TO THE EDITOR: Secondary/therapy-related neoplasms, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), occur infrequently in adult patients with acute lymphoblastic leukemia (ALL) . Most frequently, therapy-related/secondary myeloid neoplasms are associated with breast cancer and lymphoproliferative diseases . These patients frequently have complex karyotype including many structural abnormalities indicating a poor prognosis . Here, we report a case of secondary AML in an adult patient with B-ALL on maintenance chemotherapy with an unusual complex karyotype.
A 60-year-old female presented in December 2015 with fever, generalized weakness, and dizziness in the last 2 months. On ultrasonography, she had mild splenomegaly. Complete blood count showed hemoglobin of 77 g/L, total leukocyte counts of 2.84×109/L and platelets of 70×109/L with 2% blasts in peripheral blood smear. Bone marrow aspirate smears were hemodiluted, showing fairly cellular imprint smears with 80% blasts (Fig. 1A). Bone marrow biopsy (Fig. 1B) showed sheets of blasts which are positive for CD10 (Dako, 56C6), PAX5 (Biogenix, ZP007) and negative for MPO and CD33 (Bio SB, RBT-CD33). On flow cytometric immunophenotyping (Fig. 1C), these blasts were positive for CD19, CD10, CD34, HLA-DR, CD22, CD71 (dim), and CD20 (partial), while they were negative for cCD3, cMPO, CD7, CD13, CD33, CD14, CD56, CD4, CD8, CD5, and CD3; these results were consistent with the diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL). Karyotype at this time showed 46,XX. Real-time polymerase chain reaction for t(1;19)(q23 ;p13.3) or TCF-3-PBX1(E2A-PBX1), t(11;19)(q23;p13.3) or MLL-ENL, t(12;21) (p13;q22) or ETV6-RUNX1(TEL-AML1), t(4;11)(q21;q23) or MLL-AF4, t(9;11)(p21-22;q23) or (MLL-AF9), and BCR-ABL1 were negative. She was started on chemotherapy according to the UK ALL protocol. The chemotherapeutic drugs included in the UK ALL treatment regimen were vincristine, daunorubicin, L-asparaginase, prednisolone, and intrathecal methotrexate. Bone marrow after induction therapy was in morphological remission and minimal residual disease by flow cytometry was negative (<0.01%). In February 2017, bone marrow after consolidation therapy was also in morphological remission and minimal residual disease by flow cytometry was negative, and she was started on maintenance chemotherapy. However, in February 2019, she presented with persistent cough. Complete blood count showed hemoglobin of 85 g/L, total leukocyte count of 1.19×109/L, and platelet count of 68×109/L with peripheral blood smear showing 15% blasts. Bone marrow aspirate showed 50% blasts (Fig. 2A) which are larger in size and have abundant granular cytoplasm. On bone marrow biopsy (Fig. 2B), these blasts were positive for CD34 (Dako, QBEnd10), CD33 (Bio SB, RBT-CD33), and CD117 (Biogenix, YR145), and negative for CD10 (Dako, 56C6), CD79a (Dako, JCB117), and PAX5 (Biogenix, ZP007). On flow cytometry (Fig. 1D), these blasts were positive for CD45, CD34, CD13, CD33, CD117 (partial), HLA-DR, CD38, and CD19 and negative for cCD3, cCD79a, CD7, CD22, CD10, CD14, CD64, CD123, CD11b, CD56, and CD58, consistent with the diagnosis of AML. Karyotype, which in December 2015 showed 46,XX, now showed a highly complex karyotype (Fig. 3A). Real-time quantitative PCR for
Secondary leukemia with morphologic and immuno-phenotypic features distinct from the primary leukemia following chemotherapy may be secondary to chemotherapy (therapy-related), which is clonally unrelated to the primary neoplasm or a lineage switch which represent clonal evolution of the primary neoplasm. Genetic analysis in the secondary leukemia is required to diagnose whether the second neoplasm is related to the primary neoplasm or not by comparing cytogenetic and/or molecular abnormalities between the primary and secondary leukemia. Diagnosis of lineage switch requires retention of a genetic signature in the secondary leukemia with the switched phenotype . In our cases, cytogenetic analysis demonstrated a change in cytogenetics between the initial B-ALL and relapsed AML. Therapy-related AML is caused by an acquired somatic mutation in hematopoietic stem cells and progenitor cells induced by cytotoxic chemoradiotherapy. Majority of therapy-related leukemia result from the use of alkylating agents, topoisomerase-II inhibitors, and rarely antimetabolites. Daunorubicin, a topoisomerase-II inhibitor, was used in our patient, which may have induced development of secondary AML. The risk of a secondary neoplasm from ALL in adults is lower than that in children; the majority of cases are AML and MDS, non-Hodgkin’s lymphoma (NHL), or rarely solid malignancies. Pagano
This case highlights an unusual case of secondary AML in an adult patient with B-ALL during maintenance chemotherapy, which evolved from a normal karyotype during ALL to a highly complex karyotype as AML developed. It also highlights the importance of performing immuno-phenotyping at the time of relapse in every case of acute leukemia to identify any change in immunophenotyping or any lineage switch to administer the correct therapy and to analyze minimal residual disease on follow-up.
No potential conflicts of interest relevant to this article were reported.