The marriage of chemo-immunotherapy in haematological malignancies

Dr Jasmine Ramiah discusses how chemo-immunotherapy complements each other in haematological malignancies and the promising prospects for the future.

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The evolution of chemotherapy over the last few years has been striking, now involving immunotherapy, which harnesses the immune system. 

Marrying chemo-immunotherapy holds promise for improved efficacy and better long-term outcomes especially for haematological malignancies. Although palatable and promising, balancing toxicities, timing, patient selection, and understanding the delicate biology between resistance and synergy becomes intricate. 

Introduction to the role players

The foundation of the treatment of haematological malignancies remains chemotherapy, often referred to as the backbone of care used in phases, namely induction, consolidation, or maintenance phases. 

Immunotherapy in haematological malignancies covers a range of modalities and targets an array of immune related cells and antigens, such as monoclonal antibodies (anti-CD20), immune checkpoint inhibitors (anti-PD-1/PD-L1), bispecific T- or NK-cell engagers, adoptive cellular therapies (CAR-T cells, CAR-NK cells), and donor lymphocyte infusions (DLI). Their target and utility are different in each haematological malignancy. 

Synergy in action

Why marry the two modalities since each one has been shown to be efficacious singly? The concept of synergy involves, for example, exposing targetable antigens on the tumour cell which immune therapies may respond more efficaciously towards or reduce the immunosuppressive microenvironment lowering immunological barriers.  

Reducing measurable residual disease (MRD) through complementing chemo-immunotherapy deepens the response and may be especially relevant post-haematopoietic stem cell transplant with, for example, a donor lymphocyte infusion. 

Overcoming resistance can be achieved by marrying the two approaches to target different aspects of the tumour cell, enhancing immune recognition and overcoming chemotherapy-induced resistance. 

Data-driver decisions

The consensus recommendations from the Society for Immunotherapy of Cancer (SITC) stress that immunotherapies have become integral in multiple myeloma, lymphoma, and acute leukaemia. For example, the anti-CD20 target therapy ritiximab has deepened remission and improved outcomes in mature B-cell lymphomas.

Furthermore, novel revolutionary cellular immunotherapies, such as CAR-T cell therapy, has produced remarkable remissions in relapsed or refractory acute B-cell lymphoma and other aggressive mature B-cell lymphomas after failing prior lines of chemotherapy. 

Another cellular immunotherapy is immune checkpoint inhibitors which have been promising in Hodgkin lymphoma and in some other aggressive lymphomas in combination with chemotherapy.

Considerations and constraints

The most serious and recognised complication is toxicity-related complications. Chemotherapy is toxic as an entity; immunotherapy carries its own specific risks (cytokine release syndrome (CRS), immune-related adverse events, and graft-versus-host disease in donor settings). The combination can amplify risk, this, however, can be attenuated by meticulous dosing, consideration of patient co-morbidities, and prophylactic protocols instituted to recognise potential complications.

Timing and scheduling

When to give immunotherapy relative to chemotherapy matters. Immunotherapy given too early might be less effective, however, delaying the administration may result in poor efficacy.

Immune suppression and recovery 

The haematological malignancy compounded with chemotherapy results in immunosuppression and conversely immunotherapy requires a functioning immune milieu. Balancing immunosuppression (risk of infection, poor immune recovery) with the necessity to administer potentially immunosuppressive therapy is a delicate process. 

Financial toxicity and access

Cellular immunotherapies (CAR-T) are expensive, complex to manufacture, and require infrastructure, such as a high-care facility and high-care nursing. This limits administration within our local setting. 

Resistance and escape

Tumours may down-regulate target antigens, mutate, or employ immune checkpoint pathways to escape immunotherapy. Combination strategies must anticipate escape mechanisms and neoantigen presentation.

The future: optimising the marriage

The future lies in safely administering immunotherapy employing the correct timing. Identifying biomarkers for which patients may benefit, thoughtful combinations of chemo-immunotherapy, optimising toxicity management may ensure safety and efficacy simultaneously. 

The novel cellular therapies are regarded as off the shelf and are manufactured, for example, CAR-T or CAR-NK. The allogeneic CAR allows for accessibility and a reduction in financial toxicity. 

Conclusion

The synergy of chemotherapy and immunotherapy in haematological malignancies represents one of the most dynamic frontiers in oncology. When effectively combined, these treatments can produce deeper remissions, reduced relapse, and potentially cure in settings that were once considered refractory. 

The path is complex and intricate, however, can be navigated with careful attention to patient selection, timing, toxicity, resistance mechanisms, and access 

As research continues to illuminate the biology of immune-tumour interactions and the microenvironment and as novel immunotherapies mature, the marriage of chemo-immunotherapy is likely to become less of an experimental arrangement and more of a standard paradigm and standard of care in treating haematological malignancies. 

Dr Jasmine Ramiah is a clinical haematology subspecialist (trainee) at Inkosi Albert Luthuli Central Hospital where her passion for haematology first took root in 2016. She expanded her expertise by specialising in haematopathology and qualified as a haematopathologist in 2024, sharpening her diagnostic acumen and broadening her clinical perspective.

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