Arsenic Trioxide Consolidation Research Articles

No Place like Home: Home-Based Intravenous Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia (APL)

Introduction: APL has transitioned from a highly fatal malignancy to a disease that is curable with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Intravenous (IV) administration of ATO remains the standard of care for consolidation, however, its use is associated with long infusion times, electrolyte disturbances, and QTc prolongation that has historically required frequent outpatient infusion center administration and monitoring. Following induction, patients receive a cumbersome schedule of ATO through daily infusions 5 days each week (typically Monday-Friday) 4 weeks on 4 weeks off for 4 cycles. Oral formulations of ATO are poorly water soluble, have not demonstrated adequate absorption in the gastrointestinal (GI) tract leading to significant GI upset and are not approved for use in the United States. Beginning in 2020, patients treated at our institution were given the option of receiving ATO at home through a partnership via Qualitas Specialty Pharmacy of RWJBarnabas Health. This retrospective review evaluates the feasibility, safety, and efficacy of administration of ATO in the home infusion setting for patients with APL receiving ATO consolidation. Methods: Through retrospective chart review, we evaluated patients who received consolidation therapy of ATO through home infusion from 2020-2023. Eligible patients included those with an ECOG of <2, absence of baseline QTc prolongation (defined as >500ms), and patients without significant kidney dysfunction or hepatotoxicity at baseline. We evaluated each patient for adverse effects such as QTc prolongation, electrolyte disturbances, liver function test (LFT) abnormalities, neutropenic fever, bacteremia, unplanned Emergency Room (ER) or urgent care visits, and unexpected hospitalizations (via Common Terminology Criteria for Adverse Events version 5). Results: Fifteen patients aged 19-79 (median = 43) were reviewed with 60% being male and 40% female. Sixty percent had a baseline ECOG 1 and 40% had an ECOG 0. Twenty percent of patients had a prior malignancy (n=3). Eighty percent of the patients experienced grade (gd) 1-3 electrolyte abnormalities (47% gd 1 hyperphosphatemia, 13% gd 1 hyperkalemia, 7% gd 2 hyperkalemia, 7% gd 3 hyperkalemia, 13% gd 1 hypokalemia, 13% gd 1 hypermagnesemia, 7% gd 3 hypermagnesemia, 7% gd 1 hypomagnesemia, 33% gd 1 hypernatremia, 33% gd 1 hyponatremia, & 7% gd 2 hyponatremia). Of the 15 patients receiving treatment, 27% experienced gd 1 alanine aminotransferase (ALT) increase, 13% of patients experienced gd 1 aspartate aminotransferase (AST) increase, and 7% of patients experienced gd 2 hyperbilirubinemia. For QTc prolongation, 53% of patients experienced gd 1 prolongation, 7% of patients experienced gd 2 prolongation, and 13% of patients experienced gd 3 prolongation. One out of the 15 patients experienced treatment delays due to QTc prolongation. While forty percent of patients visited either the ER and/or urgent care during consolidation therapy, no visits were deemed therapy related. Reasons for urgent evaluation included infections (n=3), vertigo (n=1), low back pain (n=1), facial numbness (n=1), fall (n=1), abdominal pain (n=1), and hemorrhoidal bleeding (n=1). Two patients were hospitalized, due to a renal infarct (n=1) and a subdural hematoma after a fall (n=1). None of the 15 patients experienced febrile neutropenia/bacteremia while receiving consolidation therapy. Of the 11 patients who completed consolidation at the time of this abstraction, all (100%) had complete remission demonstrated on post-consolidation bone marrow. One of the 11 patients relapsed within 6 months of consolidation; however, is now in remission following two additional consolidation courses and a bone marrow transplant. Four patients have not yet completed four cycles of ATO consolidation. One patient was transitioned from home infusion to clinic treatment due to out-of-pocket cost. Conclusions: Our study demonstrates that home infusion of ATO is both safe and highly effective for patients. Therapy was well tolerated with predictable and manageable toxicity. Prospective studies are needed to evaluate the efficacy and safety in comparison to patients receiving ATO in the infusion center as well as to assess patient-reported and cost outcomes. Given the safety profile of home-based ATO, we have implemented at home ATO consolidation as standard therapy for all eligible patients.

