MDS Setting Looking to BCL2 Inhibitors for Improved Survival, Sequencing Options


Combinations of the BCL2 inhibitor venetoclax with hypomethylating agents are undergoing investigation to determine benefit in high-risk myelodysplastic syndrome.

Rami Komrokji, MD

Rami Komrokji, MD

For many years, hypomethylating agents (HMAs) alone have been the only option for patients with high-risk myelodysplastic syndrome (HR-MDS). Now, BCL2 inhibitor venetoclax (Venclexta®; Genentech, Abbvie) combinations with HMA are undergoing investigation to determine benefit in this population.

“We’re trying to improve the bar because [the survival and response with HMAs are suboptimal], sothere’s definitely unmet need to improve outcomes of HR-MDS patients ,” Rami Komrokji, MD, vice chair of the Department of Malignant Hematology and head of the Leukemia and MDS Section at Moffitt Cancer Center, Tampa, Florida, said in an interview with The SOHO Daily News.

Prior to his presentation at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Komrokji discussed the current status of MDS treatment and future directions for therapeutic combinations in these patients. This included the evaluation of real-world data with venetoclax plus azacitidine, appropriate use of venetoclax in MDS vs in acute myelocytic leukemia (AML), and ongoing trials for venetoclax combinations.

Combination Venetoclax/Azacitidine in Clinical Trials

Venetoclax plus azacitidine is the combination physicians likely will use in MDS, if they are not doing so already. This combination received a Breakthrough Therapy designation from the FDA for patients with previously untreated HR-MDS based on interim results from the phase 1b M15-531 trial (NCT02942290).1 In this study, venetoclax/azacitidine exhibited encouraging efficacy with durable responses and a tolerable safety profile.2

“Venetoclax is one of the front-runners in combination with HMAs for, hopefully, approval if the studies are positive. That will translate to benefit for patients,” Komrokji said. “The availability of venetoclax in AML makes it potentially a drug that [individuals] are already using in practice.”

In M15-531, an open-label, nonrandomized, multicenter study, patients initially received 400 mg or 800 mg of venetoclax for 28 days in a 28-day cycle, similar to the dosing used in AML.2 However, the doses were subsequently lowered to an escalating dose of 100, 200, and 400 mg for 14 days per cycle due to intolerance. The 400-mg dose was identified as the recommended phase 2 dose, along with 75 mg/m2 of azacitidine subcutaneously or intravenously on days 1 through 7 of each cycle. The dosing is always adjusted for patients based on other medications they are receiving, such as prophylactic antibiotics, with need for early assessment according to Komrokji.

The interim results at 13.0 months’ median follow-up demonstrated a 77% overall response rate (ORR), with complete remission (CR) in 42% of patients and marrow CR (mCR) in 35%. Of patients who achieved mCR, 40% experienced mCR plus hematologic improvement (HI). The median overall survival (OS) was not reached (95% CI, 16.2 months–not estimable [NE]), median duration of response (DOR) was 14.8 months (95% CI, 12.9-NE), and median progression-free survival was 17.5 months (95% CI, 14.5-NE). No partial remissions (PRs) were observed.

Venetoclax/azacitidine is also being investigated in the phase 3 VERONA trial (NCT04401748) for efficacy and safety in approximately 500 patients with newly diagnosed HR-MDS.3 These patients were randomly assigned 1:1 to the experimental arm of venetoclax at 400 mg plus azacitidine at 75 mg/m2 vs placebo and azacitidine. Primary end points of VERONA are CR rate by investigator assessment and OS; secondary end points include ORR (CR plus PR), modified ORR (CR, mCR, and PR), red blood cell and platelet transfusion independence, and change in fatigue; exploratory end points are predictive biomarkers and pharmacokinetics. “That will be the pivotal study, if it confirms the activity seen from the phase 1/2 trial, that will lead to the approval of the drug [combination],” Komrokji said.

