Risk of secondary haematological malignancies in patients with follicular lymphoma: an analysis of 1028 patients treated in the rituximab era

Prusila, Roosa; Sorigué, Marc; Jauhiainen, Jyrki; Mercadal, Santiago; Postila, Aleksi; Salmi, Petteri; Tanhua, Taru; Tikkanen, Susanna; Kakko, Sakari; Kuitunen, Hanne; Pollari, Marjukka; Nystrand, Ilja; Kuusisto, Milla E.L.; Vasala, Kaija; Jantunen, Esa; Korkeila, Eija; Karihtala, Peeter; Sancho, Juan‐Manuel; Turpeenniemi‐Hujanen, Taina; Kuittinen, Outi

doi:10.1111/bjh.16090

Cited by 12 publications

(9 citation statements)

References 27 publications

(37 reference statements)

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“…The incidence of MDS/AML increases to a notably greater extent with the use of chemotherapy and/or radiotherapy (with SIRs consistently above 5 [10,15,16,24]) and there seems to be a greater dependency on dose-intensity and on the number of lines administered [26][27][28][29]. Incidence of MDS/AML in this cohort of patients is in line with the published data [30].…”

Section: Discussionsupporting

confidence: 81%

Incidence of solid cancer in patients with follicular lymphoma

et al. 2019

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Introduction: Patients with follicular lymphoma (FL) have classically had a higher risk of solid cancers than the general population, but there is little data available in patients diagnosed and treated with modern day regimens. Material and methods: We conducted a retrospective multicenter study assessing the cumulative incidence of solid cancers other than nonmelanoma skin cancer in patients with FL between 1997 and 2016 and determined the standardized incidence ratio (SIR) to compare the incidence of solid cancers with that of the general population Results: Among 1002 FL patients with 7 years of median follow-up, we found 74 solid cancers (most common breast [n ¼ 19], lung and colon [n ¼ 9 each]). The cumulative incidence was 3.8% at 5 years (95%CI 2.6-5.2) from the time of diagnosis and 4.4% at 5 years (95%CI 3.1-5.9%) from the time of front-line treatment. Although a comparison of all front-line strategies did not reveal differences in the risk of solid cancers, patients treated with anthracycline-based regimens appeared to have a lower incidence than those treated with bendamustine-based strategies (2.8% vs. 6.9%). However, patients receiving the former regimen were younger than the latter. On multivariable analysis, older age was correlated with the incidence of solid cancer and bendamustine-based treatment was of borderline significance. SIR for any solid cancer was 1.22 (95%CI 0.91-1.64), indicating no increased risk of solid cancer in patients with FL over that of the general population. However, on subgroup analyses, female patients treated with bendamustine-based strategies appeared to have a greater risk (SIR 3.85 [95%CI 1.45-10.27]) Discussion: The incidence of solid cancer in this cohort of patients with FL was low and not greater than in the general population. However, the risk may be greater in female patients treated with bendamustine.

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Section: Discussionsupporting

confidence: 81%

Incidence of solid cancer in patients with follicular lymphoma

et al. 2019

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“…The appearance of a SM represents one of the concerns of the use of cytotoxic agents, which has led to a growing interest in the development of chemotherapy-free regimens. In the rituximab era, its cumulative incidence has been estimated to be of 2.9% at 10 years for SM arising at any site 24 , and of 2.7% at 10 years for second hematological malignancies specifically 25 . In our series, the 10-year incidence of SM of any site was 10%, with no significant differences among decades, and hematological malignancies were the most common subtype.…”

Section: Discussionmentioning

confidence: 99%

Patterns of change in treatment, response, and outcome in patients with follicular lymphoma over the last four decades: a single-center experience

et al. 2020

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Although the introduction of immunotherapy has improved outcomes for follicular lymphoma (FL) patients, histological transformation (HT) and early relapse still confer a poor prognosis. We sought to describe the patterns of change in treatment, response, and outcome of FL patients at our institution over the last four decades. Seven hundred and twenty-seven patients (389 F/338 M; median age, 57 years) consecutively diagnosed with grade 1-3a FL between 1980 and 2017, categorized into four decades according to the time of diagnosis, constituted the study population. Clinical characteristics, treatment, response, absolute and relative survival, HT, second malignancies (SM), and causes of death were assessed. Median OS for the entire cohort was 17.6 years. From decade 1 to 4, there was an increase in the complete response rate (48 to 70%), progression-free survival (40 to 56% at 5 years), OS (77 to 86% at 5 years), and relative survival ratio (0.83 to 0.94 at 5 years), with no significant differences in the risk of HT or SM. Lymphoma remained the most common cause of death in all four decades. These findings illustrate the overall improvement in outcome for FL patients, but support the need for further research into risk stratification and management.

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“…Additionally, AML/myelodysplastic syndrome (MDS) were more common in HM patients who received autologous SCT than those treated without SCT ( 28 ), explained by preparative myeloablation by total body irradiation ( 28 ). Additionally, the risk of second malignancies was shown to increase with rituximab-based treatment stage in follicular lymphoma patients ( 29 ). This may be attributed to the lasting genotoxic damage that chemo/radiotherapy produces; with MSC shown to retain long-term genotoxic and functional damage years following chemotherapy ( 33 , 34 ).…”

Section: Introductionmentioning

confidence: 99%

Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected

et al. 2021

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Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.

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Risk of secondary haematological malignancies in patients with follicular lymphoma: an analysis of 1028 patients treated in the rituximab era

Cited by 12 publications

References 27 publications

Incidence of solid cancer in patients with follicular lymphoma

Incidence of solid cancer in patients with follicular lymphoma

Patterns of change in treatment, response, and outcome in patients with follicular lymphoma over the last four decades: a single-center experience

Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected

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