Acute promyelocytic leukemia with t(2;17;15): report of one case and review of literature

Objective To explore the clinical and laboratory characteristics and therapeutic effect of acute promyelocytic leukemia (APL) with t(2;17;15). Methods The G-banding technique was used for karyotypic analysis in a female patient with APL who was admitted to the First Affiliated Hospital of Zhengzhou University in December 2018. PML-RARα fusion gene was quickly detected by fluorescence in situ hybridization (FISH). The real-time quantitative polymerase chain reaction (RT-PCR) was used to detection 43 kinds of fusion gene, and the gene mutations were detected by next generation sequencing (NGS). The induction therapy was given with oral retinoic acid+ intravenous infusion of arsenic trioxide, followed by 3 courses of retinoic acid+ arsenic trioxide consolidation therapy. Results The G-banding karyotypic analysis demonstrated 46, XX, t(2;17;15) (q31;q21;q22)[8]/46, XX[2]. FISH results indicated that 62.0% of analyzed cells were positive for the PML-RARα fusion gene. RT-PCR further revealed the positive PML-RARα fusion gene transcript. NGS detection of gene mutations showed no obvious abnormalities. After 39 days of induction therapy with retinoic acid and arsenic trioxide, the patient achieved complete remission (CR). The karyotype was 46XX[20], and PML-RARα/ABL was 0/100. Then, the patient was treated with 3 courses of consolidation therapy, and the results remained in CR. Conclusions APL with complex t(2;17;15) (q31;q21;q22) is rare, and the morphological characteristics are not typical, but it is still associated with the formation of PML-RARα fusion gene. Retinoic acid+ arsenic trioxide has a good therapeutic effect, and the long-term efficacy still needs follow-up. Key words: Leukemia, promyelocytic, acute; Translocation, genetic; Gene fusion; Tretinoin; Arsenites

Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab

AbstractThe combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 × 109/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.

FLT3 Mutations in Pediatric Acute Promyelocytic Leukemia; A Report from the Children's Oncology Group AAML0631 Trial

