Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

BACKGROUND: Survival in Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. METHODS: In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov, NCT03394365, and is ongoing. FINDINGS: From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23-77) of 14 participants in the HSCT group and 15 (52%, 33-71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7-23·9) and 6·0 months (1·8-18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. INTERPRETATION: Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. FUNDING: Atara Biotherapeutics.

Tabelecleucel for EBV+ PTLD after allogeneic HCT or SOT in a multicenter expanded access protocol.

ABSTRACT: Patients with Epstein-Barr virus (EBV)-positive posttransplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months after allogeneic hematopoietic cell transplant (HCT) and 4.1 months after solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV-specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD after HCT or SOT. We now report outcomes from a multicenter expanded access protocol in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory (R/R) to rituximab with/without chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates were both 70.0% (95% confidence interval [CI], 46.5-84.7) overall, both 61.5% (95% CI, 30.8-81.8) in HCT, and both 81.5% (95% CI, 43.5-95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than nonresponders (0%). Treatment was well tolerated, with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for R/R EBV+ PTLD after HCT or SOT. This trial was registered at www.ClinicalTrials.gov as #NCT02822495.

Predictive factors of oxaliplatin neurotoxicity: the involvement of the oxalate outcome pathway.

PURPOSE: Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions. We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids. We then looked for genetic predictive factors of oxaliplatin-induced neurotoxicity. EXPERIMENTAL DESIGN: We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion. In the second stage, before treatment with FOLFOX regimen, we prospectively looked for variants in genes coding for the enzymes involved (a) in the oxalate metabolism, especially glyoxylate aminotransferase (AGXT), and (b) in the detoxification glutathione cycle, glutathione S-transferase pi, and for genes coding for membrane efflux proteins (ABCC2). RESULTS: In the first 10 patients, urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion, accompanied by increased excretions of four amino acids (glycine, alanine, serine, and taurine) linked to oxalate metabolism. In a further 135 patients, a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity. Neither glutathione S-transferase pi nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity. CONCLUSION: These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXT genotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.

Thromboembolism in patients with immune thrombocytopenia (ITP): a meta-analysis of observational studies.

This meta-analysis describes the incidence rate of arterial and venous thromboembolism (ATE and VTE) in patients with immune thrombocytopenia (ITP), and the relative risk of ATE and VTE in patients with ITP and comparable populations without ITP. MEDLINE and EMBASE were systematically searched for observational studies reporting incidence rates of ATE and VTE in populations with and without ITP between 1996 and 2013 [follow-up completed before thrombopoietin receptor (TPOr) agonists were commercially available]. Three large, population-based studies were identified from Denmark, the United Kingdom, and the United States. The incidence of ATE per 100 patient-years among patients with ITP ranged from 1.0 to 2.8, and among populations without ITP ranged from 0.7 to 1.8; the summary relative risk adjusted for matching factors (aRR) was 1.5 [95 % confidence interval (CI) 1.3, 1.8]. The incidence of VTE per 100 patient-years among patients with ITP ranged from 0.4 to 0.7, and among populations without ITP ranged from 0.1 to 0.4; the summary aRR (95 % CI) was 1.9 (1.4, 2.7). The risk of ATE and VTE among patients with ITP, based on evidence from three large, population-based observational studies, should be considered when evaluating the risk of thromboembolism attributed to ITP treatments, such as TPOr agonists.

Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal cancer.

