This month, Olatoyosi Odenike, MD, discusses a patient with a morphologic presentation suggestive of acute promyelocytic leukemia (APL), but with a negative PML/RARA fusion transcript result.
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I have a 40-year-old patient who presented with complaints of fever lasting three months. He had a few atypical cells in his peripheral smear and his bone marrow (BM) aspiration was morphologically suggestive of APL. PML/RAR alpha was not detected from peripheral blood. He was started on all-trans retinoic acid plus arsenic trioxide (ATRA). He developed cytopenia after starting hydroxyurea. How should I manage this patient? I repeated a BM aspiration and sent the aspirate for PML/RAR alpha testing. Fluorescence in situ hybridization (FISH) results are pending. Does low promyelocyte count in the BM sample influence the PML/RAR alpha transcript detection?
APL is a medical emergency. Prompt diagnosis and treatment with ATRA, coupled with supportive care, is essential to maximize the odds of a successful outcome and reduce the risk of early mortality from complications related to disseminated intravascular coagulopathy. The hallmark of diagnosis is the demonstration of the t(15; 17)(q24.1;q21.2) chromosomal translocation or the PML/RARA chimeric fusion gene. The PML/RARA fusion can be detected by reverse transcriptase PCR (RT-PCR) or by FISH. RT-PCR is generally regarded as the gold standard for diagnosis, given the heightened sensitivity and specificity and the ability to define the specific breakpoint in PML, allowing subsequent reliable monitoring of minimal residual disease. The turnaround time is variable, but in many centers these assays may take up to 48 hours or longer. Hematologists should commence ATRA as soon as a diagnosis of APL is suspected, even while genetic confirmation is pending, since the risk of early mortality from hemorrhagic complications has been correlated with delay in treatment initiation. In most cases where the morphology is consistent with APL, the diagnosis will subsequently be confirmed by the detection of the PML/RARA fusion. But what about cases where there is no evidence of a PML/RARA fusion transcript?
Variant translocations involving the RARA gene have been described in some patients whose disease has morphologic features resembling APL, but in which there is no evidence of a PML/RARA fusion. The fusion partners involved in these variant translocations include ZBTB16 (previously known as PLZF) located at 11q23.2, NUMA1 at 11q13.4, NPM1 at 5q35.1, and STAT5B at 17q21.2. Other more recently described variants include PRKAR1A/RARA and FIP1L1-RARA fusions. Collectively, these variant translocations account for approximately 1 to 2 percent of APL cases. Morphologic differences can sometimes be appreciated between these cases and classic APL. For example, APL associated with the 11;17 translocation resulting in the ZBTB16/RARA fusion often lacks Auer rods, and some cases involving the NPM1/RARA fusion have both hypergranular and hypogranular promyelocytes and an absence of Auer rods. The World Health Organization recommends that these cases be classified as APL with a variant RARA translocation.
ATRA and arsenic trioxide-based regimens have revolutionized the treatment of classic APL, turning it into a highly curable malignancy. The therapeutic implication of the diagnosis of APL with a variant RARA translocation is that some variants, including those with the STAT5B/RARA and ZBTB16/RARA fusions, are resistant to therapy with ATRA. The ZBTB16/RARA variant is the most common and best studied and is also associated with resistance to arsenic trioxide. Specific management recommendations are lacking for these ATRA-resistant variants given their rarity and the consequent paucity of available evidence, but AML-like chemotherapy approaches have been proposed. By contrast, variant cases involving NPM1/RARA, NUMA/RARA, and FIP1L1/RARA fusions have been reported to retain sensitivity to ATRA.
Metaphase cytogenetics performed on the BM aspirate sample is instrumental in detecting variant translocations. FISH analysis using a probe that spans the RARA gene can also be useful in this regard. Ultimately, for cases of APL lacking a PML/RARA fusion, the combination of metaphase cytogenetics and FISH analysis can provide complementary information that establishes the presence of a variant translocation involving RARA, allowing therapy to be tailored accordingly.
- Larson RA, Kondo K, Vardiman JW, et al. Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia. Am J Med. 1984;76:827-41.
- Arber DA, Brunning RD, LeBeau MM, et al. Acute myeloid leukemia with recurrent genetic abnormalities. In: WHO Classification of tumors of haematopoietic and lymphoid tissues (Revised 4th edition). IARC: Lyon 2017. Swerdlow SH, Carp E, Harris NL, et al.
- Zelent A, Guidez F, Melnick A, et al. Translocations of the RARα gene in acute promyelocytic leukemia. Oncogene. 2001;20:7186-203.
- Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111-21.
- Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875-91.
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NEXT MONTH'S CLINICAL DILEMMA
I am evaluating a 60-year-old man for cervical spine surgery (disc disease with neurologic symptoms) who has a prolonged prothrombin time (PT). He appears to have mild factor VII (FVII) deficiency. His bleeding history is as follows: catheter ablation for atrial fibrillation (followed by warfarin for 10 months without bleeding), shockwave lithotripsy (no bleeding problems), and tooth extractions about 30 years ago (followed by bleeding for about 2 days, with no need for reevaluation or hemostasis). He has no problems with minor lacerations (e.g., shaving) and is physically active in taekwondo. The initial abnormality that prompted referral was a baseline PT of 15.2 seconds, international normalized ratio (INR) of 1.3, with normal partial thromboplastin time. Repeat PT was 13.8 seconds, INR 1.2, with the following factor levels: FVII 46 percent, factor II 86 percent, factor V 87 percent, and factor X 87 percent. The FVII deficiency literature suggests that surgical bleeding is rare if FVII is above 10 percent. One discussion suggested that 30 percent should be okay, but I am concerned about this being a critical bleeding site.
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