Combination of Venetoclax and Hypomethylating Agents in Myeloid Malignancies in Patients Unfit for Intensive Chemotherapy - Real World Data from a Tertiary Care Centre in India. Is It Time to Bid Adieu to 3+7?

Introduction

There is no standard of care for patients with elderly Acute Myeloid Leukemia (AML), and in those unfit for Intensive Chemotherapy. When treated with intensive chemotherapy, elderly AML patients achieve 45% CR/CRi (incomplete Complete Remission) rates, however, at the cost of high induction mortality of 29%.On the other hand, patients treated with Hypomethylating agents (HMAs) alone have low response rates, median time to best response of 3-4 months and a median OS of <1 year. Relapse or refractoriness to myeloid malignancies has been attributed to quiescent leukemic stem cells (LSCs) that are resistant to conventional chemotherapy. BCL2 inhibitors like venetoclax (VEN) target oxidative phosphorylation and selectively eradicate these LSCs. In pre-clinical studies, VEN in combination with HMAs, has been shown to deplete ATP in LSCs. Interestingly, Azacytidine has not only been reported to be synergistic in combination with VEN, but also reverse the resistance associated with it. VEN monotherapy and combination therapy have been reported, both in relapsed/refractory (R/R) AML and treatment naïve elderly patients from western world. VEN in combination with HMAs/LDAC (low dose Ara-C) was recently approved in November 2018 for patients >=75 years / those with co-morbidities precluding use of intensive chemotherapy. In view of paucity of real-world data, we aim to report the remission rates and safety of VEN in combination with HMAs from India.

Methods

All treatment naïve and R/R elderly (Age >= 65years) or patients deemed unfit for intensive chemotherapy [ECOG PS 3-4, non-resolving infections after atleast 7 days of supportive therapy] who received HMAs (Azacytidine/Decitabine) + VEN during September 2018 to May 2019, with a minimum follow-up period of 90 days were retrospectively reviewed. All patients received either Azacytidine 75mg/m² SC daily for 7 days or Decitabine 20mg/m² IV daily for 5 days along with ramp up of VEN from day1 (50mg OD X 2 ays, 100mg OD X 2 days, 200mg OD X 2 days, 400mg OD till day 21/28).Maximum dose of VEN was 200mg, if on concomitant voriconazole. Antifungal prophylaxis (Azoles/Amphotericin B) and TLS prophylaxis (Rasburicase) were administered as per institutional protocol. On achievement of CR, patients were either continued on the respective HMA with VEN [400mg OD till day7/14], every 4 weekly, or received standard consolidation (High dose Ara-C or allogeneic stem cell transplant), as per fitness.

Results

Twenty patients with a median age of 60 (Range:31-75) years were treated for AML (89.4%;n=18), BPDCN (Blastic Plasmacytoid Dendritic Cell Neoplasm) (5.3%;n=1) and MDS-EB-1 (5.3%;n=1). Amongst AML patients, 12 were newly diagnosed, 5 were relapsed cases [3 post HSCT relapses], while 1 was refractory. As per ELN classification, majority of our patients with AML were intermediate risk (n=9), followed by high (n=5) and low (n=3) risk. Patient with BPDCN belonged to the high risk group, while another patient with MDS-EB-1 belonged to Very High IPSS-R risk group at diagnosis. Prior to receiving VEN + HMA combination, 15 patients had infections (fungal=10,bacterial=7,viral=1), out of which 9 (47.36%) patients had persistent infection prior to commencing chemotherapy. In our cohort, CR/CRi was seen in 60% (n=12) patients. 67% (n=8) of newly diagnosed AML, 40% (n=2) of relapsed AML, and one patient with BPDCN and MDS-EB-1 achieved CR/CRi. Median number of VEN+ HMA cycles received were 3 (1-10) cycles, while most patients achieved CR in one cycle [Median-1,Range:1-4]. Amongst patients who achieved CR (n=12), only one relapsed after a duration of 72 days. Induction mortality was observed in 15%(n=3) patients. At a median follow-up of 5.13 months (95% C.I. 5.02-5.24), 70% of patients were alive. Estimated 9 month OS was 60±13% [Figure 1].

Overall 20 patients received 74 cycles. Adverse events are enlisted as in tTble 1.

Conclusions :

Azacytidine and VEN combination is an effective regimen than HMAs alone, with CR rates of 60%, and better tolerated than intensive chemotherapy. This novel combination regimen produced responses even in high risk patients, including those with poor risk cytogenetics, AML with myelodysplasia related changes, and post-transplant relapse. In our experience, reducing the duration of VEN to 21 days in Induction lessens the duration of grade 4 myelosuppression, lesser febrile neutropenia, with similar response rates which needs to be validated.

View largeDownload slide

View largeDownload slide

Close modal