A retrospective survey of exposure history to chemotherapy or radiotherapy in 940 consecutive patients with primary myelofibrosis
Authors: Maura Nicolosi, Mythri Mudireddy, Mrinal M. Patnaik, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2018)

The World Health Organization (WHO) classification system for hematologic malignancies recognizes the etiological component of chemotherapy and radiotherapy in what is referred to as “therapy-related myeloid neoplasms” (t-MNs), which might account for 10%-20% of all incident cases of myeloid neoplasms.1, 2 The particular WHO category includes cases of therapy-related acute myeloid leukemia (t-AML), myelodysplastic syndromes (t-MDS), and myelodysplastic/myeloproliferative overlap (t-MDS/MPN); it should be noted, however, that acute lymphoblastic leukemia can also be therapy-related.3 Treatment modalities that have been implicated in t-MNs include ionizing radiation therapy, alkylating agents, topoisomerase II inhibitors, and a spectrum of other anti-cancer drugs; in relevance to MPN, hydroxyurea is currently not included in this list of “leukemogenic” drugs.1 At present, t-MNs are operationally classified into those occurring 5–10 years after exposure history (alkylating agents, ionizing radiation) and are characterized often by abnormalities of chromosomes 5 and 7, multilineage dysplasia and a preleukemic phase of MDS, and those that occur earlier (toposimerate II inhibitors) and are characterized by chromosome 11q23 rearrangements and presentation with overt AML. Other genetic lesions associated with t-MNs include loss of TP53 and certain favorable risk cytogenetic abnormalities including t(15;17)(q24.1;q21.1), and inv(16)(p13.1q22).1 In a recent communication, we described our experience with therapy-related chronic myelomonocytic leukemia (t-CMML).4 In the current study, we examined the possibility of therapy-related disease in primary myelofibrosis (PMF). The current study was approved by the Mayo Clinic institutional review board. Consecutive cases of PMF were recruited from institutional databases of the Mayo Clinic, Rochester, MN, USA, where the 2016 WHO criteria for PMF were retrospectively applied to confirm the diagnosis.1 Special precaution was taken to avoid inclusion of patients with postpolycythemia vera or postessential thrombocythemia myelofibrosis. Treatment was according to conventional standards utilized at the time of diagnosis. Clinical and laboratory data, including cytogenetic information, were collected at the time of initial referral to our institution. Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature (ISCN) criteria. Survival was calculated from time of initial referral. Nonparametric statistics was used to determine significance of differences among groups in the distribution of continuous or nominal variables. Survival data were prepared by the Kaplan–Meier method and compared by the log–rank test. Cox proportional hazard regression model was applied for multivariable analysis. The Stat View (SAS Institute, Cary, North Carolina) statistical package was used for all calculations. The study population included 940 consecutive patients with PMF (median age 65 years; 64% males). Dynamic international prognostic scoring system (DIPSS)5 risk distribution was 11% high, 41% intermediate-2, 34% intermediate-1, and 14% low; the corresponding figures for DIPSS-plus6 were 35%, 37%, 15%, and 13%. Table 1 also includes risk stratification according to the recently developed mutation-enhanced MIPSS70 model,7 as well as the revised cytogenetic risk model.8 A total of 65 (7%) patients with antecedent history of cancer, including one patient who received alkylating agent therapy for autoimmune hemolytic anemia, were identified and 34 (4%) of these patients received chemotherapy or radiation treatment while 31 (3%) did not. The cancer types for patients receiving chemotherapy/radiotherapy included breast cancer (n = 8), prostate cancer (n = 7), Hodgkin's or non-Hodgkin's lymphoma (n = 6), colorectal cancer (n = 4), endometrial cancer (n = 4), lung cancer (n = 2) and one each with pancreatic and ovarian cancer. Fifteen patients received radiation therapy alone, 12 received chemotherapy alone and 7 received both chemotherapy and radiotherapy; the chemotherapeutic agents utilized included cyclophosphamide, melphalan, 5-fluorouracil, adriamycin, carboplatin, cisplatin, and paclitaxel. The median time between exposure history and diagnosis of PMF was 92 months (range 3–323) for patients receiving chemotherapy alone or combined with radiotherapy and 86 months (range 10–235) for patients receiving radiotherapy alone. Patients with previous history of cancer and received chemotherapy or radiotherapy (n = 34. 4%) Patients with previous history of cancer and not received chemotherapy or radiotherapy (n= 31. 