Cycles Of High-dose Chemotherapy Research Articles

High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed or refractory testicular cancer: a systematic review and meta-analysis.

The role of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in the management of patients with relapsed/refractory germ-cell tumors has not been established in prospective studies. Our aim was to estimate the benefits and harm of this treatment in men with relapsed/refractory germ-cell tumors. Electronic databases, conference proceedings, and trial registers until April 30, 2023, were searched. Randomized and non-randomized prospective controlled trials were included. Risk of bias assessments were performed using either RoB2 or ROBINS-I tools. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Time-to-event data were analyzed using the hazard ratio. The primary outcome was overall survival, and a meta-analysis was not conducted to assess it because non-randomized trials were judged to have a critical risk of bias. Categorical data were analyzed using a risk ratio. All results are presented with the corresponding 95% confidence interval. Four out of 3,824 records met the inclusion criteria, and three out of four were used to assess primary and secondary outcomes. Based on the IT94 study (N = 263 participants), single high-dose chemotherapy followed by autologous hematopoietic cell transplantation may have little to no effect on overall survival [hazard ratio (HR) 0.98, 95%CI 0.68 to 1.42; p = 0.916]. Non-randomized trials (N = 43 participants) showed contrasting results, which may be explained by the number of cycles of high-dose chemotherapy administered in each study. Regarding secondary outcomes, information was only provided for event-free survival, response rate, and acute toxicities. Based on prospective data, there is insufficient evidence to support or refute the proposal that high-dose chemotherapy with autologous hematopoietic cell transplantation improves survival in men with relapsed/refractory germ-cell tumors. If this treatment is considered essential, the choice should be made by experienced clinicians at high-volume cancer centers.

MDB-83. OUTCOMES OF INFANTS AND YOUNG CHILDREN WITH NEWLY DIAGNOSED SHH MEDULLOBLASTOMA TREATED ON THE NEXT CONSORTIUM “HEAD START” 4 PROTOCOL

Abstract BACKGROUND Infants and young children with SHH medulloblastoma were demonstrated to have a favorable outcome on “Head Start (HS)” III clinical trial utilizing five cycles of induction followed by one myeloablative high-dose chemotherapy (HDCT) cycle. We present the results of “Head Start” 4 (HS-4) trial where SHH subgroup patients received either three or five cycles of induction based on response followed by one HDCT cycle (similar to HS III). METHODS Eligibility included children <6 years of age at diagnosis of localized medulloblastoma and <10 years for patients with disseminated disease. Eligible patients with SHH medulloblastoma were considered “low-risk” and non-randomly assigned to receive three cycles (five cycles if <complete response) of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate) followed by consolidation with single HDCT cycle (thiotepa, carboplatin, etoposide) and autologous hematopoietic stem-cell rescue. RESULTS Thirty-nine children with SHH medulloblastoma were enrolled on HS-4 with median age of 2.18 years (range: 0.28-6.88 years). Median follow-up for this cohort is 41 months (range: 18-67 months). Patients with localized SHH medulloblastoma (n=28) had significantly better 3-year event-free (EFS) compared to disseminated patients (n=11): 96.4% (95% CI: 90-100%) and 36.4% (95% CI: 16.6-79.5%), respectively (p<0.0001); however, there was no significant difference in 3-year overall survival (OS) between the two groups: 100% and 90.0% (95% CI: 73.2-100%), respectively (p=0.10). The estimated 3-year EFS for localized SHH subtype 1 and 2 patients was 100% and 95%, respectively (p=0.63). None of trial patients received irradiation prior to progression. All patients, except for four, underwent three cycles of induction. Germline variants were detected in 27% of patients tested (8/30). CONCLUSION We report excellent results for young children with localized SHH medulloblastoma when treated with only three cycles (reduced) of induction and single HDCT cycle on HS-4 trial without irradiation. Molecular data will be presented.

MDB-82. TRANSFUSION-RELATED IRON OVERLOAD MIMICKING METASTATIC DISEASE IN A PEDIATRIC PATIENT WITH MEDULLOBLASTOMA ON A RADIATION-DELAYING CHEMOTHERAPY REGIMEN

