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Among patients with IDH1 -mutated relapsed or refractory leukemia, daily oral ivosidenib, an IDH1 inhibitor, induced molecular clearance of leukemic cells from bone marrow in 21% of patients and was associated with transfusion independence and a low rate of serious adverse events.

Older adults with acute myeloid leukemia (AML) who are not fit for standard chemotherapy historically have poor outcomes. Approximately 12–15% of older patients with AML harbor isocitrate dehydrogenase 2 ( IDH2 ) gene mutations. Enasidenib is an oral inhibitor of mutant IDH2 proteins. Among 39 patients with newly diagnosed mutant- IDH2 AML who received enasidenib monotherapy in this phase I/II trial, median age was 77 years (range 58–87) and 23 patients (59%) had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0 (range 1–35). The most common treatment-related adverse events were indirect hyperbilirubinemia (31%), nausea (23%), and fatigue, decreased appetite, and rash (18% each). Treatment-related grade 3–4 cytopenias were reported for eight patients (21%); there was no treatment-related grade 3–4 infections. Twelve patients achieved a response (overall response rate 30.8% [95% CI 17.0%, 47.6%]), including seven patients (18%) who attained complete remission. At a median follow-up of 8.4 months, the median duration of any response was not reached (NR). Median overall survival for all patients was 11.3 months (95% CI 5.7, 15.1), and was NR for responders. Oral, outpatient targeted treatment with enasidenib may benefit older adults with newly diagnosed mutant- IDH2 AML who are not candidates for cytotoxic regimens.

PurposeIsocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839).MethodsPatients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity.ResultsIvosidenib was rapidly absorbed and slowly eliminated (half-life 72–138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119–168% at 500-mg QD ivosidenib.ConclusionsIvosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation.Clinical trial registrationClinicalTrials.gov NCT02074839.

A 60-year-old man was seen in the outpatient cancer center because of bone pain that had lasted for 2 months and the presence of lytic bone lesions on imaging studies. Biopsy specimens of bone marrow and bone lesions showed increased mast cells. A diagnostic procedure was performed. Presentation of Case Nurse Practitioner Mark S. Brezina (Hematology): A 60-year-old man was seen in the outpatient cancer center at this hospital because of bone pain and skeletal lesions on imaging. The patient had been well until approximately 2 months before this evaluation, when he had a gradual onset of pain in the back of his neck and shoulders, which was followed later by a sharp pain in the middle of his back that began suddenly after sneezing. The pain increased after exercise and did not decrease with physical therapy, massage therapy, or a course of prednisone. Dr. Ambrose J. . . .

A 49-year-old man was admitted to this hospital because of perinephric collections of fluid and acute renal failure. Seven years earlier, routine testing revealed an elevated hematocrit; regular phlebotomy was begun. Ten months before admission to this hospital, dyspnea on exertion developed; imaging studies showed pleural effusions and bilateral perinephric cystic lesions. One month before admission, left-flank pain developed suddenly, and the left perinephric collection of fluid had enlarged; a drain was placed, and acute renal failure developed. A diagnostic procedure was performed. Presentation of Case Dr. David B. Sykes (Hematology–Oncology): A 49-year-old man was admitted to this hospital because of erythrocytosis, perinephric collections of fluid, and acute renal failure. The patient had been well until 7 years earlier, when routine testing at another facility revealed a hematocrit of 58.1%; the level of erythropoietin was 16.2 mIU per milliliter (reference range, 4.1 to 19.5). Ultrasonography of the abdomen reportedly revealed normal-size kidneys, with no hydronephrosis or cysts, and several hepatic lesions (approximately 1 cm in diameter) that were consistent with hemangiomas. A presumptive diagnosis of polycythemia vera was made, and therapeutic phlebotomy was . . .

The Axl receptor tyrosine kinase is a transforming oncogene in NIH3T3 cells. In order to define structural requirements of the Axl receptor necessary for transformation we passaged recombinant retroviruses carrying the axl cDNA in NIH3T3 cells, generating randomly mutated axl variants. Using this strategy, we have isolated three axl viral strains (1B1, SV8, and FFa4) that show augmented 3T3 cell transforming capacity associated with elevated p140Axl. Upon sequencing, the 1B1 and SV8 proviruses possessed only silent mutations, making p140Axl overexpression the most likely explanation for their increased transformation activity. However, the characterization of FFa4 revealed a deletion of sequences encoding the carboxy-terminal 45 amino acids leading to the generation of a chimeric transcript comprised of a truncated Axl receptor with a segment of the 3' UTR region. Mutational analysis revealed that the transforming activity of FFa4 was specific to the formation of the chimeric receptor rather than to the carboxyl-terminal truncation. Intriguingly, none of the viral strains were able to transform the murine cell lines NR-6 and 32D despite equivalent expression of surface p140Axl protein. Further analysis showed that Axl's transforming potential is dependent on the host cell type, the presence of a putative pp190 as a facilitator for transformation, and the level of p140Axl expression. Taken together, these results underscore the complexity of Axl biology which is dependent on receptor stoichiometry and the cellular background.