BackgroundSurvival for acute promyelocytic leukemia (APL) has improved dramatically in recent decades through use of targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Early deaths, principally due to complications of APL coagulopathy, remain a significant barrier to cure. White blood cell (WBC) count at diagnosis is a well validated risk marker for early death and relapse. While APL is characterized by t(15;17), mutations of the FLT3 gene are prevalent. Prior reports in both adult and pediatric APL have demonstrated variable impact of FLT3 mutation status on outcomes. In a pediatric cohort from the Intergroup Study CALGB 9710, our group previously found an association of FLT3 mutations with early death. The more recent Children's Oncology Group (COG) APL trial AAML0631 included addition of two courses of arsenic trioxide (ATO) during consolidation. Relapse rate on this study was low, but survival, particularly for the high risk patients, was impacted by early deaths. In a prior analysis we reported that a significant proportion of patients on AAML0631 experienced clinically significant bleeding and clotting events. Here we report our analysis of the prevalence of FLT3 mutations and their association with outcomes for pediatric APL patients treated on the AAML0631 study.MethodsDiagnostic bone marrow samples were collected from consenting patients with newly diagnosed APL enrolling onto COG AAML0631. FLT3 mutation testing of these bone marrow samples included evaluation for internal tandem duplications (FLT3/ITD) of the juxta-membrane domain and point mutations of the activating loop (FLT3/ALM) of the tyrosine kinase domain. FLT3 mutation status was correlated with clinically significant bleeding/clotting, early death during induction and relapse. Significance of correlation was determined using the chi-square test and relapse risk for patients who achieved CR by end of Induction 1 was calculated using cumulative incidence.Eligible patients were age ≥ 2 years and < 22 years and required confirmation of PML-RARA by PCR testing. Risk group was defined by WBC at diagnosis: standard risk (SR) WBC < 10,000 and high risk (HR) WBC ≥ 10,000. Treatment regimen has been previously reported [Kutny et al, ASH Abstract, 2015].ResultsThere were 101 evaluable patients on AAML0631 including 35 HR APL and 66 SR APL. A total of 94 patients had specimens available for FLT3 mutation testing. Patients with unknown FLT3 status (3 HR and 4 SR) were excluded from the following analyses. FLT3 mutations were present in 43% (N=40) including 35% (N=33) with FLT3/ITD, 4% (N=4) with FLT3/ALM, and 3% (N=3) with both FLT3/ITD and FLT3/ALM. The median WBC was 24,450 for FLT3 mutant APL compared to 7,130 for FLT3 wild type, and the rate of FLT3 mutation was significantly higher in HR APL compared to SR APL (66% vs. 31%, P=0.001). Four patients died during induction (all HR APL with WBC of 16200-173800), but early death did not correlate with FLT3 mutation (2/4 patients had FLT3 mutations). We analyzed association of FLT3 mutations with prevalence of clinically significant (Grade III-IV) bleeding or clotting events during induction. There was no difference in prevalence of coagulopathy events (N= 19) between those with and without FLT3 mutations (18% vs. 22%, P=0.57).While OS and EFS were not significantly different, the relapse rate from end of Consolidation 1 was significantly higher at 6% (N=3) in FLT3 mutant patients versus 0% in FLT3 wild-type (P=0.039) [Figure 1].ConclusionsFLT3 mutations are highly prevalent (43%) in pediatric APL. The COG AAML0631 study represents the second largest group of pediatric APL patients with outcome data treated on a cooperative group trial and to our knowledge the current report is the largest group of pediatric APL patients evaluated for outcome based on FLT3 mutation status. This study failed to show an association of FLT3 mutations with early death or bleeding/clotting events in induction. With ATO consolidation, the relapse rate was low on this trial. However, it is of great interest that the relapse rate following ATO consolidation was significantly higher in FLT3 mutant patients. Evaluation of a larger (international) cohort of pediatric APL patients is warranted to further define of role of FLT3 in relapse risk, but the current results give further support to consideration of integrating FLT3 inhibitors into relapsed/refractory APL treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Comparison of Outcomes Between Adolescents and Young Adults (AYA) and Children with Acute Promyelocytic Leukemia (APL): North American Intergroup Study CALGB 9710 (Alliance)

Purpose: Recent studies have demonstrated differential outcomes for adolescents and young adults (AYAs) vs. children treated for acute myeloid leukemia. Here we analyze outcomes by age group for APL patients treated on the North American Intergroup Study C9710.Methods: Patient characteristics and outcomes were compared between children (<15 yr, n=55) vs. AYAs (15-31 yr, n=42). To control for differences in treatment center, only young adults registered at Children’s Oncology Group (COG) treatment sites were included. Treatment included induction with daunorubicin, cytarabine and ATRA. All patients (pts) received two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Pts ≥15 yr were randomized to an additional two cycles of arsenic trioxide (ATO). Sub-group analysis was also performed to exclude pts ≥15 yr who received ATO and thus compare only patients <15 yr vs. ≥15 yr who had not received ATO.Results: Children and AYAs had similar characteristics of gender, race/ethnicity, Sanz risk grouping and M3v histology. Among all pts enrolled at COG sites on the study, complete response (CR) rates were similar (<15yr =85% vs. ≥15yr =81%, P=0.59). AYAs had improved 5 yr disease-free survival (DFS) from time of CR compared to younger pts (<15 yr =47% vs. ≥15 yr =70%, log rank P=0.05), and there was a trend toward difference in 5 yr event-free survival (EFS) (<15 yr =46% vs. ≥15 yr =63%, log rank P=0.13). Overall survival (OS) at 5 years was not significantly different (<15 yr =82% vs. ≥15 yr =75%, log rank P=0.47). Twenty-three of 42 pts ≥15 yr received ATO consolidation cycles, which may have contributed to their improved DFS and EFS. Thus, we analyzed outcomes by removing from the analysis patients ≥15 yr who received ATO consolidation cycles, and compared pts <15 yr who did not receive ATO (n=55) to pts ≥15 yr who were randomized to no ATO (n=19). CR rates were again similar (<15 yr =85% vs. ≥15 yr no ATO =84%, P=1.0). There was no significant difference in other outcomes including 5-yr DFS from time of CR (<15 yr =47% vs. ≥15 yr no ATO =63%, log rank P=0.31), 5-yr EFS (<15 yr =46% vs. ≥15 yr no ATO=53%, log rank P=0.89), or 5-yr OS (<15 yr =82% vs. ≥15 yr no ATO=79%, log rank P=0.78).Conclusions: The C9710 study demonstrated improved EFS, DFS and OS among adult patients receiving ATO consolidation compared to those who did not receive ATO (Powell et al., Blood, 2010). The current analysis of results for AYAs versus younger pediatric pts showed improved DFS among the whole AYA cohort (of which 55% received ATO consolidation) compared to pts <15 yr (of which 0% received ATO). When the analysis was restricted to AYA pts not receiving ATO, however, the results of this intergroup APL trial showed similar CR, DFS, EFS and OS for AYAs and younger pts. Thus, unlike other subtypes of AML, APL appears to have a consistent response across the pediatric and AYA age groups. The most recent COG clinical trial in APL is now evaluating whether pediatric patients can also benefit from ATO consolidation. DisclosuresOff Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

