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. 2023 Nov 15:65:102307.
doi: 10.1016/j.eclinm.2023.102307. eCollection 2023 Nov.

Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY

Thomas Chatzikonstantinou  1 , Lydia Scarfò  2 , Georgios Karakatsoulis  1   3 , Eva Minga  1 , Dimitra Chamou  1 , Gloria Iacoboni  4 , Jana Kotaskova  5   6 , Christos Demosthenous  7 , Lukas Smolej  8 , Stephen Mulligan  9 , Miguel Alcoceba  10 , Salem Al-Shemari  11 , Thérèse Aurran-Schleinitz  12 , Francesca Bacchiarri  13 , Mar Bellido  14 , Fontanet Bijou  15 , Anne Calleja  12 , Angeles Medina  16 , Mehreen Ali Khan  17 , Ramona Cassin  18 , Sofia Chatzileontiadou  19 , Rosa Collado  20 , Amy Christian  21 , Zadie Davis  21 , Maria Dimou  22 , David Donaldson  23 , Gimena Dos Santos  24 , Barbara Dreta  25 , Maria Efstathopoulou  26 , Shaimaa El-Ashwah  27 , Alicia Enrico  28 , Alberto Fresa  29   30 , Sara Galimberti  31 , Andrea Galitzia  32 , Rocío García-Serra  20 , Eva Gimeno  33 , Isabel González-Gascón-Y-Marín  34 , Alessandro Gozzetti  13 , Valerio Guarente  35 , Romain Guieze  36 , Ajay Gogia  37 , Ritu Gupta  37 , Sean Harrop  38 , Eleftheria Hatzimichael  39 , Yair Herishanu  40 , José-Ángel Hernández-Rivas  34 , Luca Inchiappa  12 , Ozren Jaksic  41 , Susanne Janssen  42 , Elżbieta Kalicińska  43 , Kamel Laribi  44 , Volkan Karakus  45 , Arnon P Kater  42 , Bonnie Kho  46 , Maria Kislova  47 , Eliana Konstantinou  48 , Maya Koren-Michowitz  49   50 , Ioannis Kotsianidis  51 , Robert J Kreitman  52 , Jorge Labrador  53 , Deepesh Lad  54 , Mark-David Levin  55 , Ilana Levy  56 , Thomas Longval  57 , Alberto Lopez-Garcia  58 , Juan Marquet  59 , Lucia Martin-Rodríguez  4 , Marc Maynadié  60 , Stanislava Maslejova  6 , Carlota Mayor-Bastida  61 , Biljana Mihaljevic  62   63 , Ivana Milosevic  64 , Fatima Miras  65 , Riccardo Moia  66 , Marta Morawska  67   68 , Roberta Murru  32 , Uttam Kumar Nath  69 , Almudena Navarro-Bailón  10 , Ana C Oliveira  70 , Jacopo Olivieri  71 , David Oscier  21 , Irina Panovska-Stavridis  72 , Maria Papaioannou  19 , Tomas Papajík  73 , Zuzana Kubova  73 , Punyarat Phumphukhieo  74 , Cheyenne Pierie  42 , Anna Puiggros  75 , Lata Rani  37 , Gianluigi Reda  18 , Gian Matteo Rigolin  76 , Rosa Ruchlemer  77 , Marcos Daniel de Deus Santos  78 , Mattia Schipani  66 , Annett Schiwitza  79 , Yandong Shen  9 , Martin Simkovic  8 , Svetlana Smirnova  80 , Dina Sameh Abdelrahman Soliman  81 , Martin Spacek  82 , Tamar Tadmor  56 , Kristina Tomic  62 , Eric Tse  83 , Theodoros Vassilakopoulos  48 , Andrea Visentin  84 , Candida Vitale  85 , Julia von Tresckow  86 , George Vrachiolias  51 , Vojin Vukovic  62   63 , Renata Walewska  21 , Ewa Wasik-Szczepanek  87 , Zhenshu Xu  88 , Munci Yagci  89 , Lucrecia Yañez  90   91 , Mohamed Yassin  92 , Jana Zuchnicka  93 , Maria Angelopoulou  48 , Darko Antic  62   63 , Bella Biderman  94 , Mark Catherwood  23 , Rainer Claus  95   96 , Marta Coscia  85 , Antonio Cuneo  76 , Fatih Demirkan  97 , Blanca Espinet  75 , Gianluca Gaidano  66 , Olga B Kalashnikova  98 , Luca Laurenti  29   30 , Eugene Nikitin  47 , Gerassimos A Pangalis  26 , Panagiotis Panagiotidis  22 , Viola Maria Popov  99 , Sarka Pospisilova  5   6 , Paolo Sportoletti  35 , Niki Stavroyianni  7 , Constantine Tam  38 , Livio Trentin  84 , Anastasia Chatzidimitriou  1 , Francesc Bosch  4 , Michael Doubek  5   6 , Paolo Ghia  2 , Kostas Stamatopoulos  1
Affiliations

Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY

Thomas Chatzikonstantinou et al. EClinicalMedicine. .

