Original Study A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia Aliihsan Gemici, 1 Fahir Ozkalemkas, 2 Mehmet Hilmi Dogu, 3 Atakan Tekinalp, 4 Inci Alacacioglu, 5 Tekin Guney, 6 Idris Ince, 7 Ayfer Geduk, 8 Gulsum Akgun Cagliyan, 9 Senem Maral, 10 Istemi Serin, 11 Eren Gunduz, 12 Volkan Karakus, 13 Huseyin Saffet Bekoz, 1 Rafet Eren, 14 Ibrahim Ethem Pinar, 2 Ahmet Kursad Gunes, 6 Fatma Deniz Sargın, 1 Omur Gokmen Sevindik 1 Abstract Venetoclax is a selective B-cell lymphoma 2 (BCL2) inhibitor, which is approved to treat elderly patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). A total of 60 patients with a median age of 67 years from different centers were included in the final analysis. Our real-life data support the use of venetoclax in patients with both newly diagnosed and relapsed high-risk MDS and AML. Introduction: Venetoclax is a selective B-cell lymphoma 2 (BCL2) inhibitor, which is approved to treat elderly patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in combination with either low-dose cytarabine (ARA-C) or hypomethylating agents. We aimed to collect and share data among the efficacy and safety of venetoclax both as a monotherapy or in combination with other drugs used to treat high-risk MDS or AML. Materials and Methods: A total of 60 patients with a median age of 67 (30-83) years from 14 different centers were included in the final analysis. Thirty (50%) of the patients were women; 6 (10%) of the 60 patients were diagnosed with high-risk MDS and the remaining were diagnosed with AML. Results: The best objective response rate (complete remission [CR], complete remission with incomplete hematological recover y (CRi), mor phological leukemia- free state [MLFS], partial response [PR]) was 35% in the entire cohort. Best responses achieved during venetoclax per patient number were as follows: 7 CR, 1 CRi, 8 MLFS, 5 PR, and stable disease. Median overall survival achieved with venetoclax was 5 months in patients who relapsed and not achieved in patients who were initially treated with venetoclax. Nearly all patients (86.7%) had experienced a grade 2 or more hematologic toxicity. Some 36.7% of these patients had received granulocyte colony stimulating factor (GCSF) support. Infection, mainly pneumonia (26.7%), was the leading nonhematologic toxicity, and fatigue, diarrhea, and skin reactions were the others reported. Conclusion: 1 Department of Hematology, Medipol University, Istanbul, Turkey 2 Department of Hematology, Uluda ̆g University, Bursa, Turkey 3 Department of Hematology, Istinye University, Istanbul, Turkey 4 Department of Hematology, Necmettin Erbakan University, Konya, Turkey 5 Department of Hematology, Dokuz Eylul University, Izmir, Turkey 6 Department of Hematology, University of Medical Sciences, Ankara City Hospital, Ankara, Turkey 7 Division of Hematology, Dr. Ersin Arslan Training and Research Hospital, Gaziantep, Turkey 8 Department of Hematology, Kocaeli University, Kocaeli, Turkey 9 Department of Hematology, Pamukkale University, Denizli, Turkey 10 Division of Hematology, Diskapi Training and Research Hospital, Ankara, Turkey 11 Division of Hematology, Istanbul Training and Research Hospital, Istanbul, Turkey 12 Department of Hematology, Osman Gazi University, Eskisehir, Turkey 13 Department of Hematology, Alaaddin Keykubat University, Alanya, Turkey 14 Division of Hematology, Bozyaka Training and Research Hospital, Izmir, Turkey Submitted: Jan 15, 2021; Revised: Apr 5, 2021; Accepted: Apr 6, 2021; Epub: 20 April 2021 Address for (AML) correspondence: Aliihsan Gemici, MD, Department of Hematology, Medipol University, ̇Istanbul, Turkey. E-mail contact: inci.alacaciogl@deu.edu.tr e686 Clinical Lymphoma, Myeloma and Leukemia 2021 2152-2650/$ - see front matter © 2021 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2021.04.004 http://crossmark.crossref.org/dialog/?doi=10.1016/j.clml.2021.04.004&domain=pdf mailto:inci.alacaciogl@deu.edu.tr https://doi.org/10.1016/j.clml.2021.04.004 Aliihsan Gemici et al Our real-life data support the use of venetoclax in patients with both newly diagnosed and relapsed high-risk MDS and AML. Clinical Lymphoma, Myeloma and Leukemia, Vol. 21, No.xxx, e686–e692 © 2021 Elsevier Inc. All rights reserved. Keywords: Bcl2, Inhibitor, Venetoclax, Acute myeloid leukemia, Real life Introduction Acute myeloid leukemia and high-risk myelodysplastic syndrome (MDS) are related to a poor survival outcome, even in the era of novel agents. 