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Cancer Immunotherapy During Pregnancy for Relapsed Lymphoma

Evens, Andrew M. DO, MSc

doi: 10.1097/01.COT.0000834200.61220.b9
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The management of cancer during pregnancy poses significant diagnostic, therapeutic, and ethical challenges. One out of approximately 1,000 pregnancies in the United States is affected by the coexistence of cancer.1-3 Among these, lymphoma (i.e., Hodgkin lymphoma and non-Hodgkin lymphoma) represents one of the most common cancers during pregnancy.4,5

The diagnosis of lymphoma during pregnancy is often delayed due to the considerable overlap between symptoms of malignancy and normal pregnancy, namely fatigue, abnormal blood counts, difficulty breathing, etc. Diagnostic testing during pregnancy is guided by a benefit-to-risk ratio that considers the short-term risks for a patient and her pregnancy and the long-term risks, including delayed recognition.

The decision to initiate anti-cancer treatment during pregnancy is highly personalized with the collaboration of a multidisciplinary team to weigh the adverse effects of delaying antenatal cancer therapy against the potential benefits.6 A multidisciplinary team should include hematology/oncology, maternal-fetal medicine, neonatology, and other relevant subspecialties (e.g., radiation oncology, radiology, anesthesiology, primary care, etc.). Factors to be considered in selecting a treatment plan include gestational age, the subtype of lymphoma, symptomology, and anatomic sites of disease.

There is a general consensus to avoid chemotherapy during the first trimester when a patient is clinically stable, and deferment of therapy is unlikely to negatively impact the prognosis.7 Accordingly, it is rare that termination of pregnancy would be medically indicated outside of these situations. There is increasing evidence that standard non-antimetabolite multiagent chemotherapy may be safely administered in the second and third trimesters with good maternal and fetal outcomes.4 However, there is a paucity of data regarding the safety and feasibility of treatment with targeted anti-cancer therapeutics, such as newer immunotherapy agents. With the increasing use of immune checkpoint inhibitors as standard therapy regimens for numerous cancer subtypes, the absence of data for the use of these agents in pregnancy represents a void for a uniquely vulnerable population of patients.

In a recent publication in the American Journal of Hematology,8 we reported details associated with a 31-year-old female with a history of Hodgkin lymphoma who presented with relapsed/refractory disease during pregnancy. The patient presented to an outside hospital with fatigue, severe anemia, and abdominal pain at 11 weeks gestation. A biopsy documented relapsed/refractory Hodgkin lymphoma. The patient had received 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (known as ABVD) 3 years prior for the treatment of Stage IV Hodgkin lymphoma. She entered clinical remission and had remained in remission before her current presentation.

At 19 weeks gestation, the patient presented to our cancer center with persistent severe fatigue and progressive abdominal pain and several life-threatening laboratory abnormalities. She was admitted to the hospital for urgent stabilization. The patient received modified multi-agent chemotherapy and had brisk improvement in her symptoms and laboratory abnormalities. However, she developed increased abdominal pain, progressive lab alterations, and advancing cancer at 25 weeks' gestation after the second cycle of salvage chemotherapy.

The patient subsequently initiated single-agent intravenous checkpoint inhibitor immunotherapy at 26 weeks gestation. There was rapid clinical improvement in the patients' symptoms and laboratory data after one dose. She continued this therapy every 2-3 weeks for 6 total antenatal treatments. She tolerated immunotherapy well, and it resulted in partial remission of cancer. Moreover, the patient had spontaneous induction of labor at 38 weeks with an uncomplicated delivery of a male child. The neonate had no laboratory or clinical abnormalities during a routine hospitalization of 2 days.

Two weeks after delivery, a whole-body positron emission tomography scan confirmed the patient was cancer-free, achieving complete metabolic remission. She ultimately proceeded postpartum to a potentially curative autologous stem cell transplant, and she remains in complete remission 1 year later.