Abstract BACKGROUND Transfusion-related iron overload (TRIO) is a known complication of administering numerous packed red blood cell (pRBC) transfusions in pediatric oncology patients undergoing myelosuppressive therapy. Infant medulloblastoma regimens attempt to avoid or delay radiation and its adverse effects in this population, with intensive myelosuppressive chemotherapy. We report a case of TRIO first suspected as hepatic metastatic disease at time of CNS recurrence in a young patient with medulloblastoma after completion of a high-dose chemotherapy protocol. METHODS Case Report RESULTS A five-year-old male presented with four months of headaches, dizziness, imbalance, and emesis. MRI revealed a posterior fossa mass with near total resection of the mass confirming classic medulloblastoma, non-WNT, non-SHH. The patient received five cycles of induction chemotherapy. This was followed by a single cycle of high-dose chemotherapy (HDCSCR) with autologous stem cell rescue. During therapy, he received 26 pRBC transfusions to correct severe anemia. CNS recurrence occurred 19 months after therapy. Abdominal imaging revealed enlarging hepatic lesions concerning for metastases. Ferritin was 1,268 ng/mL (normal: 7-142 ng/mL) and MRI of liver revealed severe iron load with LIC of 11 mg Fe/g dry weight (dw) (normal: 0.4-2.2 mg Fe/g dw). Ultimately, hepatic lesions were thought to be non-cancerous, and he proceeded with craniospinal irradiation. He was diagnosed with TRIO. He underwent phlebotomy for 33 months with ferritin and MRI liver LIC within normal limits. CONCLUSION This case illustrates an occurrence of TRIO presenting as hepatic lesions concerning for metastatic disease during CNS recurrence in a patient who underwent an infant medulloblastoma regimen with HDCSCR. Our patient required phlebotomy for nearly 3 years to return ferritin and LIC to normal limits. Further investigation on the prevalence of TRIO in medulloblastoma survivors treated with radiation delaying/sparing protocols is necessary to improve outcomes and avoid end organ damage due to iron overload.

Ototoxicity associated with high-dose carboplatin for patients with previously treated germ cell tumors.

High-dose carboplatin is an essential part of curative high-dose chemotherapy (HDCT) for patients with previously treated germ cell tumors (GCTs). Although hearing loss (HL) is a known side effect of HDCT, data on its severity and characteristics are limited. Eligible patients received HDCT for GCTs from 1993 to 2017 and had audiograms before and after HDCT. HL severity was classified by American Speech-Language-Hearing Association criteria, and mean change in hearing threshold at each frequency (0.25-8kHz) was estimated from pre- to post-HDCT and between HDCT cycles. Of 115 patients (median age, 32 years), 102 (89%) received three cycles of HDCT. Of 106 patients with normal hearing to mild HL in the speech frequencies (0.5-4kHz) before HDCT, 70 (66%) developed moderate to profound HL in the speech frequencies after HDCT. Twenty-five patients (22%) were recommended for hearing aids after HDCT. Patients with moderate to profound HL isolated to the higher frequencies (6-8kHz) before HDCT were more likely to develop moderate to profound HL in the speech frequencies after HDCT (94% vs. 61%; p=.01) and to be recommended for hearing aids (39% vs. 18%; p=.05). HL was frequent after HDCT for GCTs, with most patients developing at least moderate HL in the speech frequencies and approximately one in five recommended for hearing aids. Moderate to profound HL isolated to high frequencies at baseline was predictive of more clinically significant hearing impairment after HDCT. Some patients with germ cell tumors, the most common malignancy in adolescent and young adult men, are not cured with standard-dose chemotherapy and require high-dose chemotherapy (HDCT). Using detailed hearing assessments of patients receiving HDCT, we found that most patients developed significant hearing loss and that one in five needed hearing aids. Thus, strategies to reduce this side effect are urgently needed, and all patients receiving HDCT should have a hearing test after therapy.

Paclitaxel, gemcitabine, oxaliplatin regimen in induction therapy of patients with relapsed and refractory germ cell tumors before high-dose chemotherapy: results of a pilot study

Purpose: to evaluate the efficacy of TGO (paclitaxel, gemcitabine, oxaliplatin) regimen as induction therapy for hematopoietic stem cells mobilization (HSC) before high-dose chemotherapy (HDCT) in patients with recurrent nonseminomatous germ cell tumors (NSGCT).Patients and methods: the study enrolled patients with relapsed and/or refractory NSGCT after frontline chemotherapy. Modified TGO regimen (paclitaxel 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on day 1 + oxaliplatin 130 mg/m2 on day 1, once every 14 days) was administered with filgrastim support 10 mcg/kg subcutaneous from day 8 and until the completion of leukapheresis. Maximum 3 cycles of TGO regimen was administered. After harvesting the required volume of CD34+ cells, HDCT was initiated which consisted of 3 cycles of the CE regimen (carboplatin AUC8 on day 1–3 + etoposide 400 mg/m2 on day 1–3) with further HSC autologous stem cell transplantation (ASCT).Results: Five patients with NSGCT with poor IGCCCG prognosis according were enrolled. All of them received ifosfamide-containing chemotherapy as initial treatment. The required HSC were collected for three cycles of HDCT in all patients (100 %); in four (80 %) patients the required number of cells was collected after the 1st cycle of TGO. Four (80 %) patients started the HDCT phase, one patient prematurely terminated treatment due to the rapid progression. One patient who received full planned therapy demonstrated complete and durable tumor regression at the time of data analysis (with 37 months follow-up).Conclusions: the TGO regimen can be used to collect PBSC from patients with relapsed and/or refractory NSGCT before HDCT, further study of this approach is required.

