Incidence and survival trends in mantle cell lymphoma

The last surveillance, epidemiology and end results (SEER) update on mantle cell lymphoma (MCL) was published in 2008. This analysis used data from November 2006 SEER data submission (Zhou et al, 2008) and precedes the broader use of rituximab, the availability of novel agents, and more widespread use of haematopoietic cell transplantation (HCT). We hypothesized that survival for patients diagnosed with MCL in the U.S. has since improved and intended to measure outcome improvements and identify possible disparities. We used the population-based SEER-18 registry to calculate the incidence and relative survival rates (RSR) of MCL in the US for two time-periods consistent with notable changes in MCL treatment, 2000–6 (time period 1: pre-evidence supporting rituximab and novel agents) and 2007–13 (time period 2: introduction of rituximab and novel agents). We identified MCL cases using the third edition of the International Classification of Diseases for Oncology (ICD-O-3) histology code 9673/3, diagnosed between 2000 and 2013, with MCL as first malignancy. We calculated age-adjusted incidence rates and corresponding 95% confidence intervals using the rate function and RSR employing the survival function in SEER*Stat 8.3.2 (https://seer.cancer.gov/seerstat/). The RSR is defined as the ratio of the observed and expected survival in the general population of similar age, race, and gender. The use of RSR, as opposed to overall survival (OS), minimizes the effect of competing causes of death and better indicates the effect of the disease on survival. Contrary to disease-specific survival, RSR is not influenced by cause of death attribution. Continuous variables were compared using the Mann–Whitney test for non-parametric data and proportions using Z-test. A two-sided P-value ≤0·05 was considered statistically significant. All analyses were conducted using SPSS, v22.0 (IBM, Armonk, NY, USA). There were a total of 8755 MCL patients diagnosed between 2000 and 2013, of which 3799 were diagnosed during time period-1 and 4956 diagnosed during time period-2. The median age at diagnosis in both the time periods was 67 years. Patient characteristics are outlined in Table 1. MCL incidence (MCL cases/100 000 persons) increased from 0·711 in 2000–6 to 0·800 in 2007–13 (P < 0·001). An increase in the incidence rate was significant among older patients (≥65 years) (3·662–4·321, P < 0·001), both males (1·128–1·267, P < 0·001) and females (0·386–0·427, P = 0·008); non-Hispanic Whites (NHW, 0·814–0·924, P < 0·001) and Hispanics (0·557–0·708, P = 0·002), but not among those aged <65 years (0·284–0·290, P = 0·54) and non-Hispanic Blacks (NHB, 0·309–0·360, P = 0·16). The RSR at 5 years (RSR-5), compared between 2000–6 and 2007–13, improved for the overall population (50·7–54·5%, P = 0·01). In particular, significant improvement was noted among patients diagnosed with stage IV disease (48·0–55·1%, P < 0·001, Fig 1B), age 50–64 years (61·3–67·4%, P = 0·004, Fig 1D), and age 65–74 years (49·4–56·6%, P = 0·01, Fig 1E). Improvement in RSR-5 was not significant among patients with stage I–III disease (54·3–53·8%, P = 0·85, Fig 1A), <50 years (75·6–75·4%, P = 0·90, Fig 1C) or age ≥75 (35·7–36·2%, P = 0·90, Fig 1F). Improvement in RSR-5 was significant among Hispanics (43·0–52·7%, P = 0·04) but not NHW (51·4–53·3%, P = 0·24) and NHB (51·4–58·1%, P = 0·90). Improvements in OS occurred at similar magnitude of improvements in RSR (Fig S1). Five-year OS reached 74·2%, 64·1%, 50·4% and 24·5% for patients aged <50, 50–64, 65–74 and ≥75 years respectively, at the time of diagnosis. Our study has several important observations. Firstly, there has been a significant increase in the MCL incidence over the last 7 years, mostly due to increased incidence among older patients. Secondly, there was a modest, yet significant increase in RSR-5 for the entire population over the last 7 years, most notably among patients <65 years of age and those with stage IV disease. The year 2007 was chosen for the onset of the second time period, as most of the data on rituximab and novel agents for the treatment of MCL came after 2007. The finding of increased MCL incidence in the time period 2 may be attributed to greater awareness among the pathologists and clinicians, in that cases that would have been missed in the time period 1 (being labelled as other B-cell lymphomas) are now more recognizable with widespread testing for the presence of t(11;14) (Swerdlow & Williams, 2002). The incidence of MCL in older patients has been increasing over the past two decades and may be related to genotoxic exposures and 'cohort effect', i.e., change in the disease incidence noted for individuals born at a particular time due to differential exposure of birth cohorts to a particular risk factor (Aschebrook-Kilfoy et al, 2013). This trend is confirmed in the period studied by the increased incidence of MCL seen only among individuals' aged ≥65 years. There was a significant increase in incidence among NHW and Hispanics but not NHB in time period 2. This may reflect racial disparities in seeking health care or simply the lower number of cases among racial minorities liming the detection of trends. We found significant gain in RSR-5 for MCL patients in time period 2, probably due to the introduction of rituximab (Lenz et al, 2005; Geisler et al, 2008; Hermine et al, 2016), intensification of induction regimens (Geisler et al, 2008; Hermine et al, 2016), and the advent of novel agents, such as bortezomib, lenalidomideand ibrutinib (Fisher et al, 2006; Goy et al, 2013; Wang et al, 2013). In addition to rituximab and novel agents, it is likely that higher utilization of HCT in MCL has contributed to improved survival in time period 2 (Geisler et al, 2008; Fenske et al, 2014; Hermine et al, 2016). In fact, data from the Center for International Blood and Marrow Transplant Research indicates an 116% increase in autologous HCT for MCL from time period-1 to time period-2 (M. Hamadani, unpublished observations). The fact that we noted improved survival in patients younger than 65 years is possibly due to their ability to tolerate intensified therapies and HCT. Of note, the numbers of allogeneic HCT have also increased, by 41% in time period 2 compared to time period 1, possibly salvaging some patients with relapsed/refractory MCL(Fenske et al, 2014). In conclusion, although our findings confirm continuous improvement in the outcomes of MCL patients over the past decade, they also highlight the challenge of improving long-term outcomes, particularly among older patients. NE and LJC designed the study. NE and LJC collected data. NE and LJC wrote the first version of the manuscript. NE, MH, TF and LJC analysed the data and edited the manuscript. All authors reviewed and approved the final manuscript. The authors do not have any relevant conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.