Canine lymphoma is a major clinical burden, accounting for roughly 7 to 24 percent of all cancers in dogs, with T-cell tumors representing 10 to 38 percent of high-grade, multicentric cases. The standard of care for decades has been CHOP chemotherapy, a multi-drug combination of vincristine, cyclophosphamide, doxorubicin, and prednisone. While CHOP achieves an overall response rate of about 96 percent in T-cell lymphoma, dogs respond less well and relapse sooner than their B-cell counterparts, with a median progression-free survival of just 133 days and a median survival time of around 235 days. The T-cell immunophenotype itself is a recognized negative prognostic indicator, making protocol selection a pressing clinical question.

The biological rationale for turning to alkylating agents lies in the mechanics of drug resistance. T-cell lymphomas in both humans and dogs carry more chromosomal aberrations than B-cell neoplasms, suggesting a greater capacity for acquired drug resistance. Overexpression of ATP-binding cassette transporter proteins, which pump drugs such as doxorubicin and vincristine out of tumor cells, has been documented in canine lymphoma. Crucially, alkylating agents are not substrates for these efflux pumps and show no cross-resistance with them, which has driven interest in alkylator-heavy combinations like LOPP, comprising lomustine, vincristine, procarbazine, and prednisone, and MOPP, which substitutes mechlorethamine for lomustine.

Historically, both protocols have reported response rates comparable to CHOP when used as first-line therapy. LOPP has been associated with overall response rates of 94 to 97 percent and complete response rates of 83 to 90 percent, while MOPP has shown a 98 percent overall response rate and a 78 percent complete response rate in earlier reports. Median survival times have ranged from about 9 months for MOPP to 10 to 17 months for LOPP, both figures generally exceeding the roughly 8 months historically attributed to CHOP in T-cell disease. Until now, however, no study had directly compared the two protocols head to head in dogs with T-cell or hypercalcemic lymphoma, leaving the choice largely to clinician experience, practicality, owner preference, and cost.

The new study included dogs with confirmed intermediate to large cell T-cell lymphoma of multicentric distribution, excluding T-zone lymphoma and cases with gastrointestinal or cutaneous involvement because of their distinct prognoses. Thirty-seven dogs received LOPP and 34 received MOPP, each given on a 28-day cycle for up to six cycles. Diagnosis was established through cytology, histopathology, flow cytometry, and polymerase chain reaction for antigen receptor rearrangement, with immunophenotyping completed in every dog. Flow cytometry, performed in nearly 86 percent of cases, revealed that the dominant immunophenotype was CD4-positive CD8-negative, present in 49 of the 71 dogs. More than half of the dogs were hypercalcemic at diagnosis, and among those undergoing thoracic imaging, just over half harbored a cranial mediastinal mass.

The headline results favored LOPP decisively on two of the four key endpoints. Complete response was achieved in 86 percent of LOPP-treated dogs versus 65 percent of MOPP-treated dogs, a statistically significant difference. Median progression-free survival was 208 days under LOPP compared with 102 days under MOPP, also significant, and multivariable analysis confirmed that LOPP reduced the risk of progression or death by more than two-thirds. Overall response rates, at 97 percent versus 91 percent, did not differ significantly, and median overall survival times were statistically indistinguishable at 298 days for LOPP and 231 days for MOPP. The authors suggest that the survival equivalence likely reflects the wide variety of rescue chemotherapies used after relapse and differing decisions about when to discontinue treatment.

Toxicity profiles were broadly similar between the groups, though the details matter for practicing clinicians. Grade III or higher adverse events occurred in 45.9 percent of LOPP-treated dogs versus 20.6 percent of MOPP-treated dogs, driven largely by myelosuppression, which affected 35.1 percent of LOPP patients. Febrile neutropenia was more frequent with LOPP at 8.1 percent compared with 2.9 percent for MOPP, consistent with lomustine’s dose-limiting toxicity being neutropenia. Hospitalization was required in 18.9 percent of LOPP dogs and 11.8 percent of MOPP dogs, and notably, prophylactic antibiotics, given to more than 62 percent of LOPP patients, did not appear to prevent febrile neutropenia. Treatment delays and dose reductions were common in both arms, and the authors caution that the lower-than-historical doses used in this cohort may explain why survival figures fell short of some earlier LOPP reports.

