Auro Viswabandya

Single-Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Long-Term Follow-Up Data

PURPOSE We previously reported our results with a single-agent arsenic trioxide (ATO) -based regimen in newly diagnosed cases of acute promyelocytic leukemia (APL). The concern remained about the long-term outcome of this well-tolerated regimen. We report our long-term follow-up data on the same cohort. PATIENTS AND METHODS From January 1998 to December 2004, 72 patients with PML/RARalpha+ APL were enrolled. All patients were treated with a single-agent ATO regimen. Results Overall 62 (86.1%) achieved a hematologic remission (complete remission). After the initial report, an additional seven patients have relapsed for a total of 13 relapses. There were no additional toxicities to report on follow-up. At a median follow-up 60 months, the 5-year Kaplan-Meier estimate (+/- SE) of event-free survival, disease-free survival, and overall survival (OS) was 69% +/- 5.5%, 80% +/- 5.2%, and 74.2% +/- 5.2%, respectively. The OS in the good risk group as defined by us remains 100% over this period. CONCLUSION Single-agent ATO as used in this study in the management of newly diagnosed cases of APL is safe and is associated with durable responses. Results in the low-risk group are comparable to that reported with conventional therapy while additional interventions would probably be required in high-risk cases.

Role of minimal residual disease monitoring in acute promyelocytic leukemia treated with arsenic trioxide in frontline therapy

Data on minimal residual disease (MRD) monitoring in acute promyelocytic leukemia (APL) are available only in the context of conventional all-trans retinoic acid plus chemotherapy regimens. It is recognized that the kinetics of leukemia clearance is different with the use of arsenic trioxide (ATO) in the treatment of APL. We undertook a prospective peripheral blood RT-PCR-based MRD monitoring study on patients with APL treated with a single agent ATO regimen. A total of 151 patients were enrolled in this study. A positive RT-PCR reading at the end of induction therapy was significantly associated on a multivariate analysis with an increased risk of relapse (relative risk = 4.9; P = .034). None of the good risk patients who were RT-PCR negative at the end of induction relapsed. The majority of the relapses (91%) happened within 3 years of completion of treatment. After achievement of molecular remission, the current MRD monitoring strategy was able to predict relapse in 60% of cases with an overall sensitivity and specificity of 60% and 93.2%, respectively. High-risk group patients and those that remain RT-PCR positive at the end of induction are likely to benefit from serial MRD monitoring by RT-PCR for a period of 3 years from completion of therapy.

Acute myeloid leukaemia: challenges and real world data from India

The management of acute myeloid leukaemia (AML) in India remains a challenge. In a two‐year prospective study at our centre there were 380 newly diagnosed AML (excluding acute promyelocytic leukaemia, AML‐M3) patients. The median age of newly diagnosed patients was 40 years (range: 1–79; 12·3% were ≤ 15 years, 16·3% were ≥ 60 years old) and there were 244 (64·2%) males. The median duration of symptoms prior to first presentation at our hospital was 4 weeks (range: 1–52). The median distance from home to hospital was 580 km (range: 6–3200 km). 109 (29%) opted for standard of care and were admitted for induction chemotherapy. Of the 271 that did not take treatment the major reason was lack of financial resources in 219 (81%). There were 27 (24·7%) inductions deaths and of these, 12 (44·5%) were due to multidrug‐resistant gram‐negative bacilli and 12 (44·5%) showed evidence of a fungal infection. The overall survival at 1 year was 70·4% ± 10·7%, 55·6% ± 6·8% and 42·4% ± 15·6% in patients aged ≤15 years, 15 ‐ 60 years and ≥60 years, respectively. In conclusion, the biggest constraint is the cost of treatment and the absence of a health security net to treat all patients with this diagnosis.

The t(6;9)(p22;q34) in myeloid neoplasms: a retrospective study of 16 cases

Among patients with acute myeloid leukemia (AML), the t(6;9) (p22;q34) is a rare but defined subset with a poor prognosis. We report 16 patients with the t(6;9), of whom 13 had AML, 2 had myelodysplastic syndrome (MDS), and 1 had chronic myeloid leukemia in myeloid blast crisis (CML-BC). All except for one were evaluated at diagnosis. The median age was 34.5 (range: 7-62 years), with 12 adults and 12 males. Trilineage dysplasia was present in 13 (81%). Marrow basophilia was seen in only two patients, one of whom had CML-BC. HLA-DR was positive in all 12 patients assessed, CD33 in 11, CD13 in 10, and CD34 in seven. Four patients had one other abnormality apart from the t(6;9). These were the t(9;22) in the patient with CML and deletion 9q, addition 13q, and an isochromosome 8q in the other three patients. There were no complex karyotypes. Fms-related tyrosine kinase 3--internal tandem duplication (FLT3-ITD) mutations were seen in seven of 13 patients. Follow-up details were available for six patients. Three received palliative care, and follow-up details were not available for the other seven. The response to chemotherapy was poor in the remaining patients. The only patients who survived were three out of the four who had allogeneic hematopoietic stem cell transplantation (HSCT).

