5-year Event-free Survival Research Articles

P1176: RITUXIMAB IN PRIMARY CNS LYMPHOMA – LONG TERM FOLLOW-UP OF THE PHASE III HOVON 105/ALLG NHL 24 STUDY

Background: The efficacy of rituximab in Primary CNS Lymphoma (PCNSL) is still under debate. We performed an international randomized phase III study to investigate the efficacy of rituximab when added to methotrexate, BCNU, teniposide and prednisolone (MBVP) in PCNSL. The primary endpoint, event-free survival (EFS) at one year, was similar in both treatment groups and was previously reported (Bromberg et al, Lancet Oncology 2019; 20: 216-228). Aims: Here we present long-term follow up results with a median follow-up of 82 months. Methods: Between August 2010 and May 2016 200 newly-diagnosed, non-immunocompromised patients with PCNSL aged 18-70 years and WHO performance status 0-3 were randomized between treatment with MBVP chemotherapy with (arm B) or without (arm A) rituximab. The rituximab was given weekly in the first MBVP cycle, fortnightly in the second (in total 6 rituximab administrations). Responsive patients received consolidation with high-dose cytarabine, and patients aged ≤ 60 were subsequently treated with low-dose WBRT if in CR/CRu; in case of PR with an additional boost on the tumor. Patients > 60 were not irradiated. All patients gave written informed consent. Results: The modified intention-to-treat (m-ITT) population consisted of 199 eligible patients, 55% were men. The median age was 61 yrs (range 26-70), the median WHO performance status 1 (range 0-3). The primary endpoint EFS at one year was 49% (95% CI 39-58)(MBVP) vs 55% (95% CI 44-64) (R-MBVP). The EFS at 5 years was 25% (17-34) vs 36% (27-46) respectively, hazard ratio (HR) 0.85, 95% CI 0.61-1.18, p=0.33 (adjusted for age and WHO performance status). The progression-free survival (PFS) at one and 5 years were 58% (47-67) and 29% (21-39) (MBVP) and 65% (54-73) and 43% (33-53) (R-MBVP)) (HR 0.73, 95% CI 0.52-1.02, p=0.07). 80 patients were still alive. Overall survival (OS) at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. The median OS was 57 months (95% CI 38-75) in the MBVP arm and 85 months (95% CI 43–104) in the R-MBVP arm (HR 0.87, 95% CI = 0.61-1.26, p=0.47). A total of 111 patients had progression or relapse, 63 after MBVP and 48 after R-MBVP. 79% of these patients received further treatment. The median OS after progression/relapse was 9.7 months (5.9-19.9) in the MBVP arm, and 6.1 months (2.4-13.1) in the R-MBVP arm (HR 1.25, 95% CI 0.83-1.87, p=0.29). 119 patients died, 64 in the MBVP arm and 55 in the R-MBVP arm. Causes of death were PCNSL in 69% of the patients (both arms), complication of treatment (6% vs 5%), secondary malignancy (5% vs 2%) and other or unknown causes (20% vs 24%). Age was the strongest prognostic factor for EFS, PFS and OS in multivariate analysis. An unplanned subgroup analysis by age (≦60 vs > 60 yrs) showed a significant different EFS at one year for younger patients with R-MBVP, not found in patients > 60 yrs (Bromberg et al, 2019). With longer follow up the 5-year EFS in the younger group was 28% (16-41)(MBVP) vs 55% (40-68) (R-MBVP), HR 0.48, 95% CI 0.28-0.81, p=0.006. 5-year PFS was 31% (18-44) versus 57% (42-70), HR 0.47, 95% CI 0.27-0.81, p=0.007. The OS at 5 years was 54% (39-68) vs 70% (55-81) respectively (HR 0.65, 95% CI 0.36-1.19, p=0.16). Image:Summary/Conclusion: In the modified-ITT population we found no statistically significant benefit of the addition of rituximab to MBVP on EFS, PFS and OS in patients with PCNSL, even after a long follow-up of median 82 months. Therefore, the results of this study do not support the use of rituximab with MBVP in the treatment of primary CNS lymphoma.

