RIC in Allogeneic Stem Cell Transplantation

Transcription

1 RIC in Allogeneic Stem Cell Transplantation Rainer Storb, MD Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine Seattle, WA

2 Disclosure Grant Support: NIH grants P01-CA078902, P01-CA018029, P30-CA015704, P01 HL122173; the Laura Landro Salomon Endowment Fund; and a prize awarded by the Josef Steiner Krebsstiftung Industry: No employment or leadership position; no advisory role; no stock ownership; no honoraria; no financing of scientific research; no expert testimony; no other financial relationships

3 Hiroshima 1945

4 High-Intensity Conditioning for Hematologic Malignancies CY / fractionated TBI, Gy BU / CY Others VP-16 / TBI Melphalan / TBI AraC / TBI Melphalan FLU / BU No better than CY / TBI or BU / CY

5 GVL Effect vs. Chronic Malnutrition from Radiation and H-2 Disparate Graft (GVHD?) CBA/H MICE given CBA151/1 leukemia cells followed by 950 rad TBI and splenic grafts Spleen Cell Donor Survival (days) Cause of Death Syngeneic 30 Leukemia H-2 disparate Secondary disease (no leukemia) Harwell Labs Late 50s Barnes and Loutit, Br J Haematol. 3: 241, 1957

6 GVL Effect in Human Patient 20 yr with AML: rad TBI plus marrow from 6 relatives A brother s marrow engrafted Severe secondary disease 20 mos. without leukemia Paris 1960s Mathé, et al., Br Med J 2: 1633, 1963

7 Antileukemic Effect of Acute GVHD Advanced AML + ALL Cy + high-dose TBI HLA-id Sib n=196 Syngeneic n=46 Years after Marrow Transplantation Seattle Late 70s Weiden et al., NEJM 300: 1068, 1979

8 ALL + AML-CR1; CML-CP IBMTR 1990 Horowitz et al., Blood 75: 555, 1990

9 Age Limitations of Myeloablative HCT At Diagnoses (SEERS) Median Ages (years) Recent Allogeneic HCT Recipients (FHCRC) Disease Related Donor Unrelated Donor 9 CML AML NHL MM CLL HD MDS Overall (n=1428) 35 (n=1277) Molina and Storb., Current Opinion Org Transpl 5: 366, 2000

10 Conditioning Regimens Required Contributions of GVT Effects Immunosuppression TBI 2Gy Nonmyeloablative Reduced Intensity Myeloablative F-TBI 2Gy FC FlagIda MF 140 TT,M-ATG MF 180 TT-C Bu8/F/ATG TBI/Cy F TT Bu16/Cy Intensity Aggressiveness of Malignancy

11 Minimal-Intensity Conditioning 2 Gy TBI G-PBMC FLU 30 mg/m 2 /d Chimerism Analyses HLA-matched Related Unrelated CSP or TAC MMF GVHD Prevention CSP or TAC MMF

12 Minimal-Intensity HCT Regimen Allows for: Purest determination of GVT effects apart from conditioning Best determination of GVHD not augmented by regimen-related toxicities Transplant in outpatient setting

13 Storb et al., J Clin Oncol 31: 1530, 2013 First 1,092 Patients with Advanced Heme Malignancies Median age (range) 56 (7 75) yrs Donor, # Related 611 Unrelated 481 Preceding high-dose HCT, # 435 (40%) Diagnosis % AML 26 MM 20 NHL 17 CLL 11 MDS 8 Others 18 % HCT-CI Follow-up, median (range) 5 ( ) yrs

14 Marrow in CLL

15 100 T Cells Percent Donor Cells (FISH Analysis) Granulocytes Marrow B Cells CLL Days After 2 Gy TBI and HLA-id Sib HCT McSweeney et al., Blood 97: 3390, 2001.

