For patients with Waldenström macroglobulinemia whose disease returns after standard treatments, the therapeutic arsenal has long been limited. Now, a large retrospective study from France offers some of the most detailed real-world evidence yet on how the targeted drug venetoclax performs in this setting, and it points to a clear conclusion: pairing venetoclax with an anti-CD20 antibody appears to produce substantially deeper responses than venetoclax alone. The WAVE study, conducted by investigators of the French CLL/WM group within the French Innovative Leukemia Organization (FILO), was published in Annals of Hematology and analyzed 46 patients with relapsed or refractory Waldenström macroglobulinemia treated across 17 French hospitals.
Waldenström macroglobulinemia is a rare and indolent B-cell lymphoma characterized by the accumulation of malignant lymphoplasmacytic cells in the bone marrow and, crucially, by the overproduction of monoclonal immunoglobulin M, an antibody protein that thickens the blood and can cause hyperviscosity, neuropathy, and organ damage. Because the disease is uncommon, most treatment evidence comes from small trials and single-arm studies, leaving clinicians with genuine uncertainty when patients relapse after frontline therapy. This rarity is precisely why the French group’s multicenter approach matters: by pooling patients from 17 centers, the investigators assembled one of the larger cohorts ever reported for this specific treatment strategy.
The drug at the center of the study, venetoclax, belongs to a class of agents known as BH3 mimetics. These small molecules bind to BCL-2, an anti-apoptotic protein that many B-cell cancers exploit to evade programmed cell death. By occupying the BCL-2 binding groove, venetoclax releases the cellular brakes on apoptosis, allowing malignant lymphocytes to self-destruct. The drug has already transformed the treatment landscape for chronic lymphocytic leukemia, and earlier monotherapy studies suggested promising activity in relapsed or refractory Waldenström macroglobulinemia, a population with significant unmet medical need. What remained unclear was whether venetoclax should be given alone or in combination with other agents in this disease.
The WAVE investigators turned to real-world clinical practice to answer that question. The 46 patients included in the analysis had received a median of three prior lines of treatment before starting venetoclax, and 89 percent had already been exposed to a Bruton tyrosine kinase inhibitor, the class of drugs that has become a cornerstone of Waldenström macroglobulinemia therapy. This detail is important: these were heavily pretreated patients whose disease had already evaded the most effective modern targeted therapies, meaning that any meaningful response signal carries real clinical weight. Among the cohort, 25 patients, or 54 percent, received venetoclax combined with an anti-CD20 antibody, typically rituximab or a related monoclonal antibody that targets the CD20 surface protein found on B cells and recruits the immune system to destroy antibody-coated tumor cells.
The headline finding concerns response depth. At the time of best response, patients treated with the combination achieved a deep response rate, defined as very good partial response plus uncertain complete response, of 56 percent, compared with just 24 percent among those treated with venetoclax monotherapy, a difference that reached statistical significance with a p value of 0.03. In lymphoma care, depth of response is not an academic nicety. Deeper remissions, particularly those in which the monoclonal IgM protein falls to very low or undetectable levels, are consistently associated with longer periods of disease control before relapse. For a disease in which the abnormal protein itself drives many of the symptoms, pushing IgM down as far as possible translates directly into clinical benefit.
Perhaps more striking was the result of the multivariate analysis. When the investigators adjusted for other clinical variables, anti-CD20 combination therapy emerged as the only factor independently associated with achieving a deep response, with a hazard ratio of 4.07 and a p value of 0.03. In other words, the antibody combination quadrupled the odds of a deep remission regardless of other patient characteristics. This kind of signal, emerging from a retrospective dataset where treatment assignment was not randomized, cannot prove causation on its own, but it provides a strong rationale for the prospective trials that the authors say are needed to confirm the strategy.
The progression-free survival data reinforced the same direction of benefit, though with more statistical uncertainty. At two years, 78 percent of patients treated with venetoclax plus anti-CD20 had not experienced disease progression or death, compared with 54 percent of those on monotherapy. The confidence intervals were wide, spanning 54 to 90 percent for the combination arm and 27 to 74 percent for monotherapy, and the difference did not reach statistical significance with a p value of 0.25. That lack of formal significance is unsurprising given the modest sample size, but the magnitude of the gap, nearly 25 percentage points at two years, is the kind of signal that clinicians and trial designers take seriously.
Safety, as always in combination therapy, is the counterweight to efficacy, and here the picture was more nuanced. Grade 3 or higher adverse events occurred in 17 patients, or 68 percent, of those receiving the combination, versus 7 patients, or 33 percent, of those on venetoclax alone, a difference that was statistically significant with a p value of 0.02. Three cases of febrile aplasia, episodes of fever accompanied by severe suppression of blood cell production, were reported, though these did not differ significantly between the two groups. The increased toxicity of the combination is consistent with what is known about adding antibody therapy to targeted agents: the pairing amplifies immune-mediated tumor killing but also increases the burden on the bone marrow and the immune system. For a largely elderly patient population, this trade-off between deeper remissions and higher rates of serious side effects will need careful weighing in future prospective studies.
