Venetoclax plus hypomethylating agent for the salvage treatment of relapsing myeloid malignancies after hematopoietic stem cell transplantation: A multicenter retrospective study on behalf of the Zhejiang Cooperative Group for Blood and Marrow Transplantation

Abstract

Hematopoietic stem cell transplantation (HSCT) offers the highest possible curative potential for patients with hematological malignancies. However, the management of post-transplant relapse remains a challenging task. In general, the prognosis of patients with post-transplant relapse is extremely poor, since many of them cannot tolerate or are refractory to commonly used approaches. In view of this, the risks and benefits of salvage treatment must be weighed up, and novel, less toxic, more efficient treatment options are urgently needed. Venetoclax (VEN), an oral selective inhibitor of anti-apoptotic protein B-cell leukemia/lymphoma-2 (BCL-2), has been approved for the treatment of a variety of hematologic malignancies.1, 2 In relapsed/refractory (R/R) myeloid malignancies, the combination of VEN and hypomethylating agent (HMA) has exhibited an encouraging treatment effect.3 Nevertheless, research about VEN-HMA administration for post-transplant relapse is still in a preliminary stage. Herein, we conducted a multicenter retrospective study, with the aim to evaluate the efficacy and side effects of VEN-HMA for post-transplant relapse and determine which patients may benefit from this combination therapy. Between July 2018 and June 2021, 44 consecutive patients with post-transplant relapse received VEN-HMA inpatient at 5 centers of Zhejiang province. The salvage treatment consisted of VEN for 28 consecutive days (100 mg of VEN for the first day and 200 mg for the second day, then increased to the final dose of 400 mg daily or equivalent to azole co-administration). Either azacytidine (AZA, 75 mg/m2, d1-7) or decitabine (DEC, 20 mg/m2, d1-5) was used as a VEN partner. During VEN-HMA treatment, hydration and alkalization were performed for the prophylaxis of tumor lysis syndrome (TLS). The response to VEN-HMA was determined according to the 2017 European Leukemia Net (ELN) response criteria. Adverse events were accessed by the Common Terminology Criteria for Adverse Events (CTCAE5.0) Table S1 summarizes the patient baseline characteristics. Acute myeloid leukemia (AML) (n = 34) and myelodysplastic syndrome (MDS, n = 7) were the most common disease types. Each patient was analyzed for chromosomal and genetic abnormalities either at diagnosis and at post-transplant relapse. A complex/monosomal karyotype was seen in 10 (22.7%) patients. Ten patients (22.7%) had TP53 mutation or deletion, 6 (13.6%) exhibited IDH1/2 mutation (Figure 1A). Based on the 2017 ELN risk stratification, a total of 23 (52.3%) patients had adverse risk profiles. All patients experienced intramedullary relapse except two that relapsed at the chest wall and spine, respectively. Ten (22.7%) patients relapsed within 6 months, 18 (40.9%) relapsed between 6 months to 1 year, and 16 (36.4%) relapsed >1-year post-transplantation. Eighteen (40.9%) patients developed acute graft versus host disease (aGVHD) and 16 (36.4%) developed chronic graft versus host disease (cGVHD) before relapse. Thirty-nine (88.6%) patients received VEN-HMA at first relapse after transplantation, while 5 (11.4%) received VEN-HMA at second relapse after transplantation. Twenty-six (59.1%) patients were treated with VEN-HMA directly after relapse (first-line therapy). For the remaining 18 (40.9%) patients, VEN-HMA was administrated as second-line therapy after failure of chemotherapy or DLI. Twenty-three (52.3%) patients had a higher tumor burden (bone marrow blasts >20%) at the initiation of VEN-HMA. The median number of VEN-HMA cycles was 1 (range, 0.5–4). Treatment response was evaluated by bone marrow aspiration or radiological examination after each cycle of VEN-HMA therapy. Most patients were tolerant to the first cycle of VEN-HMA, except 4 (9.1%) of them developed ≥grade 3 non-hematological toxicity and discontinued the treatment on day 14. Fifteen (34.1%) patients fulfilled the criteria of CR/CRi and all of them achieved the best response in the first cycle of VEN-HMA (Table S2). Among 9 patients (including 3 CR patients) who received more than 1 cycle of VEN-HMA, delayed treatment with shortened treatment duration (14 days of VEN) was only applied in 1 CR patient who experienced prolonged myelosuppression in the first cycle. Among CR/CRi patients, 10 patients then received VEN maintenance, 4 patients underwent a second HSCT, and 1 patient received DLI from the original transplant donor after VEN-HMA. One CR patient relapsed at 7.5 months post-VEN-HMA treatment and died of disease progression. Another CR patient died of infection at 9.3 months post-VEN-HMA treatment (Figure 1B). Of those 29 patients who did not achieve CR/CRi, only 5 of them were alive at the writing of this article, 23 patients died of disease progression (16 of them had active infections at the time of death), and 1 patient died of intracranial hemorrhage. Compared with patients who did not achieve CR/CRi, CR/CRi patients had a dramatically improved OS (8.1 vs. 2.8 months, p < .0001). Considering the adverse events, neutropenia (79.5%), thrombocytopenia (68.2%), and anemia (63.6%) were the three most common regimen-related toxicities. Twenty-one (47.7%) patients developed grade III–IV infection (18 pulmonary infections and 3 bloodstream infections). Eight (18.2%) patients had bleeding episodes. No patients developed TLS during VEN-HMA. We also investigated