First-line Treatment Of Acute Promyelocytic Leukemia Research Articles

Cost-Effectiveness of the Regimen Proposed By the International Consortium on Acute Promyelocytic Leukemia in the Treatment of Newly Diagnosed Patients with Acute Promyelocytic Leukemia

Introduction Acute promyelocytic leukemia (APL) is distinguished by the presence of a translocation between chromosomes 15 and 17 [t(15;17)]. All-transretinoic acid (ATRA) plus arsenic trioxide (ATO) is considered as the first line treatment of APL, and can induce a complete remission (CR) in greater than 90% of patients, with a 2-year overall survival (OS) of 99% (Lo-Coco et al, N Eng J Med, 2013). Due to the high treatment costs of this regimen, the International Consortium on Acute Promyelocytic Leukemia (IC-APL) developed a protocol to diminish the economic burden associated with the treatment of APL (Ribeiro & Rego, Hematol Am Soc Hematol Educ Progr, 2006). We performed a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA) of the IC-APL protocol in Mexico, and compared it with the costs of the first line treatment of this disease in other countries.Methods We compared the patients in our institute, which were treated with the IC-APL protocol, with patients treated at other institutions with the first line treatment. For the CEA, the CR was compared with the cost of each protocol, and then compared by using the incremental cost-effectiveness ratio (ICER); for the CUA the quality-adjusted life years (QALY) were obtained and compared with the cost of each protocol, and then compared by using the incremental cost-utility ratio (ICUR).Results CR was achieved in 18 patients (90%) treated with the IC-APL protocol as a first line option; only 1 patient (5%) died in induction; of the patients that achieved CR, 1 relapsed (5.5%). The mean estimated OS was89 months (CI 95%; 86.619 - 101.515), with 89% of patients alive at 39 months; the mean estimated disease free survival (DFS) was 91 months (CI 95%; 83.711 - 99.818), with 94% of patients free of disease at 24 months. The median treatment cost of the IC-APL protocol was $ 21 369 USD. The median length of treatment was 29 months (range, 27 - 39 months), with a median of life without treatment of 41 months (0 - 68 months). The average number of years of life was 7.84 years, with the average QALY of 6.1 (table 1). The total cost of ATRA + ATO in Italy was $ 60 354 USD, in Canada $ 124 108 USD (QALY of 14.68) and in the USA $ 136 170 USD (QALY of 14.33). The CEA yielded $227, $603, $1241 and $1351 USD per % of CR in Mexico, Italy, Canada and the USA, respectively. When comparing the ICER between the IC-APL and the ATRA+ATO protocols, we found a difference of $6 497, $19 133 and $17 123 USD in Italy, the USA and Canada, respectively (table 2) In relation to the CUA, each QALY gained in Mexico costs $3 500 USD, in Canada $11 979 USD, and in the USA $13 955 USD. When comparing the ICUR between the IC-APL and the ATRA+ATO protocols, we founda difference of $13 955 and of $19 133 and of $11 979 USD in the USA and Canada, respectively (table 3).Conclusion Similar clinical endpoints were achieved with the IC-APL protocol when compared with first line treatment, with better outcomes in the cost-effectiveness and cost-utility analyses. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Arsenic trioxide at conventional dosage does not aggravate hemorrhage in the first-line treatment of adult acute promyelocytic leukemia.

The arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) therapy has demonstrated a tremendous success in the first-line treatment of acute promyelocytic leukemia (APL). Actually, early death (ED) is currently thought as a major challenge in APL. ATO has been reported to inhibit platelet function in vitro, and whether it increases the ED rate by exacerbating the hemorrhagic symptoms remains to be investigated. Effects of ATO on platelet aggregation and adhesion were evaluated in vitro and in thirty-two complete remission (CR) and four newly diagnosed APL patients. Furthermore, concentrations of plasma total arsenic were monitored in APL patients via ICP-MS. The inhibition of platelet function, either aggregation or adhesion, did occur in vitro when the concentration of ATO reached 2μmol/L. However, in CR APL patients receiving ATO with normal platelet count, the platelets responded normally when being activated and so did those in the newly diagnosed patients with thrombocytopenia. Our data further showed that the conventional dosage of ATO reached a plasma concentration substantially below the required concentration to inhibit platelets. In the first-line treatment of APL, the use of ATO is safe and effective and does not compromise the hemostatic potential that may eventually increase ED rate.

Induction treatments for acute promyelocytic leukemia: a network meta-analysis.

Background9 treatments for acute promyelocytic leukemia (APL) have been compared in many randomized controlled trials (RCT). The conclusions have been inconsistent and the purpose of this study is to conduct a network meta-analysis.ResultsRankings of event-free survival are ATRA+RIF (81.2%), ATRA+ATO (69.6%), ATO (50.6%). Rankings of complete remission are ATRA+RIF (79.3%), ATRA+ATO (64.8%), RIF (60.3%), ATO (55.9%). Rankings of avoiding differentiation syndromes are CT (84.3%), ATO (80.3%), RIF (71.6%), ATRA+RIF (49%), ATRA+ATO (40.8%).MethodsA total of 1,666 patients from 12 RCTs were enrolled. The frequentist method was used. Relative risks with 95% confidence intervals were calculated. We produced a network plot, a contribution plot, and a forest plot predictive intervals. The inconsistency factor, the surface under the cumulative ranking curve and the publication bias were evaluated.ConclusionsATRA+ATO is eligible to be the first-line treatment for APL. ATRA+RIF is a prospective alternative to the first-line treatment. RIF or ATO should be reconsidered as another option for de novo APL.

