Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia

2021 ◽  
pp. 107815522110247
Author(s):  
Kyle Zacholski ◽  
Bryan Hambley ◽  
Erin Hickey ◽  
Sarah Kashanian ◽  
Andrew Li ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
All Trans Retinoic Acid ◽  
Grade 3 ◽  
Disease Free

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

scholarly journals Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3751-3757 ◽  
Author(s):  
Bayard L. Powell ◽  
Barry Moser ◽  
Wendy Stock ◽  
Robert E. Gallagher ◽  
Cheryl L. Willman ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Rank Test ◽  
Consolidation Therapy ◽  
Free Survival ◽  
End Point ◽  
To Receive ◽  
Disease Free

Abstract Arsenic trioxide (As2O3) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As2O3 consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As2O3 consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As2O3 arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As2O3 arm, 90% compared with 70% at 3 years (P < .0001). The addition of As2O3 consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

Treatment of newly diagnosed acute promyelocytic leukemia without cytarabine.

1997 ◽  
Vol 15 (2) ◽  
pp. 483-490 ◽  
Author(s):  
E Estey ◽  
P F Thall ◽  
S Pierce ◽  
H Kantarjian ◽  
M Keating
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Current Treatment ◽  
Promyelocytic Leukemia ◽  
Newly Diagnosed ◽  
Current Group ◽  
Free Survival ◽  
All Trans Retinoic Acid

PURPOSE To determine the effect of omission of cytarabine (ara-C) from treatment of newly diagnosed acute promyelocytic leukemia (APL), which allows administration of more anthracycline. PATIENTS AND METHODS Induction consisted of all-trans retinoic acid (ATRA) 45 mg/m2 daily until complete remission (CR) and idarubicin 12 mg/m2 daily for 4 days beginning on day 5 of ATRA. Patients in CR received two courses of idarubicin 12 mg/m2 daily for 3 days and then, until 2 years post-CR date, alternated three cycles of mercaptopurine, vincristine, methotrexate, and prednisone (POMP) with one cycle of idarubicin 12 mg/m2 daily for 2 days. Results in the 43 patients treated (41 with t(15;17) on standard or Southern analysis) were compared with those in 57 historic newly diagnosed APL patients given ara-C with either doxorubicin, amsacrine (AMSA), or daunorubicin without ATRA, using logistic and Cox regression to assess effects of non-treatment-related covariates on patient outcomes. RESULTS The CR rate in the current group was 77% (95% confidence interval [CI], 62% to 88%) and was not significantly different from the historic rate. In contrast, disease-free survival (DFS) in CR is superior in the current group (probability at 1 year 0.87; 95% CI, 0.73 to 1.0). This has translated into superior overall DFS for the current group (P = .03 adjusting for the predictive covariates initial WBC and platelet count; 1-year DFS probability 0.67; 95% CI, 0.52 to 0.82; median follow-up 102 weeks). The current treatment appears better both in patients with and without t(15; 17) on standard cytogenetic analysis. CONCLUSION Given the difficulties inherent in comparing sequential studies and recognizing the multiple differences in treatment between current and historic groups, our results suggest that a large randomized trial incorporating use of ATRA should assess the utility of omitting ara-C from treatment of newly diagnosed APL, thus allowing delivery of more anthracycline.

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.

scholarly journals Single Cycle of Arsenic Trioxide–Based Consolidation Chemotherapy Spares Anthracycline Exposure in the Primary Management of Acute Promyelocytic Leukemia

2010 ◽  
Vol 28 (6) ◽  
pp. 1047-1053 ◽  
Author(s):  
Steven D. Gore ◽  
Ivana Gojo ◽  
Mikkael A. Sekeres ◽  
Lawrence Morris ◽  
Marcel Devetten ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Cytotoxic Agents ◽  
Single Cycle ◽  
Free Survival ◽  
All Trans Retinoic Acid ◽  
Primary Management

Purpose Event-free survival following all-trans-retinoic acid (ATRA) –based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. Patients and Methods After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m2, cardiac ejection fraction decreased by ≥ 20% in 20% of patients. Conclusion These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.

scholarly journals Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial)

