Therapy-Related Pro-B Cell Acute Lymphoblastic Leukemia: Report of Two Patients with MLL Amplification
Authors: Racke Frederick , Cole Carol , Heerema Nyla A. 
Published: October 2019

Abstract
Abstract 4911
Recent advances in cancer treatment have led to an ever increasing number of cancer survivors. Unfortunately, a small fraction of these patients develop secondary hematologic malignancies as a consequence of their exposure to genotoxic anti-cancer regimens. Most of these are myeloid malignancies, therapy-related acute myeloid leukemia (t-AML) or myelodysplasia (t-MDS). Current classification schemes separate therapy-related myeloid disorders into two classes, those related to prior exposure to alkylating agents or radiation and those with prior exposure to DNA topoisomerase II inhibitors. The alkylating/radiotherapy group often contain chromosomal abnormalities involving chromosomes 5 and 7. In contrast, those with DNA topoisomerase II inhibitor exposure frequently possess chromosomal translocations involving chromosome 11q23, where the MLL gene locus resides. MLL, or “mixed lineage leukemia”, is also frequently rearranged in lymphoblastic leukemias and mixed phenotype acute leukemias. Interestingly, MLL also can be altered in myeloid disease through partial tandem duplication or amplification of the genomic region encompassing MLL [amp(MLL)]. Amp(MLL) of an unrearranged MLL locus has also been described in therapy-related myeloid disease.
Recently, there has been a growing appreciation that therapy-related leukemias are not limited to the myeloid lineage and that therapy-related acute lymphoblastic leukemias (t-ALL) make up a small but significant percentage of therapy-related acute leukemias. Translocations involving the MLL locus have been found in a high percentage of t-ALLs. However, to our knowledge, amp(MLL) has not been reported previously in t-ALL. Herein we report 2 cases of ALL following chemotherapy for other malignancies that showed complex karyotypic abnormalities and distinct MLL amplification by FISH analysis.
Patient 1 is an 80 year old male with a past medical history significant for a stage IV diffuse large B cell lymphoma two years prior. The patient received 8 cycles of R-CHOP chemotherapy and achieved a complete remission. One year later, he had a recurrence and was treated with 7 cycles of RICE chemotherapy. Eleven months later, he presented with leukopenia. A bone marrow examination revealed involvement by B cell ALL. Cytogenetic analysis showed a hypodiploid complex karyotype which included a homogeneously staining region (hsr) at chr11(q23). Metaphase FISH analysis showed amp(MLL) in the hsr.
Patient 2 is a 62 year old male who five years prior had been diagnosed with a pleiomorphic sarcoma of the left hip. The patient received four cycles of doxorubicin and ifosfamide as well as radiation therapy. The patient remained well for five years but then presented with bleeding and a petechial rash. A complete blood count revealed anemia and thrombocytopenia. A bone marrow examination was performed which showed involvement by B cell ALL. Cytogenetic analysis showed multiple numerical and structural abnormalities including an hsr at chr11(q23) in all lines as well as a second hsr in two sidelines. Metaphase FISH analysis showed amp(MLL) in all cells and in both hsrs. Immunophenotypic analysis showed both cases to express a Pro-B cell (CD10-) phenotype with aberrant myeloid antigen expression.
Frequent molecular perturbation makes the MLL locus one of the most common genetic targets in hematologic malignancies, particular in therapy-related neoplasms. The majority of MLL genetic alterations result in translocations involving the MLL gene. These translocations result in fusion proteins with heterologous functions of MLL that result in a block of differentiation. Similarly, amp(MLL), while not creating an abnormal fusion protein involving MLL, also is considered to be a “gain of function” mutation caused by increased expression of MLL. There seems to be an increased frequency of aml(MLL) in therapy-related myeloid disorders.
In summary, we report, to our knowledge, the first cases of therapy-related pro B cell (CD10-) ALL associated with amp(MLL). The shared phenotype between B cell ALLs with MLL rearrangements and amp(MLL) suggests that both lesions may exert similar influences on the transcriptional programs of these leukemias. This observation extends the family of MLL-associated and therapy-related hematologic disorders.

Disclosures:
No relevant conflicts of interest to declare.