scholarly journals Relapse Analysis and Resistance Mutations of PML-Rara Fusion Gene in Acute Promyelocytic Leukemia Patients Treated with All-Trans Retinoic Acid and Arsenic

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2243-2243
Author(s):  
Jiaqi Chen ◽  
Hongxing Liu ◽  
Fang Wang ◽  
Xue Chen ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Primary Diagnosis ◽  
Promyelocytic Leukemia ◽  
Sustained Remission ◽  
Resistance Mutations ◽  
Secondary Tumors ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Refractory Aml

Abstract The clinical manifestations, management, and prognosis of acute promyelocytic leukemia (APL) are distinctive in acute myeloid leukemia (AML). Administration of all-trans retinoic acid (ATRA) and arsenic agents have greatly improved the outcome of APL from the most lethal to the most curable subtype AML. Unfortunately, relapse is still observed. And in the case of combined medication with ATRA and arsenic, the resistance mutation spectrum of PML-RARA is far from being revealed. We retrospectively analyzed 40 APL patients that admitted to our hospital from Jan. 2013 to Jul. 2020. There were 21 males and 19 females, aged 6-65 years (median age 31.5), and follow-up time was 3-210 months (median time 58.85 months). There were 3 cases that developed secondary tumors, although APL remission has been achieved. One developed refractory AML with KMT2A-MLLT3 fusion during the consolidation treatment one year after the diagnosis of APL. One case relapsed with APL 5 years after the initial diagnosis, and she developed refractory AML with RUNX1-MECOM fusion 3.5 years more after enduring multiple relapses and treatment courses. Another case developed AML-M2 3.5 years after the initial diagnosis of APL, and achieved sustained remission again through allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 8 cases came to our hospital at the initial onset of APL, and 1 came during remission. All these cases got sustained remission through combined triple therapy (ATRA, arsenic, and chemotherapy), with the follow-up time of 3 to 37 months (median 20.5 months). No PML-RARA resistant mutation was detected in these 9 cases. A total of 28 cases came to our hospital after APL relapse. The time from APL onset to the first relapse was 9-189 months (median 34 months). PML-RARA resistance mutations were detected in 9 cases, including 8 cases that carry single RARA mutations each, and 1 case that relapsed with multiple extramedullary infiltrations carry quadruple mutations (PML S214L-A216T and RARA R276W-H298N) (Figure 1a and b). A total of 4 cases underwent allo-HSCT after APL relapse. One of them relapsed 6 months after allo-HSCT, and the other 3 got sustained remission with the follow-up time of 47, 39, and 52 months, respectively. There were 2 cases relapsed after maintaining sustained remission for more than 5 years. One was a 58-year-old male who achieved sustained remission after 2.5 years of combined triple therapy. However, APL recurred 16 years after the primary diagnosis. He achieved remission again and now underwent the consolidation course of combined triple therapy. Another was a 23-year-old male who achieved sustained remission after combined arsenic and chemotherapy, but APL relapsed 75 months after the primary diagnosis. He was resistant to combined triple therapy and achieved remission through allo-HSCT. We failed to retrieve archived specimens at the first onset of APL for genomic variation comparison with the second onset. Therefore, we could not determine whether these two cases were relapsed from the original APL or developed another APL. Although we have achieved a high remission rate and long-term survival for APL through combined triple therapy, relapse and secondary tumors still occur in some cases. Especially for cases that endure heavy treatment, genomic toxicity may promote the oncogenesis of secondary tumors. Also, APL may recur over 5 years after the primary diagnosis and sustained remission. Whether there were inherited predisposing factors in these cases is worthy of further investigation. The incidence of PML and RARA resistant mutations in cases resistance for ATRA and arsenic is not very high. This may be related to the combination use of chemotherapeutic drugs and suggests underlying resistance mechanisms. Although both ATRA and arsenic were used in most cases, the incidence of ATRA resistance mutations is significantly higher than that of arsenic, which might attribute to the sparse interaction sites of arsenic and PML. A better combination strategy of arsenic, ATRA, with or without chemotherapy is worthy of further investigation to reduce the incidence of secondary tumors and relapse. Adhering to a systematically planed treatment course is essential for acquiring rapid remission and reduction of relapse. Treatment compliance should be paid attention to guaranteed, especially during the oral administration courses outside the hospital. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Early Detection of t(8;21) Chromosomal Translocations during Treatment of PML-RARA Positive Acute Promyelocytic Leukemia: A Case Study

