Therapy-Related Acute Lymphoblastic Leukemia: Cytogenetic Features and Hematopoietic Cell Transplantation Outcome

The clinical and pathologic characteristics and treatment outcome of therapy-related acute lymphoblastic leukemia (t-ALL) remains less defined compared to therapy-related acute myeloid leukemia. Although MLL rearrangement is the most characteristic genetic abnormality associated with t-ALL, other chromosomal alterations have been described.

We examined the pathologic features and treatment outcome of a cohort of t-ALL patients who were undergoing allogeneic hematopoietic cell transplantation (HCT) in order to better define the cytogenetic profile of t-ALL, and to determine the outcome of t-ALL with allogeneic HCT. We reviewed all consecutive cases of adult ALL that had undergone allogeneic HCT at our institution between 1998 and 2014. Data on previous malignancy, chemotherapy, radiation, cytogenetic abnormalities and survival were collected and analyzed.

We identified 28 cases of t-ALL who had history of chemotherapy and/or radiation prior to ALL diagnosis and subsequently undergone allogeneic HCT at our institution. The median age was 48 years (range 29-61), and 57% of patients were female. The most common prior diagnosis was breast cancer (n=9), followed by multiple myeloma (n=4), sarcoma (n=4), thyroid cancer/disease (n=4), lymphoma (n=3), germ cell tumor (n=2, including a case of combined germ cell and CLL), melanoma (n=1), and colon cancer (n=1). The median interval from initial diagnosis of malignancy to diagnosis of t-ALL was 7.3 years (range; 0.9-50.7). Thirty-nine percent had prior combination of chemotherapy and radiation therapy, 32% had prior radiotherapy alone and 29% had prior chemotherapy alone. Four patients had undergone autologous-HCT prior to t-ALL onset. All cases had B-cell phenotype. Median initial WBC was 8 X 10⁹/L (range 1.2-323). Interestingly, in our cohort the most common cytogenetic abnormality was t(9;22) [Philadelphia chromosome] (39%), and followed by MLL rearrangement (25%). The median interval from diagnosis of previous malignancy to ALL diagnosis was 9.3 years for Ph+ ALL, 2.1 years for MLL-rearranged ALL, and 7.9 years for other cytogenetic types of t-ALL. The median initial WBC on presentation was 8 X 10⁹/L for Ph+ ALL, 17 X 10⁹/L for MLL-rearranged ALL, and 8 X 10⁹/L for other cytogenetic types of t-ALL. Disease status at the time of HCT was as follows: 20 patients were in CR1, 2 were in CR2, 3 were in first relapse and another 3 after induction failure. Conditioning regimen was full intensity in 16 patients and reduced intensity in 12. Four-year Leukemia-free survival (LFS) and overall survival (OS) for the whole cohort were 46% and 49%, respectively. The 4-year LFS and OS for MLL-rearranged cases, Ph+ cases and other cytogenetic types were (62% vs. 43% vs. 40%, p=0.68) and (60% vs. 56% vs. 35%, p=0.71), respectively. In this cohort, only one patient relapsed with the original disease (CLL) after allogeneic HCT. The 100 days non-relapse mortality for evaluable patients was 8%.

Ph+ t-ALL is an under recognized subtype of t-ALL and appears to be at least as common as MLL rearrangement among t-ALL. The HCT outcome of t-ALL appears to be similar to de novo ALL.