Use Of High-dose Chemotherapy Research Articles

Consensus recommendations for systemic therapies in the management of relapsed Ewing sarcoma: A report from the National Ewing Sarcoma Tumor Board.

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs.

P-364 Impact on fertility outcomes in survivors after hematopoietic stem cell transplantation for benign and malignant hematologic disorders: a systematic review and meta-analysis

Abstract Study question What is the prevalence of infertility after hematopoietic stem cell transplantation (HSCT) in females and males up to the age of 1 year? Summary answer The overall prevalence of infertility (95% CI) in women treated with HSTC is 64% (0.58-0.70) and in men 39% (0.31-0.47). What is known already HSCT is a well-established treatment that has significantly increased survival in haematological malignancies and also benign diseases since its introduction in the 1980s. The use of high-dose chemotherapy and radiotherapy, myeloablative conditioning, combined with HSCT exposes serious long-term complications, including gonadal dysfunction and infertility. The risk of ovarian and testicular damage seems to be very high. Therefore, the European Society for Blood and Marrow Transplantation (EBMT) had recommended in 2015 to consider fertility preservation measures in children and adolescents requiring HSCT. However, the data on which this recommendation was based was limited and heterogeneous. Study design, size, duration The systematic review and meta-analysis is part of the FertiTOX project (www.fertitox.com) which aims to close the gap of data regarding gonadotoxicity of cancer therapies to enable more accurate counselling regarding fertility preservation. A systematic literature search was conducted in Medline, Embase and Cochrane in November 2023, considering papers published since 2000. Participants/materials, setting, methods A total of 1632 records were identified for abstract screening. Only females and males without recurrent disease and follow up of more than one year were considered. For the systematic review, 68 studies fulfilled the criteria. For the meta-analysis, studies with < 10 patients were excluded. Infertility was defined in females as very low AMH, hypergonadotropic hypogonadism, amenorrhoea and/or need for hormone replacement therapy and in males as low inhibin B and/or azoospermia. Main results and the role of chance In total, 68 out of 1632 studies were included in the final analysis. Malignant diseases were mainly acute myeloid / lymphoblastic leukemia, chronic myeloid leukemia/ lymphocytic leukemia and non-hodgkin’s and hodgkin’s lymphoma. Benign diseases were sickle cell disease, Fanconi anaemia, and β-thalassemia major. In the meta-analysis, 56 studies were included, comprising 1853 female malignant cases, 241 female benign cases, 1871 male malignant cases, and 226 male benign cases. The analysis, employing a random-effects model for estimating prevalence and its 95% confidence interval, revealed that the overall pooled prevalence of infertility exceeded 30% in all groups. The prevalence of infertility was highest in female malignant cases (65%, 95% CI: 0.58-0.71). In women with benign diseases it was 61% (95% CI: 0.48-0.73). In males with malignant diseases it reached 41% (95% CI: 0.32 to 0.51) and with benign diseases 31% (95% CI: 0.19 to 0.46). Heterogeneity of data was high as shown by female as shown by the malignant cases of 83% and benign cases of 65% in women and the malignant cases of 91% and benign cases of 74% in males. Limitations, reasons for caution The heterogeneity of the included studies due to treatment variations and diverse characteristics of the study populations with large age ranges, did not allow further subgroup analyses. Thus, an individual and reliable fertility prognosis is still difficult to give. Wider implications of the findings The results of this meta-analysis support the clinical necessity of fertility preservation counselling in females and males undergoing HSCT treatment. Further prospective studies addressing the individual impact of the HSCT treatment on gonadal function are needed Trial registration number The study protocol was registered at the international Prospective Register of Systematic Reviews, PROSPERO (Registry number CRD42023486928).

Radiotherapy in younger patients with advanced aggressive B-cell lymphoma—long-term results from the phase 3 R-MegaCHOEP trial

The role of consolidative radiotherapy (RT) for patients with aggressive B-cell lymphoma has not been fully elucidated. The R-MegaCHOEP trial investigated the use of high-dose chemotherapy and rituximab with subsequent autologous stem cell transplantations compared to conventional immunochemotherapy (R-CHOEP) for high-risk patients up to 60 years. The study protocol included RT for patients with bulky (maximum diameter ≥7.5 cm) or extranodal disease. Two-hundred sixty-one patients were analyzed, 120 of whom underwent RT. The most frequently irradiated regions were mediastinum (n = 50) and paraaortic (n = 27). Median RT dose was 36 Gray in median fractions of 1.8 Gray. Acute toxicities were mostly mild to moderate, with only 24 and 8 grade 3 and 4 toxicities reported during RT. Patients with bulky disease who received RT showed significantly better 10-year EFS, PFS and OS (EFS: 64% vs. 35%; p < 0.001; PFS 68% vs. 47%; p = 0.003; OS: 72% vs. 59%; p = 0.011). There was no significant increase in secondary malignancies with the use of RT. RT administered for consolidation of bulky disease after immunochemotherapy improved the prognosis of young high-risk patients with aggressive B-cell lymphoma and should be considered part of first-line therapy. The trial was registered with ClinicalTrials.gov, number NCT00129090.

