Successful management of the potentially fatal hyperhaemolysis syndrome of sickle cell anaemia with a regimen including bortezomib and Hemopure.

WHAT IS KNOWN AND OBJECTIVE: Hyperhaemolysis syndrome (HHS) of sickle cell anaemia (SCA) is a life-threatening condition characterized by accelerated destruction of red blood cells typically following blood transfusions. Optimal treatment strategies have not been determined; therefore, reports utilizing novel therapies are needed. CASE DESCRIPTION: A 19-year-old African American man with SCA experienced HHS following a partial red cell exchange transfusion. He was treated with methylprednisolone, rituximab, darbepoetin, Hemopure and bortezomib, with resolution of the syndrome. WHAT IS NEW AND CONCLUSION: The HHS of SCA is thought to be immune-mediated even in the absence of detectable red cell alloantibodies. New therapies, including bortezomib and Hemopure, may be useful in this syndrome.

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium.

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days -6 to -4; fludarabine 30 mg/m2/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.

Donor lymphocyte infusion and methotrexate for immune recovery after T-cell depleted haploidentical transplantation.

CD34+ cell selection minimizes graft-versus-host disease (GVHD) after haploidentical donor stem cell transplant but is associated with slow immune recovery and infections. We report a Phase I/II study of prophylactic donor lymphocyte infusion (DLI) followed by methotrexate (MTX) GVHD prophylaxis after CD34-selected haploidentical donor transplant. A prophylactic DLI was given between day +30 and +42. Rituximab was given with DLI for the last 10 patients. The goal of the study was to determine a DLI dose that would result in a CD4+ cell count > 100/µL at Day +120 in ≥ 66% of patients with ≤ 33% grade II-III, ≤ 17% grade III, and no grade IV acute GVHD by Day +180. Thirty-five patients with malignant (n = 25) or nonmalignant disease (n = 10) were treated after CD34-selected haploidentical donor peripheral blood stem cell transplant. The DLI dose of 5 × 104 /kg met the CD4/GVHD goal with 67% of patients having CD4+ cells > 100/µL and 11% grade II-IV acute GVHD. The cumulative incidence of chronic GVHD was 16%. Fatal viral and fungal infections occurred in 11%. The 2 year estimated overall survival was 69% and the relapse rate was 14% for patients in remission at transplant. There was no effect of NK alloreactivity on relapse. Nine of ten patients at the target DLI dose cohort of 5 × 104 /kg are alive with median follow-up of 18 mos (range 6-29). Delayed prophylactic DLI and MTX was associated with promising outcomes at the target DLI dose. This trial was registered at clinicaltrials.gov, # NCT01027702.

Alternative donor hematopoietic stem cell transplantation for sickle cell disease.

Most patients who could be cured of sickle cell disease (SCD) with stem cell transplantation do not have a matched sibling donor. Successful use of alternative donors, including mismatched family members, could provide a donor for almost all patients with SCD. The use of a reduced-intensity conditioning regimen may decrease late adverse effects. Ten patients with symptomatic SCD underwent CD34+ cell-selected, T-cell-depleted peripheral blood stem cell transplantation from a mismatched family member or unrelated donor. A reduced-intensity conditioning regimen including melphalan, thiotepa, fludarabine, and rabbit anti-thymocyte globulin was used. Patients were screened for a companion study for immune reconstitution that included a donor lymphocyte infusion given 30-42 days after transplant with intravenous methotrexate as graft-versus-host disease (GVHD) prophylaxis. Seven eligible patients were treated on the companion study. Nine of 10 patients are alive with a median follow-up of 49 months (range, 14-60 months). Surviving patients have stable donor hematopoietic engraftment (mean donor chimerism, 99.1% ± 0.7%). There were no sickle cell complications after transplant. Two patients had grade II-IV acute GVHD. One patient had chronic GVHD. Epstein-Barr virus-related posttransplant lymphoproliferative disorder (PTLD) occurred in 3 patients, and 1 patient died as a consequence of treatment of PTLD. Two-year overall survival was 90%, and event-free survival was 80%. A reduced-intensity conditioning regimen followed by CD34+ cell-selected, T-cell-depleted alternative donor peripheral blood stem cell transplantation achieved primary engraftment in all patients with a low incidence of GVHD, although PTLD was problematic. This trial was registered at clinicaltrials.gov as #NCT00968864.

Nelarabine: a novel purine antimetabolite antineoplastic agent.

BACKGROUND: Nelarabine was approved by the US Food and Drug Administration (FDA) in October 2005 for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. OBJECTIVES: This article reviews the pharmacology, mechanism of action, and pharmacokinetic and pharmacodynamic properties of nelarabine. Also reviewed are nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies; its toxicity profile, dosage, and administration; and areas of ongoing and future research. METHODS: Relevant literature was identified through searches of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and the American Society of Hematology database (2003-2006) using the terms nelarabine, Arranon, 506U78, and 2-amino-6-methoxypurine arabinoside. The reference lists of the identified articles were searched for additional sources. Product information obtained from the manufacturer of nelarabine was consulted, as were the FDA reviews of nelarabine. All identified publications were considered, and those meeting the objectives of this review were included. RESULTS: Nelarabine, a soluble prodrug of 9-beta-D- arabinofuranosylguanine (ara-G), is a novel purine antimetabolite antineoplastic that preferentially accumulates in T-cells. Ara-G is rapidly phosphorylated in T-cells to ara-G triphosphate (ara-GTP), which exerts cytotoxic effects. Renal elimination of ara-G is decreased in patients with mild to moderate renal impairment; however, no dose adjustment is recommended. Accumulation of ara-GTP occurs in T-cells in a dose-dependent manner, leading to preferential cytotoxicity. Nelarabine has activity in T-cell malignancies, as evaluated in 2 Phase I and 5 Phase II studies. It received accelerated approval from the FDA based on the resuits of 2 Phase II trials, one in pediatric patients (PGAA 2001) and the other in adults (CALGB 19801). In PGAA 2001, patients with T-ALL in first relapse (n = 33) had an objective response rate of 55% (16 with a complete response [CR] and 2 with a partial response [PR]), and those with T-ALL in second relapse (n = 30) had an objective response rate of 27% (7 CR and 1 PR). Among patients with central nervous system-positive T-ALL or T-cell non-Hodgkins lymphoma (T-NHL) (n = 21), 33% had an objective response (5 CR and 2 PR); among patients with T-ALL or T-NHL with extramedullary relapse (n = 22), 14% had a PR. CALGB 19801 included 39 adult patients with T-cell malignancies, of whom 7 (18%) had a CR and an additional 2 (5%) had a CR without full hematologic recovery. The recommended dose of nelarabine in adults is 1500 mg/m(2) IV given over 2 hours on days 1, 3, and 5, repeated every 21 days; the recommended dose in pediatric patients is 650 mg/m(2) IV given over 1 hour for 5 consecutive days, repeated every 21 days. Dose-limiting toxicities observed in the Phase I and II trials included central and peripheral neurotoxicity. Symptoms of central neurotoxicity included somnolence, seizures, dizziness, confusion, and ataxia; symptoms of peripheral neurotoxicity included paresthesias, pain in the extremities, and peripheral neuropathy. CONCLUSIONS: Nelarabine is indicated for the treatment of T-ALL and T-LBL that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Objective response rates in Phase II clinical trials of nelarabine have ranged from 11% to 60%. Use of nelarabine is limited by potentially severe neurotoxicity.