Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). ...Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
•In patients with RR-AML, venetoclax combination therapy resulted in responses in 31% of patients and a median OS of 6.1 months.•NPM1 mutations predicted higher response rates; adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 predicted worse OS.
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The role of allogeneic hematopoietic cell transplant (allo-HCT) as consolidation after initial venetoclax therapy and the efficacy of venetoclax salvage therapy for relapse after allo-HCT in patients ...with acute myeloid leukemia (AML) are unclear. We conducted a retrospective study of patients with AML or myelodysplastic syndrome (MDS) who received venetoclax either before or after allo-HCT at Memorial Sloan Kettering Cancer Center and Yale University from 11 August 2016 to 16 November 2020. Among 39 heavily pretreated patients who received venetoclax before allo-HCT, median OS from allo-HCT was not reached after a median follow up of 12.5 months resulting in a 12-month OS estimate of 79.0%. In 37 patients who had received venetoclax-based combinations as salvage therapy after allo-HCT, the overall response rate was 32% with a median OS of 4.7 months (12-month OS estimate: 43.4%). Four patients underwent a second allo-HCT following venetoclax-based salvage therapy suggesting it as a potential salvage treatment option.
Background: Venetoclax has shown promising activity when combined with hypomethylating agents (HMAs) and low-dose cytarabine (LDAC) with response rates in the range of 75% in untreated patients ≥65 ...years with acute myeloid leukemia (AML). DiNardo C, ASH 2015 Abstract 327 & Wei A, ASH 2016 Abstract 102. Given the favorable data in the first-line setting, we aimed to assess the efficacy of combining venetoclax with either HMA or LDAC in patients with relapsed or refractory (R/R) myeloid malignancies.
Methods: This is a retrospective, single-center review of all patients with a myeloid malignancy treated with venetoclax plus either azacitidine (AZA), decitabine (DEC), or LDAC. Patients treated between May 1, 2016 and June 7, 2017 were included in this analysis. After a 5-day ramp up period, a target dose of venetoclax 600 mg PO daily was used when combined with LDAC. Venetoclax was given continuously starting on cycle 1 day 1 and continued until progression or toxicity. Cytarabine was given 20 mg/m2 SC daily on days 1 - 10. Subsequent cycles were started at discretion of the treating physician, but typically began on day 29 to 36. When venetoclax was combined with HMA, the target venetoclax dose was 400 - 800 mg, after a 5-day ramp up period during cycle 1. AZA and DEC dosing regimens and schedules were consistent with standard of care. The dose of venetoclax was reduced by 75% and 50% in patients receiving a strong CYP3A4 inhibitors (i.e. voriconazole or posaconazole) and moderate CYP3A4 inhibitors (i.e. isavuconazole), respectively. Responses were graded using European Leukemia Net (ELN) response criteria. Overall response rate (ORR) was defined as rate of complete response (CR) + complete response with incomplete hematologic recovery (CRi) + partial remission (PR). Hematologic improvement (HI) was classified as continued improvement until next cycle of treatment in erythroid, platelet, or neutrophil response per IWG Criteria for myelodysplastic syndrome Cheson BD, Blood. 2006. Immunophenotypic minimal residual disease (MRD) was identified in bone marrow aspirates by multiparameter flow cytometry. Next generation sequencing was performed on bone marrow samples to identify characteristics of responders and non-responders.
