High-dose chemotherapy with autologous stem cell transplants in adult primary non-seminoma mediastinal germ-cell tumors. A report from the Cellular Therapy and Immunobiology working party of the EBMT.

BACKGROUND: Primary mediastinal germ-cell tumors (PMGCTs) account for 1%-3% of all germ-cell tumors (GCTs). Non-seminoma have a poorer prognosis compared to their gonadal counterpart and, according to the International Germ Cell Cancer Collaborative Group, they are considered 'poor risk' disease. Medical treatment is the same, with overall survival (OS) being ∼40%, declining to 10%-15% at 3 years in case of lung and non-visceral metastases. Patients failing first-line chemotherapy have a dismal prognosis, with only 5%-10% of cases being cured in the salvage setting. High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been successfully used to treat patients with relapsed or refractory gonadal GCTs. PATIENTS AND METHODS: This retrospective study aimed to investigate the value of HDC with ASCT in the whole population and define primary mediastinal non seminoma germ cell tumor (PMNSGCT) patient subgroups, who were registered in the European Society for Blood and Marrow Transplantation database from January 2000 to January 2018. Sixty-nine adult male patients with PMNSGCT were included. HDC consisted mainly of carboplatin/etoposide doublet, and most patients received HDC as part of a multiple sequential HDC program. RESULTS: OS was 43.3% at 2 years, and 34.7% at 5 and 10 years for the entire cohort. Analysis of outcomes showed that patients undergoing HDC as upfront therapy had a better progression-free survival (PFS) and OS compared to those treated in subsequent relapses (5-year PFS 51.8% versus 26.8% and 5-year OS 51.3% versus 25.9%). Better remission status before transplantation was predictive of the benefit of HDC. Three treatment-related deaths were recorded. CONCLUSIONS: To our knowledge, this is the most extensive retrospective study of HDC in PMNSGCTs patients and the first to thoroughly investigate potential predictors of benefit from this treatment. HDC with ASCT may well represent a therapeutic option in patients with PMNSGCTs after the first relapse or even as a front-line program.

AB079. Whole-brain radiotherapy versus high dose chemotherapy with autologous stem-cell transplantation for consolidation therapy in primary central nervous system lymphoma.

BACKGROUND: Whole brain radiotherapy (WBRT) is commonly used as consolidation therapy in primary central nervous system lymphoma (PCNSL). However, high-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) has emerged as an alternative approach for PCNSL. This systematic review aims to assess the efficacy and safety of both treatment modalities. METHODS: The systematic review follows PRISMA guidelines. A comprehensive search strategy identified relevant studies from PubMed, Europe PMC, and Cochrane Library. The following search terms were used: "primary central nervous system lymphoma", "Autologous Stem Cell Transplantation", and "whole-brain radiotherapy". We included randomized controlled trials (RCTs) cohort studies evaluating the use of whole-brain radiotherapy and high-dose chemotherapy followed by autologous stem cell transplantation in the treatment of histologically-confirmed PCNSL. Publications included were limited to English language full texts that were published in the past 10 years. Data extraction & manuscript quality assessment was done by two independent reviewers with a third reviewer to resolve any discrepancy. Primary outcomes include overall survival (OS), progression-free survival (PFS) & treatment related toxicity (TRT). Secondary outcomes were clinical neurological function and performance score assessments. Individual studies were assessed using the Jadad Scale and the Newcastle-Ottawa Scale for observational studies. RESULTS: We identified 5 studies, consisting of 2 RCTs and 3 cohort studies. After all studies considered, analysis revealed that consolidation therapy with HD-ASCT had a better overall PFS and OS compared to whole-brain radiotherapy (P<0.005). Both groups showed similar TRT with mostly haematological toxicity. Holistically clinical cognitive functions are found to be improved in HD-ASCT Patients and poorer results are exhibited by WBRT patients primarily in executive functions. Performance statuses are scored differently across all studies with slightly preferable results shown in patients treated with HDC-ASCT. CONCLUSIONS: Based on the findings of this systematic review, HDC-ASCT might be a preferable choice of consolidative therapy as shown with better OS, PFS with similar TRT. While WBRT are more feasible and cost-efficient, risks of cognitive impairment and reduced performance status after WBRT should be considered for further treatment choices. Further randomized clinical trials with a similar scoring system are needed.

