Induction Therapy For Acute Promyelocytic Leukemia Research Articles

Complications during Induction Chemotherapy in Acute Promyelocytic Leukemia: An Institutional Experience.

Stalin Chowdary BalaIntroduction Acute promyelocytic leukemia (APL) has transformed from a highly fatal disease to a highly curable one. Induction deaths continue to represent one of the major impediments in modern therapy of APL. Sepsis, hemorrhage, and differentiation syndrome are the major complications during induction therapy in APL. The present study reports the incidence and prognostic factors of major complications during induction chemotherapy in patients with newly diagnosed APL. Materials and Methods The present study was a single institutional, observational, retrospective study. All cases of APL diagnosed by morphology and confirmed by RT PCR (PML RARα) were included in this study. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 25. Results A total of 73 patients were analyzed. The median age at presentation was 30 years (range, 3-60 years) with a female to male ratio of 1.02:1. The most common symptom at presentation was fever (80%), followed by fatigue (56%) and gum bleeding (37%). The majority of the patients at presentation were high risk (42.4%), followed by intermediate risk (38.4%) and low risk (19.2%). Fifty-seven (78%) patients achieved complete hematological remission and 16 (22%) succumbed during induction chemotherapy. Infection was the most common cause of induction death (50%), followed by hemorrhage (37.5%) and differentiation syndrome (12.5%). On univariate analysis of prognostic factors, bcr3 variant, grade 3/4 bleeding during induction, and low levels of albumin at presentation were significant for induction mortality ( p = 0.034, 0.041, and 0.008 respectively). On multivariate analysis, only serum albumin < 3.5 g/dL was an independent predictor for induction mortality ( p = 0.043). Conclusion The majority of patients were high risk at presentation. Sepsis was the most common complication during induction and also the leading cause of induction death. Identifying induction complications at the earliest and providing aggressive supportive measures can further improve outcomes in APL.

Risk factors for early in-hospital death in patients who developed coagulopathy during induction therapy for acute promyelocytic leukemia: a nationwide analysis in Japan.

To prevent early death, management of coagulopathy is important in patients with untreated acute promyelocytic leukemia (APL). This study aimed to clarify factors associated with in-hospital death in patients with coagulopathy during induction therapy for APL. We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) and developed coagulopathy, using a nationwide inpatient database in Japan. Of 1115 eligible patients, 175 (15%) died at a median of 13days (interquartile range, 7-30) after admission. In the multivariable analysis, compared with younger patients (aged < 40years), the occurrence of in-hospital death was significantly more common among older patients (aged ≥ 40 and < 60years: odds ratio = 2.58 [95% confidence interval: 1.29-5.19]; aged ≥ 60 and < 80years: 7.66 [3.89-15.10]; aged ≥ 80years: 16.83 [7.41-38.21]). Delayed initiation of ATRA and no conventional chemotherapy were significantly associated with in-hospital death (1.79 [1.16-2.76] and 2.40 [1.47-3.92], respectively). A total of 699 patients (63%) received anticoagulant therapies, but none of these was significantly associated with lower mortality. Although the present study was constrained by a lack of laboratory findings because of database limitations, the results showed that untreated patients with APL, especially the elderly, had a poor prognosis. Immediate administration of ATRA may reduce in-hospital mortality.

Early Death in Patients with Disseminated Intravascular Coagulation during Induction Therapy for Acute Promyelocytic Leukemia: A Nationwide Analysis

Background: Real-world data studies showed poorer outcomes in patients with acute promyelocytic leukemia (APL) than randomized controlled trials, because elderly patients were excluded in such trials. Reportedly, the main cause of death was severe bleeding due to disseminated intravascular coagulation (DIC) during induction therapy for APL. The management of DIC was therefore crucially important especially in elderly patients. This study aimed to clarify factors associated with in-hospital death in all patients, and elderly patients with DIC during induction therapy for APL. Study Design and Methods: We retrospectively identified 1,463 patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and March 2018 from a nationwide inpatient database in Japan. In-hospital death was evaluated with multivariable logistic regression models in all patients, and in ≥60 year-old patients. Anticoagulants included recombinant human soluble thrombomodulin, delteparin (low molecular weight heparin), danaparoid sodium, gabexate mesilate, and nafamostat mesilate which were administered within three days from admission. Patients who died within three days from the admission were excluded from the study to avoid immortal time bias. Results: We identified a total of 1,138 (78%) patients who developed DIC. We excluded 23 patients who died within three days from the admission. The remaining 1,115 patients were analyzed. During hospitalization, 172 (15%) patients died at a median of 13 days (interquartile range: 7-30). Compared with younger patients (20 to 39 years old), elderly patients were significantly associated with higher in-hospital mortality (60 to 79 years old: odds ratio 5.58 [95% confidence interval 3.05-10.22], 80 years or older: 13.51 [6.07-30.08]). Patients who received ATRA monotherapy had significantly higher incidence of in-hospital death (2.48 [1.54-4.01]). Delayed initiation of ATRA was significantly associated with higher mortality (1.60 [1.11-2.30]). A total of 699 patients (63%) received anticoagulant therapies, but none of these were significantly associated with lower mortality. Use of multiple anticoagulants was significantly associated with higher in-hospital mortality (2.47 [1.16-5.26]). Subgroup analyses in patients ≥60 years old were then conducted. During hospitalization, 122 of 416 (29%) patients died at a median of 13 days (interquartile range: 7-29). Both late initiation of conventional chemotherapy and no conventional chemotherapy were significantly associated with higher in-hospital mortality (1.88 [1.01-3.49], 3.25 [1.74-6.06], respectively). Use of recombinant human soluble thrombomodulin and use of multiple anticoagulants were significantly associated with higher mortality (1.91 [1.09-3.35], 2.64 [1.01-6.90], respectively). Conclusions: Elderly patients who developed DIC during induction therapy for APL were significantly associated with higher in-hospital mortality. Immediate initiation of ATRA and early initiation of conventional chemotherapy may have contributed to preferable outcomes. Disclosures Matsuda: Kyowa Kirin: Speakers Bureau. Jo:Tsumura: Other: Belongs to joint program with Tsumura, Research Funding. Toyama:Bristol-Myers Squibb: Speakers Bureau; Eisai: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Chugai Pharmaceutical,: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Kurokawa:Ono: Research Funding, Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Teijin: Research Funding; Eisai: Research Funding, Speakers Bureau; Shire Plc: Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Bioverativ Japan: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide.

Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37). Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.