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Journal of Clinical Oncology : Official... Jul 2023Rituximab improves progression-free survival (PFS) and time to next treatment (TTNT) when compared with the watch and wait strategy for patients with low-tumor burden... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Rituximab improves progression-free survival (PFS) and time to next treatment (TTNT) when compared with the watch and wait strategy for patients with low-tumor burden follicular lymphoma (FL). Prolonged rituximab maintenance did not prolong TTNT, whereas it raises concerns about resources use and patient adhesion. Our aim was then to investigate the use of short rituximab maintenance using the subcutaneous (SC) route in patients with low-tumor burden FL.
METHODS
Patients with histologically confirmed CD20 low-tumor burden FL were randomly assigned to receive either rituximab, 375 mg/m once daily on D1, D8, D15, and D22, intravenous route (IV, control arm), or rituximab, 375 mg/m, on day 1 (D1), IV followed by rituximab 1,400 mg total dose, SC once daily on D8, D15, and D22, with maintenance at months 3 (M3), M5, M7, and M9 (experimental arm). The primary end point was PFS. Secondary end points included safety, overall response rates, TTNT, and overall survival (OS).
RESULTS
Two hundred two patients with low-tumor burden FL were randomly assigned to the experimental (n = 100) or control arm (n = 102). The primary end point was met: the 4-year PFS was 58.1% (95% CI, 47.5 to 67.4) and 41.2% (95% CI, 30.6 to 51.6) in experimental and control arms, respectively (hazard ratio, 0.585 [0.393 to 0.871]; = .0076). Complete response (CR) rates were 59.0% (95% CI, 48.7 to 68.7) in the experimental arm and 36.3% (95% CI, 27.0 to 46.4) in the control arm ( = .001). TTNT and OS were not significantly different. CR was associated with longer PFS and TTNT. High rituximab exposure during the first three months was independently associated with higher CR, PFS, and TTNT.
CONCLUSION
SC rituximab improves PFS for patients with low-tumor burden FL when used in induction followed by short maintenance. High rituximab exposure during the first 3 months after treatment initiation is, however, the only parameter influencing patient outcomes.
Topics: Humans; Rituximab; Lymphoma, Follicular; Tumor Burden; Antineoplastic Combined Chemotherapy Protocols; Progression-Free Survival
PubMed: 37071836
DOI: 10.1200/JCO.22.02327 -
JAMA Oncology Aug 2023Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers.
Weekly Adaptive Radiotherapy vs Standard Intensity-Modulated Radiotherapy for Improving Salivary Function in Patients With Head and Neck Cancer: A Phase 3 Randomized Clinical Trial.
IMPORTANCE
Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers.
OBJECTIVE
To assess whether adaptive radiotherapy (ART) improves salivary function compared with IMRT in patients with head and neck cancer.
DESIGN, SETTING, AND PARTICIPANTS
This phase 3 randomized clinical trial was conducted in 11 French centers. Patients aged 18 to 75 years with stage III-IVB squamous cell oropharyngeal cancer treated with chemoradiotherapy were enrolled between July 5, 2013, and October 1, 2018. Data were analyzed from November 2021 to May 2022.
INTERVENTIONS
The patients were randomly assigned (1:1) to receive standard IMRT (without replanning) or ART (systematic weekly replanning).
MAIN OUTCOMES AND MEASURES
The primary end point was the frequency of xerostomia, measured by stimulating salivary flow with paraffin. Secondary end points included salivary gland excretory function measured using technetium-99m pertechnetate scintigraphy, patient-reported outcomes (Eisbruch xerostomia-specific questionnaire and the MD Anderson Symptom Inventory for Head and Neck Cancer questionnaire), early and late toxic effects, disease control, and overall and cancer-specific survival.
RESULTS
A total of 132 patients were randomized, and after 1 exclusion in the ART arm, 131 were analyzed: 66 in the ART arm (mean [SD] age at inclusion, 60 [8] years; 57 [86.4%] male) and 65 in the standard IMRT arm (mean [SD] age at inclusion, 60 [8] years; 57 [87.7%] male). The median follow-up was 26.4 months (IQR, 1.2-31.3 months). The mean (SD) salivary flow (paraffin) at 12 months was 630 (450) mg/min in the ART arm and 584 (464) mg/min in the standard arm (P = .64). The mean (SD) excretory function of the parotid gland at 12 months, measured by scintigraphy, improved in the ART arm (48% [17%]) compared with the standard arm (41% [17%]) (P = .02). The 2-year-overall survival was 76.9% (95% CI, 64.7%-85.4%) in both arms.
