Validation of novel prognostic models in symptomatic Waldenström's macroglobulinemia based on real-world data
Abstract
Abstract Introduction Waldenström's macroglobulinemia (WM) is a rare, indolent, IgM-producing lymphoplasmacytic lymphoma with diverse clinical outcomes. Prognostic models have evolved alongside treatment shifts from chemotherapy to chemoimmunotherapy and targeted therapies. In addition to the original International Prognostic Scoring System for WM (IPSSWM), newer models such as the revised IPSSWM (rIPSSWM) and the Modified Staging System for WM (MSSWM) have been developed, incorporating markers such as lactate dehydrogenase and albumin. However, their performance has not yet been thoroughly validated. Aim: To evaluate the performance of prognostic models in a large, real-world patient cohort and to examine treatment patterns and survival outcomes of symptomatic WM (sWM) in the Czech Republic over the past ten years. Methods sWM patients who started first line (L1) treatment between January 2014, and January 2024 were included. The primary data source was the Czech Myeloma Registry and Czech Lymphoma Study Group Project (NCT03199066). The primary endpoint was overall survival (OS) (calculated from L1 initiation), secondary endpoints were preferred regimen, treatment responses and progression-free survival (PFS). Patients with complete data for scoring systems were included in multivariable analysis and validation of existing prognostic models. The Kaplan-Meier method was used for survival analysis, and groups were compared using pairwise log-rank tests with Benjamini-Hochberg correction. Results In total, 315 patients were included in the analysis (median age 69 years at L1 initiation, 58% male). Molecular genetic testing data for MYD88 and CXCR4 were available for 143 (45%) and 27 (11%) patients, with 137 (96%) and 11 (41%) positively tested for MYD88 and CXCR4 mutations, respectively. Cytopenia, IgM-associated complications, and B symptoms were the most frequent indications for treatment. In the front-line setting, 96% of patients received chemoimmunotherapy (76% cyclophosphamide, 22% bendamustine, and 2% bortezomib-based combinations), 2% rituximab monotherapy and 2% other combinations. With a median follow-up (FU) of 4.8 y (IQR 2.8; 6.8) the overall response rate (ORR) was 86% (257/296 patients with known response: CR 12%, VGPR 17%, PR 67%). Median PFS was 5.3 years (4.5-7.1 years, 95% CI). The 3-year and 5-year probability of OS were 87% (84–91%, 95% CI) and 80% (75–86%, 95% CI), respectively. Among 76 patient deaths 26 (34%) was directly related to WM (progression, histologic transformation, treatment related complications, secondary malignancies). We were able to evaluate the IPSSWM risk score in 304 (97%) patients (low 16%, intermediate 36%, high 48%), rIPSSWM in 291 (92%) patients (very low 15%, low 23%, intermediate 29%, high 21%, very high 12%) and MSSWM in 302 (96%) patients (low 19%, low-intermediate 29%, intermediate 31%, high 21%). The 5-year OS according to the IPSSWM was 95%, 89% and 71% for low, intermediate and high risk respectively, for rIPSSWM was 95%, 95%, 75%, 70% and 64% for very low, low, intermediate, high and very high risk respectively, and for MSSWM 96%, 83% 74% and 70% for low, low-intermediate, intermediate and high risk respectively. All models significantly differentiated between high-risk and low-risk groups, while intermediate groups provided poor resolution. Additionally, in a direct comparison using a subset of 291 patients with all risk system available, the respective C-index and AIC values were: 0.72 and 455 for rIPSSWM; 0.68 and 464 for MSSWM; and 0.66 and 461 for IPSSWM. Interestingly, Beta-2microglobulin (B2M) was a significant prognostic factor, both as a continuous variable and as a binary variable (≥ 4 mg/L). In the binary form, B2M was significant in both univariable (HR: 2.79; p < 0.001) and multivariable Cox regression analyses adjusted for age, LDH, and albumin (HR: 2.2; p = 0.004). Conclusion Over the past decade, rituximab-based immunochemotherapy has been the most commonly used treatment for WM in the Czech Republic. In our real-world cohort, rIPSSWM was the best-performing model, achieving the highest concordance index and the lowest AIC. However, the MSSWM provided comparable results using fewer predictors, potentially simplifying its clinical application.
