Treatment of Philadelphia‐negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

Andriani, Alessandro; Elli, Elena Maria; Trapè, Giulio; Villivà, Nicoletta; Fianchi, Luana; Niscola, Pasquale; Centra, Antonia; Anaclerico, Barbara; Montanaro, Guido; Martini, Vincenza; Carmosino, Ida; Voso, Maria Teresa; Breccia, Massimo; Montanaro, Marco; Foà, Roberto; Latagliata, Roberto

doi:10.1002/hon.2635

Cited by 14 publications

(8 citation statements)

References 17 publications

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“…The provisionally defined subgroup of accelerated-phase myelofibrosis used a 10% blast cutoff arbitrarily based on limited retrospective data. 21 Some studies suggest that acceleratedphase should be treated more aggressively, for example, including hypomethylating agents, 11,22,23 aiming to delay the time to leukemic transformation, and to also implement curative therapies (stem cell transplantation) in fit patients. This is the first study to evaluate outcome for accelerated-phase myelofibrosis undergoing curative treatment with reduced intensity allogeneic stem cell transplantation.…”

Section: Discussionmentioning

confidence: 99%

Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis

et al. 2022

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Accelerated-phase (AP) myelofibrosis, currently defined by circulating blasts 10-19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for AP myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had AP myelofibrosis. In comparison with chronic-phase (CP, <10% blasts), median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the AP group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval, 49-81%) versus 64% (95% confidence interval, 59-69%) for the CP group (P=0.91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% confidence interval, 32-67%) versus 55% (95% confidence interval, 50-61%) for the CP group (P=0.65). Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% confidence interval, 24-35%; P=0.25) for the CP group. In terms of relapse, 5-year incidence was 30% (95% confidence interval, 14-46%) for the AP group versus 15% (95% confidence interval, 11-19%) for the CP group (P=0.02). Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for AP myelofibrosis.

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Section: Discussionmentioning

confidence: 99%

Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis

et al. 2022

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“…A retrospective analysis of 19 MPN patients (developing MPN-BP) who were treated with azacitidine showed that 5 patients (26.3%) achieved CR, 1 had a partial response, 4 had stable disease, and 3 displayed hematological improvement; since the time of BP evolution, the median cumulative survival was 9.9 months [104]. Andriani and colleagues [105] conducted another recent retrospective study in 39 patients who were in MPN-AP/BP and were treated with azacitidine in the frontline setting at 10 hematologic centers in Italy. Hematologic responses were noted in 24 patients: 8 (20.5%) and 7 (17.9%) achieved complete and partial responses, respectively, whereas hematologic improvement was noted in 9 (23.1%); 4 responders underwent allo-HSCT.…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

“…Hematologic responses were noted in 24 patients: 8 (20.5%) and 7 (17.9%) achieved complete and partial responses, respectively, whereas hematologic improvement was noted in 9 (23.1%); 4 responders underwent allo-HSCT. The overall response rate was 61.5%, and the entire cohort had a median OS of 13.5 months; the median OS for responders was about 4 months longer (17.6 months) [105]. Another phase 1b study evaluated the safety and maximum tolerated dose of ruxolitinib in combination with azacitidine in a small cohort of patients comprising 7 with MPN-AP (including MDS) and 7 with MPN-BP.…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

Accelerated Phase of Myeloproliferative Neoplasms

et al. 2021

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Background: Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20–25% of the cases. MPN-AP and MPN-BP are characterized by 10–19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival. Summary: MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3–5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.

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“…To date, therapeutic options for patients with aCML are limited, and although therapy with ruxolitinib can be associated with responses in patients with CSF3R mutations, 5,12,13 particularly in the absence of SETBP1 mutations, there is insufficient evidence on the optimal therapeutic strategies for these patients. Although several reports including small patient cohorts have described the potential use of hypomethylating agents (HMAs) such as decitabine and azacitidine for the treatment of aCML, 3,14‐18 an evaluation of the survival benefit or clinical activity of these compounds in a larger cohort and a comparison with other therapeutic approaches are needed.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia

Bravo

Kanagal‐Shamanna

Sasaki

et al. 2021

Cancer

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Background There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). Methods The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46‐89 years). Results The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035‐0.593; P = .007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1‐ and 3‐year survival. Conclusions aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients.

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Treatment of Philadelphia‐negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

Cited by 14 publications

References 17 publications

Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis

Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis

Accelerated Phase of Myeloproliferative Neoplasms

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia

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