A Case of Clozapine and Cancer

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SPECIAL REPORT: SCHIZOPHRENIA

Early in my career, I first started noticing a trend among some of my patients with schizophrenia who were treated with clozapine: They were receiving diagnoses of hematological malignancies at a higher rate than their peers on other antipsychotics. I had 3 patients receive cancer diagnoses within a year of each other—and all 3 of these patients had been treated with clozapine for more than 5 years. At that time, I knew that the increased prevalence of cancer diagnoses had to be more than just a coincidence, but I had no way of validating my hypothesis.

Sadly, however, my hypothesis was confirmed years later by a nationwide case-control and cohort study conducted in Finland.¹ The study was constructed by “individually matching cases of lymphoid and haematopoietic tissue malignancy with up to 10 controls without cancer by age, sex, and time since first schizophrenia diagnosis,” but ethnicity data were not available or included. Analysis was conducted using conditional logistic regression (adjusting for comorbid conditions) and the study demonstrated a 2.7-fold increased risk of hematological malignancies with clozapine use (dose-dependent) compared with exposure to other antipsychotics.¹ According to the Centers for Disease Control and Prevention, lymphoma, myeloma, and leukemia are all common types of hematological malignancies.²

I still remember my first patient’s cancer diagnosis, follicular lymphoma. According to the American Cancer Society, about 90% of patients survive 5 years or more after diagnosis.³ That was good news, as this patient was in their mid-40s and was otherwise generally physically healthy. However, what did their cancer treatment mean for their psychiatric treatment with clozapine?

As we know, clozapine treatment is not considered a first-line treatment in schizophrenia. In fact, according to the US Food and Drug Administration (FDA), it is used to treat patients with schizophrenia who have not responded to other antipsychotic therapies.⁴ So this was obviously not my patient’s first attempt to be stabilized on an antipsychotic. In fact, the patient had been on quite a difficult journey before being stabilized on clozapine.

Now that they were diagnosed with cancer, would I have to take them off the medication that had given them their hard-fought stability? Would it be possible to keep them on clozapine while they were undergoing treatment for cancer? How would I cross-taper or directly substitute another medication if needed? And would that medication be efficacious? I had more questions than answers.

I reached out to the Risk Evaluation and Mitigation Strategy (REMS) safety program, which was instituted by the FDA to enforce safety monitoring for the potential risk of severe neutropenia (absolute neutrophil count [ANC] less than 500/µL) associated with clozapine.⁵ I thought that because REMS is the gatekeeper for the medication to be dispensed, then of all organizations, surely it would be able to offer some guidance. The American Society of Clinical Oncology indicates that chemotherapy can result in neutropenia 7 to 12 days after treatment.⁶

The REMS program had to be aware of this fact and would have some guidance for psychiatric clinicians, right? Wrong. I was met with silence.

A literature search through my local hospital yielded sparse and inconsistent information as well. I turned to my colleagues, who gave me the best advice and support they could, but it was ultimately my patient and my decision. After discussing the risks and benefits with the patient and their caregiver, we decided to attempt to continue clozapine throughout the patient’s cancer treatment and coordinate care with their oncologist.

The oncologist turned out to be a brilliant clinician who was very receptive to coordinating care to work toward the most optimal outcome for our mutual patient. Our now shared client was in the maintenance phase of clozapine treatment, meaning that their ANC was now required to be drawn only monthly to be entered into the REMS program. That was all about to change.

When the patient started cancer treatment, their ANC level began to decline. The oncologist’s office was drawing labs frequently throughout chemotherapy, and now, because of neutropenia, we needed additional labs. Each of our offices began drawing ANC levels as clinically indicated and exchanging this information as rapidly as possible. The patient never went more than 2 weeks without labs throughout their entire cancer treatment. I frequently met with the patient and updated them and their caregiver on the ANC lab values between appointments.

Ultimately, even though neutropenia did occur, it did not become severe enough to require the discontinuation of clozapine. The patient remained psychiatrically stable throughout their cancer treatments, and after several rounds of chemotherapy, our patient’s cancer was treated to remission.

Since that time, further research has concluded that “It is possible to continue clozapine in a patient with chronic schizophrenia undergoing chemoradiation for cancer with close supervision and collaboration with oncology clinicians.”⁷ I can confirm this finding now from my clinical experiences over the years as well. I have yet to take anyone off clozapine therapy because of the impacts of their cancer treatments.

So what does a cancer diagnosis and treatment mean for patients with schizophrenia who are currently being treated with clozapine? It means I am going to work even harder to collaborate with other clinicians, frequently monitor my patients, and continue to do my part in helping them navigate the complexities of 2 difficult diagnoses.

As far as my use of clozapine, I will continue utilizing it until it is no longer in a patient’s best interest, and I will certainly continue to educate my patients on the risks of not only agranulocytosis, but also cancer (no matter how small the risk may be).

Mr Hickman is a psychiatric mental health nurse practitioner on the seacoast of New Hampshire.

References

1. Tiihonen J, Tanskanen A, Bell JS, et al. Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry. 2022;9(5):353-362.

2. Hematologic cancer incidence, survival, and prevalence. Centers for Disease Control and Prevention. Reviewed September 1, 2022. Accessed February 1, 2023. https://www.cdc.gov/cancer/uscs/about/data-briefs/no30-hematologic-incidence-surv-prev.htm

3. Survival rates and factors that affect prognosis (outlook) for non-Hodgkin lymphoma. American Cancer Society. Updated March 2, 2022. Accessed February 1, 2023. https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/factors-prognosis.html

4. Information on clozapine. US Food and Drug Administration. Updated November 2, 2022. Accessed February 1, 2023. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-clozapine

5. What is the Clozapine REMS? Clozapine REMS. Accessed February 1, 2023. https://www.newclozapinerems.com/home

6. Neutropenia. Cancer.Net. September 2019. Accessed February 1, 2023. https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-physical-side-effects/neutropenia

7. Deodhar JK, Prabhash K, Agarwal JP, Chaturvedi P. Clozapine and cancer treatment: adding to the experience and evidence. Indian J Psychiatry. 2014;56(2):191-193.