Abstract 3845: Elucidating the role and mechanisms by which siglec-15 promotes immune dysregulation in lymphoma

Abstract Despite important advances in therapeutic options accounting for improved outcomes in childhood cancers, there remains a significant subset of patients with hematologic malignancies for whom outcomes remain dismal. Notably among this group are patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). DLBCL accounts for approximately 10-20% of pediatric Non-Hodgkin’s Lymphoma (NHL) cases and with intensive multiagent chemotherapy the 5-year event free survival is ~90%. However, for those with progressive or relapsed disease, survival is dismal at <30% and remains a clinical challenge even with use of intensive salvage regimens. As such, identifying novel agents that will increase survival in this group highlights an unmet need. Siglec-15, a member of the sialic acid binding immunoglobulin-like lectin family of proteins, has recently been identified as a critical immune suppressor that is highly expressed in human cancers and intra-tumoral myeloid cells. Importantly, inhibiting Siglec-15, either through genetic knockout or knockdown, had a restorative effect on local anti-tumor immune responses and abrogated tumor progression. While reported in solid malignancies, a role for Siglec-15 in promoting disease progression in hematologic malignancies has not yet been described. We have evaluated Siglec-15 expression in primary human lymphoma patient samples as well as various lymphoma (human and mouse) cell lines using western blot, quantitative PCR as well immunohistochemistry and immunofluorescence methods. We are evaluating the effect of inhibiting expression of Siglec-15 through genetic downregulation in human lymphoma cell lines as well as the well-established murine lymphoma cell line A20 on T cell function and proliferation using methods such as flow cytometry and ELISA. Analyses of public RNA-seq data sets demonstrates higher Sig15 expression in DLBCL cells compared to normal B cells. Western blot shows higher Sig15 expression in lymphoma cell lines compared to PBMC. IHC of a tumor microarray and validation samples from children shows high Sig15 expression in NHL samples with distinct staining patterns based on subtype. Specifically, Sig15 appears to be highly expressed and associated with the cell membrane in most DLBCL and Burkitt’s lymphoma, with more variable expression in anaplastic large cell lymphoma, primarily in the cytoplasm at low levels and/or in cells with morphology consistent with macrophages. In addition, preliminary data suggest more than one isoform of Sig15, raising the possibility of alternative functions. Lastly, knockdown of Sig15 in A20 cells abrogates disease progression in immune competent but not immune deficient recipients, consistent with a role for Sig15 in immune evasion in lymphoma. Together, these data implicate Sig15 as an immune checkpoint that may be inhibited therapeutically to promote an immune response to lymphoma cells. Citation Format: Dailia B. Francis, Jodi Dougan, Claire Pillsbury, Sunita Park, Linda Liu, Christopher Porter. Elucidating the role and mechanisms by which siglec-15 promotes immune dysregulation in lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3845.

Ponatinib, chemotherapy, and transplant in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

AbstractPromising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). The PONALFIL (Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia) trial combined ponatinib (30 mg/d) with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly diagnosed Ph+ ALL patients aged 18 to 60 years. Ponatinib was only given pre-emptively after alloHSCT. Primary end points were hematologic and molecular response before alloHSCT and event-free survival (EFS), including molecular relapse as event. Thirty patients (median age, 49 years; range, 19-59 years) entered the trial. All exhibited hematologic response, and alloHSCT was performed in 26 patients (20 in complete molecular response and 6 in major molecular response). Only 1 patient died (of graft-versus-host disease), and 5 patients exhibited molecular relapse after alloHSCT. No tyrosine kinase inhibitor was given after HSCT in 18 of 26 patients. Twenty-nine patients are alive (median follow-up, 2.1 years; range, 0.2-4.0 years), with 3-year EFS and overall survival (OS) of 70% (95% confidence interval, 51-89) and 96% (95% confidence interval, 89-100), respectively. Comparison of the PONALFIL and the ALLPh08 (Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph [BCR-ABL] Positive; same schedule, using imatinib as the tyrosine kinase inhibitor) trials by propensity score showed significant improvement in OS for patients in PONALFIL (3-year OS, 96% vs 53%; P = .002). The most frequent grade 3 to 4 adverse events were hematologic (42%), infectious (17%), and hepatic (22%), with only one vascular occlusive event. The combination of chemotherapy with ponatinib followed by alloHSCT is well tolerated, with encouraging EFS in adults with newly diagnosed Ph+ ALL. Cross-trial comparison suggests improvement vs imatinib (clinicaltrials.gov identifier #NCT02776605).

