乌鸦传媒

Chronic lymphocytic leukemia (CLL) is typically a disease of the elderly, but not exclusively. It does occasionally strike younger patients.

In the U.S., the median age of individuals at diagnosis is approximately 70, according to the National Cancer Institute's Surveillance, Epidemiology, and End Results . A small proportion of patients, however -- fewer than 1% -- are in the adolescent/young adult (AYA) category, ages 15-39.

Researchers at the University of Texas MD Anderson Cancer Center in Houston, led by Hua-Jay Cherng, MD, recently examined some of the clinical and molecular characteristics of these younger patients, on 227 AYA patients with CLL diagnosed at the institution over the past 2 decades.

The researchers found that the 5-year overall survival rate was 90%, and the 10-year rate was 78%. When the team examined prognostic biomarkers, they found that pre-treatment elevated beta-2 microglobulin, advanced Rai stage, del(11q) or del(17p) by fluorescence in situ hybridization (FISH), unmutated immunoglobulin heavy-chain variable region gene (IGHV), and CD38 positivity were all associated with shorter time to first treatment and shorter overall survival times.

"The clinical implications here are that the same prognostic biomarkers we rely on for all CLL patients are applicable and relevant for the very rare subset of AYA patients, particularly in the era of oral targeted therapy," Cherng told 乌鸦传媒 via email.

One of the challenges in treating younger patients with CLL is narrowing down the broad range of therapeutic choices, he said. Because AYA patients are often fitter and tend to lack prohibitive comorbidities, they are more likely to be candidates for all approved therapies, including novel oral agents like venetoclax (Venclexta), ibrutinib (Imbruvica), and acalabrutinib (Calquence).

"Therefore, treatment choice must be individualized to each patient and their preferences," Cherng explained. "Does a 35-year-old patient who takes no medications want to start taking a continuous daily medication in the form of ibrutinib or acalabrutinib, or do they want time-limited venetoclax-based therapy that involves intensive early monitoring and infusions that may interfere with a busy work schedule?"

Chemoimmunotherapy is also an option for many of these patients, Cherng noted. "For low-risk patients with mutated IGHV and lacking TP53 aberration, we still do not know whether oral therapy is more effective than aggressive chemoimmunotherapy such as the FCR [fludarabine, cyclophosphamide, and rituximab] regimen. AYA patients are more likely to tolerate chemoimmunotherapy than older patients, so some providers may still offer it in this scenario."

Again, patient preference comes into play: "Do they want chemoimmunotherapy that may cure their disease but carries a risk of therapy-related myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML]? These are the questions that providers and their AYA patients struggle with. Younger patients are great candidates for clinical trials as well," Cherng said.

Another issue is that AYA patients tend to live much longer than older patients, so physicians must be vigilant for CLL-related complications, he added. "The risk of Richter transformation, treatment-related MDS/AML, and second cancers increases over time," Cherng explained. "An AYA patient may enjoy long-term disease control with respect to their CLL but face one of the above life-limiting disease complications, so monitoring and early detection is important. We know that CLL patients are at higher risk for developing other cancers, so they should undergo age-appropriate cancer screening and skin exams."

Direct Comparison of Young vs Old Patients

Although Cherng's group did not directly compare younger CLL patients with older patients to look for similarities or differences, other scientists have. For example, a group led by Sameer Parikh, MBBS, of the Mayo Clinic in Rochester, Minnesota, 844 newly diagnosed patients age 55 and younger with 2,324 patients older than 55 treated over nearly 2 decades at their institution.

The study found some significant differences. Younger patients were more likely to present with intermediate Rai risk disease (P<0.0001), to be IGHV unmutated (P=0.002), and to express zeta-chain-associated protein kinase 70 (ZAP-70) (P=0.009). Although the overall survival of younger patients was longer (12.5 vs 9.5 years for older patients, P<0.0001), survival was markedly shorter compared with an age- and sex-matched general population.

"These differences persisted when we limited our analysis to non-referred patients and became even more pronounced when patients ≤55 years old underwent further age sub-stratification," Parikh and co-authors wrote. "This observation suggests that young CLL patients are more likely than older patients to have biologically aggressive disease."

Median time to first treatment was shorter in the younger group (4.0 vs 5.2 years, P=0.001). However, this difference disappeared after adjusting for Rai stage and IGHV mutation status, "suggesting that differences in disease stage and biological characteristics (rather than age) were responsible for this difference," the researchers said.

Similar to the results reported by Cherng and colleagues, Parikh's group found that the molecular biomarkers ZAP-70, CD38, IGHV mutation status, and cytogenetic abnormalities on FISH each independently predicted time to first treatment and overall survival in the younger patients after adjusting for age, sex, and Rai stage.

In an email, Parikh noted that treatment paradigms have changed since the time of his group's study. "It's important to recognize that these patients were cared for at Mayo Clinic between 1995 and 2012. There has been a paradigm shift in the management and outcomes of CLL patients since that time, given the availability of novel agents," he said. "The oral agents have significantly improved the survival of CLL patients, including those with high-risk disease. The outcomes of young CLL patients will need to be re-examined in the era of novel agents."

A more recent of younger and older patients with CLL was conducted by researchers at Memorial Sloan Kettering Cancer Center in New York City, led by Bartlomiej Getta, MD, comparing 71 patients age 40 or younger with 142 patients older than 40 treated at the institution from 2005 to 2015.

Some of their findings confirmed other research. Similar to what the Cherng and Parikh teams reported in terms of prognostic biomarkers, Getta and co-authors found that CD38 expression, IGHV status, lactate dehydrogenase, and beta-2 microglobulin all predicted time to first treatment. The group also reported a trend toward longer 5-year survival in the younger versus older patients (93% vs 82%, P=0.082).

However, in contrast to Parikh's group, Getta and colleagues did not find any significant differences between younger and older patients in presenting characteristics such as Rai stage, IGHV status, or ZAP-70 expression.

Neither Getta nor any co-authors were available to discuss the findings, but they noted in the paper that the study was smaller than previous studies and underpowered to assess survival biomarkers. In addition, cytogenetic data were missing for some of the younger patients. These factors might account for the contrast with previous research, the investigators suggested.

"Our results suggest that biomarkers in this group of patients are not different than in older patients, and that the disease is not more aggressive at presentation and during its course," Getta and co-authors wrote. "We validated traditional CLL prognostic factors in their ability to predict time to first therapy; results of this analysis will assist clinicians when counseling patients in this age group."

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