A 73-year-old woman was seen in the cancer center at this hospital for management of a myelodysplastic syndrome. She had had anemia for 2 years, and a diagnosis of a myelodysplastic syndrome with isolated del(5q) had been made 1 year earlier. She required red-cell transfusions every 2 months to maintain a hematocrit of 30%; she did not have recurrent infections or bleeding. A management decision was made. Presentation of Case A 73-year-old woman was seen in the cancer center at this hospital for management of a myelodysplastic syndrome. Approximately 2.5 years earlier, exertional dyspnea developed and worsened during the subsequent 6 months. Two years before this evaluation, a transthoracic echocardiogram showed moderate aortic stenosis. Furosemide was administered, with little improvement. Increasing shortness of breath at rest and a brief episode of syncope occurred. The patient came to the emergency department at this hospital. On examination, the blood pressure was 137/70 mm Hg, the pulse 112 beats per minute, the respiratory rate 20 breaths per minute, and the . . .

A young woman was seen because of anemia and evidence of increased iron stores. She was of Italian descent. Her father, a paternal aunt, and one sister had Diamond–Blackfan anemia, and her mother had been told she had β-thalassemia trait. A young woman was seen because of anemia and evidence of increased iron stores. Her father had Diamond–Blackfan anemia, and her mother had been told she had β-thalassemia trait. Presentation of Case A 25-year-old woman was seen in the hematology clinic at this hospital because of anemia and laboratory evidence of increased iron stores. The patient had been admitted to another hospital one month earlier because of pain in the left lower abdominal quadrant that radiated to the back and was associated with headache and shortness of breath. Computed tomography (CT) of the abdomen and pelvis showed calculi in the left kidney and fat stranding along the left iliopsoas muscle. Laboratory studies revealed a normochromic, normocytic anemia; the serum iron level was 213 μg per deciliter (38.1 μmol per . . .

The preferred post-remission therapy for older patients with acute myeloid leukemia (AML) in first complete remission (CR1) remains uncertain. In this retrospective, multicenter study, we compared the outcomes for older AML patients (age 60–77 years) receiving allogeneic hematopoietic cell transplantation (alloHCT) ( n  = 431) with those treated on prospective National Clinical Trials Network induction and nontransplantation chemotherapy (CT) consolidation trials ( n  = 211). AlloHCT patients were younger (median age: 64.2 versus 67.9 years, p  < 0.001), but more frequently had high-risk AML (high WBC, secondary AML, and unfavorable cytogenetics). Overall survival (OS) was worse in alloHCT during the first 9 months after CR1 (HR = 1.52, p  = 0.02), but was significantly better thereafter (HR = 0.53, p  < 0.0001) relative to CT. Treatment-related mortality (TRM) following HCT was worse in the first 9 months (HR = 2.8, 95% CI: 1.5–5.2, p  = 0.0009), while post-HCT relapse was significantly less frequent beyond 9 months (HR = 0.42, 95% CI: 0.29–0.61, p  < 0.0001). Despite higher early TRM, alloHCT recipients had superior long-term OS [29% (24–34%) versus CT 13.8% (9–21%) at 5 years]. Although this is a retrospective analysis with potential biases, it indicates that alloHCT led to heightened early risks from TRM, yet reduced relapse and superior long-term survival relative to CT in older AML patients in CR1.

A 49-year-old HIV-positive man was seen in the hematology clinic because of rapidly progressive anemia. He had been HIV-positive for 20 years and had discontinued antiretroviral therapy 6 months earlier. The hemoglobin level was 6 g per deciliter, the hematocrit 16.9%, the reticulocyte count 0.2%, and the white-cell count 2600 per cubic millimeter, with a normal differential count. Diagnostic procedures were performed. A 49-year-old HIV-positive man was seen in the hematology clinic because of rapidly progressive anemia. The hemoglobin level was 6 g per deciliter, the hematocrit 16.9%, the reticulocyte count 0.2%, and the white-cell count 2600 per cubic millimeter, with a normal differential count. Presentation of Case A 49-year-old man infected with the human immunodeficiency virus (HIV) was seen in the hematology clinic at this hospital for evaluation of anemia. Five weeks earlier (1 week before a routine follow-up visit with his infectious-disease specialist), laboratory testing showed anemia (Table 1). Treatment with iron and multiple vitamins was initiated, and the patient was referred for hematologic evaluation. HIV infection had been diagnosed approximately 20 years earlier, and he was followed by an infectious-disease specialist at this hospital. Eleven months earlier, the patient had discontinued antiretroviral therapy because of lipoatrophy, hyperlipidemia, and “pill fatigue” (the number . . .