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Myelofibrosis (MF) is characterized by constitutional symptoms, splenomegaly, and anemia.1 Anemia is a major issue in this disease and it has been estimated that approximately 60% of patients with MF become transfusion-dependent within one year of diagnosis.2 JAK1/2 inhibitors such as ruxolitinib and fedratinib are the standard of care (SOC) first-line treatment for patients with MF. However, although these drugs help control spleen size and symptoms, they also contribute to worsening of anemia, which can result in treatment discontinuation. Patients who discontinue ruxolitinib and fedratinib are known to have poor outcomes, and in addition, second-line treatments for MF are not well defined.1
In recent years, momelotinib has emerged as a promising alternative for patients with MF who are anemic. Indeed, in contrast to other JAK1/2 inhibitors, it not only inhibits the JAK/STAT pathway which decreases myeloproliferation and inflammation, but it also inhibits ACVR1/ALK2, which suppresses hepcidin expression, therefore increasing iron availability, eventually resulting in anemia improvement.1
The Phase III studies SIMPLIFY-1 (NCT01969838) comparing momelotinib versus ruxolitinib in JAK inhibitor-naïve patients with MF, and SIMPLIFY-2 (NCT02101268) comparing momelotinib versus best available therapy (BAT) in anemic or thrombocytopenic patients with MF who have been treated with a JAK inhibitor both demonstrated that a significantly higher number of patients achieved or maintained transfusion independence with momelotinib.1
In this video, Srdan Verstovsek, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, TX, discusses the rationale, design, and key results of MOMENTUM, a Phase III study comparing momelotinib versus danazol, which is currently recommended for the management of anemia, in patients with MF previously treated with a JAK inhibitor (NCT04173494).3
The study met both its primary endpoint of total symptom score (TSS) response rate at week 24 (24.6% momelotinib vs 9.2% danazol), and secondary endpoints of transfusion independence (TI; 30.8% momelotinib vs 20% danazol) and splenic response rate (SRR) at week 24 (40% momelotinib vs 6.2% danazol). There was also a trend toward a benefit in overall survival (OS) in the momelotinib arm. The most common adverse events included thrombocytopenia (22%, momelotinib vs 12%, danazol), and anemia (8%, momelotinib arm vs 11%, danazol).3
Dr Verstovsek concluded “We actually expect that next year momelotinib will become fully approved in the United States and in the European Union as a therapy for people that don’t feel well and are anemic (…). It’s a rather unique JAK inhibitor, as it can tackle all the three problems at the same time.”
Risk stratification is a crucial component in the adequate management of patients with myelodysplastic syndromes (MDS). Indeed, prognostication models are used for individual risk assessment, clinical trial design, and treatment recommendations. For instance, patients with lower-risk MDS are usually treated with therapies aimed to improve their quality of life (QoL) while higher-risk patients generally receive more intensive therapies including hypomethylating agents and allogeneic hematopoietic stem cell transplantation (alloHSCT).4
During the past twenty years, clinicians have used the International Prognostic Scoring System (IPSS) and IPSS-Revised (IPSS-R), which incorporate hematologic and cytogenetic features of the disease. However, multiple studies have demonstrated that several somatic mutations have an impact on the outcomes of patients with MDS and could be valuable prognostic markers.4
In this video, David Sallman, MD, Moffitt Cancer Center, Tampa, FL, comments on IPSS-Molecular (IPSS-M), a recently developed clinical-molecular prognostic system designed to improve risk stratification and facilitate treatment decisions in MDS.
The IPSS-M was developed and validated using genomic profiling data from 3711 patients with MDS, and integrates cytogenetic categories, blood counts, marrow blasts, and 31 genes, resulting in a unique risk score for individual patients which can be obtained via an open-access IPSS-M Web calculator. In addition to indicating the IPSS-M score and its corresponding risk category, this tool also provides time estimates for leukemia-free survival (LFS), overall survival (OS), and AML transformation.4
Importantly, the study identified that FLT3, MLL-PTD, and TP53 multi-hit mutations were associated with adverse outcomes whereas SF3B1 mutations were correlated with favorable outcomes.4
This valuable tool improves risk stratification for patients in MDS and will help guide clinical decision-making and design better clinical trials, which will ultimately help improve patient outcomes.4
FMS-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) occur in approximately 25% of patients with acute myeloid leukemia (AML), and are associated with a particularly adverse prognosis, a shorter response to therapy, a higher relapse rate and lower overall survival (OS).5
Patients with newly diagnosed FLT3-ITD+ AML are generally treated with a FLT3 inhibitor such as midostaurin and may subsequently undergo intensive chemotherapy with or without hematopoietic stem cell transplantation (HSCT). However, outcomes remain poor, highlighting the need for a more effective frontline treatment strategy for these patients.5
In this video, Harry Erba, MD, PhD, Duke University, Durham, NC, shares the results of QuANTUM-First (NCT02668653), a Phase III study evaluating whether the addition of quizartinib, an oral, potent, and highly selective type II FLT3 inhibitor, to standard induction and consolidation chemotherapy, and continued as a single-agent therapy, improves survival compared to chemotherapy alone in patients with newly diagnosed FLT3-ITD+ AML.6 The results were also shared in a press briefing presented at EHA.
