Histological transformation (HT) in Waldenström's macroglobulinemia (WM) is a rare complication and despite growing literature in the last years, no consensus recommendations exist. Consensus Panel 6 (CP6) of the 12th International Workshop on Waldenström's Macroglobulinemia (IWWM-12) was convened to review the current data on transformed WM and make recommendations on its diagnosis and management. The key recommendations from IWWM-12 CP6 included: (1) in case of suspected HT, tissue biopsy is the gold standard for diagnosis; (2) the initial work-up should comprise 18FDG-PET/CT for the evaluation of disease extent and, for patients with clinical suspicion or for high-risk patients (CNS-IPI, multiple and/or specific extranodal involvements), cerebrospinal fluid examination and brain MRI; (3) standard dose chemoimmunotherapy (CIT) such as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) or R-CHP + polatuzumab vedotin are the preferred front-line regimen; (4) CNS prophylaxis and consolidation with autologous stem cell transplantation (SCT) can be considered according to de novo diffuse large B-cell lymphoma (DLBCL) guidelines; (5) T-cell-engaging therapies (CAR T-cells, bispecific antibodies) should be used in the relapse/refractory setting according to international guidelines for DLBCL and local access to these therapies. Key unanswered questions include the role of TP53 abnormalities and CXCR4 mutations on the risk of HT, the prognostic role of clonal relationship between WM and HT, the optimal front-line therapy (addition of novel agents to CIT, dose-intensive CIT, consolidation with autologous SCT), and the sequence of T-cell-engaging therapies. International collaboration and consideration of and inclusion in clinical trials is critical to address these issues in a rare patient population.

1st Department of Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Bing Center for Waldenström Macroglobulinemia Dana Farber Cancer Institute Harvard Medical School Boston MA

Department of Haemato oncology St Bartholomew's Hospital London UK

Department of Hematology Amsterdam UMC University of Amsterdam Cancer Center Amsterdam LYMMCARE Amsterdam The Netherlands

Department of Hematology Colorado Blood Cancer Institute Sarah Cannon Research Institute Denver CO

Department of Hematology Hospital Clinic de Barcelona IDIBAPS University of Barcelona Spain

Department of Hematology Sorbonne Université Hematology Pitié Salpêtrière Hospital Paris France

Department of Hematology University Hospital of Reims and UFR Médecine Reims France

Department of Hematology University Hospital Ulm Institute of Experimental Cancer Research Ulm Germany

Department of Medecine Division of Oncology Stanford University Medical Center Stanford CA

Department of Medical Oncology National Cancer Center National Clinical Research Center for Cancer Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

Division of Hematology Department of Internal Medicine Mayo Clinic Rochester MN

St James's University Hospital Leeds Teaching Hospitals NHS Trust Leeds UK

State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood Diseases Haihe Laboratory of Cell Ecosystem Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin 300020 China; Tianjin Institutes of Health Science Tianjin 301600 China

Unit of Hematology Department of Biotechnology and Health Sciences University of Torino Torino Italy

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