Momelotinib for the treatment of myelofibrosis.

In September 2023, the Food and Drug Administration approved momelotinib for the treatment of myelofibrosis (MF) with anemia, marking the fourth US regulatory approval of a Janus kinase (JAK) inhibitor for MF. A positive opinion from the European Medicines Agency followed in November 2023. Momelotinib's ability to address splenomegaly, symptoms and anemia, including in thrombocytopenic patients (platelets ≥25 x 109/L), the ease of switching from ruxolitinib, and good tolerability uniquely position it to substantially impact the MF treatment landscape.

Moving toward disease modification in polycythemia vera.

Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.

STAT3 Activates the Pentraxin 3 Gene in Chronic Lymphocytic Leukemia Cells.

Pentraxin-related protein 3 (PTX3), commonly produced by myeloid and endothelial cells, is a humoral pattern recognition protein of the innate immune system. Because PTX3 plasma levels of patients with chronic lymphocytic leukemia (CLL) are high and most circulating cells in patients with CLL are CLL cells, we reasoned that CLL cells produce PTX3. Western immunoblotting revealed that low-density cells from seven of seven patients with CLL produce high levels of PTX3, flow cytometry analysis revealed that the PTX3-producing cells are B lymphocytes coexpressing CD19 and CD5, and confocal microscopy showed that PTX3 is present in the cytoplasm of CLL cells. Because STAT3 is constitutively activated in CLL cells, and because we identified putative STAT3 binding sites within the PTX3 gene promoter, we postulated that phosphorylated STAT3 triggers transcriptional activation of PTX3. Immunoprecipitation analysis of CLL cells' chromatin fragments showed that STAT3 Abs precipitated PTX3 DNA. STAT3 knockdown induced a marked reduction in PTX3 expression, indicating a STAT3-induced transcriptional activation of the PTX3 gene in CLL cells. Using an EMSA, we established and used a dual-reporter luciferase assay to confirm that STAT3 binds the PTX3 gene promoter. Downregulation of PTX3 enhanced apoptosis of CLL cells, suggesting that inhibition of PTX3 might benefit patients with CLL.

The role of therapy in the outcome of patients with myelofibrosis.

BACKGROUND: The treatment of patients with myelofibrosis (MF) has evolved in the past decade, as reflected in an increased use of various therapeutic agents that could potentially impact patient outcomes. METHODS: In this retrospective study, the authors evaluated the pattern of therapy and its possible impact on the survival of patients with MF at their institution. Patients (n = 802) with newly diagnosed, chronic, overt MF (MF fibrosis grade ≥2, <10% blasts) seen at their cancer center between 2000 and 2020 were included. RESULTS: Overall, 492 of the included patients (61%) initiated MF-directed therapy during follow-up. The most frequent initial therapy was the JAK inhibitor ruxolitinib (44% of treated patients), investigational agents excluding JAK inhibitors (21%), immunomodulatory agents (18%), other investigational JAK inhibitors (10%), and others (7%). Overall survival was superior for patients who received initial ruxolitinib therapy, with a median survival of 72 months versus approximately 50 months for the remaining approaches, excluding the last group. Thirty-two percent of patients required subsequent therapy (n = 159). The longest survival since the start of second-line therapy was observed in patients who initiated salvage ruxolitinib (median, 35 months; 95% CI, 25-45 months). CONCLUSIONS: This study demonstrated improved outcomes of patients with MF who received treatment with the JAK inhibitor ruxolitinib.

Phase II study of cladribine, idarubicin, and ara-C (CLIA) with or without sorafenib as initial therapy for patients with acute myeloid leukemia.

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival.

Relevant Clinical Factors in Patients with Myelofibrosis on Ruxolitinib for 5 or More Years.

INTRODUCTION: Median duration of therapy with the first JAK1/2 inhibitor ruxolitinib (RUX) approved for patients with intermediate or high-risk myelofibrosis (MF) is about 3 years. METHODS: In this retrospective study, we aimed to evaluate clinical features, predictive factors, and outcome of patients presenting to our institution who were able to remain on RUX for ≥5 years (RUX ≥5y, n = 73). RESULTS: Comparing baseline demographics of patients who remained on RUX ≥5y (n = 73) with patients who were on RUX for 6 months to 3 years (n = 203), we confirmed that patients on RUX ≥5y lacked advanced clinical features at the start of therapy, such as anemia, neutropenia, thrombocytopenia, higher blasts or monocytes. Predictive independent factors for staying on RUX ≥5y were hemoglobin >10 g/dL, circulating blasts <1%, platelets >150 × 109/L, neutrophils >70%, and having primary MF. Age over 65 years remained significant for outcome in patients on RUX ≥5y. CONCLUSION: In this retrospective study, we report on the relevance of absence of advanced clinical features for long RUX therapy and confirm the role of age on outcome despite therapy.

