Quantification of Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen

Introduction: A common chemotherapy regimen for Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) following solid organ transplants is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Long-term adverse consequences of CHOP, particularly the incidence, timing, and risk factors associated with these events, in any cancer survivor remain poorly understood. In this study, we review the evidence to determine how often long-term consequences associated with the components of CHOP occur. Methods: Potential long-term consequences of CHOP components were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n>100, observation study n>100, case series n>20). Studies that met the inclusion criteria were extracted and synthesized. Quantification of late effects evaluated in >3 studies were reported. Results: Long-term consequences in the 45 studies that met the pre-specified criteria included cardiac toxicity, hormone deficiencies/infertility, secondary leukemia, osteonecrosis (ON), and urotoxicity/bladder cancer. Although none of the studies focused specifically on the CHOP regimen, 30%, 23%, and 15% evaluated alkylating agents (eg, cyclophosphamide), anthracyclines (eg, doxorubicin), and corticosteroids (eg, prednisone), respectively. Time to onset from treatment was as early as 1 year for cardiac toxicity, <5 for infertility, 2 for ON, 3 for secondary leukemia, and 5 for bladder cancer. Longer follow-up times were associated with higher percentages of long-term consequences. For example, cardiac toxicity and hormone deficiencies/infertility affected >20% of patients, and secondary leukemia, ON, urotoxicity/bladder malignancy affected 10-20% of patients (Table 1). A wide range in the incidence and timing of these late effects was observed, likely due to variation in the treatment regimens, follow-up time, and event definition. The synthesized evidence supports that CHOP components increased the risk of long-term consequences in a dose-dependent manner. Cardiac toxicity risk was elevated even at anthracycline doses of <150 mg/m 2 (traditionally considered a 'safe' dose range). Hazard ratios (HRs) for heart failure at doses of ≤300 to <400 mg/m 2 were 4.33 and 13.19 for daunorubicin and doxorubicin, respectively. Studies also reported significantly elevated risk of cardiac toxicity in patients with lymphoma treated with anthracyclines (eg, HR of up to 12.2) compared with the sibling cohort. Patients <5 years of age vs ≥5 years of age at exposure had a significantly higher risk of cardiac toxicity (HR of 1.89). Patients exposed to cumulative doses of cyclophosphamide ≥6 g/m 2 had significant reproductive risks. The risk of early menopause was shown to be dose dependent and as much as 27-fold higher in patients treated with both radiation below the diaphragm and alkylating agent chemotherapy. Patients exposed to high-dose cyclophosphamide (>7.5 g/m 2) were at statistically significantly higher risk (odds ratio of 12.0) for diminished ovarian reserve as measured by their Anti-Müllerian hormone level. One study reported 3.8- and 3.2-fold increases in risk of ovarian failure in patients who had been diagnosed with Hodgkin's lymphoma and Non-Hodgkin's lymphoma, respectively. High-doses of anthracyclines and alkylating agents were associated with up to 16-fold increases in risk of secondary leukemia. The risk of bladder cancer significantly increased with increasing dose of cyclophosphamide, with a 6- and 14.5-fold increased risk at cumulative doses of 20‒49 g and ≥50 g, respectively. Intensive corticosteroid therapy was associated with significant risk of ON, with one study showing cancer survivors had a 6.2 times higher likelihood of ON as compared to their sibling comparison group. Conclusions: Patients exposed to components of CHOP have a dose-dependent risk of cardiac toxicity, infertility, secondary leukemia, ON, and bladder cancer that are often significant, impacted a high percentage of patients, and occurred as early as 1 year after treatment. Safe and effective PTLD treatments that potentially avoid these long-term consequences are urgently needed. Figure 1 Figure 1. Disclosures Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment.

