10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article Mortality among patients with low-­grade follicular lymphoma: A binational retrospective analysis 1,2 Aino Rajamäki, MD ; Mika Hujo, PhD2; Reijo Sund, PhD2; Roosa E. I. Prusila, MD, PhD 3 ; Milla E. L. Kuusisto, MD, PhD3,4; 5 2,6,7 Hanne Kuitunen, MD, PhD ; Esa Jantunen, MD, PhD ; Santiago Mercadal, MD ; Marc Sorigue, MD, PhD9; 8 Juan-­Manuel Sancho, MD, PhD ; Kaisa Sunela, MD, PhD10; and Outi Kuittinen, MD, PhD2,3,11 9 BACKGROUND: The life expectancy of patients with follicular lymphoma (FL) has improved considerably since the introduction of rituximab. This study examined the proportion of deaths from progressive lymphoma and the impact of FL on survival compared with that in the general population. METHODS: Altogether, 749 patients with grades 1 and 2 FL in 9 institutions between 1997 and 2016 were enrolled. Competing risk models were used to estimate the cumulative incidences of deaths from progressive lymphoma and from other reasons. Excess mortality was analyzed with respect to the corresponding background populations standardized for age and sex using the excess mortality model based on the penalized spline approach. RESULTS: The median follow-­up duration was 69 months (range, 0-­226 months). The estimated 10-­year overall, disease-­specific, and net survival rates were 72.4%, 86.6%, and 86.4%, respectively. The cumulative incidence of deaths from progressive lymphoma was slightly smaller than that of other causes in the study population (estimated 10-­year cumulative incidences: 12.3% [95% CI, 9.6%-­15.3%] and 15.4% [95% CI, 12.2%-­18.8%], respectively). Excess mortality was observed for up to 10 years after diagnosis, and it slightly increased with time. CONCLUSIONS: Deaths from progressive lymphoma are nearly as common as deaths from other causes in FL patients during the rituximab era. Despite the improvements in survival, there was evidence of excess mortality resulting from FL for at least 10 years after diagnosis. Cancer 2022;128:2474-2482. © 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. KEYWORDS: cause of death, follicular lymphoma, mortality, survival, survival rate. INTRODUCTION Follicular lymphoma (FL) is the second most common lymphoma subtype, accounting for approximately one-­fifth of all lymphoma cases in Western countries. The clinical course of FL is heterogeneous. Before the introduction of rituximab, the 10-­year overall survival (OS) in FL was 40% to 56%.1-­4 Advances in FL care have led to improved survival in both randomized studies and population-­based analyses,3-­6 leading to an almost 80% 10-­year OS.7-­9 Three previous studies showed that, despite the improved survival rate, most of the FL deaths were attributed to lymphoma-­related causes.4,8,10 In recent years, the estimated relative 10-­year survival after first-­line treatment has been 76% to 83%.3,4,11 However, in 1 study, mortality rates for patients with FL were lower than those for the general popu- lation more than 10 years after the diagnosis,12 and in 2 other studies, the life expectancy of patients with FL was similar to that of the general population if they exhibited complete response at 24 or 30 months after diagnosis.7,13 In the present study, we used a real-­life data set of 749 patients to examine the mortality among patients with FL. The purpose of this study was to evaluate 1) the proportion of deaths from progressive lymphoma and 2) the impact of FL on expected survival compared with that in the general population. Corresponding Author: Aino Rajamäki, MD, Department of Oncology, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland. (aino.rajamaki@ hotmail.com). 