Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blast Crisis/drug therapy , Induction Chemotherapy/mortality , Leukemia, Myeloid, Acute/drug therapy , Aged , Blast Crisis/pathology , Female , Follow-Up Studies , Humans , Induction Chemotherapy/methods , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Prognosis , Retrospective Studies , Survival RateABSTRACT
The cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1-2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.
Subject(s)
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/genetics , Gene Rearrangement , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/pathology , Oncogene Proteins, Fusion/genetics , Retinoic Acid Receptor alpha/genetics , Translocation, Genetic , Adult , Aged , Female , Humans , Prognosis , Young AdultABSTRACT
BACKGROUND: Resistance to therapy and a poor outcome characterize relapsed or refractory acute myeloid leukemia (AML). There is a clear need for additional palliative approaches with acceptable toxicities. Vincristine sulfate liposome injection (VSLI) confers enhanced pharmacokinetics and activity when compared to the parent compound. It is effective and well tolerated in heavily pretreated acute lymphoblastic leukemia (ALL) patients. Preclinically VSLI has activity in vincristine-resistant cancers. As relapsed or refractory AML patients would have minimal exposure to vincristine it was hypothesized that VSLI would be well tolerated and may have activity. METHODS: A pilot phase II clinical trial was conducted. Five patients with relapsed or refractory disease were treated using the Food and Drug Administration (FDA)-approved dose and schedule. RESULTS: Of the five patients treated none completed more than one cycle; there were no responses and two patients did not complete one cycle of therapy. Surprisingly, three of the five patients had treatment-related constipation, and two had neuropathy consistent with the known toxicities of VSLI. Given the toxicity and lack of response, the trial was terminated early. CONCLUSIONS: VSLI had no activity against relapsed or refractory AML in this limited, single institution dataset.