CONCLUSIONS AND RELEVANCE
This randomized clinical trial did not demonstrate a benefit of ART in decreasing xerostomia compared with standard IMRT. No significant differences were found in secondary end points except for parotid gland excretory function, as assessed by scintigraphy, or in survival rates.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01874587.
Topics: Humans; Male; Female; Radiotherapy, Intensity-Modulated; Paraffin; Head and Neck Neoplasms; Xerostomia; Parotid Gland; Oropharyngeal Neoplasms
PubMed: 37261806
DOI: 10.1001/jamaoncol.2023.1352 -
Journal of Clinical Oncology : Official... Oct 2023In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia.
METHODS
In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10/mm) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 10/mm or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics.
RESULTS
From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ = 9.5, = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times.
CONCLUSION
Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.
Topics: Adult; Humans; Disease Progression; Hemorrhage; Hydrazines; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Quality of Life; Single-Blind Method; Thrombocytopenia
PubMed: 37294914
DOI: 10.1200/JCO.22.02699 -
Nature Medicine Oct 2023Axicabtagene ciloleucel (axi-cel) demonstrated superior efficacy compared to standard of care as second-line therapy in patients with high-risk relapsed/refractory (R/R)...
Axicabtagene ciloleucel (axi-cel) demonstrated superior efficacy compared to standard of care as second-line therapy in patients with high-risk relapsed/refractory (R/R) large B cell lymphoma (LBCL) considered eligible for autologous stem cell transplantation (ASCT); however, in clinical practice, roughly half of patients with R/R LBCL are deemed unsuitable candidates for ASCT. The efficacy of axi-cel remains to be ascertained in transplant-ineligible patients. ALYCANTE, an open-label, phase 2 study, evaluated axi-cel as a second-line therapy in 62 patients with R/R LBCL who were considered ineligible for ASCT. The primary end point was investigator-assessed complete metabolic response at 3 months from the axi-cel infusion. Key secondary end points included progression-free survival, overall survival and safety. The study met its primary end point with a complete metabolic response of 71.0% (95% confidence interval, 58.1-81.8%) at 3 months. With a median follow-up of 12.0 months (range, 2.1-17.9), median progression-free survival was 11.8 months (95% confidence interval, 8.4-not reached) and overall survival was not reached. There was no unexpected toxicity. Grade 3-4 cytokine release syndrome and neurologic events occurred in 8.1% and 14.5% of patients, respectively. These results support axi-cel as second-line therapy in patients with R/R LBCL ineligible for ASCT. ClinicalTrials.gov Identifier: NCT04531046 .
Topics: Humans; Transplantation, Autologous; Hematopoietic Stem Cell Transplantation; Lymphoma, Large B-Cell, Diffuse; Biological Products; Cytokine Release Syndrome; Immunotherapy, Adoptive; Antigens, CD19
PubMed: 37710005
DOI: 10.1038/s41591-023-02572-5 -
Frontiers in Oncology 2023Peripheral T-cell lymphomas (PTCL) comprised more than 30 rare heterogeneous entities, representing 10 to 15% of adult non-Hodgkin lymphomas. Although their diagnosis is... (Review)
Review
Peripheral T-cell lymphomas (PTCL) comprised more than 30 rare heterogeneous entities, representing 10 to 15% of adult non-Hodgkin lymphomas. Although their diagnosis is still mainly based on clinical, pathological, and phenotypic features, molecular studies have allowed for a better understanding of the oncogenic mechanisms involved and the refinement of many PTCL entities in the recently updated classifications. The prognosis remains poor for most entities (5-year overall survival < 30%), with current conventional therapies based on anthracyclin-based polychemotherapy regimen, despite many years of clinical trials. The recent use of new targeted therapies appears to be promising for relapsed/refractory patients, such as demethylating agents in T-follicular helper (TFH) PTCL. However further studies are needed to evaluate the proper combination of these drugs in the setting of front-line therapy. In this review, we will summarize the oncogenic events for the main PTCL entities and report the molecular targets that have led to the development of new therapies. We will also discuss the development of innovative high throughput technologies that aid the routine workflow for the histopathological diagnosis and management of PTCL patients.