Chronic Myeloid Leukemia Following Exposure to Radioactive Iodine (I 131): A Systematic Review

Introduction Therapy-related leukemia or secondary leukemia are the terms that describe the occurrence of leukemias following exposure to hematotoxins and radiation to emphasize the difference from leukemia that arises de novo . Many leukemogenic agents have been described, including radiation, alkylating agents, among others . Certain host factors contribute to this predisposition, such as polymorphisms in drug-metabolizing enzymes and inherited cancer predisposition syndrome . These rising leukemias have no specific biologic features that set them apart from de novo malignancies . Therapy-related acute myeloid leukemia (t-AML) has extensive literature to support it. In contrast, therapy-related chronic myeloid leukemia (t-CML) possibly because it originates from a more potent premature progenitor cell . Radioactive iodine (RAI) with I 131 has an established role in managing differentiated thyroid carcinoma, namely papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma. However, concerns have been raised about its possible carcinogenic effects. Papers of t-CML following I 131 are increasingly reported, and thus this review is dedicated to highlighting it. Designs and methods All reports from the 1960s to date related to CML following RAI therapy were searched on Google Scholar and PubMed. Different search terms with Boolean function to search for the relevant articles. All articles were in English. Results We identified ten articles reporting 12 cases, as presented in table 1. We found that most of the reports were for men (8/12) under the age of 60 years (10/12), and the primary tumor was of PTC characteristics (5/12 were PTC, and 3/12 were mixed papillary-follicular carcinoma). The dose of I 131 ranged between 30 millicuries (mCi) to 850 mCi; the mean dose was 331 mCi. Also, t-CML developed within the first ten years (9/12), mainly between 4-7 years post-exposure. Discussion A few reports found a statistically significant increased risk of leukemia following RAI therapy; some suggested a relative risk of 2.5 for I 131 vs. no I 131 . Observed findings from these studies include a linear relationship between the cumulative dose of I 131 and the risk of leukemia, doses higher than 100 mCi were associated with a greater risk of developing secondary leukemia, and most of the leukemias developed within the initial ten years of exposure . The precise mechanism through which RAI provokes leukemia is largely unclear. Possibly, by inducing oxidative stress, reactive oxygen species production results in damage to the cellular membrane, DNA strand breakage, DNA base alterations, and eventually cancer in the instances of poor repair of damage . Many questions remain open. For example, most of the subjects had PTC histopathology in our review. Is there a relationship between PTC and the emergence of leukemia? This question is relevant because some reported that PTC has a mutation of the RET protooncogene, which has been linked to leukemia, prostate and breast cancers. Conclusion Although the risk of t-CML appears to be low based on current reports, it should not be disregarded. Further studies are needed to establish or refute a causal relationship. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Analysis of Secondary Leukemia and Myelodysplastic Syndrome After Chemotherapy for Solid Organ Tumors Using the Food and Drug Administration Adverse Event Reporting System (FAERS)

Purpose: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. Methods: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. Results: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. Conclusions: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

Hematologic indices in individuals with pathogenic germline DICER1 variants

Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic stem cell progenitors demonstrate hematologic aberrations that include reductions in red and white blood cell counts, hemoglobin volume, and impaired maturation resulting in dysplasia. We investigated whether hematologic abnormalities such as those observed in DICER1-deficient mice were observed in humans with a pathogenic germline variant in DICER1. A natural history study of individuals with germline pathogenic DICER1 variants and family controls conducted through the National Cancer Institute (NCI) evaluated enrollees at the National Institutes of Health Clinical Center during a comprehensive clinical outpatient visit that included collecting routine clinical laboratory studies. These were compared against normative laboratory values and compared between the DICER1 carriers and controls. There were no statistical differences in routine clinical hematology laboratory studies observed in DICER1 carriers and family controls. A review of the medical history of DICER1 carriers showed that none of the individuals in the NCI cohort developed myelodysplastic syndrome or leukemia. Query of the International Pleuropulmonary Blastoma/DICER1 Registry revealed 1 DICER1 carrier who developed a secondary leukemia after treatment of pleuropulmonary blastoma. We found limited evidence that the hematologic abnormalities observed in murine DICER1 models developed in our cohort of DICER1 carriers. In addition, no cases of myelodysplastic syndrome were observed in either the NCI cohort or the International Pleuropulmonary Blastoma/DICER1 Registry; 1 case of presumed secondary leukemia was reported. Abnormalities in hematologic indices should not be solely attributed to DICER1. This trial was registered at www.clinicaltrials.gov as #NCT01247597.