1 Department of Oncology, Central Finland Central Hospital, Jyväskylä, Finland; 2 University of Eastern Finland, Kuopio, Finland; 3 University of Oulu and Oulu University Hospital, Oulu, Finland; 4 Department of Hematology, Oulu University Hospital, Oulu, Finland; 5 Department of Oncology, Oulu University Hospital, Oulu, Finland; 6 Department of Medicine, Kuopio University Hospital, Kuopio, Finland; 7 Department of Medicine, North Carelia Central Hospital, Joensuu, Finland; 8 Institut Català d’Oncologia-­Hospital Duran i Reynals, L’Hospitalet, Spain; 9 Department of Hematology, Institut Català d’Oncologia-­Hospital Germans Trias i Pujol, Functional Cytomics-­ Institut Josep Carreras, Badalona, Spain; 10 Department of Oncology, Tampere University Hospital, Tampere, Finland; 11 Department of Oncology, Kuopio University Hospital, Kuopio, Finland The last 2 authors contributed equally to the study. Additional supporting information may be found in the online version of this article. DOI: 10.1002/cncr.34221, Received: January 16, 2022; Revised: March 17, 2022; Accepted: March 18, 2022, Published online April 13, 2022 in Wiley Online Library ­(wileyonlinelibrary.com) 2474 Cancer   July 1, 2022 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Mortality in follicular lymphoma/Rajamäki et al MATERIALS AND METHODS TABLE 1. Patient Characteristics Patients Variable No. = 749 This retrospective registry study was reviewed and ap- Age at diagnosis, y proved by the Regional Ethics Committee of the Northern Median (range) 60 (18-­100) Ostrobothnia Hospital District and the principles of the <60 366 (49.2%) 60-­70 224 (30.1%) Declaration of Helsinki were followed. Clinical data were >70 154 (20.7%) collected from 4 Finnish and 2 Spanish university hospitals Sex Female 380 (50.8%) and 3 Finnish central hospitals. All patients (1045) diag- Male 368 (49.2%) nosed with FL between 1997 and 2016 were included in NA 1 Stage this study: 344 from Spain and 701 from Finland. Patients I-­II 243 (32.4%) with primary cutaneous lymphomas, FL grade 3 or un- III-­IV 472 (63.0%) NA 34 known grade, composite histology at diagnosis, or histologi- FLIPI cal transformation before any treatment, or whose survival 0-­1 247 (36.8%) status or cause of death was not identified or who were lost 2 196 (29.2%) 3-­5 229 (34.1%) to follow-­up were excluded. Duodenal lymphomas were in- NA 77 cluded. Finally, 749 patients were included. In patients with LDH level Normal 421 (73.1%) watchful waiting as the first-­line approach, any proceed- Elevated 155 (26.9%) ing therapy was considered the first-­line treatment. Patient NA 173 Hb, g/dL characteristics, treatment information, disease progression, <12 95 (13.8%) possible retreatments, and death (classified as deaths from ≥12 594 (86.2%) progressive lymphoma or other causes) were verified through NA 60 B-­symptomsa an extensive review of medical records (Supporting File 1). Yes 124 (17.1%) No 602 (82.9%) NA 23 Statistical Analysis Initial treatmentb Overall survival was calculated from the date of diagnosis to Immunochemotherapy 497 (70.9%) death from any cause or the last follow-­up. Disease-­specific Chemotherapy without rituximab 69 (9.8%) Anthracycline-­containing regimens 378 (53.9%) survival (DSS) was calculated from the date of diagnosis Bendamustine 61 (8.7%) to death from progressive lymphoma or the last follow- Other chemotherapy 127 (18.1%) Rituximab monotherapy 28 (4.0%) ­up. Progression-­free survival was calculated from the first Radiation therapy only 93 (13.3%) day of treatment to the first relapse, death from any cause, Surgery only 14 (2.0%) Maintenance with rituximab after first-­line therapy 209 (29.8%) or the last follow-­up, whichever occurred first. The sub- sequent survival rates were calculated in a similar manner Abbreviations: FLIPI, Follicular Lymphoma International Prognostic Index; Hb, hemoglobin; LDH, lactate dehydrogenase; NA, not available. but considering the follow-­up duration from the first day a B-­symptoms include systemic symptoms (eg, unexplained weight loss, of the second-­and third-­line treatments. Net survival was fever, night sweats). b Of the patients who received first-­line therapy (n = 701). considered the ratio between the proportion of observed survivors in a cohort of cancer patients and the proportion of expected survivors in a comparable set of cancer-­free in- analyze a competing risk situation in which the cumu- dividuals. Excess mortality was defined