Efficacy of post-induction therapy for high-risk neuroblastoma patients with end-induction residual disease.

High-risk neuroblastoma patients with end-induction residual disease commonly receive post-induction therapy in an effort to increase survival by improving the response before autologous stem cell transplantation (ASCT). The authors conducted a multicenter, retrospective study to investigate the efficacy of this approach. Patients diagnosed between 2008 and 2018 without progressive disease with a partial response or worse at end-induction were stratified according to the post-induction treatment: 1) no additional therapy before ASCT (cohort 1), 2) post-induction "bridge" therapy before ASCT (cohort 2), and 3) post-induction therapy without ASCT (cohort 3). χ2 tests were used to compare patient characteristics. Three-year event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method and survival curves were compared by log-rank test. The study cohort consisted of 201 patients: cohort 1 (n = 123), cohort 2 (n = 51), and cohort 3 (n = 27). Although the end-induction response was better for cohort 1 than cohorts 2 and 3, the outcomes for cohorts 1 and 2 were not significantly different (P = .77 for EFS and P = .85 for OS). Inferior outcomes were observed for cohort 3 (P < .001 for EFS and P = .06 for OS). Among patients with end-induction stable metastatic disease, 3-year EFS was significantly improved for cohort 2 versus cohort 1 (P = .04). Cohort 3 patients with a complete response at metastatic sites after post-induction therapy had significantly better 3-year EFS than those with residual metastatic disease (P = .01). Prospective studies to confirm the benefits of bridge treatment and the prognostic significance of metastatic response observed in this study are warranted.

MEDB-26. Outcomes of children with standard-risk and high-risk medulloblastoma treated with pre-irradiation chemotherapy and risk-adapted craniospinal irradiation: a report on patients from the Polish Pediatric Neuro-oncology Group

BACKGROUND: The last two decades have witnessed several efforts to minimize the adverse sequelae of craniospinal irradiation (CSI), a standard of care treatment modality in medulloblastoma. This has been accomplished by adding chemotherapy to the treatment backbone. The use of pre-irradiation chemotherapy has also been previously reported. In one of the largest studies to date, we analyze treatment outcomes in children with standard and high-risk medulloblastoma treated with pre-irradiation chemotherapy followed by reduced-dose radiotherapy in SR and maintenance chemotherapy. METHODS: Data from the Polish Pediatric Neuro-oncology Group (PPNG) was analyzed in patients greater than 3 years of age with newly-diagnosed medulloblastoma. RESULTS : Among 138 patients, median age at diagnosis was 7.9 years and median follow-up was 5.5 years. Comprehensive molecular subgrouping was not available for all patients at the time of data collection. Of 60 standard-risk patients, there was pre-irradiation disease recurrence in one patient. One patient expired prior to radiation due to metastatic disease. Of 78 high-risk patients, one had pre-irradiation recurrence. Overall survival (OS) for high-risk patients at 3 and 5 years (± standard error) was 89.2 ± 4.0% and 81.3 ± 5.8%, respectively. OS for standard-risk patients at 3 and 5 years was 92.5 ± 3.8% and 88.2 ± 5.1%, respectively. Among high-risk patients, event-free survival (EFS) at 3 and 5 years was 82.5 ± 5.3% and 81.0 ± 5.6%. Among standard-risk patients, 3-year EFS was 89.2 ± 4.6% and 5-year EFS was 86.8 ± 5.3%. CONCLUSION : This study demonstrates promising survival outcomes in pediatric medulloblastoma patients treated with pre-irradiation chemotherapy followed by reduced-dose CSI and adjuvant chemotherapy. Such an approach may be helpful if delays in starting radiotherapy are expected, which is usually the case in many institutions around the globe.