Single Cycle of Blinatumomab Followed By High-Dose Chemotherapy in the Induction Therapy for Ph-Negative Acute Lymphoblastic Leukemia in Adults. Primary Endpoint Analysis of the Blina-Cell Trial

Background: Blinatumomab induces a high proportion of complete molecular responses in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and ALL with persistent or recurrent measurable residual disease (MRD) after initial therapy. However, responses are generally short if they are not followed by allogeneic stem cell transplantation (HSCT). We infer that blinatumomab needs to be incorporated sequentially into the early phase of treatment to enhance rates of MRD negativity, lower the need of HSCT and improve survival. Methods: Induction therapy in the Blina-CELL Phase 2 trial (NCT04554485) consisted of run-in phase (dexamethasone 10 mg/m2 days 1-7, cyclophosphamide 200 mg/m2 days 3-5, vincristine 2 mg day 6, and daunorubicin 45 mg/m2 days 6-7), first induction phase (blinatumomab 9 µg/day days 12-19 and 28 µg/day days 20-40), and second induction phase (dexamethasone 10 mg/m2 days 50-54, vindesine 3 mg/m2 day 50, methotrexate 1.5 g/m2 day 50, etoposide 250 mg/m2 days 53-54, and cytarabine 2x 2 g/m2 day 54). Consolidation chemotherapy was identical to the GMALL 07/2003 protocol. Intensive intrathecal prophylaxis was given in both induction and consolidation phases. The primary endpoint was MRD evaluated by quantification of IG/TR rearrangements at week 11 (at the end of induction II). The minimum sensitivity and quantitative range of all assays was 10e-4. Results: Twenty-nine patients started this treatment between May 2019 and March 2022. One patient terminated the study after 3 days of blinatumomab infusion due to elevated liver function tests, one was considered a screening failure due to the missing MRD target. Twenty-seven patients were evaluable. Median age was 41 years (range, 19-65). Median white blood cell count (WBC) at diagnosis was 6.2 x 109/L (range, 0.6-67.7). Twenty-five patients (93%) achieved complete remission (CR) at the end of induction I, 2 (7%) were refractory (both had BCR::ABL1-like phenotype). No patient died during the induction phase. Of the 25 patients in CR, 13 (52%) had complete molecular response (CMR) at day 40 (upon termination of blinatumomab infusion), 11 (44%) had positive non-quantifiable MRD and one (4%) patient had quantifiable MRD >10e-4. Primary endpoint assessment at week 11 showed 20 (80%) patients in CMR, 3 (12%) with positive non-quantifiable MRD and 2 (8%) with MRD ≥10e-4. Four (16%) patients underwent HSCT due to MRD failure or reappearance, all were pre-treated with a further 1-2 cycles of blinatumomab. Three of them (75%) entered HSCT in CMR. One patient was transplanted in CMR for high-risk features (proB, KMT2A rearrangement). The follow-up period is still ongoing. With 18 months of median follow, the overall and relapse-free survival in the study is 18.2 and 15.9 months, respectively. The most frequent grade 3-4 adverse events of blinatumomab therapy were: febrile neutropenia (15%), elevated ALT/AST (11%), soft tissue infection (7%) and low fibrinogen (7%). Only one case of grade 3 cytokine release syndrome was documented. No neurotoxicity events were observed during the induction phase of treatment. Conclusion: Remission induction strategy combining one cycle of blinatumomab with one cycle of high-dose chemotherapy provides a high molecular response rate (CMR or non-quantifiable MRD) of 92%. This approach translates into a low transplant rate due to a high MRD response and has a favourable safety profile. Longer follow-up is needed to evaluate survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sepax-2 cell processing device: a study assessing reproducibility of concentrating thawed hematopoietic progenitor cells

