Review effectiveness of low-level laser therapy (LLLT) in the curative treatment of oral mucositis (OM) in patients receiving cancer therapy. A systematic review with meta-analysis was performed ...using Medline, Embase, and Cochrane Library databases according to PRISMA guidelines, to identify randomized controlled trials (RCT) on OM in patients during and/or after cancer therapy and in which the therapeutic approach was LLLT, with wavelengths between 632 and 970 nm. We considered grade of OM as a dichotomous variable (such as an improvement or not in severe OM on the seventh day of therapy), with the analysis of subgroups of adult patients or children and adolescents and as a continuous variable with determination of the time for the complete resolution and the subgroup analysis occurred with the strata of the samples by treatment only with chemotherapy or chemotherapy and radiotherapy. This paper’s protocol was registered a priori at
https://www.crd.york.ac.uk/PROSPERO
. We found five RCT (total of 315 patients) with adequate methodology. LLLT was effective, presenting a 62% risk reduction of severe mucositis on the seventh day of evaluation (RR = 0.38 95% CI, 0.19–0.75). When we analyzed subgroups, RR was 0.28 (95% CI 0.17–0.46) in the adult studies and 0.90 (95% CI, 0.46–1.78) in the studies with children and adolescents. We demonstrated a mean reduction of 4.21 days in the time of complete resolution of OM (CI − 5.65 to − 2.76) in favor of LLLT. There is moderate evidence that LLLT is effective in resolving OM lesions in adult patients undergoing cancer therapy. LLLT demonstrates potential for decreasing the resolution time of OM lesions by approximately 4.21 days.
Summary Background Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the ...best treatment for the disease. We assessed the safety and efficacy of siltuximab—a chimeric monoclonal antibody against interleukin 6—in HIV-negative patients with multicentric Castleman's disease. Methods We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov , number NCT01024036. Findings We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1–54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 47% vs 14 54%) and serious adverse events (12 23% vs five 19%) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days range 1–1031 vs 152 days 23–666). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). Interpretation Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. Funding Janssen Research & Development.
Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The phase III IKEMA study (clinicaltrials gov. Identifier: ...NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) versus Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Addition of Isa prolonged progression-free survival (PFS) in patients with RI (hazard ratio: 0.27; 95% confidence interval CI: 0.11-0.66; median PFS not reached for Isa-Kd versus 13.4 months for Kd 20.8-month follow-up). Complete renal responses occurred more frequently with Isa-Kd (52.0%) versus Kd (30.8%) and were durable in 32.0% versus 7.7% of patients, respectively. Treatment exposure was longer with Isa-Kd, with median number of started cycles and median duration of exposure of 20 versus 9 cycles and 81.0 versus 35.7 weeks for Isa-Kd versus Kd, respectively. Among patients with RI, the incidence of patients with grade ≥3 treatment-emergent adverse events was similar between the two arms (79.1% in Isa-Kd vs. 77.8% in Kd). In summary, the addition of Isa to Kd improved clinical outcomes with a manageable safety profile in patients with RI, consistent with the benefit observed in the overall IKEMA study population.
Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a ...prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1-3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42-0.79; median PFS 35.7 95% CI: 25.8-44.0 vs 19.2 95% CI: 15.8-25.0 months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26-3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55-4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients.Clinical trial information: ClinicalTrials.gov, NCT03275285.
Variant Philadelphia (Ph) chromosome can be observed in 5–10 % of chronic myelogenous leukemia (CML) patients. However, there are only a few studies which have analyzed the prognostic implications of ...these complex translocations in CML patients after the advent of imatinib mesylate and the results found are conflicting. We investigated the clinical features and cytogenetic response of Brazilian chronic phase (CP) CML patients with variant Ph treated with imatinib mesylate. Among 93 CP CML patients, eight (8.6 %) exhibited complex translocations, involving one (
n
= 6), two (
n
= 1), or three (
n
= 1) additional chromosomes. At 6, 12, and 18 months, a complete cytogenetic response was observed in 100 % of variant Ph patients, respectively. No significant difference was found between variant Ph and standard translocation patients regarding the response to IM treatment at 6, 12, and 18 months. Likewise, there was no statistically significant difference between the two groups concerning the overall survival, failure-free survival, progression-free survival, and event-free survival. The results obtained in our study, despite our sample size, suggest, in agreement to other data found in the literature, that the presence of variant Philadelphia chromosome does not bestow a prognostic disadvantage when compared to the group with classic Ph. This observation does not suggest the need to adjust the treatment protocol due to the presence of variant Ph. However, further studies with larger sample sizes and evaluating both the cytogenetic and molecular response to IM treatment should be conducted to confirm our findings.
Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus ...bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM).
This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10
sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk.
After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR.
These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status.
ClinicalTrials.gov, NCT02136134 . Registered 12 May 2014.
Isatuximab (Isa, anti-CD38 monoclonal antibody) is approved in combination with carfilzomib (K) and dexamethasone (d), for relapsed multiple myeloma (MM) patients (pts) after ≥1 prior therapy. Final ...progression free survival (PFS) analysis after 2 years showed mPFS of 35.65 mo (Isa-Kd) vs 19.15 mo (Kd). Here, we report the final overall survival (OS) from IKEMA planned 3 years after the primary PFS analysis.
Pts with 1−3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n=179) or Kd (n=123). Treatment (tx) was given until progressive disease, unacceptable toxicity, or pt wish. Safety was assessed in all treated pts.