Long-term outcomes in patients with localized Ewing sarcoma treated with interval-compressed chemotherapy: A long-term follow-up report from Children’s Oncology Group study AEWS0031.

11505 Background: Children’s Oncology Group study AEWS0031 demonstrated superior 5-year event-free survival (EFS) in patients with localized Ewing sarcoma (ES) receiving interval-compressed (IC) chemotherapy (every 2 weeks) compared to standard timing (ST) chemotherapy (every 3 weeks). We assessed the long-term outcome of patients treated on AEWS0031 to determine whether the survival advantage of IC chemotherapy was maintained at 10 years. Methods: AEWS0031 enrolled 568 eligible patients with localized ES. Patients were stratified into four groups by age (&lt;18 years and ≥ 18 years) and primary site (pelvic and non-pelvic), and randomized to receive 14 cycles of alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide given every 3 weeks (ST; Regimen A) vs. every 2 weeks (IC; Regimen B). For this updated report, one patient was excluded due to uncertainty of original diagnosis giving a total of 567 patients in this analysis. Data for tumor measurements and histologic response were collected retrospectively from institutional reports. EFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test and Gray’s test for cumulative incidence (CI). Results: The 10-year EFS for patients treated with IC chemo was 70% compared to 61% for ST chemo (p = 0.03), and the OS was 76% with IC chemo compared to 69% for ST chemo (p = 0.03). The 10-year CI of second malignant neoplasms (SMNs) for ST chemo was 4.2% [95% confidence interval: 2.4-7.5] compared to 3.2% (95% confidence interval: 1.6-6.3) for IC chemo (p = 0.5). There was a trend towards improved 10-year EFS in those receiving IC chemo both with non-pelvic (N = 477; 71% vs. 64%) and pelvic (N = 90; 67% vs. 43%) primary tumors. Similarly, the 10-year EFS was superior for patients treated with IC chemo in both the &lt; 18 years (N = 500; 73% vs. 64%) and ≥ 18 years (N = 67; 53% vs. 37%) age groups. Among the 184 patients with available histologic response data, the 10-year EFS from the time of local control was 76% for those with &lt; 10% viable tumor and 56% for those with ≥ 10% viable tumor (p = 0.01). Additional analysis comparing patients with any viable tumor vs. no viable tumor (NVT) by treatment regimen demonstrated that patients with NVT who received IC chemo had 10-year EFS and OS from local control of 91% and 97%, respectively. In the 210 patients for whom tumor volume calculations were possible, there was no difference in the 10-year EFS for patients with tumors &lt; 200 mL vs. ≥ 200 mL. Conclusions: With longer term follow-up, IC chemotherapy for localized ES is associated with superior EFS and OS without an increase in SMNs. This study suggests patients ≥ 18 years with poor necrosis or pelvic primary tumors remain at high risk for relapse despite IC chemo, emphasizing the need for alternative treatment strategies to improve their outcomes. Clinical trial information: NCT00006734.

Brentuximab vedotin and association with event-free survival (EFS) in children with newly diagnosed high-risk Hodgkin lymphoma (HL): A report from the Children's Oncology Group phase 3 study AHOD1331 (NCT 02166463).

7504 Background: The anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) is approved for adults with advanced stage HL but its use has not been established in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin. Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (PET2) identified slow responding lesions (SRL) defined as Deauville score &gt; 3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was 3-year EFS; events include relapse/progression, second malignant neoplasm (SMN) or death. Final data cutoff was 31 December 2021. Results: 600 participants were enrolled across 151 institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4-21). Patient and disease characteristics were balanced across study arms. Histology was nodular sclerosing in 76.5%. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB. At a median follow-up of 42.1 mos (0.1-80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 82.5% (77.4, 86.5) with ABVE-PC and 92.1% (88.4, 94.7) with Bv-AVE-PC (HR 0.41 (0.25, 0.67), p = 0.0002). Median time to 1st event was 9.4 months for both arms but the range differs by arm (3.6-57.8 ABVE-PC; 1.3, 25.8 Bv-AVE-PC). Relapse rate was 17% following ABVE-PC and 7% with Bv-AVE-PC. One SMN is noted in each arm: thyroid cancer at 57.8 mos and acute myeloid leukemia at 20.3 mos. 3-year overall survival (95%CI) was 98.5% (96.0, 99.4) for ABVE-PC and 99.3% (97.3, 99.8) for Bv-AVE-PC (p = 0.38). PET2 SRL rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p = 0.8). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p = 0.69). No difference in grade 3/4 adverse events was observed; myelosuppression, reflected in a 32% incidence of &gt; grade 3 febrile neutropenia, did not differ by arm (p = 0.67). Only 19% of patients experienced &gt; grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p = 0.86). Conclusions: Brentuximab vedotin with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 59% risk reduction in EFS was achieved with no increase in toxicity and with fewer patients receiving ISRT compared to prior pediatric trials for high-risk HL. Clinical trial information: 02166463.

