Older Age Is Associated With Worse Survival Outcomes in MCL

Reem Karmali, MD

Patients with newly diagnosed mantle cell lymphoma (MCL) who were 65 years of age or older had worse progression-free survival (PFS) and overall survival (OS) at 1 and 2 years compared with patients under the age of 65 years, according to findings from a retrospective, multicenter analysis published in the American Journal of Hematology.¹

With a median follow-up of 4.0 years in the younger cohort and 2.7 years in the older cohort, the 1-year PFS rates were 88.7% in patients under the age of 65 years vs 82.4% in patients 65 years of age or older, and the 1-year OS rates were 96.8% vs 92.7%, respectively.

The 2-year PFS rates were 78.6% in patients under the age of 65 years vs 67.1% in patients 65 years of age or older, and the 2-year OS rates were 92.1% vs 85.5%, respectively.

“Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab [Rituxan] era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival,”lead study author Reem Karmali, MD, an associate professor at the Feinberg School of Medicine at Northwestern Medicine, and coauthors, wrote in the study publication.

To better understand the clinical outcomes and prognostic factors for survival in patients with newly diagnosed MCL treated in the rituximab era, investigators compiled data on patients treated between 2000 and 2015 from 12 academic centers in the United States.

A total of 1162 patients were included in the analysis; 697 were younger and 465 were older.

In the younger cohort, 527 patients (76%) were male. Among 395 younger patients with an MCL International Prognostic Index (MIPI) score, 218 (55%), 108 (27%), and 69 (17%) had a low-, intermediate-, and high-risk MIPI score, respectively.

In the older cohort, 320 patients (69%) were male. Among 281 older patients with an evaluable MIPI score, 23 (8%), 110 (39%), and 148 (53%) had a low-, intermediate-, and high-risk MIPI score, respectively.

Younger patients were more likely to have bone marrow involvement (P = .031), a better performance status (P ≤ .001) and were less likely to have diabetes, coronary artery disease, heart failure, and chronic kidney disease (P < .001 to .003).

Among younger patients, the median time from diagnosis to first treatment was 31 days (range 0-5576). In 643 younger patients with documented frontline treatment, 268 (42%) were treated with a high-dose cytarabine-containing regimen and 9 (1%) were treated with a low-dose cytarabine regimen. Additional treatments include R-CHOP with or without methotrexate (n = 188; 29%), bendamustine/rituximab (BR; n = 88; 14%), lenalidomide ([Revlimid]; n = 5; < 1%), or other therapy apart from BTK inhibitors (n = 85; 13%).

No patients received a BTK inhibitor as first-line treatment. In 595 patients with accessible data on autologous transplant status, 350 (59%) received transplant after frontline induction. In 562 patients with accessible data on maintenance therapy, 199 (35%) received maintenance rituximab, including 94 patients posttransplant.

For younger patients with relapsed/refractory disease, data on subsequent treatments were accessible for 257 patients who relapsed (n = 224) or had stable disease (SD) or progression after frontline therapy (n = 33).

Sixty-seven patients (26%) were treated with BTK inhibitor combinations; 107 patients (42%) received salvage chemotherapy; and 51 (20%) received lenalidomide and/or bortezomib (Velcade)-based therapy. Forty-seven patients (18%) received allogeneic transplant, and 1 patient received allogeneic transplant after first relapse. One hundred seventy of 523 patients (32.5%) with available data on study participation were recruited to a clinical trial.

Among older patients, frontline treatment data was available in 407 patients, including 222 patients between the ages of 65 and 69 years and 243 patients at least 70 years of age. The median time from diagnosis to first treatment was 31 days (range 0-2611).

Fifty-seven patients (14%) were treated with a high-dose cytarabine-containing regimen and 8 patients (2%) were treated with a low-dose cytarabine regimen. In the older cohort receiving high-dose cytarabine, 48 patients (84%) were between the age of 65 and 69 years, and 9 patients (16%) were at least 70 years of age. Ninety-three patients (23%) received R-CHOP with or without methotrexate, 148 (36%) received BR, 9 (2%) received lenalidomide, and 92 (23%) received other treatments that excluded BTK inhibitors. No patients received a BTK inhibitor as first-line treatment.

Transplant status was captured in 369 patients, including 186 patients (50%) between the ages of 65 and 69 years and 183 patients (50%) at least 70 years of age. Eighty-eight patients (24%) received autologous transplant after frontline induction. In 351 patients with available data on maintenance therapy, 155 (44%) received maintenance rituximab, including 22 after autologous transplant.

In the older cohort who received autologous transplant as consolidation, 71 patients (80%) were between the ages of 65 and 69 years, and 17 patients (20%) were at least 70 years of age.