as the difference lative incidences of deaths from progressive lymphoma between mortality in patients with FL in relation to mor- and deaths from other causes were estimated. Pearson χ2 tality in the general population. The excess mortality haz- test was used to evaluate the differences between the age ard and its corresponding net survival were analyzed with groups. Statistical significance was set at P < .05. respect to corresponding Finnish and Spanish background Statistical analyses were performed using IBM SPSS populations standardized for age and sex.14 All patients Statistics (version 27; IBM Corp, Armonk, NY) and R (including those in watchful waiting) were included in the software (version 4.0.3; R Foundation for Statistical survival analysis, which started from the diagnosis. Computing, Vienna, Austria).16 A multidimensional penalized hazard model was used to estimate the hazards and different survivals.15 RESULTS The technique is based on multiple penalized splines Patient Characteristics and allows the estimation of excess hazard and net sur- Patient characteristics are presented in Table 1 and vival (Supporting File 1). The same method was used to treatment patterns in Supporting Table 1. The median Cancer   July 1, 2022 2475 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article FIGURE 1. Flow chart of the 749 patients with follicular lymphoma. follow-­up duration was 69 months (range, 0-­226 months); 68.3%-­ 76.1%) and 86.6% (95% CI, 83.2%-­ 89.3%), 58.3% of the patients were followed for more than 5 years ­respectively (Supporting Fig. 1). and 16.8% for more than 10 years. Information regarding the line of treatment, disease progression, and mortality is Net Survival and the Impact of Lymphoma on presented in the flowchart in Figure 1. Life Expectancy Figure 2 shows the total and excess mortality of FL pa- tients over 10 years. Excess mortality was observed during Survival the entire study period, and it slightly increased with time The 5-­year OS was 86.6% (95% CI, 84.0%-­88.8%). (Fig. 2A). The 5-­year net survival rate was 94.6% (95% The 5-­year DSS was 93.8% (95% CI, 91.8%-­95.3%). CI, 92.0%-­96.3%) and the estimated 10-­year net survival The estimated 10-­year rates were 72.4% (95% CI, was 86.4% (95% CI, 81.7%-­89.9%) (Fig. 2B). 2476 Cancer   July 1, 2022 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Mortality in follicular lymphoma/Rajamäki et al (A) 0.20 total excess 0.15 Hazard 0.10 0.05 0.00 0 2 4 6 8 10 time since diagnosis (years) No. at risk: 743 643 504 358 227 126 (B) 100 80 Probability of survival (%) 60 40 20 overall survival net survival 0 0 2 4 6 8 10 time since diagnosis (years) No. at risk: 743 643 504 358 227 126 FIGURE 2. (A) The total and excess mortality of patients with follicular lymphoma. (B) The overall and net survival of patients with follicular lymphoma. Survival Estimates After Second-­and was 74.1% (95% CI, 62.8-­82.4%) and the 2-­year DSS Third-­Line Treatments was 79.1% (95% CI, 68.0%-­86.8%) (Fig. 3B). DSS and OS after the second-­and third-­line treatments are shown in Figure 3. The 2-­year OS after the second-­line Treatment and Relapse Patterns and treatment was 87.8% (95% CI, 82.9%-­91.3%) and the Causes of Death 5-­year OS was 73.8% (95% CI, 66.7%-­79.7%). The re- During the follow-­ up period, 147 deaths occurred. spective 2-­year DSS was 92.9% (95% CI, 88.2%-­95.8%) Among these, 66 (44.9%) were due to progressive lym- and the 5-­year DSS was 79.9% (95% CI, 72.2%-­85.7%) phoma and 81 (55.1%) were due to other causes. The (Fig. 3A). The 2-­year OS after the third-­line treatment proportion of patients with disease progression and death Cancer   July 1, 2022 2477 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article (A) 100 80 Probability of survival (%) 60 40 20 DSS OS 0 0 2 4 6 8 10 time since 2nd line treatment (years) No. at risk: 185 138 90 62 37 22 (B) 100 80 Probability of survival (%) 60 40 20 DSS OS 0 0 2 4 6 8 10 time since 3rd line treatment (years) No. at risk: 71 38 21 15 7 3 FIGURE 3. (A) DSS and OS after second-­line treatment. (B) DSS and OS after third-­line treatment. DSS indicates disease-­specific survival; OS, overall survival. from progressive lymphoma increased after each line of Prognostic Impact of Age treatment. After the first-­line treatment, 24 deaths from Patients aged >70 years were left without treatment more progressive lymphoma were noted (3.4%). After the frequently than were younger patients (10.4% vs 5.4%, second-­and third-­line treatments, 20 (8.5%) and 16 P = .025). The former group received less immuno- (21.6%) deaths were noted, respectively, from progressive chemotherapy in general (58.4% vs 68.3%, P = .021), lymphoma. The risk of death from progressive lymphoma anthracycline-­ containing regimens (33.1% vs 54.9%, over time remained relatively stable for 10 years after di- P < .001), and rituximab maintenance (19.5% vs 30.3%, agnosis (Fig. 4). The cumulative incidence of deaths from P = .008) but more less-­intensive therapies (20.1% vs other causes was a little higher than that of progressive 9.8%, P < .001) than the latter. lymphoma in the study population (the estimated 10-­ The cumulative incidences of both causes of year cumulative incidences were 15.4% [95% CI, 12.2%-­ death increased with age. In patients aged <60 years 18.8%] and 12.3% [95% CI, 9.6%-­15.3%], respectively) and 60 to 69 years at diagnosis, the cumulative inci- (Fig. 5A and Supporting Table 2). dences of deaths from the studied causes were virtually 2478 Cancer   July 1, 2022 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Mortality in follicular lymphoma/Rajamäki et al 0.1 0.08 0.06 Hazard 0.04 0.02 0 0 2 4 6 8 10 time since diagnosis (years) No. at risk: 748 646 506 358 227 126 FIGURE 4. The risk of death from progressive lymphoma with time. Hazard indicates probability for death from progressive lymphoma in certain times on the condition that the event has not yet occurred. similar (estimated 10-­ year cumulative incidence for A recent report from the Memorial Sloan Kettering patients aged <60 years: progressive FL, 7.6% [95% Cancer Center involving 1088 patients with FL reported CI, 4.7%-­ 10.9%] vs other causes. 6.7% [95% CI, a 5-­year OS of 92% and a 10-­year OS of 80%, which are 3.9%-­10.6%]; 60-­69 years: 15.6% [95% CI, 9.5%-­ higher than our findings.17 Although that study included 22.9%] vs 16.3% [95% CI, 9.5%-­23.1%], respectively) patients with grade 1 through 3A FL, there might be (Fig. 5B,C). However, in patients aged older than 70 differences in patient selection because Memorial Sloan years at diagnosis, the cumulative incidence of deaths Kettering Cancer Center is a private center and the pop- from other causes surpassed that of deaths from pro- ulation setting might be different from our real-­life, mul- gressive lymphoma (10-­ year cumulative incidence: ticenter setting involving public university hospitals and 41.2% [95% CI, 29.8%-­52.9%] vs 21.1% [95% CI, central hospitals. Junlén et al studied the survival of 2641 12.2%-­31.8%], respectively) (Fig. 5D). patients with FL with any grade disease diagnosed be- tween 2000 and 2010. In the rituximab era (2003-­2010), DISCUSSION the 10-­year OS was 59% and the 10-­year relative survival In this study, we analyzed patient survival in a real-­life, un- was 76%,3 which are lower than the rates observed in our selected data set of 749 patients with FL. The probability study. Inclusion of patients with any grade of FL might of death from progressive lymphoma was slightly smaller have an impact on the difference in the results. than that of other reasons. However, age had a major im- Three recent studies have shown that, despite the pact on the results. Deaths from other reasons dominated improved survival of FL patients, most of the deaths are among patients aged more than 70 years, whereas among lymphoma related.4,8,10 A recent single-­center study by younger patients the probability of death from both stud- Mozas et al including 727 patients with grade 1 through ied causes was similar. We also observed that FL shortened 3A FL reported that, although the proportion of deaths the lifespan of patients