Contributions
Abstract: S858
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:15 - 16:30
Location: Room A2
Background
Although the allogeneic graft versus leukemia (GVL) effect is operational in poor-risk AML, the relapse rate remains high. In order to exploit GVL more effectively, we explored the early initiation of epigenetic therapy after alloHSCT, interspersed with successive, low dosage donor lymphocyte infusion (DLI).
Aims
1. First, feasibility of epigenetic therapy, consisting of either panobinostat (PNB) alone or PNB combined with decitabine, was evaluated with toxicities and DLT as endpoints. 2. Following the feasibility phase, the study continued as phase II focusing on outcome after transplantation.
Methods
Pts were registered early after diagnosis. Patients qualifying for alloHSCT all received standard reduced intensity conditioning (Flu/TBI). GVHD prophylaxis consisted of post-transplant (PT) cyclophosphamide and a short course of ciclosporine. First, feasibility of epigenetic therapy, consisting of either panobinostat (PNB) alone (20 mg orally at days 1, 4, 8, 11 of a 4 wk-cycle) or PNB combined with decitabine (DCB, either 10 or 20 mg/m2 i.v. at days 1-3 of every 4 wk-cycle) was evaluated. After the feasibility phase, the study continued as phase II focusing on toxicities, GVHD, non-relapse mortality (NRM), relapse, residual disease (MRD), overall survival (OS), and relapse free survival (RFS) as from alloHCT.
Results
140 Pts were registered early after diagnosis and 110 actually proceeded to alloHSCT at a median number of 110 days (range: 56-205) after diagnosis. 67 pts were in hematological CR, 38 in CR without complete blood recovery, and 5 in PR. Median age was 59 years (18-71). Donors included 41 sib and 69 MUD. Combining PNB with DCB at a dose of 20 mg/m2 proved not feasible due to prolonged cytopenia, which was a dose limiting toxicity (DLT), but either PNB alone or the combination of PNB/DCB 10 mg/m2 did prove feasible. Altogether, 87 out of 110 transplanted pts received PT epigenetic therapy, including 39 PNB alone, 13 PNB/DCB (20 mg/m2), and 35 PNB/DCB (10 mg/m2). Pts started at a median time point of 33 days (range: 27-90) after transplantation. CTC grade 3 and 4 side-effects after the first cycle of PNB/DCB included nausea in 7 pts (5 grade 3; 2 grade 4)), febrile neutropenia in 1 pt and general fatigue in 1 pt. No CTC grade 3 or 4 opportunistic infections were observed after the first 2 cycles of PNB/DCB. Outcome of 110 transplanted pts showed OS at 12 and 24 months from transplantation of 71% (se 5%) and 49% (se 6%), respectively. 44 Pts died, including 17 due to NRM and 27 due to relapse. RFS at 12 and 24 months was 64% (se 5%) and 46% (se 6%), comparing favourably to historical matched HOVON-pts with RFS of 43% and 39% at 12 and 24 m, respectively. So far, DLI could be administered in 62 pts, including 38 pts receiving 2 DLI's, and 20 pts a third DLI. None of the pts developed grade 3 or 4 acute GVHD before DLI. Out of 62 recipients of DLI, severe chronic GVHD occurred in 15 (24%) pts.
Conclusion
Collectively, these results suggest that: 1. alloHSCT with GVHD-prophylaxis by cyclophosphamide PT allows for early initiation of epigenetic therapy and DLI, and 2. as compared to a matched historical HOVON-cohort, encouraging results with respect to relapse, RFS, and OS were observed. 3. Limited side effects were observed in recipients of PNB alone or the combination of PNB and DCB at a dose of 10 mg/m2; the incidence GVHD also appeared limited. Altogether these results might suggest enhanced GVL and, therefore, will be followed by an international prospective randomized study in (very) poor-risk AML patients.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): Acute Myeloid Leukemia, Allogeneic hematopoietic stem cell transplant, Epigenetic, HDAC inhibitor
Abstract: S858
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 16:15 - 16:30
Location: Room A2
Background
Although the allogeneic graft versus leukemia (GVL) effect is operational in poor-risk AML, the relapse rate remains high. In order to exploit GVL more effectively, we explored the early initiation of epigenetic therapy after alloHSCT, interspersed with successive, low dosage donor lymphocyte infusion (DLI).