For older patients, data on subsequent treatments were available for 157 patients who relapsed (n = 115) or had SD or progression with frontline therapy (n = 42). Fifty-eight patients (37%) were treated with BTK inhibitor combinations; 49 (31.2%) received salvage chemotherapy; and 25 (16%) received lenalidomide- and/or bortezomib-based therapy. One hundred out of 350 patients (29%) with data on study participation were recruited to a clinical trial. Eight (5%) patients received allogeneic transplant and 2 (1%) received autologous transplant after first relapse.

In 559 younger patients with accessible response data, 409 (73%) had a complete response (CR), 117 (21%) had a partial response (PR), 10 (2%) had SD, and 23 (4%) had progressive disease (PD) after completion of frontline treatment. Eighty-one patients (12%) had early relapse/primary refractory disease defined as progression within 12 months of diagnosis or SD/PD as best response to induction therapy. Significant predictors of relapse/primary refractory disease on univariate analysis included high-risk MIPI (P = .004), blastoid histology (P < .001) and Ki-67 greater than 30% (P = .004); Clinical trial enrollment with initial therapy was effective in preventing early relapse/primary refractory disease (P = .014).

In 357 older patients with accessible response data, 242 (68%) had a CR, 73 (20%) had a PR, 16 (4%) had SD, and 26 (7%) had PD. Eighty-one (33%) patients with a CR and 49 (67%) with a PR to frontline therapy progressed during observation. Sixty-six of 370 evaluable patients (18%) had early relapse/primary refractory disease. Significant predictors of early relapse/primary refractory disease on univariate analysis included blastoid histology (P < .001) and Ki-67 greater than 30% (P = .004).

Younger and older patients had similar rates of high-risk features, such as blastoid histology, p53, complex karyotype, and Ki-67 of greater than 30%.

On unadjusted univariate analysis in younger patients, high-risk MIPI, advanced stage, bone marrow involvement, Ki-67 greater than 30%, greater than 3 cytogenetic abnormalities, and lack of autologous transplant were associated with inferior PFS (P < .001 to .034). High-risk MIPI, ECOG performance status of 2 or more, bone marrow involvement, blastoid histology, and lack of rituximab maintenance were associated with inferior OS (P = < .001 to .038).

Consolidation with autologous transplant in first CR did not impact OS. On multivariate analysis, ECOG performance status of at least 2, blastoid histology, and lack of rituximab maintenance continued to show statistical relevance to poor OS. Survival in younger patients with autologous transplant was comparable regardless of induction regimen. The 2-year OS rate with BR (n = 30) vs high-dose cytarabine (n = 183) vs R-CHOP plus or minus methotrexate (n = 114) was 100% vs 94.4% vs 93.7%, respectively (P = .99).

Survival was also compared in patients who received autologous transplant and maintenance rituximab (n = 94) vs maintenance rituximab alone (n = 102) vs autologous transplant alone (n = 204) vs neither (n = 110). Here, the 2-year PFS rates were 89.3% vs 85.4% vs 84.1% vs 56.4%, respectively (P < .001), and the 2-year OS rates were 97.5% vs 98.9% vs 94.2% vs 85.6%, respectively (P < .02).

No difference was seen in PFS (P = .43) or OS (P = .45) in younger patients treated with autologous transplant followed by maintenance rituximab (n = 94) vs maintenance rituximab alone (n = 102).

PFS and OS were also compared based on induction regimens that are more commonly used in practice with or without maintenance rituximab and/or autologous transplant. For BR alone (n = 23) vs BR + maintenance rituximab (n = 21) vs BR + autologous transplant (n = 25) vs BR + autologous transplant + maintenance rituximab (n = 4), the 2-year PFS rates were 56% vs 79% vs 79% vs 100%, respectively (P = .08), and the 2-year OS rates were 89% vs 100% vs 100% vs 100%, respectively (P = .3).

For high-dose cytarabine alone (n = 36) vs high-dose cytarabine + maintenance rituximab (n = 25) vs high-dose cytarabine + autologous transplant (n = 126) vs high-dose cytarabine + autologous transplant + maintenance rituximab (n = 42), the 2-year PFS rates were 64% vs 92% vs 87% v 86% (P = .04), and the 2-year OS rates were 87% vs 100% vs 94% vs 97%, respectively (P = .5).

For R-CHOP plus or minus methotrexate alone (n = 26) vs R-CHOP plus or minus methotrexate + maintenance rituximab (n = 23) vs R-CHOP plus or minus methotrexate plus autologous transplant (n = 42) vs R-CHOP plus or minus methotrexate + autologous transplant plus maintenance rituximab (n = 37), the 2-year PFS rates were 43.5% vs 86.1% vs 83.3% vs 94.4%, respectively (P < .001), and the 2-year OS rates were 83.8% vs 100% vs 95.2% vs 97.2%, respectively (P = .039).

