Interferon Gamma Signaling Drives Drug Resistance in AML

Our growing understanding of the role of immune signalling in AML that fails treatment is rapidly challenging our current models of the disease. New research published in Blood this week has shown that interferon gamma signalling, often associated with pro-immune functions, may confer treatment resistant leukaemia and could inform choice of treatment, monitoring and health system planning for patients with AML.

Why It Matters

Resistance is not only genetic

For most patients with acute myeloid leukemia (AML), earlier initiation and more effective therapy is associated with improved outcomes. However, many patients experience rapid relapse after treatment. While resistant AML has often been discussed in terms of the mutations that allow leukemia to become treatment resistant, the process of clonal evolution that allows AML to become more drug resistant over time, and the question of whether any particular therapy targets a “targetable lesion,” resistance is a dynamic and complex process influenced by signals from the bone marrow environment. One such pathway is interferon gamma signaling, which has recently been implicated in leukemia resistance.

Interferon gamma (IFN-γ) is a cytokine that functions as an immune messenger molecule helping the body to fight off infection and carry out surveillance on cells that may become malignant. Persistent or repetitive exposure to interferon gamma induces stress-adaptation in leukemia cells leading to resistance to chemotherapy and reduced sensitivity to select targeted therapies. As a result, many patients will have persistent minimal residual disease even with a reduction of the blast count.

How interferon gamma can protect leukemia cells

Chronic exposure to interferon gamma (IFN-?) can instate cellular programs that make interferon-regulated leukemias, such as AML, sensitive to treatment-induced stress. Here we show that these gene expression programs induce antigen presentation, metabolic, cell cycle, and survival functions. Leukemia cells that become drug tolerant (DT) do not immediately become irreversibly resistant (IR) but remain viable long enough to acquire secondary mutations that make all remaining leukemic cells relapse-refractory. The delay to relapse, often months after induction of remission, may be due, in part, to the presence of leukemia stem cells that are resistant to the direct cytotoxic effects of chemotherapy via protection by the immune microenvironment.

Interferon gamma effects are context dependent. Brief immune activation with interferon gamma can result in anti-leukemic effects, whereas longer interferon gamma exposure can promote leukemic cell adaptation and survival. The net effect of interferon gamma can be dramatically altered by concomitant infections and/or inflammatory diseases, prior therapy, and repeated marrow stress. Thus, the same cytokine may function alternatively as a friend or foe.

Why this changes therapy planning

Do interferon gamma signaling pathways allow AML to acquire treatment resistant proliferation? While future decisions regarding optimal drugs (and combinations) for a given patient will still be based on choosing treatment sensitive leukemia with good fitness, age appropriate tolerability, certain cytogenetic features that allow for use of targeted therapy, and additional genotype driven selections, immune pathway activity could begin to play a role in predicting effective therapy, relapse early in treatment, and potential benefit of earlier combination therapy regimens. The ideal treatment regimen will require integration of information regarding the leukemia genotype with assessment of key features of the immune and inflammatory environment in the marrow and blood.

However, the way in which these regimens affect patients is not simply additive. The approach to the management of toxicity and patient support will change. The interactions between anti-leukemic therapy and the immunomodulatory drugs will affect the indications for blood product transfusions and the evaluation of fever. Consideration will need to be given to the use of prophylaxis against infection. The delayed cytopenias seen after stopping therapy will also require a different perspective.

System implications and cost

Interferon gamma guided care may increase short term treatment complexity while improving long term outcome. The diagnostic pathway may become more complex in that many existing and new diagnoses will be tested for interference with interferon gamma, increasing the cost of the laboratory tests and diagnostic turnaround time. Treatment may be more individualized with more use of combination therapy, closer follow up, and more reevaluation of individual patients. From the perspective of the hospital, third party payer, or other entity absorbing the cost of cancer care, the near term increased expenditure must be weighed against the potential for decreased long term expenditure resulting in fewer failed therapies, fewer salvage admissions for relapse, and longer duration of remission.

As the clinical utility of immune biomarkers becomes more apparent, current clinical guidelines and reimbursement frameworks will need to be revised and expanded. Current coverage policies are based on established indications and typical treatment approaches and are not easily adapted to alternative strategies that are designed based on the immune signature of a patient’s cancer. Developing flexible frameworks for the use of immune biomarkers will require the participation of all stakeholders including health systems and payers. These frameworks will need to clearly outline who, when and how these biomarkers should be tested and used to select the best cancer therapy for a patient.

Who It Affects

Newly diagnosed AML patients

Activity of the interferon gamma immune pathway in the interferon gamma pathway study may predict early treatment response and risk of relapse in patients with newly diagnosed AML. Patients with high levels of baseline pathway activity may benefit from more frequent monitoring for minimal residual disease, earlier consideration of combination therapy, or earlier consideration of transplant in eligible patients. While these findings may not directly change a patient’s or physician’s treatment decisions, they can help frame these decisions with expectations of treatment outcomes and intensity of follow-up.

