Background
B‐precursor cell acute lymphoblastic leukemia (B‐ALL) in adults is an aggressive and challenging condition, and patients with relapsed/refractory (R/R) disease after allogeneic stem cell ...transplantation (SCT), or noncandidates for SCT, have a particularly poor prognosis. The authors investigated the activity of the Fc‐modified anti‐CD19 antibody tafasitamab in adults with R/R B‐ALL (NCT01685021).
Methods
Adults with R/R B‐ALL received single‐agent tafasitamab 12 mg/kg weekly for up to four 28‐day cycles. Patients with complete remission (with or without neutrophil/platelet recovery; complete remission CR or complete remission with incomplete count recovery CRi) after cycles 2, 3, or 4 could continue tafasitamab every 2 weeks for up to 3 further months. The primary end point was overall response rate (ORR).
Results
Twenty‐two patients were treated (median, 2 prior lines of therapy; range, 1‐8). Six patients completed 2 cycles, and 2 of these patients responded for an ORR of 9%; 16 patients (73%) progressed before their first response assessment. Responses lasted 8 and 4 weeks in the 2 patients with CR and minimal residual disease (MRD)–negative CRi, respectively. Tafasitamab produced rapid B‐cell/blast depletion in 21 of 22 patients within 1 to 2 weeks of first administration. Tafasitamab was well tolerated, with the most frequent adverse events being infusion‐related reactions (59.1%) and fatigue (40.9%). Grade 3 to 4 febrile neutropenia (22.7%) was the most common hematologic adverse event.
Conclusions
Tafasitamab monotherapy was associated with clinical activity in a subset of patients with R/R B‐ALL, including short‐lasting CR and MRD‐negative CRi. Given its favorable tolerability profile, further development of tafasitamab in chemoimmunotherapy combinations and MRD settings should be explored.
In patients with relapsed/refractory B‐precursor acute lymphoblastic leukemia, monotherapy treatment with the Fc‐modified anti‐CD19 antibody tafasitamab was associated with clinical activity, including short‐lasting complete remission and minimal residual disease (MRD)–negative complete remission with incomplete count recovery. In conjuntion with its favorable tolerability profile, further exploration of tafasitamab in chemoimmunotherapy combinations and MRD settings is warranted.
Aims and background
There are only limited data on the safety and efficacy of panitumumab in patients who experienced severe infusion reactions during cetuximab antibody therapy.
Case report
We ...report the case of a 69-year-old woman with chemotherapy-refractory metastatic colorectal cancer who received single-agent cetuximab treatment but experienced a severe reaction during the first infusion, despite premedication with corticosteroids/antihistamines. Cetuximab was discontinued and treatment with panitumumab initiated approximately 14 days later (without premedication); no infusion reactions occurred and there was a rapid improvement in her general condition. She experienced a partial response that was sustained for 7 months before progression.
Conclusions
This case supports the use of panitumumab in patients with chemotherapy-refractory metastatic colorectal cancer and suggests that panitumumab may be used in some patients with prior infusion reactions to cetuximab.
•AUTO3 ± pembrolizumab for r/r LBCL was safe and, therefore, used in outpatient administration.•AUTO3 ± pembrolizumab showed durable remissions beyond 12 months in 54.4% of complete responders and ...was associated with robust expansion.
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Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response CR; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval CI: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation–AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.
When targeting 1 cell surface antigen with chimeric antigen receptor (CAR) T cells results in durable efficacy in only a minority of patients with relapsed large B-cell lymphoma (LBCL), efforts to enhance antitumor responses are needed. Roddie and colleagues report on the results from a phase 1 trial designed to reduce failure by using a novel bicistronic anti-CD19 and CD22 dual-targeted autologous CAR T-cell product in combination with pembrolizumab. The data from 52 heavily pretreated patients with relapsed/refractory LBCL indicate durable remissions but only in a minority of patients, indicating that further technical advances in CAR T-cell design are necessary.
Bendamustine has achieved widespread international regulatory approval and is a standard agent for the treatment for chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma and multiple ...myeloma. Since approval, the number of indications for bendamustine has expanded to include aggressive non-Hodgkin lymphoma and Hodgkin lymphoma and novel targeted therapies, based on new bendamustine regimens/combinations, are being developed against CLL and lymphomas. In 2010, an international panel of bendamustine experts met and published a set of recommendations on the safe and effective use of bendamustine in patients suffering from hematologic disorders. In 2014, this panel met again to update these recommendations since the clarification of issues including optimal dosing and management of bendamustine-related toxicities. The aim of this report is to communicate the latest consensus on the use of bendamustine, permitting the expansion of its safe and effective administration, particularly in new combination therapies.
The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell ...cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 µg/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0–3, 7–10, 28, and 42 (50 µg/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4+ and CD8+ T cell responses was shown for several tumor-associated antigens (TAA) using interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.
In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3Amut) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic ...alterations and the European LeukemiaNet (ELN) classification. DNMT3Amut were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3Amut did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects—unfavorable for R882 on RFS (all: hazard ratio HR, 1.29 P = .026; CN-AML: HR, 1.38 P = .018) and favorable for non-R882 on OS (all: HR, 0.77 P = .057; CN-AML: HR, 0.73 P = .083). In our statistically high-powered study with minimized selection bias, DNMT3Amut represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3Amut type.
•DNMT3A mutations are frequent in younger adults with AML and have no significant impact on survival end points.•Only moderate effects on outcome, depending on molecular subgroup and DNMT3A mutation type, could be observed.
Purpose
Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy ...settings. The pharmacokinetic, metabolic and excretion profiles of
14
Carbon-isotope (
14
C)-labelled vistusertib were characterised in this open-label phase I patient study.
Methods
Four patients with advanced solid malignancies received a single oral solution dose of
14
C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed.
Results
14
C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (
T
max
) < 1.2 h in all subjects). Overall, > 90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~ 78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an
N
-methylamide circulate at low concentrations each < 10% area under the concentration–time curve from zero to infinity (AUC
0–∞
). No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.
Conclusions
The pharmacokinetic (PK) profile of vistusertib is similar to previous studies using the same dosing regimen in solid malignancy patients. The majority of vistusertib elimination occurred via hepatic metabolic routes.
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