1 The standard curative treatment of AML/high-risk MDS consists of intensive chemotherapy aimed at achieving complete remis- sion (CR) followed by consolidation with additional chemother- apy or allogeneic hematopoietic stem-cell transplantation (HSCT) to prevent relapse. 2 Regarding high-risk MDS, the outcome and treatment choices are comparable with de novo AML. 3 Unfortu- nately, intensive chemotherapy is not a viable option for many older patients with considerable comorbidities, baseline organ dysfunc- tion, or poor performance status, in whom the risk of complications and treatment-related mortality is unacceptably high. 4 In addition, older patients have a higher frequency of adverse-risk features, such as secondary AML, complex karyotype and TP53 mutation, which are associated with decreased responses to cytarabine-based intensive chemotherapy approaches. 5 , 6 Therefore these elderly patients with AML/high-risk MDS are routinely treated with noncurative, low- intensity chemotherapy approaches, aimed at controlling the disease and maintaining an acceptable quality of life for an extended period. Low-intensity treatments for AML have historically included low- dose cytarabine (LDAC) or hypomethylating agents (HMA) azaci- tidine or decitabine, which prolong survival when compared with best supportive care, but prognosis remains poor, with an expected survival of less than 12 months. 7-9 Besides relatively poor outcomes achieved after frontline therapy, the treatment of relapsed/refractory AML/high-risk MDS is also challenging with devastating short survival outcomes. 10 Venetoclax is a BH3 mimetic and small molecule inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL2). Preclinical studies have demonstrated that AML cells, especially leukemic stem cells, are dependent on BCL2 for survival, and inhibition by veneto- clax can lead to rapid initiation of apoptotic AML cell death. 11 , 12 Based on this rationale, venetoclax was first evaluated in relapsed or refractory AML showing single-agent efficacy with an overall response rate (ORR) of 19% and a good safety profile. 13 Despite modest results as a single agent in the relapsed/refractory setting, clear synergy with venetoclax and both HMAs and cytarabine was identified preclinically, leading to the multicenter phase I/II clinical trials of venetoclax in combination with either LDAC or HMA for patients with newly diagnosed untreated AML ineligible for inten- sive chemotherapy. 13 , 14 In a phase II trial, venetoclax monotherapy was investigated for the treatment of AML in the relapsed/refractory and frontline settings and produced a modest response, with an ORR of 19%. 13 Our study aims to document the real-life data among the efficacy and safety of venetoclax in a previously treated or treatment naive AML/high-risk MDS patient cohort. Material and Methods Patient Population This study was approved by the local ethical committee of Istan- bul Medipol University, with an approval number of 1009 and date of 11/27/2019. Patients who were diagnosed as AML/high-risk MDS were included in the study if they were older than 18 years of age and received venetoclax as a single agent or in combination with other therapeutic agents. We collected data regarding patient demograph- ics, clinical characteristics, the number and types of prior thera- pies, cytogenetics and leukemia mutation profile, and data regarding outcome and safety from 14 different centers throughout Turkey, retrospectively, starting from January 1, 2019 to November 1, 2020. Disease-related risk stratification was based on recommendation of European Leukemia Net (ELN). 