A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL-1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/venetoclax in relapsed/refractory AML, we conducted a phase I multicenter openlabel study in 16 adults with relapsed/refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission (CR) in 5 of 7 (71.4%) patients who were naïve to the hypomethylating agent/venetoclax. No measurable residual disease (MRD) was detected in 80.0% of the patients who achieved CR. The median time to best response was 50 (range: 23 - 77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).

CPX-351 Pharmacokinetics and Safety in Adults with Hematologic Malignancies and Renal Function Impairment: Phase 1 Trial.

This open-label phase 1 study (clinicaltrials.gov, NCT03555955) assessed CPX-351 pharmacokinetics (PK) and safety in patients with hematologic malignancies with normal or impaired renal function. Patients were enrolled into three cohorts based on their creatinine clearance (CrCl): ≥90 mL/min (Cohort 1, normal renal function, n = 7), 30 to <59 mL/min (Cohort 2, moderate renal impairment, n = 8), or <30 mL/min (Cohort 3, severe renal impairment, n = 6). Patients received intravenous CPX-351 for initial induction; blood and urine samples were collected for PK analysis. The primary objective was to assess the PK parameters for cytarabine, daunorubicin, and their respective metabolites, arabinosyluracil (Ara-U) and daunorubicinol. Renal impairment did not significantly impact the cytarabine, daunorubicin, or daunorubicinol exposure, but it caused a slight increase in the Ara-U exposure. The CPX-351 side effect profile was similar in patients with impaired renal function compared to those with normal renal function. All the patients reported ≥1 treatment-emergent adverse event (TEAE), most commonly febrile neutropenia and nausea (57% each) and hyperglycemia (43%); no patients discontinued treatment due to TEAEs. These data suggest that CPX-351 dose adjustment is not required for patients with hematologic malignancies with moderate or severe renal impairment.

Diagnostic Precision or Pitfalls: How to Apply the New Acute Myeloid Leukemia Classification Systems?

BACKGROUND: The classification of acute myeloid leukemia (AML) has long been overseen by the World Health Organization (WHO) and published into a series of "Blue Books." These ledgers serve as the reference manual for AML classification and, in turn, classification-based treatment decisions. In 2022, two separate groups, each of which included hematologic oncologists, hematopathologists, and geneticists - developed and published two parallel classification systems for AML. One is from the WHO (WHO 5th edition), and a second is from an International Advisory Consortium (International Consortium Classification [ICC]). SUMMARY: Both modern classification systems originated from the revised 4th edition of the WHO Blue Books and thus share many similarities. There are never-the-less several important differences with the potential to substantially alter disease classification, access to clinical trials, and treatment decision-making. In this manuscript, we review the organization of the WHO and ICC classification systems for AML with emphasis on their similarities and differences, followed by areas in which their application to clinical scenarios may present difficulties. KEY MESSAGES: (1) The ICC and WHO 5th edition are concordant for the majority of AMLs. (2) Key differences between AML classification by the ICC and WHO 5th edition include (a) the overall framework of classification, (b) AML-defining blast threshold, definition of myelodysplasia-related AML, and (c) strategy for assigning therapy-related or germline-associated AML modifiers.

How I diagnose and treat thrombocytopenia in geriatric patients.

ABSTRACT: Thrombocytopenia in older individuals is a common but diagnostically challenging condition that has variable clinical impact to those who are affected. Diagnostic approach requires evaluation of the preexisting clinical conditions, detailed review of medications, and assessment for disorders that warrant urgent treatment. In this article, we describe a systematic approach to diagnosis of thrombocytopenia and present a schematic review for management strategies. Three clinical scenarios are presented that are relevant for their prevalence and management challenges in an older adult population. The first scenario addresses primary immune thrombocytopenia (ITP) and reviews different treatment options. The second one addresses complications of thrombocytopenia in management of the myelodysplastic syndrome. The last one reviews diagnostic challenges of drug-induced ITP.

Standardising acute myeloid leukaemia classification systems: a perspective from a panel of international experts.

The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised.

PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in Patients with Myelofibrosis.

PURPOSE: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. PATIENTS AND METHODS: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. RESULTS: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. CONCLUSIONS: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.

A Pilot Clinical Study to Investigate the Hypomethylating Properties of Freeze-dried Black Raspberries in Patients with Myelodysplastic Syndrome or Myeloproliferative Neoplasm.

Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are bone marrow disorders characterized by cytopenias and progression to acute myeloid leukemia. Hypomethylating agents (HMAs) are Food and Drug Administration-approved therapies for MDS and MDS/MPN patients. HMAs have improved patients' survival and quality of life when compared with other therapies. Although HMAs are effective in MDS and MDS/MPN patients, they are associated with significant toxicities that place a large burden on patients. Our goal is to develop a safer and more effective HMA from natural products. We previously reported that black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice. In addition, BRBs exert hypomethylating effects in patients with colorectal cancer and familial adenomatous polyposis. In the current study, we conducted a pilot clinical trial to evaluate the hypomethylating effects of BRBs in patients with low-risk MDS or MDS/MPN. Peripheral blood mononuclear cells (PBMCs) were isolated before and after three months of BRB intervention. CD45+ cells were isolated from PBMCs for methylation analysis using a reduced-representation bisulfite sequencing assay. Each patient served as their own matched control, with their measurements assessed before intervention providing a baseline for post-intervention results. Clinically, our data showed that BRBs were well-tolerated with no side effects. When methylation data was combined, BRBs significantly affected methylation levels of 477 promoter regions. Pathway analysis suggests that BRB-induced intragenic hypomethylation drives leukocyte differentiation. A randomized, placebo-controlled clinical trial of BRB use in low-risk MDS or MDS/MPN patients is warranted.

Prognostic impact of immunophenotypic aberrancies of blasts in lower risk myelodysplastic syndrome.

OBJECTIVE/BACKGROUND: Low risk myelodysplastic syndrome (MDS) is a marrow failure state eventually leading to transfusion dependence. Flow cytometry has previously been demonstrated as prognostic tool in MDS, however not thoroughly studied in lower risk MDS. In this study, we assessed whether assessment for immunophenotypic blast aberrancies by flow in low risk MDS patients has a prognostic role in these patients. METHODS: A total of 63 consecutive patients diagnosed with low/intermediate risk MDS were included. We recorded initial flow results, and collected time to transfusion dependence, and AML progression. RESULTS: On multivariate cox regression analysis, increasing IPSS-R score, an increase in the number of blast aberrancies on flow cytometry, and aberrant expression of CD7 on myeloid blasts increased likelihood of transfusion dependence. CONCLUSION: Low risk MDS patients with increasingly aberrant blast phenotypes by flow may be at risk for earlier transfusion dependence.

Project 2025: Proposals for the Continued Success of Drug Development in Acute Myeloid Leukemia.

The Food and Drug Administration Oncology Center of Excellence initiated Project 2025 to develop 5-year goals in specific areas of oncology drug development. This meeting, in October 2020, brought together a panel of regulators and academic experts in acute myeloid leukemia (AML) to discuss opportunities to maximize the success that has recently occurred in AML drug development. The panel discussed challenges and opportunities in clinical trial design and novel endpoints, and outlined key considerations for drug development to facilitate continued growth in the field.

Is there an optimal adjunct therapy to traditional cytotoxic induction?

The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic (such as daunorubicin or idarubicin), commonly known as "7 + 3." Many studies have been conducted to find an additional agent that might improve efficacy. Data from select studies has shown, in certain populations, benefit to adding cladribine, clofarabine and lomustine to a traditional backbone. For mutation-based chemotherapy regimens, midostaurin with 7 + 3 is the current standard of care for FLT3-mutant, younger AML patients. As we learn more about the synergism of molecular agents and traditional anti-cancer treatments, we can hopefully develop novel regimens without abandoning some of the benefits of these mutation agnostic historical therapies.

Avapritinib in the Treatment of Systemic Mastocytosis: an Update.

PURPOSE OF REVIEW: Patients with systemic mastocytosis, a dangerous and rare myeloid neoplasm, have long had few therapies available to them and, historically, rarely achieved from significant disease control. However, research and translational developments over the last decade have led to promising new options for disease management. In this review, we briefly outline the history of treatment for systemic mastocytosis and subsequently focus on the clinical development and potential applications of avapritinib (previously known as BLU-285), a potent and selective oral inhibitor of the tyrosine kinase most commonly mutated in this condition. RECENT FINDINGS: Phase I data and recent phase II data have demonstrated both safety and efficacy of this agent used as monotherapy, even in patients who have progressed on other targeted therapy. Studies to date have focused on patients with the most aggressive disease, but new trials in indolent mastocytosis are accruing currently. Over the next several years, one may anticipate finalized, peer-reviewed, and formally published data for this agent in both advanced systemic and indolent mastocytosis. Evidence from these early studies will also likely highlight where more research is needed.