Results: As of June 7, 2017, 24 patients have been treated with the combination of venetoclax and HMA (n=8) or venetoclax and LDAC (n=16). 21 patients were evaluable for response to cycle 1. (Tables 1 and 2) 6 out of 21 patients achieved PR or better on venetoclax regimens with ORR of 28.6% (95% CI 11.3-52.2%). (Table 3) 5 out of 21 patients (23.8%) experienced CR. No CRs were seen in 6 patients treated after prior allogeneic stem cell transplant (alloSCT). (Table 4)HI was observed in 8 out of 21 patients (38.1%). Patients who showed HI were more likely to have had no prior 7+3 compared to patients who did not show HI (87.5% vs. 23.1%, p=0.008). Other factors were not associated with HI. Median follow-up among survivors from start of treatment was 4.1 months (range 1.2- 13.4). 8 out of 21 patients died, and 3-month OS was 72% (95%CI 54-97%). Based on landmark analysis, 5 patients achieved HI by 42 days following treatment start. 2-month OS for patients who achieved HI by 42 days was 100%, compared with 60% among 13 patients who did not achieve HI by 42 days (p=0.057). (Figure 1) No CRs were seen in patients with FLT3 or RAS mutations, but a larger cohort may be necessary to further evaluate molecular predictors. There was no significant association between ELN Risk Group and response. Notably, CRs were seen even among ELN adverse risk patients, including one 50 year-old man with AML associated with inv(3), refractory to induction chemotherapy, high-dose cytarabine, investigational BET inhibitor, and salvage chemotherapy with mitoxantrone, etoposide, and cytarabine, who achieved MRD+ CR after 1 cycle of AZA + venetoclax and went on to alloSCT. One other patient with inv(3) did not respond after 2 cycles of LDAC + venetoclax.
Conclusions: Venetoclax in combination with HMA or LDAC shows activity in patients with R/R myeloid malignancies. Although data are limited by small numbers and short-term follow-up, there is a trend toward prolonged OS for patients who achieve early HI within 42 days of treatment initiation. Updated responses and survival estimates for all patients will be presented, including those evaluable after data cut-off.
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Goldberg:ADC Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Research Funding. Horvat:Agios: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Mauro:Bristol-Myers Squibb: Consultancy. Stein:Constellation Pharma: Research Funding; Pfizer: Consultancy, Other: Travel expenses; Seattle Genetics: Research Funding; GSK: Other: Advisory Board, Research Funding; Novartis: Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding.
The objective of this study was to analyze the validity of the stereomicroscopic evaluation of vitrified–warmed (V–W) porcine blastocysts. Unhatched blastocysts were obtained from Large-white gilts (
...n
=
10). Blastocysts (
n
=
156) were vitrified using the Open Pulled Straw technology. After warming, V–W blastocysts were cultured for 24
h (V24). Then, their developmental progression was morphologically assessed by stereomicroscopy and classified as: V24 viable re-expanded blastocysts; V24 viable hatched blastocysts or V24 degenerated. Blastocysts which re-expanded or hatched after warming were considered viable. Some fresh blastocysts were not vitrified and were evaluated after 24
h in culture (F24). By stereomicroscopic analysis all the fresh blastocysts were considered viable. Some F24, V24 re-expanded viable, V24 hatched viable and V24 degenerated blastocysts were processed for transmission electron microscopy (
n
=
13, 19, 9 and 9, respectively) or assessed by TUNEL for cell-death evaluation (
n
=
16, 21, 11 and 21, respectively). All V24 hatched blastocysts showed similar ultrastructure to fresh blastocysts. However, some V24 re-expanded blastocysts considered viable (6/19) revealed ultrastructural alterations. Degenerated V24 blastocysts showed ultrastructural disintegration. Hatched V24 blastocysts did not differ (
p
>
0.05) from F24 hatched blastocysts with regard to the ratio of dead cells (2.8
±
0.5%
versus 1.9
±
0.3%, respectively). However, V24 expanded blastocysts had higher (
p
<
0.01) cell death levels (4.3
±
3.4%) than those observed in the F24 expanded blastocysts (1.1
±
0.3%). The degenerated blastocysts showed the highest cell-death index (19.4
±
6.3%). In summary, V–W blastocyst hatching during
in vitro culture appears to coincide with good ultrastructure and low cell-death index, suggesting that the hatching rate assessed by stereomicroscopy is more appropriate than embryo re-expansion for an evaluation of V–W blastocyst quality.
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