Ohio State's ASH Review 2017 - Blood and Marrow Transplantation
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Transcript of Ohio State's ASH Review 2017 - Blood and Marrow Transplantation
Ohio State’s 2017 ASH ReviewBlood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACPAssistant Professor of Internal MedicineBlood and Marrow Transplant Program
Why do we do Hematopoietic Stem Cell Transplantation (HCT)?• To deliver high dose of chemotherapy (Autologous transplant with stem cell rescue)• To “consolidate” remissions in hematological malignancies• To “reset” the immune system in autoimmune diseases
• To “install” a new immune system (GVL effect for hematological malignancies)• Comes at a cost (GVHD)• Conditioning regimen intensity
• To replace defective hematopoiesis (primary marrow failure, sickle cell, genetic diseases)• No need for graft against anything (or GVHD)
Why do we do Hematopoietic Stem Cell Transplantation (HCT)?• To deliver high dose of chemotherapy (Autologous transplant with stem cell rescue)• To “consolidate” remissions in hematological malignancies• To “reset” the immune system in autoimmune diseases
• To “install” a new immune system (GVL effect for hematological malignancies)• Comes at a cost (GVHD)• Conditioning regimen intensity
• To replace defective hematopoiesis (primary marrow failure, sickle cell, genetic diseases)• No need for graft against anything (or GVHD)
Treatment Principles of Autologous TransplantII.
Apheresis and
Storage
III.High-dose
therapy
IV.Infusion of the graft
“Transplant”
V.Supportive care until
engraftment
I.Mobilization
Sibling Unrelated Cord blood
Treatment Principles of Allogeneic TransplantII.
High-dose therapy +/-Radiation
III.Infusion of the graft
“Transplant”
V.Prevention of
GVHD/infections
IV.Supportive care until
engraftment
HLA matched siblingHaplo‐identical
I.Donor search (HLA typing)
Current Challenges in Hematopoietic Cell Transplantation (HCT)• Intensity/Toxicity of the conditioning regimen• Donor availability • Selection of suitable candidates for transplant
• Patient characteristics (age, functional status, co‐morbid conditions)• Disease characteristics (chemoresistance, sensitivity to GVL)• Timing of transplant (in the era of “novel” agents)
• Relapse after HCT (prevention, monitoring, treatment)• Infections after HCT (prevention, monitoring, treatment)• Graft vs Host Disease (prevention, monitoring, treatment)• Access and financial burden of transplant• Evolving landscape of complex cellular therapies (adoptive cellular therapies and CAR‐T cells)
Conditioning Regimen SelectionHigh‐Dose Chemotherapy with Autologous Hematopoietic Stem Cell Support for Relapsed or Refractory Primary CNS Lymphoma – a Prospective Multicentre Trial By the German Cooperative PCNSL Study Group a781
• Patients with relapsed PCNSL had a median OS of 2 months ‐ historically• 39 pts from German centers received salvage with rituximab, high dose cytarabine, thiotepa followed by ASCT with rituximab‐BCNU‐thiotepa
• 2‐year PFS and OS rates were 46.0% and 56.4% with TRM 10% and no increased mortality beyond first year
• ASCT 2‐year EFS/OS 76.8% and 88.9% in 27 pts in CR1 from a single center in Korea Seo, et al a3462
• Meta‐analysis of 181 pts from 7 trials of ASCT in CR1 2‐year PFS/OS 44% and 65% with better outcomes with TP‐based regimens Kerbauy, et al a2272
Kasenda, et al. a781 - Seo, et al. a3462, Kerbauy, et al. a2272
Timing of Transplant: Myeloma
Is autologous transplant still needed for myeloma in the era of novel agents?
Timing of transplantComparison of Autologous Hematopoietic Cell Transplant (autoHCT), Bortezomib, Lenalidomide (Len) and Dexamethasone (RVD) Consolidation with Len Maintenance (ACM), Tandem Autohct with Len Maintenance (TAM) and Autohct with Len Maintenance (AM) for up‐Front Treatment of Patients with Multiple Myeloma (MM): Primary Results from the Randomized Phase III Trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial) LBA‐1
• The primary results of the largest randomized US transplant trial in MM demonstrated comparable PFS and OS. The addition of RVD consolidation or a second auto‐HCT was not superior to a single auto HCT followed by Len maintenance in the upfront treatment of MM – at 38M;• PFS 57%, 56%, 52%• OS 86%, 82%, 83%
• Beyond first ASCT and lenalidomide maintenance the role of additional therapy for MM is uncertain
Stadtmauer et al. Abstract LBA-1
Timing of transplantIntensification Therapy with Bortezomib‐Melphalan‐Prednisone Versus Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial) a673
• PFS was 44 months in the VMP arm and was not yet reached in the HDM arm
• 3‐year estimates of PFS were 57.5% and 66%, respectively (HR=0.73; P=0.003).
