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1.
Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group
Streby, K. A., Parisi, M. T., Shulkin, B. L., LaBarre, B., Bagatell, R., Diller, L., Grupp, S. A., Matthay, K. K., Voss, S. D., Yu, A. L., et al
Pediatric blood & cancer. 2023;:e30418
Abstract
BACKGROUND Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy. OBJECTIVE We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532. STUDY DESIGN A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index. RESULTS For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002). CONCLUSION In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.
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2.
Minimal residual disease detected by droplet digital PCR in peripheral blood stem cell grafts has a prognostic impact on high-risk neuroblastoma patients
Nino, N., Ishida, T., Nakatani, N., Lin, K. S., Win, K. H. N., Mon, C. Y., Nishimura, A., Inoue, S., Tamura, A., Yamamoto, N., et al
Heliyon. 2022;8(10):e10978
Abstract
More than half of high-risk neuroblastoma (NB) patients have experienced relapse due to the activation of chemoresistant minimal residual disease (MRD) even though they are treated by high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although MRD in high-risk NB patients can be evaluated by quantitative PCR with several sets of neuroblastoma-associated mRNAs (NB-mRNAs), the prognostic significance of MRD in PBSC grafts (PBSC-MRD) is unclear. In the present study, we collected 20 PBSC grafts from 20 high-risk NB patients and evaluated PBSC-MRD detected by droplet digital PCR (ddPCR) with 7NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNA). PBSC-MRD in 11 relapsed patients was significantly higher than that in 9 non-relapsed patients. Patients with a higher PBSC-MRD had a lower 3-year event-free survival (P = 0.0148). The present study suggests that PBSC-MRD detected by ddPCR with 7NB-mRNAs has a prognostic impact on high-risk NB patients.
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3.
Clinical implication of residual MIBG-positive disease in the follow-up of high-risk neuroblastoma treated with tandem high-dose chemotherapy and autologous stem cell transplantation
Seo, E. S., Shin, M., Lim, H., Cho, H. W., Ju, H. Y., Cho, Y. S., Yoo, K. H., Koo, H. H., Lee, J. W., Sung, K. W.
Pediatric blood & cancer. 2022;69(7):e29502
Abstract
BACKGROUND The implication of residual metaiodobenzylguanidine (MIBG)-positive disease in the era of tandem high-dose chemotherapy (HDCT) with autologous stem cell transplantation (auto-SCT) has not yet been established in neuroblastoma. Moreover, most published studies have not evaluated the long-term prognosis of patients with residual MIBG-positive disease following treatment completion. Therefore, we investigated the prognostic significance of residual MIBG-positive disease at each treatment phase and after treatment completion. METHODS We assessed MIBG scans labeled with either iodine-123 ((123) I) or (131) I from 150 patients with MIBG-avid and high-risk neuroblastoma enrolled in the NB-2004, -2009, and -2014 trials at postinduction, posttandem HDCT/auto-SCT, and completion of treatment. RESULTS The residual MIBG-positive disease at postinduction and posttandem HDCT/auto-SCT evaluation was highly correlated with the risk of progression. However, at treatment completion, there was no significant difference in survival and risk of progression between patients with residual MIBG-positive disease and MIBG-negative patients. Patients with persistent MIBG-positive disease at the end of treatment were more likely to have indolent tumor characteristics, such as favorable histology at diagnosis, lower incidence of MYCN amplification, and slow response to chemotherapy. CONCLUSION Residual MIBG-positive disease during treatment predicted unfavorable outcomes for patients with high-risk neuroblastoma, even under tandem HDCT/auto-SCT. However, persistent MIBG uptake at the completion of all treatments may not always indicate an active disease.
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Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma
Lucas, J. T., Jr., Wakefield, D. V., Doubrovin, M., Li, Y., Santiago, T., Federico, S. M., Merchant, T. E., Davidoff, A. M., Krasin, M. J., Shulkin, B. L., et al
Clinical and translational radiation oncology. 2022;34:42-50
Abstract
PURPOSE This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients. METHODS AND MATERIALS Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later. RESULTS MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors. CONCLUSIONS Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.
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5.