Abstract

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work.

Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022.

Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001).

Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS.

Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.

Keywords: Chronic lymphocytic leukemia; Other cancers; Other malignancies; Second primary malignancies.

PubMed Disclaimer

Conflict of interest statement

TC received honoraria from AbbVie. LS received consulting fees from AbbVie, BeiGene, AstraZeneca, Lilly, and Janssen, honoraria from Janssen and Octapharma, support for attending meetings from BeiGene and Janssen and advisory board fees from Merck. SMu received advisory board fees from AbbVie, AstraZeneca, Janssen, Roche and BeiGene. JAHR received honoraria as a consultant from Janssen, AbbVie, AstraZeneca, Lilly, and BeiGene and support for attending meetings from Janssen, AbbVie, AstraZeneca, and BeiGene. LI received honoraria from AbbVie, Roche, and Janssen-Cilag. APK received advisory board fees and research money from Janssen, AbbVie, BMS, AstraZeneca, Roche/Genentech, support for attending meetings from Janssen and AbbVie. M-DL received travel expenses from Janssen and AbbVie. GMR received honoraria for participation to speaker's bureau from AbbVie, Astra Zeneca, Beigene, and Janssen, and support for attending meetings from Janssen. JVT received consulting fees from AbbVie, AstraZeneca, BeiGene, and Janssen, honoraria for scientific talks from AbbVie, AstraZeneca, BeiGene, Janssen, Lilly, and Roche, travel support from AbbVie, AstraZeneca, BeiGene, Janssen, Roche, and Lilly, and advisory boards fees for AbbVie, Amgen, AstraZeneca, BeiGene. GI received honoraria from Novartis, BMS, Sandoz, AstraZeneca, Janssen, Kite/Gilead, and Miltenyi, support for attending meetings from Kite/Gilead, AstraZeneca, and AbbVie and advisory board fees from Kite/Gilead, Novartis, BMS, and Autolus. FBi received support for attending meetings from AbbVie. RCo received support for attending meetings from Janssen-Cilag and S.A. SG received honoraria support for attending meetings from AbbVie, AstraZeneca, Jazz, Novartis, and Incyte, honoraria from Roche, Celgene, Pfizer, and Janssen, and support for attending meetings from Jazz, AstraZeneca, and Roche. RGS received support for attending meetings from AbbVie and S.L.U. RG received honoraria, consulting fees, and support for attending meetings from AbbVie, Beigene, Roche, Janssen, AstraZeneca. YH received honoraria from Janssen, AbbVie, Roche, AstraZeneca, Medion, and Lilly. OJ received honoraria from Johnson and Johnson, AstraZeneca, and Lilly, honoraria from Johnson and Johnson, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Johnson and Johnson, and AbbVie. LK received consulting fees from AbbVie, AstraZeneca, Janssen, Beigene, Takeda, and Novartis. MKM received honoraria from Novartis, Pfizer, and Gad Medical LTD and support for attending meetings from Novartis. IKo received honoraria and consulting fees from AbbVie and Janssen. IM received honoraria from AbbVie, Roche, Sandoz, AstraZeneca, and Janssen, and support for attending meetings from AbbVie, Roche, and Takeda. ANB received honoraria, advisory board fees and support for attending meetings from AbbVie, AstraZeneca, Takeda, Janssen, and Beigene. JO received honoraria from AbbVie, AstraZeneca, and Janssen. GR received consulting fees from AbbVie, AstraZeneca, Janssen, and Beigene, and is currently employed by AstraZeneca. TP received honoraria and advisory board fees from AbbVie, Janssen-Cilag, and AstraZeneca and support for attending meeting from AstraZeneca. MS received honoraria and support for attending meeting from AstraZeneca, AbbVie, and Janssen-Cilag and owns shares of stock in AbbVie, AstraZeneca, Merck, Eli Lilly, Sanofi, Johnson and Johnson, Pfizer, Gilead, and GSK. MSp received honoraria and consulting and advisory board fees, and support for attending meeting from AbbVie, AstraZeneca, and Janssen. ET received support for attending meetings from Takeda. TV received honoraria from Takeda, Roche, Genesis Pharma, Merck, Novartis, Gilead, Sandoz, AstraZeneca, Integris, and