Case Report: Durable response to PD-1 blockade after failure of ALK-targeted therapy and chemoimmunotherapy in ALK-positive large B-cell lymphoma

Background: Anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL) is an exceedingly rare and aggressive subtype of B-cell non-Hodgkin lymphoma, comprising less than 1% of all LBCL cases. These tumors often exhibit resistance to standard chemoimmunotherapy and targeted approaches, resulting in poor clinical outcomes and a median overall survival of approximately 20 months. Despite the identification of ALK rearrangements and activating mutations, effective treatment strategies remain elusive.

Case presentation: We report a case of an adult diagnosed with stage IV ALK+ LBCL, confirmed via lymph node biopsy and fluorescence in situ hybridization (FISH) demonstrating ALK rearrangement in 91% of nuclei. The patient progressed through four lines of therapy, including R-CHOP, alectinib, lorlatinib with involved-field radiation, and brentuximab vedotin plus bendamustine. Comprehensive genomic profiling revealed a CLTC-ALK fusion and two ALK gain-of-function mutations (p.L1196M and p.G1202R), which are typically sensitive to lorlatinib, suggesting ALK-independent resistance mechanisms. Repeat biopsy demonstrated 20%–30% PD-L1 expression in tumor cells. With no standard options remaining, the patient elected to receive off-label nivolumab. Remarkably, despite an initial disease flare, a rapid clinical and radiological response was observed after just two cycles. As of the latest follow-up after 16 cycles, the patient remains on treatment with sustained clinical benefit and no adverse events reported.

Discussion: This case highlights the therapeutic challenges of ALK+ LBCL, including its refractoriness to both standard chemotherapy and ALK inhibitors, even in the presence of targetable mutations. The exceptional response to PD-1 blockade, possibly facilitated by acquired PD-L1 expression and an inflammatory tumor microenvironment, suggests an immunologically active tumor niche. Comparison with prior cases supports the hypothesis that PD-L1 expression, even at moderate levels, may predict responsiveness to immune checkpoint inhibitors in this rare lymphoma subtype.

Conclusion: This case underscores the potential of immune checkpoint inhibition in ALK+ LBCL, particularly in patients with relapsed or refractory disease. PD-L1 testing and repeat biopsy at progression may offer critical insights for guiding therapy. Prospective studies are warranted to explore checkpoint blockade alone or in combination with targeted agents in this aggressive lymphoma.

Introduction

Anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL) is an extremely rare and aggressive subtype of B-cell non-Hodgkin lymphoma, accounting for less than 1% of all LBCL cases, with fewer than 200 cases reported in the literature as of the beginning of this decade (1). First described in 1997, when Delsol et al. (2) reported seven cases of ALK-expressing large immunoblast-like cell lymphomas with an aggressive clinical course, additional cases of ALK+ LBCL have since continued to be reported in the literature. In the 2017 classification by the World Health Organization of hematopoietic and lymphoid neoplasms, ALK+ LBCL was defined as an aggressive neoplasm composed of ALK-positive monomorphic large immunoblast-like B cells exhibiting a plasma cell phenotype, distinguishing it from diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (3). This classification underscores its unique nature and clinical significance within the spectrum of aggressive lymphoid neoplasms.

These tumors pose both diagnostic and therapeutic challenges due to their rarity and resistance to standard treatment. Their rarity complicates early identification, while current therapeutic approaches offer limited survival benefits. Patients have a median overall survival of 20.3 months (4), with a 5-year survival rate of only 25%, primarily due to chemotherapy-refractory disease, possibly driven by immune evasion and other tumor microenvironment factors.

In this report, we illustrate a case of primary refractory ALK+ LBCL that progressed on four lines of systemic therapy, including anthracycline-based chemoimmunotherapy, two different ALK inhibitors, and antibody–drug conjugate therapy, before experiencing a remarkable response to single-agent nivolumab.

Case presentation

A 58-year-old male patient with no previous relevant medical or family history initially presented with complaints of constipation and low pelvic pain in December 2023 at the emergency department (ED), with symptom onset in November 2023 and progressive worsening. Imaging studies performed during evaluation in the ED revealed bulky para-aortic lymphadenopathy, and subsequent imaging demonstrated pathologic adenopathy in the left supraclavicular region. An ultrasound (US)-guided biopsy of a left cervical level III lymph node established the diagnosis of anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL) (Figure 1). Fluorescence in situ hybridization (FISH) analysis confirmed ALK rearrangement in 91% of nuclei.

