CAR-T therapy and secondary hematological malignancies

Background

Myeloma patients, especially the newly diagnosed, are made aware at the start of their treatment journey that the risk of their treatment regimen may end up causing secondary hematological malignancies (often also called second primary cancers). For example, patients starting with a standard of care regimen that contains lenalidomide (Revlimid) should be aware that higher incidences of Second Primary Malignancies (SPM) were observed in controlled trials of patients with multiple myeloma receiving Revlimid, as disclosed in the Prescribing Information For The Product [See “Warnings and Precautions”].

FDA regulations

FDA has a body of regulations for labeling of Prescription Medications that follow a well-declared template of all that needs to be declared on the Insert of each medication. Each dispensing bottle of medication comes with an “insert”, a printed copy of all FDA wants the prescriber to know. As a patient you typically won’t see this “insert” as it is typically removed by the dispensing pharmacist, but it can be rapidly found through an internet query “Prescribing information for [insert a drug name]", and bingo, you have what the pharmacist has removed.

The prescribing information always has a series of warnings for the drugs in question that the prescriber should be aware of : such as Contraindications [situations when the risk from use clearly outweighs any possible therapeutic benefit, and the medicine must not be used], Warnings and Precautions [situations when the risk from use clearly outweighs any possible therapeutic benefit, and the medicine must not be used].

There is also another and more important caution that FDA requires in some medicines called a “Boxed Warning”  [page 11 of that document] (or sometimes called a “Black Box warning”). This is a statement at the front of the prescribing information printed in bold and placed inside a black box that jumps from the page. This warning is used when:

• There is an adverse reaction so serious in potential benefit for the medication.
• There is a serious adverse reaction that can be prevented or reduced in frequency or severity by the appropriate use of the medication.
• The medications are approved with restrictions on safe use (REMS product).

CAR-T Products

In 2024 FDA decided to add a “Black Box Warning” to all the CAR-T products approved in the US. In a communication from the Agency they explained their rationale:

“FDA concluded, based on the evaluation of data from post-marketing adverse event and clinical trial reports, that mature T cell malignancies, including CAR-T positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. FDA has determined that the serious risk of T cell malignancies is applicable to all currently approved BCMA-directed and CD-19-directed modified autologous CAR T cell immunotherapies.”

The reaction by the medical community and the industry was swift. “The industry complained that the FDA treated CAR-T unfairly while there are drugs with larger or similar numbers of secondary cancer reports that are being marketed without this boxed warning item. [For example, Revlimid does not have a Black Bow warning.] Besides, people with blood cancers already have various risk factors related to the secondary development of cancer in the first place.”

What should patients know?

Over the past week, two scientific papers provided guidance:

1. The Journal Bone Marrow Transplantation provides the analysis of 555 patients that were treated over the past few years for Diffuse Large Cell Lymphoma, Mantle Cell Lymphoma Primary Mediastinal B-cell Lymphoma, Follicular Lymphoma, Chronic Lymphocytic Lymphoma. [No myeloma patients were included because of the more recent regulatory approval for Carvykti/Abecma in Europe compared to the US.]
2. The Journal Nature Medicine  presents the follow-up of 783 patients that were treated in Cell Therapy Trials. Myeloma patients were part in this analysis.

There are two key questions for patients :

1. Is there an incidence of secondary myeloid Neoplasms (NSM) following Car-T therapy?  Yes, there is. The report from The Journal Bone Marrow Transplantation shows an incidence rate of 2.5%, with 7.9 months as a median time of onset, and with myelodysplastic syndrome (MDS) occurring in over 90% of cases. The Nature Medicine article reports that 2.3% developed secondary malignancies after treatment, with a median onset of 1.94 years.
2. Is CAR-T treatment the cause of NSM’s ? NO, there isn’t !! The Journal Bone Marrow Transplantation team explains, ”Among the variables analyzed, elevated CAR-HEMATOTOX scores and thrombocytopenia at 3 months were the only ones significantly associated with SMN development.” [The CAR-HEMATOTOX represents an easy-to-use risk-stratification tool that is helpful in ruling out patients at risk of hematotoxicity.]  The Nature Medicine article comments, “The researchers indicated that the rare occurrences of secondary cancers that did occur following CAR T-cell therapy could be attributed to a suppressed immune system from first-line cancer treatments such as radiation and chemotherapy. However, none of the cases among the patients involved in the study were caused by CAR T-cell therapy.” 

Conclusion

While secondary cancers can occur after myeloma treatments, current research shows that CAR-T therapy itself is not the direct cause. To improve outcomes, patients should stay informed about medication warnings and talk with their care team about any concerns, especially when considering CAR-T as part of their treatment plan.

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