Improved survival of patients with myelofibrosis in the last decade: Single-center experience.

BACKGROUND: The management of myelofibrosis (MF) has changed over the last several years and could have an impact on patient outcome. This study evaluates the survival of patients with MF at the authors' institution to determine whether it changed in the last decade. METHODS: This retrospective study consists of 844 patients (64% male; median age, 66 years; range, 20-90 years) who were examined between 2000 and 2020 with a new diagnosis of MF. Only patients with available marrow biopsy who had reticulin fibrosis of grade 2 or higher were included. Patients were compared by year of presentation: 2000-2010 (n = 373) and 2011-2020 (n = 471). RESULTS: A statistically significant improvement in median survival in the last decade was noted: from 48 months (95% CI, 42-54 months) to 63 months (95% CI, 55-71 months) (P < .001; HR, 0.78 [95% CI, 0.64-0.95]). Improved survival was observed also in patients 65 years old or older and those having intermediate 2 or high-risk Dynamic International Prognostic Scoring System (DIPSS) or DIPSS-Plus risk scores. Among 532 patients treated with MF-directed therapy, patients exposed to JAK inhibitor ruxolitinib had superior outcomes with median overall survival of 84 months (95% CI, 70-94 months). CONCLUSIONS: The results demonstrate that survival of patients with MF has improved in the last decade. This improvement is likely due to increased disease awareness, advances in supportive care, and the development of effective treatments.

Ibrutinib and Venetoclax for First-Line Treatment of CLL.

BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

Clinicopathologic spectrum of myeloid neoplasms with concurrent myeloproliferative neoplasm driver mutations and SRSF2 mutations.

Myeloproliferative neoplasms (MPNs) are frequently associated with classic driver mutations involving JAK2, MPL or CALR. SRSF2 is among the most frequently mutated splicing genes in myeloid neoplasms and SRSF2 mutations are known to confer a poor prognosis in patients with MPNs. In this study, we sought to evaluate the clinicopathologic spectrum of myeloid neoplasms harboring concurrent MPN-driver mutations and SRSF2 mutations. The study cohort included 27 patients, 22 (82%) men and five (19%) women, with a median age of 71 years (range, 51-84). These patients presented commonly with organomegaly (n = 15; 56%), monocytosis (n = 13; 48%), morphologic dysplasia (n = 11; 41%), megakaryocytic hyperplasia and/or clustering (n = 10; 37%) and bone marrow fibrosis >MF-1 (17/22; 77%). About one third of patients either initially presented with acute myeloid leukemia (AML) or eventually progressed to AML. Eighteen (68%) patients had a dominant clone with SRSF2 mutation and nine (33%) patients had a dominant clone with a classic MPN-associated driver mutation. Our data suggest that the presence of an SRSF2 mutation preceding the acquisition of a MPN driver mutations is not a disease-defining alteration nor is it restricted to any specific disease entity within the spectrum of myeloid neoplasms. In summary, patients with myeloid neoplasms associated with concurrent SRSF2 and classic MPN driver mutations have clinical and morphologic features close to that of classic MPNs often with frequent dysplasia and monocytosis.

Mechanistic basis and efficacy of targeting the ß-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors.

The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear ß-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the ß-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear ß-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the ß-catenin-TCF7L2-JMJD6-c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.

Perspective: Pivotal translational hematology and therapeutic insights in chronic myeloid hematopoietic stem cell malignancies.

Despite much of the past 2 years being engulfed by the devastating consequences of the SAR-CoV-2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show-cased at the 15th Post-American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th-10th December 2020 and 7th-10th October 2021, respectively. The inaugural Post-ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases.

Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

Low-dose dasatinib 50 mg/day versus standard-dose dasatinib 100 mg/day as frontline therapy in chronic myeloid leukemia in chronic phase: A propensity score analysis.

Low-dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). No randomized trials have compared the outcome with standard-dose dasatinib. This study aims to compare the outcome of patients with CML-CP treated with frontline dasatinib 50 versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML-CP treated with low-dose dasatinib (N = 83) or standard-dose dasatinib (N = 150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response (MMR), molecular response (MR)4, and MR4.5. Failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) were also compared. Patients on low-dose dasatinib with suboptimal response by European LeukemiaNet (ELN) 2013 criteria had the option to increase the dose to 100 mg/day. The overall median follow-up time was 60 months. The 3-year MMR rates were 92% and 84% for low-dose and standard-dose dasatinib, respectively (p = .23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4 (77% vs. 66%; p = .04) and MR4.5 (77% vs. 62%; p = .02) at 3 years. The 4-year FFS, EFS and OS rates were 89% versus 77% (p = .04), 95% versus 92% (p = .06), and 97% versus 96% (p = .78) with low-dose and standard-dose dasatinib, respectively. The rate of any grade pleural effusion was 5% with dasatinib 50 mg/day compared to 21% with 100 mg/day. Dasatinib 50 mg/day is at least as effective as 100 mg/day with a better safety profile and drug exposure.