Older patients and those with chronic inflammatory diseases such as COPD could be particularly affected by immune-driven resistance to treatment of AML. As individuals get older, their immune system changes to allow controlled inflammation. In AML patients, this pre-existing inflammatory environment may limit the efficacy of therapy. AML patients have many medical comorbidities at diagnosis, including chronic infections, autoimmune diseases, active metabolic diseases that could result in chronic immune activation, and multiple medications that could affect the immune system. In addition, poor tolerance of therapy and high relapse rate are characteristic of older AML patients, and immune-driven resistance to therapy could explain a portion of these less than optimal clinical outcomes.

Patients with relapsed or refractory disease

The second-line treatment of patients who relapse following an initial therapeutic response to antileukemic therapy is often challenging. Immune-driven adaptation to leukemia may play a role in the process that leads to relapse. In the case of a relapse, the original diagnosis is revisited to determine if new mutations have emerged. The leukemia may have adapted to the host environment to become a more indolent yet resistant cancer incited by host immune mechanisms. A better understanding of these adaptive processes will inform second-line strategies, particularly as it relates to the combination of drugs most capable of inducing cancer cell death by targeting key survival pathways as opposed to simply replacing one antileukemic agent with another.

In addition to enhancing the sensitizing effect of prior therapy, patients on a repeated line of therapy will have experienced cumulative effects of treatment on the immune system that tip the balance to interferon signaling. Each cycle of prior therapy will have perturbed the composition of the marrow, effects the balance of certain immune populations and changed cytokine signaling pathways. Moreover, the effects of prior therapy on the tumour microenvironment can generate drug tolerance particularly after an infection and inflammatory event.

Clinicians and care teams

Future management of patients with both hematological malignancies and solid tumours will require that hematologists and oncologists incorporate understanding of immune biology into their common sense approach to patient care. Clinicians will need to interpret results of studies targeting several different biological pathways to cancer. Patients and clinicians will need to develop a sophisticated understanding of what constitutes meaningful interferon gamma results and make informed decisions about the uncertainty of the side effects of immune-modulating therapies and potential long-term benefit.

As the field moves towards immune pathway assessment, services in Pathology and Laboratory Medicine will be focused in new ways. Some of these tests will incorporate gene-expression signatures or measure 10 or more cytokines, others will involve flow cytometric immune characterization or algorithm scores. Consideration will need to be given to validation, reporting format and specimen procurement guidelines. Importantly, AML patients and their families want to know time to treatment, therefore efficiency of workflow in the lab will be critical.

Pharmacists, nurses, and supportive care services will play a crucial role in safely delivering these treatments. Immune-modulating combinations are likely to require adjustments to standard antimicrobial prophylaxis and monitoring for toxicity, as well as a heightened index of suspicion for febrile episodes. Patients receiving these regimens will require updated management protocols at oncology infusion centers for overlapping cytopenias, hepatotoxicity, and other potential toxicities.

Health systems, payers, and policymakers

Although Immune-enabled diagnostics and combination therapy for Hodgkin lymphoma will initially increase costs to hospitals and payers, improved Strker® Immunochemistry pathology-driven patient stratification can reduce costs associated with relapse and subsequent “salvage” therapies by reducing the number of cycles of ineffective treatment. Policymakers must consider a broad definition of value and play an active role in ensuring that novel strategies like these are covered and accessible to patients in community programs outside of major academic centers.

If interferon gamma signaling is a key driver of resistance then everyone involved in developing research and clinical trials will also feel the burn. Trials designing to demonstrate efficacy for drugs active in the “right” patient population will fail due to ignorance of the immune context in which treatments are administered. Future clinical trials in cancer should therefore consider stratifying patients in trials by underlying immune signature and include immune monitoring as a primary endpoint in the trial.

What Changes

Diagnostics

Predicting treatment tolerance in AML is a challenging problem that is critical to improving outcomes. Predicting tolerance to therapy includes assessing the function of the interferon gamma pathway, which can be objectively evaluated using immune-related gene-expression scores, measuring cytokine levels, and performing a marrow immune assessment. This immune assessment will be incorporated into routine diagnosis and follow-up evaluation after induction therapy, as well as at early molecular relapse, and will be performed in parallel to and not replace mutation assessment.

Standardization will likely play a crucial role in ensuring that different groups and programs are providing consistent yet useful information for clinical decision-making. A health system would need to define for its clinicians what level of interferon gamma activity constitutes “low,” “intermediate,” or “high,” and how that information can be used in clinical decision making. What one center considers “high” might be another center’s borderline.