compared with the general popula- from progressive FL had decreased over the decades, it tion, with a net survival of 86% at 10 years after diagnosis. was still higher than other-­cause mortality.4 Hester et al Before the rituximab era, most of the deaths among studied cause-­specific mortality among 6703 elderly pa- FL patients were related to progressive lymphoma and the tients with FL (aged ≥66 years) of any grade and found 10-­year OS was 40% to 56%.1-­4 In the 21st century, rit- that the cumulative incidence of FL-­specific mortality was uximab has provided a remarkable survival advantage. In slightly higher compared with other-­cause mortality at our study, the 5-­year OS was 87%, the estimated 10-­year 5 years (21.8% vs 15.7%).10 Sarkozy et al reported an OS was 72%, and the 10-­year net survival was 86%. even greater proportion of lymphoma-­ related deaths. Cancer   July 1, 2022 2479 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Original Article (A) (B) 0.5 0.5 Lymphoma Lymphoma Other Other 0.4 0.4 Cumulative incidence Cumulative incidence 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 10 0 2 4 6 8 10 time since diagnosis (years) time since diagnosis (years) No. at risk: 748 646 506 358 227 126 No. at risk: 367 336 283 228 158 86 (C) (D) 0.5 0.5 Lymphoma Lymphoma Other Other 0.4 0.4 Cumulative incidence Cumulative incidence 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 10 0 2 4 6 8 10 time since diagnosis (years) time since diagnosis (years) No. at risk: 223 187 137 87 48 32 No . at risk: 154 121 84 43 21 8 FIGURE 5. Cumulative incidence for the competing risks of cause of death. (A) Cumulative incidence by cause of death for the entire study population. (B) Cumulative incidence by cause of death for patients aged <60 years. (C) Cumulative incidence by cause of death for patients aged 60 to 69 years. (D) Cumulative incidence by cause of death for patients aged ≥70 years. After 10 years of follow-­up, lymphoma progression was of deaths from progressive lymphoma was comparably a still the most common cause of death (including 140 little lower than that of other reasons for at least 10 years. of 248 deaths) in their cohort of 1654 patients with FL Although we observed a higher proportion of competing grade 1 through 3A.8 Similar findings were observed causes of death compared with the previous studies, our even among the oldest patients (aged >70 years). In our results strengthen the understanding that progressive lym- study, nearly one-­half of the deaths (45%) during a me- phoma remains an important cause of death, even in the dian follow-­up of 69 months were caused by progressive rituximab era and among patients with low-­grade FL. lymphoma and the rest were from other reasons, includ- In our study, the risk of death from progressive ing treatment-­related deaths. The cumulative incidence lymphoma increased with age, which is consistent with 2480 Cancer   July 1, 2022 10970142, 2022, 13, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34221 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Mortality in follicular lymphoma/Rajamäki et al previous findings.3,8 Junlén et al showed that, although With the rapid evolution of treatment, such data would the relative survival rates had improved in all age groups, already be outdated when they become available. The patients aged older than 70 years maintained higher 69-­month follow-­up provided a good balance between excess mortality compared with others.3 Moreover, follow-­up and an up-­to-­date treatment paradigm that can Sarkozy et al reported that the cumulative incidence of still inform care for present-­day patients. Additionally, we lymphoma-­related deaths increased with age at diagno- acknowledge that uncertainty increases with increasing sis and was higher than that of non–­lymphoma-­related lines of therapy, and because of the limited follow-­up, deaths in all age groups.8 In our study population, among ­patients with an adverse outcome dominate. patients aged more than 70 years, the cumulative inci- In conclusion, deaths from