• PFS benefit with HDM was retained across predefined subgroup
• No difference is OS demonstrated (yet)• ASCT should remain standard of care in myeloma
Cavo M et al. Abstract 673
Role of second transplantUpfront Single Versus Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial) a991
• 614 pts were randomly assigned to either VMP (n=199) or ASCT‐1 (n=208) or ASCT‐2 (n=207)
• the median PFS was 45 months in the ASCT‐1 arm and was not yet reached for patients in the ASCT‐2 arm
• 3‐year estimates of PFS were 60% and 73%, respectively (HR=0.66; 95% CI=0.45‐0.96; P=0.030)
• PFS benefit of ASCT in high‐risk group• ASCT‐2 should be considered in high‐risk myelomaCavo M et al. Abstract 991
Second ASCT
R2: Does a second transplant offers an additional benefit?
Patient characteristics –is there is an age‐limit?• EBMT analysis of 6046 patients from 270 centers 65y (1132 70y) who had allo‐HCT
• NRM 27% and 35% at 1 and 3y in G‐I and was 29% and 39% in G‐II Basak at al. a681
• Analysis of 72 patients 75y with myeloma from MDACC showed comparable outcomes to younger patients Bashir et al. a3453
• Analysis of 62 patients with median age of 71.3y with myeloma from Germany showed TRM of 0% with median OS > 5 years Brockhoff et al. a3461
• All patients should be initially considered for transplant regardless of age
Miklos et al. Abstract LBA-3
Renal impairment and ASCT in Myeloma‐ASH 2016• CIBMTR analysis: myeloma ptsundergoing ASCT: of 1240 had normal/mild, 185 pts had moderate and 67 pts had severe renal impairment. 35 pts were on dialysis prior to ASCT: No impact of RI on outcomes and 34/35 patients achieved dialysis independence Mahindra, et al. a994
•Medical University of Vienna: 195 pts with myeloma undergoing ASCT. No impact of RI on Antlanger, et al. a46421
Disease characteristicsDouble‐Hit and Double‐Expressor Lymphomas Are Not Associated with an Adverse Outcome after Allogeneic Stem Cell Transplantation a830
• Retrospective analysis of 103 pts with DH or DEL DLBCL DFCI/COH
• Archival tissue examined by FISH and IHC; myc ≥ 40% bcl‐2 ≥ 50%
• Neither DH or DEL status was associated with outcomes. Patients with refractory disease had worse outcomes still
• At least 30‐40% patients had extended survival• Early treatment failures were associated with poor outcomes (a513)
Herrera AF et al. Abstract 830, Costa et al. Abstract 513
Treatment of chronic GVHDMulticenter Open‐Label Phase 2 Study of Ibrutinib in Chronic Graft Versus Host Disease (cGVHD) after Failure of Corticosteroids LBA‐3
• 42 pts with cGVHD were treated with ibrutinib420 mg daily
• ORR 67%, 1/3 had CR• 79% responded at the time of first response assessment
• 71% of the 28 responders had a sustained cGVHD response of at least 5 months
• Well‐tolerated with rare serious AEs• Possibly practice changing for chronic GVHD
Miklos et al. Abstract LBA-3
0%
20%
40%
60%
80%
100%
SD PD
Respon
ders, %
Best cGVHD Response (N = 42)*
9
19
72
Slides courtesy of Dr Jaglowski
GVHD; re‐kindled warning!Checkpoint Blockade for Treatment of Relapsed Lymphoma Following Allogeneic Hematopoietic Cell Transplant: Use May be Complicated By Onset of Severe Acute Graft Versus Host Disease a1163
• Retrospective analysis of 27 pts (26 with classic HL) from 21 centers • ORR to anti‐PD1 was 79% (CR+PR) in 24 assessable pts (13 CRs)• 37% developed aGVHD and in 19% it was severe • 9/10 experienced liver aGVHD (4 stage IV, 1 stage III, 4 stage I)• 3/4 cases with stage IV liver aGVHD• Overall 52% (14/27) of the pts in this analysis developed new or worsening acute or chronic GVHD after PD1 blockade (10 aGVHD, 4 cGVHD)