Determinants of Interpatient Variability in Treosulfan Pharmacokinetics in AML Patients Undergoing Autologous Stem Cell Transplantation.

Limited data on treosulfan pharmacokinetics in adults, particularly regarding autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML), is available to date. Furthermore, correlations between treosulfan exposure, toxicity, and clinical outcome remain understudied. In this single-center retrospective study, we analyzed data from 55 AML patients who underwent HDCT with treosulfan (14 g/m2) and melphalan (140 mg/m2 or 200 mg/m2) (TreoMel) between August 2019 and November 2023 at the University Hospital of Bern. We assessed treosulfan pharmacokinetics and correlations with several physiological parameters with potential impact on its interpatient variability. We further analyzed how treosulfan exposure correlates with toxicity and clinical outcomes. Women above 55 years showed higher area under the curve (AUC) levels (median: 946 mg*h/L, range: 776-1370 mg*h/L), as compared to women under 55 (median: 758 mg*h/L, range: 459-1214 mg*h/L, p = 0.0487). Additionally, women above 55 showed higher peak levels (median: 387 mg/L, range: 308-468 mg/L), as compared to men of the same age range (median: 326 mg/L, range: 264-395 mg/L, p = 0.0159). Treosulfan levels varied significantly with body temperature, liver enzymes, hemoglobin/hematocrit., and treosulfan exposure correlated with diarrhea severity in women over 55 (p = 0.0076). Our study revealed age- and gender-related variability in treosulfan pharmacokinetics, with higher plasma levels observed in female patients above 55. Moreover, our data suggest that treosulfan plasma levels may vary with several physiological parameters and that higher treosulfan exposure may impact toxicity. Our study underlines the need for further research on treosulfan pharmacokinetics, especially in older patients undergoing HDCT in the ASCT setting.

Impact of age on safety of Busulfan-Melphalan followed by autologous hematopoietic stem-cell transplantation versus standard chemotherapy in the patients of the EURO-E.W.I.N.G. 99 and Ewing 2008 clinical trials.

INTRODUCTION: Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials. METHODS: We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12-17 years, 18-24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models. RESULTS: The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group. CONCLUSION: The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups.

The role of autologous stem-cell transplantation in classical Hodgkin lymphoma in the modern era.

Despite excellent cure rates with modern front-line regimens, up to 20% of patients with Hodgkin lymphoma will progress through front-line therapy or experience disease relapse. Worldwide, salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) is considered the standard of care for these patients and can cure approximately 50% of relapsed or refractory (R/R) patients in the second line. Brentuximab vedotin (BV), an anti-CD30 antibody drug conjugate, and PD1 inhibitors like nivolumab and pembrolizumab, have high response rates in patients who recur after HDT/ASCT. When used prior to HDT/ASCT, BV and PD1 inhibitors appear to dramatically increase the effectiveness of salvage therapies with complete response rates often double those seen with historic chemotherapy-based regimens and durable progression free survival (PFS) post-HDT/ASCT. Emerging data in adults and from pediatric trials showing a durable PFS in a subset of relapsed patients raises the question of whether HDT/ASCT is essential for cure in R/R patients after PD1 based salvage. Future studies will help clarify if ASCT can omitted PD1 based salvage to avoid the potential toxicity of HDT/ASCT without compromising cure.

Immune reconstitution after transplantation of autologous peripheral stem cells in children: a comparison between CD34+ selected and nonmanipulated grafts.