The 2-year OS rates for older patients with early relapse/primary refractory disease vs those with durable responses (those with non–early relapse/primary refractory disease) was 55% vs 91%, respectively (P < .001).

On unadjusted univariate analysis in older patients, an ECOG performance status of at least 2, advanced stage, bone marrow involvement, blastoid histology, at least 3 cytogenetic abnormalities, and lack of rituximab maintenance were associated with inferior PFS (P < .001 to .028). High-risk MIPI, an ECOG performance status of at least 2, bone marrow involvement, blastoid histology, more than 3 cytogenetic abnormalities, and lack of rituximab maintenance were associated with inferior OS (P = .012 to < .001).

Among patients who did and did not receive maintenance rituximab, the 2-year PFS rates were 81% vs 58%, and the 2-year OS rates were 96% vs 80%, respectively (P < .001). In older patients treated with frontline BR, maintenance rituximab provided a PFS (P < .001) and OS (P = .004) benefit; only 7 (5%) of these 148 patients also underwent autologous transplant. After multivariate analysis, maintenance rituximab continued to show a significant association with improved PFS and OS (P < .001); high-dose cytarabine treatment was associated with a trend toward improved OS (P = .065) in older patients.

In older patients, autologous transplant in first remission did not affect PFS or OS. OS in older patients with autologous transplant was similar regardless of induction regimen. The 2-year OS rate with BR (n = 7) vs high-dose cytarabine (n = 26) vs R-CHOP plus or minus methotrexate (n = 48) was 100% vs 87.1% vs 95.7%, respectively (P = .51).

Survival was also compared in patients who were treated with autologous transplant and maintenance rituximab (n = 22) vs maintenance rituximab alone (n = 129) vs autologous transplant alone without maintenance rituximab (n = 56) vs neither (n = 109). The 2-year PFS rates were 82.7% vs 79.6% vs 75.5% vs 45.9%, respectively (P < .001), and the 2-year OS rates were 100% vs 95.6% vs 86.8% vs 74.8%, respectively (P < .001).

Like what was seen in the younger cohort, no difference in PFS (P = .3) or OS (P = .95) was reported in older patients who received autologous transplant followed by maintenance rituximab (n = 22) vs maintenance rituximab alone (n = 129).

PFS and OS was again compared based on induction regimens commonly used in practice with or without maintenance rituximab and/or autologous transplant. For BR alone (n = 56) vs BR + maintenance rituximab (n = 59) vs BR + autologous transplant (n = 4) vs BR + autologous transplant + maintenance rituximab (n = 3), the 2-year PFS rates were 43% vs 78% vs 50% vs not evaluable, respectively (P = .006), and the 2-year OS rates were 70% vs 96% vs 100% vs 100%, respectively (P = .002).

For high-dose cytarabine alone (n = 10) vs high-dose cytarabine + maintenance rituximab (n = 12) vs high-dose cytarabine + autologous transplant (n = 23) vs high-dose cytarabine + autologous transplant + maintenance rituximab (n = 3), the 2-year PFS rates were 67% vs 75% vs 81% vs 100%, respectively (P = .7), and the 2-year OS rates were 67% vs 100% vs 85% vs 100%, respectively (P = .16).

For R-CHOP plus or minus methotrexate alone (n = 9) vs R-CHOP plus or minus methotrexate plus maintenance rituximab (n = 16) vs R-CHOP plus or minus methotrexate plus autologous transplant (n = 24) vs R-CHOP plus or minus methotrexate plus autologous transplant plus maintenance rituximab (n = 14), the 2-year PFS rates were 22.2% vs 73.3% vs 87.1% vs 83.3%, respectively (P < .001), and the 2-year OS rates were 66.7% vs 93.3% vs 91.7% vs 100%, respectively (P = .014).

Older patients that were not treated with high-dose cytarabine or maintenance rituximab had inferior PFS (P ≤ .001) and OS (P < .001) vs younger patients. However, there was no difference in 2-year PFS and OS rates in younger and older patients treated with high-dose cytarabine or maintenance rituximab.

The effect of salvage therapy was also evaluated across age groups and showed that although the 2-year PFS rate was comparable across age cohorts, the 2-year OS rate was inferior in older patients despite the use of BTK inhibitors (93.5 vs 77.7%; P = .04).

Reference

1. Karmali R, Switchenko JM, Goyal S, et al. Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era. Am J Hematol. 2021;96(11):1374-1384. doi:10.1002/ajh.26306