Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC) regimens reduce rejection and improve outcome in Indian patients undergoing allogeneic stem cell transplantation for severe aplastic anemia

Thirty-five patients (25 men and 10 women) with a median age of 20 years with severe aplastic anaemia (SAA) underwent HLA identical stem cell transplantation (HSCT) using a combination of fludarabine and cyclophosphamideanti-thymocyte globulin between 2004 and 2006. Cyclosporine and mini methotrexate were used as GVHD prophylaxis. Graft source included peripheral blood stem cells (28) or G-CSF stimulated bone marrow (7). Two patients expired <7 days post-HSCT while 32 (91.5%) patients engrafted with a median neutrophil and platelet engraftment time of 12 days each. Three patients (8.5%) developed veno-occlusive disease while acute GVHD occurred in 29% of evaluable patients, with chronic GVHD in 32%. At a mean follow-up of 22 months, 29 (82.8%) are alive and well. When compared with 26 patients previously transplanted using Cy200/antilymphocyte globulin, there was faster neutrophil engraftment (12 vs 16 days; P=0.002) with significantly lower rejection rates (2.9 vs 30.7%; P=0.003) and a superior event-free (82.8 vs 38.4%; P=0.001) and overall survival (82.8 vs 46.1%; P=0.005). A combination of fludarabine with cyclophosphamideanti-thymocyte globulin reduces rejection and improves overall and event-free survival in Indian patients undergoing HSCT for severe aplastic anaemia

Pre-transplant reduction of isohaemagglutinin titres by donor group plasma infusion does not reduce the incidence of pure red cell aplasia in major ABO-mismatched transplants

Major ABO incompatibility in stem cell transplant recipients has been associated with pure red cell aplasia (PRCA). Reduction of incompatible isohaemagglutinin titres pre-transplant by various methods has been thought to reduce the incidence of PRCA. Our data suggest that pre-transplant reduction of incompatible isohaemagglutinin titres by donor group plasma infusion does not reduce the incidence of PRCA. We also failed to find any relationship between pre-transplant ABO isohaemagglutinin titre and the risk of developing PRCA

Salvage with a mini-allograft after primary engraftment failure following autologous transplant for multiple myeloma

This article does not have an abstract

Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience

A total of 11 children (five males and six females) with hypergranular type of acute promyelocytic leukemia (APML) were treated with intravenous arsenic trioxide (As2O3) between December 1998 and October 2003. Eight cycles of As2O3 (0.15 mg/kg/day) were administered (induction, consolidation and six cycles of maintenance) over a period of 12 months. The median WBC count at diagnosis was 3400/mm3 (range: 800-9800). In all, 10 patients (91%) achieved hematological remission at a mean duration of 48 days (range: 41-60) with all 10 patients achieving molecular remission at a median duration of 81 days (range: 64-109). Toxicity was minimal with leukocytosis in six patients, ichthyosis and hyperpigmentation of skin in five and mild peripheral neuropathy in one patient. One patient who relapsed 6 months after completing therapy achieved a second hematological and molecular remission with As2O3. With a median follow-up of 30 months (range: 4-62), the overall (OS) survival is 91% with a relapse-free survival (RFS) of 81%. As2O3 achieves hematological and molecular remission in majority of newly diagnosed children with APML with minimal toxicity, but long-term follow-up is required to evaluate late effects of As2O3 and study the minimum dose and duration required for a sustained remission

Molecular remission with arsenic trioxide in patients with newly diagnosed acute promyelocytic leukemia

Thirty six APML patients achieving hematological remission with As2O3 were serially monitored using RT-PCR. Though only 5.5% achieved molecular remission at induction remission, 94.5% became negative during consolidation. At 20 months follow-up, 85% remain in remission but longer follow up studies are needed to monitor late relapses

Response to high-dose dexamethasone for acquired pure red cell aplasia following ABO-mismatched allogeneic stem cell transplantation

This article does not have an abstract

Fludarabine-based conditioning for allogeneic stem cell transplantation for multiply transfused patients with Fanconi's anemia

A fludarabine-based protocol (fludarabine (25 mg/m/day × 6 days), cyclophosphamide (10 mg/kg/day × 2 days) and ATG (ATGAM 10 mg/kg/day × 4 days)) was used in four multiply transfused Fanconi's anemia (FA) patients aged 5-15 years to reduce rejection during allogeneic bone marrow transplantation (BMT). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mini methotrexate. The graft source was G-CSF-stimulated bone marrow or peripheral blood stem cells (PBSC) in two patients each. All patients engrafted with median time to ANC>500/mm being 14 days (range: 12-17) and unsupported platelet count >20 ,000/mm being 13 days (range: 11-18). One patient had secondary graft rejection on day 56 and expired on day 69 due to fungal pneumonia. One patient who developed acute myeloid leukemia on day 56 underwent successful induction with cytosine and daunorubicin followed by peripheral blood stem cell (PBSC) rescue on day 70 and is presently in remission with complete donor chimerism and grade I GVHD. At a median follow-up of 13 months (range: 4-21), three patients (75%) are well with complete donor chimerism. Addition of fludarabine to the conditioning regimen for BMT in FA can provide additional immunosuppression for engraftment without increasing toxicity

