A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia): Results of CALGB 100801 (Alliance).

Relapse remains the major cause of death in older patients transplanted for acute myeloid leukemia (AML) in first complete remission or for patients with advanced myelodysplastic syndrome (MDS) at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with reduced-intensity conditioning when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (BU) exposure, combined with the administration of azacitidine (AZA) post-transplant would mitigate the risk of relapse while reducing nonrelapse mortality and ultimately improve progression-free survival (PFS). On this phase II multicenter study, 63 patients (40 unrelated donors and 23 matched related donors) received a uniform conditioning regimen consisting of fludarabine i.v. (days -7 to -3), BU targeted to a daily area under the curve (AUC) of 4000 µM/min (days -6 to -3) after the administration of a 25-mg/m2 i.v. test dose on 1 day between days -14 to -9, and antithymocyte globulin (days -6, -5, and -4 (2 doses for matched related donors and 3 for matched unrelated donors only). Beginning on days +42 to +90, all patients were planned to receive up to 6 monthly cycles of AZA at 32 mg/m2 subcutaneously for 5 days. The median age was 62 years (range, 44 to 74); 13 had AML and 50 had MDS; 87% of patients were within 20% of the target AUC based on a validation sample. Forty-one patients (65%) started AZA at a median of 61 days (range, 43 to 91) post-transplant, and 17 patients (41%) completed all 6 cycles of AZA. The cumulative incidence of nonrelapse mortality at 2 years was 33.4% (95% confidence interval [CI], 22%-45%). The cumulative incidence of relapse was 25% (95% CI, 15%-37%) at 2 years. With a median follow-up of 58.9 months, the estimated PFS probability at 2 years and 5 years after transplantation was 41.2% (80% CI, 33.9%-49.9%) and 26.9% (80% CI, 20.4%-35.5%), respectively, for the entire group with a median PFS of 15.8 months (95% CI, 6.7 to 28.3). The probability of overall survival at 2 and 5 years was 45.7% (95% CI, 34.9%-59.9%) and 31.2% (95% CI, 21.3% to 45.8%), respectively, for the entire group with a median overall survival of 19.2 months (95% CI, 8.7 to 37.5). In summary, we demonstrated the feasibility of a novel reduced-intensity conditioning regimen with test dose BU targeted to an AUC of 4000 µM/min. The feasibility of AZA in this setting appears to be limited if applied to an unselected population of older hematopoietic stem cell transplantation recipients. (ClinicalTrials.gov Identifier: NCT01168219.).

A fatal case of transfusion-transmitted babesiosis in the State of Delaware.

BACKGROUND: Most cases of human babesiosis in North America are caused by Babesia microti, which is endemic in the northeastern and upper midwestern United States. Although the disease is usually transmitted by a tick bite, there has been an increase in the number of transfusion-transmitted cases reported. We describe a fatal case of transfusion-transmitted babesiosis in a nonendemic state, Delaware. CASE REPORT: The patient was a 43-year-old Caucasian woman with history of transfusion-dependent Diamond-Blackfan syndrome, hepatitis C, and splenectomy. She was admitted initially for presumptive pneumonia. The next day, a routine examination of the peripheral blood smears revealed numerous intraerythrocytic ring forms, consistent with Babesia. The parasitemia was approximately 5% to 6%. The diagnosis was confirmed by positive polymerase chain reaction (PCR) for B. microti DNA and high titer of antibody to B. microti (1:2048). Despite aggressive therapy including clindamycin and quinine antibiotics, the patient expired 3 days after admission. Subsequently, 13 blood donors were tested for B. microti. All tested donors were negative by PCR. However, one donor living in New Jersey had a significant elevated B. microti antibody titer (1:1024). CONCLUSIONS: We believe that this is the first reported case of transfusion-transmitted babesiosis in Delaware, a nonendemic state. Our case illustrates that clinicians should consider babesiosis in the differential diagnosis of immunocompromised patients who have fever and recent transfusion history, even in areas where babesiosis is not endemic. It also demonstrates the need for better preventive strategies including more sensitive, specific, and rapid blood donor screening tests to prevent transfusion-transmitted babesiosis.

Cytoprotection in acute myelogenous leukemia (AML) therapy.

Planning therapy for acute myelogenous leukemia (AML) is difficult because of the heterogeneous nature of the disease and varying patient age at presentation. Cytogenetics and patient age at the time of diagnosis are two major factors determining treatment outcome in AML. Patients with poor-risk cytogenetics have much lower complete remission rates than other groups. In addition, AML in patients greater than 55 to 60 years of age often exhibits a resistant phenotype, more akin to secondary AML or AML arising from myelodysplastic syndromes. This group is also characterized by lower complete remission rates, and often requires the delivery of intensive therapy to a patient population that is the least likely to tolerate it. At the Jefferson Health System (Philadelphia, PA), we wished to develop a regimen that was maximally intensive to treat stubborn disease, but gentle enough to be given to all patients regardless of age. Toward this end, 33 patients received a maximal dose of the cytoprotective agent, amifostine, before each infusion of idarubicin in the "7 + 3" regimen, escalating the dose of idarubicin in a phase I fashion to a maximum dose of 24 mg/m2 . The data indicate that the addition of amifostine to "7 + 3" AML induction therapy enables a substantial escalation of the idarubicin dose through the 21-mg/m2 dose level, without a concomitant increase in side effects, thus providing a regimen that is both intensive and applicable to patients of all ages. Currently, phase II studies are ongoing on a national basis to evaluate the efficacy of this regimen.

Novel BCR-ABL1 fusion identified by targeted next-generation sequencing in a patient with an atypical myeloproliferative neoplasm.

An unusual case of a BCR-ABL1-positive myeloproliferative neoplasm is presented with discordant molecular and cytogenetic characterization at diagnosis. More extensive molecular characterization of the fusion messenger RNA transcript using a next-generation sequencing approach identified a novel BCR-calcineurin-binding protein 1-ABL1 variant, which has not been described previously. This case highlights the potential utility of next-generation sequencing for a single-target application to resolve rare and unusual tumor genetic variants when standard molecular diagnostic methods are inconclusive. Although the relationship of this novel BCR-ABL1 fusion to the atypical pathologic features and initially suboptimal therapeutic response profile remains speculative, this case indicates that accurate molecular characterization of rare variants has diagnostic and potentially prognostic relevance.