Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia.

Venetoclax is approved for older untreated acute myeloid leukemia (AML) patients. Venetoclax was available prior to approval off-label. We assessed our single-institution off-label experience with venetoclax/azacitidine, comparing outcomes with a clinical trial cohort that administered this regimen at the same institution. Thirty-three untreated AML patients unfit or unwilling to receive induction chemotherapy and prescribed venetoclax/azacitidine off-trial were retrospectively analyzed and compared with 33 patients who received the same therapy on trial. Outcomes were compared, and comparisons were made to a theoretical scenario in which off-trial patients received induction. Digital droplet polymerase chain reaction evaluated measurable residual disease (MRD). Off-trial venetoclax was attainable in nearly all patients for whom this was desired. The complete remission (CR)/CR with incomplete blood count recovery rate was 63.3% for off-trial patients who received treatment and 84.9% for trial patients (P = .081). The median overall survival for off-trial patients who received treatment was 381 days (95% confidence interval [CI], 174, not reached) vs 880 days (95% CI, 384, not reached) for trial patients (P = .041). Prior exposure to hypomethylating agents was associated with worse outcomes. Response rates with venetoclax/azacitidine were not inferior to a theoretical scenario in which patients received induction, and early death rates were less than expected with induction. MRD negativity was achievable. Newly diagnosed AML patients treated in a "real-world" scenario with off-trial venetoclax/azacitidine had inferior outcomes compared with patients treated in the setting of a clinical trial. Additionally, this therapy may be as effective, and less toxic, when compared with induction chemotherapy.

The Role of Advanced Practitioners in Optimizing Clinical Management and Support of Patients With Polycythemia Vera.

CASE STUDY Mr. M, a 65-year-old male, presented to his primary care physician with progressive fatigue, difficulty sleeping, and daily headaches for the past 3 weeks. His headaches were not associated with visual disturbances, cognitive deficits, or nausea/vomiting, and he had no history of migraines. He had a history of hypertension and hyperlipidemia, did not smoke, rarely drank alcohol, and had no recent illnesses or hospitalizations. His previous physical examination and laboratory studies 2 years ago were normal. The current physical examination revealed a plethoric yet well-appearing, well-nourished male in no acute distress. His lungs were clear to auscultation bilaterally without wheezes, rales, or rhonchi. He had a regular heart rate and rhythm without murmur. His abdomen was soft, without tenderness, distension, or palpable hepatosplenomegaly. Examination of the extremities was negative for edema. Distal pulses and sensation in the hands and feet were intact and equal bilaterally. Cranial nerves II to XII were deemed intact, and no gross focal deficits were observed. Complete blood count (CBC) revealed a slightly elevated white blood cell (WBC) count (14.6 × 109/L [normal range, 3.9-10.7 × 109/L; Wians, 2015]), erythrocytosis (red blood cell [RBC] count, 6.5 × 1012/L [normal range, 4.2-5.9 × 1012/L; Wians, 2015], hemoglobin, 19 g/dL [normal range, 14-17 g/dL; Wians, 2015], and hematocrit, 54.3% [normal range, 41%-51%; Wians, 2015]), thrombocytosis (platelet count, 500 × 109/L [normal range, 150-350 × 109/L; Wians, 2015]), and microcytosis (mean cell volume [MCV], 75 fL [80-100 fL; Wians, 2015]), which combined were cause for referral to a hematology/oncology clinic. During his hematology/oncology evaluation, Mr. M described "never feeling rested" and being unable to sleep with uncertain snoring habits. He was experiencing itching during hot showers yet did not have rashes and had not recently introduced a new soap. He had no family history of blood disorders and no personal history of blood clots. The second CBC and laboratory tests confirmed erythrocytosis (RBC count, 6.5 × 1012/L; hemoglobin, 18.9 g/dL; hematocrit, 54%) and microcytosis (MCV, 75 fL). Serum iron (22 µg/dL [normal range, 60-160 µg/dL]) and ferritin (5 ng/mL [normal range, 15-200 ng/mL]) were suggestive of iron deficiency, serum erythropoietin was 8 mU/mL (normal range, 4.0-18.5 mU/mL), and a Janus kinase 2 (JAK2) mutation analysis was positive for JAK2V617F. Platelet count remained 500 × 109/L and WBC count was 10.2 × 109/L.