Introduction to a review series on secondary leukemia

In this commissioned series of reviews introduced by Associate Editor Jean Soulier, experts provide new insights into the pathobiology of secondary acute myeloid leukemias arising in diverse genetic or acquired, benign or malignant hematologic disorders.

A Comparison of Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Treated on Versus Off Study

Introduction: Despite decades of research, acute myeloid leukemia (AML) remains difficult to treat, and clinical trials are recommended as first line therapy by the NCCN. Although many new drugs show promise in early trials, further experience often does not confirm these results. One possible explanation is that patients on trials are not broadly representative. Here, we retrospectively compared characteristics, response, and survival in patients given the same investigational regimens according to whether treatment was given on versus off study. Methods: Patients treated for AML or high-risk MDS at FHCRC/UW between 2008 and 2015 were included. Investigator-initiated protocols for newly diagnosed (ND) and relapsed / refractory (RR) disease were included if ≥15 patients were treated off study. Analyses used Fisher's exact test, Wilcoxon rank sum test, the Kaplan-Meier method, and Cox multivariate models. Results: 165 ND patients received either escalating doses of G-CLAM or idarubicin, cytarabine, and pravastatin while 243 RR patients received G-CLAM, decitabine-primed MEC or G-CLAC. Overall, 216 were treated on study and 192 were treated off study; reasons for the latter were: protocol not open (n=64), high treatment-related mortality score (n=21), poor health / organ function (n=26), physician or patient preference (n=25), lack of insurance (n=6), and not identified (n=50). No significant differences were found in age, gender, cytogenetic risk, or primary vs. secondary leukemia, but those treated on study in dose escalation protocols were more likely to receive higher doses. RR patients treated off study had typically received more salvage regimens. The 86 ND patients treated on study had higher rates of CR/CRi (90% vs. 64%, P<0.001) and CR without MRD (67% vs. 36%, P<0.001) than the 79 treated off study. These associations remained after adjusting for treatment date, age, gender, secondary leukemia, adverse cytogenetics, and regimen type (OR 3.99 [95% CI: 1.60-9.97] and OR 2.93 [1.39-6.17] respectively). In contrast, neither CR/CRi nor CR without MRD rates differed for RR patients treated on (n=130) or off (n=113) protocol: 52% vs. 41%, P=0.07 and 28% vs. 19%, P=0.14. The same applied after adjusting for the above factors as well as duration of first remission and salvage number: OR 1.79 [0.95-3.40] and OR 1.73 [0.80-3.71]. Despite having higher remission rates, ND patients treated on vs. off study had comparable OS, and, among patients achieving remission, RFS (Figure 1a and 1b). After multivariate adjustment, there remained no association with OS (HR 0.87 [0.52-1.47]) or RFS (HR 0.96 [0.53-1.75]). Survival outcomes were also similar regardless of study assignment among RR patients (Figure 1c and 1d), in both univariate and multivariate analysis (OS, HR 0.82 [0.58-1.17]; RFS HR 0.72 [0.39-1.34]). Patients treated on or off dose escalation protocols at the maximum tolerated dose were no more likely to achieve remission or have longer survival, and incorporating subsequent allogeneic transplant as a time-varying covariate did not significantly affect outcomes. Conclusions: The higher response rates in ND patients treated on vs. off study suggests a measure of selection bias unrelated to readily assessable covariates, while the fundamental determinant of response in RR patients and survival in all patients appears to be unfavorable disease features (adverse cytogenetics, number of prior salvages, duration of CR1). Routine reporting of off study data for investigator-initiated studies could provide a clearer picture of regimen response rates and would grant further insight into the effects of selection bias. Figure 1 Kaplan-Meier curves for on and off study patients depicting OS and, among patients achieving remission, RFS. Outcomes are depicted in ND patients (a and b) and in RR patients (c and d). Figure 1. Kaplan-Meier curves for on and off study patients depicting OS and, among patients achieving remission, RFS. Outcomes are depicted in ND patients (a and b) and in RR patients (c and d). Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Shadman:Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding.