In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after ...the failure of conventional therapy.
In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10
anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.
Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.
In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
It is estimated that in the United States in 2018 there will be 22,240 new cases of ovarian cancer and 14,070 deaths due to this malignancy. The most common subgroup of this disease is high-grade ...serous ovarian cancer (HGSOC), which is known for its aggressiveness, high recurrence rate, metastasis to other sites, and the development of resistance to conventional therapy. It is important to understand the ovarian cancer tumor microenvironment (TME) from the viewpoint of the function of pre-existing immune cells, as immunocompetent cells are crucial to mounting robust antitumor responses to prevent visible tumor lesions, disease progression, or recurrence. Networks consisting of innate and adaptive immune cells, metabolic pathways, intracellular signaling molecules, and a vast array of soluble factors, shape the pathogenic nature of the TME and are useful prognostic indicators of responses to conventional therapy and immunotherapy, and subsequent survival rates. This review highlights key immune cells and soluble molecules in the TME of ovarian cancer, which are important in the development of effective antitumor immunity, as well as those that impair effector T cell activity. A more insightful knowledge of the HGSOC TME will reveal potential immune biomarkers to aid in the early detection of this disease, as well as biomarkers that may be targeted to advance the design of novel therapies that induce potent antitumor immunity and survival benefit.
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.
This study evaluates the safety and efficacy of plerixafor (AMD3100), a CXCR4 antagonist, in mobilizing hematopoietic stem cells for autologous stem-cell transplantation in non-Hodgkin's lymphoma ...(NHL) patients.
This is a phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study. Patients with non-Hodgkin's lymphoma requiring an autologous hematopoietic stem-cell transplantation in first or second complete or partial remission were eligible. Patients received granulocyte colony-stimulating factor (G-CSF; 10 microg/kg) subcutaneously daily for up to 8 days. Beginning on evening of day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until > or = 5 x 10(6) CD34+ cells/kg were collected. The primary end point was the percentage of patients who collected > or = 5 x 10(6) CD34+ cells/kg in 4 or fewer apheresis days.
This report presents all data for all patients (n = 298) through 12 months follow-up. Eighty-nine (59%) of 150 patients in the plerixafor group and 29 (20%) of 148 patients in the placebo group met the primary end point (P < .001). One hundred thirty-five patients (90%) in plerixafor group and 82 patients (55%) in placebo group underwent transplantation after initial mobilization. Median time to engraftment was similar in both groups. The most common plerixafor-associated adverse events were GI disorders and injection site reactions.
Plerixafor and G-CSF were well tolerated and resulted in a significantly higher proportion of patients with non-Hodgkin's lymphoma achieving the optimal CD34+ cell target for transplantation in fewer apheresis days, compared with G-CSF alone.
The phase 3 AETHERA trial established brentuximab vedotin (BV) as a consolidative treatment option for adult patients with classical Hodgkin lymphoma (cHL) at high risk of relapse or progression ...after autologous hematopoietic stem-cell transplantation (auto-HSCT). Results showed that BV significantly improved progression-free survival (PFS) vs placebo plus best supportive care alone. At 5-year follow-up, BV continued to provide patients with sustained PFS benefit; 5-year PFS was 59% (95% confidence interval CI, 51-66) with BV vs 41% (95% CI, 33-49) with placebo (hazard ratio HR, 0.521; 95% CI, 0.379-0.717). Similarly, patients with ≥2 risk factors in the BV arm experienced significantly higher PFS at 5 years than patients in the placebo arm (HR, 0.424; 95% CI, 0.302-0.596). Upfront consolidation with BV significantly delayed time to second subsequent therapy, an indicator of ongoing disease control, vs placebo. Peripheral neuropathy, the most common adverse event in patients receiving BV, continued to improve and/or resolve in 90% of patients. In summary, consolidation with BV in adult patients with cHL at high risk of relapse or progression after auto-HSCT confers a sustained PFS benefit and is safe and well tolerated. Physicians should consider each patient's HL risk factor profile when making treatment decisions. This trial was registered at www.clinicaltrials.gov as #NCT01100502.
•Early consolidation with BV improves 5-year PFS vs best supportive care and reduces the need for subsequent therapy.•At 5-year follow-up, BV shows long-term tolerability, with peripheral neuropathy continuing to improve and/or resolve.
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Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial ...to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval CI, 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299.
This randomized phase 3 clinical trial evaluated the potential benefit of the addition of gemtuzumab ozogamicin (GO) to standard induction and postconsolidation therapy in patients with acute myeloid ...leukemia. Patients were randomly assigned to receive daunorubicin (45 mg/m2 per day on days 1, 2, and 3), cytarabine (100 mg/m2 per day by continuous infusion on days 1–7), and GO (6 mg/m2 on day 4; DA+GO) vs standard induction therapy with daunorubicin (60 mg/m2 per day on days 1, 2, and 3) and cytarabine alone (DA). Patients who achieved complete remission (CR) received 3 courses of high-dose cytarabine. Those remaining in CR after consolidation were randomly assigned to receive either no additional therapy or 3 doses of GO (5 mg/m2 every 28 days). From August 2004 until August 2009, 637 patients were registered for induction. The CR rate was 69% for DA+GO and 70% for DA (P = .59). Among those who achieved a CR, the 5-year relapse-free survival rate was 43% in the DA+GO group and 42% in the DA group (P = .40). The 5-year overall survival rate was 46% in the DA+GO group and 50% in the DA group (P = .85). One hundred seventy-four patients in CR after consolidation underwent the postconsolidation randomization. Disease-free survival was not improved with postconsolidation GO (HR, 1.48; P = .97). In this study, the addition of GO to induction or postconsolidation therapy failed to show improvement in CR rate, disease-free survival, or overall survival. This trial is registered with www.clinicaltrials.gov as #NCT00085709.
• The addition of gemtuzumab ozogamicin to induction or maintenance therapy failed to improve the complete response rate or overall survival in patients with acute myeloid leukemia.
Summary Background High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients ...might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. Methods We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30–45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01100502. Findings Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio HR 0·57, 95% CI 0·40–0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4–42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5–not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 56% of 167 patients vs 25 16% of 160 patients in the placebo group) and neutropenia (58 35% vs 19 12% patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. Interpretation Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. Funding Seattle Genetics and Takeda Pharmaceuticals International.
Although ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, ...which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD.
The Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level.
There was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32).
ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.
Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic ...graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% P = .04 and 59% v 74% P = .034, respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.
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