A new real-world study from Turkey suggests that when patients with diffuse large B-cell lymphoma develop low antibody levels may matter as much as whether they develop them at all. The research, published in Annals of Hematology, followed 181 adults with newly diagnosed diffuse large B-cell lymphoma, the most common form of non-Hodgkin lymphoma, as they underwent rituximab-based immunochemotherapy, the standard first-line treatment that combines the anti-CD20 monoclonal antibody rituximab with chemotherapy. The investigators found that nearly six in ten patients experienced hypogammaglobulinemia, a condition in which serum immunoglobulin G, the principal antibody class defending against bacterial and viral infections, falls below the protective threshold. More importantly, the clinical meaning of that decline differed sharply depending on whether it was present before treatment began or emerged only after therapy.
The study team, led by hematologists at Akdeniz University in Antalya, defined hypogammaglobulinemia as a serum IgG concentration below 7 grams per liter, a commonly used laboratory cutoff. Patients were then divided into three categories: those with baseline hypogammaglobulinemia, meaning low IgG already detectable at diagnosis; those with treatment-emergent hypogammaglobulinemia, meaning normal IgG at baseline that subsequently fell below threshold during or after therapy; and those who never developed the condition. Among the 181 patients, 107, or 59.1 percent, developed hypogammaglobulinemia at some point. Thirty patients, representing 16.6 percent of the cohort, already had low IgG when they walked in the door, while 77 patients, or 42.5 percent, developed it as a consequence of treatment.
The distinction proved clinically consequential. Patients whose low antibody levels predated treatment carried a demonstrably worse baseline profile. They tended to have poorer Eastern Cooperative Oncology Group performance status, a standard measure of functional ability and daily activity tolerance, and they exhibited higher-risk disease features at presentation. In other words, baseline hypogammaglobulinemia appears to be less an isolated laboratory anomaly and more a marker of an already vulnerable patient, one whose lymphoma and general health trajectory were adverse from the outset. This observation aligns with a growing understanding that the immune system and the tumor engage in a dynamic relationship long before any therapy is administered, and that B-cell dysfunction, of which impaired antibody production is one visible signature, may reflect deeper biological disturbance.
Response to treatment differed significantly across the three groups. Complete response rates, the proportion of patients achieving full disappearance of detectable lymphoma after frontline therapy, varied from 73.3 percent among patients with baseline hypogammaglobulinemia to 88.3 percent among those with treatment-emergent hypogammaglobulinemia and 94.6 percent among patients who never developed low IgG. The difference across groups was statistically significant, with a p-value of 0.008, meaning the probability of observing such a spread by chance alone was less than one percent. Patients with pre-existing antibody deficiency were, by a wide margin, the least likely to achieve a complete remission, reinforcing the picture of baseline hypogammaglobulinemia as a red flag at the moment of diagnosis.
Survival analysis painted a similarly stark picture for that same group. Patients with baseline hypogammaglobulinemia experienced the poorest outcomes of the cohort, with median progression-free survival, the length of time patients lived without their lymphoma advancing, of 26.4 months, and median overall survival of 30.9 months. Progression-free survival and overall survival are the twin gold-standard endpoints in oncology, and medians well below three years in a disease where many patients are cured by frontline therapy underscore how much worse this subgroup fared. The survival gap relative to patients with treatment-emergent hypogammaglobulinemia or no hypogammaglobulinemia at all was substantial, and it persisted across the study’s observation window.
Yet when the investigators moved from simple comparisons to multivariable analysis, a statistical technique that adjusts for confounding factors such as age, disease stage, and performance status, the story became more nuanced. Baseline hypogammaglobulinemia remained an independent predictor of infectious complications, meaning that even after accounting for other known risk factors, patients who started treatment with low IgG were still more likely to suffer infections during their care. However, it did not independently predict progression-free survival. The implication is that the excess mortality and disease progression observed in this group may partly reflect the composite burden of frailty, advanced disease, and infection susceptibility, rather than low antibody levels serving as a standalone driver of lymphoma outcomes.
Treatment-emergent hypogammaglobulinemia, by contrast, presented a different analytical puzzle. In the primary multivariable model, developing low IgG during treatment was associated with shorter progression-free survival, a finding that would, on its face, suggest that rituximab-induced antibody depletion carries prognostic weight of its own. But that association dissolved under scrutiny. The researchers had prespecified a six-month landmark analysis, a methodological safeguard in which only patients who survive and remain in follow-up beyond a fixed early time point are compared, with their exposure status assessed as of that point. This approach helps remove bias arising from patients whose events occur very early or whose laboratory monitoring was irregular. In that landmark analysis, the link between treatment-emergent hypogammaglobulinemia and shortened progression-free survival was not confirmed, leading the authors to urge caution in interpreting the initial signal.
