The power of combinations in blood cancers

Advances in research and development and the utilisation of combination treatment strategies are revolutionising the haematology care landscape, but more must be done to address patients’ individual needs. There are more than 150 identified types of leukaemia’s, lymphomas and myelomas¹ and given that each blood cancer is unique, their heterogenous nature makes them some of the most challenging cancers to treat.²

To redefine standards of care in haematology and close gaps to improve patients’ lives, we must work to achieve the following:

• Develop a deeper understanding of these diseases’ biology to identify new vulnerabilities that can be explored therapeutically
• Rapidly advance the development of combination regimens, incorporating drugs with no overlapping mechanisms of actions to address tumour heterogeneity³
• Introduce treatments early in the course of disease to improve curative potential.

Advances in disease understanding and combination strategies in haematology

We now know that blood cancers are characterised by molecular and phenotypic heterogeneity.² It is this complexity that necessitates powerful, targeted combination therapies.

To bring us closer to curing cancer, a combination of effective drugs with non-overlapping mechanisms of action is required. ³ This concept was established more than three decades ago in diffuse large cell lymphoma (DLBCL) and Hodgkin lymphoma, when they became among the first cancers to be cured with the chemotherapy combinations of CHOP (Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone) and ABVD (Adriamycin, Bleomycin, Vinblastine and DTIC), respectively.^{4, 5}

More recently, new combination regimens have emerged that incorporate targeted therapies to treat a variety of blood cancers, including multiple myeloma (MM), chronic lymphocytic leukaemia (CLL) and acute myelogenous leukaemia (AML).⁶ In all these examples, an effective backbone drug was first developed, before adding one or more drugs to establish the new regimens. These regimens frequently include one or two small molecule inhibitors and immuno-oncology (IO) therapies, such as monoclonal antibodies and T-cell engagers.

Next-generation modalities and combinations

As research further progresses beyond chemotherapy and small-molecule inhibitors, the emergence of next-generation modalities is unlocking new ways to target cancer. This includes developments with innovative IO agents, such as bispecific antibodies, T-cell engagers and cell therapies, and modalities that directly kill cancer cells, such as antibody drug conjugates (ADCs) and epigenetic therapies.

These options are creating opportunities to develop more sophisticated, novel combination regimens for patients. For example, combining IO agents with ADCs to mount a two-pronged attack against cancer by activating an anti-cancer immune response and directly killing cancer cells may drive stronger and more durable responses in the clinic.⁷ The availability of these novel modalities provides more options to tailor combinations based on an individual patient’s disease characteristics, which is critical in haematology since all blood cancers are different.²

Early intervention and interception strategies

While CHOP and ABVD demonstrated the power of combination regimens to cure some cancers, even in the most advanced stages; introducing regimens early in the course of disease is likely to be more effective. ⁸ Many types of blood cancers currently cannot be cured with therapy, leading to the use of a “watch and wait” strategy and delays in treatment initiation.⁹ This delayed treatment is implemented in patients with follicular lymphoma, CLL, mantle cell lymphoma and multiple myeloma, among others.

As we build innovative regimens using more effective drugs than traditional chemotherapy, it will be imperative to rapidly test the curative potential earlier in the disease course. The challenge with this early intervention approach is the need to follow up with patients for a long period of time. To be successful, surrogate or intermediate endpoints will need to be established to accelerate the development of the new regimens. At AstraZeneca and beyond we are exploring the use of cell-free DNA (cfDNA) methods to assess minimal residual disease as a possible intermediate endpoint across several disease types.

Ultimately, novel early detection methods will need to detect cancer cells before they become clinically visible by imaging studies, and preferably in a premalignant state.¹⁰ For example, current deep sequencing methods can detect clonal haematopoiesis of indeterminate potential (CHIP), which may predispose to AML.¹¹ Similarly, modern flow cytometry analysis of peripheral blood samples can detect monoclonal B-cell lymphocytosis (MBL), which may predispose patients to the development of CLL.¹² Intercepting these cells with precise, effective and tolerable medicines may pre-emptively prevent the development of cancer or delay its onset by several years.¹² These approaches will require early detection methods that are specific and sensitive, in addition to predictive models to select patients at the highest risk of developing cancers before therapeutic intervention.

Driving cutting-edge research to identify cures

We’re in an era of cancer research that is pushing the boundaries of science and moving the needle in treating more haematological malignancies to increase the chance of cures. At AstraZeneca, we are researching multiple innovative combination therapies and harnessing next-generation technologies that could lead to earlier treatment and improved care for as many patients as possible.

This article was written and developed by AstraZeneca.

References

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