Real-World Data of Venetoclax/Azacitidine in MDS

In 2021, Moffitt Cancer Center conducted and presented a real-world analysis of patients with HR-MDS receiving first-line HMA alone (n = 1158), first-line venetoclax plus an HMA (n = 35), or second-line venetoclax as an add-back strategy after HMA failure (n = 31) to assess differences in survival and response.4 Investigators found that the combination as frontline therapy achieved significantly higher CR rates vs HMA alone. The data also suggest the OS benefit is encouraging for patients who received HMA and venetoclax and then went on to allogeneic hematopoietic stem cell transplant (AHSCT).

There was median follow-up of 96 months for HMA alone, 15 months for venetoclax/HMA, and 36 months for venetoclax added back. The ORR was 77% and 40% for the combination therapy and monotherapy, respectively (Pm<.005), TABLE4).

For patients who received the combination, the median OS was 21 months (95% CI, 11-32), and the median was 20 months (95% CI, 19-22) in those who received only HMA (P=.86). However, for those who later had an AHSCT (n = 269), the median OS was not reached in the 13 patients given venetoclax/HMA vs 38 months in the 256 given HMA alone (P= .2). For the AHSCT patients, the 2-year survival probability rate was 91% with the combination and 51% with the monotherapy.

Patients with ASXL1 somatic mutations were also included in this analysis, a group of patients with lower response to HMA alone. Komrokji said, “In our cohort, we looked at that subset of patients and indeed we see that the responses almost tripled in those patients [receiving venetoclax/HMA], suggesting that the preclinical observation of ASXL-1 resistance to HMA may be mediated by BCL-2 overexpression can be overcome with the combination.

Venetoclax added back to HMA therapy after progression also showed clinical activity and increased OS. The ORR in this group was 61%, with a 13% CR rate and 48% mCR rate. There was a 33-month OS in this group—higher than both other groups. Other analyses of venetoclax in the real-world setting have shown similar data for adding venetoclax as salvage therapy for patients who progressed on HMAs, such as those published by our collaboration with Memorial Sloan Kettering Cancer Center and by Mayo Clinic group.5,6

TP53 Mutations and Safety Concerns in MDS Treatment

Treatment for patients with a TP53 mutation has been identified as an unmet need in the MDS population. In the real-world analysis, patients with TP53 receiving venetoclax/HMA in the first line had an ORR of 75% compared with 44% in those given HMA alone.4 Yet, the CR rates were 25% and 17%, respectively; Komrokji said the responses were not durable.

Another unmet need is guidance on dosing when myelosuppressive adverse events (AEs) occur with venetoclax/azacitidine. For community oncologists who will use venetoclax, Komrokji warns that evaluating the bone marrow early is crucial. With the standard-of-care HMAs, patients can experience myelosuppression, but not to the extent seen with the combination, as shown with treatment of AML.7 Instead of ordering repeat bone marrow tests after 3 or 4 cycles with HMAs, Komrokji said repeat testing should happen after 1 cycle of therapy with venetoclax/HMA. If the bone marrow is hypoplastic when patient is responding, both the HMA and venetoclax must be held until the blood counts recovers, and then restarted and potentially dose adjusted.

“There is no clear dosing or duration that’s going to be appropriate, but it’s clear that one needs to evaluate early, back off the treatment for recovery [if necessary], and then restart. If one uses the same model of continuing the treatment 3 to 4 cycles, there is profound myelosuppression and increased risk of infection,” Komrokji explained. Because this treatment will be given to older patients and in community practices, he said more guidance from ongoing clinical trials will be essential.

The Future of BCL2 Inhibitor Therapy

Triplet therapy with a venetoclax/azacitidine backbone and other azacitidine combinations are being examined in MDS. According to Komrokji, drugs with synergism or different mechanisms of action could be utilized, although the toxicity and potential AE overlap should be kept in mind. Some of these potential therapies include magrolimab (GS-4721) and sabatolimab (MBG453).

