Acute Promyelocytic Leukemia Associated with Theraphy of Mitoxantrone in Multiple Sclerosis

Abstract

Turkish Abstract

Introduction

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease affecting central nervous cystem. Mitoxantrone was the first immunosuppressive agent for treatment of relapsing and progressive MS. In recent years, its use has decreased due to the risk of severe adverse events such as cardiotoxicity and induction of treatment related acute promyelocytic leukemia (t-APL). The incidence of acute myeloblastic leukemia (AML) in the population of MS patients treated with mitoxantrone is higher than the estimated incidence proportion of de novo AML in the global population.¹ Treatment related acute myeloblastic leukemia (t-AML) appears in 2% to 12% of cases after the use of toposiomerase II inhibitors such as mitoxantrone from two to four years after starting treatment.^2-3 T-APL typically occurs without an antecedent myelodysplastic phase.⁴ We present the patient with multiple sclerosis and t-APL because of rarity in this paper.

Case Report

A 42 years old female patient was admitted to in neurology clinic inability to walk and general status worsening. Her past medical history included of multiple sclerosis for 20 years. Patient received interferon beta-1a initally. Then she received eight cycles of mitoxantrone (10 mg/ m²; cumulative dose:120 mg) , due to lack of response to interferon. It passed 17 months, after the last dose of  mitoxantrone. After fingolimod and prolonged-release fampridine was started to the patient due to inadequate response to treatment with mitoxantrone. On evaluation of her routine laboratory tests, she was found to have haemoglobin of 11 g/dl, haematocrit of 32.3%, white blood cell count of 1.600/mm³, neutrophil count of 700/ mm³ and platelet count of 19000 µ/l. Level of serum urea was 27 mg/dl, creatinine 0.6 mg/dl, sodium 137 mEq/L, potassium 3.7 mEq/L, uric acid 7.7 mg/dl, total protein 6.7 mg/dl, albumin 4.1 mg/dl, aspartate aminotransferase 26 UI/L, alanine aminotransferase 22 UI/L, gamma glutamyl transferase 39 U/L, lactate dehydrogenase 395 UI/L. Prothrombin time and activated partial thromboplastin time were within the reference range. The patient was consulted to our clinic because of pancytopenia. A large number of blasts (90%) with abundant cytoplasmic granules detected in peripheral blood smear (Image 1and 2). The patient was transferred to our clinic. Bone marrow aspirate demonstrated a markedly hypercellular marrow with 20% blast cells and 80% abnormal promyelocytes.

Flow cytometry study demonstrated these cells to be phenotypically positive for CD13, CD33, myeloperoxidase (MPO), and negative for HLA-DR. PML/RAR-alpha fusion gene rearrangement was confirmed by fluorescence in situ hybridization and molecular analysis.  The patient was diagnosed as having t-APL, and remission induction chemotherapy with doxorubicin (45 mg/m² for 3 days), cytarabine (200 mg/ m²   for 7 days) and all-trans retinoic acid (45 mg/m² ) was administered.  A bone marrow study performed on day +28 showed complete morphologic, cytogenetic and molecular remission. Consolidation therapy could not be given to patients because of fungal pneumonia. She died   after 40 days of remission induction therapy, because of pulmonary aspergillosis.

Discussion

 Mitoxantrone hydrochloride is an anthracenedione developed as an antineoplastic agent. It reduces lymphocyte proliferation with several mechanisms such as inhibition of the DNA repair enzyme topoisomerase II. The United States Food and Drug Administration (FDA) extended approval for the treatment of aggressive, relapsing, and progressive-relapsing multiple sclerosis in 2000.⁵  Mitoxantrone therapy is associated with systolic dysfunction and therapy-related acute leukemia. Systolic dysfunction occurs in 12% of patients with MS treated with mitoxantrone, congestive heart failure occurs in 0.4%, and leukemia occurs in 0.8%.⁶

The cumulative exposure to chemotherapy with alkylating agents and topoisomerase II inhibitors is associated with t-AML that may develop any time after the completion of the treatment.⁷ T-AML following DNA-topoisomerase II inhibitors, such as anthracyclines, epipodophyllotoxins, or mitoxantrone is associated with cytogenetic abnormalities such as t(8;21), t(15;17), or balanced translocations involving 11q23 band.⁸

The incidence of t-AML in mitoxantrone treated MS patients is higher than the estimated incidence of de novo AML. The first case report of t-AML in a patient with MS was published in 1998.⁹ Cattaneo et al. described a case of promyelocytic leukaemia in a 56-year-old man, which appeared 14 months after receiving a cumulative dose of 198 mg of mitoxantrone.¹⁰ Ghalie et al. evaluated the incidence of therapy related acute leukemia after mitoxantrone reviewing the records of 1,378 mitoxantrone recipients in three MS studies (mean cumulative dose of 60 mg/m² and mean follow-up of 36 months) and found only one case of t-AML detected five years after initiating mitoxantrone (mean incidence proportion 0.07%).¹¹

In our patient, APL developed after 17 months from the end of a full-dose course of mitoxantrone. No myelodysplastic phase was documented before its onset. The patient had received neither other types of cytostatic drugs nor radiotherapy. The contributory role of ß-ınterferon cannot be excluded, but no reports exist to date on the leukaemogenic activity of ß-ınterferon.

Conclusion; acute promyelocytic leukemia with the translocation t(15;17) was over-represented in the MS population in comparison with cancer patients also treated with mitoxanrone. The timing of this complication, risk, mortality and relationship to exposure remain uncertain. Haematological monitoring should continue for at least 5 years after the last dose of mitoxantrone.¹²

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