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Pediatric Blood & Cancer Jun 2024Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases...
PURPOSE
Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity.
PATIENTS AND METHODS
Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications.
RESULTS
Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%].
CONCLUSION
This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.
Topics: Humans; Neuroblastoma; Female; Male; Child, Preschool; Infant; Child; Antineoplastic Combined Chemotherapy Protocols; Japan; Prospective Studies; Survival Rate; Adolescent; Induction Chemotherapy; Etoposide; Follow-Up Studies; Vincristine; Combined Modality Therapy; Cyclophosphamide; Prognosis; Doxorubicin; Melphalan; Cisplatin
PubMed: 38577760
DOI: 10.1002/pbc.30976 -
World Journal of Transplantation Mar 2024Conditioning regimens employed in autologous stem cell transplantation have been proven useful in various hematological disorders and underlying malig nancies; however,... (Review)
Review
Conditioning regimens employed in autologous stem cell transplantation have been proven useful in various hematological disorders and underlying malig nancies; however, despite being efficacious in various instances, negative consequences have also been recorded. Multiple conditioning regimens were extracted from various literature searches from databases like PubMed, Google scholar, EMBASE, and Cochrane. Conditioning regimens for each disease were compared by using various end points such as overall survival (OS), progression free survival (PFS), and leukemia free survival (LFS). Variables were presented on graphs and analyzed to conclude a more efficacious conditioning regimen. In multiple myeloma, the most effective regimen was high dose melphalan (MEL) given at a dose of 200/mg/m. The comparative results of acute myeloid leukemia were presented and the regimens that proved to be at an admirable position were busulfan (BU) + MEL regarding OS and BU + VP16 regarding LFS. In case of acute lymphoblastic leukemia (ALL), BU, fludarabine, and etoposide (BuFluVP) conferred good disease control not only with a paramount improvement in survival rate but also low risk of recurrence. However, for ALL, chimeric antigen receptor (CAR) T cell therapy was preferred in the context of better OS and LFS. With respect to Hodgkin's lymphoma, mitoxantrone (MITO)/MEL overtook carmustine, VP16, cytarabine, and MEL in view of PFS and regarding OS. Non-Hodgkin's lymphoma patients were administered MITO (60 mg/m) and MEL (180 mg/m) which showed promising results. Lastly, amyloidosis was considered, and the regimen that proved to be competent was MEL 200 (200 mg/m). This review article demonstrates a comparison between various conditioning regimens employed in different diseases.
PubMed: 38576761
DOI: 10.5500/wjt.v14.i1.87532 -
Hematology (Amsterdam, Netherlands) Dec 2024Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been...
Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been reported to be between 0% and 30%. In 2018, we identified a pGF incidence of 35% in our pediatric haplo-HSCT recipients with hematologic malignancies, which motivated us to enact changes to the conditioning regimen. We performed a single-center prospective, pre-post study of consecutive patients under 16 years with hematologic malignancies, from January 2015 to December 2022 who received a haplo-HSCT. Twenty-six pediatric patients received a haplo-HSCT before September 2018 (G1) and 36 patients after (G2). The main conditioning regimen for G1 was myeloablative with Flu/Cy/Bu, and for G2 the main regimen was reduced intensity Flu/Cy/Mel/TBI2. Nine patients (35%) in G1 had primary graft failure, while in G2 there were no patients with pGF. The median follow-up for G1 was 15.9 months, and for G2 was 24.8 months, with an estimated overall survival at 12 months of 63% (95% CI 47-76) versus 85% (95% CI 73-93), and at 24 months of 47% (95% CI 31-64) versus 70% (95% CI 54-82) respectively ( = .007). After September 2018 conditioning regimen modifications were implemented with the objective of reducing primary failure, consisting mainly of switching from busulfan to melphalan as the alkylating agent of choice, and adding, when clinically possible TBI. Primary failure has been significantly reduced in our institution since then.
Topics: Humans; Child; Melphalan; Prospective Studies; Transplantation, Haploidentical; Busulfan; Hematologic Neoplasms
PubMed: 38568018
DOI: 10.1080/16078454.2024.2335417 -
The Lancet. Haematology May 2024Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the...
BACKGROUND
Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30 lymphoma at high risk of relapse.
METHODS
This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30 disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 10 CAR T cells per m, 1 × 10 CAR T cells per m, or 2 × 10 CAR T cells per m) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per μL for 3 days, platelet count ≥25 × 10 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete.
FINDINGS
Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 10 CAR T cells per m, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached.
