Vaneuza Araujo Moreira Funke

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study.

Patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor need new therapeutic approaches. Hematopoietic SCT (HSCT) using mismatched or haploidentical related donors has been used in the past, but was associated with a significant risk of GVHD and mortality. Recently, the use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to prevent GVHD in recipients of haploidentical HSCT, but the majority of reports have focused on patients with hematology malignancies. We describe the outcome of 16 patients who underwent haploidentical transplantation using a reduced-intensity conditioning regimen with post-transplant Cy. Stem cell sources were BM (N=13) or PBSCs (N=3). The rate of neutrophil engraftment was 94% and of platelet engraftment was 75%. Two patients had secondary graft failure and were successfully salvaged with another transplant. Three patients developed acute GVHD being grades 2–4 in two. Five patients have died and the 1-year OS was 67.1% (95% confidence interval: 36.5–86.4%). In our small series, the use of a reduced-intensity conditioning with post-transplant Cy in haploidentical BMT was associated with high rates of engraftment and low risk of GVHD in patients with relapsed/refractory SAA.

Therapy for severe refractory acute graft-versus-host disease with basiliximab, a selective interleukin-2 receptor antagonist

Basiliximab is a chimeric monoclonal antibody that binds to the α chain of IL-2R on activated cytotoxic T-cells, inhibiting lymphocyte proliferation. We report 34 patients with refractory acute GVHD (grade III–IV) who received basiliximab from December 1998 to October 2003. Adults received 40 mg weekly (2–3 doses) and children received half of this dose. Median age was 13 years. Twenty-five donors were unrelated. The stem cell source was bone marrow in 30 and cord blood in four. Complete responses were seen in 27/32 patients (84%) with skin, 12/25 (48%) with gut and 6/23 (26%) with liver GVHD. Median duration of response was 38 days (5–1103). Overall survival at 5 years was 20%. Eleven patients (32%) are alive. The main causes of death were CMV (n=4), fungus (n=6), sepsis (n=8), hemorrhage (n=2), and relapse (n=2). Graft-versus-host disease flares were observed in 14 patients (41%), half being rescued by other therapies. In conclusion, basiliximab was able to induce complete responses in patients with refractory acute GVHD. Prospective studies are necessary to evaluate the optimal treatment schedule.

Low-dose cyclophosphamide conditioning for haematopoietic cell transplantation from HLA-matched related donors in patients with Fanconi anaemia

Allogeneic haematopoietic cell transplantation (HCT) is effective therapy for Fanconi anaemia (FA). FA patients do not tolerate conditioning with 200 mg/kg of cyclophosphamide (Cy), typically used in aplastic anaemia. We previously published results of studies in which Cy doses were gradually reduced from 200 to 100 mg/kg. Here we update results of the initial studies and report data on 30 new patients conditioned with Cy either at 80 mg/kg (n = 7) or at 60 mg/kg (n = 23), given over 4 days before HCT from human leucocyte antigen‐matched related donors. Methotrexate and cyclosporine were given for graft‐versus‐host disease (GVHD) prophylaxis. All seven patients given Cy at 80 mg/kg and 21 of 23 given Cy at 60 mg/kg had sustained engraftment, while two patients, both with clonal cytogenetics abnormalities, experienced graft failure. Grades 2–3 acute GVHD rates were 57% and 14% for patients given the higher and lower Cy doses, respectively (P = 0·001). Four patients given Cy at 80 mg/kg and 22 given Cy at 60 mg/kg were alive at a median of 47 (44–58) months and 16 (3–52) months, respectively. Cy at 60 mg/kg has acceptable toxicities, low rates of GVHD, and is sufficient for engraftment of related grafts in most FA patients.

Safety and potential efficacy of low-dose methotrexate for treatment of chronic graft-versus-host disease

Summary:Low-dose methotrexate (MTX) is widely used in autoimmune diseases because of its anti-inflammatory activity. We report here the results of a retrospective study to review the outcomes of low-dose MTX used for treatment of refractory chronic graft-versus-host disease GVHD, with the goal of reducing the amount of prednisone needed to control the disease. In all, 14 patients with refractory chronic GVHD received MTX at a dose of 7.5 mg/m2/weekly for 3–50 weeks. Also, 11 patients had skin involvement, often with scleroderma or fasciitis. The median duration of chronic GVHD at the start of MTX was 38 (range 1–135) months. In this retrospective review, we found no grade 3–4 toxicities, and none of the patients needed blood transfusion or growth factors. In 10 patients (71%), GVHD could be adequately controlled with prednisone at doses below 1 mg/kg every other day without the addition of other agents. Four patients decreased the amount of concomitant immunosuppressive treatment, five continued with the same regimen, four required an increase in immunosuppressive treatment, and one decided to discontinue all treatment. From this preliminary analysis, MTX appears to be a well-tolerated, inexpensive and possibly steroid-sparing agent that is worthy of further evaluation in prospective trials for treatment of chronic GVHD.

