Treatment of Acute Promyelocytic Leukemia with Single-Agent Arsenic Trioxide

It is well recognized that arsenic trioxide (ATO) is an efficacious agent for the treatment of acute promyelocytic leukemia (APL). Use of single agent ATO in the treatment of APL leads to remissions which are durable in the majority. ATO is probably the most effective single agent in the treatment of APL and there have been very few reports of primary resistance. It has been used both as a single agent and in combination with other conventional drugs to treat APL. Use of ATO is the accepted standard of care in the management of relapsed APL, where it is often used effectively as a bridge to a stem cell transplant. However, its role in newly diagnosed APL remains controversial. ATO probably has multiple mechanisms of action. Better understanding of its mechanisms of action/s is likely to lead to more rationale use of this agent or its derivatives either alone or in combination with other drugs. There is limited data on the kinetics of leukemia clearance and normal haematopoietic recovery after the administration of single agent ATO for the treatment of APL, preliminary data suggests that it is likely to be different from conventional therapy. There have been a number of concerns of the potential short and long term toxicity of this agent. Most such concerns arise from the toxicity profile noted in people exposed to long term arsenic exposure in the environment. With the therapeutic doses and schedules of administration of ATO in the treatment of malignancies the overall toxicity profile has been favorable. In a resource constrained environments the use of a single agent ATO based regimen is a realistic and acceptable option to treat almost all patients. In the developed world it has the potential in combination with other agents to improve the clinical outcome with reduction of dose intensity of chemotherapy and remains an option for patients who would not tolerate conventional therapy. In this review we focus on the use of single agent ATO for the treatment of APL and summarize our experience and review the literature

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

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Molecular basis of hereditary factor VII deficiency in India: five novel mutations including a double missense mutation (Ala191Glu; Trp364Cys) in 11 unrelated patients

We have studied the molecular basis of factor (F) VII deficiency in 11 unrelated Indian patients. Mutations were identified in all 11 and included 5 missense, 2 nonsense and a frame shift mutation. Five of these were novel. These mutations were considered to be causative of disease because of their nature, evolutionary conservation and molecular modeling. This is the first report of mutations in patients with FVII deficiency from southern India

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

Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362→Thr (Prothrombin Vellore 1) mutation

Prothrombin deficiency is a rare (1:200 000) autosomal recessive disorder caused by diverse mutations in prothrombin gene. We have studied the molecular basis of this disorder in four unrelated Indian patients. The diagnosis was based on prolonged prothrombin (PT) and activated partial thromboplastin times and low factor II coagulant activity (FII: C) measured using a PT based assay. FII: C levels ranged between 4.7% and 17.5%. Mutations were identified in all the four patients. Five different causative mutations including four (80%) missense and an in-frame deletion (20%) were identified. One of them was a novel, Ala362→Thr aminoacid change affecting 'B' chain of α-thrombin. This mutation was present in a compound heterozygous state with a previously reported Arg-1→Gln missense change affecting pro-peptide cleavage site. Ala362→Thr occurred at a codon, evolutionarily conserved in all the 24 different prothrombins or its related serine proteases studied. Molecular modeling of this mutation was found to cause a conformational change around the region involving a catalytic triad residue His363 and a cysteine residue at codon 364. The FII: C level in this patient was 17.5%. Three other previously reported mutations were also detected in the homozygous state: Arg271→Cys in Kringle-2 region, a Glu309?Lys in 'A' chain of α-thrombin and an in-frame deletion of 3 bp (AAG) leading to Del Lys301/302 in 'A' chain of α-thrombin. This is the first report of the molecular basis of prothrombin deficiency in Indian patients and we suggest the eponym 'Prothrombin Vellore 1' for Ala362→Thr mutation

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

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

Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity

Arsenic trioxide, as a single agent, has proven efficacy in inducing molecular remission in patients with acute promyelocytic leukemia (APL). There is limited long-term outcome data with single-agent As2O3 in the management of newly diagnosed cases of APL. Between January 1998 to December 2004, 72 newly diagnosed cases of APL were treated with a regimen of single-agent As2O3 at our center. Complete hematologic remission was achieved in 86.1%. At a median follow-up of 25 months (range: 8-92 months), the 3-year Kaplan-Meier estimate of EFS, DFS, and OS was 74.87% ± 5.6%, 87.21% ± 4.93%, and 86.11% ± 4.08%, respectively. Patients presenting with a white blood cell (WBC) count lower than 5 × 109/L and a platelet count higher than 20 × 109/L at diagnosis (n = 22 [30.6%]) have an excellent prognosis with this regimen (EFS, OS, and DFS of 100%). The toxicity profile, in the majority, was mild and reversible. After remission induction, this regimen was administered on an outpatient basis. Single-agent As2O3, as used in this series, in the management of newly diagnosed cases of APL, is associated with responses comparable with conventional chemotherapy regimens. Additionally, this regimen has minimal toxicity and can be administered on an outpatient basis after remission induction

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Background: Congenital fibrinogen deficiency is an ultra-rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. Methods: Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA\uae, Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. Results: Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean \ub1 standard deviation (SD) increase in MCF was 5.8 \ub1 2.5 mm one hour after the first HFC infusion (mean \ub1 SD dose, 61.88 \ub1 11.73 mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80 mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. Conclusions: Human fibrinogen concentrate was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia