Chimeric antigen receptor T-cell therapy as a bridge to haematopoietic stem cell transplantation for refractory/relapsed B-cell acute lymphoblastic leukemia

Although chimeric antigen receptor T cells (CAR-T) targeted at CD19 or CD22 have achieved high complete remission (CR) in refractory/relapsed B-cell acute lymphoblastic leukaemia (B-ALL), it is uncertain if allogeneic haematopoietic stem cell transplantation (allo-HSCT) should be performed after CAR-T therapy to accomplish a sustainable remission. Fifty-two cases with relapsed/refractory B-ALL who underwent allo-HSCT after CR by CD19 or CD22 CAR-T were enrolled. The median time from CAR-T infusion to allo-HSCT was 50 (34–98) days. Myeloablative reduced-intensity conditioning (RIC) with total body irradiation/fludarabine-based or busulfan/fludarabine-based regimens was used. Incidences of grade II–IV acute graft-versus-host disease (aGVHD) and severe aGVHD were 23·1% and 5·8% respectively. Of 48 evaluable cases, 16 developed chronic GVHD (cGVHD) and in three of them the pattern was extensive. With a median follow-up of 334 (41–479) days, one-year overall survival and event-free survival (EFS) were 87·7% and 73·0%. One-year relapse rate and transplant-related mortality (TRM) were 24·7% and 2·2% respectively. With quick bridge to allo-HSCT after CAR-T therapy, high EFS for refractory/relapsed B-ALL has been achieved in this relatively large cohort. Our myeloablative RIC regimens have resulted in low incidences of aGVHD, cGVHD, viral reactivation and very low TRM even majority of transplants from haploidentical donors. Long-term follow-up is warranted.     

Clinical experience of CAR T cell therapy in lymphomas

Non-Hodgkin lymphoma in relapse portends a poor prognosis due to resistance to cytotoxic chemotherapy and monoclonal antibodies. Chimeric Antigen receptor (CAR) T cell therapy has been tested in many lymphomas in the relapse refractory setting and has resulted in durable responses despite some peculiar side effects including cytokine release syndrome (CRS), neurological events (NE), prolonged cytopenias and hypogammaglobulinemia. This review summarizes the registration trials conducted in lymphomas. All products showed response rates that were far better than obtainable by salvage chemotherapy and most patients recovered from side effects including CRS and NEs. The impact of CAR T in the real world setting was discussed as well as how to approach the use of CAR T in special circumstances such as CNS involvement, management of post CAR relapses and outpatient therapy.     

Long event-free survival after anti-BCMA CAR-T cell treatment for relapsed and refractory multiple myeloma patients: Two case reports

Introduction:Chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM). The response rate and the depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse.Patient concerns:Two patients with multiple myeloma (MM) were selected to enroll in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113) because they did not have the good effect after traditional treatment. One is a 48-year-old male patient who received a diagnosis of IgG lambda MM in June 2015, he has received 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a complete response (CR). Approximately 11 months later, the disease progressed. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles); the response was poor, and the disease kept progressing. Another 65-year-old female patient received a diagnosis of IgG lambda MM in September 2016, she has received induction therapy with 1 cycle of bortezomib and dexamethasone (VD) and 4 cycles of lenalidomide and dexamethasone, the response was poor.Diagnosis:Both patients were diagnosed with RRMM according to the International Myeloma Working Group criteria.Interventions:Both patients received infusions of anti-BCMA CAR-T cells following an induction chemotherapy regimen of cyclophosphamide and fludarabine.Outcomes:Both of them achieved a stringent CR at the 30th day with minimal residual disease-negative bone marrow by flow cytometry and serum monoclonal protein was undetectable at 4 and 10 months after cell transfusion. The CR has persisted in the 2 patients for >36 months.Conclusions:Our findings demonstrate the anti-BCMA CAR-T cell treatment is a feasible therapeutic option for patients with RRMM. Fewer early lines of treatment may be beneficial to maintain the efficacy of CAR-T cells.Trial registration:ChiCTR-OPC-16009113.     