BackgroundAutologous hematopoietic progenitor cell (HPC) transplantation is currently the standard of care for a fraction of patients with newly diagnosed myelomas and relapsed or refractory lymphomas. After high-dose chemotherapy, cryopreserved HPC are either infused directly after bedside thawing or washed and concentrated before infusion. We previously reported on the comparability of washing/concentrating HPC post-thaw vs. infusion without manipulation in terms of hematopoietic engraftment, yet settled for the prior favoring cell debris and DMSO removal. For almost two decades, automation of this critical step of washing/concentrating cells has been feasible. As part of continuous process verification, we aim to evaluate reproducibility of this procedure by assessing intra-batch and inter-batch variability upon concentration of thawed HPC products using the Sepax 2 S-100 cell separation system.MethodsAutologous HPC collected from the same patient were thawed and washed either in two batches processed within a 3-4 h interval and immediately infused on the same day (intra-batch, n = 45), or in two batches on different days (inter-batch, n = 49) for those patients requiring 2 or more high-dose chemotherapy cycles. Quality attributes assessed were CD34+ cell recovery, viability and CD45+ viability; CFU assay was only performed for allogeneic grafts.ResultsIntra-batch and inter-batch median CD34+ cell recovery was comparable (75% vs. 73% and 77% vs. 77%, respectively). Similarly, intra-batch and inter-batch median CD45+ cell viability was comparable (79% vs. 80% and 79% vs. 78%, respectively). Bland-Altman analysis describing agreement between batches per patient revealed a bias close to 0%. Additionally, lower HPC recoveries noted in batch 1 were noted as well in batch 2, regardless of the CD34+ cell dose before cryopreservation, both intra- and inter-batch, suggesting that the quality of the collected product plays an important role in downstream recovery. Intrinsic (high mature and immature granulocyte content) and extrinsic (delay between apheresis and cryopreservation) variables of the collected product resulted in a significantly lower CD45+ viability and CD34+ cell recovery upon thawing/washing.ConclusionsAutomated post-thaw HPC concentration provides reproducible cell recoveries and viabilities between different batches. Implications of this work go beyond HPC to concentrate cell suspension/products during manufacturing of cell and gene therapy products.

Intensive regimens of chemotherapy with hematopoetic stem cell rescue in paediatric patients with high-risk malignant tumors

Background. One of the possible options to intensify therapy in patients with high-risk malignant tumors is high-dose chemotherapy (HDCT) with autologous hematopoetic stem cell rescue. However, this method has a high risk of acute and delayed toxicity, and, sometimes doesn’t meet the expected effectiveness. This confirms the necessity of more considerate approach for choosing the category of patients for this therapeutic option with the determination of the most significant factors on the part of the patient and the type of malignant tumor.Objective. Analysis of the results of HDCT with autologous hematopoetic stem cell transplantation (HSCT) in children with high-risk solid malignancies, conducted in the Department of pediatric oncohematology and BMT of the Federal State Budgetary Institution “V.A. Almazov National Medical Research Center”.Design and methods. We perform a retrospective analysis of 55 cycles of HDCT with autologous hematopoetic stem cell rescue provided from 2017 to 2020 in 39 patients with high-risk malignant tumors. The toxicity and efficacy of the method were assessed taking into account the frequency of infectious complications, early post-transplant mortality, event-free (EFS) and overall survival (OS).Results. The predominant category of patients were children with CNS tumors (61.5 %). Mean age of the patients was 2 years 9 months. At the time of HDCT 35.9% of patients were in complete remission (CR), 64.1 % had signs of active disease (AD). In 59% of patients, one course of HDCT was performed, in 41 % — tandem transplantation was performed according to the recommendations of the protocol for the treatment of the disease. The most common conditioning regimen was carboplatin + etoposide (27.3 %). The predominant source of hematopoietic stem cells were peripheral stem cells (87.3 %). The frequency of infectious complications in the post-transplant period was 100 %, neutropenic enterocolitis (61.8 %) and febrile neutropenia (34.5 %) were predominant. A high frequency of reactivation of CMV infection (25.4 %) was noted, meanwhile CMV disease occurred in 35.7 % of cases. The most important prognostic factor was the disease status at the time of HDCT. 2-year OS incidence of 85.7 % vs 65.3% and EFS 85.7 % vs 39 % in patients with CR and AD respectively. After completing the course of HDCT with autologous HSCT 94.8 % of patients continued anticancer therapy.Conclusion. HDCT with autologous HSCT demonstrates a satisfactory toxicity profile and can improve OS and EFS in children with high-risk malignant tumors. A reliable prognostic factor that determines the effectiveness of the method is the disease status at the time of HDCT.

Randomized phase 2 trial of maintenance oral etoposide or observation following high-dose chemotherapy for relapsed metastatic germ cell tumor.

