A 75-year-old Austrian woman with an aggressive, repeatedly relapsing blood cancer has achieved a complete remission lasting more than two years after her doctors made an unusual decision: instead of following a standard drug protocol, they sequenced the DNA shed by her tumor into the bloodstream and let the results choose her treatment. The test revealed an exceptionally high tumor mutational burden, a molecular signature that in certain solid tumors predicts responsiveness to immune checkpoint inhibitors. On that basis, the team at University Hospital Krems treated her with the PD-1 blocker nivolumab, a strategy never before reported for this disease. She entered a complete metabolic remission within about six months, remained in remission through 25 months of therapy, and is still cancer-free eight months after the drug was stopped, according to a case report and literature review published in Cancer Reports.

The cancer in question is anaplastic large cell lymphoma, or ALCL, a rare T-cell non-Hodgkin lymphoma that exists in several biologically distinct forms. Systemic ALCL is classified as ALK-positive or ALK-negative depending on whether the tumor carries the ALK fusion oncogene, while separate entities include breast implant-associated ALCL and primary cutaneous ALCL. For most adults with systemic disease, first-line therapy consists of anthracycline-based chemotherapy, with the antibody-drug conjugate brentuximab vedotin combined with cyclophosphamide, doxorubicin and prednisone, known as BV-CHP, now the preferred regimen for CD30-positive cases. When the disease returns or stops responding, options include brentuximab vedotin alone, autologous or allogeneic stem cell transplantation, and ALK inhibitors for relapsed ALK-positive disease. Brentuximab vedotin achieves complete remission in roughly 60 percent of relapsed or refractory patients, but for those who fail to reach remission, median overall survival is only 9.5 months, a statistic that underscores how desperately new strategies are needed.

The patient’s journey began in May 2017, when she presented at age 75 with chronic diarrhea and weight loss. Initial workups for infections, celiac disease and inflammatory bowel disease, along with colonoscopy, all came back negative. Her symptoms worsened, and in July 2017 she developed a small-bowel obstruction requiring surgical resection. Histopathology of the resected tissue delivered the diagnosis: ALK-negative ALCL at stage IVB, meaning the disease had already spread widely. Eight cycles of the standard CHOP chemotherapy regimen produced a complete response, but the lymphoma returned just three months after treatment ended in February 2018. What followed was a years-long cycle of remission and relapse that would exhaust nearly every established option.

Second-line brentuximab vedotin at 1.8 milligrams per kilogram of body weight brought another complete response after eight cycles. Six months after the drug was stopped, the disease relapsed again in February 2019, prompting re-initiation of brentuximab vedotin for an additional 33 cycles. Once more the patient achieved a complete metabolic response, confirmed by PET/CT imaging, and treatment was discontinued in February 2021. Fifteen months later, in May 2022, a third relapse occurred. Because she had developed grade 1 to 2 peripheral neuropathy, a known cumulative toxicity of the antibody-drug conjugate, brentuximab vedotin was withheld. The team instead chose lenalidomide, an immunomodulatory agent given at 15 milligrams daily for 21 days of each 28-day cycle, which stabilized the disease temporarily. After seven cycles, the lymphoma progressed in November 2022.

A final brentuximab vedotin re-challenge, six cycles from April to August 2023, failed entirely. At that point, with few options remaining, the clinicians turned to comprehensive genomic profiling of circulating tumor DNA using the FoundationOne Liquid assay. The September 2023 analysis revealed a tumor mutational burden of 23 mutations per megabase, a figure well above the thresholds generally considered high. Tumor mutational burden and microsatellite instability have emerged as predictive biomarkers for immune checkpoint blockade in several solid tumors, where tumors carrying many mutations produce more abnormal proteins that the immune system can recognize. On that tissue-agnostic rationale, and with no standard alternatives left, the team began nivolumab, initially at 240 milligrams every two weeks and later modified to 480 milligrams every four weeks.

The response was striking. Clinical improvement appeared within two months, and at the first formal response assessment in March 2024, roughly six months after starting therapy, imaging showed a complete metabolic remission. The treatment was not without consequences: in April 2024 the patient developed grade 2 immune-related thyroiditis, an inflammation of the thyroid gland typical of checkpoint inhibitor toxicity, which was managed with thyroid hormone replacement and did not require stopping nivolumab. She continued the drug until November 2025, completing 25 months of treatment. In December 2025 she suffered a myocardial infarction requiring percutaneous coronary intervention with stent implantation, but given her sustained remission, no further nivolumab was administered. At her most recent follow-up in July 2026, eight months after the last dose, she remains in complete metabolic remission with no detectable tumor-associated alterations on repeat liquid biopsy, and reports good overall condition with an ECOG performance status of 1.

