Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia

AbstractMost reviews on the state-of-the-art treatment in acute promyelocytic leukemia (APL) have focused mainly on the comparison of therapeutic approaches, including all-trans retinoic acid (ATRA) and chemotherapy. However, outcome of individual patients also depends on appropriate knowledge of several aspects related to APL management that are less appreciated and/or are underestimated in the literature. These aspects include appropriate diagnostic strategy, use of supportive care, early recognition and treatment of life-threatening complications typically associated with APL and its specific treatment, tools and timing for adequate evaluation of response, and, finally, management of the disease in special conditions such as older patients and pregnant women. Besides reviewing current consensus and controversies on the use of ATRA and chemotherapy in the distinct treatment phases (eg, induction, consolidation, maintenance), this article addresses the aforementioned issues on APL management (“tricks of the trade”) with special emphasis on several peculiar aspects that distinguish APL from other acute myeloid leukemias.

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Massive pulmonary embolism at the onset of acute promyelocytic leukemia

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2016.027 ◽

2016 ◽

Vol 8 ◽

pp. 2016027 ◽

Cited By ~ 2

Author(s):

Federica Sorà ◽

Patrizia Chiusolo ◽

Luca Laurenti

Keyword(s):

Pulmonary Embolism ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Massive Pulmonary Embolism ◽

Promyelocytic Leukemia ◽

Early Complication ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

First Case ◽

Life Threatening

Life-threatening bleeding is a major and early complication of acute promyelocytic leukemia (APL), but in the last years there is a growing evidence of thromboses in APL. We report the first case of a young woman with dyspnea as the first symptom of APL due to massive pulmonary embolism (PE) successfully treated with thrombolysis for PE and heparin. APL has been processed with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) obtaining complete remission.

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Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet

Blood ◽

10.1182/blood-2008-04-150250 ◽

2009 ◽

Vol 113 (9) ◽

pp. 1875-1891 ◽

Cited By ~ 586

Author(s):

Miguel A. Sanz ◽

David Grimwade ◽

Martin S. Tallman ◽

Bob Lowenberg ◽

Pierre Fenaux ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Genetic Diagnosis ◽

Treatment Strategies ◽

Promyelocytic Leukemia ◽

Cytotoxic Agents ◽

Response To Treatment ◽

International Panel ◽

All Trans Retinoic Acid ◽

Disease Biology ◽

Life Threatening

The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion–based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

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Multiple adverse drug reactions during all-trans retinoic acid treatment for acute promyelocytic leukemia: differentiation syndrome, bradycardia, intestinal necrosis

10.37349/etat.2020.00007 ◽

2020 ◽

Vol 1 (2) ◽

pp. 109-116

Author(s):

Valeria Ferla ◽

Mariarita Sciumé ◽

Umberto Gianelli ◽

Luca Baldini ◽

Nicola Stefano Fracchiolla

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Adverse Drug Reactions ◽

Leukocytoclastic Vasculitis ◽

Promyelocytic Leukemia ◽

Drug Reactions ◽

Intestinal Necrosis ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Life Threatening

Abstract All-trans retinoic acid (ATRA) induces complete remission in a high proportion of acute promyelocytic leukemia (APL). Nevertheless it is be associated with adverse drug reactions that might be life-threatening including differentiation syndrome, myocarditis, myositis, Sweet’s syndrome and ulcers. We describe a case of APL who during induction therapy developed ATRA syndrome, cardiac arrhythmia and multiple episodes of intestinal necrosis that required surgery. In particular, we report here for the first intestinal necrosis attributable to ATRA treatment in the absence of histological evidence of promyelocytes infiltration or leukocytoclastic vasculitis. Keywords Acute promyelocytic leukemia, all-trans retinoic acid, adverse drug reaction

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PML-RARα Repressed Microrna 126 Mediates Differentiation in Acute Promyelocytic Leukemia By Targeting the Protooncogene C-Myb

Blood ◽

10.1182/blood.v124.21.3558.3558 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3558-3558

Author(s):

Cindy Schödel ◽

Jens-Uwe Hartmann ◽

Dennis Gerloff ◽

Daniela Braeuer-Hartmann ◽

Christiane Katzerke ◽

...

