Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era

Mantha, Simon; Goldman, Debra A.; Devlin, Sean M.; Lee, Ju Whei; Zannino, Diana; Collins, Marnie; Douer, Dan; Iland, Harry; Litzow, Mark R.; Stein, Eytan M.; Appelbaum, Frederick R.; Larson, Richard A.; Stone, Richard; Powell, Bayard L.; Geyer, Susan; Laumann, Kristina; Rowe, Jacob M.; Erba, Harry P.; Coutre, Steven; Othus, Megan; Park, Jae H.; Wiernik, Peter H.; Tallman, Martin S.

doi:10.1182/blood-2016-10-747170

Cited by 84 publications

(38 citation statements)

References 29 publications

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“…In multicenter studies, the most frequent causes of death were identified as bleeding, differentiation syndrome, infection, and multiorgan failure. Cerebral hemorrhage and severe infection are generally involved in early deaths, which primarily occur in patients with hyperleukocytosis [ 245 ]. Delays in ATRA therapy have been suggested as a contributing factor to early deaths [ 246 ], as has initial hospitalization in nonspecialized primary care institutions [ 241 , 247 ].…”

Section: Discussionmentioning

confidence: 99%

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

Thomas

2019

Oncol Ther

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Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARa) genes. Because patients with APL present a tendency for severe bleeding, often resulting in an early fatal course, APL was historically considered to be one of the most fatal forms of acute leukemia. However, therapeutic advances, including anthracyclineand cytarabine-based chemotherapy, have significantly improved the outcomes of APL patients. Due to the further introduction of alltrans retinoic acid (ATRA) and-more recentlythe development of arsenic trioxide (ATO)containing regimens, APL is currently the most curable form of AML in adults. Treatment with these new agents has introduced the concept of cure through targeted therapy. With the advent of revolutionary ATRA-ATO combination therapies, chemotherapy can now be safely omitted from the treatment of low-risk APL patients. In this article, we review the six-decade history of APL, from its initial characterization to the era of chemotherapy-free ATRA-ATO, a model of cancer-targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

Thomas

2019

Oncol Ther

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“…Historically, high-risk APL (defined by a white blood cell count $10 3 10 3 /mL) has been associated with increased risks of early hemorrhagic death and relapse. 1,2 Although arsenic trioxide (ATO)-based regimens have clearly improved outcomes for patients with standard-risk APL, 3,4 their effects on patients with high-risk APL are less clear. Recent trials from both the North American Intergroup Study and the Medical Research Council have confirmed the benefit of ATO as frontline therapy for patients with APL and have reported similar outcomes among smaller high-risk subgroups.…”

Section: Introductionmentioning

confidence: 99%

A phase 2 study of ATRA, arsenic trioxide, and gemtuzumab ozogamicin in patients with high-risk APL (SWOG 0535)

et al. 2020

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Key Points• Regimen of ATRA 1 ATO 1 GO in high-risk APL is associated with prolonged EFS and high rate of early molecular response.• Regimen of ATRA 1 ATO 1 GO was safe and associated with a low rate of early death in high-risk APL.High-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated.With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively.Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%.The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate.Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease.

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“…High WBC, high peripheral blast count, M3v and black ethnicity were independent predictors of early hemorrhagic death in several studies. 19 , 29 However, our patients who died due to early ICH had low WBC counts (1.8 and 2.6 ×10 3 /μL), and their peripheral blast percentages were also low (10 and 58%, Table 2 ). Hypogranular APL patients of our cohort did not have severe hemorrhagic complications.…”

Section: Discussionmentioning

confidence: 67%

Acute Promyelocytic Leukemia in Children: A Single Centre Experience From Turkey

Aksu

2018

Mediterr J Hematol Infect Dis

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Background and objectivesAcute promyelocytic leukemia (APL), is a distinct subtype of acute myeloid leukemia (AML) characterized by a tendency to hemorrhage and excellent response to all-trans retinoic acid (ATRA). In this retrospective study, we aimed to determine the incidence, clinical symptoms, toxicities, and outcome of children with APL in our center.MethodsWe retrospectively reviewed the medical records of children (age < 18 years) diagnosed with APL in our pediatric hematology department between January 2006-December 2016.ResultsPediatric APL represents 20.5% of AML cases in this cohort. Most of the cases presented as classical M3, albeit hypogranular variant was described in 12% of the cohort. Patients with hypogranular variant APL were differed from classical APL by co-expression of CD2 and CD34. About ¾ of APL patients had hemorrhagic findings at admission or the induction treatment. Severe bleeding manifested as intracranial hemorrhage was present in three patients and intracranial arterial thrombosis was present in one. Six patients showed side effects of ATRA such as pseudotumor cerebri, differentiation syndrome resulting in dilated cardiomyopathy, and pulmonary infiltrates. Five-year overall survival (OS) and early death rate were found to be 82.5% and 12% respectively.ConclusionsA high frequency (20.5%) of APL was noted among children with AML in this single-center study. The overall mortality rate was 17.5%. Since the induction death rate was 12% and life-threatening bleeding was the primary problem, awareness and urgent treatment are critical factors to reduce early losses.

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Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era

Cited by 84 publications

References 29 publications

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

A phase 2 study of ATRA, arsenic trioxide, and gemtuzumab ozogamicin in patients with high-risk APL (SWOG 0535)

Acute Promyelocytic Leukemia in Children: A Single Centre Experience From Turkey

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