allele Level Matching of HLA-A, B, C, and DRB1 Is Important Pidala J, et al. Blood. 2014;124(16)2596-2606.

Improvement in Outcomes Related to Better Matching of MUD Transplants

DPB1 Mismatching Affects Outcomes of MUD Transplants Pidala J, et al. Blood. 2014;124(16)2596-2606.

Prevention of Visceral Acute GVHD By CCR5 Inhibition With Maraviroc 38 patients RIC- Flu/Bu PBSC graft MRD or MUD Maraviroc given d -2 to +30 Reshef R, et al. N Engl J Med. 2012;367(2):135-145.

Immunomodulatory Effects of Proteasome Inhibition With Bortezomib During Allogeneic HCT Selective depletion of proliferating alloreactive T-cells (NF-kB inhibition) Inhibition of Th1 cytokine production/differentiation Blocks activation of APC Preserves T reg function Sensitized tumor cells to killing by immune effector cells Direct antitumor activity against some malignancies

Phase I/II Study of Bortezomib + Tacrolimus and MTX for GVHD Prophylaxis of HLA-Mismatched Transplants Koreth J, et al. J Clin Oncol. 2012;30(26):3202-3208.

BMT CTN 1203: Study Outline 18-75y Malignant Diseases Matched donor RIC Tac/Cy/MMF Tac/MTX/ Maraviroc Tac/MTX/ Bortezomib Tac/MTX Control (CIBMTR)

Rationale For Use of Ixazomib Post Haplo-HCT Ixazomib (MLN9708) Orally-bioavailable, selective, second-generation proteasome inhibitor Shorter proteasome dissociation T1/2 than bortezomib Improved PK, PD, and anti-tumor activity over bortezomib Improved safety profile lower risk of peripheral neuropathy than bortezomib Once weekly fixed dosing

Multicenter Phase II, Double-Blind Placebo Controlled Trial of Maintenance Ixazomib After Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Multiple Myeloma BMTCTN 1302

NSH 1074 Ixazomib Maintenance Following Non-Myeloablative Haploidentical Transplantation Ixazomib weekly 3 weeks x 12 m

NSH 1074 A Phase II Trial of Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation Followed By Maintenance Therapy With the Novel Oral Proteasome Inhibitor, Ixazomib (MLN9708) in Patients With High-Risk Hematologic Malignancies Cy 14.5mg/ kg/day TBI 200cGy T cell replete PBSC (KIR selected) -7-6 -5-4 -3-2 -1 0 +5 +10 +20 +30 +40 +90 +180 +360 Busulfan Cy 110mg/mFludarabine 2 /day 14.5mg/ 30 mg/mkg/day 2 T Cy cell replete PBSC 50mg/ infusion kg/d Tacrolimus Ixazomib Ixazomib 4mg d 1,8, 15 q monthly x 12

High Risk of Relapse and Poor Survival Following Chemotherapy for FLT3 ITD Positive AML Bornhäuser M, et al. Blood. 2007;109(5):2264-2265.

Risk of Relapse Is Higher Following Allogeneic HCT for FLT3 ITD Positive Than Negative AML FLT3 ITD+ FLT3 ITD- Brunet S, et al. J Clin Oncol. 2012;30(7):735-741.

Clinical Trial of Sorafenib Maintenance Following Allogeneic Transplantation in FLT3 ITD Positive AML Dose escalation trial of sorafenib x 12 m starting d 40-120 post allotransplant 22 patients enrolled 400mg bid established as MTD No increase in GVHD 1 year PFS 85% (all patients) 95% (patients in CR) Chen YB, et al. Biol Blood Marrow Transplant. 2014;20(12):2042-2048.

Trial of Midostaurin Versus Placebo Post Allogeneic HCT in FLT3 ITD+ AML

Immunological Synapse/Checkpoint

Single-Dose Anti-CTLA4 Mab (Ipilimumab) For Relapse of Malignancy After Allogeneic HCT Bashey A, et al. Blood. 2009;113(7):1581-1588. before 6 weeks post

Phase I/Ib Clinical Trial of Anti-CTLA4 MAb Ipilimumab in Patients Who Relapse Post Allogeneic HCT Multicenter single-arm trial 3mg/kg or 10mg/kg q 3 weeks x 4 Maintenance dosing q 12 weeks up to 1 year 27 patients treated to date MTD not reached 10mg/kg used for phase 1b Immune adverse events in 4 patients - reversible 8 of 20 patients (40%) treated at 10 mg/kg demonstrated antitumor activity. Six had >PR. 1 chl PR, 1 MM PR 4 AML CR

Conclusions Allogeneic HCT is the most effective curative therapy for several hematologic malignancies In 2015 Use of Alternative Donors esp. Haploidentical Donors allows almost universal donor availability irrespective of ethnicity Allogeneic HCT is becoming safer TRM now <10% at 1 year ~15% at 2 years Relapse of malignancy remains a challenge Use of novel targeted and immune based therapies post transplant is promising

The Blood and Marrow Transplant Program at Northside Hospital