Venetoclax combinations for patients with accelerated and blast phase MPNs

Myeloproliferative neoplasms (MPN) can develop into an accelerated phase (AP) or blast phase (BP). These MPN phases are defined depending on the percentage of peripheral or bone marrow blasts:

• MPN-AP occurs when 10−19% blasts are present

• MPN-BP is defined as ≥20% blasts

The prognosis for MPN-AP and MPN-BP is poor, with a median overall survival (OS) of only 3−4 months following diagnosis. Traditional agents such as hypomethylating agents (HMAs) induced suboptimal responses in MPN-AP and MPN-BP patients. Exploring this, the MPN Hub recently reported on a study by Gangat et al. who investigated the use of venetoclax (VEN) + HMA in patients with MPN-BP.

Following that article, Amber King and colleagues reported on a multicenter, retrospective study where venetoclax was used in combination with other agents in patients with MPN-AP and MPN-BP.¹ We summarize the results below.

Study design

This study included 27 patients, 21 who had MPN-BP and 6 with MPN-AP. The median age in both groups was 72 years (range, 56−82). In the MPN-AP group, only 17% were female compared with 38% in the MPN-BP group. The patients with MPN-BP were equally split between antecedent MPN categories, whereas none of the patients with MPN-AP were in the polycythemia vera (PV) category. The most frequently observed mutations were JAK2, ASXL1, TET2, and RUNX1. Azacitidine (AZA; 7-day) or decitabine (DEC; 5-day) were the most common combinations used with venetoclax (Table 1).

Table 1. Baseline patient characteristics*

Results

MPN-BP cohort

For the MPN-BP cohort, the study recorded an overall response rate (ORR) of 52.3% along with a:

• Complete acute leukemia response of 24%
• Partial acute leukemia response of 19%
• Complete cytogenetic response of 10%

The median time between treatment and best response was 29.5 days (range, 7−114 days) and the median duration of response was 87 days (range, 21−447 days). Out of the 11 responders, 55% relapsed by the end of the study period.

Median OS was 6 months (95% CI, 4.1−not reached [NR]). Patients who were not treated with azacitidine had a significantly reduced survival (HR, 17.9; 95% CI, 2.34–136.98; p = 0.001) along with patients who carried a TP53 mutation (HR, 3.42; 95% CI, 1–11.8; p = 0.03). Patients who received a prior allogeneic stem cell transplant (allo-SCT) showed decreased survival with a median OS of only 0.85 months (p = 0.019) compared with the rest of the group.

Median event-free survival (EFS) for this cohort was 0.9 months (95% CI, 0−NR). Patients treated with low-dose cytarabine (LDAC; HR, 13.47; 95% CI, 2.27–79.84; p = 0.004) or decitabine (HR, 4.72; 95% CI, 1.21–18.4; p = 0.03) showed significantly poorer EFS compared with patients on azacitidine and patients with poor cytogenetic risk (OR, 2.7; 95% CI, 1–7.43; p = 0.04). In addition, decitabine- and LDAC-treated patients showed significantly reduced response rates compared with patients treated with azacitidine (p = 0.01).

Regarding cytogenetic profiles, patients with NRAS and ASXL1 mutations demonstrated reduced response rates, which were approaching statistical significance (p = 0.05). Of the four patients who underwent an allo-SCT, 75% were alive at the end of the study period.

Safety

Treatment with venetoclax was interrupted in 33% for non-hematological adverse events, and in 52.4% cessation of venetoclax treatment was required because of severe myelosuppression. Infections were recorded in six patients, four of which proved to be fatal (hospital acquired pneumonia and gram-negative bacteremia, n = 2 each). Grade 3 bleeding events (gastrointestinal bleed, subdural hemorrhage, hematuria, and epistaxis, n = 1 each) were documented in four patients, but no deaths occurred as a result. No clinical or laboratory tumor lysis syndrome (TLS) events were reported. Out of the total cohort, three patients died within 60 days of starting venetoclax therapy.

MPN-AP cohort

Out of the six patients with MPN-AP, half received venetoclax with decitabine (5 days) and the other half were treated with azacitidine (7 days). The ORR was 50%, with all three patients achieving a complete acute leukemia response.

Outcomes for this subgroup were as follows:

• Median time to best response, 28 days (7−58 days)
• Median duration of response, 55 days
• Median OS, 3.58 months
• Median EFS, 0.93 months

Safety

The main adverse event that was recorded for this subset was neutropenic fever for which 50% of patients with MPN-AP were hospitalized. However, no infections, bleeding events, TLS, or deaths within 60 days of treatment were documented for this subgroup. At the end of the study period, two patients were alive, and one was able to advance to allo-SCT.

Conclusion

While venetoclax was shown to display modest activity in patients with MPN-AP and MPN-BP, this was associated with significant toxicity levels which may be a factor, along with short duration of response, to limit the overall clinical benefit. The rate of infections and bleeding events mean that the risk benefit ratio of using venetoclax combination therapy should be weighed carefully. In some patients, this type of therapy allowed patients to undergo allo-SCT, which appears key for long-term survival; however, overall results are still poor for this subgroup of patients with MPN.