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Letters to the Editor
(95% CI: 10.7–36.3) for venetoclax monotherapy and 38.7% (95% CI: 25.5–53.9) for venetoclax + HMA/LDAC. There was significant heterogeneity among studies examining venetoclax + HMA/LDAC (Q=11.8; I2=66.2%; P=0.02).
The CR/CRi rate was 26.7% (95% CI: 17.6–38.3), 20.7% (95% CI: 10.7–36.3) and 32.8% (95% CI: 19.1- 50.3) for all studies combined, venetoclax monotherapy and venetoclax + HMA/LDAC, respectively. There was significant heterogeneity among studies examining vene- toclax + HMA/LDAC (Q=15.1; I2=73.5%; P=0.004).
The CR rate was 18.3% (95% CI: 11.3–28.4), 13.5% (95% CI: 2.6–47.4) and 19% (95% CI: 11.4–29.9) for all studies combined, venetoclax monotherapy and veneto- clax + HMA/LDAC, respectively. There was significant heterogeneity for studies examining venetoclax alone (Q=2.6, I2=61.6%, P=0.11).
Median OS reported in individual studies of all patients treated with venetoclax monotherapy and venetoclax + HMA/LDAC ranged between 1.8 to 7.8 months and 3.0 to 6.6 months, respectively. Among responding patients, the median OS in individual studies of all patients treated with venetoclax monotherapy and venetoclax + HMA/LDAC was 12.1 to 16.6 months and 4.8 to 12.1 months, respectively.6-8,10-12
In all studies combined, the ORR for patients with prior HMA exposure was 29% (95% CI: 19.7–40.4) (Figure 2D) and 25.9% (95% CI: 13.5–43.9) and 31.1% (95% CI: 19-46.6) for venetoclax monotherapy and vene- toclax + HMA/LDAC, respectively. Data on the compar- ative efficacy of venetoclax + HMA versus venetoclax + LDAC were not available.
Separate analyses of response rates to various treat- ment combinations were available for only 3 of the 5 studies reporting venetoclax + HMA or LDAC.5,6,11 The ORR ranged from 13-23%, 33-50%, and 0-47% for vene- toclax in combination with LDAC, azacitidine, and decitabine, respectively.5,6,11
We have previously reported ORR and CR rates for HMA monotherapy in R/R-AML of 30% and 11%, respectively.14 An ORR of 23% (18% CR) has been reported for LDAC monotherapy in R/R-AML.15 In our meta-analysis, patients treated with venetoclax + HMA/LDAC demonstrated an ORR of 38.7% and a CR rate of 19% suggesting a greater efficacy of the combina- tion treatment compared to HMA or LDAC monothera- py. Our results also suggest that prior exposure to HMA did not preclude a response to subsequent therapy with venetoclax-based therapies. Acknowledging the limita- tions of cross-study comparisons, our findings need to be verified in clinical trials directly comparing these treat- ment strategies.
Sensitivity analyses for ORR, CR/CRi and CR rate showed that exclusion of any one study did not change the overall effect size. The study by DiNardo et al. had the largest influence on the heterogeneity of the ORR, CR/CRi and CR rate.6 Removal of this study increased the ORR by 5.4% (from 38.7% to 44.1%) in the subgroup analysis of studies examining venetoclax + HMA/LDAC and led to a loss of heterogeneity (Q=4.7, I2= 36.6%, P=0.19).
Data on the mutational profile of patients were reported in five studies and the presence of TET2-, IDH1/2-, ASXL1-, and RUNX1-mutations were reported to be associated with higher response rates to treatment with venetoclax-based regimens.6-8,10,11 However, reporting of predictive biomarkers was inconsistent among the studies.
Our study has several limitations. The significant heterogeneity between studies in terms of the number of patients included in each arm and the reporting of results precluded a comparison of the response rates for the various venetoclax combination strategies in a formal meta-analysis. While response rates seemed higher for the combination of HMA with venetoclax compared to LDAC with venetoclax, our study does not support any formal conclusion and highlights the lack of evidence. Second, there were insufficient data to assess adverse events in our meta-analysis. Third, we were unable to determine whether specific mutations could serve as bio- markers to predict response to venetoclax. Additionally, we could not differentiate between primary refractory, early and late relapses as well as first or advanced relapses and the impact of prior stem cell transplantation receipt or HMA treatment duration. Finally, we were unable to assess the effect of venetoclax-based treatment on OS.
In conclusion, this systematic review and meta-analy- sis of venetoclax treatment in R/R-AML included seven studies with a total of 224 patients and demonstrated an ORR of 38.7% and 20.7% for patients treated with vene- toclax + HMA/LDAC and venetoclax monotherapy, respectively. Prior treatment with HMA did not preclude a response to subsequent venetoclax treatment. Additional studies testing venetoclax combination thera- pies in R/R-AML are ongoing and urgently needed.
Jan Philipp Bewersdorf,1 Smith Giri,2 Rong Wang,3,4 Robert T. Williams,5 Martin S. Tallman,6 Amer M. Zeidan,1,4 and Maximilian Stahl6
1Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT; 2Division of Hematology and Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL; 3Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT; 4Department of Chronic Disease Epidemiology, School of Public Health, Yale University, New Haven, CT; 5Rockefeller University,
6
New York, NY and Leukemia Service, Memorial Sloan Kettering
Cancer Center, New York, NY, USA
Correspondence: MAXIMILIAN STAHL - stahlm@mskcc.org
doi:10.3324/haematol.2019.242826
Funding: AMZ is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a National Cancer
Institute (NCI) Cancer Clinical Investigator Team Leadership Award (CCITLA). Research reported in this publication was supported by
the NCI of the National Institutes of Health under Award Number P30 CA016359. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. AMZ received research funding (institutional)
from Celgene, Acceleron, Abbvie, Otsuka, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, and ADC Therapeutics. AMZ had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene, Jazz, Ariad, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Seattle Genetics, BeyondSpring, Trovagene, Ionis, Epizyme, and Takeda. AMZ received travel support for meetings from Pfizer, Novartis, and Trovagene. MST has received research funding from Abbvie, Cellerant, Orsenix, ADC Therapeutics, and Biosight. MST has received honoraria for advisory board member- ship from Abbvie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, and Jazz Pharma. MST received patents and royalties from UpToDate. None of these relationships are related to the development of this manuscript.
All other authors report no relevant disclosures/competing interests.
haematologica | 2020; 105(11)