How I treat peripheral T-cell lymphomas

Introduction. Peripheral T-cell lymphomas (PTCL) — a rare group of lymphoproliferative diseases characterized by an aggressive course and an unfavorable prognosis. The group is represented by heterogeneous nosological forms, in which standard treatment options lead to unsatisfactory results. Aim: to present the protocols for the treatment of PTCLMain findings. In total, 12 years of experience in the treatment of 724 patients with T-cell lymphomas (430 patients with primary cutaneous forms, 110 patients with leukemic variants and 184 with peripheral T-cell lymphomas) has been accumulated. The treatment results and therapeutic algorithms were analyzed. In the general group of patients, the 3-year overall survival (OS) and relapse-free survival (EFS) were 76 % and 70 %, respectively. The best treatment results were achieved in the groups of intestinal T-cell lymphoma, specifically (EATL), and angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell ALK-positive lymphoma (ALCL ALK+), and the worst — in the group of ALCL ALK- (5-year EFS 31 %). High-dose chemotherapy under the NHL BFM-90 program in the treatment of ALK+ ALCL allows achieving 10-year OS and EFS 87 % and 84 %, respectively, but the less toxic CHOEP program was not inferior in effectiveness: 5-year OS and EFS amounted to 93 % and 88 %, respectively. High survival rates of patients with EATL were achieved with the use of high-dose chemotherapy according to the LB-M-04 program followed by auto-HSCT in the first line of therapy: 5-year OS and EFS amounted to 79 % and 74 %, respectively. The positive role of AITL maintenance therapy has been shown: 5-year OS and EFS during its implementation amounted to 75 % and 49 % versus 41 % and 20 % in the absence of it. In the protocols for the treatment of extranodal NK/T cell lymphoma, radiation therapy was used in the first line of therapy, 5-year OS and EFS were 60 % and 42 %, respectively. The role of autologous hematopoietic stem cell transplantation (auto-HSCT) in all PTCL was evaluated: 5-year OS and EFS were 82 % and 58 % compared with 67 % and 49 % without auto-HSCT. The transplantation of allogeneic hematopoietic stem cells (allo-HSCT), even in the treatment of relapses of the disease, has shown its effectiveness: 9 out of 11 patients are alive and remain in remission of the disease.

High-dose chemotherapy with transplantation of autologous hematopoietic stem cells in the first line of follicular lymphoma therapy

Introduction. The follicular lymphoma (FL) is the most common indolent lymphatic tumor with high sensitivity to immunochemotherapy un most cases. Although overall survival (OS) is generally long, the disease is characterized by multiple relapses. High-dose chemotherapy (HDCT) with transplantation of autologous hematopoietic stem cells (auto-HSCT) is used for recurrent FL. Aim: to evaluate the efficacy and safety of HDCT with aHSCT in the first line of FL therapy; identify risk factors for disease progression and refractoriness. Material and methods. A prospective single-center study (conducted from May 2015 to January 2023) included 35 patients aged 18–65 years (median 43) with PL 1–3A grade t(14;18)+ with stages III–IV or stage II with bulky, having at least one criterion for the need to start therapy (according to GELF). Patients were treated according to the FL-2015 protocol: 4 R-CHOP, 2 R-DHAP and BeEAM with auto-HSCT. The primary endpoint was the rate of overall response (OR) and/or complete remission (CR) at the end of chemotherapy. Secondary end points were 3-year survival rates: OS, relapse-free survival (RFS), progression-free survival (PFS), and event-free survival (EFS). Minimal residual disease (MRD) in blood and/or bone marrow was assessed by PCR based on immunoglobulin heavy chain (IGH) gene rearrangements and/or BCL2::IGH rearrangements. Statistical analysis (by intent to treat) was performed on January 12, 2023. Results. 86 % of patients had stage IV tumor and 79 % had 3–5 FLIPI factors. After the end of treatment, OR and PR were 90 % and 90 %, the incidence of POD24 was 3 %. After the end of induction (4 courses of R-CHOP), MRD-negativity was achieved in 77 % and 53 % of patients as determined by PCR-IGH and BCL2::IGH. After the full completion of the FL-2015 protocol, MRD was not detected in 96 % of patients (according to PCR-IGH). Three-year overall survival, disease-free survival, progression-free survival and event-free survival were respectively: 90 %, 90 %, 95 % and 85 % (with the same standarderror of 9 %) at a median follow-up (by inverse Kaplan-Meier estimate) of 19 months (range: from 1 to 91 months) There were no deaths due to early toxicity within 100 days of auto-HSCT. Prognostically unfavorable independent statistically significant (р &lt; 0.01; Wald test; hazard ratio &gt; 1) predictors of progression and refractoriness according to the results of multivariate analysis using the Fine-Grey competing risk model (р = 0.052 for the model) were: bone marrow disease, ECOG high risk, patient age &gt; 50 years, stage 4 disease, elevated serum lactate dehydrogenase and B-symptoms. Conclusion. The use of HDCT with auto-HSCT in the first line in patients with FL is highly effective and can significantly reduce the incidence of POD24 and early mortality from the tumor. The study is ongoing.

Radiotherapy in Young, High-Risk Patients with Aggressive B-cell Lymphoma: Long-Term Results from the Open-Label, Randomized, Phase 3 R-MegaCHOEP Trial

The role of consolidative radiotherapy (RT) for young (< 60 years), high-risk patients with aggressive B-cell lymphoma is discussed. The R-MegaCHOEP trial investigated the use of high-dose chemotherapy and rituximab with subsequent autologous stem cell transplantation compared to conventional R-CHOEP immunochemotherapy for patients up to 60 years1,2. Despite no prognostic difference between treatment arms even after 10-year follow-up, excellent long-term results were achieved. The presented work represents a detailed RT-analysis providing long-term data on efficacy and side-effects. The 10-year follow-up dataset of the R-MegaCHOEP trial with a median follow-up of 81.1 months (range 0.6-175.9 months) was used for this analysis. Indications for consolidative RT were extralymphatic involvement or bulky disease (maximum diameter ≥ 7.5 cm). Additionally, RT could be administered because of insufficient response at end of therapy as evaluated by CT scan. Overall, 261 patients were analyzed, 120 of whom underwent RT. Patients with RT were predominantly male (65.8 %), had an age-adjusted IPI of 2 (75 %), an elevated LDH (96.7 %) and showed an ECOG-Score of 0-1 (65 %). Bulky disease was present in 103/120 patients in the RT-arm with a bulk size of 7.5-20.0 cm (median: 11 cm) and was located predominantly in the mediastinal (44), paraaortal (17) and mesenteric (13) regions. The most frequently irradiated regions were the mediastinal (50), paraaortic (27) and mesenteric (15) regions. Median RT dose was 36 Gray in median fractions of 1.8 Gray. Toxicities were generally mild to moderate with 24 and 8 grade 3 and 4 toxicities reported during RT. During long-term follow-up, 23 secondary malignancies occurred, with RT being no significant contributing risk factor (p = 0.188). Analysis of the overall study population showed that patients with RT had an improved event-free survival (EFS; 63.9 % vs. 46.0 %; p<0.001) and progression-free survival (PFS; 67.2 % vs. 54.1 %; p = 0.025) but not overall survival (OS; 72.8 % vs. 65.9 %; p = 0.132) in comparison to non-irradiated patients after 10 years. Considering only those patients with RT after a complete remission/unconfirmed complete remission after systemic therapy, a significantly improved EFS (66.4 % vs. 46.0 %; p = 0.006), but not PFS and OS, was shown (PFS: p = 0.054; OS: p = 0.222). For patients with bulky disease, RT resulted in a significantly better outcome (10-year EFS: 64.4 % vs. 34.5 %; p<0.001; 10-year PFS: 68.3 % vs. 47.4 %; p = 0.003; 10-year OS: 71.5 % vs. 59.4 %; p = 0.011), when compared to patients without RT. For patients with extralymphatic involvement, RT improved EFS (10-year EFS: 61.7 % vs. 51.1 %; p = 0.017), but not PFS or OS (PFS: p = 0.068; OS: p = 0.305). RT improved outcome in young, high-risk patients with aggressive B-cell lymphoma and bulky disease. NCT00129090. 1 Lancet Oncol 2012;13(12):1250-1259. 2 Lancet Haematol 2021;8(4):e267-e277.

ВЫСОКОДОЗНАЯ ХИМИОТЕРАПИЯ С АУТОЛОГИЧНОЙ ТРАНСПЛАНТАЦИЕЙ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК ПРИ РЕЦИДИВАХ ОПУХОЛЕЙ ЦНС: АКТУАЛЬНЫЕ ВОПРОСЫ И ЭФФЕКТИВНОСТЬ

Intensification of antitumor treatment using high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (aHSCT) has been an effective option for many years in a number of nosological forms of central nervous system (CNS) tumors in children as the first-choice therapy. However, its benefits in relapsing forms of the disease are not obvious, which has led to ongoing discussions. Studies on the comparative efficacy of HDCT in recurrent CNS tumors are few. The heterogeneity of the studied patient cohorts should be noted additionally, which in its turn does not allow reaching a consensus on indications for its use. The Article represents current bibliographical data on the use of HDCT with aHSCT in pediatric patients with relapses of various nosological forms of CNS tumors in terms of its possible effectiveness and toxicity.