The WAVE study also illustrates a broader shift in how rare-cancer evidence is generated. Randomized trials in diseases with incidence rates as low as Waldenström macroglobulinemia’s can take years to accrue even modest numbers of patients, and many relapsed patients cannot wait. Retrospective multicenter cohorts like this one, harmonized across 17 institutions and analyzed with multivariate statistics, offer a pragmatic middle path: they capture the messy reality of clinical practice, including heterogeneous prior treatments and variable dosing schedules, and they generate hypothesis-driving signals that can justify the prospective studies that ultimately change guidelines. The French FILO network has been particularly productive in this regard, leveraging the centralized structure of French hematology care to assemble cohorts that individual centers never could.
For patients and their physicians, the practical message is cautiously encouraging. Venetoclax, with or without an anti-CD20 antibody, is an oral, targeted, chemotherapy-free approach for a disease that has historically been treated with rituximab-based chemoimmunotherapy, proteasome inhibitors, or BTK inhibitors. The WAVE data suggest that in the relapsed or refractory setting, particularly after BTK inhibitor exposure, the combination strategy offers the best chance of a deep and durable response, at the cost of more frequent severe side effects. The authors themselves frame the findings as warranting further evaluation in prospective studies, and that is the appropriate note of restraint. Until randomized data arrive, the study gives hematologists a real-world benchmark and gives patients with few remaining options a reason for measured optimism that the next generation of trials will refine exactly who benefits most from this two-pronged attack on their cancer.
Subject of Research: Venetoclax with or without anti-CD20 antibody therapy for relapsed or refractory Waldenström macroglobulinemia
Article Title: Relapsed/refractory WAldenström macroglobulinemia patients treated by VEnetoclax with or without anti-CD20 antibody: WAVE a retrospective study of the French CLL/WM group (FILO)
Article References: Vonfeld, M., Systchenko, T., Debureaux, P.-E., Dupuis, J., Roos-Weil, D., Ysebaert, L., Dilhuydy, M.-S., Malphettes, M., Croizier, C., Aurran, T., Inchiappa, L., Willems, L., Hivert, B., Lévy, V., Bussot, L., Bouclet, F., Laribi, K., Clavert, A., Durand, A., & Tomowiak, C. (2026). Relapsed/refractory WAldenström macroglobulinemia patients treated by VEnetoclax with or without anti-CD20 antibody: WAVE a retrospective study of the French CLL/WM group (FILO). Annals of Hematology. https://doi.org/10.1007/s00277-026-07293-6
Image Credits: AI Generated
DOI: 10.1007/s00277-026-07293-6
Keywords: Waldenström macroglobulinemia, venetoclax, anti-CD20 antibody, BTK inhibitor, relapsed refractory lymphoma, BCL-2, targeted therapy, retrospective study, hematology, monoclonal antibody, progression-free survival, FILO
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Nathaniel Bowman. (October 2, 2026). Adding an Antibody to Venetoclax Deepens Responses in Hard-to-Treat Lymphoma. Scienmag. https://scienmag.com/adding-an-antibody-to-venetoclax-deepens-responses-in-hard-to-treat-lymphoma/
Nathaniel Bowman. “Adding an Antibody to Venetoclax Deepens Responses in Hard-to-Treat Lymphoma.” Scienmag, 2 October 2026, https://scienmag.com/adding-an-antibody-to-venetoclax-deepens-responses-in-hard-to-treat-lymphoma/. Accessed 2 October 2026.
Nathaniel Bowman. “Adding an Antibody to Venetoclax Deepens Responses in Hard-to-Treat Lymphoma.” Scienmag. October 2, 2026. https://scienmag.com/adding-an-antibody-to-venetoclax-deepens-responses-in-hard-to-treat-lymphoma/
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Tags: anti-CD20 antibodyBCL-2BTK inhibitordeepened treatment responses in lymphomaFILOhematologyhyperviscosity syndrome in lymphomainnovative leukemia organization researchmanagement of indolent Bmonoclonal antibodymonoclonal immunoglobulin M overproductionmulticenter retrospective studiesProgression-Free Survivalreal-world evidence in Waldenström macroglobulinemiarelapsed or refractory lymphomarelapsed refractory lymphomaretrospective studyTargeted therapytargeted therapy in B-cell lymphomavenetoclaxVenetoclax and anti-CD20 antibody combinationWaldenström MacroglobulinemiaWaldenström macroglobulinemia treatmentWAVE study on Waldenström macroglobulinemia
