First-in-human study of JNJ-67571244, a CD33 × CD3 bispecific antibody, in relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome.

Relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) outcomes remain poor. A targeted cluster of differentiation (CD)33 × CD3 bispecific antibody, JNJ-67571244, was assessed to identify the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety and tolerability, and preliminary clinical activity in patients with r/rAML or r/rMDS. This first-in-human, open-label, phase I, dose-escalation/dose-expansion study included patients with r/rAML or r/rMDS who were ineligible for or had exhausted standard therapeutic options. JNJ-67571244 was administered intravenously or subcutaneously using step-up dosing until ≥1 discontinuation condition was met. Outcomes included safety/tolerability, preliminary clinical activity, and systemic pharmacokinetics and pharmacodynamics. The study was terminated after evaluating 10 dose-escalation cohorts (n = 68) and before starting dose-expansion. Overall, 11 (16.2%) patients experienced ≥1 dose-limiting toxicity; all experienced ≥1 treatment-emergent adverse event (TEAE; treatment related: 60 [88.2%]); and 64 (94.1%) experienced ≥1 TEAE of Grade ≥3 toxicity (treatment related: 28 [41.2%]). Although some patients had temporary disease burden reductions, no responses were seen. JNJ-67571244 administration increased multiple cytokines, which coincided with incidence of cytokine release syndrome, infusion-related reactions, and elevated liver function tests. A prolonged step-up strategy was tested to improve tolerability, though this approach did not prevent hepatotoxicity. T-cell activation following treatment suggested target engagement but did not correlate with clinical activity. Safely reaching the projected exposure level for JNJ-67571244 efficacy was not achieved, thus MTD and RP2D were not determined.

Which FLT3 Inhibitor for Treatment of AML?

OPINION STATEMENT: Treatment options in acute myeloid leukemia (AML) have improved significantly over the last decade with better understanding of disease biology and availability of a multitude of targeted therapies. The use of FLT3 inhibitors (FLT3i) in FLT3-mutated (FLT3mut) AML is one such development; however, the clinical decisions that govern their use and dictate the choice of the FLT3i are evolving. Midostaurin and gilteritinib are FDA-approved in specific situations; however, available data from clinical trials also shed light on the utility of sorafenib maintenance post-allogeneic stem cell transplantation (allo-SCT) and quizartinib as part of combination therapy in FLT3mut AML. The knowledge of the patient's concurrent myeloid mutations, type of FLT3 mutation, prior FLT3i use, and eligibility for allo-SCT helps to refine the choice of FLT3i. Data from ongoing studies will further precisely define their use and help in making more informed choices. Despite improvements in FLT3i therapy, the definitive aim is to enable the eligible patient with FLT3mut AML (esp. ITD) to proceed to allo-SCT with regimens containing FLT3i incorporated prior to SCT and as maintenance after SCT.

The role of cladribine in acute myeloid leukemia: an old drug up to new tricks.

Despite advances in understanding the pathogenesis of acute myeloid leukemia (AML), the standard therapy remained nearly unchanged for several decades. There have been many efforts to improve the response and survival by either increasing the cytarabine (ARA-C) dose or adding a third agent to the standard chemotherapy regimen. Several studies have evaluated the addition of cladribine (CdA) to standard induction, exploiting its property to potentiate ARA-C uptake. Response rates for combination regimens including CdA in relapsed/refractory (R/R) adults are approximately 50% and approximately 70% in de novo AML. Recently, a low intensity combination of CdA and ARA-C alternating with decitabine has shown promising results in older patients with AML. In this review, we will discuss the role of CdA in the treatment of AML, summarizing the recent clinical data regarding its incorporation into the induction therapy for adult AML.

Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of patients with T-PLL, it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL, and will thus support clinical decision making, as well as the approval of new therapeutics by healthcare authorities.

Myeloid cell leukemia-1 dependence in acute myeloid leukemia: a novel approach to patient therapy.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, affecting approximately 21,000 people annually (nearly 11,000 deaths) in the United States. B-cell lymphoma 2 (BCL-2) family proteins, notably myeloid cell leukemia-1 (MCL-1), have been associated with both the development and persistence of AML. MCL-1 is one of the predominant BCL-2 family members expressed in samples from patients with untreated AML. MCL-1 is a critical cell survival factor for cancer and contributes to chemotherapy resistance by directly affecting cell death pathways. Here, we review the role of MCL-1 in AML and the mechanisms by which the potent cyclin-dependent kinase 9 inhibitor alvocidib, through regulation of MCL-1, may serve as a rational therapeutic approach against the disease.

Updates on the pathophysiology and treatment of aplastic anemia: a comprehensive review.

INTRODUCTION: The past decade or longer has witnessed an acceleration in our understanding of previously developed immune system and clonal evolution mechanisms, and the genesis of more novel concepts of telomere attrition. Many of these concepts are steadily finding their way into translation in various aspects of clinical practice, and provide prospects to improve AA management and inform therapeutic strategy development. In this review, we intend to discuss the pathophysiology and treatments with an emphasis on most recent developments to provide an update on our understanding of disease mechanisms. Areas covered: A literature search was undertaken addressing various aspects of pathophysiology with a focus on the role of immune system repertoire, telomeres and mutational events surrounding AA. We also reviewed upon the temporal evolution of treatment strategies in AA to the contemporary management of today and commented briefly upon the more recently investigated novel therapies and their expanding niche especially in the transplant and salvage setting. Expert commentary: Immune-mediated destruction of hematopoietic stem and progenitor cells, leading to a marrow devoid of hematopoietic elements, and peripheral pancytopenia are the hallmarks of AA. Recent studies have shed light on another facet of the disease - as a clonal disorder characterized by karyotypic abnormalities, genomic instability, telomere attrition, and recurrent somatic mutations reminiscent of myeloid malignancies. Further understanding of this underlying pathophysiology can help in improving prognostication and treatment of this disease.

Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia.

Despite being considered "good-risk" acute myelogenous leukemia (AML), long term outcomes in core binding factor (CBF) AML suggest room for improvement. We report on a regimen consisting of fludarabine, cytarabine, granulocyte colony stimulating factor, and low dose gemtuzumab ozogamicin (FLAG-GO) as front-line therapy of patients with CBF AML. Forty-five patients were enrolled (median age 48 years). Remission rate was 95% with 5% induction deaths. The overall survival (OS) and relapse free survival (RFS) probability at 3 years are 78% and 85%, respectively. FLAG-GO regimen results in high rates of RFS and OS in CBF AML. Our data along with recent data from several large groups strongly argues in favor of incorporation of gemtuzumab ozogamicin in frontline regimens for CBF AML.