2010 ◽  
Vol 4 ◽  
pp. CMO.S6446 ◽  
Author(s):  
Walter Kleine Neto ◽  
Mariana Serpa ◽  
Sabri Saeed Sanabani ◽  
Patricia Torres Bueno ◽  
Elvira Deolinda Rodrigues Pereira Velloso ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Genetic Screening ◽  
Treatment Initiation ◽  
Single Case ◽  
Promyelocytic Leukemia ◽  
Chromosomal Translocations ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Here we describe a female patient who developed acute promyelocytic leukemia (APL) characterized by t(l5;17) translocation at diagnosis. The patient began treatment with all-trans retinoic acid (ATRA) + chemotherapy. During follow up, the patient was found to be negative for the t(15;17) transcript after 3 months of therapy which remained undetectable, thereafter. However, the emergence of a small clone with a t(8;21) abnormality was observed in the bone marrow and peripheral blood (PB) cells between 3 and 18 months following treatment initiation. The abnormal translocation observed in PB cells obtained at 3 months was detected after the second cycle of consolidation therapy and reappeared at 15 months during maintenance treatment, a period without ATRA. Although based on a single case, we conclude that genetic screening of multiple translocations in AML patients should be requested to allow early identification of other emerging clones during therapy that may manifest clinically following treatment.

scholarly journals Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin

2009 ◽  
Vol 27 (4) ◽  
pp. 504-510 ◽  
Author(s):  
Farhad Ravandi ◽  
Eli Estey ◽  
Dan Jones ◽  
Stefan Faderl ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
High Risk ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Promyelocytic Leukemia ◽  
Platelet Recovery ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Purpose We examined the outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO) but without traditional cytotoxic chemotherapy. Patients and Methods From February 2002 to March 2008, 82 patients with APL were treated with a combination of ATRA plus ATO. The first cohort of 65 patients received ATRA and ATO (beginning on day 10 of ATRA). High-risk patients (WBCs ≥ 10 × 109/L) received GO on the first day. From July 2007, the second cohort of 17 patients received ATRA and ATO concomitantly on day 1. They also received GO on day 1, if high risk, and if their WBC increased to more than 30 × 109/L during induction. Monitoring for PML-RARA fusion gene was conducted after induction and throughout consolidation and follow-up. Results Overall, 74 patients achieved complete remission (CR) and one achieved CR without full platelet recovery after the induction, for a response rate of 92%. Seven patients died at a median of 4 days (range, 1 to 24 days) after inclusion in the study from disease-related complications. The median follow-up is 99 weeks (range, 2 to 282 weeks). Among the responding patients, three experienced relapse at 39, 52, and 53 weeks. Three patients died after being in CR for 14, 21, and 71 weeks, all from a second malignancy. The estimated 3-year survival rate is 85%. Conclusion The combination of ATRA and ATO (with or without GO) as initial therapy for APL was effective and safe and can substitute chemotherapy-containing regimens.