PURPOSE: Oxaliplatin is active in colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity. It may come from an effect on neuronal voltage-gated Na channels, via the liberation one its metabolite, oxalate. We decided to use Ca and Mg as oxalate chelators. EXPERIMENTAL DESIGN: A retrospective cohort of 161 patients treated with oxaliplatin + 5-fluorouracil and leucovorin for advanced colorectal cancer, with three regimens of oxaliplatin (85 mg/m(2)/2w, 100/2w, 130/3w) was identified. Ninety-six patients received infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin (Ca/Mg group) and 65 did not. RESULTS: Only 4% of patients withdrew for neurotoxicity in the Ca/Mg group versus 31% in the control group (P = 0.000003). The tumor response rate was similar in both groups. The percentage of patients with grade 3 distal paresthesia was lower in Ca/Mg group (7 versus 26%, P = 0.001). Acute symptoms such as distal and lingual paresthesia were much less frequent and severe (P = 10(-7)), and pseudolaryngospasm was never reported in Ca/Mg group. At the end of the treatment, 20% of patients in Ca/Mg group had neuropathy versus 45% (P = 0.003). Patients with grade 2 and 3 at the end of the treatment in the 85 mg/m(2) oxaliplatin group recovered significantly more rapidly from neuropathy than patients without Ca/Mg. CONCLUSIONS: Ca/Mg infusions seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy, especially in 85 mg/m(2) oxaliplatin dosage.

Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures.

Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Acute neurotoxicity is characterized by the rapid onset of cold-induced distal dysesthesia and/or paresthesia. Sensory symptoms may also be accompanied by cold-dependent muscular contractions of the extremities or the jaw. The symptoms, often occurring during or shortly after infusion, are usually transient and mild. A persistent sensory peripheral neuropathy may also develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment. Studies have shown patients with acute sensory symptoms to display little or no axonal degeneration, suggesting a specific effect of oxaliplatin on sensory neurons and/or motor neurons or muscle cells that is not observed with other platinum agents. The similarity of the acute symptoms induced by oxaliplatin with those caused by several drugs or toxins acting on neuronal or muscular ion channels suggests that these symptoms may result from a specific interaction of oxaliplatin with ion channels located in the cellular membrane. Recent data indicate that oxaliplatin may act on specific isoforms of the voltage gated sodium (Na(+)) channel to increase the excitability of sensory neurons, an action inhibited by the Na(+) channel blocker carbamazepine. This contention is supported by recent clinical findings indicating that pharmacologic blockade of Na(+) channels may prevent and/or repress the acute neurotoxicity of oxaliplatin. Although there is no indication at the moment that a common cellular mechanism induces both the acute and the cumulative neurotoxicity of oxaliplatin, controlled clinical trials are currently underway to establish the value of Na(+) channel blockade against both acute and cumulative oxaliplatin neurotoxicities.

[Oxaliplatin neurotoxicity]. / Neurotoxicité de l'oxaliplatine.

Oxaliplatin is a reference drug in the treatment of digestive-tract tumors, especially colorectal cancer. Its toxicity profile is dominated by a peripheral sensitive neuropathy, with neuromuscular manifestations. This neurotoxicity has 2 components: an acute toxicity characterized by a rapid onset of cold-induced distal dysesthesia and/or paresthesia, muscular contractions, numbness, stiffness, usually transient but able to evolve into a chronic, persistent sensory peripheral neuropathy that eventually causes functional impairment. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment. This neurotoxicity is frequent, 80%of the patients and becomes chronic in 15 to 20%of the patients, sometimes irreversible. The mechanism of this neurotoxicity has been elucidated: an increased neuronal excitability is due to the action of oxaliplatin on voltage-gated sodium channels through chelation of calcium by the oxaliplatin metabolite. The prevention of this neurotoxicity is a major goal, taking in account the wide indications of this drug. Different approaches have been or are evaluated, based on pathogenic or practical concepts: 1) modifications of the administration schedule; 2) substances acting upon sodium channels : calcium-magnesium, carbamazepine, gabapentine, venlafaxin; 3) detoxifying agents and antioxydants: glutathion, amifostine, alphalipoic acid, tocopherol ; 4) substances used in other kinds of neuropathy: glutamine, alphalipoic acid; 5) neurotrophic factors: NGF, LIF; 6) oxaliplatin analogs, with a DACH platin, without oxalate. Calcium-magnesium infusion seem to be an efficient and safe approach. Further studies are necessary for a better understanding and prevention of this neurotoxicity, potentially severe.