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Acute promyelocytic leukemia (APL) is a distinct subtype of acute myelogenous leukemia (AML) distinguished by a balanced reciprocal translocation between chromosomes 15 and 17 responsible for the molecular rearrangement PML/RARα. We read with interest the article by Bolognesi et al1 concerning data on HLA association in acute promyelocytic leukemia (APL). The authors’ data, obtained from 102 patients with newly diagnosed APL provided by the clinical centers belonging to the Italian Cooperative Group GIMEMA, showed a different distribution of alleles between bcr1 and bcr3 patients, and a statistically significant association between HLA-B13 and risk of relapse suggesting a possible identification of patients at high risk of relapse in which more aggressive consolidation therapies should be used. The HLA genes have always played an important part in the search for the hereditary contribution to a disease. Regarding leukemia, pioneering work showed that resistance and susceptibility to murine leukemia virus is mapped to the major histocompatibility complex gene region. In Bolognesi et al's report,1 the comparison of HLA frequencies in Italian APL patients with those of an ethnically matched control population did not show any difference. Although realized on a smaller series, the frequency of HLA-A, -B, -Cw tested alleles (determined by serological typing) in our recent APL patients was quite similar to that reported in the Italian APL population (Table 1). Despite an apparent similarity in HLA phenotypes among APL patients and a regular population, a genetic susceptibility to APL may be questionable. Indeed, different features suggest a genetic predisposition or susceptibility to APL related or not to exposure to distinct environmental factors. First of all, relationship between ethnicity and APL has been strongly suggested, APL cases being more frequent in patients from Latino origin.2 Secondly, population studies have identified possible genetic markers of increased susceptibility to leukemia.3 In order to illustrate this, we first report the observation of two cases of APL, sharing HLA alleles and bcr1 breakpoint, occurring in the same family, and then discuss the different features sustaining these data.
Table 1 HLA class I phenotypic frequencies (%) in APL patients and in healthy controls
Case 1, a 35-year-old woman originating from the Christian community of Lebanon, was admitted to our hospital in October 1993. She was first hospitalized in Beirut in August 1993 complaining of bleeding gums and spontaneous bruising. Peripheral blood showed anemia, thrombopenia and white blood cell count of 2.2 × 109/l (7% blast cells). Biological tests showed coagulation disorders with low fibrinogen levels and presence of fibrin degradation products. Bone marrow aspirates confirmed a diagnosis of AML, and the patient received three courses of chemotherapy (one course every 2 weeks) combining daunorubicin (20 mg/day for 4 days) with cytarabine (100 mg/day for 5 days) and etoposide (200 mg/day for 4 days). The patient developed pneumonia. Her WHO performance status progressively declined and her family decided on hospitalization in France. Upon arrival in our institution, peripheral blood showed pancytopenia. Pneumonia was proven to be due to aspergillosis and was treated by amphotericin B and then itraconazole. The bone marrow was markedly hypocellular, but had typical findings of APL with hypergranular blasts, many with multiple Auer rods. Cytogenetic study confirmed APL showing the t(15;17)(q22;q21). Molecular biology showed PML/RARα rearrangement with bcr1 breakpoint. She was re-treated according to our schedule combining oral ATRA therapy (45 mg/m2/day) from day 1 to complete remission (CR) achievement followed by EMA-timed sequential chemotherapy. While pneumonia was improving under itraconazole, neurological complications occurred on day 41 of ATRA therapy. The patient abruptly presented with headache and seizures without localized neurologic deficit. Cranial CT scan showed a right mass, in frontal and parietal areas, suggestive of subdural hematoma. Neurosurgical excision was successfully performed. CR was achieved by day 77. Then the patient received EMA-timed sequential chemotherapy combining mitoxantrone 12 mg/m2/day for 3 days, etoposide 200 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days. Case 1 had three sibling donors (Table 2). From HLA phenotypes, parents’ haplotypes could be deduced showing a haplotype in common strongly suggesting a notion of consanguinity between them. Despite the presence of suitable familial donors, she received a second course of EMA chemotherapy as consolidation therapy. The patient is currently alive more than 6 years after CR achievement. She is still in cytological CR and has no detectable PML/RARα rearrangement by RT-PCR determinations.
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References
Bolognesi E, Cimino G, Diverio D, Rapanotti MC, D'Alfonso S, Fleischhauer K, Migliaretti G, Momigliano-Richiardi P . HLA class I in acute promyelocytic leukemia (APL): possible correlation with clinical outcome Leukemia 2000 14: 393–398
Douer D, Preston-Martin S, Chang E, Nicols PW, Watkins KJ, Levine AM . High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia Blood 1996 87: 308–313