Randomized trial of two different conditioning regimens for bone marrow transplantation in thalassemia - the role of busulfan pharmacokinetics in determining outcome

In total, 94 patients with homozygous beta thalassemia were randomized to two different conditioning regimens: busulfan 600 mg/m2+cyclophosphamide 200 mg/kg or busulfan 16 mg/kg+cyclophosphamide 200 mg/kg and antilymphocyte globulin (47 in each group), for bone marrow transplantation, to see whether increased myeloablation or increased immunosuppression would reduce rejection. Busulfan pharmacokinetics in determining outcome was evaluated. There was no significant difference in engraftment, graft-versus-host disease, rejection, and overall and disease-free survival in the two groups. Systemic exposure to busulfan was significantly higher in the 600 mg/m2 group, but in both groups there was a wide interindividual variation in the busulfan kinetics. Six patients rejected the graft, two in the busulfan 600 mg group and four in busulfan 16 mg group (P=0.677 CI -0.17, 0.07), but in five patients (pharmacokinetic data not available in one patient) who rejected the graft busulfan first dose trough level (Cmin-1) was below 150 ng/ml while it was above this level in the 66 of 68 patients with successful engraftment (P0.001). This randomized trial shows that rejection is influenced by busulfan levels and suggests that monitoring of busulfan levels and dose adjustment based on first-dose kinetics may reduce the risk of rejection

Six novel mutations including triple heterozygosity for Phe31Ser, 514delT and 516T→G factor X gene mutations are responsible for congenital factor X deficiency in patients of Nepali and Indian origin

Factor X (FX) deficiency is a rare (1 : 100000) autosomal recessive disorder caused by heterogeneous mutations in FX gene. We have studied the molecular basis this disease in six Indian and one Nepali patients. Diagnosis was confirmed by measuring the FX coagulant activity (FX: C) using a PT based assay. Six of them had a FX: C of < 1% and one patient had 24% coagulant activity. Mutations were identified in all the seven patients. These included eight (88.8%) missense and one frame-shift (11.2%) mutations of which six were novel. Three of the novel mutations, a Phe31Ser affecting 'Gla' domain and 514delT and 516T?G mutations affecting Cys132 in 'connecting region' were identified in a triple compound heterozygous state in a Nepali patient presenting with a severe phenotype. Two other novel mutations, Gly133Arg, may affect the disulphide bridge between Cys132-Cys302 in the connecting region while Gly223Arg may perturb the catalytic triad (His236, Asp282 and Ser379). The other novel mutation, Ser354Arg, involves the replacement of a small-buried residue by a large basic aminoacid and is likely to have steric or electrostatic effects in the pocket involving Lys351-Arg347-Lys414 that contributes to the core epitope of FXa for binding to FVa. Three previously reported mutations, Thr318Met; Gly323Ser; Gly366Ser were also identified. This is the first report of the molecular basis of FX deficiency in patients from the Indian subcontinent

Developing an algorithm of informative markers for evaluation of chimerism after allogeneic bone marrow transplantation

Analysis of chimerism by polymerase chain reaction amplification of STR or VNTR has become a routine procedure for the evaluation of engraftment after allogeneic stem cell transplantation. Knowledge of the frequency of different STR or VNTR alleles in unrelated individuals in a population is useful for forensic work. In the context of HLA identical sibling bone marrow transplantation the informativeness of these markers needs to be evaluated. We evaluated five STRs (THO1, VWA, FES, ACTBP2, and F13A1) and 1 VNTR (APOB) for informativeness in stem cell transplants from HLA identical sibling donors. All four markers used individually allowed us to discriminate 20-56% of the patient donor pairs. Using a combination of all these markers along with a polymorphic marker in the β-globin gene and the sex chromosome specific amelogenin marker, we were able to discriminate 99% of the patient donor pairs. We have established an algorithm for evaluating chimerism following HLA identical sibling donor transplants in the Indian population using molecular markers in 310 patients. Analysis of heterozygote frequencies in different populations is similar suggesting that this algorithm can be used universally for transplant centers to evaluate chimerism following allogeneic bone marrow transplantation