Very Late Relapse of a Philadelphia Positive Acute Megakaryocytic Leukemia Post Allogenic Bone Marrow Transplant

Abstract 4518

A 33 year old male initially diagnosed with myelodysplastic syndrome presented with acute leukemia, his bone marrow demonstrating sheets of abnormal megakaryocytes. Cytogenetics revealed two cell lines, 44X –Y, –C and 46XY, both positive for the Philadelphia chromosome mutation. He underwent busulphan and cyclophosphamide conditioning and allogeneic bone marrow transplant in the absence of a course of induction chemotherapy. One year later he was free of leukemia. Ten years after the transplant he was discharged from hematology follow-up, declared cured.

Twenty-two years later, the patient re-presented with significant anemia and circulating blasts. One year previous he had normal blood counts. Bone marrow biopsy revealed acute megakaroblastic leukemia (M7), with cytogenetics demonstrating Philadelphia chromosome positivity and two identified cell lines, one with deletion of the Y chromosome. The patient underwent induction chemotherapy with idarubicin and cytarabine in addition to imatinib. His recovery marrow revealed no residual leukemia, including normal cytogenetics. He remained BCR-ABL fusion gene transcript positive, and was maintained on single agent imatinib. Four hundred and forty one days after induction chemotherapy he received a second sibling matched allogeneic stem cell bone marrow transplant. One year later he remains free of leukemia with no detectable BCR-ABL fusion gene transcript.

Acute megakaryoblastic leukemia is a rare entity representing <1% of AML seen in adults. Prognosis is poor due to a high rate of relapse with disease free survival of 17% at 5 years. Even with allogeneic stem cell transplant, overall survival at 3 years is 43% with a relapse rate of 64%. With definitive diagnostic criteria for megakaryoblastic leukemia only being first described in 1985, at the time of our patient’s first transplant he was one of the first M7-AML to receive a transplant.

How did this patient, with such an aggressive subtype of leukemia, manage to stay in remission for over 20 years? Looking at all types of AML relapse, very late relapse, defined as occurring >5 years from the day that complete remission, occurs in 1–3% of cases. To our knowledge, this is the first reported case of very late relapse in an M7 leukemia. Fortunately, the rate of achieving a second complete remission state is higher in those patients who have a very late relapse with a second remission attained in up to 87% of cases. This may be influenced by the aggressiveness of the initial consolidation regime; those having more intense initial chemotherapy may have subsequently developed more resistant disease rendering them less sensitive to the second chemotherapy regimen. The fact that our patient never received induction chemotherapy when he initially presented may have contributed to the success of attaining remission when he was exposed to the standard 3+7 model used today.

The pathogenesis for very late relapses remains a topic of debate. One hypothesis suggests that cells with malignant potential retain viability after chemotherapy treatments awaiting re-activation into a malignant state via either intrinsic errors in genetic division or an external stressor such as a viral infection or acquired immunodeficiency state. In this circumstance, the immune system is able to keep the tumor burden below the limits of minimal residual disease detection. It is also possible that residual very slow growing malignant cells remain after chemotherapy that are resistant to anti-tumor treatments. A third possibility is the presumed relapse is actually a de novo tumor with characteristics similar to its predecessor. Other late recurrences of AML have demonstrated both identical and different cytogenetic and molecular profiles to the original disease, which substantiates the premise for multiple mechanisms.

In this case, one could also question whether the second transplant was necessary. He was maintained with a 2–3 log reduction in BCR/ABL fusion transcript level, but no morphologic evidence of leukemia, on only imatinib for over one year. The rationale for pursuing transplantation was the presumed aggressiveness of an M7 leukemia; it is unknown how long he could have been maintained on only a tyrosine kinase inhibitor. A second generation tyrosine kinase inhibitor would have been an option if the major molecular response was not maintained, and remains an option if our patient is unfortunate enough to have a second relapse.