Therapy-related myelodysplastic syndrome after successful treatment of acute promyelocytic leukemia: case report and literature review

AbstractIn the 2016 revision of the World Health Organization classification the term therapy-related myeloid neoplasia (t-MN) defines a subgroup of acute myeloid leukemia (AML) comprising patients who develop myelodysplastic syndrome (MDS-t) or acute myeloid leukemia (AML-t) after treatment with cytotoxic and/or radiation therapy for various malignancies or autoimmune disorders. We report the case of a 36 year old patient with t-MN (t-MDS) after achieving complete remission (CR) of a PML-RARA positive acute promyelocytic leukemia (APL) at 32 months after diagnosis. Initially classified as low risk APL and treated according to the AIDA protocol - induction and 3 consolidation cycles - the patient achieved a complete molecular response in September 2013 and started maintenance therapy. On follow-up PML-RARA transcript remained negative. In January 2016 leukopenia and thrombocytopenia developed and a peripheral blood smear revealed hypogranular and agranular neutrophils. Immunophenotyping in the bone marrow aspirate identified undifferentiated blast cells that did not express cytoplasmic myeloperoxidase. The cytogenetic study showed normal karyotype. The molecular biology tests not identified PMLRARA transcript. A diagnosis of t-MDS (AREB-2 - WHO 2008) was established. Treatment of AML was started with 2 “3+7” regimens and 1 MEC cycle. Two months from diagnosis, while in CR, an allogeneic HSCT from an unrelated HLA compatible donor was performed after myeloablative regimen. An unfavorable clinical evolution was followed by death on day 9 after transplantation. The occurrence of t-MNs during CR of APL represents a particular problem in terms of follow-up and differential diagnosis of relapse and constitutes a dramatic complication for a disease with a favorable prognosis.This work was supported by the grants PN 41-087 /PN2-099 from the Romanian Ministry of Research and Technology

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Invasive Fungal Infections in Acute Promyelocytic Leukemia Patients. Results of a Prospective Multicenter Study in Italy

Blood ◽

10.1182/blood.v124.21.3682.3682 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3682-3682

Author(s):

Maria Stamouli ◽

Alessandro Busca ◽

Luisa Verga ◽

Anna Candoni ◽

Chiara Cattaneo ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Prospective Study ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Antifungal Prophylaxis ◽