2 Adverse events were recorded according to the upmost CTCAE v5.0. 15 Statistical Analysis Patient characteristics were summarized by median (range) values for continuous variables and frequency (percentage) for categori- cal variables. Logistic regression was used to assess the odds ratio (OR) of certain risk factors on the response achieved by venetoclax. The Kaplan-Meier method was used to plot survival curves. Overall survival (OS) was calculated from the date of initiation of venetoclax treatment to the date of last follow-up or death from any cause. Results A total of 60 patients with a median age of 67 (30-83) years from 14 different centers were included in the final analysis. Thirty (50%) of the patients were women; 6 (10%) of the 60 patients were diagnosed with high-risk MDS and the remaining were diagnosed with AML. Regarding all patients who were diagnosed with AML, 19 (35.2%) were diagnosed with de novo AML, and the remaining were diagnosed with secondary AML according to the biopsy findings, which indicated the presence of myelodysplasia-related changes and the presence of a prior history of MDS. All patients who were diagnosed with MDS were harboring a complex karyotype with at least 4 different clonal abnormalities. Regarding patients who were diagnosed with AML, 10 (18.5%) patients had a high-risk disease, 4 (7.4%) had a favorable disease, and the remaining (40, 74.1%) had intermediate-risk disease according to ELN classification of AML. Six patients with AML received venetoclax as a frontline therapy, both combined with azacitidine/decitabine or subcutaneous (sc) ARA-C. Three out of these 6 patients managed to achieve a full count recovery and a CR just in the first cycle of therapy. They have managed to preserve their remission status until the data cutoff. Two Clinical Lymphoma, Myeloma and Leukemia 2021 e687 A Real Life Turkish Experience of Venetoclax Figure 1 Overall survival according to the line of therapy in which venetoclax was used. e688 patients were able to achieve a morphological leukemia free-state (MLFS), and one patient progressed on frontline decitabine and venetoclax. One of the patients who received azacitidine/venetoclax as an initial therapy also harbored FLT3-ITD, NPM1, DNMT3A , and TET2 mutations in the next-generation sequencing analysis at the time of diagnosis, and this particular patient was in remission for 15 months at the data cutoff. The remaining 54 patients received venetoclax as a salvage option, with a median 2 (1-3) prior lines of therapy. Eight (13.3%) patients received an allogeneic HSCT (6 of them received as a consolidation after the first-induction therapy and 2 of them received after relapse) before using venetoclax. Regarding all, 10 patients received veneto- clax as monotherapy, only 4 patients received venetoclax in combi- nation with sc ARA-C, and the remaining received venetoclax in combination with HMAs (36 with azacitidine, 10 with decitabine). The best ORR (CR, CRi, MLFS, PR) was 35% in the entire cohort. Best responses achieved during venetoclax per patient number were as follows: 7 CR, 1 CRi, 8 MLFS, 5 PR, and stable disease. Out of 6 patients who received venetoclax as a frontline treatment approach, 4 were able to achieve a CR (50%), 1 was able to achieve a CRi (16.7%), 1 was able to achieve an MLFS (16.7%), and the remaining 1 had a progressive disease ( Table 1 ). The only significant predictor of a better response than stable disease and a significantly longer OS was the line of the therapy in which venetoclax was used. Patients who received venetoclax as a Clinical Lymphoma, Myeloma and Leukemia 