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I. Aldoss et al.
an independent predictor of survival per se when included in multivariate analysis in this cohort (P=0.11).
Discussion
We present here the largest retrospective study of t-ALL with analysis solely restricted to cases with prior exposure to cytotoxic therapies. Unlike some previously published reports, we excluded cases of ALL that were preceded by other malignancies but did not receive cytotoxic chemotherapy or radiation in an attempt to more narrow- ly define the entity of t-ALL.7,8 Although t-ALL does not have unique defining pathologic features, we show that certain recurrent cytogenetic abnormalities are more com- mon in t-ALL compared to de novo ALL.
The cytogenetic features of t-ALL bear some resem- blance to t-AML and may help define t-ALL. Therapy- related leukemia with balanced translocations has been observed in t-AML, especially in patients with prior expo- sure to topoisomerase II inhibitors.3,17,18 MLL (11q23) is the prototypic cytogenetic finding among t-AML patients exposed to topoisomerase II inhibitors, and here we have shown that the incidence of MLL is also more common among t-ALL compared to de novo cases. However, we could not demonstrate association between prior topoiso- merase II exposure and MLL findings, and this is likely due to the frequent administration of radiation and alkylator therapy along with topoisomerase II inhibitors. Consistent with t-AML data, we show that the latency for t-ALL onset was shorter among patients carrying the MLL gene rearrangement compared to other cytogenetic findings. Furthermore, similarly to t-MN, our t-ALL cases were asso- ciated with a higher occurrence of long arm deletions or monosomy 5 and 7.3 These cytogenetic findings support the etiologic role of prior chemotherapy in pathogenesis of attribution of t-ALL in a manner similar to t-MN. Philadelphia (Ph) chromosome is another balanced translo- cation and was more commonly noted among t-ALL cases, but this was not statistically significant in this cohort. Ph chromosome is rarely observed among T-cell phenotype ALL and AML cases, and prior reports have shown that some of those cases were potentially therapy-related and developed after cytotoxic exposure.6,19 Nonetheless, we have observed a trend toward higher rates of additional cytogenetic abnormalities among Ph+ t-ALL compared to Ph+ de novo ALL (73% vs. 50%, P=0.07), and this likely reflects various levels of genomic instability as a result of prior cytotoxic therapy. The incidence of Ph-like ALL would have been an interesting comparison to make between de novo and t-ALL, but unfortunately, we did not have the necessary data available in our cohort.
The latency for ALL development from time of prior diagnosis was 6.8 years in our series, which is slightly longer than what is observed in t-MN (4-4.5 years).1,3 Both B and T-cell ALL phenotypes were observed in a similar proportion compared to de novo ALL. Breast cancer was the most common prior malignancy, likely related to the elevated utilization of alkylator and topoisomerase II inhibitor chemotherapy as well as radiation in early stage disease, and excellent long-term survival for breast cancer patients, allowing time for hematopoietic clonal evolution to acute leukemia.
The patient demographics of our cohort also support the existence of t-ALL as a distinct entity. Interestingly,
although the overall majority of ALL patients in our series were Hispanics, t-ALL was twice as common in whites compared to Hispanics. In the United States, ALL is more common in Hispanics in general20,21 and is characterized by unique genetic profiles such as the Ph-like signature,22 which in turn is associated with inherited genetic poly- morphisms in the GATA3 gene.23 Although we do not have data on Ph-like ALL in our cohort, it would likely have been higher in our de novo ALL cohort given the demo- graphics of our patient population. In contrast, the higher proportion of whites in our t-ALL cohort may be reflective of the ethnic distribution of the antecedent malignancies (e.g., breast cancer) in the t-ALL population.
Given the prior exposure to chemotherapy, side effects
Table 3. Prior diagnoses and characteristics associated with t-ALL.
Number
Median latency in years for all patients (range)
Prior diagnosis
Solid cancer
Hematological cancer
Benign
Both solid and hematological cancers
Prior diagnoses
More than one prior diagnosis Breast cancer Lymphoproliferative neoplasms# Multiple myeloma
Thyroid cancer/disease Sarcoma
Testicular
Prostate cancer Gastrointestinal malignancies Gynecological malignancies Rheumatological disease
Head and neck malignancies Others
The type of prior therapy
Chemotherapy
Radiation
Combination of chemo/radiation
Topoisomerase II inhibitors Yes
No
PrecededorconcurrentMDS
Original disease relapse during or after ALL diagnosis Induction regimen +/- TKI
HyperCVAD Linker
BFM CALGB-9511 DVP
Others
No treatment
93
6.8 (0.8-50.7)
52 (56) 33 (35) 6 (6)
2 (2)
4 (4) 23 (25) 21 (23) 11 (12) 8 (8) 8 (8) 4 (4) 3 (3) 3 (3) 3 (3) 2 (2) 2 (2) 8 (8)
35 (38) 26 (28) 32 (34)
38 (41) 55 (59) 2 (2) 9 (10)
48 (52)
8 (9)
8 (9)
7 (7)
6 (6)
15 (16)
1 (1)
MDS: myelodysplastic syndrome; TKI: tyrosine kinase inhibitor #includes non- Hodgkin’s lymphoma, chronic lymphocytic leukemia, and Hodgkin’s lymphoma.
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