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Therapy-related ALL
leukemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS).2 T-MNs, in general, carry poor cytogenetic and molecular features at the time of diagnosis compared to de novo MNs, and are characterized by poor responsiveness to conventional treatment and inferior rates of overall out- come, such as complete remission (CR), death in remis- sion, relapse and survival.1,3,4
Similar to t-MN, acute lymphoblastic leukemia (ALL) may also develop after prior exposure to cytotoxic thera- pies and is often referred to as therapy-related ALL (t- ALL).5-11 Similar to t-MNs, the pathogenesis of t-ALL is likely attributed to the genotoxic effect of cytotoxic ther- apies on hematopoietic progenitor cells. However, to date, this entity has not been fully recognized and only a few relatively small series have been reported.5-11 Unfortunately, several of these studies also include “sec- ondary ALL,” i.e., cases with a history of prior malignan- cies (including non-lymphoid cancers), but no cytotoxic therapy exposure, making the accurate identification of t- ALL- specific clinical and genetic features somewhat chal- lenging. Few large registry series of secondary ALL have been reported and have highlighted the inferior survival of this entity.12,13 However, these registry studies have not drawn a distinction between cases with prior malignan- cies that did not receive cytotoxic therapies and those that did. Additionally, these studies lack specific details on ALL genetics as well as details on prior cancer-specific therapies due to limitations of registry data.12,13 Furthermore, the optimal therapy for t-ALL as well as t- ALL patients’ ability to tolerate intensive treatment remain poorly defined. This becomes particularly impor- tant when a t-ALL patient has high risk features and is being considered for allogeneic hematopoietic cell trans- plantation (HCT). A particular concern in this regard is higher treatment-related morbidity and mortality given the prior exposure to cytotoxic therapies in t-ALL patients. Therefore, studies that clearly distinguish t-ALL are necessary in order to fill the scientific and clinical knowledge gap in this field.
We report here a large, single institutional, t-ALL cohort defined using strict inclusion criteria that restrict analysis only to cases with documented exposure to cytotoxic therapy prior to developing ALL. In contrast to registry data, we were able to gather details regarding prior malig- nancies and therapies, clinical and genetic characteristics of the ALL, treatment, and outcomes of t-ALL from our institutional database. Our study aims to estimate the fre- quency of t-ALL among adult patients, to evaluate unique clinical and genetic features associated with t-ALL that are distinctive from de novo ALL, and to evaluate the prog- nostic impact of prior exposure to cytotoxic therapy (t- ALL) on clinical outcomes, including response to induc- tion therapy, utilization and outcomes of allogeneic HCT and survival.
Methods
Patients
We reviewed all consecutive cases of adult ALL seen at City of Hope between 2000 and 2017 in order to identify cases of t-ALL. For the purposes of this study, t-ALL was defined as ALL occurring after prior exposure to chemotherapy and/or radiation. Any cases of ALL preceded by a malignancy but without exposure to cyto-
toxic therapy were classified as de novo ALL. t-ALL and de novo ALL cases were then compared for distinctive demographic, clini- cal, and cytogenetic features and for outcomes. The study was approved by the City of Hope Institutional Review Board.
Endpoints
Overall survival (OS) for all patients was defined as the time interval from ALL diagnosis to date of death from any cause or date of last contact. When analyzing patients who underwent allo- geneic HCT, OS was defined as the time from transplant to date of death from any cause or date of last contact. Non-relapse mor- tality (NRM) was measured from time of transplant to death from any cause other than relapse/progression. Relapse/progression was treated as a competing event for NRM.
Statistical analyses
Demographic, disease, and treatment characteristics were sum- marized using descriptive statistics. Two sample t-test, chi- squared test, and fisher’s exact test were used to determine differ- ences in demographics and disease characteristics of interest. Survival estimates were calculated using the Kaplan-Meier prod- uct-limit method and differences between Kaplan-Meier curves were assessed using the log-rank test.14 The cumulative incidence of NRM was calculated using competing risk analysis and differ- ences between cumulative incidence curves were tested using the Gray method.15
Prognostic variables analyzed include age and white blood cell (WBC) count as continuous variables, cytogenetics (NK, Ph+, MLL, complex [≥5 abnormalities], or other/unknown), prior therapy (chemotherapy, radiation, or chemotherapy plus radiation), prior disease (solid tumor vs. blood cancer), allogeneic HCT treated as a time dependent variable, race/ethnicity (white, Hispanic, other), phenotype (T vs. B), sex (female vs. male), and use of topoiso- merase II inhibitor (no vs. yes). The significance of demographic, disease, and treatment features was assessed using logistic regres- sion to determine effect on type of ALL diagnosis and Cox propor- tional hazards regression analysis to determine effect on survival. All analyses performed using SAS version 9.4 (SAS Institute, Cary, NC). Data were locked for analysis January 17, 2018.
Results
Comparison of clinical and pathologic characteristics t-ALL and de novo ALL
Between 2000 and 2017, 1022 cases of adult ALL were evaluated and/or treated at City of Hope; 93 (9.1%) had t-ALL. When compared to de novo ALL, t-ALL patients were older (55 years vs. 37 years, P<0.01), and were more often female (57% vs. 42%, P<0.01). There was no differ- ence in proportions of leukemia phenotypes (precursor B-cell versus T-cell) between t-ALL and de novo ALL. t-ALL patients were more often whites (52% vs. 34%) and less often Hispanics (29% vs. 48%) compared to de novo ALL (P<0.01). t-ALL cases were associated with different cyto- genetic profiles (P<0.01) compared to de novo ALL. t-ALL cases were enriched with MLL gene rearrangement (KMT2A) (17% vs. 4%, P<0.01) and have less normal karyotype (18% vs. 30%, P=0.017) when compared to de novo ALL. Among patients with available conventional cytogenetics, monosomy and/or long arm deletion of chromosomes 5 and/or 7 were more common in t-ALL compared to de novo ALL (16% vs. 8%, P=0.02) (Table 1).
In multivariate analysis, t-ALL was associated with older age (OR= 1.06; 95% CI:1.04-1.07, P<0.0001), female
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