Figure 1

Figure 1. Diagnostic left cervical lymph node biopsy. (A) Infiltrate of large atypical cells with foci of necrosis; hematoxylin and eosin (H&E) stain, 100× magnification. (B) HE stain 400x. (C) CD30 100x. (D) CD138 100x. (E) ALK 100x. (F) OCT2 100x. The neoplastic cells were negative for CD19, CD20, immunoglobulin light chains, T-cell markers, multiple cytokeratins, and EBV by in situ hybridization.

Staging with baseline positron emission tomography–computed tomography (PET-CT) demonstrated extensive fluorodeoxyglucose (FDG)-avid lymphadenopathy both above and below the diaphragm (Figure 2A), with findings concerning for splenic and possible bone marrow involvement. A staging bone marrow biopsy, however, showed no lymphoma involvement (stage III disease). Laboratory evaluation was notable for elevated lactate dehydrogenase (LDH) (316 U/L; upper normal limit [UNL]: 222 U/L), resulting in an initial International Prognostic Index (IPI) score of 3.

Figure 2

Figure 2. (A) Baseline PET-CT scan at initial diagnosis showing extensive FDG-avid lymphadenopathy above and below the diaphragm, demonstrating the initial extent of ALK+ large B-cell lymphoma. (B) PET-CT scan beforestart of nivolumab salvage treatment illustrating disease progression and metabolic changes. (C) Interim evaluation after two cycles of nivolumab (December 2024), demonstrating partial metabolic response (Lugano 2014). (D) PET-CT scan after 16 cycles of Nivolumab (June 2025) depicting marked metabolic response and reduction in original FDG-avid lymphadenopathy. Small mesenteric adenopathy with mild FDG activity was noted (not visible in frame shown in D). This was consistent with progressive disease by Lugano 2014 criteria and with an indeterminate response type 2 (IR2) by the LYRIC criteria. Given overall clinical improvement, decision was made to continue therapy and repeat PET-CT in 8-12 weeks).

The patient initiated first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in January 2024. After four cycles, he did not report any adverse events or toxic side effects; however, PET-CT demonstrated disease progression. Given the lack of response, ALK inhibition with off-label alectinib (600 mg twice daily) was pursued. Treatment was complicated by mild (grade 1) normocytic anemia (hemoglobin: 12.8 g/dL), mild (grade 1) acute kidney injury (creatinine: 1.45 mg/dL; UNL: 1.35 mg/dL), and mild (grade 1) photosensitivity. Subsequent imaging after 8 weeks of therapy revealed disease progression, with recurrent elevation of LDH (364 U/L; UNL: 222 U/L). The patient was then transitioned to off-label lorlatinib (100 mg once daily), a third-generation ALK inhibitor, in combination with radiation therapy (4005 cGy in 15 fractions to the retroperitoneal lymph nodes and spleen and 2500 cGy in five fractions to the right cervical lymph node). No symptoms or complaints were reported by the patient; however, laboratory evaluation demonstrated an elevation in low-density lipoprotein cholesterol (from a baseline of 150 mg/dL to 296 mg/dL after lorlatinib initiation). Due to low overall cardiovascular risk, statin therapy was deferred. Despite this approach, disease progression occurred within 2 months.

At this point, the patient underwent repeat biopsy (Figure 3A) of a cervical lymph node. Despite denial of constitutional symptoms, abdominal pain, or other systemic complaints, laboratory evaluation showed marked elevation in LDH (671 U/L; UNL: 222 U/L). Salvage therapy with brentuximab vedotin plus bendamustine (BV–bendamustine) was initiated while biopsy results were pending. The patient reported drenching night sweats following the first cycle, with spontaneous resolution during subsequent cycles. Biopsy results confirmed recurrent ALK+ LBCL, and the neoplastic cells were found to be focally PD-L1–positive (20%–30%) (Figure 3B). Despite continued therapy, the patient experienced rapid disease progression, including bulky cervical and axillary masses, with recurrent pain in the cervical lymph nodes and abdomen (Figure 2B).

Figure 3

Figure 3. Recurrent ALK+ LBCL in the left cervical lymph node. (A) HE 100x (Inset: ALK 100x). (B) PD-L1 100x.

Comprehensive genomic profiling via the Tempus xT panel identified a CLTC-ALK translocation alongside two ALK gain-of-function missense mutations, p.L1196M and p.G1202R. These mutations are typically sensitive to lorlatinib (5), highlighting that disease progression was likely due to ALK-independent resistance mechanisms.