Isavuconazole as Primary Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-label, Prospective, Phase 2 Study.

BACKGROUND: Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug-drug interactions compared with other triazoles. METHODS: In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. RESULTS: Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. CONCLUSIONS: ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. CLINICAL TRIALS REGISTRATION: NCT03019939.

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia.

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.

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.

Myeloid/lymphoid neoplasms with FLT3 rearrangement.

Myeloid/lymphoid neoplasms (M/LN) with 13q12/FLT3 rearrangement have been suggested as candidates for possible inclusion in the World Health Organization classification group of M/LN with eosinophilia (M/LN-eo). We report 12 patients with confirmed FLT3 rearrangement, six with t(12;13)/ETV6-FLT3; one with ins(13;22)/BCR-FLT3; and five with an unconfirmed partner gene located on chromosome bands 2p16, 3q27, 5q15, 5q35, and 7q36. Disease presentations were heterogeneous, including lymphoblastic leukemia/lymphoma, myeloid sarcoma, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. However, some common features were observed, such as extramedullary involvement (n = 7, 58%), associated eosinophilia in blood, bone marrow, or tissue (n = 8, 67%), multilineage involvement, either as biphasic myeloid/lymphoid neoplasms (n = 2) or mixed phenotype acute leukemia (n = 2). Mutations were detected in 4/8 (50%) patients by next-generation sequencing. None (0/10) had FLT3 or KIT mutations. Eleven patients received disease-based chemotherapy or hypomethylating agents, three received FLT3 inhibitors, and five patients proceeded to hematopoietic stem cell transplant. Together with a review of 16 cases published in the literature, it is apparent that M/LNs with FLT3 rearrangement show disease features reminiscent of members in the category of M/LN-eo with PDGFRA, PDGFRB, FGFR1, and PCM1/JAK2 rearrangement, characterized by a specific gene rearrangement, frequent eosinophilia, multi-lineage involvement and therapeutic benefit from kinase inhibitors.

Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment-related mortality.

Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are "fit" or "unfit" for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10-day decitabine with venetoclax (DEC10-VEN) vs IC. DEC10-VEN consisted of daily venetoclax with decitabine 20 mg/m2 for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m2 /d. A validated treatment-related mortality score (TRMS) was used to classify patients at high-risk or low-risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10-VEN cohort (n = 85) was 72 years (range 63-89) and 28% patients were at high-risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10-VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P < .001), and lower rate of relapse (34% vs 56%, P = .01), 30-day mortality (1% vs 24%, P < .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29-0.79, P < .01). In patients at both at high-risk and low-risk of TRM, DEC10-VEN showed significantly higher CR/CRi, lower 30-day mortality, and longer OS compared to IC. Patients at both high-risk and low-risk of TRM had comparable outcomes with DEC10-VEN. In conclusion, DEC10-VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high-risk of TRM.

STAT3-Induced Wnt5a Provides Chronic Lymphocytic Leukemia Cells with Survival Advantage.

The wingless and integration site growth factor-5a (Wnt5a) is a ligand of the receptor tyrosine kinase-like orphan receptor-1 (ROR1). Because both Wnt5a and ROR1 are expressed in circulating chronic lymphocytic leukemia (CLL) cells, and because in other cell types, STAT3, which is constitutively activated in CLL, induces Wnt5a signaling, we wondered whether STAT3 induces the expression of Wnt5a in CLL cells. Sequence analysis detected four putative STAT3 binding sites in close proximity to the Wnt5a gene promoter's start codon. Chromatin immunoprecipitation and EMSA revealed that STAT3 binds to the Wnt5a gene promoter, and a luciferase assay showed that STAT3 activates the Wnt5a gene. Additionally, transfection of peripheral blood CLL cells with STAT3 short hairpin RNA downregulated Wnt5a mRNA and protein levels, suggesting that STAT3 binds to the Wnt5a gene promoter and induces the expression of Wnt5a in CLL cells. Flow cytometry and confocal microscopy determined that both Wnt5a and its receptor ROR1 are coexpressed on the surface of CLL cells, and Western immunoblotting showed an inverse correlation between Wnt5a and ROR1 protein levels, implying that, regardless of CLL cells' ROR1 levels, blocking the interaction between Wnt5a and ROR1 might be beneficial to patients with CLL. Indeed, transfection of CLL cells with Wnt5a small interfering RNA reduced Wnt5a mRNA and protein levels and significantly increased the spontaneous apoptotic rate of CLL cells. Taken together, our data unravel an autonomous STAT3-driven prosurvival circuit that provides circulating CLL cells with a microenvironment-independent survival advantage.

Accelerated Phase of Myeloproliferative Neoplasms.

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.