16 Ranges of Relapse Rates per Pt Year* Among 1,092 Patients Years Low (n=243) Standard (n=537) High (n=342) MPD CLL CR Waldenström NHL Any Low-grade and Mantle Cell; High-grade CR ALL CR1 MM CR CLL No CR CML CP1 MM No CR AML CR MDS RA/RARS NHL High-grade No CR AML No CR; evolved from MDS HL After failed auto MDS RAEB; CMML CML AP, BC ALL CR2; No CR HLA-Matched Related (n=611) and Unrelated (n=481) 5-yr Relapse Mortality 34.5% *per Kahl, et al., Blood 110: 2744, 2007 Storb et al., J Clin Oncol 31: 1530, 2013.

17 Acute GVHD (n=1,092*) % Acute GVHD *HLA-matched related (n=611) or unrelated (n=481) individuals Storb et al., J Clin Oncol 31: 1530, 2013

18 Non-Relapse Mortality (n=1,092) % NRM 24% Storb et al., J Clin Oncol 31: 1530, 2013

19 % 5-yr NRM: Effects of Comorbidity and GVHD GVHD CI 0-2 Related CI 3+ CI 0-2 Unrelated CI 3+ None Acute no chronic with chronic De novo chronic Overall Storb et al., J Clin Oncol 31: 1530, 2013

20 GVHD: Relapse, NRM, Overall Mortality* (n=1,092) GVHD Relapse/Prog. NRM Overall Mortality HR* P HR* P HR* P No Acute Acute < <.0001 Chronic after acute < De novo chronic.46 < < * Adjusted for relapse risks, comorbidity index scores, TAC vs. CSP, FLU (yes, no). Prior to chronic GVHD. Storb et al., J Clin Oncol 31: 1530, 2013

21 % Survival 60% 42% % Survival 50% 35% Years After Transplantation Years After Transplantation % Survival 30% 25% Years After Transplantation Storb et al., J Clin Oncol 31: 1530, 2013

22 CIBMTR: AML + MDS TRM Relapse NMA = nonmyeloablative conditioning RIC = reduced intensity conditioning 22 Luger et al., BMT advance online pub (2011). doi: /bmt

23 NMDP Study: URD HCT for AML, ALL, CLL, MDS Conditioning MA RIC NMA NRM % Yr Relapse % Survival % Pulsipher et al., Blood 114: 2606, 2009

24 GVHD Trials

25 Unrelated HCT Flu: 30 mg/m 2 on days -4, -3, -2 TBI: MMF: Single fraction (2 3 Gy) at 7 cgy/min 15 mg/kg p.o. tid Arm 1: Day 0 until day +30, then bid until day +150, taper to day Arm 2: Day 0 until day +30 then bid until day +40 (Arm 2) CSP: 5.0 mg/kg p.o. bid -3 until day +96, taper until day +150 Sirolimus: 2.0 mg p.o. q.d. start day -3 until day Taper until day +180 (target 3-12 ng/ml) Protocol 2448: Current

26 Advanced Heme Malignancies (n=112) 26 Protocol 2448

27 Advanced Heme Malignancies (n=112) Protocol 2448

28 One HLA Locus Mismatched HCT Triple Immunosuppresion with MMF/CSP/Sirolimus 28

29 Reduce Relapse Risk After HCT: Donor NK cell infusion Delay relapse until I.S. is D/C, e.g. TKI in Ph1+ ALL AC 220 in AML Before HCT Intensifying conditioning CAR-T cells in B-cell malignancies

30 Day-14 Chimerism, GVHD, Relapse % Acute GVHD HR Relapse % Donor Chimerism Day 14 T-Cells NK Cells T-Cells NK Cells Trend Test* P=.01 P=.38 P=.1 P=.0009 *Cox model. Chimerism time-dependent co-variate. Adjusted for URD vs. MRD, disease stage, previous HCT, HCT-CI. Baron et al., BBMT 15: 580, 2009.