INTERPRETATION
Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings.
FUNDING
National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Male; Female; Middle Aged; Transplantation, Autologous; Adult; Immunotherapy, Adoptive; Ki-1 Antigen; Aged; Adolescent; Hodgkin Disease; Young Adult; Child; Receptors, Chimeric Antigen; Antineoplastic Combined Chemotherapy Protocols; Melphalan; Lymphoma, Non-Hodgkin; Carmustine; Etoposide; Child, Preschool; Cytarabine
PubMed: 38555923
DOI: 10.1016/S2352-3026(24)00064-4 -
Acta Clinica Croatica Aug 2023Despite being extremely rare, Guillain-Barré syndrome (GBS) has been recognized as a neurological complication of multiple myeloma, with variable responses to...
Despite being extremely rare, Guillain-Barré syndrome (GBS) has been recognized as a neurological complication of multiple myeloma, with variable responses to plasmapheresis (PEX), intravenous immunoglobulins (IVIG), and anti-myeloma therapies. In this paper, we report a case of a female patient with asymptomatic multiple myeloma (aMM) who initially presented as PEX- and IVIG-refractory GBS. After failure of PEX, IVIG, and anti-myeloma therapy (bortezomib, melphalan, and prednisone), the patient was eventually successfully treated with low-dose rituximab (100 mg/m week in four doses). To the best of our knowledge, this is the first case to report successful treatment of refractory GBS potentially associated to aMM with low-dose rituximab. Additional studies are needed to elucidate the pathophysiological processes and the interplay between the dysregulated immune response, monoclonal immunoglobulin (MG), and neural tissue damage in GBS patients. Also, the potential role of rituximab in the treatment of MG-associated GBS warrants further exploration.
Topics: Humans; Female; Guillain-Barre Syndrome; Immunoglobulins, Intravenous; Rituximab; Smoldering Multiple Myeloma; Plasmapheresis
PubMed: 38549594
DOI: 10.20471/acc.2023.62.02.19 -
Haematologica Mar 2024There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We...
Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.
There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the EBMT registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 μmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100mg/m2 in 23%, 140mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pre-transplant to 66% at Day +100 post-ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median eGFR increased from 44 to 51 ml/min/1.73 m2. There was no further change between 3 and 12 months post- ASCT. No patient who was RRT-independent at ASCT became RRT dependent by Day + 100 post-ASCT. Median follow-up post-ASCT was 84 months (IQR: 46-122). At 6-years post ASCT, overall survival (OS) was 88% (95% CI: 78-98%) and PFS was 44% (95% CI: 28-60%). The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 17% (95% CI: 6-27%) and 2% (95% CI: 0-6%), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favourable with low NRM and good long-term OS.
PubMed: 38546696
DOI: 10.3324/haematol.2023.284520 -
Viruses Mar 2024The sudden emergence of SARS-CoV-2 demonstrates the need for new vaccines that rapidly protect in the case of an emergency. In this study, we developed a recombinant MVA...
The sudden emergence of SARS-CoV-2 demonstrates the need for new vaccines that rapidly protect in the case of an emergency. In this study, we developed a recombinant MVA vaccine co-expressing SARS-CoV-2 prefusion-stabilized spike protein (ST) and SARS-CoV-2 nucleoprotein (N, MVA-SARS-2-ST/N) as an approach to further improve vaccine-induced immunogenicity and efficacy. Single MVA-SARS-2-ST/N vaccination in K18-hACE2 mice induced robust protection against lethal respiratory SARS-CoV-2 challenge infection 28 days later. The protective outcome of MVA-SARS-2-ST/N vaccination correlated with the activation of SARS-CoV-2-neutralizing antibodies (nABs) and substantial amounts of SARS-CoV-2-specific T cells especially in the lung of MVA-SARS-2-ST/N-vaccinated mice. Emergency vaccination with MVA-SARS-2-ST/N just 2 days before lethal SARS-CoV-2 challenge infection resulted in a delayed onset of clinical disease outcome in these mice and increased titers of nAB or SARS-CoV-2-specific T cells in the spleen and lung. These data highlight the potential of a multivalent COVID-19 vaccine co-expressing S- and N-protein, which further contributes to the development of rapidly protective vaccination strategies against emerging pathogens.