2021 frontline therapy had a better response rate (OR, 11.88; 95% confi- dence interval [CI], 1.28-109.89; P = .029), which was defined as a response better than stable disease, and a significantly longer OS (hazard ratio [HR], 0.17; 95% CI, 0.03-0.96; P = .039) when compared with others. Patients who have received venetoclax as a single-agent approach had a significantly worse OS (HR, 2.40; 95% CI, 1.00-5.77; P = .048) when compared with patients who received venetoclax in combination with either HMAs or sc ARA-C ( Table 2 ). Median OS achieved with venetoclax was 5 months in patients who relapsed and not achieved in patients who were initially treated with venetoclax ( Figure 1 ). Patients who were able to achieve a response better than stable disease had a significantly longer OS when compared with nonresponders (not achieved (NA) vs. 5 months, P = .003) ( Figure 2 ). Nearly all patients (86.7%) had experienced a grade 2 or more hematologic toxicity. Some 36.7% of these patients received GCSF support. Infection, mainly pneumonia (26.7%), was the leading nonhema- tologic toxicity, and fatigue, diarrhea, and skin reactions were the others reported. Discussion Our real-life experience proved venetoclax as a viable treatment option for AML/high-risk MDS with a manageable toxicity profile. Aliihsan Gemici et al Table 1 Patient Demographics and Treatment Outcomes All Patients ( n = 60) Patients Diagnosed with AML ( n = 54) Patients Diagnosed with High-Risk MDS ( n = 6) Median age 67 (30-83) 67.5 (30-83) 64.5 (46-82) Sex (n, %) Female 30, 50% 27, 50% 3, 50% Male 30, 50% 27, 50% 3, 50% AML type (n, %) De novo AML - 19, 35.2% - Secondary AML - 35, 64.8% - Cytogenetic/molecular risk Favorable (n, %) - 4, 7.4% - Intermediate - 40, 74.1% - Adverse - 10, 18.5% - Unknown R-IPSS (n, %) Intermediate - - 4, 66.6% High - - 1, 16.7% Very high - - 1, 16.7% Extramedullary disease (n, %) Yes 4, 6.7% 4, 7.4% 0, 0% No 56, 93.3% 50, 92. 6% 6, 100% Prior allogeneic HCT (n, %) Yes 8, 13.3% 7, 13% 1, 16.7% No 52, 86.7% 47, 87% 5, 83.3% Prior exposure to HMAs (n, %) Yes 22, 36.7% 17, 31.5% 5, 83.3% No 38, 63.3% 37, 68.5% 1, 16.7% Median number of prior lines of therapy 2 (1-3) 2 (0-3) 1 (1-2) Accompanying therapy to venetoclax (n, %) Single agent 10, 16.7% 9, 16.7% 1, 16.7% Venetoclax + azacitidine 36, 60% 33, 61.1% 3, 50% Venetoclax + decitabine 10, 16.7% 9, 16.7% 1, 16.7% Venetoclax + low-dose sc ARA-C 4, 6.6% 3, 5.5% 1, 16.7% Best response achieved (n, %) CR 7, 11.7% 7, 13% - CRi 1, 1.7% 1, 1.9% - MLFS 8, 13.3% 8, 14.8% - PR 5, 8.3% 4, 7.4% 1, 16.7% SD 17, 28.3% 14, 25.9% 3, 50% Best response achieved in patients who received venetoclax as a part of frontline therapy (n%) CR 3, 50% - - CRi 1, 16.7% - - MLFS 1, 16.7% - - Median duration of therapy (mos) 3 (1-11) 3 (1-11) 2 (1-6) Abbreviations: AML = acute myeloid leukemia; CR = complete remission; CRi = complete remission with incomplete hematological recovery; HCT = hematopoietic cell transplantation; HMAs = hypomethylating agents; MDS = myelodysplastic syndrome; MLFS = morphological leukemia-free state; PR = partial response; R-IPSS = revised international prognostic scoring system; sc ARA-C = subcutaneous cytarabine; SD = stable disease. Clinical Lymphoma, Myeloma and Leukemia 2021 e689 A Real Life Turkish Experience of Venetoclax Table 2 Predictors of a Better Response than Stable Disease and Overall Survival Best Response Better than Stable Disease (OR, 95% CI, P ) Overall Survival (HR, 95% CI, P ) Age ( < 65 vs. ≥ 65 years) 1.90 (0.63-5.73, .254) 0.72 (0.34-1.54, .402) Sex 2.10 (0.71-6.22, .179) 1.09 (0.52-2.31, .813) Male vs. female Prior allogeneic HCT 0.34 (0.04-3.12, .340) 0.59 (0.18-1.97, .393) Yes No Prior exposure to HMAs 0.93 (0.32-2.71, .891) 1.11 (0.52-2.36, .778) Yes No Median number of prior lines of therapy (1 vs. > 1) 11.88 (1.28-109.89, .029 a ) 0.17 (0.03-0.96, .039) a Accompanying therapy to venetoclax 