3%) Patients with no history of cancer prior to PMF diagnosis (n= 875, 93%) Hemoglobin category Severe; n (%) Moderate; n (%) Mild; n (%) No anemia; n (%) 322 (34) 135 (14) 347 (37) 136 (15) 13 (38) 7 (21) 10 (29) 4 (12) 12 (39) 6 (19) 11 (36) 2 (6) 297 (34) 122 (14) 326 (37) 130 (15) DIPSS risk distribution High; n (%) Intermediate-2; n (%) Intermediate-1; n (%) Low; n (%) 99 (11) 382 (41) 322 (34) 137 (14) 4 (12) 17 (50) 10 (29) 3 (9) 4 (13) 12 (39) 11 (35) 4 (13) 91 (10) 353 (40) 301 (35) 130 (15) DIPSS-plus risk distribution* “N” evaluable = 929 (%) High; n (%) Intermediate-2; n (%) Intermediate-1; n (%) Low; n (%) 321 (35) 344 (37) 146 (15) 118 (13) 15 (44) 9 (26) 7 (21) 3 (9) 9 (29) 13 (42) 5 (16) 4 (13) 297 (34) 322 (37) 134 (16) 111 (13) MIPSS 70 risk stratification** “N” evaluable = 275(%) High; n (%) Intermediate; n (%) Low; n (%) 107 (39) 138 (50) 30 (11) 2 (25) 5 (63) 1 (12) 4 (33) 8 (67) 0 (0) 101 (40) 125 (49) 29 (11) MIPSS 70- plus risk stratification*** “N” evaluable = 413(%) High; n (%) Intermediate-2; n (%) Intermediate-1; n (%) Low; n (%) 54 (13) 185 (45) 75 (18) 99 (24) 1 (8) 6 (50) 2 (17) 3 (25) 1 (6) 9 (53) 5 (29) 2 (12) 52 (14) 170 (44) 68 (18) 94 (24) Driver mutational status “N” evaluable = 709(%) JAK2; n (%) CALR type 1/like; n (%) CALR type 2/like; n (%) MPL; n (%) Triple-negative; n (%) 467 (66) 112 (16) 24 (3) 38 (5) 68 (10) 19 (73) 2 (8) 1 (4) 0 (0) 4 (15) 16 (66) 2 (8) 0 (0) 3 (13) 3 (13) 432 (66) 108 (16) 23 (4) 35 (5) 61 (9) ASXL1-mutated; n (%) “N” evaluable =475 SRSF2-mutated; n (%) “N” evaluable = 466 SF3B1-mutated; n (%) “N” evaluable = 408 U2AF1-mutated; n (%) “N” evaluable =448 Revised cytogenetic rick model “N” evaluable = 854 Very high risk karyotype; n (%) Unfavorable karyotype; n (%) Favorable karyotype; n (%) 59 (7) 148 (17) 647 (76) 2 (6) 5 (16) 24 (78) 0 (0) 2(8) 24 (92) 57 (7) 141 (18) 599 (75) As outlined in Table 1, patients with history of cancer prior to diagnosis of PMF, regardless of whether or not they received chemotherapy/radiotherapy, were significantly older (P < .01), but otherwise displayed clinical and laboratory features that were similar to those displayed by patients without antecedent history of cancer. Especially noteworthy, in this regard, was the similarity in terms of cytogenetic and mutation patterns (Table 1). In particular, among 854 cytogenetically-annotated cases, all 10 cases of 11q- and all 9 cases of 5q- abnormalities were included in patients without exposure history for chemotherapy/radiotherapy, and only 2 of the 32 instances of very high risk karyotype, that included monosomy 7, were seen in patients with exposure history to chemotherapy/radiotherapy. At a median follow-up of 3 years (range 0–31), 655 (70%) deaths and 68 (7%) AML conversions were documented. Causes of death in patients with exposure history for chemotherapy/radiotherapy included progression of their cancer in 4 cases and AML in 5 cases. In univariate analysis, exposure history was significantly (P < .001) associated with shortened survival for both patients receiving chemotherapy/radiotherapy (P = .002; HR 1.8, 95% CI 1.2-2.6) and those who did not receive such therapy (P = .002; HR 1.9; 95% CI 1.3-2.8) (Figure 1); there was no difference in survival among patients with antecedent history of cancer, based on whether or not they received chemotherapy/radiotherapy (P = .88). Leukemia-free survival was not affected by history of cancer or exposure to chemotherapy/radiotherapy (P = .3). Significance for the shortened survival in patients with cancer history appeared to be accounted for by their older age distribution (P = .36 for chemotherapy/radiotherapy exposed and 0.11 for untreated cases). Survival data in 940 patients with primary myelofibrosis stratified by the presence or absence of antecedent history of cancer and whether or not patients received chemotherapy or radiotherapy [Color figure can be viewed at wileyonlinelibrary.com] In the current study, we provide evidence against the role of chemotherapy or radiation treatment in the development of PMF. Other than their older age distribution, PMF patients with antecedent history of cancer, regardless of whether or not they recieved chemotherapy or radiotherapy, did not display significantly different phenotype, in terms of either clinical or genetic features, including specific cytogenetic abnormalities that are typical of t-MNs. Furthermore, their shortened survival was in line with their older age distribution and the distinct possibility that their history of another malignancy might have contributed to premature death, directly or indirectly; this possibility is consistent with the inclusion of cancer progression in the list of causes of death for the current study population and the observation that age-adjusted P values for differences in survival reflected weakened rather than fully abrogated correction. Regardless, the fact that survival data were superimposed in patients with history of treated vs. untreated cancer, undermines the possible contributory role of chemotherapy/radiotherapy to the observed shortened survival exhibited by patients with exposure history. Finally, it should be noted that similar observations were made in a recent communication that included patients with post-PV and post-ET myelofibrosis.9 None. None of the authors declared any conflict of interest. All authors declare no conflict of interest regarding matters pertinent to the current manuscript. All authors have reviewed and approved the manuscript. NG, MMP, and AP contributed patients and assisted in data extraction. MN and MM assisted in data extraction and analysis and preparation of tables and figures. AT developed the study concept and design, contributed patients, assisted in data extraction, performed statistical analysis and wrote the article.