Summary
Myeloproliferative neoplasms in blastic phase (MPN-BP) have a dreadful prognosis. We report the characteristics and outcomes of five MPN-BP patients treated with a never-before-described combination of azacytidine and venetoclax (to control BP transformation), added to ruxolitinib (needed to control constitutional symptoms). Median age was 76 years (range 72–84), and worst performance status was 2. The overall response rate was 80%, and the complete remission rate was 40%. With median follow-up of 10.0 months (range 4.2–13.4), median overall survival was 13.4 months (95% CI 4.2–13.4). We did not detect any unexpected treatment-related toxicity, and quality of life was improved.
INTRODUCTION
Philadelphia-negative myeloproliferative neoplasms in blastic phase (MPN-BP) have a dreadful prognosis with median survival of fewer than 6 months. For non-transplant candidates, there is still no standard treatment.1 The combination of azacitidine (AZA, hypomethylating agents [HMA]) and venetoclax (VEN) has become the new standard of care for de-novo acute myeloid leukaemia (AML),2 particularly for non-transplant candidates. To note, post-MPN AML was excluded from the registering trial. The combination of HMA and ruxolitinib (RUX) has been reported to achieve prolonged overall survival (OS) for MPN in accelerated and blast phase in a phase 2 study.3 However, none of these treatments have become the standard of care for MPN-BP. The AZA-VEN combination seems the most attractive therapy for leukaemic transformation, and the addition to RUX appears of interest as a way of keeping the constitutional symptoms and/or splenomegaly of myelofibrosis under control. To the best of our knowledge, no data have evaluated the safety and effectiveness of the combination of AZA, VEN and RUX in this setting. In the present work, we report the characteristics and outcomes of five patients with MPN-BP treated with this combination.
METHODS
Study design and patients
We reported data from five patients with MPN-BP who received AZA, VEN and RUX in our institution. MPN-BP was defined by ≥20% blasts in the peripheral blood or bone marrow, with a documented prior diagnosis of essential thrombocythemia (ET), polycythemia vera (PV) or myelofibrosis (MF).4 This study was conducted in accordance with ‘good clinical practice’ (GCP) and applicable regulatory requirements, including the 2008 version of the Declaration of Helsinki. This study complies with the reference methodology MR-004 concerning research reusing data already collected. Patients have the right to access, rectify, oppose and delete their data or to limit their processing.
Treatments
RUX was administered at a dose ≥10 mg twice daily to control constitutional symptoms and/or splenomegaly of myelofibrosis. AZA-VEN was added to treatment after the leukaemic transformation: VEN was administered orally at a daily dose of 200–400 mg on days 1 through 14 at 28 based on expected and observed cytopenia; AZA at a dose of 50 or 75 mg/m2 (dose changed to manage haematological toxicity), subcutaneously on days 1 through 7 every 28-day cycle. None of the patients were eligible for allogeneic SCT.
Response and safety
We used modified Cheson criteria for response assessment: complete remission (CR) is defined by no peripheral blood blasts, bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; leukocytes ≥4 ×109/L, haemoglobin ≥10 g/L and platelets ≥100 ×109/L; incomplete remission CRi is defined by no peripheral blood blasts with incomplete count recovery; partial remission (PR) is defined as ≥50% decrease in peripheral blood blasts irrespective of blood counts.5 As patients were cytopenic at leukaemic transformation, we retained haematological grade ≥ 3 adverse events that appeared only after the initiation of treatment.
Statistical analysis
OS was estimated using the Kaplan–Meier method and compared between groups by the log-rank test. OS was defined as the time from initiation of treatment to death from any cause. Patients alive at the data cut-off date (February 1, 2023) were censored. The main results are given with their 95% confidence interval (95% CI). Statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc.).
RESULTS
Patient characteristics
At the time of leukaemic transformation, the five patients had myelofibrosis: four secondary MF (two post-PV, one post-ET and one JAK2V617F negative postmyelodysplasic/myeloproliferative neoplasm unclassifiable) and one primary myelofibrosis. The median age was 76 years (range 72–84), and the worse performance status was 2. RUX was administered to control constitutional symptoms for four patients and splenomegaly for two patients. Four patients had RUX before leukaemic transformation. For the first patient, RUX was discontinued at AZA-VEN initiation and resumed after two cycles due to disabling constitutional symptoms. For the next three patients, RUX was continued because the combination appeared safe and effective for the first. Patient characteristics are summarized in Table 1.