BACKGROUND AND AIMS: High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) improves the prognosis in pediatric patients with several solid tumors and lymphomas. Little is known about the reconstitution of the immune system after ASCT and the influence of CD34+ cell selection on the reconstitution in pediatric patients. METHODS: Between 1990 and 2001, 94 pediatric patients with solid tumors and lymphomas received autologous CD34+ selected or unmanipulated peripheral stem cells after HDC. CD34+ selection was carried out with magnetic microbeads. The absolute numbers of T cells, B cells and natural killer (NK) cells were measured and compared in both groups at various time points post-transplant. RESULTS: Recovery of T cells was significantly faster in the unmanipulated group at day 30, with no significant difference later on. Reconstitution of B and NK cells was similar in both groups without significant differences at any time. The CD34+-selected group was divided into patients receiving less or more than 5.385 × 106/kg CD34+ cells. Patients in the CD34+ high-dose group displayed significantly faster reconstitutions of neutrophiles and lymphocyte subsets than the CD34+ low-dose group. CONCLUSIONS: Engraftment and reconstitution of leukocytes, B cells and NK cells after transplantation of CD34+ selected stem cells were comparable to that in patients receiving unmanipulated grafts. T-cell recovery was faster in the unmanipulated group only within the first month. However, this delay could be compensated by transplantation of >5.385 × 106 CD34+ cells/kg. Especially for patients receiving immunotherapy after HDC large numbers of immune effector cells such as NK and T cells are necessary to mediate antibody-dependent cellular cytotoxicity. Therefore, in patients receiving autologous CD34+-selected grafts, our data emphasize the need to administer high stem cell counts.

High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

BACKGROUND: Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. METHODS: The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. RESULTS: The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. CONCLUSIONS: Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

Efficacy and safety of high-dose chemotherapy as the first or subsequent salvage treatment line in patients with relapsed or refractory germ cell cancer: an international multicentric analysis.

BACKGROUND: In relapsed or refractory (RR) metastatic germ cell cancer (GCC), high-dose (HD) chemotherapy (CTX) plus autologous stem cell transplantation is considered the standard of care. Limited data exist regarding the efficacy of HD-CTX following conventionally dosed salvage regimens (CDRs). This analysis explores and contrasts the efficacy of HD-CTX as the first or subsequent salvage regimen. PATIENTS AND METHODS: Data were retrospectively collected to explore the efficacy of HD-CTX administered as the first (group A) or subsequent salvage CTX (group B) after a CDR. The primary endpoint was OS from the time of HD-CTX. Associations of survival, overall response rate (ORR), and toxicity with clinical characteristics were explored using stratified Kaplan-Meier and Cox regression models. RESULTS: Overall, 283 patients with GCC were included from 11 international centers, with 159 patients (56%) in group A and 124 patients (44%) in group B. The first salvage treatment was administered between 1998 and 2022, with a median follow-up of 27.0 [standard deviation (SD) 46.2] months for group A and 17.0 (SD 48.5) months for group B. The median OS from HD-CTX treatment initiation was not reached in group A, compared with 25 months in group B (P = 0.00027), associated with 2- and 5-year OS rates of 74% and 63% (group A) versus 53% and 37% (group B), respectively. When administered as the first salvage treatment, HD-CTX was associated with a higher ORR (79% versus 60%; P = 0.013) and lower nonhematologic grade ≥3 toxicity rate (78% versus 97%; P < 0.001). Concerning risk factor analysis for the total cohort, the International Prognostic Factors Study Group score was the only independent predictor of OS in multivariable analysis (P = 0.006). CONCLUSIONS: When administered as the initial salvage treatment or after CDR, HD-CTX exhibits curative potential for patients with RR GCC. The efficacy and safety outcomes were more favorable when HD-CTX was conducted as the first salvage treatment line.

Safety and Efficacy of High-Dose Chemotherapy with TreoMel 200 vs. TreoMel 140 in Acute Myeloid Leukemia Patients Undergoing Autologous Stem Cell Transplantation.

