Jennifer L. Holter

Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

Results of a prospective multicentre myeloablative double‐unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia

Double‐unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high‐dose myeloablative double‐unit CB transplantation (CBT) trial in adults with high‐risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1‐year overall survival in a multi‐centre setting. Fifty‐six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 107/kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80–96). Day 180 grade II‐IV acute graft‐versus‐host disease (GVHD) incidence was 64% (95%CI: 51–76) and 36% (95%CI: 24–49) of patients had chronic GVHD by 3‐years. At 3‐years post‐transplant, the transplant‐related mortality (TRM) was 39% (95%CI: 26–52), and the 3‐year relapse incidence was 11% (95%CI: 4–21). With a median 37‐month (range 23–71) follow‐up of survivors, the 3‐year disease‐free survival was 50% (95%CI: 37–63). Double‐unit CBT is a viable alternative therapy for high‐risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.

Disseminated Fusariosis Occurring in Two Patients Despite Posaconazole Prophylaxis

ABSTRACT Posaconazole is widely used for prophylaxis against invasive fungal infections in patients undergoing myeloablative therapy. Disseminated fusariosis is a serious invasive mold infection in such patients. Preclinical and clinical studies indicate activity of posaconazole against Fusarium. We describe two cases of disseminated fusariosis that occurred despite posaconazole prophylaxis.

Effect of radiotherapy and chemotherapy on bone marrow activity: a 18F-FLT-PET study

BackgroundRadiotherapy (RT) and chemotherapy are important treatment modalities for a variety of malignant tumor types. During therapy for malignant diseases, often the limitation for further therapy is determined by the capability of the bone marrow to withstand radiochemotherapeutic effects. Evaluation of hematologic toxicity is commonly performed with peripheral blood counts, and occasionally, sampling of marrow through a bone marrow biopsy. Neither method provides a comprehensive assessment, as bone marrow biopsy is invasive, and both are subject to sampling variability. Fluorine-18–3′-fluoro-3′-deoxy-L-thymidine–PET (18F–FLT–PET) is a noninvasive method and related to the rate of DNA synthesis and visualizes the high cycling activity of hematopoietic cells in the bone marrow compartment. To prove the clinical consistency of marrow function and imaging, we investigated populations of patients typically seen in clinical practice, after radiation and chemotherapy. In this feasibility study, patients were evaluated (i) to prove the ability of visualization and quantification of the activity of the bone marrow compartment with 18F–FLT–PET and (ii) to examine the effect of RT and chemotherapy on bone marrow activity and the correlation with clinical findings. MethodsBone marrow activity in the cervical region of 10 patients with laryngeal carcinoma who received a mean total dose of 68 Gy (range 30–41 fractions) was evaluated with 18F–FLT–PET, before and 1 month after RT. Whole body FLT images were assessed in nine patients with nonseminomatous testicular germ cell tumor, before and 6 months after the last chemotherapy, consisting of four courses of bleomycin, cisplatin, and etoposide. The maximum standardized uptake value (SUVmax) was used to quantify FLT uptake in bone marrow at the standard bone marrow regions. ResultsA significant decrease in 18F–FLT–PET uptake was observed in all the studied laryngeal carcinoma patients in the cervical region after RT of the adjacent bone marrow compartment. Tumor stage and additional field-of-view of RT were inversely related to the 18F–FLT uptake in bone marrow. The mean 18F–FLT SUVmax before RT was 3.0±1.34 and after RT was 1.94±0.60 (P=0.013). The mean 18F–FLT SUVmax of the spine (Th5–Th12) regions outside the field-of-view of RT were stable and reproducible and not significantly different (5.56±1.56 vs. 5.16±1.35, P=0.16). Chemotherapy did not result in a significant difference of whole body SUVmax value, with a mean SUVmax of 4.99±1.15 prechemotherapy, and a mean SUVmax of 5.28±1.0 postchemotherapy (P=0.21). Laboratory analysis of the hematologic parameters confirmed repopulation of the bone marrow. Conclusion18F–FLT uptake in the bone marrow decreases after RT, but not after chemotherapy. We conclude that 18F–FLT–PET is a potential noninvasive tool that can be used in the assessment of quantification of cellular division in the hematopoietic organ.

Extraosseous Ewing's sarcoma of the pancreas

The Ewing’s family of tumors (EFT) comprises a molecularly defined group of “small round blue cell tumors”, consisting of Ewing’s sarcoma of bone (ESB), extraosseous Ewing’s sarcoma (EES), peripheral primitive neuroectodermal tumor (pPNET), and Askin’s tumor. Characteristic translocations that disrupt the EWSR1 gene located at 22q12 create novel fusion genes that are central to the pathogenesis. The EFT also shares certain clinical characteristics, such as a peak incidence during the teenage years, a tendency to spread rapidly, and responsiveness to the same chemotherapeutic regimens and radiation therapy. Nearly all patients have occult disseminated disease at diagnosis; hence, chemotherapy is routinely used. Improvements in multimodality treatment have had a dramatic impact on outcomes. EES/pPNET has been reported in a variety of sites, including the pancreas, though this is extremely rare. We describe a case of pancreatic EES/pPNET in a 35-year-old woman and provide a brief review of the relevant literature.

High-dose cytosine arabinoside-induced symptomatic bradycardia.

Cardiac complications of high-dose cytosine arabinoside (HiDAC), although rare, predominantly include pericarditis, pericardial effusion and cardiomyopathy (with concurrent use of cyclophosphamide). Clinically significant arrhythmias associated with HiDAC, although reported in the literature, are rare. The following case report has for the first time used the Naranjo Scale to document a high-probability association (definite adverse drug reaction) of cytarabine with symptomatic sinus bradycardia.