Impact of pretransplant splenectomy on patients with β-thalassemia major undergoing a matched-related allogeneic stem cell transplantation

Abstract:u2002 Impact of pretransplant splenectomy in patients with β‐thalassemia major undergoing an allogeneic SCT has never been addressed. Twenty‐seven class III patients (29 transplants) had a pretransplant splenectomy. The outcome of these 29 transplants was compared with 76 transplants in class III who did not have a splenectomy. Patients in the splenectomy group were older (11.7u2003±u20035.0 vs. 8.5u2003±u20033.5u2003yr; pu2003=u20030.003) and had a larger liver size (5.7u2003±u20031.8 vs. 4.4u2003±u20031.6u2003cm; pu2003=u20030.000). Splenectomized patients had a significantly faster time to ANC >500/mm3 (15.4u2003±u20035.9 vs. 17.5u2003±u20034u2003days; pu2003=u20030.002) and platelet >20u2003000/mm3 (22.5u2003±u20036.7 vs. 32.5u2003±u200313.6u2003days; pu2003=u20030.000). The splenectomized group had a significantly reduced requirement of blood transfusion in the first 100u2003days post‐transplant (5.5u2003±u20035.1 vs. 7.2u2003±u20035.4 units; pu2003=u20030.017). There were significantly more deaths related to peri‐transplant infections in the post‐splenectomy group (24% vs. 5.3%; pu2003=u20030.0001). The graft rejections were comparable between the two groups (20.7% vs. 14.5%; pu2003=u20030.55). The incidence of acute and chronic GVHD, late infections, and deaths from RRT was not significantly different between the two groups. The five‐yr EFS (31.0u2003±u20038.6 vs. 60.8u2003±u20035.98; pu2003=u20030.003) and OS (39.7u2003±u20039.3 vs. 71.8u2003±u20035.5; pu2003=u20030.002) was significantly worse in the splenectomized group. In conclusion, pretransplant splenectomy among patients with β‐thalassemia major was associated with faster engraftment, reduced transfusion support, a higher incidence of peri‐transplant infection related deaths, and a reduced EFS and OS.

Mutations in coagulation factor XIII A gene in eight unrelated Indians Five novel mutations identified by a novel PCR-CSGE approach

Factor XIII deficiency is a rare autosomal (1:2,000,000) recessive disorder of blood coagulation usually attributed to mutations in the coagulation factor XIII (FXIII) A gene. We have studied the molecular basis of FXIII deficiency in eight unrelated South Indian patients. Their diagnosis was based on clinical history, normal plasma clotting times and increased solubility of fibrin clot in 5 mol/l urea. Genomic DNA was screened for FXIII A gene defects by a novel PCR and CSGE strategy. Mutations were identified in all these patients. Five of these were novel mutations occurring in four patients. These included a novel c.210T > G transversion in homozygosity in exon 3 predicting a Tyr69X in the beta-sandwich domain in one patient. Another patient was compound heterozygote for a novel c.791C > T transition predicting a Ser263Phe in the core domain and a novel c.2045-1G > A transition at the acceptor splice junction of intron 14. Two novel frame shifts were also identified in two patients in a homozygous condition. One of them resulted from a single base G duplication (c.892_895dupG) at codons Ser290/Ala291fs affecting the core domain and the other was due to a single base A duplication (c.1642_1644dupA) and at codonTyr547fs affecting barrel-1 domain. The remaining four patients had the previously reported Arg260His, Ser413Leu, and Val414Phe (n = 2) missense mutations in the core domain. The novel mutations identified were considered to be disease causative by studying the nature of mutation, the degree of conservation of the mutated aminoacid among transglutaminases of different species and by molecular modeling. Apart from describing a significant number of novel mutations, this report is the first study from Southern India to describe FXIII A gene mutations.

Management of Hemophilia in Patients with Inhibitors: The Perspective from Developing Countries

Data are limited on inhibitors in people with hemophilia (PWH) in developing countries. There is a perception that the overall prevalence of inhibitors, ranging from 7 to 19% in different reports, may be lower in these countries as compared with that reported from developed countries. This is possible given the fact that most patients are treated after 2 years of age with plasma-derived clotting factor concentrates. Whether genetic or other environmental factors also contribute to this needs further evaluation. There is a need to develop laboratory infrastructure and establish quality control programs for laboratory tests for inhibitors in developing countries. Management options vary widely given the socioeconomic diversity among these countries. Significant individualization of approach to management is therefore required depending on the available resources, particularly with regard to the use of bypassing agents. The limited data on immune tolerance induction with some low-dose regimens deserve further evaluation. Even in resource-constrained environments, education and a policy of systematic screening of patients associated with judicious use of bypassing agents can significantly improve the care of PWH who develop inhibitors.

