Worse Neurotoxicity Research Articles

Change in Neurocognitive Performance Among Patients with Non-Hodgkin Lymphoma in the First Year after Chimeric Antigen Receptor T Cell Therapy

The success of chimeric antigen receptor (CAR) T cell therapy in treating patients with relapsed/refractory hematologic malignancies is leading to a growing number of survivors treated with this regimen. To our knowledge, no previous studies have examined neurocognitive performance in adult CAR T cell therapy recipients, despite high rates of neurotoxicity and cytokine release syndrome (CRS) in the acute treatment period. This study examined changes in neurocognitive performance in the first year after CAR T cell therapy for non-Hodgkin lymphoma (NHL). Putative risk factors for worsening neurocognitive performance (eg, neurotoxicity, CRS) were explored as well. Neurocognition was assessed before initiation of CAR T cell therapy and at 30, 90, and 360 days post-treatment. Clinical variables were abstracted from medical records. Mixed models were used to examine change in total neurocognitive performance (TNP) and cognitive domains (ie, attention, executive function, verbal ability, immediate and delayed memory, and visuospatial abilities). Among 117 participants (mean age, 61 years; 62% male), TNP and executive function declined slightly on average from baseline to day 90 and then improved from day 90 to day 360 (P < .04). Small but significant linear declines in visuospatial ability on average were also observed over time (P = .03). Patients who had 4 or more lines of previous therapy and those with worse neurotoxicity (but not CRS) demonstrated worse TNP. CAR T cell therapy recipients reported transient or persistent deterioration in several cognitive domains, although changes were slight. These findings may be useful when educating future patients on what to expect when receiving CAR T cell therapy.

Quality of Life, Tryptophan Metabolites, and Neurotoxicity Assessments of Patients with Relapsed or Refractory B Cell Malignancies Undergoing CAR 20/19 - T Cell Therapy

Introduction Chimeric antigen receptor (CAR) T cell immunotherapy represents a novel and increasingly used treatment modality for patients with relapsed and/or refractory B cell malignancies. Acute neurological toxicities of CAR-T cell therapy (e.g. immune effector cell-associated neurotoxicity syndrome) are well described, though delayed cognitive and emotional functioning and quality of life (QOL) are less well studied, with mechanisms of all incompletely understood. Given the known bidirectional relationship between neuroinflammation and depression, and the role of kynurenine (Kyn) metabolism in both, we studied QOL through patient-reported outcomes (PROs) and neurotoxicity and their relationship to Kyn metabolites. Methods Patients with relapsed refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia treated with CAR-20/19-T cells on our Phase I/Ib clinical trial (NCT03019055) (N=16) were included. Patients were excluded if they had a history of previous allogeneic hematopoietic stem cell transplantation. Study subjects provided serum and PROs through self-report surveys at the following time points: baseline/ apheresis, Day-14 (D14), D28, and D90 post-intervention. The following scales were used to assess QOL: Inventory of Depression and Anxiety Symptoms (IDAS), Brief Pain Inventory (BPI), Fatigue Severity Index (FSI), and Pittsburgh Sleep Quality Index (PSQI). Tryptophan and its metabolites (kynurenine (Kyn), 3-Hydroxy-anthranilic Acid (3-HAA), 3-Hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA)) and neurotoxicity grades were measured for all 16 subjects. Patients were evaluated for neurotoxicity with the CTCAE 5.0. The measurements were log-transformed to stabilize the variances and allow modeling of the expected multiplicative effects. A mixed effects longitudinal model was used for all eligible patients to evaluate the impact of time on all PRO variables over the 4 timepoints through 90 days post CAR-T infusion. Neurotoxicity was evaluated two ways: as a categorical variable with 5 levels (0 to -4) and as a continuous variable. Results Depression symptoms improved over time with the lowest value at Day 90, though the changes were not statistically significant (P = .072). Remaining QOL PRO variables did not show statistically significant changes, tending to improve or remain stable over time (Table 1 &amp; Figure 1). Mean Kyn levels significantly changed over time (P = .028; Table 2). This effect is most pronounced in patients with Grade 3/4 neurotoxicity where Kyn levels rise at Day 14 and Day 28 followed by a decrease by Day 90 (Figure 2). Among patients who exhibited neurotoxicities, baseline levels of 3-HAA and 3-HK before CAR-T therapy were elevated; though nonsignificant, similar trends were not observed in the other metabolites (Figure 2). These observations however were significant when neurotoxicity was evaluated as a continuous variable (Table 2) with 3-HAA and 3-HK higher in patients with higher grade neurotoxicities (P = .015 and .070). Conclusions Our findings suggest that CAR-T therapy does not impair QOL and may in fact result in improved mood in the early months following cell infusion, adding to recent literature about long-term QOL in CAR-T survivors. Here, we also identify elevated baseline 3-HAA and 3-HK levels as well as increased Kyn levels following CAR-T therapy, with the first two associated with worse neurotoxicity. Most interestingly, we find higher levels of 3-HAA and 3-HK in patients who experience neurotoxicities. Correlational studies will be needed to confirm potential relationships between PROs and metabolites. Disclosures Hari: Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Kite Pharma: Consultancy, Honoraria; Lily: Consultancy, Honoraria.

Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in patients with refractory or relapsed acute lymphocytic leukaemia. Various anti-CD19 CAR T-cell constructs have been trialled and responses vary widely among different studies. We aimed to systematically analyse the outcomes of patients with acute lymphocytic leukaemia treated with anti-CD19 CAR T cells and identify factors associated with differences in outcomes. We did a systematic review and meta-analysis of published and unpublished clinical trials that reported data on the outcomes of adult or paediatric patients that were treated with anti-CD19 CAR T cells for relapsed or refractory B-cell acute lymphocytic leukaemia, reported between Jan 1, 2012, and April 14, 2020. Studies with two patients or fewer were excluded and summary data were extracted from the reports. The primary outcome was the number of patients who had complete remission at any time after anti-CD19 CAR T-cell infusion. This study is not registered in PROSPERO. From 1160 studies, we identified 40 potentially appropriate studies, 35 (88%) of which met the eligibility criteria and were included in the final analysis (n=953 patients). The pooled complete remission was 80% (95% CI 75·5-84·8) and heterogeneity between studies was moderate (I2=56·96%). In the prespecified subgroup analyses, 195 (75% [95% CI 66·9-82·9, I2=35·22%]) of 263 patients in adult studies and 242 (81% [72·9-87·2, I2=54·45%]) of 346 patients in paediatric studies achieved complete remission, p=0·24. The pooled complete remission did not significantly differ with anti-CD19 CAR T-cell construct type or single-chain variable fragment clone, but was higher with autologous T-cell origin (727 [83%, 78·5-86·5, I2=44·34%] of 901 patients), compared with allogeneic T-cell origin (29 [55%, 30·6-79·0, I2=62·64%] of 52 patients; p=0·018). 242 (26% [95% CI 18·5-34·1]) of 854 patients developed grade 3 or worse cytokine release syndrome and 97 (12% [6·6-19·2]) of 532 developed grade 3 or worse neurotoxicity. There was no difference in the proportion of patients who achieved complete remission or who had cytokine release syndrome or neurotoxicity between different anti-CD19 CAR T-cell constructs. The risk of bias was assessed as low in 17 studies and moderate in 18 studies. The high response rates after anti-CD19 CAR T-cell therapy can be used to guide the use of therapy in patients with relapsed or refractory acute lymphocytic leukaemia. Comparison studies are required to further determine differences in efficacy between different anti-CD19 CAR T-cell constructs in the setting of relapsed or refractory acute lymphocytic leukaemia. National Cancer Institute, National Comprehensive Cancer Network, Mayo Clinic K2R Research Pipeline, and Mayo Clinic Center for Individualized Medicine.