As of 7 Feb 2023, 23.5% (Isa-Kd) and 5.7% (Kd) pts were on tx. Median follow-up: 56.61 mo. OS benefit was more in Isa-Kd pts (mOS was NR; 95% CI: 52.172−NR vs 50.6 mo 95% CI: 38.932−NR; HR: 0.855; nominal one-sided p=0.1836). Isa-Kd had longer TTNT vs Kd (median 43.99 vs 25.0 mo; nominal one-sided p=0.0002), as was PFS2 (median 47.18 vs 32.36 mo; nominal one-sided p=0.0035). The safety profiles were comparable to interim and final PFS analyses. Grade ≥3 TEAEs: 84.2% (Isa-Kd) vs 73.0% (Kd).
This final OS analysis shows a meaningful trend for OS benefit with Isa-Kd vs Kd despite subsequent tx with anti-CD38 agents, introduction of tx with novel mechanism of action among further therapies, and the COVID-19 pandemic. Improvements in TTNT and PSF2 were observed and sustained PFS benefit still observed at PFS2. The Isa-Kd safety profile was consistent with previous analyses, supporting it as a standard-of-care therapy for relapsed MM pts.
Background
Given the incurable nature of multiple myeloma (MM), efforts are made to improve the efficacy of anti‐CD38 monoclonal antibodies via combinations with other potentially synergistic ...therapies. This Phase 1/2 trial (NCT03194867) was designed to determine whether cemiplimab (anti‐PD‐1) enhances the anti‐myeloma activity of isatuximab (anti‐CD38) in patients with relapsed and refractory multiple myeloma (RRMM), to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety.
Methods
Patients received isatuximab 10 mg/kg once weekly for 4 weeks followed by every 2 weeks (Isa), or isatuximab 10 mg/kg plus cemiplimab 250 mg every 2 (Isa + CemiQ2W) or every 4 weeks (Isa + CemiQ4W).
Results
Overall, 106 patients with RRMM treated with a median of 4 prior lines were included; 25.5% had high‐risk cytogenetics, 63.2% were refractory to proteasome inhibitors and immunomodulatory agents, 26.4% were previously exposed to daratumumab, and 84.0% were refractory to their last treatment line. There were no major changes in the safety or pharmacokinetic profile of isatuximab with the addition of cemiplimab. As assessed by investigators, four patients (11.8%) in the Isa arm, nine patients (25.0%) in the Isa + CemiQ2W arm, and eight patients (22.2%) in the Isa + CemiQ4W arm were responders. Though response rates were numerically higher in cemiplimab‐containing arms, differences were not statistically significant and did not translate to improved progression‐free or overall survival after a median follow‐up of 9.99 months.
Conclusion
Our results suggest a marginal benefit by adding cemiplimab to isatuximab, despite demonstration of target engagement, without additional observed safety issues.
Preclinical data suggest that concurrent treatment of anti‐CD38 and anti‐PD‐1/PD‐L1 antibodies can substantially reduce primary tumor growth by reversing T‐cell exhaustion, and thus may synergize with anti‐PD‐1/PD‐L1 treatment. This Phase 1/2 trial was designed to determine whether cemiplimab (anti‐PD‐1) enhances the anti‐myeloma activity of isatuximab (anti‐CD38) in patients with relapsed and refractory multiple myeloma, to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety. We observed a marginal benefit by adding cemiplimab to isatuximab, with target engagement confirmed, and without additional safety issues observed.
Objective: The anti-CD38 antibody Isa in combination with Kd is approved in various countries for patients (pts) with relapsed MM after ≥1 prior therapy, based on primary interim analysis (IA) of the ...Phase 3 IKEMA study (NCT03275285). Here we report updated efficacy and safety Results from IKEMA. Methodology: This prespecified final analysis (Isa-Kd 179, Kd 123 pts) evaluated updated PFS (primary endpoint), PFS2, CR rate, MRD- rate, and MRD- and CR rate in ITT population, and safety with 2 additional years of follow-up. Isa 10mg/kg was given IV qw for 4 wks and then q2w; Kd 20/56mg/m² biw, 3/4 weeks. Hydrashift Isa IF assay was used to rule out potential Isa interference in CR determination. At cutoff (14Jan2022; median follow-up 44 mo), 49 (27.4%) Isa-Kd, 11 (8.9%) Kd pts were still on treatment. Results: Updated PFS was consistent with primary IA Results, showing significant benefit of Isa-Kd (vs Kd): PFS HR 0.58; PFS2 HR 0.68. Final CR rate (Isa-Kd vs Kd) was 44.1% vs 28.5%, MRD- rate 33.5% vs 15.4%, MRD- and CR rate 26.3% vs 12.2% (Table). Serious TEAEs were reported in 70.1% Isa-Kd vs 59.8% Kd pts. The most common, any-grade non-hematologic TEAEs in Isa-Kd were infusion reactions (45.8%), diarrhea (39.5%), hypertension (37.9%) and upper respiratory tract infection (37.3%). Conclusion: These Results show unprecedented mPFS, CR rate, MRD- and MRD- CR rates in a non-lenalidomide containing regimen with benefit maintained through subsequent therapies and a manageable safety profile. Safety profiles and efficacy Results in both arms were consistent with prior IKEMA findings. Our findings support Isa-Kd as a standard of care treatment for pts with relapsed MM.
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