Spectrum of BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia from India with suspected resistance to imatinib-mutations are rare and have different distributions

The introduction of tyrosine kinase inhibitors hasrevolutionized the treatment of chronic myeloidleukemia (CML). Imatinib mesylate, which compe-titively targets the adenosine 5-triphosphate (ATP)-binding site of the kinase domain of BCR-ABL [1] isnow the first choice of therapy for CML. Theincidence of CML in India varies from 0.8 to 2.2and 0.6 to 1.6 per 100 000 population in males andfemales, respectively. The overall incidence of CMLis 42.1% of all the adult leukemias as seen in ouroutpatient department from the year 1997 to 2008(1226 out of 2975 adult leukemias). Despite theimpressive rate of complete hematological responseand complete cytogenetic remissions, some casesshow primary or secondary resistance to imatinib.Several mechanisms have been attributed as thecause for clinical resistance to imatinib [2,3]. Amongthese, point mutations in the BCR-ABL kinasedomain appear to be the most common mechanismoccurring in 30–90% of patients who developresistance [4,5]. A point mutation in BCR-ABLkinase domain can cause an amino acid change andimpair imatinib binding by interrupting the criticalcontact point or by altering the conformation of theprotein [6]. To date, more than 50 different kinasedomain mutations have been identified and theyconfer different degrees of in vitro resistance toimatinib. There have been very few reports on thespectrum of BCR-ABL kinase domain mutations inAsian patients with CML [7–9]. In a recent studyfrom the Korean population, CML patients withimatinib resistance showed high rates (63%) ofmutations in the BCR-ABL kinase domain [7]. Sincethe response rate to imatinib is suboptimal in theIndian population [10,11], it is possible that this canbe attributed to a different mutation spectrum in thispopulation. The aim of the present study wastherefore to analyze the frequency and the spectrumof BCR-ABL kinase domain mutations in Indianpatients with CML with clinical resistance toimatinib.Between January 2004 and January 2009, periph-eral blood samples were collected from 76 patientswith CML with suspected clinical resistance toimatinib diagnosed in different phases of the disease(54 in chronic phase, 14 in accelerated phase, and 8in blast crisis). Eligible patients visiting the outpatientclinic at the department of Haematology, ChristianMedical College, Vellore were enrolled in the Glivec(imatinib) International Patient Assistance Program(GIPAP). Patients with CML in the chronic phase,accelerated phase, and blast crisis stage receivedstandard doses of 400, 600, and 800 mg/day ofimatinib, respectively.Primary resistance to imatinib was defined asfailure to achieve hematological remission within 3–6 months or failure to achieve any level of cytogeneticresponse at 6 months, major cytogenetic response at12 months, or complete cytogenetic response at 18months. Secondary resistance was defined as relapse

Diagnosis and management of von Willebrand disease: a developing country perspective.

Special challenges exist in the management of patients with von Willebrand disease (VWD) because of limitations in diagnostic facilities and therapeutic options. However, even within these limitations, it is possible to establish comprehensive services for this condition. Our data show that among 202 patients with VWD, 107 were type 3, 62 were type 1, and the others different categories of type 2. Basic tests such as bleeding time and activated partial thromboplastin time with factor (F)VIII coagulant are able to diagnose most of those with severe disease. We have been able to adapt the specific tests such as von Willebrand factor (VWF) ristocetin cofactor and VWF antigen from the tedious batched manual methods to cost-effective automated methods on advanced coagulometers. Discriminatory tests such as VWF collagen binding, VWF:FVIIIB, ristocetin-induced platelet agglutination (RIPA) are done in batches. Therapeutic options and for the treatment of bleeding include desmopressin, cryoprecipitate, and intermediate purity VWF-containing clotting factor concentrates. Tranexamic acid is also widely used as well as hormonal therapy for menorrhagia. We have also shown that modest doses of intermediate purity FVIII (Koate DVI; Talecris Biotherapeutics, Raleigh, NC, USA) at 35 IU/kg preoperatively and 10 to 20 IU/kg after that are sufficient for surgical hemostasis in these patients.

Efficacy of Cidofovir in Treatment of BK Virus–Induced Hemorrhagic Cystitis in Allogeneic Hematopoietic Cell Transplant Recipients

BK virus-associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with incidences up to 70%. Cidofovir is an antiviral agent with growing evidence as a therapeutic intervention. To assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC, a retrospective study was undertaken of the allo-HCT cohort who received cidofovir for symptomatic BK-HC (hematuria with BK viruria or viremia) from January 2010 until March 2017 in a single transplant center in Ontario, Canada. The primary outcome measure was a reduction in BK-HC severity (graded from 1 to 4); secondary outcomes included overall survival, BK virus titers, and the onset of acute kidney injury. Twelve allo-HCT patients received cidofovir for BK-HC, with pretreatment clinical severity of 3 (50%) or 4 (50%). Cidofovir was administered via intravenous (33%), intravesical (58%), or both modalities (8%). After a median cumulative dose of 10u2009mg/kg (range, 1 to 37), mean BK-HC grade decreased significantly by 1.8 (3.5 precidofovir, 1.7 postcidofovir, Pu2009<u2009.01). Sixty-six percent of patients had at least partial response to cidofovir, with similar response rates between intravenous (66%) and intravesical (62%) administration. Sixty-seven percent of patients died, and 33% of patients experienced renal toxicity, including 2 patients receiving intravesical therapy. In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration; most patients achieved at least partial response after cidofovir administration. Even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. Although cidofovir may be an efficacious therapy for BK-HC, albeit with potential demonstrated toxicities, further prospective trials are needed.