PubMed: 37427095
DOI: 10.3389/fonc.2023.1202964 -
Cell Death Discovery Sep 2023Muscle regeneration is a physiological process that converts satellite cells into mature myotubes under the influence of an inflammatory environment progressively... (Review)
Review
Muscle regeneration is a physiological process that converts satellite cells into mature myotubes under the influence of an inflammatory environment progressively replaced by an anti-inflammatory environment, with precise crosstalk between immune and muscular cells. If the succession of these phases is disturbed, the immune system can sometimes become auto-reactive, leading to chronic muscular inflammatory diseases, such as myositis. The triggers of these autoimmune myopathies remain mostly unknown, but the main mechanisms of pathogenesis are partially understood. They involve chronic inflammation, which could be associated with an auto-reactive immune response, and gradually with a decrease in the regenerative capacities of the muscle, leading to its degeneration, fibrosis and vascular architecture deterioration. Immunosuppressive treatments can block the first part of the process, but sometimes muscle remains weakened, or even still deteriorates, due to the exhaustion of its capacities. For patients refractory to immunosuppressive therapies, mesenchymal stem cells have shown interesting effects but their use is limited by their availability. Stromal vascular fraction, which can easily be extracted from adipose tissue, has shown good tolerance and possible therapeutic benefits in several degenerative and autoimmune diseases. However, despite the increasing use of stromal vascular fraction, the therapeutically active components within this heterogeneous cellular product are ill-defined and the mechanisms by which this therapy might be active remain insufficiently understood. We review herein the current knowledge on the mechanisms of action of stromal vascular fraction and hypothesise on how it could potentially respond to some of the unmet treatment needs of refractory myositis.
PubMed: 37726262
DOI: 10.1038/s41420-023-01605-9 -
Blood Advances Aug 2023In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), research is focused on developing fixed-duration strategies to improve long-term...
In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), research is focused on developing fixed-duration strategies to improve long-term outcomes while sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach in which after obinutuzumab-ibrutinib induction for 9 months, patients (n = 10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n = 115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 84 of 135 (62.2%) patients enrolled achieved CR with a BM MRD <0.01%. Here, we report follow-up at median 63 months. Peripheral blood (PB) MRD was assessed 6 monthly beyond the end of treatment using a highly sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in the PB MRD status were apparent per to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Cyclophosphamide; Bone Marrow; Remission Induction; Neoplasm, Residual
PubMed: 37026799
DOI: 10.1182/bloodadvances.2022009594 -
Journal of Nuclear Cardiology :... Oct 2023Dynamic acquisition allows absolute quantification of myocardial perfusion and flow reserve, offering an alternative to overcome the potential limits of relative... (Review)
Review
Dynamic acquisition allows absolute quantification of myocardial perfusion and flow reserve, offering an alternative to overcome the potential limits of relative quantification, especially in patients with balanced multivessel coronary artery disease. SPECT myocardial perfusion is widely available, at lower cost than PET. Dynamic cardiac SPECT is now feasible and has the potential to be the next step of comprehensive perfusion imaging. In order to help nuclear cardiologists potentially interested in using dynamic perfusion SPECT, we sought to review the different steps of acquisition, processing, and reporting of dynamic SPECT studies in order to enlighten the potentially critical pitfalls and artifacts. Both patient-related and technical artifacts are discussed. Key parameters of the acquisition include pharmacological stress, radiopharmaceuticals, and injection device. When it comes to image processing, attention must be paid to image-derived input function, patient motion, and extra-cardiac activity. This review also mentions compartment models, cameras, and attenuation correction. Finally, published data enlighten some facets of dynamic cardiac SPECT while several issues remain. Harmonizing acquisition and quality control procedures will likely improve its performance and clinical strength.
Topics: Humans; Artifacts; Tomography, Emission-Computed, Single-Photon; Coronary Artery Disease; Radiopharmaceuticals; Perfusion; Myocardial Perfusion Imaging
PubMed: 36598748
DOI: 10.1007/s12350-022-03165-4 -
Blood Advances Dec 2023Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of...
Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemotherapy-refractory cases. To identify earlier these higher risk patients, we performed molecular characterization of a retrospective multicenter cohort of patients treated with firstline immunochemotherapy. The traits of the patients with gene-expression profiling data (n = 120) were as follows: median age of 34 years (range, 18-67 years); female sex, 58.3%; elevated lactate dehydrogenase, 82.5%; Eastern Cooperative Oncology Group performance status score of 0 to 1, 85.7%; Ann Arbor stage I/II, 55%; International Prognostic Index score of 1 to 2, 64.4%; and median metabolic tumor volume, 290.4 cm3 (range, 15.7-1147.5 cm3). Among all 137 markers tested for correlation with survival data, only programmed death-ligand (PDL) 1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 patients (30.8%; PDL1high/PDL2high). The baseline clinical characteristics of patients with PDL1high/PDL2high were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor progression-free survival (PFS) (hazard ratio [HR], 4.292) and overall survival (OS; HR, 8.24). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR, 5.22; OS: HR, 10.368). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR, 6.11). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poorer outcomes from standard chemotherapy who might benefit from firstline checkpoint inhibitor therapy.
Topics: Adolescent; Adult; Aged; Female; Humans; Middle Aged; Young Adult; Gene Expression; Lymphoma, Large B-Cell, Diffuse; Prognosis; Progression-Free Survival; Proportional Hazards Models; Male
PubMed: 37862676
DOI: 10.1182/bloodadvances.2023011169 -
Haematologica Jun 2023ALK-negative anaplastic large cell lymphoma (ALCL) comprises subgroups harboring rearrangements of DUSP22 (DUSP22- R) or TP63 (TP63-R). Two studies reported 90% and 40%...
ALK-negative anaplastic large cell lymphoma (ALCL) comprises subgroups harboring rearrangements of DUSP22 (DUSP22- R) or TP63 (TP63-R). Two studies reported 90% and 40% 5-year overall survival (OS) rates in 21 and 12 DUSP22-R/TP63- not rearranged (NR) patients, respectively, making the prognostic impact of DUSP22-R unclear. Here, 104 newly diagnosed ALK-negative ALCL patients (including 37 from first-line clinical trials) from the LYSA TENOMIC database were analyzed by break-apart fluorescence in situ hybridization assays for DUSP22-R and TP63-R. There were 47/104 (45%) DUSP22-R and 2/93 (2%) TP63-R cases, including one DUSP22-R/TP63-R case. DUSP22-R tumors more frequently showed CD3 expression (62% vs. 35%, P=0.01), and less commonly a cytotoxic phenotype (27% vs. 82%; P<0.001). At diagnosis, DUSP22- R ALCL patients more frequently had bone involvement (32% vs. 13%, P=0.03). The patient with DUSP22-R/TP63-R ALCL had a rapidly fatal outcome. After a median follow-up of 4.9 years, 5-year progression-free survival (PFS) and OS rates of 84 patients without TP63-R treated with curative-intent anthracycline-based chemotherapy were 41% and 53%, respectively. According to DUSP22 status, 5-year PFS was 57% for 39 DUSP22-R versus 26% for 45 triple-negative (DUSP22-NR/TP63-NR/ALK-negative) patients (P=0.001). The corresponding 5-year OS rates were 65% and 41%, respectively (P=0.07). In multivariate analysis, performance status and DUSP22 status significantly affected PFS, and distinguished four risk groups, with 4-year PFS and OS ranging from 17% to 73% and 21% to 77%, respectively. Performance status but not DUSP22 status influenced OS. The use of brentuximab vedotin in relapsed/refractory patients improved OS independently of DUSP22 status. Our findings support the biological and clinical distinctiveness of DUSP22- R ALK-negative ALCL. Its relevance to outcome in patients receiving frontline brentuximab vedotin remains to be determined.
Topics: Humans; Receptor Protein-Tyrosine Kinases; Anaplastic Lymphoma Kinase; Brentuximab Vedotin; Disease-Free Survival; Lymphoma, Large-Cell, Anaplastic; In Situ Hybridization, Fluorescence
PubMed: 36453105
DOI: 10.3324/haematol.2022.281442