Abstract 6248: Inhibiting β-catenin in AML by targeting DDX5

Abstract Despite the use of high-dose chemotherapy and HSCT, less than 70% of adult AML patients enter complete remission and most patients relapse in less than two years. These poor outcomes have motivated intensive searches for effective and safe targeted agents. Asp-Glu-Ala-Asp (DEAD)-box protein DDX5 was found to be highly expressed in several solid cancers. DDX5, especially its phosphorylated form at Y593, has been reported to promote β-catenin cytoplasm-to-nucleus shuttling and subsequently facilitate the transcriptional activities of the β-catenin/T-cell factor (TCF) complex leading to enhanced expression of genes that are critical for growth, including MYC and CCND1. Knockdown of DDX5 has also been reported to reduce the growth of AML cells, indicating that DDX5 is a potential therapeutic target in AML. However, it remains unknown whether the growth dependence of AML on DDX5 is mainly mediated by β-catenin signaling. Importantly, drugs that selectively target DDX5 have not been tested in AML. In this study, we first analyzed the TCGA AML dataset and found that DDX5 gene is significantly overexpressed in the AML cohort compared to normal bone marrow samples. High DDX5 expression is associated with worse overall survival in AML patients. Moreover, DDX5 correlates with CTNNB1 which encodes β-catenin, at transcript levels. We further found that DDX5 is constitutively phosphorylated at Y593 and predominantly present in the nucleus of 10 AML cell lines tested. These results indicate the clinical relevance of DDX5 whose functional impact may link to β-catenin signaling in AML. We then determined the therapeutic efficacy of targeting DDX5 in human AML using RX-5902, a quinoxalinyl-piperazine compound. RX-5902 was previously shown to interfere with the interaction between phosphorylated DDX5 and β-catenin, inhibiting β-catenin signaling in some solid tumors. We found that RX-5902 attenuated phosphorylation of DDX5 at Y593, led to accumulation of β-catenin in the cytoplasm and consequently downregulated c-MYC in human AML cells within 24 hours. Treatment with RX-5902 dramatically increased cellular ROS level, induced cleaved-caspase3 mediated apoptosis and eventually inhibited cell growth of most human AML cell lines and primary AML cells in culture. These results mirrored what we observed following DDX5 depletion by shRNAs in AML cell lines. Also, dosing of RX-5902 in vivo significantly suppressed the growth of AML xenotransplants in immunocompromised mice and prolonged survival. Finally, we performed dynamic BH3 profiling and showed that RX-5902 increased apoptotic priming and BCL-2 dependence in AML cells. Therefore, we reasoned that simultaneous targeting DDX5 and BCL-2 may improve the therapeutic efficacy in AML. Indeed, concurrent treatment using RX-5902 and Venetoclax, a BCL-2 inhibitor, synergistically induced apoptosis in AML cells. Collectively, therapeutic targeting of DDX5 may be a novel and effective approach in AML and warrants further study. Citation Format: WEI NI, Swati Garg, Fen Zhu, Ellen L. Weisberg, Basudev Chowdhury, Martin Sattler, Amulya Jakkani, Suiyang Liu, Dana M. Sanchez, Lizi Wu, Richard M. Stone, Matthew S. Davids, James D. Griffin. Inhibiting β-catenin in AML by targeting DDX5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6248.

Pediatric Extracranial Germ Cell Tumors: Review of Clinics and Perspectives in Application of Autologous Stem Cell Transplantation

Pediatric extracranial germ cell tumors (GCTs) are rare, accounting for approximately 3.5% of childhood cancers. Since the introduction of platinum-based chemotherapy, the survival rate of patients has improved to more than 80%. However, poor-risk subtypes of pediatric extracranial GCTs do not respond well to chemotherapy, leading to refractory or relapsed (R/R) diseases. For example, long-term survival rates of mediastinal GCTs or choriocarcinoma are less than 50%. According to reports in recent years for adult patients with R/R GCTs, the use of high-dose chemotherapy (HDCT) combined with autologous stem cell transplantation (ASCT) has clinical advantages; however, HDCT combined with ASCT has rarely been reported in pediatric GCTs. The R/R and poor-risk groups of pediatric GCTs could benefit from HDCT and ASCT.

TANDEM HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS BONE MARROW TRANSPLANTATION IN GERM CELL TUMOR— EXPERIENCE FROM A TERTIARY CARE CENTER FROM SOUTH INDIA

Background: The use of high-dose chemotherapy with autologous hematopoietic cell transplantation is well established as a potentially curative approach in patients with relapsed or refractory disease in testicular Germ cell tumours after initial cisplatin-based chemotherapy. The use of tandem transplant with high-dose carboplatin and etoposide conditioning has been a tried and is a feasible option in relapse setting.Overall, HDCTand Autologous stem cell transplant can offer cure rates of up to 60% in the relapsed GCTsetting. Data on Tandem HDCTand ASCTis very limited in Indian subcontinent. Hence we report our experience with respect to safety, efcacy and tolerability, survival outcomes of HDCT/ ASCT in patients with relapsed GCT. Methods: Patients who were diagnosed with relapsed or refractory Germ cell tumours and underwent Tandem HDCT and ASCT were analysed from patient records from 2013 to 2020. Results: Both our patients received BEP (bleomycin, etoposide, and cisplatin) as rst-line therapy. HDCT was done after 2nd line salvage chemotherapies in both patients. Both patients were treated with 2 courses of High-dose carboplatin (700mg/m2) and etoposide(750mg/m2) as conditioning regimen followed by stem cell rescue(CD34+ stem cells yield – 5 to 6x106 cells/kg ) 3-4 weeks apart. Grade ¾ toxicities including myelosuppression, diarrhea, mucositis were observed in both patients. After ASCT both patients were followed up with imaging and serial monitoring of tumour markers. 1st patient died 3 months after ASCT due to disease relapse and our 2nd patient was disease free for 22 months, after which he developed progressive disease in brain and succumbed to disease. Conclusion: This is the rst report from India on tandem HDCT with ACST in relapsed GCTs. Tandem HDCT/ASCT seems to be safe and feasible option in relapsed/ refractory testicular GCT's.

