Cold agglutinin disease (CAD), a chronic indolent B-cell clonal disorder, has long posed major clinical challenges. Its counterpart, cold agglutinin syndrome (CAS), is typically triggered by infections, malignancies, or autoimmune disorders. Both conditions fall under cold-antibody autoimmune hemolytic anemia (cAIHA), a difficult-to-treat subtype.
While cases of diffuse large B-cell lymphoma (DLBCL) complicated by CAS are exceedingly rare, their disease mechanisms and treatment strategies remain unresolved issues in hematology.
Recently, a research team led by Dr. Shaomei Feng, together with colleagues Dr. Biping Deng, Dr. Meiling Sun, Dr. Haidi Liu, and Head Nurse Xiuyan Tao, published an important case report in the international journal Leukemia & Lymphoma – A patient with relapsed/refractory DLBCL complicated by CAS achieved sustained complete remission (CR) after receiving CD19 CAR-T cell therapy. This landmark case highlights the broader potential of CAR-T therapy in complex hematologic malignancies and opens new possibilities for treating rare lymphomas complicated by autoimmune conditions.
A rare case of lymphoma with autoimmune complications: repeated relapses and limited options
The patient first presented in October 2019 with a one-week history of dizziness. CBC showed hemoglobin 6.2 g/dL, reticulocyte 3.87%, and a direct Coombs test positive for C3d but negative for IgG. LDH increased to 302 U/L. No signs of malignancy or autoimmune disease were present, leading to a diagnosis of primary CAD. Hemoglobin stabilized at ~13 g/dL with corticosteroid treatment.
In January 2021, the patient underwent surgery for bowel obstruction and perforation, which revealed DLBCL.
PET-CT showed widespread lesions involving the gastrointestinal tract, spine, ribs, scapula, pelvis, and long bones. Bone marrow biopsy confirmed DLBCL. After six cycles of R-CHOP, the patient achieved complete remission.
In February 2022, the patient developed fingertip cyanosis. Cold agglutinin titer was 1:256 and IgM levels were elevated, confirming CAS.
In August 2022, PET-CT and flow cytometry suggested lymphoma relapse. After six cycles of R-GemOx, bone marrow biopsy turned negative.
In February 2023, the patient underwent autologous peripheral blood stem cell transplantation (auto-PBSCT).
In October 2023, PET-CT revealed another relapse, with 2% blasts in bone marrow and a complex karyotype.
Reaching long-term remission with CD19 CAR-T cell therapy
In November 2023, the patient sought further treatment. Five cycles of reduced-intensity R-CDOP combined with a BTK inhibitor and a PI3K inhibitor brought the disease back to remission.
In May 2024, after lymphodepleting chemotherapy, the patient received autologous CD19 CAR-T cell infusion. CAR-T cells expanded rapidly and peaked on day 7. They remained detectable in peripheral blood via NGS even 270 days after infusion.
Adverse events included grade 1 cytokine release syndrome (CRS), grade 3 hematologic toxicity, and grade 3 non-hematologic toxicity (pharyngeal edema). No ICANS occurred.
Bone marrow examinations at days +30, +60, and +90 remained negative. PET-CT at days +90, +180, and +270 showed continued complete remission. Hemolytic anemia resolved completely, Coombs test became negative, and no recurrence of CAS was observed during follow-up. The patient has now maintained complete remission for 1.5 years.
CAR-T therapy delivers new hope for complex lymphoma with autoimmune disease
This report is the first to document successful long-term remission in a patient with CAS-associated relapsed/refractory DLBCL treated with CD19 CAR-T therapy.
Notably, although CAS has been previously reported alongside lymphoma, this patient’s CAS was diagnosed one year before the lymphoma diagnosis—leading to early misclassification as primary CAD. This underscores the complexity of CAS and the importance of identifying underlying malignancy rather than focusing solely on symptomatic management.
Throughout the disease course, the patient experienced multiple relapses despite R-CHOP, R-GemOx, and auto-PBSCT, suggesting that CAS may diminish the effectiveness of conventional therapies and transplantation.
Given that CAR-T therapy is approved for relapsed/refractory large B-cell lymphoma and has shown emerging promise in autoimmune diseases, the medical team pursued CD19 CAR-T treatment after effective tumor debulking with R-CDOP plus BTK/PI3K inhibitors.
The results were remarkable:
CAR-T therapy achieved dual remission—eliminating both lymphoma and autoimmune hemolysis.
This groundbreaking case provides important insights for treating rare lymphomas complicated by CAS. It suggests that innovative therapies like CAR-T, which target the root cause, may offer deeper and more durable responses. Larger studies will be needed to confirm these findings.
