A review of the risks of long-term consequences associated with components of the CHOP chemotherapy regimen

Abstract

A common chemotherapy regimen in post-transplant lymphoproliferative disease (PTLD) following solid organ transplants (SOT) is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). This study reviews the quantitative evidence for long-term consequences associated with components of CHOP identified from the Children’s Oncology Group Long-Term Follow-Up Guidelines. Cited references were screened using prespecified criteria (English, systematic review, randomized controlled trial n > 100, observation study n > 100, case series n > 20). Relevant data were extracted and synthesized. Of 61 studies, 66% were retrospective cohort studies, 28% were in the US, and 95% enrolled pediatric patients. No study focused specifically on the CHOP regimen. Long-term consequences for CHOP components observed in >3 studies included cardiac toxicity (n = 14), hormone deficiencies/infertility (n = 14), secondary leukemia (n = 7), osteonecrosis (n = 6), and bladder cancer (n = 4). These effects are significant, impact a high percentage of patients, and occur as early as one year after treatment. Although none of the studies focused specifically on the CHOP regimen, 30%, 23%, and 15% evaluated alkylating agents (e.g. cyclophosphamide), anthracyclines (e.g. doxorubicin), and corticosteroids (e.g. prednisone), respectively. All three product classes had a dose-dependent risk of long-term consequences with up to 13.2-fold, 27-fold, 16-fold, 14.5-fold, and 6.2-fold increase in risk of heart failure, early menopause, secondary leukemia, bladder cancer, and osteonecrosis, respectively. Lymphoma patients had significantly elevated risks of cardiac toxicity (up to 12.2-fold), ovarian failure (up to 3.8‐fold), and osteonecrosis (up to 6.7-fold). No studies were found in PTLD or SOT. Safe and effective PTLD treatments that potentially avoid these long-term consequences are urgently needed.

Keywords:

• CHOP
• adverse events
• long-term outcomes
• stem cell transplant
• lymphoproliferative disease

Transparency

Declaration of funding

This study was funded by Atara Biotherapeutics. CW and AB, employees and stockholders of Atara Biotherapeutics, contributed to all aspects of the work related to this article.

Declaration of financial/other interests

CW and AB: employees and stockholders of Atara Biotherapeutics. RB, HG: Received consulting fees from Atara Biotherapeutics.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conception and design, or analysis and interpretation of the data (all authors); the drafting of the paper or revising it critically for intellectual content (all authors); the final approval of the version to be published (all authors). All authors agree to be accountable for all aspects of the work.

Acknowledgements

Jodie Worrall provided medical writing assistance in the preparation of this article.

Previous presentations

Watson C, Gadikota H, Barlev A, et al. A Review of the Risks of Long-term Consequences Associated with Components of CHOP Chemotherapy Regimen. Poster ID #112602 presented at ISPOR EU 2021

Watson C, Gadikota H, Barely A, et al. Quantification of Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen. Poster ID 4589 presented at ASH 2021

Watson C, Gadikota H, Barlev A, et al. An Evidence Review of the Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen in Transplant Recipients. Poster ID 4586 presented at ASH 2021.