RIC in Allogeneic Stem Cell Transplantation Rainer Storb, MD Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine Seattle, WA
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
Hiroshima 1945
High-Intensity Conditioning for Hematologic Malignancies CY / fractionated TBI, 12 15 Gy BU / CY Others VP-16 / TBI Melphalan / TBI AraC / TBI Melphalan FLU / BU No better than CY / TBI or BU / CY
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 23-28 Secondary disease (no leukemia) Harwell Labs Late 50s Barnes and Loutit, Br J Haematol. 3: 241, 1957
GVL Effect in Human Patient 20 yr with AML: 2 400 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
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
ALL + AML-CR1; CML-CP IBMTR 1990 Horowitz et al., Blood 75: 555, 1990
Age Limitations of Myeloablative HCT At Diagnoses (SEERS) Median Ages (years) Recent Allogeneic HCT Recipients (FHCRC) Disease Related Donor Unrelated Donor 9 CML 67 40 36 AML 68 28 33 NHL 65 33 35 MM 70 45 45 CLL 71 51 46 HD 34 29 28 MDS 68 40 41 Overall 68 40 (n=1428) 35 (n=1277) Molina and Storb., Current Opinion Org Transpl 5: 366, 2000
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
Minimal-Intensity Conditioning 2 Gy TBI G-PBMC FLU 30 mg/m 2 /d Chimerism Analyses HLA-matched Related Unrelated -4-3 -2-1 0 28 35 40 56 84 100 180 CSP or TAC MMF GVHD Prevention CSP or TAC MMF
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
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 0 2 55 3 45 Follow-up, median (range) 5 (0.5 12.6) yrs
Marrow in CLL
100 T Cells Percent Donor Cells (FISH Analysis) 80 60 40 20 Granulocytes Marrow B Cells CLL 0 0 20 40 60 80 100 120 140 160 180 Days After 2 Gy TBI and HLA-id Sib HCT McSweeney et al., Blood 97: 3390, 2001.
Ranges of Relapse Rates per Pt Year* Among 1,092 Patients Years 1-2 3-4 Low (n=243).10 -.19.00 -.14 Standard (n=537).24 -.35.00 -.17 High (n=342).48-1.03.00 -.14 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.
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
Non-Relapse Mortality (n=1,092) % NRM 24% Storb et al., J Clin Oncol 31: 1530, 2013
% 5-yr NRM: Effects of Comorbidity and GVHD GVHD CI 0-2 Related CI 3+ CI 0-2 Unrelated CI 3+ None 2.7 6.1 2.5 4.2 Acute no chronic 5.3 7.8 8.1 12.2 with chronic 4.6 12 6.4 19 11.6 23.5 13.3 31.8 De novo chronic 2.1 4.8 3.8 6.3 Overall 14.7 25.1 26 36 Storb et al., J Clin Oncol 31: 1530, 2013
GVHD: Relapse, NRM, Overall Mortality* (n=1,092) GVHD Relapse/Prog. NRM Overall Mortality HR* P HR* P HR* P No 1.0 1.0 1.0 Acute 2.92.48 2.22.001 1.45.002 Acute 3-4.63.06 13.8 <.0001 3.58 <.0001 Chronic after acute.55.0002 4.96 <.0001 1.3.03 De novo chronic.46 <.0001 3.56 <.0001.97.84 * 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
% 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
CIBMTR: AML + MDS TRM Relapse NMA = nonmyeloablative conditioning RIC = reduced intensity conditioning 22 Luger et al., BMT advance online pub (2011). doi: 10.1038/bmt.2011.69
NMDP Study: URD HCT for AML, ALL, CLL, MDS Conditioning MA RIC NMA NRM % 42 34 34 3-Yr Relapse % 23 37 37 Survival % 35 32 32 23 Pulsipher et al., Blood 114: 2606, 2009
GVHD Trials
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 +180. 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 +150. Taper until day +180 (target 3-12 ng/ml) Protocol 2448: Current
Advanced Heme Malignancies (n=112) 26 Protocol 2448
Advanced Heme Malignancies (n=112) Protocol 2448
One HLA Locus Mismatched HCT Triple Immunosuppresion with MMF/CSP/Sirolimus 28
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
Day-14 Chimerism, GVHD, Relapse % Acute GVHD HR Relapse % Donor Chimerism Day 14 T-Cells NK Cells T-Cells NK Cells 0 50 47 47 1.0 1.0 51 75 52 57.35.29 76 90 74 58.48.29 91 100 69 64.50.20 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.
Ph + ALL: FLU/2 Gy TBI Conditioning TKI for 1 Year after HCT Ram, et al., Haematologica 96: 1113, 2011
Advanced Heme Malignancies: FLU/Low-Dose TBI vs. Low-Dose TBI p = 0.59 p = 0.09 Kornblit, et al., BBMT 19: 1340, 2013
Advanced Heme Malignancies: FLU/Low-Dose TBI vs. Low-Dose TBI p = 0.09 Kornblit, et al., BBMT 19: 1340, 2013
Increase Tumor Kill without Adding Toxicity: Targeted Radio-Immunotherapy with Beta-Emitting Radionuclides Coupled to Antibody 34
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
131 I-Labeled Anti-CD45 Antibody/FLU/2 Gy TBI Conditioning for Allografts in Advanced AML & MDS Mawad, et al., BBMT 20: 1363, 2014
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
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
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
Are There Problems with Stem Cells from Older Donors?
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
Patients with Hematologic Malignancies Given HLA-Matched PBSC Grafts (n=1,541) Conditioning Related donor < 60 yrs Unrelated donor < 60 yrs Donor 60 82 yrs Myeloablative (n = 1,174) Nonmyeloablative (n = 367) 545 569 60 104 198 65 Rezvani, et al., BBMT 21:105, 2015
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
Neutrophil and Platelet Changes in Myeloablative (A,B) and Nonmyeloablative (C,D) Recipients Rezvani, et al., BBMT 21:105, 2015
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
Acute and Chronic GVHD Among Myeloablative (A,B) and Nonmyeloablative (C,D) Recipients Rezvani, et al., BBMT 21:105, 2015
NRM Among Myeloablative (A) and Nonmyeloablative (B) Recipients Rezvani, et al., BBMT 21:105, 2015
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 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
Fred Hutchinson Cancer Research Center Seattle Seattle Cancer Care Alliance Seattle Children s Hospital University of Washington Medical Center