Madhuri Vusirikala

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.

Hematogone Hyperplasia in Copper Deficiency

Copper deficiency is likely an underrecognized cause of anemia and neutropenia and may masquerade as a myelodysplastic syndrome (MDS). We report 2 cases of copper deficiency in which the diagnosis was suggested based on the characteristic morphologic findings, such as cytoplasmic vacuolization of erythroid and myeloid precursors and iron-containing plasma cells. It is interesting that both patients had hematogone hyperplasia. This phenomenon, largely absent in MDS, may aid in distinguishing nonclonal causes of cytopenias, such as copper deficiency, from MDS. It is of crucial importance to identify treatable causes of cytopenias when MDS is suspected. We recommend copper level assessment in patients suspected of having low-grade MDS, especially patients with neuropathy and normal results of cytogenetic studies.

Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis

A retrospective single center study was performed to evaluate the safety and efficacy of valacyclovir for prevention of cytomegalovirus (CMV) infection (reactivation) after allogeneic stem cell transplantation (SCT). We compared a group of 31 patients at risk for CMV reactivation (donor, recipient or both seropositive for CMV) who received valacyclovir at an oral dose of 1 g three times a day for CMV prophylaxis with a matched cohort of 31 patients who did not receive the drug or any other form of CMV prophylaxis. Valacyclovir was used as primary prophylaxis in 12 patients and as secondary prophylaxis (after a prior CMV reactivation was effectively treated with either ganciclovir or foscarnet and without CMV antigenemia at the start of valacyclovir) in the remaining 19 patients. The two treatment groups were well matched for the donor–recipient CMV serological status and other pre-transplant characteristics. CMV reactivation was detected by blood antigenemia testing using a commercially available immunofluorescence assay for CMV lower matrix protein pp65 in circulating leukocytes. For primary prophylaxis, 3/12 patients who received valacyclovir reactivated CMV compared to 24/31 patients in the control group (P < 0.001). For secondary prophylaxis, 5/19 valacyclovir patients reactivated compared to 16/24 control patients (P < 0.05). Valacyclovir was well tolerated except for infrequent and mild gastrointestinal side-effects. There was no difference in the incidence of CMV disease in the two groups. Prophylaxis with valacyclovir appears to be safe and efficacious in preventing both primary and secondary CMV reactivation in at-risk patients after allogeneic SCT. Larger prospective randomized studies will be required to confirm these observations. Bone Marrow Transplantation (2001) 28, 265–270.

Successful Treatment of Relapsed and Refractory Extramedullary Acute Promyelocytic Leukemia With Tamibarotene

Case Report A 25-year-old man presented in 2004 with extensive ecchymosis and lower extremity compartment syndrome requiring emergency surgery. At this time he was diagnosed with acute promyelocytic leukemia (APL). Conventional cytogenetic analysis of the bone marrow showed additional material on chromosome 7p, whereas molecular studies revealed promyelocytic leukemia gene-retinoic acid receptor alpha (PML-RARA) rearrangement (details of the patient’s cytogenetic and molecular analysis have been previously published). He was treated with all trans retinoic acid (ATRA) and idarubicin followed by two cycles of consolidation chemotherapy with doxorubicin and ATRA. In 2006, while he was on maintenance chemotherapy with methotrexate, 6 mercaptopurine, and ATRA, he developed pain in his shoulder. Diagnostic studies showed promyelocytic sarcoma (PS) of the scapula. A bone marrow biopsy showed relapse in the bone marrow. He was treated with a combination of ATRA, gemtuzumab ozogamicin, and arsenic trioxide (ATO) and achieved a complete molecular remission. In January 2007, he presented with back pain and was diagnosed with PS of the thoracic vertebra, confirmed by both fluorescent in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction, with no evidence of relapse in the bone marrow. He was treated with ATO and idarubicin and local radiation to the affected spine. This resulted in a complete remission and he then underwent matched unrelated allogenic stem-cell transplantation in February 2007, using high-dose cyclophosphamide and busulfan as the preparative regimen. He developed mild chronic graft versus host disease which was controlled with prednisone 10 mg every other day. He did well until January 2009 when he developed cough and shortness of breath. A CT scan of his chest showed a mass, measuring 8.5 2.5 cm in the superior vena cava extending into the right atrium. He underwent surgical resection of this mass revealing PS. His CSF analysis was negative for leukemic cells. He received ATO and ATRA and intensity modulated radiotherapy to the atrium and superior vena cava at a dose of 25.20 Gy in 14 treatments. After the radiation, he was treated with one cycle of high-dose cytarabine. After recovering from the chemotherapy, he was put on maintenance therapy with ATRA and ATO. In September 2009, he developed a mass in the left supraclavicular fossa measuring 2.5 2.2 cm. A biopsy confirmed recurrence of PS and a positron emission tomography (PET) scan showed multiple [F]fluorodeoxyglucose (FDG) avid masses in the soft tissue and bone, in the chest and pelvis. A bone marrow biopsy done at this time did not show any evidence of bone marrow involvement. He did not have any neurological symptoms and he declined a lumbar puncture for CSF analysis. He was treated with gemtuzumab ozogamicin and ATRA, but a repeat PET scan done in December 2009 showed only a mixed response. At this time there were more than 20 FDG avid nodules in the abdomen, chest, and deep muscles and subcutaneous tissues. These nodules ranged from 3 3 mm to 2 2 cm in diameter and standard uptake values in these nodules ranged from 2.2 to 13.6. An FDG avid PS involving the rectum is shown in (Fig 1). At this time he was started on tamibarotene on a compassionate basis at a dose of 6 mg/m/d orally divided into two daily doses for 56 days. He then had a 14-day rest period from medication, followed by resumption of tamibarotene for 28 days, followed again by a 14-day rest period. At this time he began a maintenance schedule, in which tamibarotene was administered in cycles for 28 days in a row followed by 28 days off. No other concomitant chemotherapy was administered. Four weeks after the initiation of tamibarotene, a PET scan showed tumor shrinkage (Fig 2) and 16 weeks after the initiation of the drug a PET scan showed complete resolution of his FDG avid PS sites (Fig 3). Eight months after the initiation of tamibarotene, his PET scan remained negative for FDG avid sites. The drug was well tolerated with only mild headache, nausea, and loss of appetite during the first cycle, with the symptoms improved over subsequent cycles. He is now 12 months out from initiation of tamibarotene with no evidence of disease and we plan to continue therapy indefinitely.

Panobinostat monotherapy and combination therapy in patients with acute myeloid leukemia, results from two clinical trials

Patients with acute myeloid leukemia (AML), who are refractory to induction therapy or experience relapse after a first complete remission (CR), have an unfavorable prognosis.[1][1] Epigenetic dysregulation is frequent in AML. In preclinical studies, the pan-deacetylase inhibitor (DACi) panobinostat

Novel Application of Extracorporeal Photopheresis as Treatment of Graft-versus-Host Disease Following Liver Transplantation

A 48-year-old man with hepatitis C virus (HCV) cirrhosis complicated by hepatocellular carcinoma underwent liver transplantation. His course was complicated by fever, diarrhea, abdominal pain, and pancytopenia. He developed a diffuse erythematous rash, which progressed to erythroderma. Biopsies of the colon and skin were consistent with acute graft-versus-host disease. Donor-derived lymphocytes were present in the peripheral blood. The patient was treated with corticosteroids and cyclosporine; however, he had minimal response to intensive immunosuppressive therapy. Extracorporeal photopheresis was initiated as a salvage therapy. He had a dramatic response, and his rash, diarrhea, and pancytopenia resolved. He is maintained on minimal immunosuppression 24 months later.