(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. The aim of this study was to compare two melphalan dose schedules in regard to the safety of TreoMel HDCT and patient outcomes. (2) Methods: We retrospectively analyzed the safety and efficacy of two melphalan dose schedules combined with standard-dose treosulfan in AML patients undergoing HDCT and ASCT at the University Hospital of Bern, Switzerland, between August 2019 and August 2023. Patients received treosulfan 42 g/m2 combined with either melphalan 140 mg/m2 (TreoMel 140) or melphalan 200 mg/m2 (TreoMel 200). Co-primary endpoints were progression-free survival (PFS), overall survival (OS), as well as safety profile. (3) Results: We included a total of 51 AML patients: 31 (60.8%) received TreoMel 140 and 20 (39.2%) TreoMel 200. The patients' basal characteristics were comparable between both cohorts. No significant differences in the duration of hospitalization or the adverse event profile were identified. There were no statistically significant differences in relapse (0.45 vs. 0.30, p = 0.381) and mortality rates (0.42 vs. 0.15, p = 0.064) between the melphalan 140 mg/m2 and 200 mg/m2 cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29-2.28, p = 0.70) or OS (HR: 0.70, 95% CI: 0.19-2.57, p = 0.59) for the TreoMel 140 vs. TreoMel 200 cohort. (4) Conclusions: A higher dose of melphalan (TreoMel 200) was well tolerated overall. No statistically significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and the short follow-up. A longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit.

Case report: Multidrug resistant gestational trophoblastic neoplasia: focus on failure of immunotherapy and success of high-dose chemotherapy.

Gestational trophoblastic neoplasia (GTN) is extremely rare, but has a very good prognosis, with a cure rate close to 100%, for low-risk diseases. This article describes the case of a healthy 28-year-old nulliparous patient with GTN resistant to multiple lines of treatment. The era of immunotherapy is revolutionizing oncology, having already proved its worth in the treatment of many cancers. This article will have a specific focus on the emerging role of immunotherapy in the treatment of GTN. Unfortunately, the use of an immune checkpoint inhibitor (ICI) failed in our case, emphasizing on the necessity to clearly define the future role of immune therapy in GTN. Finally, given the rapid progression of the disease after hysterectomy, induction with Paclitaxel- Ifosfamide and then intensification with high-dose Carboplatin and Etoposide with peripheral blood stem cell support was given as a rescue therapy with still curative intent.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Salvage Therapy of Relapsed/Refractory Germ Cell Tumors: A Single-Center Experience.

INTRODUCTION: The optimal management of relapsed/refractory germ cell tumors remains unsettled. In this study, we aimed to evaluate the efficacy of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as salvage therapy in patients who progressed after at least one line of cisplatin-based chemotherapy. METHODS: We retrospectively reported the results of 133 patients who underwent HDCT and ASCT as salvage therapy from 2016 to 2021. Patients received 3 cycles of paclitaxel, ifosfomide and cisplatin (TIP) regimen as induction and 1 cycle of carboplatin 700 mg/m2 on days 1-3 plus etoposide 750 mg/m2 on days 1-3, followed by ASCT. Demographic and clinicopathological features of patients, the International Germ Cell Cancer Collaborative Group (IGCCCG) risk group at diagnosis, serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) levels before HDCT, treatment-related complications and survival outcomes were recorded. RESULTS: The median age of the patients was 31 (range 18-62). The median follow-up was 31.1 months (95% CI, 28.9-33.3 months). During the median follow-up period, 74 of the 133 patients were still alive, and 63 of these were in complete remission. The median progression-free survival (PFS) was 25.8 months (95% CI, 8.1-43.4 months). The 2-year PFS rate was 50.3% and the 2-year overall survival (OS) rate was 60.8%. Variables that remained statistically significant in multivariable analysis and were associated with poor prognosis were mediastinal primary tumor location, presence of brain metastases, and higher AFP and HCG levels at baseline. CONCLUSION: One course of HDCT and ASCT after induction with TIP is an effective and feasible treatment option for salvage treatment of relapsed/refractory germ cell tumors, with cure rates of up to 60%.

High-dose chemotherapy for Ewing sarcoma and Rhabdomyosarcoma: A systematic review by the Australia and New Zealand sarcoma association clinical practice guidelines working party.

