Coexistence of PML–RARα and BCR–ABL in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a biologically distinct form of acute myeloid leukemia (AML), characterized by a translocation of the retinoic acid receptor α (RARα) gene on chromosome 17 [1]. Over 95% of cases result from t(15;17)(q22;q21), which allows fusion of the promyelocytic leukemia (PML) gene on chromosome 15 to RARα, although a small minority of cases arise from variant translocations including t(11;17) and t(5;17) [1]. RARα is believed to be important in the proliferation and differentiation of promyelocytes into neutrophils, and thus APL is characterized by the halting of granulocytes at the promyelocytic stage of differentiation in the bone marrow and peripheral blood. Also unique to APL compared to other forms of myeloid leukemia is the dramatic improvement in response with the use of differentiation agents. The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with or without chemotherapy, has achieved complete remission rates of ≥ 95% with 2-year overall survival > 90% [2,3].

The prognosis of APL with additional cytogenetic abnormalities has also been studied. De Botton et al. [4] reported on the prognostic significance of secondary chromosomal changes in 292 patients treated with ATRA and chemotherapy, finding no significant difference in complete remission, event-free survival, relapse or overall survival at 2 years between patients with t(15;17) alone and those with other cytogenetic abnormalities. Twenty-six percent of patients included in this study were found to have additional chromosomal abnormalities, the most common of which was trisomy 8 in 45% of patients, followed by deletions or translocations involving chromosomes 9, 7, 21 and 17 [4]. In 2010, Cervera et al. [5] published data on 495 patients with APL treated with ATRA and chemotherapy, finding a similar overall rate of additional chromosomal abnormalities (28%), again with trisomy 8 as the most frequently noted. Similar complete remission rates were again observed, although patients with additional cytogenetic abnormalities had higher rates of coagulopathy, lower platelet counts and higher relapse-risk scores compared to those with t(15;17) alone [5]. Although additional cytogenetic abnormalities were significantly associated with lower relapse-free survival, they were not identified as independent risk factors for relapse [5].

In this issue of Leukemia and Lymphoma, Xiaolin et al. [6] describe a patient admitted with fever, pancytopenia and peripheral blood smear suggestive of APL. Subsequent cytogenetic evaluation showed a complex karyotype with 46,XY t(9;22)(q34;q11) in addition to the t(15;17)(q22;q21) conventionally seen in APL, as well as trisomy 8 and t(9;14)(q10;q10). t(9;22)(q34;q11) creates a fusion gene between the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9, present in the vast majority of patients with chronic myeloid leukemia (CML).

There are two previously reported cases of the coexistence of t(15;17) and t(9;22) in APL [7,8]. The first patient was treated with ATRA and ATO, but unfortunately died of an intracranial hemorrhage shortly after initiation of treatment [7]. The second patient was treated with ATRA monotherapy and achieved a complete remission, with post-induction bone marrow demonstrating persistence of the PML–RARα translocation, but without further detection of the BCR–ABL protein [8].

Whether patients with concurrent t(9;22) and t(15;17) represent primary APL versus blast crisis of previously undiagnosed CML can be difficult to distinguish. Evidence of splenomegaly, lymphadenopathy or other pre-existing symptoms suggestive of CML would be informative. In the second case report, described above, after treatment with ATRA monotherapy, which is not known to impact CML, the BCR–ABL protein was no longer detected. This implies that the t(9;22) in this patient likely represented a secondary cytogenetic abnormality which resolved after the primary APL was treated.

The overall impact of the t(9;22) in APL is unknown. The prognosis of APL appears to be largely unaffected by the presence of additional cytogenetic abnormalities, but this has not been studied in the setting of APL with t(9;22). Interestingly, Xiaolin et al. [6] report initiation of treatment with the tyrosine kinase inhibitor imatinib in addition to ATRA and ATO for APL. Given that there are no other reported cases using imatinib in the setting of combined t(15;17) and t(9;22), it is unknown whether imatinib contributed to the achievement of complete remission in this case. As the occurrence of these simultaneous mutations is rare, the appropriate treatment and prognosis has yet to be determined. This case demonstrates that both known molecular aberrations can be simultaneously targeted. As an increasing number of mutations are now known to be present in AML, it is expected that novel therapies will be developed to target these abnormalities. It will be of increasing importance to understand the biologic role of each mutation to assess the importance of targeting those abnormalities. A secondary or bystander mutation that is a “druggable” target may not need to be treated, especially if it comes with an increase in toxicity and unknown benefit. As an increasing number of novel agents with direct targets become available for clinical study, these questions will need to be considered.

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