The authors are candid about the limitations that temper this finding. The study was retrospective, meaning it relied on medical records generated in routine clinical practice rather than a prospectively designed protocol. Immunoglobulin monitoring was not standardized, so the frequency and timing of IgG measurements varied between patients, creating the possibility of ascertainment bias, the distortion that occurs when a condition is more likely to be detected in patients who are tested more often, typically because they are sicker. A patient who develops infections may be more likely to have IgG checked, and a low result recorded then may appear to precede adverse outcomes simply because testing was triggered by symptoms. These considerations explain why the researchers explicitly state that the prognostic significance of treatment-emergent hypogammaglobulinemia should be interpreted cautiously.
Rituximab’s role in the biology is worth understanding on its own terms. The drug binds CD20, a surface protein expressed on most B lymphocytes, and eliminates those cells through immune mechanisms including antibody-dependent cellular cytotoxicity and complement activation. Because plasma cells, the antibody factories of the immune system, generally lack CD20, they are spared directly, but their replenishment depends on a continuing supply of new B cells, which rituximab depletes. Over repeated treatment cycles, this can progressively starve the antibody repertoire, particularly when combined with chemotherapy agents that further suppress immune function. Previous research has documented that hypogammaglobulinemia after rituximab-based therapy can persist for months to years and that severe, recurrent infections, including bacterial pneumonia and sinopulmonary disease, can follow. What this new study adds is the recognition that the timing of the antibody decline separates two different clinical populations.
The practical implications are tangible for clinicians managing lymphoma care. Baseline IgG measurement, which is inexpensive and widely available, could help identify the minority of patients who arrive at diagnosis with compromised humoral immunity and who may warrant closer surveillance, prophylactic strategies, or immunoglobulin replacement during treatment. The study’s data suggest these patients are not only more vulnerable to infection, which alone justifies monitoring, but also less likely to achieve complete remission and more likely to die sooner. For the larger group that develops low IgG after treatment, the message is more measured: the condition is common, affecting more than four in ten patients in this cohort, and while it may signal immune perturbation, the evidence linking it to worse lymphoma outcomes is not yet firm enough to change treatment decisions on its own.
What the study does not settle, and what future research must address, is whether standardized, protocol-driven immunoglobulin surveillance would alter these conclusions, and whether interventions such as prophylactic immunoglobulin replacement can improve outcomes in either group. The authors emphasize that the two states, baseline and treatment-emergent hypogammaglobulinemia, represent distinct clinical conditions in diffuse large B-cell lymphoma, and that conflating them, as much of the earlier literature implicitly did, obscures their differing implications. In a treatment era defined by B-cell-directed therapies, from rituximab to CAR T-cell engineering, understanding which patients can tolerate antibody depletion safely, and which are already too depleted to begin with, is becoming an increasingly important dimension of personalized cancer care. This Turkish cohort study offers a clear, if preliminary, map of that terrain.
Subject of Research: Diffuse large B-cell lymphoma patients treated with rituximab-based immunochemotherapy, focusing on the distinct clinical associations of baseline and treatment-emergent hypogammaglobulinemia
Subject of Research: Cancer
Article Title: Distinct clinical associations of baseline and treatment-emergent hypogammaglobulinemia in diffuse large B-cell lymphoma: a retrospective real-world cohort study
Article References: Iltar, U., Karacamli, T., Oztekin, S., Atas, U., Vural, E., Yucel, O. K., Salim, O., & Undar, L. (2026). Distinct clinical associations of baseline and treatment-emergent hypogammaglobulinemia in diffuse large B-cell lymphoma: a retrospective real-world cohort study. Annals of Hematology. https://doi.org/10.1007/s00277-026-07169-9
Image Credits: AI Generated
DOI: 10.1007/s00277-026-07169-9
Keywords: Diffuse large B-cell lymphoma, Hypogammaglobulinemia, Rituximab, Immunochemotherapy, Immunoglobulin G, Infection, Prognosis, Progression-free survival, Overall survival, Complete response, Real-world cohort study
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Nathaniel Bowman. (September 5, 2026). Low immunoglobulin levels carry different risks in lymphoma patients before and during treatment. Scienmag. https://scienmag.com/low-immunoglobulin-levels-carry-different-risks-in-lymphoma-patients-before-and-during-treatment/
Nathaniel Bowman. “Low immunoglobulin levels carry different risks in lymphoma patients before and during treatment.” Scienmag, 5 September 2026, https://scienmag.com/low-immunoglobulin-levels-carry-different-risks-in-lymphoma-patients-before-and-during-treatment/. Accessed 5 September 2026.
Nathaniel Bowman. “Low immunoglobulin levels carry different risks in lymphoma patients before and during treatment.” Scienmag. September 5, 2026. https://scienmag.com/low-immunoglobulin-levels-carry-different-risks-in-lymphoma-patients-before-and-during-treatment/
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