Anti-CD 19 CAR-T Cell Therapy with Tisagenlecleucel for Ritcher Syndrome

About 2-10 percent of patients with chronic lymphocytic leukemia (CLL) will transform into an aggressive large cell lymphoma, called Ritcher syndrome (RS). The transformation is to DLBCL in 90-95% of cases and Hodgkin lymphoma in the remaining 5-10%. Current treatment strategies that typically mirror DLBCL have not significantly improved the historically dismal outcomes of RS. Chimeric antigen receptor-modified T (CAR-T) cells have revolutionized the treatment of B-cell malignancies and are currently approved for relapsed/refractory DLBCL. The impact of CAR-T cell therapy in the management of RS is limited by the small number of affected patients and published reports. We report the outcomes in 2 patients with RS treated with tisagenlecleucel (Tisa-cel) at our institution.

Patient 1.

This is a 75-year-old lady diagnosed with CLL at the age of 64, Rai stage 1, trisomy 12, mutated IGVH. She was on observation until she became symptomatic 5 yrs. after diagnosis and had a biopsy which showed CLL with RS, fluorescent in-situ hybridization (FISH) negative for C-MYC, BCL2 and BCL6. She was treated with RCHOP x 6 cycles with complete remission (CR) on PET. She received high dose chemotherapy with R-BEAM followed by autologous stem cell transplant, followed by 4 cycles of maintenance brentuximab given every 3 weeks for her CD30 positive large B cell lymphoma. About 5 yrs. later, surveillance PET showed hypermetabolic cervical lymph nodes and excisional biopsies showed CLL and DLBCL, non-germinal center type, concerning for relapsed RS. She was referred to us for CAR-T cell therapy evaluation. Bone marrow biopsy was negative for marrow involvement, minimal residual disease (MRD) by ClonoSEO was positive. She received lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR-T cell infusion with tisa-cel 5x10^8 anti CD19 CAR-T cells on 4/18/22. Treatment was complicated by grade 1-2 cytokine release syndrome (CRS) (treated with tocilizumab and dexamethasone) requiring brief hospitalization. Day 90 PET showed CMR and bone marrow biopsy was negative for disease, MRD negative. She continues to be in CR 100 days post CAR-T cell therapy.

Patient 2.

A 63 years-old lady originally diagnosed with CLL in 2016 at the age of 57, with 17p deletion, 13q deletion and IgHV unmutated. She was started on ibrutinib shortly after due to a short lymphocyte doubling time. Three years later (in 2020), she developed worsening lymphadenopathy while on ibrutinib, underwent excisional biopsy and this showed RS with TP53 mutation, 17p deletion, gain of 13q, BCL2 positive. Venetoclax was added to ibrutinib and later, 2 cycles of Obinutuzumab were also given. Subsequent PET 7 months after showed disease progression with a lugano score of 5. She received 6 cycles of RCHOP in addition to venetoclax/ibrutinib but end of treatment PET showed disease progression. She was then referred to us for CAR-T cell evaluation. She received lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR-T cell infusion with tis-cel 3.7 x 10^8 cells anti CD19 CAR-T cells on 6/7/21. This was complicated by grade 2 CRS that was treated with tocilizumab. Day 30 PET showed PR. Ibrutinib was resumed and the patient received radiation to right cervical lymph nodes. Day 100 PET reaffirmed PR and she subsequently underwent FluCyTBI RIC followed by haploidentical alloSCT from her daughter on 09/29/21. On day 180 post-transplant, the patient remained in CR by PET and bone marrow biopsy. She continues to be in CR now 1 year since her CAR-T cell infusion.

Conclusion

CAR-T cell therapy with Tisagenlecleucel shows promising activity in patients with RS. It is an evolving treatment strategy and more follow up is needed to assess the durability of the responses observed in these patients.

No relevant conflicts of interest to declare.