A single-arm, phase 2 study of perioperative ipilimumab, nivolumab, and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.

TPS617 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER &lt; 10%, PR &lt; 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 80 pts will be enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686.

ARST2031: A study to compare early use of vinorelbine and maintenance therapy for patients with high risk rhabdomyosarcoma.

TPS11591 Background: Patients with high-risk rhabdomyosarcoma (HR-RMS) continue to have poor outcomes with 3-year event free survival (EFS) rates of 30% or less despite chemotherapy dose intensification on recent cooperative group RMS trials. Vinorelbine (VINO) has demonstrated clinical activity in RMS patients with relapsed/refractory disease and shown to provide a survival benefit when given with oral cyclophosphamide as maintenance chemotherapy for a select group of patients that achieved first complete remission. Methods: ARST2031 is a randomized Phase 3 trial with the primary aim to compare event-free survival (EFS) of patients with HR-RMS treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by maintenance with vinorelbine and oral cyclophosphamide (VINO-CPO) or vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by maintenance with VINO-CPO. Patients are stratified by histology and randomly assigned to VAC followed by VINO-CPO maintenance or VINO-AC followed by VINO-CPO maintenance. To be eligible, patients must be ≤ 50 years of age at the time of enrollment with newly diagnosed RMS except adult-type pleomorphic, based upon institutional histopathologic classification. All patients must have Stage 4 disease and patients diagnosed with embryonal RMS (ERMS) must be ≥ 10 years of age. Patients with malignant cytology in cerebrospinal fluid, intra-parenchymal brain metastases, or diffuse leptomeningeal disease are excluded. The study was activated on September 13, 2021 and is anticipated to enroll approximately 4 patients per month. The planned sample size is 100 patients, with approximately 50 patients randomized to each arm. Safety and feasibility of VINO-AC will be assessed in the first 8 patients prior to randomization. The study will have power of 0.8 to detect a hazard ratio of 0.61 (74 events in total) when the one-sided Type I error rate is 0.10, with 30 months of accrual and 2 years of follow-up. The hazard ratio of 0.61 was determined by assuming piecewise exponential distributions and specifying the 2-year EFS of 46% vs. 28% and long-term EFS of 32% vs. 16%, based on prior outcome data. Biospecimens will be collected and banked for future use. Clinical trial information: NCT04994132.

Efficacy and safety of outpatient based therapy in childhood acute lymphoblastic leukemia.