Promyelocytic Leukemia ◽

Antifungal Treatment ◽

Newly Diagnosed ◽

Acute Myeloid

Abstract OBJECTIVES Aim of this prospective study was to evaluate the risk of invasive fungal infection (IFI) in patients (pts) with acute promyelocytic leukemia (APL) and to compare APL pts with patients affected by non promyelocytic acute myeloid leukemia (npAML) in order to evaluate factors potentially linked to IFI in these two subsets of acute myeloid leukemia. PATIENTS AND METHODS From January 2010 to April 2012 all pts with newly diagnosed AML were registered in 33 Italian participating centers. A minimum follow up of 90 days after 1st induction chemotherapy was requested for all pts. A prolonged follow up until June 2014 was made only for APL. Data were collected about age, gender, AML subtype, treatment and also about post chemotherapy risk factors for IFI (duration of neutropenia, mucosal damages, vomiting, diarrhea, presence of medical devices), antifungal prophylaxis, onset of IFI, level of certainty (possible/probable/proven), and antifungal treatment. Only for APL the survey was prolonged for at least 3 months in order to analyze if these pts have an IFI risk during other than first induction phases. RESULTS 1,192 consecutive newly diagnosed adult AML pts (npAML:1,086/APL:106) were enrolled in the study. Among npAML pts, those receiving low dose chemotherapy and/or palliative treatment were excluded from the analysis; in the remaining 881 pts 214 cases (24%) of IFI were recorded. Considering APL, 3 pts were excluded from the analysis due to early death (1 pt) or bad performance status (2 pts). The remaining 103 pts received APL treatment according to local protocols: all trans retinoic acid (ATRA) plus chemotherapy (90 pts) or ATRA plus arsenic trioxide (ATO)(13 pts). Only 8 (8%) APL pts developed an IFI after the induction phase: 1 proven, 3 probable and 4 possible IFI. All cases were caused by molds. All APL were followed for a median follow up of 36 months (range 3-54). During this time only 2 other cases of IFI were observed: 1 possible IFI during consolidation at 16 weeks from APL diagnosis and 1 probable aspergillosis in a rare case of APL relapse at 132 weeks from APL diagnosis. All the IFI occurred in pts treated with ATRA plus chemotherapy. IFI was fatal in only 1 case (cerebral aspergillosis), all the other pts recovered after antifungal treatment. A comparison between npAML and APL was made in order to analyze the risk of IFI within 90 days after induction treatment among these 2 groups of patients (see table). A significantly lower number of overall IFI and systemic antifungal treatment was observed in the APL group, in spite of the fact that systemic anti mold prophylaxis was significantly less frequently utilized. Table 1Comparison between APL and npAML in induction phaseAPLnpAMLpNumber of pts103881Mean age51550.01m/f50/53448/433N.S.Performance status (WHO)0-1>1. 76 27. 284 597. <0.0001Central venous catheter52 (50%)687 (78%)<0.0001Neutropenia (<1000/mm3)103 (100%)874 (99%)N.S.Mean duration of neutropenia (<1000/mm3)23 days25 days0.1Mean duration of deep neutropenia (<500/mm3)17.5 days24 days0.04Antifungal prophylaxis94 (91%)837 (95%)N.S.Topical antifungal prophylaxis 17 (17%)60 (7%)0.0005Drug in prophylaxisfluconazoleitraconazoleposaconazoleother.33 (32%)13 (12%)38 (37%)1 (1%).168 (19%)117 (13%)513 (58%)23 (3%).0.002N.S. <0.0001IFIsall casesproven/probable.8 (8%)4 (4%).214 (24%)77 (9%).0.00010.08moldsall casesproven/probable.8 (8%)4 (4%).191 (22%)55 (6%).0.0006N.S.yeastsall cases.0.23 (3%). <0.0001Antifungal treatmentMean duration11 (11%)17 days275 (31%)14 days<0.0001 N.S.Overall mortality at 30 days8 (8%)110 (12%)N.S.Mortality due to IFI at 30 days1 (1%)25 (3%)N.S. Comparing APL among them in order to identify parameters that could be correlated to IFI presentation, no significant factors were identified. DISCUSSION In our prospective study we specifically analyzed the incidence and the type of IFI in APL during a prolonged follow-up. Only 10 cases of IFI were documented and in most cases (6 pts) the infection was only possible. Comparing APL to npAML a lower incidence of overall IFI was observed despite less use of mold active drugs as prophylaxis. It could be attributed to the different chemotherapy (less aggressive in APL) and to lower duration of deep neutropenia. No yeast infection was observed in APL. On the basis of this study, APLs may be considered at low risk of IFI so probably the use of a mold active antifungal prophylaxis could be omitted. Disclosures No relevant conflicts of interest to declare.

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Unexpected Concomitance of BCR-ABL and PML-Rarα Leukemia - Three-Year Follow-up

Blood ◽

10.1182/blood-2019-132259 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5038-5038

Author(s):

Caique Pereira de Moura Martins ◽

João Vítor Ternes Rech ◽

Lee I-Ching ◽

Giovanna Steffenello Durigon ◽

Joanita Angela Del Moral ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Promyelocytic Leukemia ◽