Gemcitabine,cisplatin, and dexamethasone and ifosfamide,carboplatin, and etoposide regimens have similar efficacy as salvage treatment for relapsed/refractory aggressive lymphoma: A retrospectively comparative study

In this study, our aim was to compare the efficacy and toxicity profiles of gemcitabine, cisplatin, and dexamethasone (GDP) and ifosfamide, carboplatin, and etoposide (ICE) regimens in the salvage treatment of relapsed/refractory lymphoma. A total of 110 patients with refractory/relapsed classical Hodgkin lymphoma (n = 22) or non-Hodgkin lymphoma (n = 88) who received GDP or ICE salvage regimens from January 2011 to July 2018 were retrospectively analyzed. Of the 110 patients, 50 patients received GDP, and 60 patients received ICE. The response could be evaluated in all patients. In the GDP group, 30 (60.0%) patients achieved overall response rate (ORR), and in the ICE group, the ORR was 56.6%. Of the classical Hodgkin lymphoma patients, the ORR were 72.8% and 54.6% in the GDP and ICE groups, respectively. Of the non-Hodgkin lymphoma patients, the ORR were 56.4% and 57.1% in the GDP and ICE groups, respectively. Grade I-II toxicity occurred in 16 (32.0%) patients in the GDP group and 18 patients (30.0%) in the ICE group; 14 (28.0%) patients had Grade III-IV toxicity in the GDP group, as did 20 (33.3%) patients in the ICE group. As a result, both GDP and ICE regimens are suitable for the treatment of recurrent/refractory lymphoma. The overall adverse reactions of both regimens are acceptable.     

Phase I/II trial of vorinostat with rituximab,cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B‐cell lymphoma not eligible for autologous stem cell transplantation

The standard treatment of relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients ≥aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R‐CVEP [R 375 mg/m² intravenously (IV), day 1; C 600 mg/m² IV days 1, 8: E 70 mg/m² IV day 1, 140 mg/m² days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m² PO days 1–10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69–88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17·5 months. Median progression‐free survival was 9·2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R‐CVEP was tolerated at MTD and produced durable responses with improved QoL.     

Evolution to plasmablastic lymphoma evades CD19‐directed chimeric antigen receptor T cells

A patient with relapsed and refractory chronic lymphocytic leukaemia with Richter transformation was treated with chimeric antigen receptor (CAR)‐modified T cells targeted for CD19 but later relapsed with a clonally related plasmablastic lymphoma. The loss of most routine markers of pre‐plasma cell or B lymphoid differentiation (including CD19) highlights the ability of such mature lymphomas to evade lineage‐specific targeted immunotherapy by differentiating along pathways comparable to their normal cellular counterparts. Molecular genetic evaluation demonstrated multiple independent lines of CD19‐negative disease that eventually evolved in this single patient. Such plasticity represents potential challenges for antigen‐directed CAR‐T cell therapy, while serving as a testament to the selective pressure exerted by these engineered T cells over time.     

How I treat refractory/relapsed diffuse large B-cell lymphomas with CD19-directed chimeric antigen receptor T cells

Chimeric antigen receptor (CAR) T cells targeting CD19 represent a promising salvage immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), offering ~40% of long-term responses. In everyday clinical practice, haematologists involved in CAR T cell treatment of patients with R/R DLBCL have to deal with diagnostically complex cases and difficult therapeutic choices. The availability of novel immunotherapeutic agents for R/R DLBCL and recent advances in understanding CAR T-cell failure mechanisms demand a rational approach to identify the best choice for bridging therapy and managing post-CAR T-cell therapy relapses. Moreover, positron emission tomography/computerised tomography may result in false-positive interpretation, highlighting the importance of post-treatment biopsy. In this review, we discuss all above issues, presenting four instructive cases, with the aim to provide criteria and new perspectives for CAR T-cell treatment of DLBCL.     

A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T‐cell lymphomas

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) and peripheral T‐cell lymphoma (PTCL). We conducted a phase I/II trial with bortezomib (dose‐escalated to 1·6 mg/m²) given concurrently with gemcitabine (800 mg/m²) days 1 + 8 q21 d. Of 32 patients, 16 each had relapsed/refractory PTCL and DLBCL. Median prior therapies were 3 and 35% had failed transplant. Among the first 18 patients, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia resulting in repeated treatment delays (relative dose intensity: 46%). Thus, the study was amended to give bortezomib and gemcitabine days 1 + 15 q28 d, which resulted in markedly improved tolerability. Among all patients, the overall response rate (ORR) was 24% with 19% complete remission (CR; intent‐to‐treat (ITT) ORR 16%, CR 13%), which met criteria for futility. The ORR for DLBCL was 10% (CR 10%) vs. 36% for PTCL (CR 27%). Among 6 PTCL patients treated on the modified schedule, ORR by ITT was 50% (CR 30%). Altogether, concurrent bortezomib/gemcitabine given days 1 + 8 q21 d was not tolerable, while modification to a bi‐monthly schedule allowed consistent treatment delivery. Whereas efficacy of this combination was low in heavily pre‐treated DLBCL, there was a signal of activity in relapsed/refractory PTCL utilizing the modified schedule.     

Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T-cell therapy

Mechanisms of prolonged cytopenia (PC) after chimeric antigen receptor (CAR) T-cell therapy, an emerging therapy for relapsed or refractory diffuse large B-cell lymphoma, remain elusive. Haematopoiesis is tightly regulated by the bone marrow (BM) microenvironment, called the ‘niche’. To investigate whether alterations in the BM niche cells are associated with PC, we analysed CD271⁺ stromal cells in BM biopsy specimens and the cytokine profiles of the BM and serum obtained before and on day 28 after CAR T-cell infusion. Imaging analyses of the BM biopsy specimens revealed that CD271⁺ niche cells were severely impaired after CAR T-cell infusion in patients with PC. Cytokine analyses after CAR T-cell infusion showed that CXC chemokine ligand 12 and stem cell factor, niche factors essential for haematopoietic recovery, were significantly decreased in the BM of patients with PC, suggesting reduced niche cell function. The levels of inflammation-related cytokines on day 28 after CAR T-cell infusion were consistently high in the BM of patients with PC. Thus, we demonstrate for the first time that BM niche disruption and sustained elevation of inflammation-related cytokines in the BM following CAR T-cell infusion are associated with subsequent PC.     

Expression of CD 25 (Tac antigen) in lymphoid leukemias and non-Hodgkin lymphomas

A monoclonal antibody to IL2 receptor Tac/CD 25 antigen was included in the phenotyping panel of 92 leukemic proliferations. Spontaneous expression of this molecule was observed in one disorder of T-phenotype only, but in 75% of B-chronic lymphocytic leukemia (CLL) and on cells from B-cell leukemic lymphomas. These findings provide further evidence for a non-T-cell restriction of IL2 receptor and raise the question of multiple gene derepression in hematologic disorders of B-lineage.     

Impact of prior rituximab on outcomes of autologous stem‐cell transplantation in patients with relapsed or refractory aggressive B‐cell lymphoma: a multicentre retrospective Spanish group of lymphoma/autologous bone marrow transplant study

The use of highly effective rituximab‐containing therapy for treating diffuse large B‐cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. Autologous stem‐cell transplantation (ASCT) is the reference treatment for these patients, but the impact of previous exposure to rituximab on the subsequent results of ASCT remains unknown. We analysed 248 patients with relapsed or refractory DLBCL or grade 3B follicular lymphoma pre‐treated with rituximab as part of first‐line therapy (R+ group) who received ASCT, in comparison with a control group of 127 patients without previous exposure to rituximab (R? group). The complete remission (CR) rates were similar in both groups. Multivariate analysis identified age‐adjusted International Prognostic Index at diagnosis, extranodal involvement and disease status at transplant, and the number of previous chemotherapy lines as independent factors with a negative influence on CR rate. Compared with R? patients, those in the R+ group had a significantly better progression‐free survival (63% vs. 48% at 5 years) and overall survival (72% vs. 61% at 5 years). This observation was independent of other prognostic factors that affected these outcomes. In conclusion, ASCT is no less effective in patients with relapsed or refractory aggressive B‐cell lymphoma pre‐treated with first‐line rituximab‐containing therapy than in rituximab‐naive patients.     

Germinal center B (GCB) and non-GCB cell-like diffuse large B cell lymphomas have similar outcomes following autologous haematopoietic stem cell transplantation

Patients with germinal center B cell-like (GCB) and non-GCB diffuse large B cell lymphomas (DLBCL) receiving first line therapy have distinct prognosis. We explored the differences in outcome following salvage autologous hematopoietic stem cell (HSC) transplantation between patients with GCB and non-GCB DLBCL. Forty-four patients with relapsed and 15 patients with primary refractory chemosensitive disease undergoing BEAM (BCNU [carmustine], etoposide, cytarabine, melphalan) conditioning and autologous HSC were included. Immunohistochemical analysis was performed for CD10, BCL-6, MUM1 (allowing classification into GCB and non-GCB-like DLBCL) and BCL-2. Median follow-up of survivors was 25 months; median age at the time of transplantation was 60 years (range 17–77). Thirty-two patients (54%) were classified as having GCB and 27 (46%) as having non-GCB-like DLBCL. Patients with GCB and non-GCB DLBCL did not differ in the risk of progression after HSC transplant ( P  = 0·78) or overall survival ( P  = 0·48). In multivariate analysis, only time to progression after initial treatment impacted overall survival. We conclude that patients with relapsed or primary refractory chemosensitive GCB and non-GCB-like DLBCL derive similar benefit from autologous HSC transplant.     

Addition of lenalidomide to rituximab,ifosfamide, carboplatin,etoposide (RICER) in first‐relapse/primary refractory diffuse large B‐cell lymphoma

Relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first‐relapse or primary refractory DLBCL. Dose‐escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose‐limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high‐risk DLBCL patients.