2021 ◽  
Vol 118 (6) ◽  
pp. e2020382118
Author(s):  
Li Chen ◽  
Hong-Ming Zhu ◽  
Yan Li ◽  
Qi-Fa Liu ◽  
Yu Hu ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Link Type ◽  
Kaplan Meier ◽  
Risk Patients ◽  
The Difference ◽  
Grade 3

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO–based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA–anthracycline for low-/intermediate-risk patients, or ATRA-ATO–anthracycline versus ATRA–anthracycline–cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of –5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI –0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan–Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA–chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

scholarly journals Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5650-5659 ◽  
Author(s):  
Martin S. Tallman ◽  
Haesook T. Kim ◽  
Pau Montesinos ◽  
Frederick R. Appelbaum ◽  
Javier de la Serna ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retinoic Acid ◽  
Cumulative Incidence ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Disease Free

Abstract Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid–based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.

scholarly journals Treatment Outcome of Acute Promyelocytic Leukemia with Modified Aida Protocol

2010 ◽  
Vol 2010 ◽  
pp. 1-3 ◽  
Author(s):  
Kátia B. Barbosa Pagnano ◽  
Gustavo de Carvalho Duarte ◽  
Irene Lorand-Metze ◽  
Márcia Torresan Delamain ◽  
Eliana Cristina Miranda ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Newly Diagnosed ◽  
Molecular Remission ◽  
Free Survival ◽  
Induction Failure ◽  
Disease Free

We analyzed the outcome of a series of 19 newly diagnosed patients with acute promyelocytic leukemia treated with AIDA modified protocol, using mitoxantrone in place of idarubicin. Eleven patients achieved morphologic CR (58%). The remaining 8 patients had induction failure due to death during induction. Ten of eleven patients in CR achieved molecular remission after induction therapy and all the 8 patients had molecular remission after consolidation. Eight patients completed the three consolidation courses as scheduled and then proceeded to maintenance therapy. After a median follow up of 52 months, no molecular or hematological relapse has occurred. The 4-year disease-free survival is 82%. The study showed the antileukemic efficacy of mitoxantrone and that it could be used as a reasonable option in anthracycline-based strategies in APL.

Phase I Study of Fludarabine Plus Cyclophosphamide in Patients With Previously Untreated Low-Grade Lymphoma: Results and and Long-Term Follow-Up—A Report From the Eastern Cooperative Oncology Group

2000 ◽  
Vol 18 (5) ◽  
pp. 987-987 ◽  
Author(s):  
Howard S. Hochster ◽  
Martin M. Oken ◽  
Jane N. Winter ◽  
Leo I. Gordon ◽  
Bruce G. Raphael ◽  
...  
Keyword(s):  
Phase Ii ◽  
Bone Marrow Involvement ◽  
Survival Rates ◽  
Eastern Cooperative Oncology Group ◽  
Disease Free Survival ◽  
Low Grade ◽  
Survival Times ◽  
Free Survival ◽  
Disease Free

PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1,000 mg/m2. Fludarabine 20 mg/m2 was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required. RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m2), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively. CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1,000 mg/m2 day 1 and fludarabine 20 mg/m2 days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.

A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARα transcript after consolidation therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 study

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 59-66 ◽  
Author(s):  
Norio Asou ◽  
Yuji Kishimoto ◽  
Hitoshi Kiyoi ◽  
Masaya Okada ◽  
Yasukazu Kawai ◽  
...  
Keyword(s):  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Randomized Study ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Consolidation Therapy ◽  
Maintenance Chemotherapy ◽  
Free Survival ◽  
Significant Difference ◽  
Disease Free

To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RARα at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n = 89) or observation (n = 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P = .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P = .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RARα fusion transcript after 3 courses of intensive consolidation therapy.

Studies on Treatment of Acute Promyelocytic Leukemia With Arsenic Trioxide: Remission Induction, Follow-Up, and Molecular Monitoring in 11 Newly Diagnosed and 47 Relapsed Acute Promyelocytic Leukemia Patients

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3315-3324 ◽  
Author(s):  
Chao Niu ◽  
Hua Yan ◽  
Ting Yu ◽  
Hui-Ping Sun ◽  
Jian-Xiang Liu ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Pcr Analysis ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
First Choice ◽  
Wbc Count

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.

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