e22001 Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. With the improvements in effective antileukemic drugs and the risk stratification treatment approach, the cure rate for pediatric ALL has increased to &gt;90%. The effect of outpatient treatment and developing supportive care have a very important role in this success. We evaluated the disease outcomes and severe complications (complication causes hospitalization in ICU, encephalitis) of children who had been treated with the Children’s Oncology Group (COG) protocols, and follow-up protocol during a 20-year study period. Methods: From 1999 to 2020, 134 patients who had been diagnosed with ALL in the Department of Pediatric Hematology-Oncology at the Istanbul University Oncology Institute were included in the present study. Nine patients excluded from all analysis that 5 of them admitted with relapse, 2 had been diagnosed with mature aggressive B-cell acute leukemia, and 2 had been diagnosed with mixed phenotype and 7 who had been lost to follow-up were also excluded from survival analyses. Results: Mean age was 7.7±4.89 years old in 125 patients (Table). The 5- and 10-year and 20-year Event Free Survival (EFS) rates were 90.2% (standard error [SE], 4.2%) in standart risk B-ALL (n=54) and Overall Survival (OS) rates were 100%, 96% and 96% ([SE], 3.9%), respectively. In high risk group B-ALL (n=53) 5-year EFS was 80.7% (standard error [SE], 5.8%) and 78.2% ([SE], 6.1%) for both 10 and 20 year period and OS rates were 76.9% ([SE], 5.9%) for all periods. Although the number of patients is low in T-ALL (n=11), 5- and 10-year and 20-year EFS and OS rates were 63.6% (standard error [SE], 14.5%) for all periods. Fifteen severe complication recorded in 12 patients (10 B-ALL, 2 T-ALL). One patient hospitalized in ICU due to gram negative sepsis for 3-times and epidural hemorrhage. Conclusions: The survival rate for pediatric ALL has increased in recent years according to improvements of treatment.In our cohort, 20-year OS rate is 96% for standart risk B-ALL and 76.9% for high risk B-ALL. Additionally, regularly and closely monitored patients, complications can be effectively prevented, treated, and eliminated. In our study, the short hospitalization period, rapid analysis of laboratory tests, continuous supportive care, efficient education given to the parents of children increased the success of the therapy and ensured low complication rates. [Table: see text]

Low-dose apatinib combined with neoadjuvant chemotherapy in the treatment of early-stage triple-negative breast cancer (LANCET): A single-center, single-arm, phase II trial.

e12613 Background: Anti-angiogenic therapy combined with chemotherapy could improve pathologic complete response for breast cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and standard chemotherapy in patients with triple negative breast cancer (TNBC). Methods: This single-arm, phase II study enrolled patients aged 18-70 years with previously untreated stage IIA-IIIB TNBC. Patients received oral apatinib at a dose of 250 mg once daily and intravenously docetaxel every three weeks for four cycles, followed by epirubicin plus cyclophosphamide every three weeks for four cycles. The primary endpoint was the pathological complete response (pCR) rate in the breast and lymph nodes. Secondary endpoints included objective response rate, event-free survival (EFS), overall survival (OS), and safety. Results: Between August 1, 2018 and March 10, 2021, we screened 34 patients and enrolled 31 patients. At the date of cut-off on December 31, 2021, the median follow-up time was 22.9 months (range: 10.1-41.6 months). The pCR in both breast and lymph nodes were achieved in 17 (54.8%; 95%CI: 36.0–72.7) of 31 patients. Objective responses were achieved in 29 patients (93.5%; 95%CI: 78.6-99.2), and disease control was achieved in 31 patients (100%; 95%CI: 88.8–100.0). The 2-year EFS and 2-year OS were 90.9% and 94.4%, respectively. The five most common treatment-related adverse events were fatigue (51%), hypertension (41%), anorexia (39%), hand-foot syndrome (35%), and diarrhea (32%). Few grade 3 or more adverse events were observed. Conclusions: The combination of apatinib with docetaxel followed by the epirubicin plus cyclophosphamide showed excellent efficacy and manageable toxicities; further randomized controlled phase III trials are warranted. Clinical trial information: NCT03243838.

Long-term outcome and relapse patterns in Ewing sarcoma patients with extensive lung/pleural metastases after a complete response to systemic therapy.

