Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: a single center experience

Arsenic trioxide (As2O3) has been found effective in the treatment in the treatment of acute promyelocytic leukemia (APML). Most studies with As2O3 involve patients with APML who have relapsed following standard therapy. Between January 1998 and July 2000, 14 patients were recruited for an ongoing trial of As2O3 in the treatment of newly diagnosed APML. Arsenic trioxide was administered at a dose of 10 mg/day until complete remission (CR) was achieved. Afterward, a consolidation course and a maintenance schedule consisting of As2O3 as a single agent were administered over 6 months. There were 3 early deaths related to intra-cerebral hemorrhage: two on day 3 and one on day 4. Of the 11 evaluable patients, one died on day 21 secondary to uncontrolled sepsis, while the remaining 10 (91%) have attained CR. The average time to CR was 52.3 days (range: 34-70 days). One patient developed an isolated central nervous system (CNS) relapse and subsequently went into a second CR following therapy with triple intrathecal chemotherapy, cranial irradiation, and an additional 4-week course of systemic As2O3. This patient, as well as the remaining nine, has continued to remain in CR at a median follow up of 15 months (range: 2-33 months). Eight out of 10 patients achieved molecular remission at variable periods during their consolidation and maintenance schedules. One patient developed an ATRA syndrome and was administered daunorubicin (40 mg/day) for 2 days. The side effects with this therapy were minimal and did not require cessation of therapy in any patient. There was no significant hepatic toxicity. In our experience, arsenic trioxide is effective in inducing and maintaining remission in patients with APML with minimal side effects. The optimal regimen and total dose required need to be defined

Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: A Single Center Experience

Arsenic trioxide (As 2 O 3 ) has been found effective in the treatment in the treatment of acute promyelocytic leukemia (APML). Most studies with As 2 O 3 involve patients with APML who have relapsed following standard therapy. Between January 1998 and July 2000, 14 patients were recruited for an ongoing trial of As 2 O 3 in the treatment of newly diagnosed APML. Arsenic trioxide was administered at a dose of 10 mg/day until complete remission (CR) was achieved. Afterward, a consolidation course and a maintenance schedule consisting of As 2 O 3 as a single agent were administered over 6 months. There were 3 early deaths related to intra-cerebral hemorrhage: two on day 3 and one on day 4. Of the 11 evaluable patients, one died on day 21 secondary to uncontrolled sepsis, while the remaining 10 (91%) have attained CR. The average time to CR was 52.3 days (range: 34-70 days). One patient developed an isolated central nervous system (CNS) relapse and subsequently went into a second CR following therapy with triple intrathecal chemotherapy, cranial irradiation, and an additional 4-week course of systemic As 2 O 3 . This patient, as well as the remaining nine, has continued to remain in CR at a median follow up of 15 months (range: 2−33 months). Eight out of 10 patients achieved molecular remission at variable periods during their consolidation and maintenance schedules. One patient developed an ATRA syndrome and was administered daunorubicin (40 mg/day) for 2 days. The side effects with this therapy were minimal and did not require cessation of therapy in any patient. There was no significant hepatic toxicity. In our experience, arsenic trioxide is effective in inducing and maintaining remission in patients with APML with minimal side effects. The optimal regimen and total dose required need to be defined. Am

Generation of an integration-free iPSC line (CSCRi005-A) from erythroid progenitor cells of a healthy Indian male individual

Reprogramming of somatic cells with higher genome integrity, and use of non-integrating gene delivery methods and xeno-free cell culture conditions aid in the generation of iPSCs which are more suitable for disease modelling and clinical applications. We describe here an iPSC line generated using such conditions, which expressed all the pluripotency markers, retained normal karyotype and exhibited the potential for tri-lineage differentiation, both in-vitro and in-vivo. This is the first iPSC line available from a healthy Indian individual for researchers

Generation of an induced pluripotent stem cell line that mimics the disease phenotypes from a patient with Fanconi anemia by conditional complementation

Generation of Fanconi anemia (FA) patient-specific induced pluripotent stem cells (iPSCs) has been reported to be technically challenging due to the defects in the FA-pathway in the patients' somatic cells. By inducible complementation of FA-pathway, we successfully reprogrammed the fibroblasts of an FA patient to iPSCs. CSCR19i-indCFANCA, one of the iPSC lines generated by the inducible complementation of FA-pathway, was extensively characterized for its pluripotency and karyotype. In the absence of doxycycline (DOX) and FANCA expression, this line showed the cellular phenotypes of FA, suggesting it is an excellent tool for FA disease modeling and drug screening

