Ezhilarasi Chendamarai

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.

Comparison of Newly Diagnosed and Relapsed Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide: Insight into Mechanisms of Resistance

There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.

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

International Reporting Scale of BCR-ABL1 Fusion Transcript in Chronic Myeloid Leukemia: First Report from India

Achieving a major molecular response (MMR) is an important predictor of progression-free survival in chronic myeloid leukemia patients treated with imatinib. This requires accurate measurement of BCR-ABL1 transcripts normalized to a control gene, as well as defining a level (BCR-ABL1/control gene ratio) that will correlate with sustained clinical response. To make these measurements comparable between laboratories, an international scale (IS) is necessary. A BCR-ABL1/control gene ratio of 0.10% represents MMR in the IS. In collaboration with an international reference laboratory in Adelaide, S.A., Australia, we have established and validated a lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS. In this report, we explain the process and steps involved in obtaining a valid lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS.