Quantification of Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen
Authors: Watson Crystal , Gadikota Hemanth , Barlev Arie , Beckerman Rachel 
Published: November 2021

Abstract
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&gt;100, observation study n&gt;100, case series n&gt;20). Studies that met the inclusion criteria were extracted and synthesized. Quantification of late effects evaluated in &gt;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, &lt;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 &gt;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 &lt;150 mg/m 2 (traditionally considered a 'safe' dose range). Hazard ratios (HRs) for heart failure at doses of ≤300 to &lt;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 &lt;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 (&gt;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.