Ongoing Treatment ◽

Clinical Conditions ◽

Acute Myeloid

Introduction Acute promyelocytic leukemia (APL) with PML-RARα is a variant type of acute myeloid leukemia (AML), halting granulocytes at the promyelocytic stage1, primarily associated with the t(15;17)(q22;q11-12) translocation2. The fusion gene BCR-ABL1, attributed to the t(9;22) translocation, is widely associated with chronic myeloid leukemia (CML)3, but rarely found in APL. In this report we explore the occurrence of both BCR/ABL and PML-RARα and in a patient with ongoing treatment for confirmed CML. Case report A 25-year-old woman with ongoing treatment for chronic myeloid leukaemia (CML) in use of Imatinib. Presented to the ER with fever, metrorrhagia, splenomegaly, cutaneous mycosis by Fusarium sp. Investigation upon admission showed pancytopenia, complete blood count showed white blood cells 1.290/mm3, hemoglobin 7,5 g/dL and platelets 13.000/mm3. Bone marrow trephine biopsy showed diffuse infiltration by blasts with large nuclei - round to oval, some irregular, some invaginated- and with hypergranulated cytoplasm(Fig. 01). The bone marrow aspiration showed hypocelular marrow with 67,9% pathological blasts (MPO++, CD13+, CD33++, CD117+, , CD34 -/+, CD15-, CD11b-). Chromosome analysis displayed 46, XX, t(9;22) (q34;q11) and t(15;17)(q22;q11-12). PCR showed amplification for both PML/RARα and BCR/ABL. The patient was treated under Intensive Care with DA regimen and nilotimib associated retinoic acid (ATRA), as well as cefepime, metronidazole, B Amphotericin and vancomycin for cellulitis and fusariosis. The patient was discharged after fifty-three days in good clinical condition, and followed the treatment with consolidation phase therapy and presented remission of both CML and APL. After two years in good clinical conditions, follow-up exams evidentiated new onset of APL (PCR with only t(15;17)(q22;q11-12) and BCR-ABL negative). Due the new condition, the patient is undergoing therapy with arsenic trioxide (ATO) (10mg/d) with good improvement of clinical conditions and a bone marrow transplant is scheduled at this point. Discussion Late progression of CML emcompasses uncontrolled proliferation and loss of control mechanisms and of differentiation, in a terminal status termed acutephase or blast crisis, typically resembling acute myeloid leukemia (AML)4. The presence of t(15;17)(q22;q11-12) translocation, closely associated with the diagnosis of PML (over 95% of cases), and t(9;22)(q34;q11) creates a fusion gene between BCR on chromosome 22 and ABL1 on chromosome 9 (BCR-ABL1), that is present in the wide majority of patients affected by CML1. The rarity of PML in CML patients, associated with similarity between acute phase CML (AML-like) and PML, may cause confusion among clinicians and a difficult treatment course, since PML and CML follow different treatment protocols. Unlike other forms of myeloid leukemia, APL substantially improves in response with the combination of ATO and ATRA, with or without chemotherapy, achieving complete remission rates of ≥95% with 2-year overall survival >90%1, while treatment of CML have tyrosine kinase inhibitors with assessment of molecular response as the primary therapeutic intervention3,5. Considering that coexistence of CML and PML is a rare disorder, we present a case of a patient with ongoing treatment of CML (BCR-ABL positive) that developed acute promyelocytic leukemia (PML-RARα positive). Cytogenetic findings and a description of the clinical course are explored in the light of recent literature. Figure Disclosures No relevant conflicts of interest to declare.

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Therapy-related acute myeloid leukemia with t(9;11)(p12;q23) in a patient treated for acute promyelocytic leukemia

The Hematology Journal ◽

10.1038/sj.thj.6200256 ◽

2003 ◽

Vol 4 (4) ◽

pp. 289-291 ◽

Cited By ~ 2

Author(s):

Mario Annunziata ◽

Salvatore Palmieri ◽

Barbara Pocali ◽

Mariacarla De Simone ◽

Luigi Del Vecchio ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Promyelocytic Leukemia ◽

Acute Myeloid

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Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

Therapeutic Advances in Hematology ◽

10.1177/2040620720976984 ◽

2021 ◽

Vol 12 ◽

pp. 204062072097698

Author(s):

Xiaoyan Han ◽

Chunxiang Jin ◽

Gaofeng Zheng ◽

Yi Li ◽

Yungui Wang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

Specific Factor ◽

Acid Receptor ◽

Response To Chemotherapy ◽

Acute Myeloid

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

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Acute myeloid leukemia with mutated NPM1 mimics acute promyelocytic leukemia presentation

International Journal of Laboratory Hematology ◽

10.1111/ijlh.13357 ◽

2020 ◽

Author(s):

