To the editor,
Relapsed or refractory (R/R) acute myeloid leukemia (AML) is associated with a poor prognosis and limited treatment options [1]. The Bcl-2 inhibitor venetoclax (VEN), in combination with hypomethylating agent (HMA) or low-dose cytarabine, was approved by the FDA in 2020 for newly-diagnosed AML in adults 75 years or older, or in patients with comorbidities precluding intensive chemotherapy [2], while its role in R/R disease was not well defined yet. In this study, we provided an overview of the latest updates of VEN-based therapy for R/R AML from the 2022 American Society of Hematology (ASH) meeting.
Anzeige
VEN combined with epigenetic drugs for R/R AML
The combination of VEN and HMA in R/R AML were investigated by several studies from different countries, which showed overall response rates (ORR) of 44% [3], 52% [4], and 58.8% [5], respectively. Highlighting the regional difference using this combination for R/R AML. 1-year and 2-year overall survival (OS) was 49.6% (95% CI; 39.9-61.8%) and 39.0% (95% CI; 27.2-55.9%) [5], respectively.
ASTX727 is an oral agent that combines decitabine with the cytidine deaminase inhibitor cedazuridine. The combination of VEN with ASTX727 [6] achieved an ORR of 53%. With a median follow-up of 7 months, the median OS was not reached. It demonstrates that this combination is feasible with significant efficacy in patients with R/R AML.
Chidamide is a subtype-selective benzamide inhibitor of histone deacetylase. In one phase II study [7], the triple combination of VEN, azacitidine (AZA), and chidamide (VCA) achieved an ORR of 75%, and no grade III or IV non-hematologic adverse events (AE) was observed. It shows that VCA is promising with acceptable toxicity for patients with R/R AML.
Homoharringtonine (HHT), a natural alkaloid derived from the cephalotaxus, is a well-defined anti-AML agent. The triplet of VEN, HMA, and HHT (VAH) [8] had significantly higher rate of complete remission (CR)/CR with incomplete count recovery (CRi) (63.8% vs. 40.9%, P = 0.003), OS (no reach vs. 16.0 months, P = 0.023) and event-free survival (EFS) (7.1 vs. 2.3 months, P < 0.001) than VEN + HMA group. Subsequently, the data were updated [9] with a median follow-up of 14.7 months, the median OS was 22.1 months, and EFS was 14.3 months. The 1-year OS was 61.5%, and EFS was 51.0%.
Anzeige
In this series, the novel VCA and VAH regimes appear to have higher response rate, and the efficacy is worth further exploration.
VEN combined with chemotherapy drugs for R/R AML
Cladribine is an adenosine deaminase resistant analog of adenosine. After one cycle of VEN, cladribine plus low-dose Ara-C (CAV) [10] for R/R AML, the ORR was 90.5%, the estimated 1-year OS was 91.7%, and the EFS was 74.9%. It suggests that the CAV regimen is a very effective salvage strategy in R/R AML.
One phase I/II trial [11] evaluated the combination of VEN with high-dose Ara-C and mitoxantrone (HAM) in patients with R/R AML. The combination was well tolerated and led to CR/CRi of 92%, and 62.5% of evaluable patients were categorized as minimal residual disease (MRD) negative.
Desikan et al. [12] updated results of a phase IIb trial, which evaluated the efficacy of the combination of VEN, fludarabine, Ara-C, G-CSF (FLAG), and idarubicin in R/R AML. It had an ORR of 60% with a composite remission rate (CRc) of 53%. Six-month and 12-month OS was 69% and 60%, respectively. 71% of CRc patients attained a MRD negative remission and 68% of responding patients proceeded to transplant.
In this series, CAV and HAM regimens seem to have deeper remissions. The efficacy and durability of responses need to be further assessed.
VEN combined with antibodies or targeted drugs for R/R AML
Pivekimab sunirine (PVEK) can target CD123, which is expressed on the majority of AML blasts and leukemic stem cells. In a phase Ib/II study [13], the combination of VEN, AZA, and PVEK achieved an ORR of 51%, with a composite complete remission (CCR) rate of 31%. Compared to patients with prior VEN exposure, VEN-naïve patients had higher ORR (62% vs. 37%) and CCR (47% vs. 11%).