TPS429 Background: High-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) is effective salvage therapy in patients with relapsed germ-cell tumors (GCT). Utilizing HDCT and PBSCT in the 2nd line setting, cures can be achieved in about 60% of patients with relapsed non-seminoma. Maintenance daily oral etoposide after salvage therapy has been shown effective in inducing remissions (J Clin Oncol 1995;13:1167-9). We evaluate the efficacy and safety of maintenance daily oral etoposide after HDCT+PBSCT in patients with relapsed non-seminoma. Methods: This randomized phase II open label trial is evaluating maintenance oral etoposide after HDCT+PBSCT. Eligible patients are adults with metastatic non-seminomatous GCT who have progressive disease after first-line cisplatin-based combination chemotherapy. All patients will complete initial salvage with HDCT+PBSCT with the carboplatin/etoposide Indiana protocol x2 tandem cycles. All patients should have normal or declining tumor markers (AFP and/or hCG) at time of randomization and absence of progressive disease on imaging. Adverse events from prior therapy, including hematologic toxicity, should be recovered to grade≤2 at time of randomization. Randomization should occur within ≤16 weeks from time of the 2nd cycle of HDCT. Patients with primary mediastinal non-seminoma are eligible. Patients with relapsed pure seminoma are excluded. Patients are randomized in 1:1 ratio to receive maintenance etoposide vs. standard of care surveillance post HDCT. Randomization will be stratified by platinum refractory status defined as progression within 4 weeks of first-line chemotherapy (yes vs no). Patients randomized to treatment arm will receive oral etoposide 50mg/m2 daily for 21 consecutive days of 28 day cycles. A total of 3 cycles will be delivered. Weekly labs including CBC w differential will be checked to detect hematological toxicity. The primary objective is to compare the 12-month progression-free survival (PFS) for maintenance etoposide vs observation in patients with relapsed non-seminoma post HDCT. Secondary objectives include to assess the toxicity and tolerability of maintenance etoposide, and 12-month overall survival. Exploratory analysis of the biomarker micro-RNA371 at time of randomization and correlation with disease progression/relapse will be performed. As of September 20, 2021, 5 of the total sample (N = 64) have been enrolled and randomized. Clinical trial information: NCT04804007.

Central Nervous System Tumors in Children.

Central Nervous System Tumors in Children.

Hematopoietic stem cell mobilization strategies to support high-dose chemotherapy: A focus on relapsed/refractory germ cell tumors.

High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors (GCTs) who failed to be cured by conventional chemotherapy. Hematopoietic stem cells (HSCs) collected from the peripheral blood, after appropriate pharmacologic mobilization, have largely replaced bone marrow as the principal source of HSCs in transplants. As it is currently common practice to perform tandem or multiple sequential cycles of HDCT, it is anticipated that collection of large numbers of HSCs from the peripheral blood is a prerequisite for the success of the procedure. Moreover, the CD34+ cell dose/kg of body weight infused after HDCT has proven to be a major determinant of hematopoietic engraftment, with patients who receive > 2 × 106 CD34+ cells/kg having consistent, rapid, and sustained hematopoietic recovery. However, many patients with relapsed/refractory GCTs have been exposed to multiple cycles of myelosuppressive chemotherapy, which compromises the efficacy of HSC mobilization with granulocyte colony-stimulating factor with or without chemotherapy. Therefore, alternative strategies that use novel agents in combination with traditional mobilizing regimens are required. Herein, after an overview of the mechanisms of HSCs mobilization, we review the existing literature regarding studies reporting various HSC mobilization approaches in patients with relapsed/refractory GCTs, and finally report newer experimental mobilization strategies employing novel agents that have been applied in other hematologic or solid malignancies.

Survival outcomes and toxicity in patients 40 years old or older with relapsed metastatic germ cell tumors treated with high-dose chemotherapy and peripheral blood stem cell transplantation.

High-dose chemotherapy (HDCT) plus peripheral blood stem cell transplantation (PBSCT) is effective salvage therapy for relapsed metastatic germ cell tumors (GCTs) but has potential toxicity. Historically, an age of ≥40 years has been associated with greater toxicity and worse outcomes. This is a retrospective analysis of 445 consecutive patients with relapsed GCT treated with HDCT and PBSCT with tandem cycles at Indiana University from between 2004-2017 per our institutional regimen. Kaplan-Meier methods and log-rank tests were used for progression-free survival (PFS) and overall survival (OS) analysis. A total of 329 patients were <40 years of age, whereas 116 patients were ≥40 years of age; HDCT was used as second-line therapy in 85% and 79%, respectively. Median follow-up time was 42.5 months (range, 0.3-173.4 months). Grade ≥3 toxicities were similar between either group, except for greater pulmonary (P = .02) and renal toxicity (P = .01) in the ≥40-years-of-age group. Treatment-related mortality was similar between both age groups: 10 patients (3%) in the <40-years-of-age group and 4 patients (3.5%) in ≥40-years-of-age group died from complications of HDCT. Two-year PFS for <40 years of age versus ≥40 years of age was 58.7% versus 59.6% (P = .76) and 2-year OS was 63.9% versus 61.5% (P = .93). Factors predicting worse PFS included Eastern Cooperative Oncology Group performance status ≥1, platinum refractory disease, nonseminoma histology, and not completing 2 cycles of HDCT. Age was not an independent predictor of worse outcomes. HDCT plus PBSCT is effective salvage therapy in patients ≥40 years of age with relapsed metastatic GCT. Patients ≥40 years of age experience similar rates of toxicity and treatment-related mortality as those <40 years of age.

Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma

AimTo examine whether anesthesia exposure is associated with neurocognitive decline in pediatric medulloblastoma. MethodsPatients were treated at St. Jude Children's Research Hospital and completed ≥2 protocol-directed neurocognitive assessments (n = 107) as part of a multisite clinical trial for pediatric medulloblastoma (NCT00085202). Patients received risk-adapted craniospinal photon irradiation, followed by four cycles of high-dose chemotherapy and stem cell rescue. Neurocognitive testing was completed at study baseline (after surgery and <2 weeks of starting radiation therapy) and annually for 5 years. Data on anesthesia exposure during treatment was abstracted from medical records. ResultsPatients were 10.2 years at diagnosis on average (SD = 4.5; 37% female, 73% average-risk). Mean cumulative anesthesia duration was 20.4 h (SD = 15.2; range 0.7–55.6 h). In the overall group, longer anesthesia duration was associated with greater declines in IQ (Estimate = −0.08, P < 0.001), attention (Estimate = −0.10, P < .001) and processing speed (Estimate = −0.13, P < 0.001). Similar results were shown in subgroups of patients who were <7 years at diagnosis (IQ = −0.14, P = 0.027; Attention = −0.25: P = 0.011), ≥7 years at diagnosis (Attention = −0.07, P = 0.039; Processing Speed = −0.08, P = 0.022), treated for high-risk disease (IQ = −0.09, P = 0.024; Attention = −0.11, P = 0.034; Processing Speed = −0.13, P = 0.001), or treated for average-risk disease (IQ = −0.05, P = .022; Attention = −0.08, P = 0.011; Processing Speed = −0.10, P < 0.001). ConclusionGreater anesthesia exposure is a risk factor for clinically significant neurocognitive decline, in addition to factors of age at diagnosis and treatment risk arm. This result is notable as there are evidence-based strategies that can limit the need for anesthesia. Limiting anesthesia exposure, as feasible, may mitigate neurocognitive late effects, and thus, improve quality of life for survivors.

Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial

R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial. In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18-60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00129090. Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1-11·1), 10-year event-free survival was 51% (95% CI 42-61) in the R-MegaCHOEP group and 57% (47-67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9-1·8], p=0·23). 10-year progression-free survival was 59% (50-68) in the R-MegaCHOEP group and 60% (51-70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7-1·7], p=0·64). 10-year overall survival was 66% (57-76) in the R-MegaCHOEP group and 72% (63-81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8-2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11-22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group. Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted. Deutsche Krebshilfe (German Cancer Aid).

Differences in clinical characteristics and outcomes between white (W) and non-white (NW) patients with metastatic germ cell tumor (mGCT) treated at Indiana University (IU).

376 Background: Patients (pts) with mGCT are curable even when presenting at advanced stages, however its incidence is rising in NW populations. There is lack of data evaluating differences in disease characteristics and outcomes between W and NW pts. Methods: 701 pts with mGCT treated at IU with first-line chemotherapy (FLC) and 462 patients with relapsed mGCT treated with HDCT (high-dose chemotherapy) between 2004 and 2017 at IU were evaluated. Results: Pts treated with FLC had a median follow-up since diagnosis of 4.9 (0.03-19.46) years. 660 (94.1%) W pts and 41 (5.9%) NW (49% Hispanic, 26% Asian, 20% African American and 5% Native American). There were no significant differences in median age at diagnosis, rates of primary tumor site, pathology type (seminoma vs non-seminoma), metastasis sites, mortality, median hCG levels pre-chemotherapy, rates of progression after FLC, or late relapse rates. Higher rates of good risk disease and lower rates of poor risk disease were present among W compared to NW, as well as higher median AFP levels pre-chemotherapy and rates of platinum refractory disease in NW (p&lt;0.05). Patients treated with HDCT had a median follow up time of 2.08 (0.02-14.49) years since diagnosis. 412 (89.1%) were W and 50 (10.1%) were NW (48% Hispanic, 18% Asian, 26% African American, 2% Native American and 6% other). There were no significant differences in rates pathology type, disease risk, tumor markers, platinum refractory disease, completion of 2 cycles of HDCT, progression after HDCT or status at last follow up. W pts were more likely to receive HDCT as initial salvage chemotherapy compared to NW (P&lt;0.05). Conclusions: This single-institution study demonstrates that amongst patients undergoing FLC for mGCT, there were higher rates of poor risk disease and platinum refractory disease amongst NW patients. W patients were more likely to receive HDCT as initial salvage chemotherapy compared to NW patients. However these findings did not reflect a significant difference in disease progression or mortality. [Table: see text]

ATRT-21. RHABDOID PREDISPOSITION SYNDROME: REPORT OF MOLECULAR PROFILES AND TREATMENT APPROACH IN THREE CHILDREN WITH SYNCHRONOUS ATYPICAL TERATOID/RHABDOID TUMOR AND MALIGNANT RHABDOID TUMOR