High-dose chemotherapy for relapsed testicular germ cell tumours.

Relapsed testicular germ cell tumours (GCTs) might be cured with salvage chemotherapy. Accepted salvage treatment is conventional-dose chemotherapy (CDCT) or high-dose chemotherapy (HDCT). HDCT with peripheral blood stem cell transplant might produce a higher number of durable responses than CDCT. We discuss studies reporting on outcomes of salvage HDCT in relapsed GCTs. The most reproducible results were achieved with HDCT with two cycles of etoposide and carboplatin or three cycles of the paclitaxel, ifosfamide, carboplatin and etoposide regime. Using these two regimens, sustained cure rates of 50-66% were reported in phase I, phase II and retrospective studies published in the past two decades. Cure rates in patients with cisplatin-resistant disease are between 30% and 45%. Two phase III randomized studies were conducted with certain limitations and were unsuccessful in showing a survival benefit of HDCT. Thus, salvage treatment remains a controversial topic. Salvage HDCT with peripheral blood stem cell transplant and CDCT are two recommended treatment options for relapsed GCTs. Consistently reported cure rates from phase I, phase II and large retrospective studies support the use of HDCT in the hands of an experienced team of oncologists.

QOL-25. Neurocognitive assessment of pediatric medulloblastoma treated by MBMET_MEYER trial. Censullo M.L1, Bertoluzzo G2, Fonte C1, Pavone R1, Guidi M1, Enrico G1, Gori C.G1, Martin R2, Teodori C2, Sardi I1 1Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s University Hospital, Florence, Italy2Psychology Unit, Meyer Children’s University Hospital, Florence, Italy

Abstract The MBMET_MEYER is an interventistic monocentric trial of Meyer Children’s Hospital. The goal of this protocol is to reduce toxicity by use of protontherapy and reducing chemo-induced neurotoxicity by limited use of high dose chemotherapy. To date, a neurocognitive assessment is the standard in medulloblastomas but it is very difficult an assessment at baseline for clinical problems such as age, intracranial hypertension and immediate intervention. 10 neurocognitive assessments were reviewed in patients with medulloblastoma treated by MBMET_MEYER protocol: 3 anaplastic medulloblastoma M0 and 7 classic (2 M0, 1 M1, 1 M2, 3 M3). The median age was 10 years (range 5-18). All the patients were treated with surgery (gross total removal), 2 received chemotherapy and conventional radiotherapy, 8 chemotherapy and protontherapy and only 1 received autologos-hemotopoietic stem cell transplant for progression disease after induction chemotherapy. As for protocol, the neurocognitive assessment was defined by Weschler Intelligence Scales, fonemic and semantic fluency, immediate and deferred memory, tests for working memory, attention and visuo-spatial tests at baseline, after treatment and at the end of follow-up. For 3 patients it was not possible a baseline assessment for bad clinic conditions, 8 are still in treatment. From interviews and assessments emerged that 80% of patients had neurocognitive deficits: at baseline 5 had speed elaboration difficulties, 1 of these also presented verbal deficit, 1 showed problems in recalling verbal material and 1 in working memory; after two years from chemotherapy and radiotherapy 2 presented speed processig and working memory deficit. In conclusion, an assessment at baseline is very difficult for post-surgical problems but necessary to perform as soon. In this way, it is possible to evaluate the impact of the treatment on neurocognitive impairment. Further investigations are necessary to well understand the appropriate schedule of neurocognitive assessment of pediatric medulloblastoma.

High-dose melphalan-based chemotherapy and autologous stem-cell transplantation for high-risk osteosarcoma in children: A single-institute experience and review of the literature

BackgroundThe prognosis of high-risk osteosarcoma, defined by the presence of chemo-resistance, metastatic disease at diagnosis, and relapse, remains poor. The efficacy of high-dose chemotherapy (HDC) and autologous stem-cell transplantation (ASCT) for high-risk osteosarcoma is still unclear. MethodsWe retrospectively reviewed pediatric patients with high-risk osteosarcoma who underwent HDC and ASCT at our institution between 2002 and 2018 and performed a review of the literature regarding the efficacy of HDC and ASCT for high-risk osteosarcoma. ResultsSix patients with high-risk osteosarcoma underwent high-dose melphalan (180 mg/m2)-based chemotherapy followed by ASCT. Two patients received HDC consisting of ifosfamide and melphalan. Three patients received HDC consisting of etoposide, carboplatin, and melphalan. One patient underwent tandem HDC consisting of thiotepa and etoposide followed by melphalan, thiotepa, and etoposide. Non-hematological toxicities presented mainly as mucositis and diarrhea. Two patients developed grade 3 mucositis. No life-threatening toxicities were observed in any of the six patients. One patient with disease progression before HDC died of multiple metastases, while five patients, with no evidence of disease in the peri-transplant periods, were alive at the time of publication; there was no disease recurrence at a median follow-up period of 144 months (range, 24–215 months). Our review of the literature supports the use of HDC with a higher dose of melphalan (180–280 mg/m2) for high-risk osteosarcoma. ConclusionsMelphalan-based HDC and ASCT can be a promising treatment for high-risk osteosarcoma. Additionally, surgical removal of macroscopic residual lesions may be essential in peri-transplant periods.