Keyword(s):

Fusion Protein ◽

Acute Promyelocytic Leukemia ◽

Conflicts Of Interest ◽

Promyelocytic Leukemia ◽

Small Noncoding Rnas ◽

Endogenous Expression ◽

All Trans Retinoic Acid ◽

Myeloid Leukemias ◽

Important Regulator ◽

Transient Overexpression

Abstract Almost one tenth of acute myeloid leukemias (AML) are related to t(15;17) translocation. This aberration leads to the PML-RARα fusion protein, which causes a transcriptional block of differentiation and could be resolved by all-trans-retinoic acid (ATRA). MicroRNAs (miRs) are small noncoding RNAs which are ascribed to be important regulators of cell proliferation, development, differentiation and apoptosis. MiR-126 is regarded as tumor suppressor in diverse tissues, but relatively little is known about its functional role in normal and malignant hematopoiesis. In this report, we reveal that oncogenic PML-RARα fusion protein is a repressor of miR-126 expression. Thus, we could demonstrate a significant downregulation of miR-126 expression in presence of the PML-RARα fusion protein in APL versus other AML patient samples and in a PML-RARα Knock in mouse model. We further show that ATRA induced differentiation of APL cell line NB4 comes along with an increase of miR-126 expression. The transient overexpression of miR-126 enhances ATRA stimulated differentiation of myeloid cells, whereas the opposite effect was noticed when endogenous expression of miR-126 was knocked down. Most interestingly, we observed a significant upregulation of miR-126 expression in APL blasts during ATRA treatment of APL patients. C-Myb proto-oncogene was found to be a putative target of miR-126 by analysing the 3’UTR. We could show a reduced c-Myb protein level after enforced expression of miR-126. Further, we reveal that miR-126 leads to a posttransciptional downregulation of c-Myb expression by directly targeting its 3`UTR. Our data suggest miR-126 as an important regulator of differentiation in acute promyelocytic leukemia, targeting the proto-oncogene c-Myb and recommend microRNAs to be potential therapeutic agents. Disclosures No relevant conflicts of interest to declare.

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Monocytic Acute Myeloid Leukemias with KM2TA Translocations to Chromosome 17q that May Clinically Mimic Acute Promyelocytic Leukemia

Laboratory Medicine ◽

10.1093/labmed/lmaa078 ◽

2020 ◽

Author(s):

Raisa I Balbuena-Merle ◽

Christopher A Tormey ◽

Autumn DiAdamo ◽

Henry M Rinder ◽

Alexa J Siddon

Keyword(s):

Acute Promyelocytic Leukemia ◽

Correct Diagnosis ◽

Prognostic Significance ◽

Promyelocytic Leukemia ◽

Specific Gene ◽

Monocytic Differentiation ◽

All Trans Retinoic Acid ◽

Myeloid Leukemias ◽

Prognostic Implications ◽

Acute Myeloid

Abstract Objective Acute promyelocytic leukemia (APL) with variant RARA translocation, eg, t(11;17), is not sensitive to all-trans retinoic acid and requires distinct chemotherapy. However, there are some leukemic entities that may mimic aspects of the clinical and/or laboratory picture of APL and cause confusion because of karyotype nomenclature. Therefore, recognition of such entities may be of therapeutic and prognostic significance. Methods We present 2 cases of acute myeloid leukemia (AML) with t(11;17) that were clinically concerning for APL based primarily on clinical presentation but were ultimately diagnosed as AML with monocytic differentiation. Results Both leukemias harbored KMT2A translocations, one located near but not involving RARA and the other with SEPT9. Conclusion In leukemias that clinically and/or immunophenotypically mimic APL, identification of specific gene translocations can lead to the correct diagnosis and may carry therapeutic/prognostic implications.

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Interleukin-8 is not a predictive biomarker for the development of the acute promyelocytic leukemia differentiation syndrome

10.21203/rs.3.rs-35297/v2 ◽

2020 ◽

Author(s):

Luciana Yamamoto de Almeida ◽

Diego Antonio Pereira-Martins ◽

Ana Sílvia Gouvêa Lima ◽

Márcia Sueli Baggio ◽

Luisa Corrêa de Araujo Koury ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Predictive Biomarker ◽

Promyelocytic Leukemia ◽

Atra Treatment ◽

All Trans Retinoic Acid ◽

Tnf Α ◽

Cytokine Levels ◽

Peripheral Blood Plasma ◽

Life Threatening ◽

The Relationship

Abstract Background Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported. Methods In this study, we followed an APL cohort (n=17) over seven days of ATRA therapy in DS (n=6) and non-DS groups (n=11). Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method. Results In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment (34.16; 6.99 to 147.11 pg mL -1 in D0 vs. 10.9; 0 to 26.81 pg mL -1 in D7; p = 0.02) whereas their levels did not discriminate between DS and non-DS development during the entire induction period (all p > 0.05 in D0, D3, and D7). No significant differences were found in IL-6 levels between groups ( p > 0.05 in D0-D7). Other cytokines tested were all undetectable in patients with APL or healthy controls. Conclusions We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.