Cost-Effectiveness Of Arsenic Trioxide In The Treatment Of Relapsed/Refractory Acute Promyelocytic Leukemia In Canada

Acute promyelocytic leukemia (APL) is a distinct and rare morphological, clinical and pathological variant of acute myeloid leukemia (AML). It represents approximately 10% to 15% of AML. APL is characterized by a high incidence of coagulopathy caused by disseminated intravascular coagulation and/or excessive fibrinolysis and is associated with a high early mortality. Current first-line treatments consist of all-trans retinoic acid (ATRA), anthracyclines and conventional chemotherapy (CT). Although considerable progress has been made in the first-line treatment of APL, about 20 to 30% of patients who achieved complete remission (CR) still relapseTrisenox® is a sterile injectable solution of arsenic trioxide (ATO) and has been approved in several countries, including Canada, for the induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. At this time, ATO is recognized as the standard treatment for relapsed or refractory APL. However, it is not reimbursed yet by provincial public health care systems and was available through a special access program in Canada until product availability.The objective of this study was to assess, from a Canadian perspective, the economic impact of ATO in the treatment of patients with relapsed or refractory APL.A time-dependent Markov model was constructed to assess the cost-effectiveness of ATO compared to ATRA+CT in the treatment of relapsed/refractory APL. Because there was no head-to-head clinical trial available, data from the ATO treatment arm were taken from Soignet, 2001, while data for ATRA+CT were taken from Thomas, 2000. The comparative treatment was composed of ATRA + sequential CT including cytarabine, mitoxantrone or etoposide, followed by autologous hematopoietic stem cell transplantation (HSCT) in consolidation as described in Thomas, 2000. The Markov model comprises five health states: induction, second remission, treatment failure/relapse, post-failure, and death. The length of each Markov cycle was one month for the first 24-month study period then of one year. The model continued to run until all patients reached the absorbing state of death. All patients started in the induction state and could move to other health states thereafter. In case of treatment relapse/failure, patients were subsequently assigned to receive an allogeneic HSCT. The model also takes into account the incidence of treatment-induced grade 3-4 toxicity reported in both clinical trials (Soignet, 2001 and Thomas, 2000). Analyses were conducted from both a Canadian Ministry of Health (MoH) and a societal perspective over a lifetime horizon.In the treatment of relapsed/refractory APL, ATO is a cost-effective strategy over ATRA+CT, from both a health care system and a societal perspective. In fact, compared with ATRA+CT, ATO is associated with an incremental cost-effectiveness ratios (ICERs) of $20,443 per QALY and $22,219 per QALY, from a MoH and societal perspective respectively.Moreover, the results of the exhaustive sensitivity analysis confirm the robustness of the base-case results. In fact, according to the deterministic analysis results, ATO remained a cost-effective strategy compared with ATRA+CT from both perspectives. The ICERs vary between $9,785 and $40,732 / QALY from a MoH perspective and between $11,561 and $44,271 / QALY from a societal perspective. Results of the probabilistic sensitivity analysis indicated that, according to a willingness to pay of $50,000, ATO remains a cost-effective strategy in 99.37% and 98.98% of the simulations, from a MoH and a societal perspective respectively.In conclusion, this economic evaluation demonstrates that ATO+ATRA is a cost-effective strategy in the treatment of relapsed/refractory APL. Disclosures:Lachaine:Lundbeck Canada: Research Funding. Barakat:Lundbeck Canada: Employment.

Oral Tetra-Arsenic Tetra-Sulfide Formula Versus Intravenous Arsenic Trioxide As First-Line Treatment of Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trial

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL). In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m(2)) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin. The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups. Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.

Therapy-Related Myeloid Neoplasms in Patients With Acute Promyelocytic Leukemia Treated With All-Trans-Retinoic Acid and Anthracycline-Based Chemotherapy

We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR). From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy. Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with > or = 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months. t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.

