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LETTER TO THE EDITOR
Year : 2016  |  Volume : 53  |  Issue : 1  |  Page : 59-60
 

Occurrence of myelodysplasia/acute myeloid leukemia 'on therapy' in two patients with acute promyelocytic leukemia


1 Department of Clinical Hematology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
2 Laboratory of Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
3 Clinical Research Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France

Date of Web Publication28-Apr-2016

Correspondence Address:
X Thomas
Department of Clinical Hematology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon
France
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.180843

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How to cite this article:
Chelghoum Y, Plesa A, Ducastelle S, Elhamri M, Thomas X. Occurrence of myelodysplasia/acute myeloid leukemia 'on therapy' in two patients with acute promyelocytic leukemia. Indian J Cancer 2016;53:59-60

How to cite this URL:
Chelghoum Y, Plesa A, Ducastelle S, Elhamri M, Thomas X. Occurrence of myelodysplasia/acute myeloid leukemia 'on therapy' in two patients with acute promyelocytic leukemia. Indian J Cancer [serial online] 2016 [cited 2020 Jun 6];53:59-60. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/59/180843


Sir,

Acute promyelocytic leukemia (APL), for which the incorporation of all-trans retinoic acid (ATRA) into chemotherapy has dramatically improved treatment outcome, is distinguished by a translocation between chromosomes 15 and 17 responsible for the molecular rearrangement PML/RARa. Although therapy was not suspected to be extremely leukemogenic, several cases of secondary myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have recently been reported during the course of APL, with no clear explanations.[1],[2],[3]

Among 19 APL treated over a 3-year period in our institution according to the ongoing APL-2006 trial,[4] two cases with the t(15;17) (q22;q21) and bcr1 breakpoint PML/RARa re-arrangement developed such malignancies, although not randomized in the same arm for consolidation therapy. Case 1, a 42-year-old man, admitted in January 2007, received an induction combining ATRA (45 mg/m 2/day) from day 1 to complete remission (CR) achievement and chemotherapy with cytarabine (200 mg/m 2/day) for 7 days and idarubicin (12 mg/m 2/day) for 3 days. The patient received two identical consolidation courses combining idarubicin for 3 days with arsenic trioxide (0.15 mg/kg/day) 5 days/week for 5 weeks. While on maintenance therapy combining 6-mercaptopurine, methotrexate, and ATRA, in March 2009, he presented fever, leukopenia (0.6 × 109/l) with neutropenia, and thrombocytopenia. In August 2009, he presented exophtalmia with decreased visual acuity. Cranial CT scan confirmed a 3-cm retro-ocular mass, corresponding to a leukemic infiltration. Bone marrow was infiltrated by 95% M5-AML blasts. Cytogenetic analysis showed loss of Y chromosome, trisomy 8, and t(10;11) (p12;q21). PML/RARa remained undetectable. The patient was resistant to re-induction chemotherapy and AML rapidly progressed. General condition altered, and the patient died from multi-organ failures by January 2010.

Case 2, a 46-year-old woman, admitted in April 2007, received the same induction. Consolidation courses consisted of ATRA for 15 days combined with idarubicin for 3 days. Because of venous thrombosis, maintenance therapy only combined 6-mercaptopurine and methotrexate. From January 2008, maintenance therapy was intermittently interrupted because of pancytopenia. Bone marrow showed dysmyelopoiesis and infiltration by 15% of immature precursors. PML/RARa was still undetectable. Karyotypic analysis revealed a monosomy 7 as sole anomaly. The patient was resistant to an initial treatment by a hypomethylating agent and then to two courses of chemotherapy. She finally died of leukemia progression by March 2011.

These two cases displayed features explaining their particular resistance to treatment. Chromosome abnormalities were those usually observed in secondary AML. Both cases developed progressive cytopenia (initially related to maintenance treatment toxicity and/or concomitant viral infection) before overt MDS/AML. Such findings were concordant with a diagnosis of alkylating agent-related MDS/AML, but the time of latency was too short, and none of our patients received alkylating drugs. Although unlikely, it is possible that APL could result from the acute transformation of an undiagnosed underlying MDS, which continued its evolution after APL remission. No any features in baseline bone marrow and cytogenetics could sustain this hypothesis. However, a massive blastic infiltration could mask minor morphological abnormalities. Secondary MDS/AMLs could correspond to relapse in a cytogenetically unrelated clone, since diagnosed while in molecular remission of APL.[5] Nevertheless, the recent increase of reported cases should raise the question of the involvement of new targeted therapies. It has previously been suggested that gene-based therapy (such as ATRA) may facilitate a complete shift of karyotype from a common underlying stem cell abnormality.[3] Case 1 also received arsenic trioxide, for which the apoptotic mechanism may be associated with DNA damage. Secondary AML after such treatments could become an important issue in the near future.

 
  References Top

1.
Latagliata R, Petti MC, Fenu S, Mancini M, Spiriti MA, Breccia M, et al. Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: An emerging problem. Blood 2002;99:822-4.  Back to cited text no. 1
    
2.
Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: The European APL Group experience. Blood 2010;115:1690-6.  Back to cited text no. 2
    
3.
Andersen MK, Pedersen-Bjergaard J. Therapy-related MDS and AML in acute promyelocytic leukemia. Blood 2002;100:1928-9.  Back to cited text no. 3
[PUBMED]    
4.
Ades L, Raffoux E, Chevret S, Pigneux A, Thomas X, Bordessoule D, et al. Arsenic trioxide (ATO) in the consolidation treatment of newly diagnosed APL:First interim analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL Group. Blood (ASH Annual Meeting Abstracts) 2010;116:505.  Back to cited text no. 4
    
5.
Lo Coco F, Latagliata R, Diverio D, Breccia M, Chiusolo P, Mandelli F. Independent clonal origin of therapy-related MDS-AML developing after treatment of acute promyelocytic leukemia. Blood 2002;100:1929.  Back to cited text no. 5
    



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