31 Ph + ALL: FLU/2 Gy TBI Conditioning TKI for 1 Year after HCT Ram, et al., Haematologica 96: 1113, 2011

32 Advanced Heme Malignancies: FLU/Low-Dose TBI vs. Low-Dose TBI p = 0.59 p = 0.09 Kornblit, et al., BBMT 19: 1340, 2013

33 Advanced Heme Malignancies: FLU/Low-Dose TBI vs. Low-Dose TBI p = 0.09 Kornblit, et al., BBMT 19: 1340, 2013

34 Increase Tumor Kill without Adding Toxicity: Targeted Radio-Immunotherapy with Beta-Emitting Radionuclides Coupled to Antibody 34

35 Older Patients with Advanced NHL (n=40) 90 Y-Labeled Anti-CD20 mab/flu/2 Gy TBI 35 Gopal, et al., Blood 118: 1132, 2011

36 131 I-Labeled Anti-CD45 Antibody/FLU/2 Gy TBI Conditioning for Allografts in Advanced AML & MDS Mawad, et al., BBMT 20: 1363, 2014

37 Radio-immunotherapy (RIT) Alpha Versus Beta Particles Isotope t½ Energy Path length 131 I 8 days 0.7 MeV 0.7 mm 90 Y 2.7 days 2.3 MeV 5 mm 188 Re 17 hours 1.1 MeV 4.4 mm 213 Bi 46 minutes 8.4 MeV 0.08 mm 211 At 7.21 hours 5.9 MeV 0.06 mm 37

38 211 At-anti-CD45 as Conditioning in DLA-id HCT 200 cgy TBI Median number of tranfusions : 1 (range 1-2) (only for thrombocytopenia) Chen et al., Blood 119: 1130, 2012

39 RIT Using 211 At-Labeled Anti-CD45 mab Older patients: Advanced heme malignancies Conditioning: FLU/Low-dose TBI and RIT dose escalation Related or unrelated HCT

40 Are There Problems with Stem Cells from Older Donors?

41 Effect of Donor Age on Fitness of Hematopoietic Cells Controversial murine data Comparable responses of young and aging canine hematopoietic cells to supranormal stresses Concerns in humans Older stem cells less fit Quasi-monoclonal hematopoiesis in older individuals Long-lived hematopoietic cells ideal targets for mutagenic changes

42 Patients with Hematologic Malignancies Given HLA-Matched PBSC Grafts (n=1,541) Conditioning Related donor < 60 yrs Unrelated donor < 60 yrs Donor yrs Myeloablative (n = 1,174) Nonmyeloablative (n = 367) Rezvani, et al., BBMT 21:105, 2015

43 CD34 + Cell Dose 10 6 /kg Donors Young (< 60 yrs) 7.7 Old ( 60 yrs) 5.6 P <.0001 Rezvani, et al., BBMT 21:105, 2015

44 Neutrophil and Platelet Changes in Myeloablative (A,B) and Nonmyeloablative (C,D) Recipients Rezvani, et al., BBMT 21:105, 2015

45 Clonal Blood Disorders Not seen Donor-derived leukemias in young patients with young donors estimated to be 124 in 100,000 (BBMT, 17: 771, 2011) Rezvani, et al., BBMT 21:105, 2015

46 Acute and Chronic GVHD Among Myeloablative (A,B) and Nonmyeloablative (C,D) Recipients Rezvani, et al., BBMT 21:105, 2015

47 NRM Among Myeloablative (A) and Nonmyeloablative (B) Recipients Rezvani, et al., BBMT 21:105, 2015

48 Reduced Intensity Conditioning Depends largely on allogeneic GVT effects Allows treating older and medically infirm patients Stem cells from younger vs. older donors comparable Early results encouraging Catch 22: Patients referred after other therapies fail thereby acquiring comorbidities Two challenges: Reduce: Relapse risk NRM and morbidity associated with or preceded by GVHD

49 49 THANKS FHCRC Transplantation Teams Colleagues Storb Lab Transplantation Teams Physicians Nurses Physician Assistants Pharmacists Support Staff Patients Statisticians, Research Nurses and Data Staff Administrative Staff Colleagues at Collaborating Academic Centers

50 Fred Hutchinson Cancer Research Center Seattle Seattle Cancer Care Alliance Seattle Children s Hospital University of Washington Medical Center