Current and emerging therapies for patients with acute myeloid leukemia: a focus on MCL-1 and the CDK9 pathway.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that largely impacts the elderly population. Not all AML patients are candidates for the mainstay induction and consolidation treatment options. In addition, despite available therapies, most patients will eventually relapse on, or be refractory to, standard induction therapy, with limited subsequent choices and poor prognosis. Recently, several new and emerging therapies, with a variety of mechanisms of action, have broadened the treatment landscape in newly diagnosed and relapsed/refractory (R/R) AML, providing patients and healthcare providers with more options and several targeted treatment approaches. Preclinical data indicate that the anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) is important to AML cell survival. Cyclin-dependent kinase 9 (CDK9), a transcriptional activator necessary for the expression of MCL-1, represents a promising target for future AML therapies. A number of CDK9 inhibitors, as well as several direct MCL-1 inhibitors, are currently in clinical or preclinical development. The CDK9 inhibitors alvocidib, atuveciclib, and TG02 have completed phase 1/2 clinical trials, with results available for the alvocidib trial showing improved complete remission rates (70% vs 46%; P = .003) for alvocidib in combination with cytarabine and mitoxantrone, versus cytarabine/daunorubicin, in patients with newly diagnosed AML. In addition, several phase 1 clinical trials with CDK9 inhibitors are currently recruiting for treatment of advanced AML. A phase 1b study is also ongoing to investigate alvocidib in combination with B-cell lymphoma-2 inhibitor venetoclax for R/R AML. Although further research is needed, CDK9 inhibitors represent a promising new approach for the treatment of AML.

Iron Overload in Myelodysplastic Syndromes: Pathophysiology, Consequences, Diagnosis, and Treatment.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms varying in severity affecting one or more lines of hematopoiesis. Ineffective erythropoiesis results in dysregulation of iron metabolism. Most MDS patients have anemia, and some require regular red blood cell transfusions. These transfusions, in addition to factors of the disease itself, can result in iron overload (IO). Retrospective analyses suggest that MDS patients with IO have reduced overall survival and poorer outcomes following allogeneic stem cell transplant vs. those without IO. Iron chelation therapy (ICT; deferoxamine, deferasirox, or deferiprone) has been used to alleviate IO in other transfusion-dependent hematologic conditions (e.g., thalassemia), but its role in MDS has not been firmly established. A growing body of evidence suggests that ICT in MDS patients is an effective means for reducing transfusional IO and may significantly improve outcomes such as survival. The orally administered iron chelator deferasirox has been widely studied in MDS, and available studies have shown it to be generally well tolerated and effective in reducing IO in this population. The pathophysiology and clinical consequences of IO in MDS, as well as current methods for diagnosing and treating IO in these patients, are discussed.

Human occupation of northern Australia by 65,000 years ago.

The time of arrival of people in Australia is an unresolved question. It is relevant to debates about when modern humans first dispersed out of Africa and when their descendants incorporated genetic material from Neanderthals, Denisovans and possibly other hominins. Humans have also been implicated in the extinction of Australia's megafauna. Here we report the results of new excavations conducted at Madjedbebe, a rock shelter in northern Australia. Artefacts in primary depositional context are concentrated in three dense bands, with the stratigraphic integrity of the deposit demonstrated by artefact refits and by optical dating and other analyses of the sediments. Human occupation began around 65,000 years ago, with a distinctive stone tool assemblage including grinding stones, ground ochres, reflective additives and ground-edge hatchet heads. This evidence sets a new minimum age for the arrival of humans in Australia, the dispersal of modern humans out of Africa, and the subsequent interactions of modern humans with Neanderthals and Denisovans.

Novel hematological parameters for the evaluation of patients with myeloproliferative neoplasms: the immature platelet and reticulocyte fractions.

New automated hematology analyzers have led to the availability of novel hematological parameters, including the immature platelet fraction (IPF) and the immature reticulocyte fraction (IRF), both of potential interest in patients with myeloproliferative neoplasms (MPNs). We performed a prospective analysis of 217 patients with MPN, including 32 (15%) with essential thrombocythemia (ET), 43 (20%) with polycythemia vera (PV), and 142 (65%) with myelofibrosis (MF); the IPF and IRF were measured by the Sysmex XN analyzer. As compared to patients with ET, both a higher IPF and IRF were observed among patients with PV and MF. Factors associated with high IPF among patients with PV/ET were male sex, thrombocytopenia, and diagnosis of PV; among patients with MF, they were elevated peripheral blasts, low platelet count, JAK2 V617F mutation, and previous therapy. Factors associated with high IRF among patients with PV/ET were low hemoglobin, high reticulocyte count, and PV diagnosis; among patients with MF, they were peripheral blasts and elevated reticulocytes. The IPF and IRF represent novel parameters in patients with MPN with potential relevant clinical implications. Comparison with healthy subjects and those with secondary polycythemia is needed to confirm our preliminary findings.