Manuel J. Arana Rosainz ◽

Nghia Nguyen ◽

Amer Wahed ◽

Laura C. Lelenwa ◽

Nfn Aakash ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Promyelocytic Leukemia ◽

Acute Myeloid

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ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression

Blood ◽

10.1182/blood-2005-07-3068 ◽

2006 ◽

Vol 107 (8) ◽

pp. 3330-3338 ◽

Cited By ~ 139

Author(s):

Beatrice U. Mueller ◽

Thomas Pabst ◽

José Fos ◽

Vibor Petkovic ◽

Martin F. Fey ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

All Trans Retinoic Acid ◽

Conditional Expression ◽

Neutrophil Differentiation ◽

Acute Myeloid

Abstract Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor α (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).

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Comment on Geoffroy, M.-C.; de Thé H. Classic and Variants APLs, as Viewed from a Therapy Response. Cancers 2020, 12, 967

Cancers ◽

10.3390/cancers13235883 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5883

Author(s):

Zhan Su ◽

Xin Liu

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Therapy Response ◽

Promyelocytic Leukemia ◽

Acute Myeloid

Acute promyelocytic leukemia (APL) is a unique and very deeply studied acute myeloid leukemia [...]

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Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

Hematology ◽

10.1182/asheducation-2003.1.82 ◽

2003 ◽

Vol 2003 (1) ◽

pp. 82-101 ◽

Cited By ~ 54

Author(s):

Bob Löwenberg ◽

James D. Griffin ◽

Martin S. Tallman

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Promyelocytic Leukemia ◽

Tyrosine Kinases ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Treatment Strategies ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Novel Drugs ◽

Acute Myeloid

Abstract The therapeutic approach to the patient with acute myeloid leukemia (AML) currently evolves toward new frontiers. This is particularly apparent from the entree of high-throughput diagnostic technologies and the identification of prognostic and therapeutic targets, the introduction of therapies in genetically defined subgroups of AML, as well as the influx of investigational approaches and novel drugs into the pipeline of clinical trials that target pathogenetic mechanisms of the disease. In Section I, Dr. Bob Löwenberg reviews current issues in the clinical practice of the management of adults with AML, including those of older age. Dr. Löwenberg describes upcoming possibilities for predicting prognosis in defined subsets by molecular markers and reviews experimental strategies to improve remission induction and postinduction treatment. In Section II, Dr. James Griffin reviews the mechanisms that lead to activation of tyrosine kinases by mutations in AML, the consequences of that activation for the cell, and the opportunities for targeted therapy and discusses some examples of developing novel drugs (tyrosine kinase inhibitors) and their effectiveness in AML (FLT3). In Section III, Dr. Martin Tallman describes the evaluation and management of patients with acute promyelocytic leukemia, a notable example of therapeutic progress in a molecularly defined entity of leukemia. Dr. Tallman focuses on the molecular genetics of APL, current curative treatment strategies and approaches for patients with relapsed and refractory disease. In addition, areas of controversy regarding treatment are addressed.

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Acute promyelocytic leukemia: preventing early complications and late toxicities

Hematology ◽

10.1182/asheducation-2016.1.10 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 10-15 ◽

Cited By ~ 20

Author(s):

Sameem Abedin ◽

Jessica K. Altman

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Early Death ◽

Promyelocytic Leukemia ◽

Early Complications ◽

Younger Patients ◽

Success Stories ◽

Acute Myeloid

Abstract Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML), which presents with a distinct coagulopathy. Therapeutic advances have made APL one of the true success stories in oncology, transforming this once lethal disease into the most curable form of AML. For many patients, cure will now be achieved without the use of chemotherapy. It is hoped that limiting chemotherapy will reduce mortality even further, particularly among more vulnerable older adults whose survival lagged behind that of younger patients. It should be noted that early death persists in patients with APL and continues to negatively affect survival. Further, among survivors treated with chemotherapy or even arsenic trioxide (ATO), there remains the potential for long-term toxicities that must be monitored. Understanding the management of these issues is an important complement to ensure maximal survival for patients with APL.

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