0.41 (0.08-2.13, .287) 2.40 (1.00-5.77, .048) a Single agent vs. combination with HMA or sc ARA-C AML classification b 1.11 (0.34-3.69, .857) 0.61 (0.28-1.38, .236) De novo vs. secondary Abbreviations: AML = acute myeloid leukemia; CI = confidence interval; HCT = hematopoietic cell transplantation; HMAs = hypomethylating agents; HR = hazard ratio; OR = odds ratio; sc ARA- C = subcutaneous cytarabine. a P < .05. b Analysis was carried out on patients with AML only. Figure 2 Overall survival according to the response status. e690 Clinical Lymphoma, Myeloma and Leukemia 2021 Aliihsan Gemici et al • • • • Best outcome was achieved in patients who received venetoclax with either azacitidine/decitabine or sc ARA-C in newly diagnosed AML/high-risk MDS. With cumulative data regarding the efficacy and safety of this combination approach will possibly identify this combo as a standard of care in the treatment of newly diagnosed de novo AML/high-risk MDS. 16 Despite this appealing survival benefit in previously untreated patients, the OS was limited to 5 months regarding the patients who have received venetoclax as a salvage option. Considering the median age of the patients who were included in the current study, allogeneic HSCT was applied to a limited number of patients. The high frequency of patients who received venetoclax as a salvage option and as a single agent after a relapsed/refractory disease and a limited number of patients who were able to proceed with an allogeneic HSCT should be the possible explanation of the relatively short OS. In the era of novel agents, there is a constant increase in the number of available options to treat patients with AML/high-risk MDS. One of these options was venetoclax, which was first showed as a promising activity against chronic lymphocytic leukemia. This allowed it to be tested among other hematologic malignancies. First reports as a single agent demonstrated a potential role also in the treatment of AML/high-risk MDS. Efficacy of venetoclax as a single-agent therapy was first demon- strated in 2 small case series. In a single-arm phase II study evaluating 800-mg daily venetoclax in patients with high-risk relapsed/refractory AML or who were unfit for intensive chemother- apy, overall response rate was calculated as 19%; with an additional 19% of patients who demonstrated antileukemic activity not meeting international working group (IWG) criteria (partial bone marrow response and incomplete hematologic recovery). 13 Similarly, in a very small case series of 7 patients with secondary AML who were not eligible for intensive chemotherapy and were refractory to HMA treatment, 2 patients were reported to achieve a CR with venetoclax monotherapy that was durable with a progression-free survival of 505 days and 352 days. 17 Even though it was associated with a substantial response as a single-agent option, the duration of these responses were not appealing. That is why venetoclax was combined with some other agents and tested among AML/high-risk MDS in following trials. In a multicenter study, 23 patients with AML who were refrac- tory to HMA treatment or relapsed after HMA therapy were treated with a combination of venetoclax and HMA. Forty-three percent achieved a CR or CRi in this patient cohort, whereas OS was 74% at 6 months. 18 Similar results were seen in 33 patients with relapsed and refractory (r/r) AML treated with HMA plus venetoclax outside a clinical trial. The overall response rate here was 64% [18]. Thus combination therapy consisting of HMA and venetoclax is promis- ing in patients with r/r AML. Our study has demonstrated a reason- able response rate of 62.5% in patients who have received a median of 2 prior lines of therapy both as a single agent or in combination with HMAs. None of our patients received venetoclax in combina- tion with intensive chemotherapy. The beneficial effect of venetoclax is more