The study also yielded prognostic insights specific to T-cell disease. Dogs with a cranial mediastinal mass and those with the CD4-positive CD8-negative immunophenotype were more likely to achieve complete remission, an intriguing reversal of the mediastinal mass’s usual status as a negative prognostic marker in mixed-immunophenotype lymphoma populations. Achieving any response, and especially a complete response, strongly prolonged progression-free survival, and complete response also extended overall survival on univariate analysis. Stage V disease emerged as an independent negative prognostic factor for progression-free survival in multivariable analysis. Notably, more MOPP-treated dogs had stage V disease, 47 percent versus 22 percent, which the authors acknowledge could partly account for that protocol’s weaker performance, alongside schedule modifications and the possibility of type II error.

Perhaps the most encouraging finding is the existence of a long-surviving subgroup. A quarter of the dogs treated with these alkylator-rich protocols were still alive at 487 days with LOPP and 389 days with MOPP, echoing historical reports of 25 to 35 percent two-year survival with LOPP and a quarter of MOPP-treated dogs alive at 939 days. Such prolonged survival has not been reported with CHOP in T-cell lymphoma, and identifying which dogs belong to this favorable subset is now a priority. The authors conclude that clinicians considering alkylator-rich multi-drug chemotherapy should favor LOPP over MOPP for its higher complete response rate and longer progression-free survival, while stressing that prospective randomized trials are needed to confirm the result. For now, the median outlook for dogs with multicentric T-cell lymphoma remains a guarded 8 to 9 months, but these data sharpen the treatment algorithm and offer a concrete reason for hope in a meaningful fraction of patients.

Subject of Research: Comparison of LOPP and MOPP alkylator-based chemotherapy protocols for first-line treatment of canine multicentric T-cell lymphoma

Article Title: Retrospective comparison of MOPP versus LOPP for first-line treatment of canine multicentric T-cell lymphoma

Article References: Lounsberry, C., Lindley, S. S., Bergman, N., LaRue, M., Haas-Linden, S., & Smith, A. A. (2025). Retrospective comparison of MOPP versus LOPP for first-line treatment of canine multicentric T-cell lymphoma. Veterinary Oncology, 2(1), Article 22. https://doi.org/10.1186/s44356-025-00039-y

Image Credits: AI Generated

DOI: 10.1186/s44356-025-00039-y

Keywords: canine lymphoma, T-cell lymphoma, LOPP, MOPP, chemotherapy, veterinary oncology, lomustine, mechlorethamine, alkylating agents, complete response, progression-free survival, drug resistance

The study focused on a molecularly defined subset of patients: those whose tumors carry methylation of the MGMT promoter, a chemical modification that silences a key DNA repair gene. This silencing matters enormously for treatment, because the chemotherapy drugs used against glioblastoma, temozolomide and lomustine, work by damaging tumor DNA. When the MGMT repair protein is suppressed, cancer cells cannot efficiently undo that damage, making them more vulnerable to the alkylating agents. Patients with MGMT-methylated tumors therefore respond better to chemotherapy, and the German CeTeG/NOA-09 trial demonstrated that these patients benefit from an intensified first-line regimen combining radiotherapy with both temozolomide and lomustine, also known as CCNU, rather than temozolomide alone.

Earlier work by a group led by Wiewrodt and colleagues had reported that among patients with MGMT-methylated, IDH-wildtype glioblastoma, those with blood group O lived longer than those with A, B, or AB blood types, an effect seen mainly in patients receiving standard temozolomide-based radiochemotherapy. But the association remained untested in patients receiving the intensified lomustine-temozolomide combination, and only a small fraction of the original cohort had received that regimen. The Bonn team, led by Julia Scheuble and Johannes Weller, set out to close that gap by examining an independent cohort treated uniformly under the CeTeG/NOA-09 protocol between 2008 and 2023.

The researchers assembled a cohort of 61 adults with newly diagnosed MGMT-methylated, IDH-wildtype glioblastoma, all of whom had documented ABO blood groups from routine preoperative typing and had received first-line radiochemotherapy with lomustine and temozolomide. Of these, 24 patients, or 39.3 percent, had blood group O, a proportion almost identical to the 39.2 percent prevalence of blood group O among German blood donors, which argues against any selection distortion. Baseline characteristics, including age, sex, Karnofsky Performance Status, and extent of surgical resection, were well balanced between the O and non-O groups, strengthening the credibility of the survival comparison.

The survival differences were substantial. Patients with blood group O lived a median of 42.1 months overall, compared with 23.7 months for patients with non-O blood groups, a difference that reached statistical significance with a log-rank p-value of 0.04. Progression-free survival, the time before the tumor began growing again, showed a similar trend: 21.8 months for blood group O versus 17.5 months for non-O groups, though this unadjusted comparison fell just short of significance. Median follow-up in the cohort was 56.1 months, and the majority of patients underwent surgery in the later years of the study period, reflecting the growing routine availability of molecular tumor characterization.