Patient-reported outcomes at discontinuation of anti-angiogenesis therapy in the randomized trial of chemotherapy with bevacizumab for advanced cervical cancer: an NRG Oncology Group study

IntroductionTo describe patient-reported outcomes and toxicities at time of treatment discontinuation secondary to progression or toxicities in advanced/recurrent cervical cancer patients receiving chemotherapy with bevacizumab.MethodsSummarize toxicity, grade, and health-related quality...

Phase III randomized, placebo‐controlled, double‐blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin‐induced peripheral neurotoxicity in stage II/III colorectal cancer

BackgroundMonosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin‐based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin‐induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin‐based chemotherapy.MethodsIn total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI‐CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ‐CIPN20), time to grade 2 neurotoxicity (NCI‐CTCAE or the oxaliplatin‐specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3‐year disease‐free survival (DFS) and adverse events.ResultsThere were no significant differences between the arms in the rate of NCI‐CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ‐CIPN20 or time to grade 2 neurotoxicity using NCI‐CTCAE and the oxaliplatin‐specific neuropathy scale. GM1 substantially decreased participant‐reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3‐year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms.ConclusionPatients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (http://ClinicalTrials.gov number, NCT02251977).

Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside in prevention of oxaliplatin-induced neurotoxicity in stage II/III colorectal cancer patients.

674 Background: Monosialotetrahexosylganglioside (GM1) is a glycosphingolipid, which has antioxidant and neuroprotective properties. Cumulative neurotoxicity is a prominent toxicity of oxaliplatin-based therapy. This study was designed to assess the efficacy of GM1 for preventing oxaliplatin-induced neurotoxicity in colorectal cancer (CRC) patients. Methods: A total of 186 patients with stage II/III CRC undergoing adjuvant chemotherapy with modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) were randomly assigned to intravenous GM1 80mg per day or placebo from day 0 to day 4 during chemotherapy. The primary end point was the rate of grade 2 or worse cumulative neurotoxicity, measured by investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. The secondary end point were the chronic cumulative neurotoxicity measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity by using the NCI-CTCAE or the oxaliplatin-specific neuropathy scale, the rates of acute neurotoxicity measured by a numerical analog scale ranging from 0 to 10, and the rates of dose reduction or withdrawal of both arms. Results: There were no statistically significant differences in the rate of NCI-CTCAE grade 2 or worse neurotoxicity between the study arms (GM1: 33.7% vs. placebo: 31.6%; P= 0.76). Similarly, there were no significant differences measured by EORTC QLQ-CIPN20 neuropathy scale ( P= 0.89) or additional measures of neuropathy, including measurement of the time to grade 2 neurotoxicity by using the NCI-CTCAE ( P= 0.99) or an oxaliplatin-specific neuropathy scale ( P= 0.98). In addition, GM1 did not substantially decrease oxaliplatin-induced acute neuropathy. The rates of dose reduction or withdrawal of both arms were not significantly different (GM1: 64.6% vs. placebo: 54.6%, P= 0.15). Conclusions: This study does not support using GM1 to prevent oxaliplatin-induced neurotoxicity. (NCT02251977) Clinical trial information: NCT02251977.

Gastric cancer: toward a cisplatin-free disease?

Historically, the cornerstone of treatment of advanced gastric cancer (GC) is 5-fluorouracil (5-FU)-based chemotherapy that increases median overall survival (OS) compared to best supportive care by some months. The addition of cisplatin (CDDP) to chemotherapy doublets showed a limited but significant benefit in term of OS according to a Cochrane meta-analysis. However, the recent individual patient-data GASTRIC meta-analysis, confirms this benefit in term of progression-free survival (PFS) but not OS, in randomized eight trials that include or not CDDP. The substitution of CDDP with a modern agent (oxaliplatin, irinotecan or taxanes) has been poorly evaluated in the literature. The REAL-2 phase III trial confirmed the equivalence of oxaliplatin and CDDP-based triplets, and a meta-analysis of three oxaliplatin-based randomized trials demonstrated that these combinations are better that CDDP-based doublets or triplets, improving both PFS (HR =0.88) and OS (HR =0.88). In particular, oxaliplatin-based chemotherapy was associated with less neutropenia and thromboembolic events, but with worse neurotoxicity. Given that the role of chemotherapy in advanced GC is palliative, CDDP-free regimens, and in particular oxaliplatin-based chemotherapy, may be considered for both CDDP-fit and unfit patients (that are those with poor renal function, older age, bad performance status or who cannot tolerate forced hydration for example). The limited absolute survival benefit of chemotherapy in advanced GC (few weeks at best), the cumbersome vascular toxicity of CDDP and the activity of several new drugs such irinotecan, oxaliplatin, taxanes and oral fluoropyrimidines make nowadays possible to consider CDDP-free regimens for the treatment of this incurable disease.