To understand how unusual this outcome is, the authors systematically reviewed the literature and found only three previously published adult cases of relapsed or refractory ALCL treated with immune checkpoint inhibitors. Chan and colleagues described a 35-year-old woman with ALK-negative disease who, after multiple chemotherapy failures, autologous transplantation and a relapse three months after allogeneic transplantation, achieved complete response on pembrolizumab within about 70 days, with elevated transaminases as the only side effect. Hebart and colleagues reported a 19-year-old man with ALK-positive disease who had relapsed despite chemotherapy, brentuximab vedotin, the ALK inhibitor crizotinib and autologous transplantation; nivolumab produced complete response within one month, with pneumonitis after 12 cycles treated successfully with corticosteroids. Barta and colleagues included one ALK-negative ALCL patient in a phase 2 trial of PD-1 or PD-L1 inhibition in relapsed T-cell lymphomas; although the trial was halted early for limited efficacy overall, that single patient remained in complete remission for 18 months at publication. A pediatric case reported by Rigaud and colleagues, a 17-year-old with ALK-positive disease treated third-line with nivolumab, adds further support, with rapid response and remission maintained 18 months after initiation.

Taken together, all four adult patients, including the present case, achieved complete remission and remained progression-free across reported observation periods of 4, 9, 18 and 33 months. Where safety data were available, adverse events were manageable and consistent with the established immune-related toxicity profile of PD-1 inhibitors, though the authors caution that patients treated after allogeneic stem cell transplantation face an elevated risk of graft-versus-host disease. The authors are equally clear about the limits of this evidence. Case reports carry strong publication bias, because unsuccessful treatments are far less likely to be published, making it impossible to estimate the true response rate of checkpoint blockade in ALCL. There is currently no validated evidence that tumor mutational burden predicts benefit from immunotherapy in ALCL or other T-cell lymphomas, so the treatment selection in this case was extrapolated from tissue-agnostic approvals in TMB-high solid tumors and should be regarded as hypothesis-generating rather than evidence-based.

Two additional findings may shape future research. Retrospective immunohistochemical analysis of the patient’s original 2017 tumor sample, performed during preparation of the manuscript, showed PD-L1 expression in 95 percent of tumor cells, though whether this contributed to the favorable response remains speculative. The biology of PD-L1 expression also differs between ALCL subtypes: in ALK-positive disease, PD-L1 is driven by oncogenic signaling downstream of ALK with constitutive STAT3 activation playing a central role, whereas ALK-negative disease lacks this driver and PD-L1 may be regulated through alternative STAT3- and MYC-dependent transcriptional programs, a distinction the authors argue demands separate evaluation of the subtypes in future studies. Serial circulating tumor DNA assessment, which tracked this patient’s response and confirmed molecular remission, may also warrant investigation as a monitoring tool in ALCL. The authors conclude that immune checkpoint inhibition should not yet be considered standard treatment for relapsed or refractory ALCL, but may be considered individually, preferably within a clinical trial or structured translational program, for patients who have exhausted established alternatives, and that prospective studies are needed to define efficacy, safety, optimal treatment duration and biomarker-guided patient selection, including rational combinations with brentuximab vedotin whose mechanisms of action may prove complementary.

Subject of Research: Immune checkpoint inhibitor therapy guided by genomic profiling in relapsed or refractory anaplastic large cell lymphoma

Article Title: Immune Checkpoint Inhibitors in Relapsed/Refractory Anaplastic Large Cell Lymphoma (ALCL): A Case Report and Review of the Literature

Article References: Klenner, C., & Singer, J. (2026). Immune Checkpoint Inhibitors in Relapsed/Refractory Anaplastic Large Cell Lymphoma ( ALCL ): A Case Report and Review of the Literature. Cancer Reports, 9(9), Article e70684. https://doi.org/10.1002/cnr2.70684

Image Credits: AI Generated

DOI: 10.1002/cnr2.70684

Keywords: anaplastic large cell lymphoma, immune checkpoint inhibitors, nivolumab, PD-1 blockade, tumor mutational burden, liquid biopsy, circulating tumor DNA, brentuximab vedotin, PD-L1 expression, T-cell lymphoma, precision oncology, case report

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