Crucially, the association survived statistical adjustment for the established prognostic factors. In multivariable Cox proportional hazards models accounting for age, extent of resection, and performance status, patients with non-O blood groups faced nearly double the hazard of progression, with a hazard ratio of 1.86, and more than double the hazard of death, with a hazard ratio of 2.29, compared with blood group O. Sensitivity analyses that sequentially removed individual covariates produced consistent estimates, with overall survival hazard ratios ranging from 2.02 to 2.42, indicating that the finding was not an artifact of any single adjustment variable. Tests of the proportional hazards assumption showed no violations, and salvage treatments at recurrence, including re-resection, re-irradiation, temozolomide rechallenge, bevacizumab, and regorafenib, were distributed similarly between the two blood group strata, suggesting that differences in second-line care did not drive the survival gap.

What could a blood type possibly have to do with brain cancer biology? The ABO system is defined by glycosyltransferase enzymes that decorate cell surfaces with specific sugar structures, and these glycans influence far more than transfusion compatibility. Experimental studies in non-glioma tumor models have linked fucosyltransferase activity, the enzymatic machinery that distinguishes blood group O from other types, to cellular mobility and resistance to apoptosis, the programmed cell death that chemotherapy is designed to trigger. In MGMT-methylated glioblastoma, where impaired DNA repair already heightens sensitivity to alkylating agents, the authors speculate that ABO-dependent glycosylation could theoretically modify how tumor cells respond to temozolomide or lomustine, altering the balance between treatment-induced damage and cellular survival.

The researchers are careful, however, to emphasize the limits of this mechanistic reasoning. There is currently no experimental evidence demonstrating a direct interaction between ABO glycosyltransferase activity, MGMT promoter methylation, and chemotherapy sensitivity in glioblastoma. The observed association could equally reflect differences in intrinsic tumor biology or the tumor microenvironment rather than a treatment-specific effect. The study itself carries the inherent constraints of a retrospective, single-center design with a limited sample of 61 patients, and the restriction to patients considered fit enough for intensified lomustine-temozolomide therapy produced a clinically selected population with relatively favorable performance status, limiting generalizability to frail patients. Residual confounding also cannot be excluded, and the 15-year study window may have introduced historical shifts in surgical technique, imaging, and salvage strategies, although the cohort was concentrated in the later years.

Despite these caveats, the consistency of the result across two independent cohorts, both restricted to MGMT-methylated patients and both showing the same direction of effect, gives the finding unusual weight for a biomarker study of this size. The Bonn cohort’s uniform treatment under a single protocol minimizes the treatment-related heterogeneity that has plagued earlier ABO studies, many of which predate the WHO 2021 integrated molecular classification of brain tumors and mixed together molecularly distinct entities. If validated in larger, multicenter cohorts, blood group typing, a test already performed routinely before any craniotomy, could become a virtually free addition to the prognostic toolkit, helping clinicians and patients calibrate expectations and potentially guiding the design of future trials.

The authors describe their results as hypothesis-generating, and the next step is translational: understanding whether ABO glycans genuinely modulate the response of glioma cells to alkylating chemotherapy, or whether blood group O simply tags some other, still unknown biological advantage. Either answer would deepen scientific understanding of how the most ancient of human genetic markers, the ABO system, interacts with modern cancer medicine. For now, patients with MGMT-methylated glioblastoma and blood group O can be told they carry a statistically favorable sign, while researchers pursue the biology that might one day turn that sign into a therapeutic target for everyone else.

Subject of Research: Association of ABO blood group O with survival outcomes in MGMT-methylated glioblastoma patients receiving lomustine-temozolomide radiochemotherapy

Article Title: Prognostic impact of blood group O in MGMT-methylated glioblastoma patients receiving radiochemotherapy with temozolomide and lomustine

Article References: Prognostic impact of blood group O in MGMT-methylated glioblastoma patients receiving radiochemotherapy with temozolomide and lomustine. (n.d.). https://doi.org/10.1007/s11060-026-05813-y

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05813-y

Keywords: glioblastoma, ABO blood group, MGMT promoter methylation, temozolomide, lomustine, radiochemotherapy, prognostic biomarker, overall survival, progression-free survival, CeTeG/NOA-09, glycosylation, neuro-oncology