pronounced in patients who are treatment naive. A very recent randomized phase 3 trial, VIALE-A, by DiNardo et al., 19 has included 431 patients, in which 286 were treated with the combination of azacitidine and venetoclax and the remaining 145 received azacitidine combined with placebo. At a median follow-up of 20.5 months, the median OS was 14.7 months in the azacitidine–venetoclax group and 9.6 months in the control group (HR for death, 0.66; 95% CI, 0.52-0.85; P < .001). Also, the azacitidine–venetoclax group was able to achieve a signif- icantly higher complete response when compared with azacitidine– placebo (36.7% vs. 17.9%; P < .001). 19 Comparably, all of our patients who received venetoclax with azacitidine/decitabine or sc ARA-C as a frontline therapy were able to achieve a CR and were able to sustain their responses at a data cutoff of 10 months. Main safety concerns were hematologic with a leading incidence of neutropenia in the trials incorporating venetoclax for the treat- ment of AML. Accordingly, we have observed a grade 3 or more neutropenia in 68.8% of patients included in our study. There is a need for GCSF support in nearly half of these patients experi- encing grade 3 or more neutropenia. However, this high incidence of neutropenia was not translated into a febrile neutropenic episode. Other nonhematologic toxicities were listed as fatigue, diarrhea, and skin reactions. The retrospective nature and unavailable detailed mutational analysis regarding all patients should represent as a potential limita- tion to our study. As venetoclax was not approved in Turkey, and a large amount of patients have failed with the prior administration of HMAs and/or chemotherapy, they have received venetoclax as a single agent at the discretion of the physician. In those patients who received venetoclax as a single agent in the relapsed refractory setting, the response rates were low, and the OS was significantly short. Also, to our knowledge, this is the first real-life study report- ing the outcome of venetoclax in an Eastern population. We hope these data obtained from our study should accelerate the approval and reimbursement of venetoclax in combination with either HMAs or sc ARA-C in Turkey. Venetoclax worked flawlessly in patients who were newly diagnosed when combined with a hypomethylating agent or sc ARA-C. They are still on therapy with a complete response, and the objective response rate achieved in patients who relapsed was not inferior to conventional salvage options. No early death was reported, and besides hematologic toxicities, venetoclax has offered a manageable toxicity profile. Conclusion Our real-life data support the use of venetoclax in patients with both newly diagnosed and relapsed high-risk MDS and AML. Clinical Practice Points Venetoclax is approved for the treatment of patient with both newly diagnosed and relapsed AML. Preliminary data documented the beneficial role of venetoclax in high-risk MDS. Even the combination of venetoclax with HMAs or sc ARA-C further increased the overall response rate with a favorable toxicity profile in phase 3 trials. Real-world data regarding the use of venetoclax either as a single agent or in combination with HMAs lack in different patient populations. Clinical Lymphoma, Myeloma and Leukemia 2021 e691 A Real Life Turkish Experience of Venetoclax • e692 Our study confirms the real-life safety and efficacy of venetoclax in patients with both newly diagnosed and relapsed AML and high-risk MDS. Disclosure The authors have stated that they have no conflicts of interest. References 1. Cancer Stat Facts: Leukemia—Acute Myeloid Leukemia (AML). National Cancer Institute Surveillance, Epidemiology, and End Results Program. 2020. https://seer. cancer.gov/statfacts/html/amyl.html , accessdate: April 4th, 2021. 2. Dohner H , Estey E , Grimwade D . 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