INTRODUCTION: Patients with high-risk or metastatic Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) have a guarded prognosis. High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) has been evaluated as a treatment option to improve outcomes. However, survival benefits remain unclear, and treatment is associated with severe toxicities. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether utilization of HDT/ASCT impacts the outcome of patients with ES and RMS compared to standard chemotherapy alone, as part of first line treatment or in the relapse setting. Medline, Embase and Cochrane Central were queried for publications from 1990 to October 2022 that evaluated event-free survival (EFS), overall survival (OS), and toxicities. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Of 1,172 unique studies screened, 41 studies were eligible for inclusion with 29 studies considering ES, 10 studies considering RMS and 2 studies considering both. In ES patients with high-risk localised disease who received HDT/ASCT after VIDE chemotherapy, consolidation with melphalan-based HDT/ASCT as first line therapy conveyed an EFS and OS benefit over standard chemotherapy consolidation. Efficacy of HDT/ASCT using a VDC/IE backbone, which is now standard care, has not been established. Survival benefits are not confirmed for ES patients with metastatic disease at initial diagnosis. For relapsed/refractory ES, four retrospective studies report improvement in outcomes with HDT/ASCT with the greatest evidence in patients who demonstrate a treatment response before HDT, and in patients under the age of 14. In RMS, there is no proven survival benefit of HDT/ASCT in primary localised, metastatic or relapsed disease. CONCLUSION: Prospective randomised trials are required to determine the utility of HDT/ASCT in ES and RMS. Selected patients with relapsed ES could be considered for HDT/ASCT.

Long-term Outcomes of Protocol-Based Treatment for Newly Diagnosed Medulloblastoma.

PURPOSE: The Korean Society of Pediatric Neuro-Oncology (KSPNO) conducted treatment strategies for children with medulloblastoma (MB) by using alkylating agents for maintenance chemotherapy or tandem high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) according to the risk stratification. The purpose of the study was to assess treatment outcomes and complications based on risk-adapted treatment and HDC. MATERIALS AND METHODS: Fifty-nine patients diagnosed with MB were enrolled in this study. Patients in the standard-risk (SR) group received radiotherapy (RT) after surgery and chemotherapy using the KSPNO M051 regimen. Patients in the high-risk (HR) group received two and four chemotherapy cycles according to the KSPNO S081 protocol before and after reduced RT for age following surgery and two cycles of tandem HDC with ASCR consolidation treatment. RESULTS: In the SR group, 24 patients showed 5-year event-free survival (EFS) and overall survival (OS) estimates of 86.7% (95% confidence interval [CI], 73.6 to 100) and 95.8% (95% CI, 88.2 to 100), respectively. In the HR group, more infectious complications and mortality occurred during the second HDC than during the first. In the HR group, the 5-year EFS and OS estimates were 65.5% (95% CI, 51.4 to 83.4) and 72.3% (95% CI, 58.4 to 89.6), respectively. CONCLUSION: High intensity of alkylating agents for SR resulted in similar outcomes but with a high incidence of hematologic toxicity. Tandem HDC with ASCR for HR induced favorable EFS and OS estimates compared to those reported previously. However, infectious complications and treatment-related mortalities suggest that a reduced chemotherapy dose is necessary, especially for the second HDC.