Systematic evaluation of markers used for the identification of human induced pluripotent stem cells

Low efficiency of somatic cell reprogramming and heterogeneity among human induced pluripotent stem cells (hiPSCs) demand extensive characterization of isolated clones before their use in downstream applications. By monitoring human fibroblasts undergoing reprogramming for their morphological changes and expression of fibroblast (CD13), pluripotency markers (SSEA-4 and TRA-1-60) and a retrovirally expressed red fluorescent protein (RV-RFP), we compared the efficiency of these features to identify bona fide hiPSC colonies. The co-expression kinetics of fibroblast and pluripotency markers in the cells being reprogrammed and the emerging colonies revealed the heterogeneity within SSEA-4+ and TRA-1-60+ cells, and the inadequacy of these commonly used pluripotency markers for the identification of bona fide hiPSC colonies. The characteristic morphological changes in the emerging hiPSC colonies derived from fibroblasts expressing RV-RFP showed a good correlation between hiPSC morphology acquisition and silencing of RV-RFP and facilitated the easy identification of hiPSCs. The kinetics of retroviral silencing and pluripotency marker expression in emerging colonies suggested that combining both these markers could demarcate the stages of reprogramming with better precision than with pluripotency markers alone. Our results clearly demonstrate that the pluripotency markers that are routinely analyzed for the characterization of established iPSC colonies are not suitable for the isolation of pluripotent cells in the early stages of reprogramming, and silencing of retrovirally expressed reporter genes helps in the identification of colonies that have attained a pluripotent state and the morphology of human embryonic stem cells (hESCs)

Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2

<div><p>Cytarabine (Ara-C) and Daunorubicin (Dnr) forms the backbone of acute myeloid leukemia (AML) therapy. Drug resistance and toxic side effects pose a major threat to treatment success and hence alternate less toxic therapies are warranted. NF-E2 related factor-2 (Nrf2), a master regulator of antioxidant response is implicated in chemoresistance in solid tumors. However, little is known about the role of Nrf2 in AML chemoresistance and the effect of pharmacological inhibitor brusatol in modulating this resistance. Primary AML samples with high <i>ex-vivo</i> IC50 to Ara-C, ATO, Dnr had significantly high <i>NRF2</i> RNA expression. Gene-specific knockdown of <i>NRF2</i> improved sensitivity to these drugs in resistant AML cell lines by decreasing the expression of downstream antioxidant targets of Nrf2 by compromising the cell’s ability to scavenge the ROS. Treatment with brusatol, a pharmacological inhibitor of Nrf2, improved sensitivity to Ara-C, ATO, and Dnr and reduced colony formation capacity. AML cell lines stably overexpressing <i>NRF2</i> showed increased resistance to ATO, Dnr and Ara-C and increased expression of downstream targets. This study demonstrates that Nrf2 could be an ideal druggable target in AML, more so to the drugs that function through ROS, suggesting the possibility of using Nrf2 inhibitors in combination with chemotherapeutic agents to modulate drug resistance in AML.</p></div

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

This article does not have an abstract

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/RAR&#945;+ 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% &#177; 5.5%, 80% &#177; 5.2%, and 74.2% &#177; 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

<i>NRF2</i> overexpression in AML cell lines increases IC50 of ATO & Dnr by up-regulating downstream target expression.

<p>Two AML cell lines (HL-60 and MOLM-13) with relatively low expression of <i>NRF2</i> were made to stably over express <i>NRF2</i>. <b>(A)</b> Overexpression was further confirmed by quantitative real-time PCR (i) and western blot (ii) for Nrf2 <b>(B)</b> Nrf2 downstream target genes (<i>GCLC</i>, <i>GCLM</i>, <i>NQO1</i>, <i>and HMOX-1</i>) were analyzed by real time quantitative PCR. <b>(C)</b> <i>In-vitro</i> cytotoxicity of overexpressed cells to Dnr and ATO was compared with control cells. Overexpression increases resistance to Dnr and ATO.</p