Incidence of Secondary Neoplasms In Patients with Acute Promyelocytic Leukemia Treated with All-Trans-Retinoic Acid (ATRA) with Chemotherapy or with Arsenic Trioxide (ATO).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1085-1085
Author(s):  
Alireza Eghtedar ◽  
Stefan Faderl ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Secondary Neoplasms ◽  
Secondary Cancers ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Abstract 1085 Background: Progress in the treatment of patients (pts) with acute promyelocytic leukemia (APL) with the use of modern all-trans retinoic acid (ATRA)-containing regimens has resulted in the majority of pts achieving long-term disease-free survival. There is little data on the incidence and patterns of secondary neoplasms in pts treated with these regimens. Objective: To compare the incidence of secondary neoplasms in pts with APL treated with two different ATRA-containing regimens. Methods: We retrospectively examined the charts of 160 pts with APL treated with ATRA plus chemotherapy (n=54) or ATRA plus arsenic trioxide (ATO)(n=106) as their initial induction regimen at the University of Texas – M. D. Anderson Cancer Center from 1991 to 2009. Twenty seven (17%) pts had a remote history of a prior unrelated cancer. Pt characteristics and the incidence of secondary cancers per unit time of follow-up were compared. Results: The median age at diagnosis of the entire population was 44 years (range, 13 – 81) and the median age for the chemotherapy plus ATRA group was 38 years (range, 13–67) vs. 46 years (range, 14 – 81) for the pts treated with ATO plus ATRA (p= 0.001). Thirty (55%) and 54 (50.9%) in each cohort were women (p=0.52) and 2 (3.7%) and 26 (24.5%) were older than 60 years of age, respectively (p= 0.001). Twenty (37%) and 30 (28.3%) had high risk disease (WBC > 10 × 109/l)(p= 0.3), and 34 (62.9%) and 76 (71.6%) had low risk disease (WBC ≤ 10 × 109/l), respectively. Fifty one (94.4%) and 105 (99%) pts treated using the two regimens achieved a CR. The median follow-up time for the two cohorts was 136 and 29 months [ranges, (5 to 193) and (1 to 93), respectively]. Nine and 2 pts in the two groups developed secondary cancers including 2 breast cancers, 3 MDS/AML, 1 vulvar cancer, 1 prostate cancer, 1 colon cancer and 1 soft tissue sarcoma in the chemotherapy group vs. 1 melanoma and 1 pancreatic cancer in ATO group. The cumulative incidence of secondary cancers in the two cohorts is shown in figure 1. Conclusion: Treatment of pts with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p=0.29) adjusted for unit time exposure. Disclosures: Off Label Use: Use of arsenic trioxide in frontline therapy of APL. Ravandi:Cephalon: Honoraria, Research Funding, Speakers Bureau.

Molecular Remissions Induced by Liposomal-Encapsulated All-Trans Retinoic Acid in Newly Diagnosed Acute Promyelocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2230-2235 ◽  
Author(s):  
Elihu H. Estey ◽  
Francis J. Giles ◽  
Hagop Kantarjian ◽  
Susan O’Brien ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Effective Means ◽  
Promyelocytic Leukemia ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Wbc Count

All-trans retinoic acid administered orally (oral ATRA) may not regularly lead to either molecular complete remissions (CRs) or prolonged hematologic CRs (HCR) unless combined with chemotherapy. Because serum tretinoin concentrations are higher, and maintained longer, after use of liposomal-encapsulated ATRA (lipoATRA) rather than oral ATRA, we investigated lipoATRA monotherapy in newly diagnosed acute promyelocytic leukemia (APL). Patients received lipoATRA 90 mg/m2 every other day for remission induction. The same dose was given 3 times a week until 9 months had elapsed from HCR date. Treatment then stopped. Chemotherapy (idarubicin 12 mg/m2daily days 1-2 for 2 courses) was to be added only if 2 polymerase chain reaction (PCR) tests, performed 2 weeks apart, were positive at 3, 6, or 9 months from HCR date. The sensitivity level of the PCR was 10−4. We treated 18 patients (median age, 54 years; median white blood cell [WBC] count 4,500/μL). The HCR rate was 12/18 (67%, 95% confidence interval [CI], 41% to 87%). This rate was similar to that we observed in a previous study using oral ATRA + idarubicin. Nine of 10 patients studied at HCR date were PCR-positive. Subsequently, however, overall (+/− idarubicin) rates of PCR positivity were 0/12 at 3 months, 1/10 at 6 months, 1/7 at 9 and 12 months, and 0/4 at 15 to 17 months. Idarubicin has been added in 3 patients, with this addition occurring at 6 months in 2 patients and at 9 months in 1 patient. Among patients who had not received idarubicin when the PCR was evaluated, 0 of 12 were PCR-positive at 3 months, 1 of 10 was positive at 6 months, 1 of 6 was positive at 9 months, 0 of 4 were positive at 12 months, and 0 of 3 were positive at 15 to 17 months. Morphologic APL has recurred in 1 patient, with a median follow-up time of 13 months in the 11 patients remaining in first CR. The median follow-up time is 9½ months (range, 3 to 17) in the 9 patients who have received only lipoATRA and who remain PCR-negative and in first CR. Our data suggest that lipoATRA is an effective means of producing molecular CR in newly diagnosed APL.

