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Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

Axicabtagene ciloleucel (Axi-cel) is a CD-19 Chimeric Antigen Receptor T cell therapy approved for the treatment of relapsed/refractory diffuse large B cell lymphoma. We treated ten patients with DLBCL post-FDA approval in an inner-city tertiary center in the Bronx. Eight patients (80%) had received ≥ 3 lines of therapy, six patients had received prior radiation, and seven had recurrent disease after prior autologous hematopoietic stem cell transplant (AHCT). Our cohort included one patient with HIV, two patients with hepatitis B, and two patients with CNS involvement of lymphoma. Axi-cel treatment led to significant responses with 8/10 patients achieving a complete remission at 3 months, including both patients with prior CNS involvement. The treatment was generally well tolerated with 20% of patients experiencing grade ≥ 2 CRS. One patient each with HIV and hepatitis B responded without significant toxicities. In conclusion, Axi-cel led to significant efficacy with manageable toxicity in DLBCL in a real-world setting.

Anti-CD19 chimeric antigen receptor T-cell therapies have shown striking clinical activity in diffuse large B-cell lymphoma but robust biomarkers predictive of responsiveness are still needed. We treated a multi-ethnic cohort of 31 diffuse large B-cell lymphoma patients with axicabtagene ciloleucel with an overall response rate of 71%. Analysis of various biomarkers identified a significant decrease in overall survival with elevated lactate dehydrogenase, measured both at time of cell infusion and before lymphodepletion. Lactate dehydrogenase was prognostic in a multivariate analysis [HR = 1.47 (1.1–2.0)] and a value of 400 U/L at time of infusion and a value of 440 U/L before lymphodepletion provided the best prognostic cutoffs for overall survival in our cohort. These data demonstrate efficacy of anti-CD19 chimeric antigen receptor T-cell therapy in a diverse inner city population and demonstrate novel lactate dehydrogenase cutoffs as prognostic biomarkers.

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.

Optimal treatment of acute myeloid leukemia (AML) arising in elderly patients remains a challenge. FDA approval of Ivosidenib and Enasidenib, small molecule inhibitors of isocitrate dehydrogenase enzymes (IDH1 and 2) have opened new avenues of treatment. We present a 60-year-old woman with refractory AML, achieving complete response to the combination therapy of hypomethylating agent, Azacytidine with the IDH2 inhibitor, Enasidenib, and BCL2 inhibitor, Venetoclax. To our knowledge, this is the first case report of a patient with IDH2 mutated refractory AML achieving complete response to combination therapy with azacytidine, enasidenib and venetoclax.

In 101 patients with refractory large B-cell lymphoma, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel) resulted in an overall response rate of 82%, with a 52% survival at 18 months, despite serious toxic effects.

Key Clinical Message Ibrutinib, an inhibitor of the Bruton's tyrosine kinase of the B‐cell receptor pathway, is an effective therapeutic agent for B‐cell lymphomas. As these drugs are novel, long‐term or rare adverse events are not yet known. We report the first case of ibrutinib‐induced severe liver injury in a patient with relapsed/refractory CLL. Ibrutinib, an inhibitor of the Bruton's tyrosine kinase of the B‐cell receptor pathway, is an effective therapeutic agent for B‐cell lymphomas. As these drugs are novel, long‐term or rare adverse events are not yet known. We report the first case of ibrutinib‐induced severe liver injury in a patient with relapsed/refractory CLL.

SOS is a rare complication of stem cell transplantation and has significant morbidity and mortality. We present three cases of SOS and highlight underlying risk factors for its development, such as impaired clearance of alkylating agents (especially melphalan) in patients with renal failure and prolonged infection. Although, melphalan and cyclophosphamide cause SOS less commonly than alkylating agents such as busulfan, physicians must use caution when administering these drugs to patients with underlying comorbidities such as renal failure that may increase the likelihood of development of SOS. This is due to unpredictable pharmacokinetics in patients with renal failure and therefore close drug monitoring is required. With the recent FDA approval of defibrotide in 2016, outcomes of SOS have improved and physician awareness is important for prompt diagnosis and treatment.