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

Melflufen, also known as melphalan flufenamide, is a peptide-drug conjugate designed to deliver an alkylating payload preferentially into myeloma cells by exploiting peptidase activity within the tumor microenvironment. The OCEAN trial compared melflufen-dexamethasone against pomalidomide-dexamethasone in patients with relapsed or refractory disease, while HORIZON evaluated melflufen in heavily pretreated patients. The current European approval restricts melflufen use to patients who have not undergone autologous stem cell transplant or whose time to progression is three years or more, a restriction grounded in a post-hoc analysis of OCEAN showing that patients with a time to progression under 36 months fared significantly worse on melflufen than on the comparator, with median overall survival of 15.7 versus 28.7 months and a hazard ratio of 1.8 that reached statistical significance.

The commentators focus their first major criticism on Patient 1 from the case series, whose time to progression after autologous stem cell transplant was 28 months, placing this individual squarely within the subgroup that the OCEAN post-hoc analysis identified as being disadvantaged by melflufen treatment. The original paper acknowledged this discrepancy only briefly, noting that the long duration of response occurred despite the unfavorable time to progression. Bhise and colleagues contend that this framing creates a subtle but consequential problem: a single case with an atypically favorable outcome is being used to soften the message about a subgroup that randomized trial evidence indicates is harmed, on average, by this treatment relative to the alternative. They emphasize that case reports are inherently susceptible to selective emphasis because exceptional outliers are precisely what prompt such reports in the first place.

The statistical logic underlying this criticism reflects a well-known pitfall in clinical evidence interpretation. Subgroup analyses of randomized trials estimate average effects within defined patient populations, and individual outcomes within any subgroup can deviate dramatically from that average without invalidating the population-level finding. When a case report highlights an outlier who thrived despite belonging to a subgroup that trial data show is disadvantaged, presenting that case alongside arguments for extending treatment to patients outside the approved population risks leaving readers with the impression that individual favorable responses can offset subgroup-level harm demonstrated in a randomized comparison. The commentators argue that explicitly restating, within the discussion of this specific case, that the OCEAN subgroup data indicate a significant survival disadvantage for similar patients would prevent the exceptional case from being misread as evidence against the very population-level finding it contradicts.

The second major criticism concerns the safety data used to reassure readers about the risk of second primary malignancies. Patient 1 received 46 cycles of melflufen-dexamethasone over approximately four years before developing a second primary myelodysplastic neoplasm, a type of bone marrow disorder that can progress to acute leukemia. The original authors attributed this malignancy largely to the patient’s prior exposure to alkylating agents and immunomodulatory drugs, citing the low reported rate of second primary malignancies across the HORIZON and OCEAN trials as reassurance about melflufen’s own mutagenic contribution. The commentators find this reassurance statistically unsound for a specific and important reason rooted in the relationship between cumulative exposure and carcinogenic risk.

That reason is exposure duration. The median progression-free survival among trial responders was 8.5 months in both study populations, meaning that most trial patients received only a small fraction of the cumulative melflufen exposure that Patient 1 accumulated before the malignancy developed. Cumulative-dose-related carcinogenesis is a well-established feature of alkylating agents, and the commentators point out that the trial population’s exposure was systematically too brief to detect such a risk even if it existed. A second primary malignancy rate calculated from a population whose treatment was, on average, cut short after several months by disease progression or intolerance therefore provides limited reassurance about mutagenic risk in patients who go on to receive several years of continuous alkylating exposure. Because the original discussion favors considering melflufen for extended use in exceptional responders, the very population capable of accumulating multi-year exposure, the safety reassurance drawn from short-exposure trial populations does not address the risk profile most relevant to the patients the recommendation would actually affect.

The commentators propose a concrete methodological remedy: reporting cumulative melflufen dose or treatment duration alongside second primary malignancy incidence, where such data are available from trial extensions or real-world follow-up, would provide a more directly applicable estimate of risk for long-term responders being considered for extended therapy. This recommendation aligns with broader principles in oncology pharmacovigilance, where the relevance of safety signals depends critically on matching the exposure profile of the safety data to the exposure profile of the patients in question. Similar concerns about second primary malignancies have been raised in other novel therapy contexts, including systematic reviews of malignancy risk following CAR T-cell therapy, underscoring that long-duration follow-up is essential whenever powerful cytotoxic or immunologic treatments achieve durable disease control.

Despite these pointed criticisms, the commentary is not a rejection of the original work. Bhise and colleagues explicitly acknowledge that the case series offers a genuinely useful clinical contribution by illustrating that meaningful, durable responses to melflufen-dexamethasone are achievable in carefully selected patients. They note that such granular, longitudinal case detail complements population-level trial reporting in ways that aggregate statistics cannot, capturing the clinical course of individual patients over years of treatment. They also credit the original authors with appropriate transparency for explicitly acknowledging that the cases were retrospectively selected for their exceptional duration of response, an admission that properly frames the study’s inherent selection bias. This balanced tone reflects a growing recognition in the medical literature that case reports retain value precisely when their limitations are stated plainly and their conclusions are calibrated to the strength of the evidence.

The clinical implication drawn by the commentators is direct and specific. Before these exceptional cases inform practical guidance about extending melflufen use beyond the currently approved target population or into multi-year continuous therapy, two reconciliations are needed. First, the discussion of Patient 1 should explicitly confront the unfavorable OCEAN subgroup data for patients with a time to progression under 36 months, rather than allowing a favorable outlier to stand in implicit tension with randomized evidence. Second, reassurance about second primary malignancy risk during extended use should be grounded in exposure-matched safety data rather than incidence rates drawn from a trial population whose average treatment duration was substantially shorter. Until those conditions are met, the commentators suggest, the exceptional responses should be viewed as intriguing observations rather than as a basis for broadening treatment recommendations.

The exchange highlights a broader lesson for the era of precision oncology and expanding immunotherapies. As treatment landscapes grow more complex, with novel agents such as antibody-drug conjugates, bispecific antibodies, and CAR T-cell therapies entering practice alongside older cytotoxic backbones, the temptation to generalize from spectacular individual responses will only increase. The commentary by Bhise, Akotkar, Bhandari, and Gite serves as a reminder that the evidentiary weight of a case report is bounded by the statistics of the trials that contextualize it, and that safety conclusions are only as strong as the exposure profiles on which they rest. For patients with relapsed or refractory multiple myeloma, a disease where treatment sequencing decisions carry profound survival consequences, the difference between an exceptional anecdote and population-level evidence can be a matter of years of life, making rigorous interpretation of both not an academic nicety but a clinical imperative.

Subject of Research: Critical appraisal of melflufen-dexamethasone case reports for relapsed/refractory multiple myeloma

Article Title: Comment on “Exceptional long-term responses from OCEAN and HORIZON trials: melflufen-dexamethasone as an expansion of treatment options for relapsed/refractory multiple myeloma in the era of new immunotherapies?”

Article References: Bhise, M. R., Akotkar, A., Bhandari, S., & Gite, K. V. (2026). Comment on “Exceptional long-term responses from OCEAN and HORIZON trials: melflufen-dexamethasone as an expansion of treatment options for relapsed/refractory multiple myeloma in the era of new immunotherapies?”. Journal of Cancer Research and Clinical Oncology, 152(9), Article 176. https://doi.org/10.1007/s00432-026-06608-4

Image Credits: AI Generated

DOI: 10.1007/s00432-026-06608-4

Keywords: melflufen, dexamethasone, multiple myeloma, OCEAN trial, HORIZON trial, relapsed/refractory myeloma, second primary malignancy, subgroup analysis, case report, alkylating agents, clinical trials, oncology