Magrolimab is an anti-CD47 therapy that blocks a “do not eat me” signal, allowing macrophages to engulf the cells.8 This drug is undergoing investigation in the phase 3 ENHANCE (NCT04313881) and ENHANCE-2 (NCT04778397) trials in combination with azacitidine. Although ENHANCE-2 is primarily looking at patients with TP53-mutated AML, preliminary data of magrolimab plus azacitidine in 24 evaluable patients with untreated HR-MDS in the study showed strong activity. There was an ORR of 92%, CR rate of 50%, mCR rate of 33%, and HI rate of 8% in these patients.9

The TIM3 inhibitor sabatolimab engages T cells and targets stem cells. Sabatolimab plus HMA demonstrated durable clinical responses in patients with HR-MDS in a phase 1b trial (NCT03066648).10 There were 51 patients evaluable for response, and the ORR was 56.9%, with a CR of 19.6%, mCR of 23.5%, and PR of 3.9%. The median DOR was 16.1 months, but it was 21.5 months for those with a CR. This combination is also being investigated in the phase 2 STIMULUS-MDS1 trial (NCT03946670). “[Magrolimab and sabatolimab] don’t have that profound myelosuppression. There are studies already ongoing with the triplet combinations of azacitidine, venetoclax, and those agents,” Komrokji said.

The STIMULUS-MDS3 trial (NCT04812548) is enrolling patients with HR-MDS and very HR-MDS to receive sabatolimab/venetoclax/azacitidine. Magrolimab in combination with venetoclax and azacitidine as a triplet combination is being evaluated in patients with AML and MDS in the ENHANCE-3 study (NCT05079230), which is also enrolling.

But at the forefront for patients with MDS, Komrokji and his colleagues are waiting on randomized phase 3 data to confirm the advantages of venetoclax and other combinations. “The most [important thing] in my mind is first improving the outcomes for the up-front therapy, and then finding options for second line after the up-front therapy failed,” Komrokji said. “It’s a really exciting time. Sometimes we are impatient—we want to transform those to approved drugs that we can offer our patients tomorrow in the clinic. I think that’s the challenge sometimes: How fast can we get those studies done and improve the outcomes?”


1. FDA grants breakthrough therapy designation for Venclexta in combination with azacitidine for the treatment of patients with myelodysplastic syndromes. News release. Genentech. July 21, 2021. Accessed September 6, 2022.

2. Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study. Blood. 2020;136(suppl 1):55-57. doi:10.1182/blood-2020-139492

3. Zeidan AM, Garcia JS, Fenaux P, et al. Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(suppl 15):TPS7054. doi:10.1200/JCO.2021.39.15_suppl.TPS7054

4. Komrokji RS, Ali NA, Chan O, et al. Assessing the role of venetoclax in combination with hypomethylating agents in higher risk myelodysplastic syndromes. Blood. 2021;138(suppl 1):536. doi:10.1182/blood-2021-146634

5. Ball BJ, Famulare CA, Stein EM, et al. Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure. Blood Adv. 2020;4(13):2866-2870. doi:10.1182/bloodadvances.2020001482

6. Morsia E, McCullough K, Joshi M, et al. Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients. Am J Hematol. 2020;95(12):1511-1521. doi:10.1002/ajh.25978

7. Richard-Carpentier G, DiNardo CD. Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy. Ther Adv Hematol. 2019;10:2040620719882822. doi:10.1177/2040620719882822

8. Garcia-Manero G, Daver NG, Xu J, et al. Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): the phase 3, randomized, ENHANCE study. J Clin Oncol. 2021;39(suppl 15):TPS7055. doi:10.1200/JCO.2021.39.15_suppl.TPS7055

9. Forty Seven, Inc. announces updated data from ongoing clinical trial of magrolimab showing robust, durable activity in patients with myelodysplastic syndrome and acute myeloid leukemia. News release. Forty Seven, Inc. December 9, 2019. Accessed August 25, 2022.

10. Brunner AM, Esteve J, Porkka K, et al. Efficacy and safety of sabatolimab (MBG453) in combination with hypomethylating agents (HMAs) in patients (Pts) with very high/high-risk myelodysplastic syndrome (vHR/HR-MDS) and acute myeloid leukemia (AML): final analysis from a phase Ib study. Blood. 2021;138(suppl 1):244. doi:10.1182/blood-2021-146039

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