Julie Bergeron

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3‐positive T cells to recognize and eliminate CD19‐positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B‐cell precursor ALL on the basis of single‐group trials that showed efficacy and manageable toxic effects. Methods In this multi‐institutional phase 3 trial, we randomly assigned adults with heavily pretreated B‐cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard‐of‐care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event‐free survival than that with chemotherapy (6‐month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem‐cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B‐cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167.)

Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission

For adults with Philadelphia chromosome‐negative (Ph−) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric‐inspired chemotherapy may also offer durable leukemia‐free survival in the absence of HCT. We compared 422 HCT recipients aged 18–50 years with Ph‐ALL in CR1 reported to the CIBMTR with an age‐matched concurrent cohort of 108 Ph− ALL CR1 patients who received a Dana‐Farber Consortium pediatric‐inspired non‐HCT regimen. At 4 years of follow‐up, incidence of relapse after HCT was 24% (95% CI 19–28) versus 23% (95% CI 15–32) for the non‐HCT (chemo) cohort (P=0.97). Treatment‐related mortality (TRM) was higher in the HCT cohort [HCT 37% (95% CI 31–42) versus chemo 6% (95% CI 3–12), P<0.0001]. DFS in the HCT cohort was 40% (95% CI 35–45) versus 71% (95% CI 60–79) for chemo, P<0.0001. Similarly, OS favored chemo [HCT 45% (95% CI 40–50)] versus chemo 73% [(95% CI 63–81), P<0.0001]. In multivariable analysis, the sole factor predictive of shorter OS was the administration of HCT [hazard ratio 3.12 (1.99–4.90), P<0.0001]. For younger adults with Ph− ALL, pediatric‐inspired chemotherapy had lower TRM, no increase in relapse, and superior overall survival compared to HCT. Am. J. Hematol. 91:322–329, 2016.

Prevalence of α-Globin Gene Deletions Among Patients with Unexplained Microcytosis in a North-American Population

Increasing multi-ethnicity is likely to make α-thalassemia (α-thal) more prevalent in Western metropolitan areas. Multiplex polymerase chain reaction (m-PCR) allows rapid and precise identification of most of α-thal carriers. With this method, we sought to determine the prevalence of α-thal and the corresponding genotype, among all non repetitive consecutive blood samples that had an unexplained microcytosis. These specimens had been sent to the hematology laboratory for a blood count analysis, found to be microcytic, and secondarily tested for ferritin level and hemoglobin (Hb) high performance liquid chromatography (HPLC) profile. Five hundred and sixteen microcytic blood samples were evaluated and 197 samples with normal ferritin and Hb HPLC were studied by m-PCR. Among 196 interpretable PCRs, 48 α-thal cases (24.5%) were identified: 28 with a single α-globin gene deletion and 20 with two α-globin gene deletions. Of these 20 cases, six showed two deletions in cis. None of the erythrocytic parameters studied predicted the presence of α-thal deletions. We conclude that a significant proportion (24.5%) of blood counts with microcytosis not explained by an iron deficiency, an inflammatory state or an abnormal Hb on HPLC, are caused by an α-globin gene deletion. The pertinence of genetic counseling for α-thal based on molecular diagnosis should be evaluated more formally in urban centers where this genetic condition is likely to have an increasing prevalence and clinical relevance.

A phase II study of topotecan in patients with anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma.

To determine the efficacy and toxicity of a novel chemotherapeutic approach with topotecan, a camptothecin analog, for progressive or recurring anaplastic oligodendroglioma or mixed oligoastrocytoma.Patients from seven centers with recurrent or progressive disease were treated with topotecan, 1.5 mg/m2 intravenously (i.v.), 30 min daily×5 days every 3 weeks. Efficacy and toxicity were assessed clinically and radiologically. The study was planned to accrue up to 30 evaluable patients if there was at least one response among the first 15 patients treated.Sixteen eligible patients entered the study. No response was documented in 14 evaluable patients. Eleven patients had stable disease of a median of 3.8 months and three had progressive disease. Sixteen patients were evaluable for toxicity. The most significant toxic effect was myelosuppression. Grade 3 or 4 granulocytopenia was experienced by 15 of 16 patients and led to dose reduction in nearly half of the cycles delivered. Other adverse effects were fatigue, nausea, stomatitis, alopecia, and vomiting.Topotecan, delivered in the daily×5 regimen, is relatively well tolerated. We could not demonstrate significant activity among the population studied to justify completing accrual to 30 patients. Topotecan did not demonstrate, with this small sample size, efficacy as a salvage chemotherapy monotherapy after exposure to procarbazine, CCNU and vincristine. Further trials with different agents in this indication are certainly warranted.