SWOG S0715: Randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy.

9018 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect of taxanes that leads to suboptimal treatment and diminished quality of life. Acetyl-L-Carnitine (ALC) is a natural compound involved in tubulin acetylation and neuronal protection. Pre-clinical and phase II studies suggest ALC may be effective for the prevention and treatment of CIPN. Methods: A randomized, double-blind, multi-center, phase III trial comparing ALC (1000 mg TID) vs placebo for 24 wks in women with stage I-III breast cancer undergoing adjuvant taxane therapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale (low score = worse NTX) at 12 wks. Secondary objectives included change at 24 wks, change in the Trial Outcome Index (TOI), fatigue (FACIT Fatigue) and NTX grade. Patients were stratified by planned treatment, and age (&lt;60, ≥60). Results: 409 patients were evaluable (208 ALC, 201 placebo). No imbalances were observed by age, ethnicity, race, planned taxane treatment, performance status, or stage. The mean FACT-NTX score was 5.2 points lower at 12 wks on ALC and 4.5 points lower on placebo. In a linear regression adjusting for baseline score, planned treatment and age, wk 12 scores were 0.9 points lower on ALC than placebo (95% CI: -2.2 to 0.4, p=.17). At 24 wks, the mean observed FACT-NTX score was lower for ALC (5.3 vs. 3.6). In the multivariate model, wk 24 scores were 1.8 points lower on ALC (95% CI: -3.2 to -0.4, p=.01), representing more self-reported NTX. Grade 3/4 NTX was more frequent in the ALC arm (p=.04). Also at 24 wks, 38% on ALC had &gt;5 point decrease score compared to 28% on placebo (OR=1.57, p=.05), and FACT-TOI scores were 3.5 points lower on ALC (95% CI: -6.5 to -0.4, p=.03). No differences between arms were observed for the FACIT-Fatigue scale or for other toxicities. Conclusions: There is no evidence that ALC has a positive impact on CIPN at 12 wks. However, ALC increases CIPN by 24 wks. Correlative studies are ongoing to explain this unexpected finding. Patients should be discouraged from using ALC and other supplements without proven efficacy.

Neurotoxicity of purine analogs: a review.

The purine analogs, fludarabine, cladribine, and pentostatin, are active against a broad spectrum of indolent lymphoid malignancies. They also have similar toxicities, including myelosuppression, immunosuppression, and sporadic neurotoxicity. This review compares the spectrum of neurotoxicity of each of these agents. Now that these drugs are commercially available and are being widely used, physicians should be aware of potentially serious side effects that may be encountered. The literature was searched using MedLine and Cancerline, as well as the bibliographies of published reports through the fall of 1993. In addition, case records from National Cancer Institute (NCI) Group C protocols were reviewed for fludarabine in chronic lymphocytic leukemia (CLL), and cladribine and pentostatin in hairy cell leukemia (HCL), as well as adverse drug reactions reported to the NCI from January 1980 through September 1993. At higher than recommended doses, life-threatening and fatal neurotoxicity were encountered with all three drugs. At the recommended doses, each agent induced neurotoxicity in approximately 15% of patients, mostly mild and reversible. However, severe neurologic complications were reported; these were occasionally delayed, sometimes fatal, but often at least partially reversible. The doses of these three agents should not be increased above the recommended levels. Development of moderate or worse neurotoxicity should result in discontinuation of that drug.