Imatinib mesylate versus allogeneic BMT for patients with chronic myeloid leukemia in first chronic phase.

Imatinib mesylate (IM) is now first-line treatment for CML. To study the results of treatment with IM after IFN failure/intolerance versus allogeneic BMT (allo-BMT), we retrospectively analyzed 264 patients treated for CML in first chronic phase in three different institutions. Over a 6-year period (2001–2006), 174 patients received IM after failure of or intolerance to IFN. During the same period of time, 90 patients received an allo-BMT from an HLA-matched sibling (n=83) or an unrelated donor (n=7). The IM group was older (41 versus 33 years, P<0.001). Five-year EFS was 62% among patients receiving IM and 52% among patients undergoing allo-BMT (P=0.0002). OS at 5 years was 93% for IM-treated patients and 59% for patients undergoing allo-BMT (P<0.0001). Allo-BMT cannot be considered as first-line treatment for CML patients in first chronic phase.

Bone marrow transplantation in patients with storage diseases: a developing country experience

Bone marrow transplantation (BMT) is a therapeutic option for patients with genetic storage diseases. Between 1979 and 2002, eight patients, four females and four males (1 to 13 years old) were submitted to this procedure in our center. Six patients had mucopolysaccharidosis (MPS I in 3; MPS III in one and MPS VI in 2), one had adrenoleukodystrophy (ALD) and one had Gaucher disease. Five patients had related and three unrelated BMT donor. Three patients developed graft versus host disease (two MPS I and one MPS VI) and died between 37 and 151 days after transplantation. Five patients survived 4 to 16 years after transplantation. Three patients improved (one MPS I; one MPS VI and the Gaucher disease patient), one patient had no disease progression (ALD) and in one patient this procedure did not change the natural course of the disease (MPS III).

Allogeneic hematopoietic stem cell transplantation from an alternative stem cell source in Fanconi anemia patients: analysis of 47 patients from a single institution

We transplanted 47 patients with Fanconi anemia using an alternative source of hematopoietic cells. The patients were assigned to the following groups: group 1, unrelated bone marrow (N = 15); group 2, unrelated cord blood (N = 17), and group 3, related non-sibling bone marrow (N = 15). Twenty-four patients (51%) had complete engraftment, which was not influenced by gender (P = 0.87), age (P = 0.45), dose of cyclophosphamide (P = 0.80), nucleated cell dose infused (P = 0.60), or use of anti-T serotherapy (P = 0.20). Favorable factors for superior engraftment were full HLA compatibility (independent of the source of cells; P = 0.007) and use of a fludarabine-based conditioning regimen (P = 0.046). Unfavorable factors were > or = 25 transfusions pre-transplant (P = 0.011) and degree of HLA disparity (P = 0.007). Intensity of mucositis (P = 0.50) and use of androgen prior to transplant had no influence on survival (P = 0.80). Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD were diagnosed in 47 and 23% of available patients, respectively, and infections prevailed as the main cause of death, associated or not with GVHD. Eighteen patients are alive, the Kaplan-Meyer overall survival is 38% at approximately 8 years, and the best results were obtained with related non-sibling bone marrow patients. Three recommendations emerged from the present study: fludarabine as part of conditioning, transplant in patients with < 25 transfusions and avoidance of HLA disparity. In addition, an extended family search (even when consanguinity is not present) seeking for a related non-sibling donor is highly recommended.

Neurological complications of hematopoietic stem cell transplantation (HSCT): a retrospective study in a HSCT center in Brazil

We present the neurological complications evaluated in a series of 1000 patients who underwent hematopoietic stem cell transplantation (HSCT). Central nervous system (CNS) neurological complications, particularly brain hemorrhages, were the most common, followed by seizures and CNS infections. An unusual neurological complication was Wernickes encephalopathy. Less frequent neurological complications were metabolic encephalopathy, neuroleptic malignant syndrome, reversible posterior leukoencephalopathy syndrome, brain infarct and movement disorders. The most common neurological complication of the peripheral nervous system was herpes zoster radiculopathy, while peripheral neuropathies, inflammatory myopathy and myotonia were very rarely found.

BCR-ABL Mutations in Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors and Impact on Survival

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.

Nilotinib post-liver transplantation for acute hepatic failure related to imatinib

This is the case report of a 47-year-old woman referred to our institution due to acute liver failure related to imatinib, who was submitted to a successful liver transplantation. Nilotinib was safely used post-transplant.