Article Details
Authors (44)
Michal Kascak
14Medical Faculty of the Ostrava University and University Hospital, Department of Hematology, Ostrava, Czech Republic
Prokop Vodička
1First Department of Medicine, First Faculty of Medicine Charles University and General Hospital, Prague, Czech Republic
Klara Mensikova
3Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic, Department of Internal Medicine, Hematology and Oncology, Brno, Czech Republic
Stork Martin
4University Hospital Brno and Masaryk University, Brno, Czech Republic
Zdenek Adam
3Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic, Department of Internal Medicine, Hematology and Oncology, Brno, Czech Republic
David Salek
4Department of Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital, Brno, Czech Republic
Andrea Janíková
26Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
Josef Karban
1First Faculty of Medicine, Charles University and General Hospital, First Department of Medicine, Prague, Czech Republic
Jana Salkova
1First Faculty of Medicine, Charles University and General Hospital, First Department of Medicine, Prague, Czech Republic
Martin Spacek
2First Department of Medicine, First Faculty of Medicine, Charles University and General Hospital, Prague, Czech Republic, First Department of Medicine, Prague, Czech Republic
David Belada
4th Department of Internal Medicine - Haematology, University Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic
Alice Sykorova
Martin Simkovic
254th Department of Internal Medicine-Hematology, Faculty of Medicine in Hradec Kralove, University Hospital and Charles University, Hradec Kralove, Hradec Kralove, Czech Republic
Pavla Stepankova
6Faculty of Medicine, Charles University and University Hospital Hradec Kralove, Fourth Department of Internal Medicine – Hematology, Hradec Kralove, Czech Republic
Jakub Radocha
4th Department of Internal Medicine–Hematology, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic
Alexandra Jungova
5Charles University Hospital Pilsen, Pilsen, Czech Republic
Tereza Dekojova
5Department of hematooncology, University hospital Pilsen , (Charles University), Department of hematooncology, Pilsen, Pilsen, Czech Republic
Pavel Jindra
9Charles University Hospital, Pilsen, Czech Republic
Katerina Steinerova
6Department of Haematology and Oncology, Faculty of Medicine, Charles University and University Hospital Pilsen, Pilsen, Czech Republic
Tomas Prochazka
6Department of Haematology and Oncology, Faculty of Medicine, Charles University and University Hospital Pilsen, Pilsen, Czech Republic, Department of Haematology and Oncology, Pilsen, Czech Republic
Tomas Jelinek
Department of Hemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic
David Zihala
9Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Juraj Ďuraš
11Department of Hematology, Medical Faculty of the Ostrava University and University Hospital, Ostrava, Czech Republic
Vit Prochazka
Ales Obr
8Faculty of Medicine and Dentistry, Palacky University and University Hospital, Department of Haemato-Oncology, Olomouc, Czech Republic
Veronika Hanackova
5Faculty of Medicine and Dentistry, Palacky University and University Hospital, Department of Haemato-Oncology, Olomouc, Czech Republic
Jiri Minarik
1Palacky University and University Hospital Olomouc, Olomouc, Czech Republic
Adriana Heindorfer
8Department of Clinical hematology, Regional Hospital Liberec, Czech Republic, Department of Clinical hematology, Liberec, Czech Republic
Jana Klcova
8Department of Clinical hematology, Regional Hospital Liberec, Czech Republic, Department of Clinical hematology, Liberec, Czech Republic
Heidi Mocikova
Jan Soukup
9Department of Haematology, University Hospital Královské Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic., Department of Haematology, Prague, Czech Republic
Michal Sýkora
Petr Kessler
11Department of Hematology and Transfusion medicine, Pelhrimov Hospital, Czech Republic, Department of Hematology and Transfusion medicine, Pelhrimov, Czech Republic
Radka Schulzova
12Department of Hematology and Transfusion Medicine, Regional Hospital Mladá Boleslav, Department of Hematology and Transfusion Medicine, Mlada Boleslav, Czech Republic
Marek Wrobel
13Hematology department, Hospital in Novy Jicin, Novy Jicin, Hematology department, Novy Jicin, Czech Republic
Lukas Stejskal
5University Hospital Ostrava, Department of Hemato-Oncology, Ostrava, Czech Republic
Petr Mikula
1Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic, Department of Haematooncology, Ostrava, Czech Republic
Vit Campr
19Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
Jitka Dlouha
10Czech Lymphoma Study Group, Datacenter, Prague, Czech Republic
Petra Blahovcova
2General University Hospital in Prague, Brno, Czech Republic, First Department of Medicine, Prague, Czech Republic
Ingrid Kovacova
1Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic, Department of Haematooncology, Ostrava, Czech Republic
Ludek Pour
Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czech Republic
Marek Trneny
Roman Hajek