After a median follow-up of 39.2 months, the study reported a median OS of 31.9 months in the quizartinib arm vs 15.1 months in the placebo arm, thereby meeting its primary endpoint. CR/CRi rates were 71.6% and 64.9%, respectively. The study also reported a longer relapse-free survival (RFS) in the quizartinib arm.6
In addition, while grade ≥3 adverse events were similar in both arms, patients treated with quizartinib experienced greater rates of neutropenia and QT prolongation, and deaths occurred in 11.3% of patients treated with quizartinib vs 9.7% of patients treated with chemotherapy alone.6
Dr Erba concluded: “The results show that when we use this Type II second-generation, more potent, more specific FLT3 inhibitor, we can improve the survival of patients up to the age of 75 with FLT3-ITD-mutated AML when it’s used in combination with intensive chemotherapy and continued for three years afterwards.”
The results from this study could provide further evidence for a potential approval of this agent by the FDA in patients with newly diagnosed FLT3-ITD+ AML. Nevertheless, with no head-to-head comparison between midostaurin and quizartinib, it will be important for clinicians to determine which agent to use in their patients.6
The introduction of tyrosine kinase inhibitors (TKIs) has transformed the treatment landscape of chronic myeloid leukemia (CML), and the life expectancy of most patients with BCR-ABL1+ chronic phase (CP) CML is now comparable to that of healthy individuals. Currently, four TKIs have been approved for the treatment of CML. These include imatinib, dasatinib, nilotinib, and bosutinib.7
However, patients who develop primary or secondary resistance, or experience intolerance to these TKIs have limited effective treatment options and the use of subsequent second-generation TKIs following is associated with poor efficacy or safety concerns. Treatments for this patient population therefore represent an unmet clinical need.8
In this video, Timothy Hughes, MD, FRACP, FRCPA, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia, outlines the results of ASCEMBL (NCT03106779), a Phase III study comparing asciminib to bosutinib in patients with CML previously treated with two or more TKIs.
Asciminib is a novel Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor that inhibits BCR-ABL1. It has been shown to remain active against mutations that confer resistance to approved TKIs and has been shown to induce durable response rates in a Phase I study evaluating this agent in heavily pre-treated patients (NCT02081378). Bosutinib is a second-generation TKI that has also been shown to be effective in patients who have been treated with prior TKIs.8
Data at week 24 presented at ASH 2021 had shown that the major molecular response (MMR) rate was 25.5% with asciminib vs 13.2% with bosutinib, and the response rate (RR) was also higher in patients across demographic and prognostic subgroups.8
At this year’s EHA congress, updated efficacy and safety data were presented from this trial after a median follow-up of 2.3 years. The study reported an MMR rate of 37.6% for asciminib vs 15.8% for bosutinib. In addition, 45.1% of patients treated with asciminib vs 19.4% of patients treated with bosutinib had a BCR-ABL1 transcript decline ratio combined (BCR-ABL1IS)≤1%, a measure associated with improved long-term survival. 9
In addition, the study showed that asciminib’s safety profile was better than that of bosutinib. The most common adverse events included thrombocytopenia (22.4% asciminib vs 15.8 % bosutinib), neutropenia (18.6% asciminib vs 14.5% bosutinib), diarrhea (0% asciminib vs 10.5% bosutinib), and increased alanine aminotransferase (0.6% asciminib vs 14.5% bosutinib).9
Overall, after this 2-year follow-up, asciminib continued to be superior to bosutinib in terms of efficacy and tolerability, therefore supporting the use of asciminib as an option for patients who are intolerant or develop resistance to TKIs.
Data from the Phase IV BYOND trial (NCT02228382) also released at EHA showed that bosutinib was active in patients who had been treated with two or three prior TKIs and were either resistant or intolerant to the last TKI, reporting a complete cytogenetic response (CCyR) of 58.5% at 4 years and an MMR at 4 years of 54.3%.10
Together, these data suggest that remains necessary to determine which patients could benefit from either drug. In addition, it is necessary to conduct a longer follow-up of the ASCEMBL study to identify any long-term safety signals that may arise.
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