BACKGROUNDRhabdoid predisposition syndrome is characterized by germline alterations in SMARCB1 or SMARCA4, leading to synchronous or metachronous central nervous system (CNS) and extra-CNS rhabdoid tumors. Rare survivors have been reported to date.METHODSWe describe the molecular profiling and treatment regimen of three patients with synchronous atypical teratoid/rhabdoid tumor (ATRT) and malignant rhabdoid tumor of the kidney (MRT-K). All patients underwent radical nephrectomy of the kidney, and gross total resection of the primary CNS tumor was achieved for two patients. An intensive chemotherapy regimen was administered; an induction phase based on the modified Third Intergroup Rhabdomyosarcoma Study (IRS-III) for ATRT followed by a consolidation phase with three cycles of high-dose chemotherapy and autologous hematopoietic progenitor cell rescue, without irradiation. All three patients were enrolled on an institutional comprehensive genomic profiling protocol.RESULTSA germline focal 22q deletion, including SMARCB1, was detected in two patients, while the third patient had a maternally-inherited heterozygous frameshift variant in SMARCB1. Somatic loss of heterozygosity of 22q was identified in all patients, resulting in biallelic inactivation of SMARCB1. Divergent tumor subgroups were described using DNA methylation. The three MRT-K samples were classified as MYC subtype. One ATRT was classified as SHH while the other as TYR. One patient is currently three years off-therapy without evidence of disease, while the other two patients have completed the consolidation phase without recurrent disease.CONCLUSIONMolecular profiling of CNS and extra-CNS rhabdoid tumors revealed different epigenetic subgroups. An intensive multimodal therapeutic approach without irradiation may achieve prolonged survival.

ETMR-15. USE OF HIGH-DOSE CHEMOTHERAPY FOR TWO CHILDREN WITH EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES

Embryonal tumor with multilayered rosettes (ETMR) is new entity defined in the 4th revised edition of the WHO classification of tumors of the central nervous system. Although radical resection, radiotherapy, and multiagent chemotherapy are considered to be necessary for ETMR, the efficacy of chemotherapy for ETMR in Japan has not been established. Here, we report different clinical courses for two children with localized ETMR treated with the St. Jude medulloblastoma-96 (SJMB96) regimen, which consists of four cycles of high-dose chemotherapy with autologous peripheral blood stem cell transplantation. For both children, the diagnosis of ETMR, C19MC-altered was confirmed after gross total tumor resection. Multiagent chemotherapy was administered following cranio-spinal irradiation with local boost. One month after completion of the treatment, one patient experienced local recurrence but has been in remission for over 2 years after tumor resection and stereotactic irradiation with a CyberKnife and treatment every three weeks with bevacizumab. The other patient also experienced local recurrence after the third cycle of chemotherapy and several times thereafter. Although she again underwent tumor resection and local irradiation, her tumor grew larger and invaded. Because her prognosis was very poor, her parents choose only palliative care. Based on our experience, we believe that continuous chemotherapy at conventional doses is preferred over intensive-dose chemotherapy such as SJMB96. However, the number of reports on chemotherapy for ETMR is still small, and a prospective multicenter trial is needed to establish effective chemotherapy for ETMR.

MBCL-48. OUTCOMES OF TREATMENT BASED ON THE ST. JUDE MEDULLOBLASTOMA-96 REGIMEN FOR JAPANESE CHILDREN WITH MEDULLOBLASTOMA

Medulloblastoma is a type of malignant embryonal tumor in childhood that is considered to require multiagent chemotherapy followed by radical resection and craniospinal irradiation (CSI). However, the outcomes of chemotherapy for this tumor in Japan are unclear. Here, we performed a multicenter retrospective study to determine the prognosis of pediatric medulloblastoma patients in Japan treated with the St. Jude medulloblastoma-96 (SJMB96) regimen. Thirty patients with newly diagnosed medulloblastoma received treatment with the SJMB96 regimen at Juntendo University Hospital in Tokyo (n=10), Saitama Medical University International Medical Center in Saitama (n=10), and Tohoku University Hospital in Miyagi (n=10) from 2011 to 2018. All patients underwent tumor resection and CSI, with radiation doses of 23.4Gy for standard-risk patients (n=11) and 39.6Gy for high-risk patients (n=19). Six weeks after radiation therapy, patients received four cycles of high-dose chemotherapy with autologous peripheral blood stem cell transplantation according to the SJMB96 regimen. We found that 5-year overall survival was 80.8% among standard-risk patients and 74.2% among high-risk patients. No treatment-related deaths occurred. Eight patients who experienced recurrence died within 80 months of diagnosis. As these treatment outcomes are comparable to those previously reported outside of Japan, our findings indicate that this regimen is a therapeutic option for medulloblastoma patients in Japan.

