Prognostic Implications of Specific Comorbidities in Mantle Cell Lymphoma Patients, a Swedish Lymphoma Registry Study
Authors: Glimelius Ingrid , Ekstroem Smedby Karin , Jerkeman Mats , Eloranta Sandra , Weibull Caroline 
Published: October 2019

Abstract
Purpose
The prognosis for patients with mantle cell lymphoma (MCL) is rather dismal where particularly elderly patients, often with comorbidities, have difficulties tolerating the intensive treatments needed for long-term remission. Our aim was to describe the frequency and spectrum of comorbidities among patients with MCL in a population-based setting, and assess the impact of comorbidities on treatment choice, lymphoma-specific and overall survival as well as causes of death in MCL patients by age and sex.
Methods
In the nationwide Swedish Lymphoma Register, we identified 1,385 MCL patients (1,009 males and 376 females) diagnosed 2000-2015 at all ages. Comorbid diseases within 10 years prior to diagnosis were identified from the national Swedish In- and Outpatient registers and included somatic diseases defined according to the Charlson comorbidity index (CCI; 0, 1 and 2+), with the addition of psychiatric disorders. Comorbidities were both categorized and presented individually. Hazard ratios (HR) with 95% confidence intervals (CIs) comparing lymphoma-specific and all-cause mortality among patients with different levels of CCI were estimated from flexible parametric survival models, adjusted for calendar year of diagnosis, age at diagnosis, sex, educational level, and MCL international prognostic index (MIPI). Model-based predictions were used to obtain cumulative probabilities of death due to lymphoma and other causes.
Results
In the cohort, 24% were <59 years of age, 32% between 60-69, 30% between 70-79 and 14% >80 years. In total, 606 out of 1,385 patients (44%) had a history of one or more comorbidities at the time of diagnosis, among which 388 (28%) had a CCI=2+. The most common specific comorbidities were prior malignancy (17%), (prostate cancer was most frequent), and prior coronary heart disease (14%). Moreover, 9% of the patients had diabetes, 7% had pulmonary disease, 3% renal disease, 3% connective tissue disease and 1% had dementia. In addition, 2% had a psychiatric disorder. With a mean follow-up of 3.7 years (range: 0.0-15.6), 633 (46%) patients died from lymphoma. Lymphoma was the major cause of death among males, irrespective of CCI (Figure 1A). Lymphoma was also the major cause of death among females with CCI=0 whereas among females with comorbidities (CCI≥1), approximately half of the patients died due to other causes (Figure 1B). A CCI=2+ was associated with worse overall and lymphoma-specific survival (adjusted lymphoma-specific HR=1.31; 95% CI: 1.04-1.65). Specific comorbidities associated with significantly worse lymphoma-specific survival were history of coronary heart disease, connective tissue disease, renal disease, dementia and psychiatric disorders (Figure 1C). Patients aged below 70 years at diagnosis who presented with no comorbidities were primarily treated according to the NLG-MCL2/3 protocol* (177 out of 437, 41%). However, this was not the case among patients in the same age range but with CCI=1 (24 out of 177, 34%) or CCI=2+ (13 out of 112, 12%). Primary treatment concepts for comorbid patients were CHOP, bendamustine, or chlorambucil with the addition of rituximab.
*NLG-MCL2/3= R-maxi-CHOP alternating with high dose cytarabine, rituximab, and consolidation with high-dose therapy and autologous stem-cell transplantation
Conclusions
A large fraction of MCL patients are elderly and comorbidity was present in almost half of the patients overall. A CCI of 2+ was an independent negative prognostic factor. Lymphoma-death was the major cause of death among males, motivating the need for MCL-specific treatment irrespectively of a high burden of comorbidities, while approximately 50% of comorbid-females died due to other reasons. Patients with comorbidities were less often treated according to intensive first-line chemotherapy protocols. In the introduction and development of new treatment regimens, consideration of toxicity and tolerability specifically in patients with comorbidities is warranted, particularly in patients with coronary heart disease, connective tissue disease and renal disorders.
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Disclosures
Ekstroem Smedby: Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals. Eloranta:Janssen Pharmaceuticals: Other: S Eloranta is currently employed as a project coordinator and her salary is funded via a public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals.