Immunotherapeutic Approaches Have the Potential to Brighten the Future Not Only for Patients With del(17p13.1), but for All CLL Patients

Large multicenter trials have established that combination chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab (Rituxan) (FCR) is the current standard of care for young fit patients with chronic lymphocytic leukemia (CLL).[1] This approach is neither curative, nor is it suited to the majority of patients. In addition, some patients respond poorly to chemo-immunotherapy or relapse early. Over the past decade considerable research in this disease has focused on the identification of those factors predictive of outcome. The tumor suppressor gene TP53 on chromosome 17 is one of the key elements in this context. Patients with del(17p13.1) with and without TP53 mutations have been repeatedly identified as having poor response and outcomes after standard therapy, underscoring the unmet need for alternative and novel treatment approaches, especially in this subgroup.

In their concise and up-to-date review, Drs. Stephens and Byrd outline the pathophysiology associated with del(17p13.1). They summarize the poor outcome of these patients across different treatment regimens and clinical studies, and they discuss the potential of new agents currently under clinical investigation. The paramount role of TP53 and its implications for the clinical management of CLL patients has recently also been emphasized in the work of Zenz et al, who proposed incorporating TP53 loss and/or mutation into a hierarchical risk model of CLL.[2] According to this model, TP53 loss and/or mutation put patients at “highest risk” to fail FCR therapy, establishing the need to include these patients in trials exploring alternative approaches.

As critically discussed by the authors, a multitude of previous trials and currently available treatment regimens, including rituximab-based chemo-immunotherapy, have largely failed to show satisfactory efficacy in patients with del(17p13.1), both in the front-line and relapsed/ refractory settings. In contrast, the anti-CD52 antibody alemtuzumab (Campath) seems to be able to partly overcome the adverse effects of del(17p13.1), especially when combined with high-dose corticosteroids. However, this comes at the price of severe hematologic and infectious side effects-and to further complicate matters, CLL is no longer an approved indication for this agent in the European and US markets.[3] While ongoing access to the drug will at least in the short term be ensured within clinical trials and through patient access programs, it will be considerably harder to pursue alemtuzumab-based research and treatment strategies in the future.

New agents, such as B-cell receptor antagonists, cyclin-dependent-kinase inhibitors, and B-cell lymphoma 2 (BCL-2) antagonists have shown exciting clinical activity, even in relapsed/ refractory patients, while exhibiting relatively low toxicity, and the authors summarize promising up-to-date clinical data in their review. These agents are showing considerable promise in overcoming the problems of failure to respond to standard chemotherapy in patients with TP53 defects, and they will likely play an increasing role in the management of these high-risk patients. Another drug with promising results and activity even in relapsed/refractory patients is the immunomodulatory drug lenalidomide (Revlimid). Although its exact molecular mechanisms are still not well described, its activity across a variety of hematologic malignancies, including myeloma, myelodysplastic syndromes, and lymphoma, suggests that it has multiple modes of action. Various laboratory-based studies are ongoing to elucidate the exact mechanism of action of lenalidomide in CLL and to explore the full potential of the drug in combination with conventional chemo-immunotherapy and novel agents.

Targeting the immune system is a very attractive approach for several reasons: first, several studies have indicated that allogeneic stem-cell transplantation is currently the only treatment with curative potential in patients with del(17p13.1) on the basis of its capacity to induce graft-versus-leukemia (GVL) activity.[4-6] As outlined by Stephens and Byrd, this approach should be restricted to patients who meet the criteria for transplant in this disease-and in first remission this includes only patients with del(17p13.1) (or TP53 mutations).[7] CLL is associated with a wide range of immune dysfunctions and defects, leading to failure to mount an effective antitumor immune response. Based on the cancer immuno-editing hypothesis that the immune system not only protects the host against tumor formation but also promotes the tumor,[8] “repairing” these defects should restore the anti-tumor response and result in detectable and durable clinical responses. Autoimmune disorders and/or increased susceptibility to infections are observed in the majority of CLL patients. Reconstituting the immune system would also substantially improve the patient’s ability to fight infections, contributing significantly to increasing the quality of life. Lenalidomide is not only able to impact signaling pathways, but also to modulate the immune system by modifying cytokine patterns, influencing the microenvironment, and restoring defective T-cell functions.[9] These features make lenalidomide and other immunomodulatory drugs highly attractive candidates for the treatment of CLL, and ways to incorporate this agent into optimal treatment approaches for patients with del(17p.13.1) are needed.

Another exciting immunotherapy approach not discussed in the article is the use of chimeric antigen receptor (CAR) T cells. CAR T cells are genetically modified autologous T cells that have the ability to specifically recognize targeted antigens, thus overcoming the limitations of major histocompatibility complex (MHC) restriction.[10] However, the target antigens must be carefully selected to avoid “on-target, off-organ” effects, which can occur when the antigen is also expressed and recognized in nonmalignant tissues and organs. Currently, attractive targets in CLL include CD19, CD20, and receptor tyrosine kinase–like orphan receptor 1 (ROR1). A number of phase I/II clinical trials are currently under way using anti-CD19 CAR T cells.[11] One of the most impressive results was seen in a heavily pretreated CLL patient with del(17p13.1) and TP53 mutation; the patient entered a complete remission after receiving second-generation anti-CD19 CAR T cells following conditioning with pentostatin and cyclophosphamide, while experiencing no acute side effects.[12] However, there are also reports of serious adverse events associated with this treatment, and further efforts are needed to optimize CAR function and to investigate potential long-term side effects.

In summary, in most cases the clinical management of CLL patients with del(17p13.1) poses enormous challenges, and patients should be included in clinical trials whenever possible. However, there are a number of promising novel drugs and immunotherapy strategies under investigation, which lead us to believe that an intelligent and individualized combination of these approaches will shape the future treatment not only for poor-risk patients with del(17p13.1), but also for CLL patients in general.

Financial Disclosure:Dr. Gribben has received honoraria for serving on the advisory boards of Celgene, Roche/Genentech, and Pharmacyclics. Dr. McClanahan has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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