Subsequently, the patient elected to discontinue cytotoxic therapy. Given the lack of established standard-of-care treatment options for ALK+ LBCL in this context, allogeneic stem cell transplantation was offered; however, the patient declined and opted to receive off-label PD-1 checkpoint inhibition with nivolumab as salvage therapy. He was admitted for the first dose of nivolumab, after which fever and tachycardia were reported. Due to progressive symptoms, the patient elected to transition to hospice care.

After a single cycle of nivolumab and 2 months on hospice, the patient contacted our service reporting clinical improvement and scheduled a follow-up appointment. Palpable reduction in tumor size was noted on physical examination, despite initial tumor growth during the first 2 weeks following nivolumab initiation. A second cycle of nivolumab was administered.

Evaluation after two cycles demonstrated a decrease in previously palpable and visible tumors. PET-CT imaging performed in December 2024 (Figure 2C) demonstrated decreased metabolic activity and visible reduction in tumor burden, achieving a partial response per Lugano 2014 criteria (6).

In March 2025, the patient underwent an outside PET-CT, with results reviewed by Mayo Clinic Radiology, demonstrating complete metabolic response per Lugano 2014 criteria (6). Images from this scan were not available for inclusion in this report. The patient continued treatment with nivolumab.

As of the time of writing, the patient has received 16 cycles of nivolumab, reporting sustained symptom improvement and no treatment-related adverse events. He returned to our service on June 24, 2025, and PET-CT imaging demonstrated remarkable improvement of original hypermetabolic lesions (Figure 2D) with new mild hypermetabolic activity in small mesenteric lymph nodes. This was consistent with progressive disease by Lugano 2014 criteria (6) and with an indeterminate response type 2 (IR 2) by the LYRIC criteria (7). Given the overall clinical improvement since initiation of checkpoint inhibitor, he was continued on therapy with plan to repeat PET-CT in 8-12 weeks.

Discussion

This case illustrates several notable aspects of anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL), particularly its resistance to conventional therapies and the potential role of immune checkpoint inhibition. Our patient presented with advanced disease, characterized by extensive FDG-avid lymphadenopathy both above and below the diaphragm, consistent with the typical aggressive presentation of this rare entity.

The pathological findings in the initial biopsy align with the classical features of ALK+ LBCL, demonstrating large atypical cells with cytoplasmic ALK expression, CD30 positivity (although not typically associated with this entity and reported in approximately 15% of cases), and weak, partial expression of CD45 and CD138 (2, 8). The presence of clonal immunoglobulin gene rearrangement and OCT2 expression confirmed the B-cell lineage of this neoplasm despite its somewhat unusual immunophenotype.

Comparison of the initial diagnostic biopsy with the subsequent biopsy performed after multiple lines of therapy revealed both consistent and evolving features. Both specimens demonstrated the characteristic cytoplasmic ALK positivity (typical of ALK+ LBCL) and retained partial CD30 and CD45 expression. However, notable differences were observed in the expression pattern of CD138, which appeared more prominent in the second biopsy compared with the weak expression in only a small subset of cells in the initial sample. This evolution in CD138 expression may reflect therapy-induced plasmacytic differentiation, a phenomenon reported in other aggressive B-cell lymphomas after treatment exposure (9).

Importantly, the second biopsy revealed focal PD-L1 expression (20%–30%) in the neoplastic cells, a finding not assessed in the initial diagnostic specimen due to insufficient tissue. Whether this PD-L1 expression was present at diagnosis or emerged as an adaptive resistance mechanism in response to prior therapies remains uncertain. Therapy-induced PD-L1 upregulation has been documented in various malignancies, including lymphomas, and can occur through diverse mechanisms, including genomic alterations, epigenetic modifications, and inflammatory cytokine signaling (10). The acquisition or enhancement of PD-L1 expression may have contributed to resistance to conventional therapies while simultaneously creating a vulnerability to PD-1 blockade, as evidenced by the subsequent remarkable response to nivolumab.

The clinical course of this patient underscores the significant therapeutic challenges in managing ALK+ LBCL. Despite the theoretical rationale for ALK inhibition in this molecular subtype, the patient demonstrated primary resistance to both alectinib and lorlatinib. The identification of ALK gain-of-function mutations (p.L1196M and p.G1202R) is intriguing, as these mutations are typically associated with resistance to first- and second-generation ALK inhibitors in ALK-positive non-small cell lung cancer (NSCLC) (11). However, lorlatinib was specifically designed to overcome these resistance mutations (5, 12), suggesting that disease progression in this case was likely driven by ALK-independent mechanisms rather than target-specific resistance.

