Сase report: Ibrutinib as a bridge to allogeneic stem cells transplantation in a patient with Richter transformation
Luibov A. Tsvetkova, Natalya B. Mikhailova, Kirill V. Lepik, Elena V. Kondakova, Elena I. Darskaya, Maria V. Barabanschikova, Vadim V. Baykov, Yuriy R. Zalialov, Boris V. Afanasyev
R. M. Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
IntroductionChronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. Richter syndrome (RS) is defined as the transformation of CLL into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RS occurs in approximately 2% to 10% of CLL patients and is associated with very rapid disease progression and generally bad prognosis and poor survival. The experience with intense combination chemotherapy-based regimens suggests that traditional chemotherapy (R-CHOP, R-DHAP, R-ICE) does not always allow to achieve adequate response sufficient to proceed for allogeneic stem cells transplantation (alloHSCT) in most patients. Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK), is an effective drug for treatment of resistant CLL, including bridge therapy to alloSCT. The role of ibrutinib in RS therapy has not studied enough. The goal of present study was to analyze the case of ibrutinib as bridge-therapy to allogeneic stem cells transplantation in patient with Richter transformation.
Materials and methodsRetrospective analysis of medical documentation, results of instrumental (PET/CT) and laboratory tests.
Case descriptionA 35-year-old man was admitted to the clinic in September 2014. He presented with B symptoms and palpable peripheral lymph nodes enlargement. The CBC showed leukocytosis up to 70х109/l, 94% lymphocytosis and thrombocytopenia below 52х109/l. CT scanning showed enlargement of supraclavicular, mediastinal, axillary, retroperitoneal, mesenteric, pelvic, inguinal lymph nodes. The peripheral blood and bone marrow FACS analysis revealed a monoclonal B-cell population of lymphocytes with CD5, CD19, CD20 and CD23 co-expression. Based on this data, the patient was diagnosed with CLL, Binet stage C.
Over Sept 2014 to Jan 2016, the patient had received three lines of therapy: RB №6, FCR №4 and R-CHOP №3. Any of these therapies was not effective, and the disease was constantly progressing constantly. Further on, the patient received 2 cycles of monotherapy of Rituximab as a palliative treatment. In March 2016, the biopsy of neck lymph node was performed. The IHC investigation revealed the histological picture of DLBCL with retained CD5 and CD23 immunophenotype. The patient was diagnosed with Richter syndrome. FISH assay revealed ATM gene deletion in 90% cells in peripheral blood. In May 2016, Ibrutinib treatment was started at the dose 420 mg/day per os. In November 2016, PR was achieved, with B symptoms completely resolved, with reduced size of lymph nodes. Due to young age and poor prognosis in the patient, it was recommended to proceed with alloHSCT.
In February 2017, the patient continued to be in PR. CT scan demonstrated neck, supraclavicular, axillary, retroperitoneal, mesenteric, pelvic lymphadenopathy and hepatosplenomegaly with mildly FDG-avid foci (max. Deauville of 3). Bone marrow biopsy identified 25% lymphocytes, and FISH showed deletion of ATM gene in 15% cells of bone marrow. No leukocytosis was revealed by CBC. In March of 2017, a mismatched (9/10, locus A mismatch, O+ donor, A+ recipient) unrelated donor alloHSCT was performed with reduced-intensity conditioning (RIC) of FBR (fludarabine, bendamustine and rituximab). The acute graft-versus-host disease (aGVHD) prophylaxis consisted of posttransplant cyclophosphamide, tacrolimus and MMF. The stem cells source was PBSC. The patient was transfused with 4.0 х10*6 CD34+ cell per kg of body weight. During the posttransplant period, severe complications were observed such as sepsis, bilateral pneumonia, invasive aspergillosis, stage 3 aGVHD of skin, reactivation of CMV. The engraftment was achieved on day +25 after alloHSCT. Ibrutinib was continued from day +30 after HSCT for the relapse prophylaxis,. The complete remission was confirmed of day +60 after alloHSCT, and the patient remained in CR at the time of last follow-up (05.08.2017). The Ibrutinib treatment is continued up to now.