• Cautious use of PD1 inhibitors after (and before) allo‐HCT is warranted!Haverkos et al. Abstract 1163
Prevention of Relapse after HCTRituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group a145
Le Gouill at al. a145
R‐DHAP: Rituximab 375mg/m2; aracytine 2g/m2 x2 IV 3 hours injection 12hours interval;dexamethasone 40mg d1‐4; Cisplatin 100mg/m2 d1 (or oxaliplatin or carboplatin)
R‐BEAM: Rituximab 500mg/m2 d‐8; BCNU 300mg/m2 d‐7; Etoposide 400mg/m2/d d‐6 to ‐3; aracytine 400mg/m2/d d‐6 to d‐3; melphalan 140mg/m2 d‐2
Slides courtesy of Prof. Le Gouill
Prevention of Relapse after HCTRituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group a145
Le Gouill at al. a145
RM after ASCT prolongs EFS, PFS and OS. Thus, 4 courses of R‐DHAP plus ASCT followed by RM maintenance (one infusion every 2 month for 3 years) is a new standard of care for young MCL patients Slides courtesy of Prof. Le Gouill
Complications of transplant
• CHIP is an age‐related phenomenon characterized by the presence of somatic mutations in peripheral blood
• Exome sequencing data in 7/10 TMN patients, mutations were also detectable in the pre‐ASCT sample. PPM1D, TP53 (2 pts), TET2 (2 pts) and PRPF8 (1 pt)
• In ASCT cohort of 401 pts, 30.2% had CHIP and 4% developed TMN
• CHIP predicted for 10y TMN (12.4% vs. 3.5%) and OS (31% vs. 61%) but not relapse
• CHIP predicts for worse outcomes after ASCT – results may have clinical implications
Clonal Hematopoiesis Associated with Adverse Outcomes Following Autologous Stem Cell Transplantation for Non‐Hodgkin Lymphoma a986
CAR‐T cells‐ASH 2016
CAR‐T cells
• 111 pts from 22 institutions with rel/ref aggressive lymphomas
• Received 2 x 106 anti‐CD 19 CAR‐T/kg after FluCy chemotherapy
• ORR 76%, CR 47%, 92% responses within 1m• Responses across all groups; 76% chemorefractory, 80% relapsed after ASCT
• PFS at 1/3 m were 92% and 56%• G≥3 AE were hematological• G≥3 CRS and encephalopathy 20% and 29%
Kte‐C19 (anti‐CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B‐Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA‐1 LBA‐6
HCT Take‐home messages‐ASH 2016• Autologous stem cell transplantation should be considered in all patients with myeloma; upfront and on progression
• Advanced age is no longer a contraindication for transplant
• Severe renal impairment is not a contraindication for autologous transplant in myeloma and patients may achieve dialysis independence
• Patients with high risk lymphomas (“double‐hit” or “double‐expressor”) should be referred early for transplant and/or participation in clinical trials
• Patients with primary CNS lymphoma should be considered for autologous transplant utilizing thiotepa based regimen
• Rituximab maintenance is the new standard of care in younger patients with mantle cell lymphoma after autologous transplant
• Ibrutinib is a safe and effective agent for cGVHD
• Checkpoint inhibitors (PD‐1 inhibitors) should be used with caution in patients who had, or are being considered for, allogeneic transplant
• CAR‐T cell therapy holds great promise however cytokine‐release syndrome remains a major concern
Appropriate referrals for Transplant• All patients with myeloma upon diagnosis and upon progression• All adult patients with acute leukemias• Patients with myelodysplastic syndrome• Patients with CP‐CML failing first line TKI or any advanced phase CML• Patients with MPD/MF• Patients with relapsed/refractory or high‐risk lymphomas (myc or “double hit”, mantle, peripheral T‐cell lymphomas)
• Patients with CTCL who are needing systemic treatment• Unexplained cytopenias• Relapsed germ‐cell tumors• All patients should be considered for transplant regardless of age!
Thank youQuestions?