the association between treatment effect and patient characteristics (Figure 1C). We found that male patients tended to have a lower CR/CRi rate than female patients (20.8% vs. 50.0%, p = .042). Patients that relapsed within 1-year post-transplantation had a poorer treatment effect than other patients (21.4% vs. 56.3%, p = .019). In addition, patients with ELN adverse risk also had a lower CR/CRi rate (21.7% vs. 47.6%, p = .070). While, other factors such as diagnosis, patient age, status at transplant, tumor burden at the onset of VEN-HMA did not affect the CR/CRi rate. Among patients with a complex/monosomal karyotype, only 1 of them achieved CR/CRi (10.0% vs. 41.2%, p = .127). Patients with TP53 abnormities (10.0% vs. 41.2%, p = .127) and ASXL1 mutation (0.0% vs. 38.5%, p = .149) seemed to have a lower chance to benefit from VEN-HMA therapy. In contrast, DNMT3A mutation (66.1% vs. 31.7%, p = .264), NPM1 mutation (60.0% vs. 30.8%, p = .319), and IDH1/2 mutation (50.0% vs. 31.6%, p = .394) were associated with a favorable CR/CRi rate. In multivariate analysis, TP53 mutation (HR = 17.339, p = .033) and relapse within 1-year post-transplantation (HR = 6.261, p = .026) were identified as independent risk factors that influenced the CR/CRi rate (Table S3). Altogether, the VEN-HMA treatment yielded a favorable response rate. Interestingly, the CR/CRi rate (56.3%) in patients who relapsed >1-year post-transplantation was very impressive. Meanwhile, the treatment outcome was dismal for patients with a short duration of post-transplant remission. We hypothesize that several reasons such as aggressive tumor biology, incomplete immune reconstitution, and unfitness for cytotoxic therapies may account for the poor prognosis. Consistently with our results, Byrne et al. also reported that among patients exhibiting no response to VEN-HMA, 7 of 8 relapsed within 1-year post-transplantation.4 However, a recent study revealed that the combination of VEN and DLI yields a promising response rate in early relapsed AML post-transplantation: half of their patients achieved CR/CRi/MLFS, and low WBC count at relapse and GVHD were associated with high chances of remission.5 In addition, VEN-based combination therapy (VEN, low-dose Cytarabine, Actinomycin D, and DLI maintenance) treatment exhibited a 70% CR/CRp rate in relapsed AML patients after HSCT (80% of these patients relapsed within 1-year post-transplantation).6 These results suggest that combining VEN with other therapies may have a synergistic treatment effect for early post-transplant relapse. Regarding treatment effects and chromosomal/genetic profiles, response rates differ greatly among patient groups. The relationship between TP53 mutation and treatment response has also been described in other publications. Byrne et al. reported that none of 4 patients with complex karyotype and TP53 mutation responded to VEN-HMA.4 Stahl et al. also suggested that TP53 was associated with a poor CR/CRi rate.3 Nevertheless, results from Joshi et al. did not show a difference in response rate between TP53 mutated and wild type patients.7 Additionally, patients with IDH1/2 and NPM1 mutations may be sensitive to VEN-based therapy, while patients with NOTCH1, FLT3, and PTPN11 mutations are more likely to be resistant.1 In the future, the associations between cytogenetic/mutational alterations and VEN response still need to be validated by large-scale prospective studies. Remarkably, 3 of 21 (14.3%) responders in our cohort lost their initial response to VEN-HMA. One patient relapsed after achieving CR, while failing to attain a second CR status to VEN-HMA. The other two patients (1 PR and 1 blast reduction) had disease progression in the following cycles of VEN-HMA treatment. Recently, several studies have revealed that potent mechanisms of VEN resistance. For instance, the mutations of BCL-2 protein could reduce the binding affinity of VEN; and the upregulation of other anti-apoptotic signals such as MCL-1 and BCL-XL could block the apoptosis of AML cells.1 Based on these findings, combination strategies such as VEN plus MCL-1 inhibitors have been applied and exhibited synthetic effects in some pre-clinical studies.8 Since there are limited clinical experiences for the treatment of VEN-resistant patients, monitoring emergent genetic mutations and combining VEN with targeting regimens may overcome drug resistance and improve the anti-leukemia activity. In conclusion, VEN-HMA is a safe and efficacious treatment option for patients with myeloid malignancies relapsing after transplantation. Patients without TP53 mutation or relapsing >1-year post-transplantation may stand a greater chance to achieve CR/CRi. This work was supported by the National Natural Science Foundation of China (82170210 and 82070179) and the Key Project of Science and Technology Department of Zhejiang Province (2020C03G2013586). The authors declare that there is no conflict of interest. Yanmin Zhao, Jimin Shi, and He Huang designed the study and supervised the analyses and manuscript preparation. Yanmin Zhao, Fei Gao, and Yang Gao collected and analyzed the data, Fei Gao and Yang Gao wrote the manuscript. All other authors discussed and interpreted the results. All authors approved the final version of the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1 Baseline characteristics Table S2 Outcomes, adverse events, and treatment details of VEN-HMA Table S3 Multivariate analysis of factors influencing the CR/CRi rate of VEN-HMA Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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