1. Nalley, Catlin

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NEW YORK CITY-With a median age at diagnosis of 72 years, chronic lymphocytic leukemia (CLL), the most prevalent adult leukemia, is a disease of elderly patients who often require special consideration when developing a line of defense.

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"The challenge of CLL is that, as of today, we still cannot cure the disease, which means we have to choose the best therapy frontline because it is the most bang for your buck," noted Jacqueline Claudia Barrientos, MD, Associate Professor, Division of Hematology and Medical Oncology, Department of Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. "The time to remission between therapies shortens and shortens, and overall the second- and third-line therapies are not as successful as the first-line therapies."


During her presentation, "State-of-the-Art Management of CLL in Older Adults," at the Chemotherapy Foundation Symposium, held Nov. 8-10, Barrientos took a closer look at the treatment options for the most vulnerable CLL patients.


Treatment Challenges

Developing an effective treatment plan for elderly CLL patients is especially challenging due to the increase in comorbidities that comes with age.


The problem, Barrientos explained, is that since most of the patients are diagnosed at such a late age they have already acquired several comorbidities such as hypertension, arrhythmia, liver or renal insufficiency, and other conditions.


"On average, most patients have four comorbidities at the time of their initial therapy," she said, which often doesn't occur until 4-5 years after diagnosis because the standard practice is to employ observation until the patient exhibits symptoms of disease progression.


Given this practice, "elderly patients typically receive their first therapy at an age when they may be too frail to tolerate a regimen that may be associated with severe toxicities to the liver, kidney, or bone marrow."


With aging comes comorbidities, which requires consideration of whether the person will be able to withstand a strong chemotherapy or a drug with significant side effects, emphasized Kanti R. Rai, MD, moderator of the session and Professor of Medicine and Molecular Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.


"So, the most important outlook predictors not only include del(17p) and mutation status of the IDH gene, but also age," noted Barrientos during her presentation. "And the reason for that is because depending on your age is how you are going to respond to the therapies we recommend."


Determining Optimal Strategies

Significant progress has been made in the treatment of CLL in recent years. "Survival is markedly improving with new small molecule inhibitors, especially for high-risk patients, such as del(17p) CLL," William G. Wierda, MD, PHD, the D.B. Lane Cancer Research Distinguished Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, noted previously in Oncology Times. "Standards of care are rapidly evolving with expanding options, and forthcoming results of several phase III trials will amplify this.


"First treatment is the best opportunity to use the most effective agents to achieve the deepest and most durable remission. This holds for chemoimmunotherapy-based treatments and oral small molecule inhibitors of the B-cell receptor signaling pathway, such as the Bruton's tyrosine kinase inhibitor ibrutinib," he continued.


Over the course of the past decade, the oncology community has developed a more advanced understanding of the biology of CLL with the discovery of "chromosomal abnormalities and genetic mutations that contribute to the heterogeneity of the disorder and help predict its clinical course."


So how do these breakthroughs impact the treatment of elderly patients?


"As we all know, frontline FCR (fludarabine, cyclophosphamide, rituximab) is considered the gold standard," noted Barrientos. However, for many elderly patients, they are not able to tolerate the full dose and intensity, she explained. FCR as well as bendamustine and rituximab (BR) can both cause severe infections that impact quality of life. Therefore, "in this day and age, I would recommend using a different alternative."


Researchers have shown the benefits of several chemoimmunotherapy regimens (i.e., obinutuzumab with chlorambucil, ofatumumab and chlorambucil, rituximab and chlorambucil), and although these options are available to elderly patients, according to Barrientos, this approach is not heavily utilized in the U.S.


A growing body of research supports the clinical value of ibrutinib for patients with CLL. Data presented at ASH 2016 showed high and lasting responses through 5 years (Abstract 233). Updated results from a phase Ib/II trial demonstrated an overall response rate of 89 percent, including patients with genetic mutations associated with poor outcomes. A complete response was observed in 29 percent of patients treated in the first-line setting. Progression-free survival was improved with earlier initiation of therapy across treatment-naive and relapsed/refractory patients, according to study authors.


"These longer-term results demonstrate that ibrutinib can help patients keep chronic lymphocytic leukemia and small lymphocytic lymphoma in a remission for an extended period of time, through 5 years, without chemotherapy," said Susan O'Brien, MD, Associate Director for Clinical Science of the Chao Family Comprehensive Cancer Center, and Medical Director of the Sue and Ralph Stern Center for Clinical Trials & Research, at UC Irvine Health, and study investigator, in a statement. "In addition, these data indicate the time without disease progression is longer for patients when treatment with ibrutinib is started as early as possible in the course of the disease."


"Most of the patients on average are still, at 5 years, on ibrutinib," Barrientos added during her presentation. "It is a small group of patients, but still very promising that this is regimen we could use."


Additional follow-up data in patients with CLL treated with ibrutinib through 29 months from the phase III RESONATE-2 trial continue to support the use of this regimen. Updated findings from the trial demonstrated that at a median of 29 months of follow-up, ibrutinib continued to have substantial efficacy as first-line therapy in CLL (ASH 2016; Abstract 234).


Ongoing Research

Continued research is underway to continue to refine the best course of treatment for elderly patients with CLL.


Combination therapies are being explored worldwide, such as ibrutinib and obinutuzumab, or venetoclax with obinutuzumab or chemotherapy combinations, according to Barrientos. For optimal management, treatments must be tailored to the patients, she concluded.


Catlin Nalley is associate editor.