Effect of high-dose chemotherapy plus stem cell rescue on the survival of patients with neuroblastoma modified by MYCN gene gain/amplification and remission status: a nationwide registration study in Japan
Saito, Y., Urashima, M., Takahashi, Y., Ogawa, A., Kiyotani, C., Yuza, Y., Koh, K., Watanabe, K., Kosaka, Y., Goto, H., et al
Bone marrow transplantation. 2021
Abstract
In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [=PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation's national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and =PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/?=?PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91-4.09; P?0.001). The interaction between MYCN-GA and =PR was significant (p(interaction)?=?0.006). Hence, the patients with MYCN-GA with non-remission status at HDC-autoSCR had a significantly poorer prognosis than the other subgroups, suggesting that HDC-autoSCR may be effective in patients with CR/VGPR regardless of MYCN gene status and in patients with MYCN-NGA regardless of remission status.
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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
Agrawal, V., Abonour, R., Abu Zaid, M., Althouse, S. K., Ashkar, R., Albany, C., Hanna, N. H., Einhorn, L. H., Adra, N.
Cancer. 2021
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Long-term survival in a fraction of patients with metastatic breast cancer who received consolidation therapy with high-dose chemotherapy and autologous stem cell transplant between 2000 and 2015: an EBMT registry-based study
Martino, M., Pitino, A., Gori, M., Viens, P., Siena, S., Tripepi, G., Canale, F. A., Ballestrero, A., Zamagni, C., Musso, M., et al
Bone marrow transplantation. 2021
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Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase 2 trial PNET HR+5
Dufour, C., Foulon, S., Geoffray, A., Masliah-Planchon, J., Figarella-Branger, D., Guerrini-Rousseau, L., Faure-Conter, C., Icher, C., Bertozzi, A. I., Leblond, P., et al
Neuro-oncology. 2020
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Abstract
BACKGROUND High-risk medulloblastoma are defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5 to 19 years with newly diagnosed high-risk medulloblastoma treated according to the phase 2 trial PNET HR+5. METHODS All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m 2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). RESULTS Fifty-one patients (median age, 8 years; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95%CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (p-value=0.039) with large-cell/anaplastic being of worse prognosis, as well as molecular subgroup (p-value=0.012) with SHH and group 3 being of worse prognosis than WNT and group 4. Therapy was well tolerated. CONCLUSIONS This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.
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Factors Impacting Time to Engraftment in Patients With High-risk Neuroblastoma Following Autologous Stem Cell Transplant
Hillier, K., Cheng, W. S., Whittle, S. B., Krance, R., Foster, J. H.
Journal of pediatric hematology/oncology. 2020
Abstract
BACKGROUND Despite advances in supportive measures, myeloablative chemotherapy with stem cell rescue remains limited by toxicity and treatment-related mortality. The purpose of this study was to identify factors influencing the rate of hematopoietic recovery following autologous stem cell transplant in high-risk neuroblastoma. PROCEDURE We retrospectively studied 54 patients with high-risk neuroblastoma who received a single autologous stem cell transplant between 2006 and 2016. Race, sex, conditioning regimen, chemotherapy delays and bone marrow involvement were analyzed using Kaplan-Meier Log-Rank test while the amount of cells infused, age, and length of hospital stay were analyzed using univariate Cox Proportional Hazards Regression. RESULTS The conditioning regimen administered was significant (P=0.016) for time to engraftment of neutrophils, with busulfan/melphalan (Bu/Mel) at 16.6 days, and carboplatin/etoposide/melphalan at 12.1 days. A delay of chemotherapy during induction (n=24) was significant (P<0.001) for time to platelet engraftment of >75,000/microL. Female patients had a longer time to engraftment (P=0.029). CONCLUSION Patients receiving Bu/Mel as a conditioning regimen, patients who had a delay in induction chemotherapy and patients of female sex were found to be significant for delayed engraftment of neutrophils, platelets, and hemoglobin, respectively, in patients with high-risk neuroblastoma undergoing autologous stem cell transplant. Knowing these factors may lead to new expectations and possible interventions to decrease the morbidity and mortality of treatment and recovery.
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Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation
Ortmann, C. A., Dorsheimer, L., Abou-El-Ardat, K., Hoffrichter, J., Assmus, B., Bonig, H., Scholz, A., Pfeifer, H., Martin, H., Schmid, T., et al
Cell reports. 2019;27(7):2022-2028.e3
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.