The remarkable response to single-agent nivolumab observed after failure of multiple lines of therapy, including ALK inhibitors and an antibody–drug conjugate, is particularly noteworthy. This response correlates with the focal PD-L1 expression (20%–30%) observed in the neoplastic cells upon repeat biopsy.

This case shares important similarities with a previously reported adult patient with ALK+ LBCL who also achieved a remarkable response to nivolumab after failing multiple lines of conventional chemotherapy (13). However, several key distinctions exist between the two cases. First, the patient described here failed not only conventional chemotherapy but also targeted therapy with two different ALK inhibitors (alectinib and lorlatinib) and an antibody–drug conjugate (brentuximab vedotin), representing a broader spectrum of therapeutic resistance. The failure of ALK inhibitors in this case, despite the presence of the CLTC-ALK fusion, suggests that ALK signaling may not be the sole driver of disease progression in all cases of ALK+ LBCL, highlighting the complexity of oncogenic signaling in this entity.

Second, while the previously reported case demonstrated higher PD-L1 expression (approximately 50% of tumor cells) compared with this case (20%–30%), both patients achieved significant clinical responses to nivolumab. This observation suggests that even modest PD-L1 expression may predict benefit from PD-1 blockade in this aggressive lymphoma subtype.

Third, the previously reported case did not explore ALK inhibitors as a therapeutic strategy, whereas this case demonstrates that even after failure of ALK-targeted therapy, immune checkpoint inhibition may provide clinical benefit. This observation raises important questions regarding the optimal sequencing of targeted therapies and immunotherapies in ALK+ LBCL and suggests potential opportunities for combination approaches in future studies.

Interestingly, the morphological features observed in the second biopsy, including the presence of necrosis, may reflect a tumor microenvironment.

The mechanisms underlying the response to PD-1 blockade in this case may involve both tumor cell–intrinsic and microenvironment-dependent factors. ALK signaling has been shown to activate multiple oncogenic pathways, including STAT3, which can directly upregulate PD-L1 expression (14).

The response observed with nivolumab in this patient, who had previously been considered for hospice care, underscores the potential of immune checkpoint inhibition as a salvage strategy in chemorefractory ALK+ LBCL. This observation is particularly relevant given the poor prognosis of patients with relapsed or refractory disease, who typically have a median survival of less than 1 year with conventional salvage approaches (15).

This case has several limitations. As a single case report, the generalizability of these findings to the broader ALK+ LBCL population remains uncertain. Furthermore, the long-term durability of this response remains to be determined, as the patient continues on treatment at the time of this report.

Nevertheless, this case provides preliminary evidence supporting the potential utility of immune checkpoint inhibition in chemorefractory ALK+ LBCL. These findings suggest that PD-L1 testing should be considered in patients with relapsed or refractory ALK+ LBCL to identify potential candidates for immunotherapy. The observed immunophenotypic evolution between the initial and subsequent biopsies also highlights the importance of repeat biopsy at progression to capture therapy-induced changes that may inform subsequent treatment decisions. Furthermore, this case highlights the need for prospective studies evaluating the efficacy of immune checkpoint inhibitors, either as monotherapy or in combination with ALK inhibitors, in this rare and aggressive lymphoma subtype.

Conclusion

In conclusion, this case illustrates that, despite the aggressive nature and poor prognosis associated with ALK+ LBCL, targeted immunotherapy approaches may offer hope for patients with otherwise treatment-refractory disease. The temporal evolution of the tumor’s immunophenotype, particularly the emergence or enhancement of PD-L1 expression, underscores the dynamic nature of this disease and the potential value of sequential biopsies in guiding precision medicine approaches. As understanding of the molecular and immunological landscape of this rare entity continues to evolve, personalized therapeutic strategies guided by comprehensive genomic and immune profiling may ultimately improve outcomes in this challenging disease.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Ethics statement

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Author contributions

GG: Project administration, Methodology, Writing – review & editing, Conceptualization, Writing – original draft. AA: Writing – original draft, Data curation, Conceptualization, Writing – review & editing. OC: Writing – review & editing, Writing – original draft, Investigation, Data curation. DJ: Validation, Writing – review & editing, Writing – original draft, Resources, Formal analysis. JV: Investigation, Supervision, Writing – review & editing, Conceptualization, Validation, Writing – original draft.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declared that generative AI was not used in the creation of this manuscript.

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