All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.

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Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2

Cancers ◽

10.3390/cancers12030648 ◽

2020 ◽

Vol 12 (3) ◽

pp. 648 ◽

Cited By ~ 1

Author(s):

Károly Jambrovics ◽

Iván P. Uray ◽

Jeffrey W. Keillor ◽

László Fésüs ◽

Zoltán Balajthy

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Transglutaminase 2 ◽

Promyelocytic Leukemia ◽

Dependent Manner ◽

Wild Type ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Tnf Α

Randomized trials in acute promyelocytic leukemia patients have shown that treatment with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior in efficacy to monotherapy, with significantly decreased mortality. So far, there are little data available to explain the success of the ATRA and ATO combination treatment in molecular terms. We showed that ATRA- and ATO-treated cells had the same capacity for superoxide production, which was reduced by two-thirds in the combined treatment. Secreted inflammatory biomarkers (monocyte chemoattractant protein-1 [MCP-1], interleukin-1 beta [IL-1β] and tumor necrosis factor-α [TNF-α]) were significantly decreased and were further reduced in a transglutaminase 2 (TG2) expression-dependent manner. The amount of secreted TNF-α in the supernatant of NB4 TG2 knockout cells was close to 50 times lower than in ATRA-treated differentiated wild-type NB4 cells. The irreversible inhibitor of TG2 NC9 not only decreased reactive oxygen species production 28-fold, but decreased the concentration of MCP-1, IL-1β and TNF-α 8-, 15- and 61-fold, respectively in the combined ATRA + ATO-treated wild-type NB4 cell culture. We propose that atypical expression of TG2 leads to the generation of inflammation, which thereby serves as a potential target for the prevention of differentiation syndrome.

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Retinoic Acid Syndrome Induced by Arsenic Trioxide in Treating Recurrent All-Trans Retinoic Acid Resistant Acute Promyelocytic Leukemia

Leukemia & Lymphoma ◽

10.3109/10428190009060334 ◽

2000 ◽

Vol 38 (1-2) ◽

pp. 195-198 ◽

Cited By ~ 18

Author(s):

Che-Pin Lin ◽

Ming-Jer Huang ◽

Ian Y. Chang ◽

Wen-Yen Lin ◽

Yu-Tsan Sheu

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Retinoic Acid Syndrome

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Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome

Blood ◽

10.1182/blood-2009-02-204834 ◽

2009 ◽

Vol 114 (27) ◽

pp. 5512-5521 ◽

Cited By ~ 57

Author(s):

Maaike Luesink ◽

Jeroen L. A. Pennings ◽

Willemijn M. Wissink ◽

Peter C. M. Linssen ◽

Petra Muus ◽

...

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Differentiation Therapy ◽

Chemokine Production ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Pulmonary Infiltration

Abstract In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.

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