Salvage Autologous Stem Cell Transplantation in Daratumumab-Refractory Multiple Myeloma.

Simple SummaryMultiple Myeloma (MM) is the most common cancer of the bone marrow and remains incurable despite advances in novel therapy. The disease course is typically characterized by an initial response pattern to treatment followed by eventual relapse and treatment refractoriness. Patients who have progressed on several novel therapies, including the CD38-targeting monoclonal antibody Daratumumab, have a dismal outcome with a median overall survival of less than 10 months and are in dire need of therapies with new mechanisms. While emerging novel modalities have shown promising results, the current study explores the use of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in heavily pretreated Daratumumab-refractory MM patients. Our results for 69 consecutive patients treated with salvage ASCT indicate that this approach can lead to long-term MM control and should be considered a treatment modality in selected heavily pretreated Daratumumab-refractory patients.Daratumumab, a CD38-targeting monoclonal antibody, has significantly improved survival rates in multiple myeloma (MM), yet patients who progress on Daratumumab have dismal clinical outcomes with an overall median of less than 10 months. While emerging novel modalities have shown promising results, the current study explores the use of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in heavily pretreated Daratumumab-refractory MM patients. We retrospectively investigated the outcome of 69 consecutive patients who received upfront ASCT. The median progression-free survival (PFS) for the entire patient cohort was 7.2 months with a median overall survival (OS) of 19.3 months. For patients with ≥very good partial response (VGPR), median PFS and OS improved to 9 months and 34 months, respectively. Achievement of MRD negativity in ≥VGPR did not further improve the outcome. A better performance status, younger age, longer time interval from initial MM diagnosis/initial ASCT to salvage ASCT and low-risk GEP70 were all associated with improved PFS and OS after salvage ASCT. Our results suggest a role for salvage ASCT in selected heavily pretreated and Daratumumab-refractory patients.

Enhanced Expression of CXCR4 Facilitates the Trafficking of Anti-c-Kit Chimeric Antigen Receptor (CAR) T Cells to Bone Marrow and Achieves Effective Donor Stem Cell Engraftment

Allogeneic hematopoietic stem cell (HSC) transplantation is one of the curative therapeutic options for patients with a variety of inherited disorders of blood cells, including immune deficiencies and hemoglobinopathies. In addition, considerable progress has been made toward achieving clinical benefit from autologous HSC ex vivo gene therapy for some of these disorders. Generally, some level of conditioning using chemotherapy and/or radiation is needed to achieve the required engraftment of allogeneic HSC or gene corrected autologous HSC. There is considerable interest in finding less toxic and more focused approaches to achieve the conditioning. Promising results were observed using antibody-based approaches including anti-c-kit (CD117) or anti-CD45 which directly target HSCs, and these results can be enhanced by linking the antibody to a toxin such as saponin. Here, we explored a related approach in mouse models in which chimeric antigen receptor (CAR)-T cells targeting c-kit (c-kit CAR-T cells) were employed as conditioning to achieve significant engraftment of congenic HSCs. Our initial attempts at efficient conditioning with c-kit CAR-T cells failed because there was insufficient trafficking of CAR-T cells to bone marrow (BM) and insufficient CAR-T cell expansion in vivo and because we did not eliminate the CAR-T cells before transplanting congenic HSCs.To address these barriers, before injecting CAR-T cells (derived from C57BL/6 Thy1.1/CD45.2 mouse spleen on Day1 and transduced with CAR retrovirus on Day2) we pre-treated the recipient mice (Thy1.2/CD45.2) with low-dose cyclophosphamide (CY, 125 mg/kg; Day2) and co-transduced the c-kit CAR-T cells with a CXCR4 (CD184) expression vector (Day2), followed by injection of 5×106 CAR-T cells on Day3. We later removed these CAR-T cells by treating the mice with anti-Thy1.1 antibody (Ab) on Day11 prior to HSC transplantation from congenic Thy1.2/CD45.1 mice (Day12; 3×106 cells/mouse).After single CAR retrovirus transduction, >90% of T cells expressed CAR. When used in vitro, CAR-T cells efficiently depleted BM c-kit+ population (10.5% reduced to 1.6%) and completely suppressed colony formation in nitrocellulose medium. In initial in vivo studies, we used a luciferase marker in the CAR-T cells to allow whole body imaging in addition to flow cytometry (FACS) of BM to assess trafficking. With no pre-treatment of mice, both in vivo imaging and FACS demonstrated poor trafficking of CAR-T cells to BM (< 1% of cells), and there was no decrease of the BM c-kit+ population. In contrast, pre-treatment with low-dose CY and overexpression of CXCR4 on the CAR-T cell surface improved the CAR-T cell expansion in vivo and the migration into BM (mean Thy1.1+ cells, 11.9%; n= 5), and this was associated with significant in vivo depletion of BM c-kit+ population (9.0% reduced to 0.0%). Severe pancytopenia was confirmed in peripheral blood (Hgb 2.2 g/dL compared to the normal, 13.0 g/dL) along with aplastic BM (Figure A), and these mice died within 4 weeks without BM transplant. Subsequent injection of anti-Thy1.1 Ab completely depleted CAR-T cells in viv o. When congenic BM cells were transplanted into mice conditioned in this manner (CY+CAR-T+Thy1.1 Ab), these mice achieved complete recovery of hematopoiesis with significant engraftment of donor BM in all lineages in peripheral blood (Figure B) and long-term HSCs in BM (> 20 % donor chimerism).Our findings provide proof-of-concept that c-kit CAR-T cells can be used to achieve sufficient conditioning to allow donor chimerism after congenic transplantation without use of high-dose chemotherapy or radiation. Low-dose CY was required to achieve the reduction of host T cells and stimulate in vivo expansion of CAR-T cells. A key element to achieve BM HSC depletion was the co-transduction of CXCR4 that greatly increased trafficking of the CAR-T cells to BM. This finding may be one of the most important aspects of this study, with broader implications for the CAR-T cell field in suggesting that use of trafficking receptors or ligands might be generalizable as a method to enhance targeting to designated organs or solid tumors. In summary, our studies add to the list of tools that should be further explored in the effort to seek less toxic conditioning regimens for BM transplantation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Results of allogeneic hematopoietic stem cell transplantation in a patient with classical Hodgkin's lymphoma