Treatment strategy

Future therapy may involve interferon gamma-targeting agents used in combination with chemotherapy or targeted therapy. From studies of the interferon gamma pathway, several potential targets have been identified that allow for the targeting of leukemia cells entering a protected state while preserving adequate anti-microbial immunity. These targets include the upstream signaling molecules, the transcription factor STAT1, and the survival pathways mediated by genes that control metabolism and stress-response.

Our strategy for sequencing patients with relapse is also likely to change. For cases with high immune pathway activity we would look to intensify therapy earlier to prevent re-emergence of drug-tolerant residual disease. On the opposite end of the spectrum, for certain patients with a highly favorable immune environment and deep early response we might use immune-informed sequencing to make decisions regarding de-escalation.

Care delivery and monitoring

The introduction of immune modulation to the treatment of leukemia and lymphoma will likely result in patients requiring closer monitoring and/or testing more frequently or in a more targeted fashion. Patients on immune modulating therapy can require closer follow up of lab values, earlier evaluation and management of fevers, and initiation of infection precautions. Monitoring of immune markers such as interferon gamma inducing cytokines in addition to minimal residual disease may be useful in identifying early resistance to therapy.

Future care of patients will increasingly require a multidisciplinary approach. Tumour boards involving Haematology, Pathology, Immunology, Infectious Diseases and Pharmacy will be critical in interpreting complex immune results and in translating these results into safe and optimal treatment for patients. Clear referral pathways will be important to ensure timely access to the advanced diagnostics and multidisciplinary specialist input required.

Trade-offs and patient safety

Combining an immune pathway inhibitor with other treatments may help to reverse leukemia resistance, but potentially at the cost of damaging other beneficial aspects of immunity and increasing the risk of infection. This consideration is especially pertinent in AML, where most patients commence treatment with already impaired immune function, and active disease is a major component of their illness. Treatment strategies which combine immune-modulating therapies, therefore, require a balanced assessment of potential benefits and risks, including consideration of comorbidities and frailty.

The toxicities identified in the new generation of cancer therapies, including the targeted therapies, may require a shift in the way we deliver supportive care. The concurrent administration of multiple medications may increase the risk of severe cytopenias, exacerbate mucosal injury, and complicate the diagnosis of and management of fever. Patients and their families need better education on the safe administration of oral medications and have a greater understanding of both warning signs of illness and the early signs of infection. Patients with low blood counts could benefit from a greater understanding of their situation.

Cost, coverage, and equity

In the near term, hospitals and payers will calculate the incremental test development cost and the cost of administering several therapies at once to target multiple disease pathways. They should remove any unnecessary barriers to access these potentially curative treatments in the near term. In the long term, the cost of these upfront efforts should be offset by decreased instances of relapse and increased rates of durable remission. Future value-based coverage decisions for these approaches may depend on data that describes immune signatures that predict for good response to these therapies.

Equity should be considered early and often in the development of these advanced programs. While certain forms of advanced immune testing and combination cancer therapies may be most effective and efficient in larger programs with more patients, this could potentially widen inequities unless strategies are thoughtfully developed to support community-based access. Shared- care models, rapid return of results from centrally performed testing, and use of telemedicine for virtual tumor boards could all support access and efficiency while reducing costs. Fair reimbursement for the evidence-based use of biomarkers must also be established to prevent small practices from being penalized for doing things right.

Looking ahead

However, progress in the near term will depend on the development and validation of assays and a consistent interpretation of results, as well as thoughtful clinical trials in which adequate numbers of patients of different racial and ethnic backgrounds are enrolled. Real-world patient registries that collect and monitor a host of data points, including the immune characteristics of patients, treatments, durations of remission, toxicities, and costs of care, can be used to validate and prove the value of such treatment algorithms to payers. Developing clinician and patient education programs will become increasingly important as well. Patients and clinicians will need a good understanding of the tests that are being conducted and the potential impact on clinical decision making.

In the short term broad immune suppression still has a role in improving survival with chemotherapy for AML. In the longer term however, it is likely that precise immune modulation, rather than broad immune suppression, will become a cornerstone of AML treatment. By targeting specific interferon gamma linked survival programmes that protect AML from anti-leukemic immunity, whilst at the same time preserving protective immunity, sustained remissions can be obtained with minimal risk of serious infection, and which translate to clinical personalisation of AML therapy.

The genetics of leukemia, adaptive gene programs, and the immune landscape all play a role in causing resistance to drugs developed to treat AML. The interferon gamma antileukemic pathway challenges fundamental aspects of AML therapy and thereby requires an integrated approach to patient diagnosis and treatment. Current diagnosis, combination treatment strategies, access, safety, and long-term benefit policies must be re-examined in the light of these new findings on a key antileukemic pathway.

References:

https://pubmed.ncbi.nlm.nih.gov/38418901/ https://pmc.ncbi.nlm.nih.gov/articles/PMC12723130/