Arsenic Trioxide Is a Well Tolerated Consolidation Regimen in Children with Newly Diagnosed Acute Promyelocytic Leukemia; Toxicity Results of the Children’s Oncology Group AAML0631 Trial

BackgroundAnthracyclines have historically been the backbone of chemotherapy regimens used to treat newly diagnosed APL in both children and adults, but large cumulative doses of these drugs are associated with long term cardiotoxicity especially in children. The Children’s Oncology Group designed trial AAML0631 to reduce the cumulative anthracycline dosing in children with APL while incorporating two courses of arsenic trioxide (ATO) during consolidation. The majority of the experience with ATO in clinical trials in newly diagnosed APL has been in adult patients. Here we present data on the tolerability of ATO consolidation in pediatric APL patients along with the results of induction therapy and targeted toxicities during induction and consolidation. Because some patients are still on maintenance therapy, survival outcome is not presented.MethodsEligibility criteria for this non-randomized study included age > 2 years and < 22 years, de novo APL with confirmation of PML-RARA translocation by PCR and no prior APL directed therapy or secondary APL. Patients were stratified by white blood cell count (WBC) at diagnosis into standard risk (SR)- WBC < 10,000 and high risk (HR)- WBC > 10,000. Induction consisted of idarubicin 12 mg/m2/dose for 3 doses and all-trans retinoic acid (ATRA) 12.5 mg/m2/dose (no max dose) PO BID on days 1-30. Consolidation 1 included 2 cycles of ATO 0.15 mg/kg/day (no max dose) IV over 2 hours on Monday through Friday for 5 weeks and ATRA 12.5 mg/m2/dose PO BID on days 1-14. Consolidation 2 included cytarabine 1,000 mg/m2/dose IV every 12 hours for 6 doses on days 1-3, mitoxantrone 10 mg/m2/dose IV on days 3 and 4 and ATRA 12.5 mg/m2/dose PO BID on days 1-14. Consolidation 3 included Idarubicin 5 mg/m2/dose IV on days 1, 3 and 5 and ATRA 12.5 mg/m2/dose PO BID on days 1-14. Consolidation 4 was given to HR patients and included cytarabine 1,000 mg/m2/dose IV every 12 hours for 6 doses on days 1-3, idarubicin 10 mg/m2/dose IV on day 4 and ATRA 12.5 mg/m2/dose PO BID on days 1-14. All patients received 9 cycles of maintenance therapy consisting of 12 week cycles of 6-mercaptopurine 50 mg/m2/day PO, methotrexate 25 mg/m2 once weekly PO and ATRA 12.5 mg/m2/dose PO BID on days 1-14. Intrathecal cytarabine was given once during each consolidation 2-4 and during the first cycle of maintenance.ResultsBetween 3/2009 and 11/2012, 108 patients were enrolled on AAML0631. A total of six patients were found to be ineligible due to being RQ-PCR negative for PML-RARA (n=3) or local issues with consent (n=3). Of the 102 eligible patients, 67 had standard risk APL and 35 had high risk APL. Regarding toxicity during induction, 4 deaths occurred with 3 occurring on day 2 of induction and 1 occurring on day 10 of induction. Patients with HR APL had a significantly increased risk of induction death (4/35 = 11.4%) compared to patients with SR APL (0/67; P=0.012). Deaths during consolidation included one HR patient death due to sepsis during consolidation 2 and one SR patient death due to suicide during consolidation 4. Adverse events (AE) reporting included non-hematologic toxicity grade ≥3 and all grades of cardiac toxicity. Cardiac AEs during the 2 ATO cycles included 18% (n=17/92) of patients experiencing at least 1 grade 1/2 event with the majority (94%, 16/17) being prolongation of the QTc interval. Only 1 patient experienced a grade 3/4 cardiac toxicity during these cycles and there were no cardiac related deaths. Hepatotoxicity during ATO cycles included few patients experiencing at least 1 grade 3/4 event including elevations of ALT (4%, n=4/92), AST (3%, n=3/92) and bilirubin (1%, n=1/92). For grade ≥3 AEs reported the percentage of patients experiencing at least one toxicity was 27% during the two cycles of consolidation 1 which was significantly less than the 81% in induction (P<0.001), 72% in consolidation 2 (P<0.001), 69% in consolidation 4 (P<0.001) and higher than the 10% in consolidation 3 (P=0.004).ConclusionsWe were particularly interested in the toxicity and tolerability of two cycles of ATO in a pediatric population. While cardiac toxicity is a concern with this medication, we found minimal significant cardiac complications. Hepatotoxicity has also been a concern with ATO but we did not find this to be a significant problem in our group of patients. In conclusion, ATO which has been reported to be a highly effective agent was found to be well tolerated in our large pediatric cohort of newly diagnosed APL patients. DisclosuresOff Label Use: Idarubicin and Mitoxantrone- labeled for use in AML/APL for adults (not pediatrics) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype

The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3-ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3-ITD mutant level was uniformly low, < 0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML–RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy.

Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia

AbstractThe optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα–negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.

Adding Mercaptopurine and Methotrexate to Alternate Week ATRA Maintenance Therapy Does Not Improve the Outcome for Adults with Acute Promyelocytic Leukemia (APL) in First Remission: Results From North American Leukemia Intergroup Trial C9710

Abstract▪258▪This icon denotes a clinically relevant abstractThis randomized phase III clinical trial was designed to evaluate the potential benefit and toxicity of (a) arsenic trioxide (ATO) as initial consolidation therapy and (b) maintenance therapy with oral tretinoin (ATRA) either alone or together with 6-mercaptopurine (MP) and methotrexate (MTX) in newly diagnosed patients with APL. All patients received induction therapy with ATRA, daunorubicin (DNR) and cytarabine. Adults (≥ 15 years) were randomized at study entry to receive a standard consolidation with 2 courses of ATRA plus DNR, or 2 courses of ATO as initial consolidation followed by 2 courses of ATRA plus DNR. Patients who remained in complete remission (CR; n=331) were then randomized (stratified by consolidation arm and age group) to one year of maintenance with ATRA alone (45 mg/m2/d) for 7 days repeated every other week (n=166) or in combination with MP 60 mg/m2/daily plus oral MTX 20 mg/m2/weekly (n=161). The target number of maintenance events was 146, and the study had 80% power to detect a hazard ratio of 1.6 at 5 years. We previously reported that the addition of ATO consolidation markedly improved event-free (EFS) and disease-free (DFS) survival (Blood 2010; 116:3751–3757). We now report the results of the maintenance randomization after a median follow up of 6.2 years. The two groups were well balanced by pretreatment characteristics. DFS, the primary endpoint, and overall survival (OS) were not statistically different for the two maintenance arms (log-rank p=0.14 and p=0.33, respectively). Evaluation by consolidation arm (by intention-to-treat, ITT) and by APL risk group also failed to demonstrate a significant advantage for either maintenance treatment. There was no interaction effect between consolidation and maintenance arms (p=0.78). Age, gender, CD56 expression and FLT3-ITD or TKD mutations at diagnosis did not have an impact on outcome by maintenance arm.ATRA*ATRA/MP/MTX*PDFS: overall41/16630/1610.14DFS by consolidation arm (ITT): ATO10/844/780.13no ATO31/8226/830.21DFS by risk group: low/intermediate25/12819/1300.20high16/3811/310.683-year DFS from CR79%87%0.056OS: overall22/16616/1650.33OS by consolidation arm (ITT): ATO8/843/810.15no ATO14/8213/840.72OS by risk group: low/intermediate14/1289/1340.20high8/387/310.733-year OS from study entry92%95%0.28*Number of events/number of patients in each group or subgroup.No treatment-related deaths were reported during maintenance therapy. Hematologic adverse events were more common in the combination arm (maximum grade 3/4, 18% vs 4%; p< 0.0001), as were non-hematologic adverse events (maximum grade 3/4, 36% vs 25%; p=0.033). Only 71 DFS events have occurred to date. Although the 3-yr DFS favors the combination arm, the differences in DFS and OS with the addition of MP and MTX to ATRA maintenance do not reach statistical significance. The addition of ATO consolidation therapy remains the most important determinant of DFS and OS for APL patients in first remission on this randomized trial. Among patients who were randomized to maintenance, only 5 patients who received ATO consolidation have relapsed – 2 from the combination arm and 3 from the ATRA alone arm. Relapse of APL is uncommon in patients who received ATO consolidation, and the need for any maintenance therapy in these patients has yet to be determined. Disclosures:Off Label Use: Arsenic trioxide as consolidation treatment for APL.