Topics: Animals; Humans; Mice; SARS-CoV-2; COVID-19; COVID-19 Vaccines; Antibodies, Viral; Spike Glycoprotein, Coronavirus; Vaccination; Antibodies, Neutralizing; gamma-Globulins; Melphalan; Viral Vaccines; Vaccines, DNA
PubMed: 38543782
DOI: 10.3390/v16030417 -
Ceska a Slovenska Oftalmologie :... 2024Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments,... (Review)
Review
Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments, represents a major parameter determining the degree of retinoblastoma according to the International Classification of Retinoblastoma. In this article we focused on vitreous seeding, one of the main limiting factors in the successful "eye preservation treatment" of retinoblastoma. This article presents an overview of the history of vitreous seeding of retinoblastoma, established treatment procedures and new-research modalities. The introduction of systemic chemotherapy in the treatment of retinoblastoma at the end of the 1990s represented a significant breakthrough, which enabled the progressive abandonment of radiotherapy with its attendant side effects. However, the attained concentrations of chemotherapeutics in the vitreous space during systemic chemotherapy are not sufficient for the treatment of vitreous seeding, and the toxic effects of systemic chemotherapy are not negligible. A significant change came with the advent of chemotherapy in situ, with the targeted administration of chemotherapeutic drugs, namely intra-arterial and intravitreal injections, contributing to the definitive eradication of external radiotherapy and a reduction of systemic chemotherapy. Although vitreous seeding remains the most common reason for the failure of intra-arterial chemotherapy, this technique has significantly influenced the original treatment regimen of children with retinoblastoma. However, intravitreal chemotherapy has made the greatest contribution to increasing the probability of preservation of the eyeball and visual functions in patients with advanced findings. Novel local drug delivery modalities, gene therapy, oncolytic viruses and immunotherapy from several ongoing preclinical and clinical trials may represent promising approaches in the treatment of vitreous retinoblastoma seeding, though no clinical trials have yet been completed for routine use.
Topics: Child; Humans; Retinoblastoma; Retinal Neoplasms; Melphalan; Antineoplastic Agents, Alkylating; Vitreous Body; Intravitreal Injections; Retrospective Studies
PubMed: 38538290
DOI: 10.31348/2023/35 -
American Journal of Hematology Jun 2024
Comparative Study
BEAM versus pharmacokinetics-directed BuCyVP16 conditioning for patients with peripheral T-cell lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Lymphoma, T-Cell, Peripheral; Transplantation Conditioning; Antineoplastic Combined Chemotherapy Protocols; Male; Middle Aged; Female; Transplantation, Autologous; Cytarabine; Carmustine; Adult; Melphalan; Aged
PubMed: 38526002
DOI: 10.1002/ajh.27291 -
Biomedicine & Pharmacotherapy =... May 2024Retinoblastoma (RB) is a type of pediatric solid tumor in the fundus. The lack of precision therapies combined with the difficulty of delivering small interfering RNA...
Retinoblastoma (RB) is a type of pediatric solid tumor in the fundus. The lack of precision therapies combined with the difficulty of delivering small interfering RNA (siRNA) into the eyes means that there is currently no nucleic acid-based therapy for RB in clinical practice. Here, we reported on anti-GD2 and glutathione-responsive spherical nucleic acids (SNAs), loaded with siRNA and the inhibitor NVP-CGM097, which jointly blocked the oncogenic factor n in RB cells (Y79 and WERI-RB-1). The SNAs were formed through the self-assembly of bifunctional cholesterol amphiphiles containing aptamers that specifically targeted GD2-positive RB cells, allowing for the formation of an SNA with a dense DNA shell. The aptamer/siRNA component functioned both as a carrier and a payload, enhancing the specific recognition and delivery of both components and constituting an active agent for MDM2 regulation. Following SNA endocytosis by RB cells, siRNA and NVP-CGM097 were released from the SNA particles by glutathione, which synergistically blocked the MDM2-p53 pathway, increasing p53 protein content and inducing cell apoptosis. This study showed a potent antitumor effect following intravitreal injection of SNAs in Y79 tumor-bearing mice through clinical manifestation and tumor pathological analysis. In hematological analysis and hepatotoxicity assays, SNAs were safer for mice than melphalan, the favored drug for treating RB in clinical practice. Our results illustrated the potential of intravitreally injected SNAs as a precision medicine for treating RB.
Topics: Animals; Humans; Mice; Apoptosis; Aptamers, Nucleotide; Cell Line, Tumor; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Proto-Oncogene Proteins c-mdm2; Retinal Neoplasms; Retinoblastoma; RNA, Small Interfering; Xenograft Model Antitumor Assays; Mice, Inbred ICR; Female
PubMed: 38522240
DOI: 10.1016/j.biopha.2024.116437