progressive lymphoma dence of other-­cause mortality was remarkably higher are as common as deaths from other causes in the ritux- than that from progressive lymphoma, which is in con- imab era in patients with FL aged younger than 70 years, trast to the findings presented in the previous studies.8,10 whereas deaths from other causes are clearly more com- In our material, however, older patients were treated with mon in patients aged older than 70 years. Despite the less-­intensive regimens and left without treatment more improvements in progression-­free survival, OS, and DSS frequently, indicating that an adverse prognosis among el- over the past decades, there was evidence of excess mortal- derly patients was associated with treatment selection and ity from FL for at least 10 years after diagnosis. treatment-­related toxicities rather than tumor biology. Because the median age of patients with FL at the time of FUNDING SUPPORT diagnosis is approximately 60 years,3,6,18,19 the impact of This work was funded by the Finnish Blood Disease Research Foundation, non–­lymphoma-­related mortality is evidently increasing. The Finnish Medical Foundation (Rajamäki Aino) and Thelma Mäkikyrö fund (Kuusisto Milla E.L.). The major strengths of our study are the relatively large sample size, detailed data collection, and the appropri- ate and relatively new methodology used to study the excess CONFLICT OF INTEREST DISCLOSURES Juan-­Manuel Sancho reports payments from Roche and Gilead for partici- mortality of patients with FL. All patients had low-­grade pating on a data safety monitoring board or advisory board. The other au- lymphoma, ensuring the homogeneity of the material. thors made no disclosures. Our study has some limitations. There are quite a lot of data indicating that the cause-­of-­death statements AUTHOR CONTRIBUTIONS are unreliable in cancer patients.20-­24 This causes doubt Aino Rajamäki: Conceptualization, data curation, formal analysis, on the value of this assessment for patients who have investigation, methodology, visualization, writing –­original draft, and ­ writing –­review and editing. Mika Hujo: Formal analysis, methodology, multiple potential factors contributing to death. For this visualization, and writing –­original draft. Reijo Sund: Formal analysis, meth- reason, we decided to classify the deaths only to those as- odology, visualization, and writing –­review and editing. Roosa E.I. Prusila: Data curation, investigation, and writing –­review and editing. Milla E.L. sociated with progressive FL and others, and treatment-­ Kuusisto: Investigation and writing –­review and editing. Hanne Kuitunen: related deaths per se were not considered a separate Conceptualization, funding acquisition, project administration, and writing –­review and editing. Esa Jantunen: Investigation and writing –­ entity but were included among other causes. However, review and editing. Santiago Mercadal: Investigation and writing –­ net survival considers all excess mortality, including review and editing. Marc Sorigue: Conceptualization, data curation, investigation, methodology, and writing –­review and editing. Juan-­Manuel treatment-­related mortality, compared with the age-­and Sancho: Investigation and writing –­review and editing. Kaisa Sunela: sex-­adjusted general population. The results concerning Conceptualization, formal analysis, methodology, and writing –­original secondary malignancies in this data set have been previ- draft. Outi Kuittinen: Conceptualization, data curation, formal analysis, funding acquisition, methodology, project administration, resources, super- ously published.25,26 The risk of secondary hematologic vision, and writing –­original draft. malignancies was low, but it increased with multiple lines of therapy. There was no increased risk of solid cancers REFERENCES compared with the general population. Possible transfor- 1. Swenson WT, Wooldridge JE, Lynch CF, Forman-­ Hoffman VL, mations were not systematically documented; therefore, Chrischilles E, Link BK. 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