The aim of the study was to study the role of allogeneic transplantation of hematopoietic stem cells in a patient with the classic course of Hodgkin's lymphoma.Materials and methods. The work was carried out on the basis of the analysis of a clinical case of the clinic of occupational pathology and hematology of the University Clinical Hospital No. Professor V.Ya. Shustov. Examinations, a course of chemotherapy in conjunction with surgery and analysis of the results of a patient with a diagnosis of classic Hodgkin's lymphoma were carried out. Results. An unfavorable prognostic effect of a large amount of previous chemotherapy on overall survival after allogeneic HSC transplantation was revealed. According to the results of PET-CT, the patient achieved PETnegative remission of the disease after all the stages of treatment. Compared to the presented PET / CT scan of 02/07/2020, there is a positive trend in the form of the disappearance of metabolic activity in the 3rd rib on the right, the body of Th 11 and the body of the left ilium.Conclusion. The use of high-dose chemotherapy with hematopoietic stem cell transplantation makes it possible to achieve success in the treatment of patients in cases where the results of chemotherapy are unsatisfactory.

Salvage autologous stem cell transplantation in daratumumab refractory multiple myeloma (MM).

e20031 Background: The advent of novel therapies has significantly improved outcomes in MM, yet most patients will eventually relapse. Patients progressing on CD38-targeting monoclonal antibodies, proteasome inhibitors (PIs) and IMiDs have dismal outcome. While treatment modalities based on novel mechanisms have shown promising results, the current study explores the use of high dose chemotherapy followed by autologous stem cell transplantation (ASCT) in these heavily pretreated MM patients. Methods: We investigated the outcome of 57 patients who received salvage ASCT after MM progression on Daratumumab. All patients had also been exposed to at least two PIs and two IMiDs. We assessed overall response using IMWG criteria, minimal residual disease (MRD) using 8 color flow cytometry with a sensitivity of 10-5, progression free (PFS) and overall survival (OS). Results: Median age of the patient cohort was 62 years (39-75) and all patients had been exposed to Daratumumab, Thalidomide, Revlimid and Velcade. 93% (53/57), 91% (52/57) and 32% (18/57) of the patients had also received Carfilzomib, Pomalidomide and Ixazomib respectively. Pre-ASCT conditioning regimen included high dose melphalan in 23% (13/57), melphalan in combination with VDT-PACE (Velcade, Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cytoxan and Etoposide) in 30% (17/57) and BEAM (BCNU, Etoposide, Ara-C and Melphalan) in 47% (27/57). Post-ASCT response was assessed in 90% (51/57) within 100 days of ASCT. Overall response rate was 81% (46/57) with a CR in 39% (22/57), a VGPR in 23% (13/57) and a PR in 19% (11/57). Stable disease was seen in 3.5% (2/57) and progressive disease in 5% (3/53) patients. MRD negativity was attained in 44% (25/57) patients, all of whom had at least a VGPR. After response assessment, patients were started on maintenance treatment with combinations of either previously used agents (pomalidomide [20/57], carfilzomib [11/57] and CD38 moAbs [16/57]) or agents with no or little prior exposure (cytoxan [11/57], selinexor [4/57] or venetoclax [3/57]). The median PFS for the entire patient cohort was 8.5 months with a median OS of 19.6 months. For patients with ≥ VGPR, median PFS and OS improved to 11 months and 24.9 months respectively. Achievement of MRD negativity in ≥ VGPR did not improve outcome, median PFS = 11 and median OS = 20 months. 17% (10/57) of patients were still alive at 36months post salvage ASCT. Conclusions: High dose chemotherapy followed by ASCT achieves substantial responses in 81% of patients with 17.5 % still alive at 3 years. The results suggest a role for salvage ASCT in selected heavily pre-treated patients, albeit there remains an obvious clinical need for novel therapies. While the achievement of ≥ VGPR improved outcome, achievement of MRD negativity had no further impact on survival in our study, although that may be due to the relative small number of patients and the major overlap between ≥VGPR and MRD negativity.

