Thursday, July 04, 2013

Pearls on mitoxantrone related leukemia and toxicity

review article  Chan A and LoCoCo F.  MTX related acute leukemia in MS. An open or closed book>
Neurology 2013; 80"1529-33.


1. Current therapy related risk is 0.81 % but varies widely among countries.  It still is current therapy in many parts of Europe with different protocols in different countries.

2. Therapy related leukemia is specifically acute promyelocytic leukemia (the "other" PML). This may be due to preferential attachment to DNA breaks at the PML gene site locus.

3.  Genetic variants of dna repair genes  BRCA 2 (rs1801406) and XRCC5 (rs207906) and detoxification enzyme CYP384(rs2740574) may predispose to apml. Combinations of first two lead to 50 fold increase in risk of MTX associated leukemia in MS patients.

4.  Early MTX cardiotoxicity is associated with a rare ABC transporter genotype leading to increased intracellular MTX levels.

5.  aPML is aggressive and often fatal within hours or days if NOT recognized, but a very treatable form of leukemia if recognized and diagnosed promptly.  80 % curable with all trans retinoic acid and arsenic trioxide together with anthracycline chemotherapy, which is true also for MTX related forms.

6.  Presentations of aPML: bruising, petechiae, anemia, thrombocytopenia, infections related to neutropenia and immune dysfunction,  lymphadenopathy and splenomegaly,  and systemic symptoms including fever and weight loss.  Leukocyte nadir occurs 10-14 days after treatment and returns after 21 days, monitoring is crucial.

7.  Other tests that hav potential value in assessing include blood smear, aPTT, fibronogen, d-dimer, LDH, and bone marrow biopsy.

8.  aPML may occur up to five years after therapy so vigilance in surveillance is indicated.