A prospective observational study of real-world treatment and outcome in secondary CNS lymphoma.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) confers a dismal prognosis and treatment advances are constrained by the lack of prospective studies and real-world treatment evidence. METHODS: Patients with SCNSL of all entities were included at first diagnosis and patient characteristics, treatment data, and outcomes were prospectively collected in the Secondary CNS Lymphoma Registry (SCNSL-R) (NCT05114330). FINDINGS: 279 patients from 47 institutions were enrolled from 2011 to 2022 and 243 patients (median age: 66 years; range: 23-86) were available for analysis. Of those, 49 (20 %) patients presented with synchronous (cohort I) and 194 (80 %) with metachronous SCNSL (cohort II). The predominant histology was diffuse large B-cell lymphoma (DLBCL, 68 %). Median overall survival (OS) from diagnosis of CNS involvement was 17·2 months (95 % CI 12-27·5), with longer OS in cohort I (60·6 months, 95 % CI 45·5-not estimable (NE)) than cohort II (11·4 months, 95 % CI 7·8-17·7, log-rank test p < 0.0001). Predominant induction regimens included R-CHOP/high-dose MTX (cohort I) and high-dose MTX/cytarabine (cohort II). Rituximab was used in 166 (68 %) of B-cell lymphoma. Undergoing consolidating high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-ASCT) in partial response (PR) or better was associated with longer OS (HR adjusted 0·47 (95 % CI 0·25-0·89), p = 0·0197). INTERPRETATION: This study is the largest prospective cohort of SCNSL patients providing a comprehensive overview of an international real-world treatment landscape and outcomes. Prognosis was better in patients with SCNSL involvement at initial diagnosis (cohort I) and consolidating HDT-ASCT was associated with favorable outcome in patients with PR or better.

Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors.

PURPOSE: This study aimed to investigate the incidence and risk factors for secondary malignant neoplasms (SMN) in pediatric solid tumors, focusing on the effects of tandem high-dose chemotherapy (HDCT). MATERIALS AND METHODS: Patients (aged < 19 years) diagnosed with or treated for pediatric solid tumors between 1994 and 2014 were retrospectively analyzed. The cumulative incidence of SMN was estimated using competing risk methods by considering death as a competing risk. RESULTS: A total of 1,435 patients (413 with brain tumors and 1,022 with extracranial solid tumors) were enrolled. Seventy-one patients developed 74 SMNs, with a 10-year and 20-year cumulative incidence of 2.680±0.002% and 10.193±0.024%, respectively. The types of SMN included carcinoma in 28 (37.8%), sarcoma in 24 (32.4%), and hematologic malignancy in 15 (20.3%) cases. Osteosarcoma and thyroid carcinoma were the most frequently diagnosed tumors. Multivariate analysis showed that radiotherapy (RT) > 2, 340 cGy, and tandem HDCT were significant risk factors for SMN development. The SMN types varied according to the primary tumor type; carcinoma was the most frequent SMN in brain tumors and neuroblastoma, whereas hematologic malignancy and sarcomas developed more frequently in patients with sarcoma and retinoblastoma, respectively. CONCLUSION: The cumulative incidence of SMN in pediatric patients with solid tumors was considerably high, especially in patients who underwent tandem HDCT or in those who received RT > 2,340 cGy. Therefore, the treatment intensity should be optimized based on individual risk assessment and the long-term follow-up of pediatric cancer survivors.

A phase II trial of netupitant/palonosetron for prevention of chemotherapy-induced nausea/vomiting in patients receiving BEAM prior to hematopoietic cell transplantation.

Objective: The purpose of this study was to investigate the efficacy and safety of netupitant/palonosetron (NEPA) for the prevention of chemotherapy-induced nausea and vomiting (CINV) for hematopoietic cell transplantation (HCT) patients receiving BEAM therapy. Study Design: This phase II, prospective, intention-to-treat, single-center, single-arm study involved 43 adult patients who received NEPA and dexamethasone for the prevention of CINV due to BEAM conditioning chemotherapy. An interim analysis, performed after 13 patients, determined utility versus futility, and supported continuation to full enrollment. Descriptive statistics were used to report complete response (CR), complete protection, incidence of emesis, and administration of rescue agents. A Kaplan-Meier curve depicted time to first emesis and first rescue medication. Patients self-reported levels of daily nausea descriptively via a CINV Questionnaire. Results: By study end, 13 of 43 patients achieved a CR with an average of 10.6 emesis-free days (SD 0.95) over the 11-day observation period, with no emetic events in any patient during the acute/chemotherapy phase. Nausea was well-controlled throughout the acute therapy phase (Day 1-6) and increased during the delayed phase (Day 7-11) with a peak mean level of 2.79/10 at Day 10. Aside from lower grade (≤2), headaches, constipation, and diarrhea were the most widely reported adverse effects. Conclusion: The combination of NEPA and dexamethasone is safe and effective for the prevention of CINV in patients receiving BEAM conditioning therapy prior to HCT. The regimen demonstrated greater effectiveness in the acute phase versus the delayed phase, with low levels of nausea throughout the study period and complete emesis prevention during chemotherapy.