Early Detection of Relapse by Prospective Reverse Transcriptase-Polymerase Chain Reaction Analysis of the PML/RARα Fusion Gene in Patients With Acute Promyelocytic Leukemia Enrolled in the GIMEMA-AIEOP Multicenter “AIDA” Trial

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 784-789 ◽  
Author(s):  
Daniela Diverio ◽  
Vincenzo Rossi ◽  
Giuseppe Avvisati ◽  
Silvia DeSantis ◽  
Alessandra Pistilli ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Fusion Gene ◽  
Promyelocytic Leukemia ◽  
Rt Pcr ◽  
Molecular Monitoring ◽  
Chain Reaction ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Polymerase Chain

Abstract Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARα fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARα+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARα, as assessed by serial dilution experiments, was 10−4. All patients were in hematologic remission and tested PCR− at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR− in ≥2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARα during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up. © 1998 by The American Society of Hematology.

Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3469-3473 ◽  
Author(s):  
Elihu Estey ◽  
Guillermo Garcia-Manero ◽  
Alessandra Ferrajoli ◽  
Stefan Faderl ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
High Risk ◽  
Arsenic Trioxide ◽  
Promyelocytic Leukemia ◽  
Low Risk ◽  
High Risk Patients ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Risk Patients

We examined whether combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) might be an alternative to ATRA plus chemotherapy in untreated acute promyelocytic leukemia (APL). Twenty-five low-risk patients (white blood cell [WBC] count less than 10 × 109/L [10 000/μL]) received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily, beginning day 10 of ATRA), and in complete remission (CR) received ATO plus ATRA, without chemotherapy, unless they were reverse transcriptase–polymerase chain reaction (RT-PCR)–positive 3 months from CR date or had molecular relapse. Nineteen high-risk patients were treated identically, but received chemotherapy, generally 9 mg/m2 gemtuzumab ozogamycin (GO) on day 1 of induction. The CR rate was 39 of 44 (24 of 25 in low-risk, 15 of 19 in high-risk). Disease recurred at 9, 9, and 15 months, respectively, in 3 high-risk patients. The median follow-up time from CR date in the 36 patients alive in first CR is 16 months (15 months in low-risk, 20 months in high-risk), with 9 patients followed for at least 24 months. Each of the 36 patients was PCR-negative at last follow-up. Thus, none of the low-risk patients has received chemotherapy, and only 3 high-risk patients (the 3 with relapsed disease) have received chemotherapy past induction. ATRA plus ATO may serve as an alternative to chemotherapy in low-risk untreated APL (eg, in older patients) and, when combined with GO, may improve outcome in high-risk patients.

scholarly journals Evaluating the Utilization of All-Trans Retinoic Acid and Arsenic Trioxide during Consolidation Therapy for Patients Receiving Treatment for Acute Promyelocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3901-3901
Author(s):  
Laura A Bowers ◽  
Maho Hibino ◽  
Rebecca Garcia Hunt ◽  
Leslie Renee Ellis ◽  
Rupali Bhave ◽  
...  
Keyword(s):  
Research Funding ◽  
Promyelocytic Leukemia ◽  
Intermediate Risk ◽  
Consolidation Therapy ◽  
Monotherapy Group ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Secondary Endpoints