High-dose chemotherapy (HDCT) and peripheral-blood stem cell transplant (PBSCT) in patients age 40 or older with relapsed metastatic germ-cell tumors (mGCT).

e17054 Background: HDCT plus PBSCT is effective salvage therapy for relapsed mGCT but has potential toxicity. Historically, age ≥ 40 years has been associated with greater toxicity and worse outcomes. Methods: 445 consecutive pts with relapsed mGCT were treated with HDCT and PBSCT with tandem cycles at Indiana University from between 2004-2017 per our institutional regimen ( N Engl J Med 2007; 357:340-8). Kaplan-Meier methods and log-rank tests were used for progression free survival (PFS) analysis. Results: 329 pts were age &lt; 40 while 116 pts were age≥40 and HDCT was being used as 2nd line in 85% and 79%, respectively. Median follow-up time was 42.5 months (range 0.3-173.4). Pulmonary metastasis was more frequent in the age &lt; 40 group (66% vs. 41%, P &lt; 0.001). Patients age≥40 were more likely to have seminoma (45% vs. 14%, P &lt; 0.001), were more likely not platinum refractory (80% vs. 63%, P = 0.0010), and were less likely to complete 2 planned tandem cycles of HDCT (86% vs. 93%, P = 0.03). Grade 3 or higher toxicities were similar between either cohort, except for greater pulmonary toxicity in age≥40 group (8% vs. 2%, P = 0.02). Treatment-related mortality was similar between both age groups: 10 patients (3%) in age &lt; 40 and 4 patients (3.5%) in age≥40 group died from complications of HDCT. 2-year PFS for age &lt; 40 vs. age ≥ 40 was 58.7% vs. 59.6% (P = 0.76) and 2-year OS was 63.9% vs. 61.5% (P = 0.93). When evaluating patients with pure seminoma: 2- year OS for age &lt; 40 vs. 40-50 vs. ≥ 50 was 100% vs 90.3%, vs 81.4%, respectively (P = 0.09). For patients with non-seminoma: 2-year OS was 58.1% vs. 37.1% vs. 54.2%, respectively (P = 0.01). In multivariable analysis for PFS: significant factors predicting worse outcomes included platinum refractory disease (HR = 1.55, P = 0.03), primary mediastinal non-seminoma (HR = 2.41, P = 0.03), not completing 2 cycles of HDCT (HR = 2.47, P = 0.01), and hCG &gt; 1000 at initiation of HDCT (HR = 1.92, P &lt; 0.001). Age was not a significant factor predicting worse outcomes. Conclusions: HDCT plus PBSCT is effective salvage therapy in pts age≥40 with relapsed mGCT. Patients age &gt; 40 experience similar rates of toxicity and treatment-related mortality as those &lt; 40 years of age.

Differences in clinical characteristics and outcomes between white (W) and non-white (NW) patients with metastatic germ cell tumor (mGCT) treated at Indiana University (IU).

e19053 Background: Patients (pts) with mGCT are curable even when presenting at advanced stages, however its incidence is rising in NW populations. There is lack of data evaluating differences in disease characteristics and outcomes between W and NW pts. Methods: 701 pts with mGCT treated at IU with first-line chemotherapy (FLC) and 462 patients with relapsed mGCT treated with HDCT (high-dose chemotherapy) between 2004 and 2017 at IU were evaluated. Results: Pts treated with FLC had a median follow-up since diagnosis of 4.9 (0.03-19.46) years. 660 (94.1%) W pts and 41 (5.9%) NW (49% Hispanic, 26% Asian, 20% African American and 5% Native American). There were no significant differences in median age at diagnosis, rates of primary tumor site, pathology type (seminoma vs non-seminoma), metastasis sites, mortality, median hCG levels pre-chemotherapy, rates of progression after FLC, or late relapse rates. Higher rates of good risk disease and lower rates of poor risk disease were present among W compared to NW, as well as higher median AFP levels pre-chemotherapy and rates of platinum refractory disease in NW (p &lt; 0.05). Patients treated with HDCT had a median follow up time of 2.08 (0.02-14.49) years since diagnosis. 412 (89.1%) were W and 50 (10.1%) were NW (48% Hispanic, 18% Asian, 26% African American, 2% Native American and 6% other). There were no significant differences in rates pathology type, disease risk, tumor markers, platinum refractory disease, completion of 2 cycles of HDCT, progression after HDCT or status at last follow up. W pts were more likely to receive HDCT as initial salvage chemotherapy compared to NW (P &lt; 0.05). Conclusions: This single-institution study demonstrates that amongst patients undergoing FLC for mGCT, there were higher rates of poor risk disease and platinum refractory disease amongst NW patients. W patients were more likely to receive HDCT as initial salvage chemotherapy compared to NW patients. However these findings did not reflect a significant difference in disease progression or mortality. [Table: see text]