Is There Still a Role for Stem Cell Transplantation in Multiple Myeloma?

No therapy in multiple myeloma has been as extensively investigated as stem cell transplantation following high-dose chemotherapy. A search of the national library of medicine in February 2023 revealed over 27,000 publications covering stem cell transplantation. No other treatment for multiple myeloma has been so vigorously investigated. However, given the rapid advances seen in the treatment of multiple myeloma, it is legitimate to ask whether the technique first introduced in 1983 by Thomas McIlwain still has relevance. In 1984,Barlogie introduced infusional vincristine, doxorubicin, and dexamethasone and in 1986 published a first series on high-dose therapy with autologous marrow-derived stem cells. At this point, the only available therapies were melphalan, prednisone, other intensive steroids such as methylprednisolone, and interferon. Cyclophosphamide was used both orally and parenterally. VBMCP was introduced as a combination therapy at Memorial Hospital subsequently shown not to be superior to melphalan and prednisone.

Case Report: Effectiveness of secukinumab in systemic sclerosis with early skin progress after autologous hematopoietic stem cell transplantation and end-stage kidney disease.

Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment option in patients with severe forms of systemic sclerosis (SSc) by resetting the immune system. Nevertheless, secondary autoimmune disorders and progressive disease after aHSCT might necessitate renewed immunosuppressive treatments. This is particularly challenging when organ dysfunction, i.e., end-stage kidney failure, is present. In this case report, we present the unique case of a 43-year-old female patient with rapidly progressive diffuse systemic sclerosis who underwent aHSCT despite end-stage renal failure as consequence of SSc-renal crisis. Therefore, conditioning chemotherapy was performed with melphalan instead of cyclophosphamide with no occurrence of severe adverse events during the aplastic period and thereafter. After aHSCT, early disease progression of the skin occurred and was successfully treated with secukinumab. Thereby, to the best of our knowledge, we report the first case of successful aHSCT in a SSc-patient with end-stage kidney failure and also the first successful use of an IL-17 inhibitor to treat early disease progression after aHSCT.

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.

PURPOSE: This review is an update of the MASCC/ESMO 2015 recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. METHODS: A systematic literature search was conducted using PubMed from June 1, 2015, through February 1, 2023. RESULTS: We identified 56 references (16 were duplications or invalid), leaving 40 manuscripts for this search. The panel classified level I evidence (three manuscripts) and level II evidence (14 manuscripts). High-dose chemotherapy and stem cell transplant were discussed in four of these manuscripts, and multiple-day chemotherapy treatment in 15. Some manuscripts covered both topics. Additionally, a search for breakthrough nausea and vomiting resulted in 12 "hits." No new relevant studies were identified. CONCLUSIONS: The recommendations for patients receiving high-dose chemotherapy with stem cell transplants and patients undergoing multiple-day cisplatin were updated. For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant is recommended. Olanzapine could be considered part of the antiemetic regimen. Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist plus dexamethasone plus aprepitant plus olanzapine. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests using a single dose of olanzapine daily for 3 days.

Evolution of Systemic Therapy in Medulloblastoma Including Irradiation-Sparing Approaches.

The management of medulloblastoma in children has dramatically changed over the past four decades, with the development of chemotherapy protocols aiming at improving survival and reducing long-term toxicities of high-dose craniospinal radiotherapy. While the staging and treatment of medulloblastoma were until recently based on the modified Chang's system, recent advances in the molecular biology of medulloblastoma have revolutionized approaches in the management of this increasingly complex disease. The evolution of systemic therapies is described in this review.