Pegcrisantastase (PegC) is a long-acting crisantastase that exhibits strong anti-leukemia activity through complete consumption of glutamine. An open-label phase Ib clinical trial [14] evaluated the combination of VEN with PegC in R/R AML. The ORR was 64%, with no serious asparaginase-related AE of interest observed. It reveals that VEN-PegC is a well-tolerated regimen.
In conclusion, the 2022 ASH annual meeting presented the new development of VEN-based therapy for R/R AML (Tables 1 and 2), including some novel and encouraging regimes, such as VCA, VAH, and HAM, etc. Further research is still needed to fully understand the optimal use of these agents.
Anzeige
Table 1
VEN combined with epigenetic drugs for R/R AML
Authors (reference) | Shahbaz [3] | Mohassel [4] | Weng [5] | Abuasab [6] | Zha [7] | Yu [8] |
|---|---|---|---|---|---|---|
Regimen | VEN + HMA | VEN + HMA | VEN + HMA | VEN + ASTX727 | VEN + AZA + Chidamide | VEN + AZA + HHT |
Study type | Pros | Retro | Retro | N/A | Phase II | Pros |
NCT number | N/A | N/A | N/A | N/A | N/A | N/A |
Study period | N/A | 2012–2022 | N/A | N/A | N/A | N/A |
Age range (years) | 20–67 | ≥ 18 | N/A | 46–92 | 35–64 | N/A |
Patients number | 44 | 25 | 136 | 37 | 29 | 231 |
Response rate | ORR 44%, CR/CRi 40% | ORR 52%, CR/CRi 36% | ORR 58.8%, CR/CRi 44.8% | ORR 53%, CR/CRi 46.7% | ORR 75%, CR/CRi 56.3% | CR/CRi 63.8% |
Grade ≥ 3 AEs | N/A | Anemia 80% | N/A | N/A | 0 | N/A |
Follow-up (months) | N/A | N/A | N/A | 7 | N/A | N/A |
Survival | N/A | Median OS 9.6 months, median RFS 10.1 months | 1- year OS 49.6%, 2-years OS 39.0% | Median OS not reached | N/A | Median OS not reached, median EFS 7.1 months |
Table 2
VEN combined with chemotherapy drugs, antibody drugs or targeted drugs for R/R AML
Authors (reference) | Li [10] | Röllig [11] | Desikan [12] | Daver [13] | Bollino [14] |
|---|---|---|---|---|---|
Regimen | VEN + Cladribine + Ara-C | VEN + HAM | VEN + FLAG-IDA | VEN + AZA + PVEK | VEN + PegC |
Study type | N/A | Phase-I/II | Phase IIb | Phase 1b/II | Phase Ib |
NCT number | NCT05190549 | NCT04330820 | N/A | NCT04086264 | NCT04666649 |
Study period | 2021–2022 | 2020–2022 | N/A | N/A | N/A |
Age range (years) | 16–68 | 40–70 | 18–68 | 25–82 | 24–76 |
Patients number | 21 | 12 | 33 | 71 | 11 |
Response rate | ORR 90.5%, CR/CRi 28.6% | CR/CRi 92% | ORR 60% | ORR 51% | ORR 64% |
Grade ≥ 3 AEs | N/A | 0 | N/A | Ferbrile neutropenia 24% | 0 |
Follow-up (months) | N/A | N/A | 15.8 | N/A | N/A |
Survival | Median OS and EFS not reached, estimated 1-year OS 91.7%, estimated 1-year EFS 74.9% | N/A | Median OS 27 months, median DOR not reached. Six-month OS 69%, 12-month OS 60% | N/A | N/A |
Acknowledgements
We are thankful to many specialists in the field whose seminal works are not cited due to space constraints. We would like to express my gratitude to all those who helped us during the writing of this review.
Declarations
Ethics approval and consent to participate
Not applicable.
Anzeige
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.