Background. Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) accounting for approximately 10% of AML cases. Advancements in the management of APL have led to complete remission (CR) rates of 90-100% and 5-year overall survival (OS) rates between 86-97%. Standard treatment of APL consists of induction and consolidation, with or without post-consolidation therapy, which is directed by risk group, age, and cardiovascular risk. A standard consolidation option consists of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) (NCCN Guidelines, AML Version 3.2019). Frequently patients are unable to obtain consolidation with ATRA due to the high prescription co-pay and limited financial assistance. This study assessed the efficacy, safety, and financial impact of APL consolidation therapy with ATRA/ATO compared to ATO monotherapy at a single institution. Methods. This single-center, retrospective, chart-review study assessed adult patients with APL who received ATRA/ATO induction, followed by consolidation with ATRA/ATO or ATO monotherapy between November 2012 to January 2018. The primary efficacy endpoint was OS. Secondary endpoints included event-free survival (EFS), relapse-free survival (RFS), hematologic CR or molecular CR (CRm), incidence of adverse drug events, and outpatient accessibility of ATRA. Numerical data were expressed as medians and interquartile range (IQR) and categorical data were evaluated using the Fisher Exact test. The Log-rank test was used for time to event data and analyzed using the Kaplan-Meier method. A P-value of < 0.05 was defined as statistically significant. Results. The final analysis included 31 patients, 25 patients received standard ATRA/ATO and 6 patients received ATO monotherapy. Patients in the ATRA/ATO group had a median age of 47 years (range 19 - 72); 8 had low risk and 15 had intermediate risk APL. Patients in the ATO monotherapy group had a median age of 73 years (range 70 - 83); 4 had low risk and 1 had intermediate risk APL. Patients in the ATO monotherapy group had more comorbidities, with all patients having a Charlson Comorbidity Index of 4 or higher compared to only 44% of the ATRA/ATO group (p=0.02). A dose reduction for ATO was required for 50% and 28% of patients in the ATO monotherapy and ATRA/ATO groups, respectively due to peripheral neuropathy. During consolidation, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group (Table 1). Five of six patients (83.3%) and 24 of 25 patients (96%) were alive at last follow-up in the ATO monotherapy and ATRA/ATO groups with a median follow-up of 33.3 months and 35.5 months, respectively (Graph 1). Secondary endpoints are provided in Table 2. There was 1 death in each group, both due to unknown causes. All adverse events occurred in a higher proportion of patients in the ATRA/ATO group (Graph 2). The incidence of headache was significantly higher in the ATRA/ATO group, occurring in 68% of patients and leading to ATRA discontinuation for 1 patient (Table 3), compared to 0 events in the ATO monotherapy group (p=0.004). Barriers to access occurred in 19.4% (6 of 31) of all patients. In addition to the 4 patients who required omission of ATRA upfront due to cost, 2 additional patients discontinued ATRA during consolidation due to affordability (Table 3). Conclusions. Patients in the ATO monotherapy group were on average older, had more comorbid conditions, and received a lower cumulative dose of ATO during consolidation. The standard dose of ATO during consolidation is 12 mg/kg administered over 4 cycles. In our study, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group. Despite discrepancies in age, comorbidities, and total dose of ATO received, outcomes were similar in the ATRA/ATO and ATO monotherapy groups. Although limited by a small sample size and retrospective design, this study suggests that elimination of ATRA from consolidation may be an acceptable option for patients that are unable to obtain ATRA or that experience intolerable side effects. These findings also suggest that lower cumulative doses of ATO during consolidation may produce similar efficacy with lesser toxicity. Future large, multicenter studies are necessary to confirm the efficacy and safety of these findings. Table Disclosures Manuel: Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Pardee:Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding.

Clinical Observation on the Efficacy of All-Trans Retinoic Acid (ATRA) Combined with Arsenic Trioxide (As2O3) in Newly Diagnosed Acute Promyelocytic Leukemia (APL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 888-888 ◽  
Author(s):  
Y.F. Liu ◽  
Z.X. Shen ◽  
J. Hu ◽  
Y.M. Zhu ◽  
J.M. Li ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Promyelocytic Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Front Line ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Fold Reduction

Abstract PURPOSE: To determine the efficacy of front-line use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) in patients with newly diagnosed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Since 2001, 61 patients have received ATRA (25mg/m2) and As2O3 (0.16mg/kg) daily till CR and all patients received 3 consolidation chemotherapy and then received 5 cycles of sequential treatment of ATRA, As2O3 and 6-MP/MTX. The efficacy of treatment protocol in induction remission, molecular response and relapse-free survival were compared with our historical control. RESULT: 58 (95.1%) patients achieved CR and all remain relapse free with the current protocol. Though ATRA/As2O3 duet did not improve the hematological/molecular remission rate and reduced the early mortality after induction, it did induce an early hematological response (26.1±4.1 days). During limited follow-up (20 to 39 months), both RFS and OS are significantly increased in patients who received the ATRA/As2O3/chemotherapy triad as post-remission therapy compared to the historical control. PML-RARa mRNA was retrospectively assessed by quantitative real-time reverse transcription-polymerase chain reaction (RQ-RT-PCR) before treatment, after CR, after consolidation and during follow-up period in 36 patients with ATRA and As2O3 combination treatment. PML-RARa normalized dose was found to be more significantly decreased after remission induction (median fold reduction: 335.8), and after consolidation (median fold reduction: 358362.2), as compared with ATRA or As2O3 mono-therapy. The addition of As2O3 into post-remission therapy can further increase the post-remission molecular response through either qualitative or quantitative RT-PCR measurement. CONCLUSION: Our current follow-up data suggested a potential benefit of front-line combination of ATRA and As2O3, which might translate into better chance of curing the disease.

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