Treatement of New Cases of Acute Promyelocytic Leukemia by Arsenic Trioxide Whitout ATRA +/− Chemotherapy and Long Term Follow up of Patients

Acute promyelocytic leukemia (APL) is a unique type of hematologic malignancies with high cure rate. ATRA and chemotherapy is current standard treatment but Arsenic Trioxide (ATO) is most potent single agent against APL.Materials and methods: between may 2000 and October 2007 we treated 193 new cases by ATO alone. Patients received 0.15 mg/kg ATO as 2 hours daily i.v infusion till complete remission or 60 days, and then received the same dose as consolidation for 28 days, one months after CR. From 2006, increased ATO consolidation to 4 doses (two 28 days in first year and two 28 days in beginning of second and third years). They received Dexamethasone for treatment of APL differentiation syndrome. Patients followed by sensitive RT-PCR for MRD detection. Median follow up was 28 months (1–88) and 38% of cases followed for more than 3 years and 15% for more than 5 years. For treatment of patients after relapse we used ATO again by the same schedule.Results: Median age of patients was 29+/−13 years and median WBC count at was 2100+/−23319 at diagnosis and 35% of cases have WBC more than 10000 at first presentation. Remission rate was 82.7%. APL differentiation syndrome happened in 31% of patients during remission induction. we observed, by long term follow up that 67.7% of patients are alive. DFS for 2,3 and 5 years were 80%+/−3, 69%+/−4 and 64%+/−5 respectively. Overall survival of patients for 2,3 and 5 years were 86%+/−2, 79+/− 3 and 66%+/−5 respectively. WBC more than 10000 count at diagnosis was associated with increased mortality during remission induction phase (p value< 0.001) but it has no association with DFS or overall survival. Also we observed that chance of relapse for patients with sustained remission at one, two, three and four years after remission induction were 24.6%,16.7%,5.8% and 3% respectively and chance of survival for these patients were 82.8%,88.9%,95% and 100% respectively. For patients who remained in CR after 3 years of remission induction DFS and OS for more than 4 years after remission induction were 94+/−3% for both. These results means that chance of cure for patients on CR is high. Patients who relapsed after first induction could achieve to CR by ATO alone again but their long term prognosis was not good and 68% of them finally died. One year, two, three and four years survival for this group were 88%+−4,72.6%,57.7% and 27+/−7%Conclusion: ATO treatment is an alternative treatment for APL with good long term result. Reduction of early mortality needs better referral system to earlier beginning of treatment and also better control o APL differentiation syndrome and bleeding (especially from lung and CNS).Also we suggest that for relapsed cases it is better to add other treatment modalities like ATRA, chemotherapy or BMT to improve long term results.