Aims
1. First, feasibility of epigenetic therapy, consisting of either panobinostat (PNB) alone or PNB combined with decitabine, was evaluated with toxicities and DLT as endpoints. 2. Following the feasibility phase, the study continued as phase II focusing on outcome after transplantation.
Methods
Pts were registered early after diagnosis. Patients qualifying for alloHSCT all received standard reduced intensity conditioning (Flu/TBI). GVHD prophylaxis consisted of post-transplant (PT) cyclophosphamide and a short course of ciclosporine. First, feasibility of epigenetic therapy, consisting of either panobinostat (PNB) alone (20 mg orally at days 1, 4, 8, 11 of a 4 wk-cycle) or PNB combined with decitabine (DCB, either 10 or 20 mg/m2 i.v. at days 1-3 of every 4 wk-cycle) was evaluated. After the feasibility phase, the study continued as phase II focusing on toxicities, GVHD, non-relapse mortality (NRM), relapse, residual disease (MRD), overall survival (OS), and relapse free survival (RFS) as from alloHCT.
Results
140 Pts were registered early after diagnosis and 110 actually proceeded to alloHSCT at a median number of 110 days (range: 56-205) after diagnosis. 67 pts were in hematological CR, 38 in CR without complete blood recovery, and 5 in PR. Median age was 59 years (18-71). Donors included 41 sib and 69 MUD. Combining PNB with DCB at a dose of 20 mg/m2 proved not feasible due to prolonged cytopenia, which was a dose limiting toxicity (DLT), but either PNB alone or the combination of PNB/DCB 10 mg/m2 did prove feasible. Altogether, 87 out of 110 transplanted pts received PT epigenetic therapy, including 39 PNB alone, 13 PNB/DCB (20 mg/m2), and 35 PNB/DCB (10 mg/m2). Pts started at a median time point of 33 days (range: 27-90) after transplantation. CTC grade 3 and 4 side-effects after the first cycle of PNB/DCB included nausea in 7 pts (5 grade 3; 2 grade 4)), febrile neutropenia in 1 pt and general fatigue in 1 pt. No CTC grade 3 or 4 opportunistic infections were observed after the first 2 cycles of PNB/DCB. Outcome of 110 transplanted pts showed OS at 12 and 24 months from transplantation of 71% (se 5%) and 49% (se 6%), respectively. 44 Pts died, including 17 due to NRM and 27 due to relapse. RFS at 12 and 24 months was 64% (se 5%) and 46% (se 6%), comparing favourably to historical matched HOVON-pts with RFS of 43% and 39% at 12 and 24 m, respectively. So far, DLI could be administered in 62 pts, including 38 pts receiving 2 DLI's, and 20 pts a third DLI. None of the pts developed grade 3 or 4 acute GVHD before DLI. Out of 62 recipients of DLI, severe chronic GVHD occurred in 15 (24%) pts.
Conclusion
Collectively, these results suggest that: 1. alloHSCT with GVHD-prophylaxis by cyclophosphamide PT allows for early initiation of epigenetic therapy and DLI, and 2. as compared to a matched historical HOVON-cohort, encouraging results with respect to relapse, RFS, and OS were observed. 3. Limited side effects were observed in recipients of PNB alone or the combination of PNB and DCB at a dose of 10 mg/m2; the incidence GVHD also appeared limited. Altogether these results might suggest enhanced GVL and, therefore, will be followed by an international prospective randomized study in (very) poor-risk AML patients.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): Acute Myeloid Leukemia, Allogeneic hematopoietic stem cell transplant, Epigenetic, HDAC inhibitor