Servier and support for attending meetings from Takeda, Roche, Genesis Pharma, Merck, Pfizer, and Winmedica. CV received honoraria from AbbVie, consulting fees from AstraZeneca and support for attending meeting from AstraZeneca, Takeda, and Janssen. RW received honoraria from AbbVie, AstraZeneca, and Beigene, support for attending meetings from Janssen, AbbVie, and AstraZeneca and advisory board fees from AbbVie, AstraZeneca, Janssen, Beigene, and SecuraBio. EWS received honoraria from AbbVie, Roche, and Janssen-Cilag and support for attending meetings from AbbVie. LY received honoraria from AbbVie, AstraZeneca, Novartis, Gilead, Janssen, Jazz, MSD, and Pfizer, support for attending meetings from AbbVie, AstraZeneca, Gilead, Janssen, and Pfizer, and advisory board fees from AbbVie, AstraZeneca, Jazz, Janssen, Beigene, and Celgene. MAn received consulting fees from AbbVie, Takeda, Janssen, Roche, Genesis, Gilead, and Amgen and honoraria from AbbVie, Takeda, Roche, Genesis, Gilead, and Novartis. MC received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, and Janssen. ACu received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, Beigene, Janssen, and Lilly. FD support for attending meetings from Janssen and AbbVie. GG received honoraria, and advisory board fees from AbbVie, AstraZeneca, Beigene, Janssen and advisory board fees from Lilly. EN received honoraria from AbbVie. LSm received consulting fees, honoraria and support for attending meetings from AbbVie, AstraZeneca, and Janssen and advisory board fees from AbbVie and AstraZeneca. NS received honoraria from Janssen, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Janssen and AstraZeneca. CT received honoraria from AbbVie, Beigene, Janssen, and LOXO. FB received consulting fees, honoraria and payment for expert testimony from AbbVie, Genentech, Novartis, Takeda, Janssen, Roche, Mundipharma, Celgene/BMS, AstraZeneca, Lilly, Beigene, Gilead and TG Therapeutics, Advantage Allogene, Lava Therapeutics, and Enterome. MDo received honoraria and advisory board fees from AbbVie, AstraZeneca and Janssen, advisory board fees from Swixx, and support for attending meetings from Janssen. PG received honoraria and consulting fees from AbbVie, AstraZeneca, BMS, Janssen, Lilly/Loxo Oncology, MSD, and Roche; grant support from AbbVie, AstraZeneca, BMS, Janssen. KS received honoraria from Janssen, AbbVie, Lilly and AstraZeneca, consulting fees and support for attending meetings from Janssen and AstraZeneca. GK, EM, DC, JK, CD, MA, SA, TAS, FBa, MB, ACa, AM, AKM, RC, SC, ACh, ZD, MDi, DD, GDS, BD, ME, SEA, AE, AF, AG, EG, IGGM, AGo, AjG, RGu, SH, EH, SJ, EKa, VK, BK, MK, EK, RJK, JL, DL, IL, TL, ALG, JM, LMR, MMa, SM, CMB, BM, FM, RM, MMo, RMu, UKN, ACO, DO, IPS, MP, ZK, PP, CP, AP, LR, RR, MDDS, AS, YS, MSi, SS, DSAS, TT, KT, AV, GV, VV, ZX, MYa, MY, JZ, DA, BB, MCa, RCl, BE, OBK, LL, GP, PPa, VMP, SP, PS, LT, AC, have no conflict of interest to disclose.

Figures

Fig. 1
Fig. 1
Other hematological and non-hematological malignancies and their relation to CLL diagnosis and CLL therapy initiation. ∗Including Richter transformation. AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
Fig. 2
Fig. 2
Overall survival from the time of CLL diagnosis. Comparison between patients with at least one other malignancy after CLL diagnosis versus patients without a second malignancy after CLL diagnosis (Patients with Richter transformation were excluded).
Fig. 3
Fig. 3
Overall survival from the time of CLL diagnosis. Comparison between patients without a second malignancy after CLL diagnosis or only non-melanoma skin cancers versus patients diagnosed with MDS or AML after CLL diagnosis, versus patients diagnosed with a hematological malignancy (excluding Richter transformation, B cell prolymphocytic leukemia, AML, and MDS) after CLL diagnosis versus patients diagnosed with a non-hematological malignancy (excluding non-melanoma skin cancers) after CLL diagnosis. Hem, hematological malignancy; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; skin, non-melanoma skin cancers.
See this image and copyright information in PMC

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