There have been reports in the medical literature of checkpoint inhibitor immunotherapy for patients with cancer with an unexpected pregnancy, including patients who were on clinical trials.9 However, this is the first known case of a lymphoma patient treated with an immune checkpoint inhibitor during pregnancy, and the only report of this therapy given past week 33 of gestation. It is critical to highlight that a full-term delivery (i.e., gestational age >37 weeks) is preferable to iatrogenic preterm delivery as gestational age drives neonatal outcomes and prematurity is associated with an increased risk of multiple medical complications for the newborn.10

Given the excellent clinical activity of checkpoint inhibitor immunotherapy in Hodgkin lymphoma, and the frequent use of these agents in other malignancies, it is critical to gather data for patients who may become pregnant or discover they are pregnant when the use of these agents would be otherwise warranted. Well-intentioned policies by ethics boards in medicine have consistently referred to pregnant patients as a vulnerable population. This leaves patients facing cancer with few options, including termination of an unexpected pregnancy or continuing therapy with potentially fewer effective treatments developed decades ago, often before the advent of these policies.

In addition, we were able to measure the blood levels of checkpoint inhibitor immunotherapy on a clinical protocol and test the umbilical cord and placenta. The blood concentrations of checkpoint inhibitor therapy were within expected ranges based on population pharmacokinetics from non-pregnant patients administered similar therapy. Furthermore, we observed that concentrations in the umbilical cord blood following the sixth dose were consistent with the simulated blood concentrations. Finally, there was no uptake of checkpoint inhibitors detected within the placental tissue.

Altogether, an overarching goal of therapy for lymphoma during pregnancy is the safety of the mother and fetus with concurrent optimization of cancer outcomes. In this unique clinical case, we illustrated that treatment with an anti-cancer checkpoint inhibitor therapy during the second and third trimesters for a patient with relapsed/refractory Hodgkin lymphoma was safe and effective. We also documented that blood levels with this immunotherapy were within expected ranges for non-pregnant cancer patients. Moreover, it resulted in cancer remission and delivery of a healthy full-term neonate. More study is needed in this important area of unmet need to bring modern precision oncology tools to pregnant patients with cancer.

ANDREW M. EVENS, DO, MSC, is Associate Vice Chancellor of Clinical Innovation & Data Analytics with Rutgers Biomedical and Health Sciences; Associate Director for Clinical Services at Rutgers Cancer Institute of New Jersey; System Director of Medical Oncology and Oncology Lead for RWJBarnabas-Rutgers Medical Group at RWJBarnabas Health; and Professor of Medicine at Rutgers Robert Wood Johnson Medical School.

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Andrew M. Evens, DO, MSc:
Andrew M. Evens, DO, MSc

References

1. Eastwood-Wilshere N, Turner J, Oliveira N, Morton A. Cancer in pregnancy. Asia-Pac J Clin Oncol 2019; https://doi.org/10.1111/ajco.13235
2. Cottreau CM, Dashevsky I, Andrade SE, et al. Pregnancy-associated cancer: a US population-based study. J Women's Health 2019;28:250–7
3. Howdeshell KL, Shelby MD. Epidemiology of cancer in pregnancy. Managing Cancer during Pregnancy: Springer; 2016:3–16
4. Evens AM, Advani R, Press OW, et al. Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 2013;31:4132–9
5. Calsteren Kv, Heyns L, Smet FD, et al. Cancer during pregnancy: An analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol 2010; doi: 10.1200/JCO.2009.23.2801
6. Shah MR, Brandt JS, David KA, Evens AM. Lymphoma occurring during pregnancy: current diagnostic and therapeutic approaches. Curr Oncol Rep 2020;22:113
7. Lishner M, Avivi I, Apperley JF, et al. Hematologic malignancies in pregnancy: management guidelines from an international consensus meeting. J Clin Oncol 2016;34:501–8
8. Evens AM, Brandt JS, Peer CJ, et al. Checkpoint inhibitor immunotherapy during pregnancy for relapsed-refractory Hodgkin lymphoma. Am J Hematol 2022; doi: 10.1002/ajh.26527
9. Mittra A, Naqash AR, Murray JH, et al. Outcomes of Pregnancy During Immunotherapy Treatment for Cancer: Analysis of Clinical Trials Sponsored by the National Cancer Institute. Oncologist 2021;26:e1883–e6.
10. Amant F, Van Calsteren K, Halaska MJ, et al. Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. Lancet Oncol 2012;13:256–64.
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