Risk-Adapted Maintenance Therapy for Acute Promyelocytic Leukemia

TO THE EDITOR: We read with great interest the article by Kelaidi et al concerning clinical trials for acute promyelocytic leukemia (APL) performed by the European APL group. This article is meaningful because the efficacy of maintenance therapy was separately analyzed in patients with high-risk APL who were defined as APL with presenting WBC count higher than 10 10/L and patients with low/intermediate-risk APL presenting WBC count lower than 10 10/L. We would like to make comments regarding risk-adapted maintenance therapy for APL. Maintenance therapy consisting of all-trans retinoic acid, 6mercaptopurine, and methotrexate has been adopted in some trials since the European APL group proved its efficacy. Kelaidi et al updated this data, and the benefit of this combination maintenance therapy in patients with high-risk APL was confirmed. In contrast, this therapy had a marginal benefit to preventing relapse to patients with low/intermediate-risk APL. This knowledge has been described for the first time. Risk-adapted strategies have been performed mainly concerning consolidation therapy and induction therapy in clinical trials for APL all over the world. There are no other reports in which it was mentioned that the benefit of this maintenance therapy was correlated with presenting WBC count. The European LeukemiaNet APL guidelines commented that the relative benefit of maintenance therapy depends on the prior induction and consolidation therapy and promyelocytic leukemia/ retinoic acid receptor-alpha (PML/RAR) mRNA status after consolidation therapy. In fact, combination maintenance therapy did not confer disease-free survival advantage for patients with negative PML/ RARA mRNA after three courses of consolidation therapy in the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) group, although the European APL group has performed maintenance therapy for patients with unknown PML/RARA mRNA status after two courses of consolidation therapy. Taking these into consideration, we should pay attention to the fact that the combination maintenance therapy has never been proven to be effective for patients with low/intermediate-risk APL. Moreover, the introduction of arsenic trioxide and gemtuzumab ozogamicin into first-line treatment for APL may reduce significance of maintenance therapy. In addition, this combination therapy often causes serious adverse events such as pancytopenia and liver dysfunction. Therefore, it is probable that the combination maintenance therapy should be omitted or amended in patients with low/intermediate-risk APL although many clinical study groups including the European APL group have continued to adopt this therapy for all patients with APL. The Southwest Oncology Group now examines whether this omission is beneficial for patients with low/intermediate-risk APL (ClinicalTrials.gov number, NCT00492856). Because the efficacy of maintenance therapy is dependent on the prior therapy as described above, the other study groups should prospectively and separately examine whether maintenance therapy has a clinical benefit for patients with low/ intermediate-risk and high-risk APL who have received the induction and consolidation therapy of their own. We believe that the answer to this topic would be of great significance in guiding therapy for patients with APL.

Arsenic trioxide as first-line treatment for acute promyelocytic leukemia

The history, clinical pharmacology and toxicities, and role of arsenic trioxide as a first-line agent for treating acute promyelocytic leukemia (APL) are described. APL is most often characterized by the hallmark reciprocal translocation between chromosomes 15 and 17, leading to the fusion of the promyelocytic gene and retinoic acid receptor alpha. Arsenic's therapeutic utility as an antileukemic agent was first described in the late 18th century. Arsenic trioxide demonstrates a dual, dose-dependent mechanism of action and can induce both partial myeloid differentiation and apoptosis. Arsenic trioxide is generally well tolerated, with reversible toxicities rarely requiring discontinuation of therapy. Toxicities associated with arsenic trioxide include leukocytosis, Q-T interval prolongation, APL differentiation syndrome, and hepatotoxicity. Since 2000, arsenic trioxide has been used as the standard of care for relapsed APL, with remission rates greater than 80% as a single agent. In an attempt to maximize disease-free survival and minimize relapse rates in patients with APL, arsenic trioxide is now being investigated as first-line therapy in the management of APL, with several studies showing promising outcomes. When used alone or in combination with tretinoin, the rates of complete remission have exceeded 85%, with high rates of molecular remission. Arsenic trioxide, alone or in combination with tretinoin, as first-line therapy in newly diagnosed APL has resulted in high rates of complete remission and molecular remission. Arsenic trioxide combined with tretinoin has shortened the time to achieve complete remission and lengthened disease-free survival, findings that suggest the usefulness of the regimen as first-line treatment for APL.

Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy

Introduction: Arsenic trioxide is effective and approved for treatment of relapsed or refractory acute promyelocytic leukemia (APL) cases resistant to all-trans retinoic acid (ATRA), but its effect on new cases of APL is not clear.Materials and methods: We studied 111 patients with APL. Arsenic trioxide was infused at 0.15mg/kg daily dose, until complete remission was achieved. Then, after 28 days of rest, arsenic trioxide was infused daily for 28 days as consolidation therapy. We studied minimal residual disease (MRD) by semi-sensitive reverse transcription polymerase chain reaction (RT–PCR) on peripheral blood samples.Results: Complete remission was observed in 95 patients (85.6%). With the median (range) follow-up period of 16.5 (1–57) months, 1- and 2-year disease-free survival was 88.3% and 63.7%, respectively; 24 patients relapsed, 19 of whom achieved a second complete remission, again by arsenic trioxide. Third and fourth remissions were seen in some relapsed patients, again by arsenic trioxide. For patients in complete remission, 1- and 3-year survival was 95.5% and 87.6%, respectively. MRD was positive in four (8.3%) out of 48 cases during 1 year after remission induction; three of them relapsed clinically.Conclusions: Arsenic trioxide is effective as first-line treatment for APL. Results of arsenic trioxide combination therapy with chemotherapy/ATRA requires further study.