The best matrix for the brain: advances in secondary CNS lymphoma

Secondary CNS lymphoma is a challenging condition and requires the effective targeting of both systemic and CNS disease. Despite the use of aggressive multimodal treatments, refractory disease and early relapses are common, and the overall prognosis remains poor.1 Only a few phase 2 and single-arm studies with small sample sizes have so far been published,2–5 exploring the use of high-dose chemotherapy followed by autologous haematopoietic stem-cell transplantation (HSCT). However, given the absence of sufficient clinical data in this patient population, the optimal treatment strategy for secondary CNS lymphoma is unclear and a standard of care regimen has not been established.

Melphalan, Etoposide, and Carboplatin Megatherapy with Autologous Stem Cell Transplantation in Children with Relapsing or Therapy-Resistant Extracranial Germ-Cell Tumors-A Retrospective Analysis.

Simple SummaryGerm cell tumors (GCTs) are malignancies derived from germ cells that originate in gonads or extragonadal localizations. They are considered highly curable in both children and adults even if distant metastases are present, but therapy-resistant or relapsing patients have a worse prognosis. The aim of our retrospective study was to analyze the outcome of 18 children with GCT treated with melphalan–etoposide–carboplatin high-dose chemotherapy and autologous stem cell transplantation. To date, this is one of the largest reported pediatric cohorts of GCT patients treated with megatherapy. We observed high survival rates—a five-year overall survival of 76%, and event-free survival of 70.8% without therapy-associated mortality. We concluded that this megatherapy protocol is feasible in heavily pretreated children, but the issue of precise indications for high dose chemotherapy (HDCT) is evident and must be answered in a well-designed controlled study to avoid unnecessary overtreatment.Pediatric germ cell tumors (GCTs) are a group of chemosensitive malignancies with a 90% curability rate. We report a series of children with relapsing or therapy-resistant GCT treated with melphalan–etoposide–carboplatin high-dose chemotherapy (HDCT) and autologous stem cell transplantation. This consisted of 18 children, either with GCTs after relapse (nine patients) or with an unsatisfactory response to first-line chemotherapy (nine patients), who underwent HDCT. The HDCT regimens MEC1 (carboplatin 1500 mg/m2, etoposide 1800 mg/m2, and melphalan 140 mg/m2) and MEC2 (carboplatin 800 mg/m2, etoposide 800 mg/m2, and melphalan 140 mg/m2) were each used in nine patients. The median observation time was 81 months, the 5-year overall survival (OS) was 76%, and the event-free survival (EFS) was 70.8%. Non-relapse mortality was 0%, and four patients died after HDCT due to progression of the malignancy. No difference in OS or EFS was noted between the MEC1 and MEC2 protocols. The 5-year OS and 5-year EFS were higher in children treated with autologous stem cell transplantation before the age of four years. The presence of metastatic disease or time of HDCT consolidation during first/subsequent line chemotherapy did not affect patient survival. The melphalan–etoposide–carboplatin protocol is feasible in pediatric GCT, but is associated with potentially life-threatening complications. In conclusion, the use of HDCT must be examined in well-designed clinical trials, and the identification of patients who can benefit from this approach is critical to avoid overtreatment.

Novel Insights in Anti-CD38 Therapy Based on CD38-Receptor Expression and Function: The Multiple Myeloma Model.

Multiple myeloma (MM) is a hematological disease characterized by the proliferation and accumulation of malignant plasmacells (PCs) in the bone marrow (BM). Despite widespread use of high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) and the introduction of novel agents (immunomodulatory drugs, IMiDs, and proteasome inhibitors, PIs), the prognosis of MM patients is still poor. CD38 is a multifunctional cell-surface glycoprotein with receptor and ectoenzymatic activities. The very high and homogeneous expression of CD38 on myeloma PCs makes it an attractive target for novel therapeutic strategies. Several anti-CD38 monoclonal antibodies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab. Here we provide an in-depth look at CD38 biology, the role of CD38 in MM progression and its complex interactions with the BM microenvironment, the importance of anti-CD38 monoclonal antibodies, and the main mechanisms of antibody resistance. We then review a number of multiparametric flow cytometry techniques exploiting CD38 antigen expression on PCs to diagnose and monitor the response to treatment in MM patients.