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Interleukin-8 is not a predictive biomarker for the development of the acute promyelocytic leukemia differentiation syndrome

10.21203/rs.3.rs-35297/v3 ◽

2020 ◽

Author(s):

Luciana Yamamoto de Almeida ◽

Diego Antonio Pereira-Martins ◽

Ana Sílvia Gouvêa Lima ◽

Márcia Sueli Baggio ◽

Luisa Corrêa de Araujo Koury ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Predictive Biomarker ◽

Promyelocytic Leukemia ◽

Atra Treatment ◽

All Trans Retinoic Acid ◽

Tnf Α ◽

Cytokine Levels ◽

Peripheral Blood Plasma ◽

Life Threatening ◽

The Relationship

Abstract Background: Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported. Methods: In this study, we followed an APL cohort (n=17) over seven days of ATRA therapy in DS (n=6) and non-DS groups (n=11). Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method. Results: In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment (34.16; 6.99 to 147.11 pg mL-1 in D0 vs. 10.9; 0 to 26.81 pg mL-1 in D7; p = 0.02) whereas their levels did not discriminate between DS and non-DS development during the entire induction period (all p > 0.05 in D0, D3, and D7). No significant differences were found in IL-6 levels between groups (p > 0.05 in D0-D7). Other cytokines tested were all undetectable in patients with APL or healthy controls. Conclusions: We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.

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Treatment of Acute Promyelocytic Leukemia

Hematology ◽

10.1182/asheducation-2006.1.147 ◽

2006 ◽

Vol 2006 (1) ◽

pp. 147-155 ◽

Cited By ~ 51

Author(s):

Miguel A. Sanz

Keyword(s):

Acute Promyelocytic Leukemia ◽

Residual Disease ◽

Promyelocytic Leukemia ◽

Controversial Issues ◽

Front Line ◽

Hematopoietic Stem ◽

Line Therapy ◽

All Trans Retinoic Acid ◽

Life Threatening ◽

Unfit Patients

Abstract Cure of acute promyelocytic leukemia (APL) is now a possibility for most patients through the use of state-of-the-art treatments, which include simultaneous administration of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy for induction and consolidation, as well as ATRA-based maintenance. Risk-adapted strategies to modulate treatment intensity may be an effective approach to minimize therapy-related morbidity and mortality while maintaining the potential of cure. In this context, there is no role for hematopoietic stem cell transplantation (HSCT) in front-line therapy, except for the small fraction of patients with persistent minimal residual disease at the end of consolidation. However, HSCT plays an important role for patients in second complete remission. In contrast, an increasing role of arsenic trioxide (ATO) is emerging. Given the high antileukemic efficacy observed with ATO in patients relapsing after ATRA-containing regimens, this agent is currently regarded as the best treatment option in this setting. However, until a randomized comparison between the standard therapy and ATO-based regimens in front-line therapy is available, this latter approach should only be recommended for unfit patients for whom chemotherapy is contraindicated. In addition to reviewing current consensus and controversial issues on antileukemic strategies, this review addresses other aspects that can be crucial for the outcome of individual patients. These aspects include supportive care, recognition and treatment of life-threatening complications, evaluation of response, and, finally, management of the disease in special conditions such as older patients, children and pregnant women.

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Acute promyelocytic leukemia, hypogranular variant: a rare presentation

Clinics and Practice ◽

10.4081/cp.2011.e11 ◽

2011 ◽

Vol 1 (1) ◽

pp. 11 ◽

Cited By ~ 2

Author(s):

Kafil Akhtar ◽

Shamshad Ahmad ◽

Rana K. Sherwani

Keyword(s):

Retinoic Acid ◽

Early Diagnosis ◽

Acute Promyelocytic Leukemia ◽

Rare Case ◽

Promyelocytic Leukemia ◽

Diagnostic Challenge ◽

Rare Presentation ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Life Threatening

Early diagnosis of acute promyelocytic leukemia (APL) is essential because of its associated life threatening coagulopathy and unique response to all trans-retinoic acid (ATRA) therapy. The characteristic cell morphology supplemented by cytochemistry offers the most rapid means for diagnosis. Here we describe a rare case of acute promyelocytic leukemia-hypogranular variant that poses particular diagnostic challenge.

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Interleukin-8 is not a predictive biomarker for the development of the acute promyelocytic leukemia differentiation syndrome

10.21203/rs.3.rs-35297/v1 ◽

2020 ◽

Author(s):

Luciana Yamamoto de Almeida ◽

Diego Antonio Pereira-Martins ◽

Ana Sílvia Gouvêa Lima ◽

Márcia Sueli Baggio ◽

Luisa Corrêa de Araujo Koury ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Predictive Biomarker ◽

Promyelocytic Leukemia ◽

Atra Treatment ◽

All Trans Retinoic Acid ◽

Tnf Α ◽

Cytokine Levels ◽

Peripheral Blood Plasma ◽

Life Threatening ◽

The Relationship

Abstract Background Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of APL-DS. However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in APL patients during the treatment with ATRA and anthracyclines has not been previously reported. Methods In this study, we followed an APL cohort (n = 17) over seven days of ATRA therapy in DS (n = 6) and non-DS groups (n = 11). Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 APL patients and 11 healthy adult controls by using the cytometric bead array method. Results In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment whereas their levels did not discriminate between DS and non-DS development. No significant differences were found in IL-6 levels between groups. Other cytokines tested were all undetectable in APL patients or healthy controls. Conclusions We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.

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