BackgroundEwing sarcoma (ES) is sensitive to systemic therapy, including chemotherapy and anti-angiogenesis Tyrosine Kinase Inhibitors(aaTKIs). However, the prognosis of patients with metastatic disease remains poor. Recurrence or distant metastasis after a complete response (CR) or near-CR due to systemic therapy is not rare.MethodsWe reviewed data from 187 ES patients between 2014–2019 treated at a single institute in China. Patients with extensive lung/pleural metastases (L/Pmeta) who had a CR or near-CR after first- or second-line chemotherapy with or without aaTKIs were retrospectively enrolled. Event-free survival (EFS) and overall survival (OS) were determined using the Kaplan–Meier method. For patients who had L/P recurrence, images were reviewed to define the exact location of each recurrent lesion, compared with the primary L/P lesion before chemotherapy and summarized as the relapse pattern.ResultsSeventeen patients and 21 cases of CR/nCR (5 by VDC/IE, 3 by VIT, and 13 by AVI) were finally analyzed. Median follow-up for surviving patients was 39.6 (range, 14.5–60.9) months. Median EFS and OS were 9.3 (95% confidence interval [CI], 2.0–16.6) months and 37.5 (95% CI, 21.8–53.1) months, respectively. The 2-year EFS was 19% and the 2-year OS was 70.6%, respectively. Most patients (82.4%) received whole lung irradiation (WLI). Lung/pleural relapse occurred in 71.4% (15/21) of CR/nCR cases. Most notably, all recurrent lesions exactly coincided with the original metastatic lesions before chemotherapy (exactly in situ) in 9 of the 15 recurrent cases, which was thus the major relapse pattern, whereas 42.9% had distant metastases other than L/Pmeta.ConclusionsSurvival of ES patients with extensive L/Pmeta remains poor, even if they have a CR after systemic therapy. Recurrence exactly in situ is the major relapse pattern. WLI is not sufficient to prevent local recurrence in lung or pleura. More aggressive local treatment for metastatic lesions is warranted.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Simple SummaryMalignant rhabdoid tumors (MRT) are deadly tumors that predominantly affect infants and young children. Even when considering the generally young age of these patients, the treatment of infants below the age of six months represents a particular challenge due to the vulnerability of this patient population. The aim of our retrospective study was to assess the available information on prognostic factors, genetics, toxicity of treatment and long-term outcomes of MRT. We confirmed that, in a cohort of homogenously treated infants with MRT, significant predictors of outcome were female sex, localized stage, absence of a GLM and maintenance therapy, and these significantly favorably influence prognosis. Stratification-based biomarker-driven tailored trials may be a key option to improve survival rates.Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Congenital spindle cell rhabdomyosarcoma: An international cooperative analysis

BackgroundSpindle cell rhabdomyosarcoma (RMS) is a rare variant of RMS accounting for up to 10% of cases in infants. In older children and adults, spindle cell RMS is associated with MYOD1 mutations and a poor prognosis. In infants, it is associated with recurring fusions involving NCOA2 and VGLL2. Reports in the literature suggest a favorable prognosis for this subset, however, little is known about treatment and outcome data of infants with spindle cell RMS. MethodsCharacteristics, treatment, and outcome of an international cohort of 40 patients aged ≤ 12 months with spindle cell RMS treated from 1997 to 2018 were evaluated. ResultsLocalized disease (LD) was diagnosed in 39 patients. The median age at diagnosis was 2.5 months (range 0–12 months). Expert pathologic review confirmed the diagnosis of spindle cell RMS in all patients. Among 26 tumors that had molecular evaluation, 13 had rearrangements of NCOA and/or VGLL. Multimodal treatment of infants with LD included conventional (age adjusted) chemotherapy (n = 37), resection (n = 31) and radiotherapy (RT) (n = 5, brachytherapy in 3). Complete remission was achieved in 37/39 patients. Progressive disease occurred in two infants, relapsed disease in three. Microscopically complete surgical resection was associated with five-year event-free survival (EFS) and overall survival (OS) of 100%. Two patients with tumors ≤ 5 cm were treated with microscopically complete resection only and were alive 1 and 4.2 years after diagnosis. The 5-year EFS and OS for infants with LD were 86% (±11; CI 95%) and 91% (±9; CI 95%), respectively. One patient had metastatic disease (NCOA fusion positive) with primary tumor in head and neck and brain metastases. This patient died despite chemotherapy and delayed resection of the primary tumor due to respiratory failure secondary to cytomegalovirus infection 1.2 years after diagnosis. ConclusionInfants with spindle cell RMS have an excellent prognosis. Multimodal treatment including microscopically complete resection of the tumor is strongly recommended.

Outcomes based on histopathologic response to preoperative chemotherapy in children with bilateral Wilms tumor: A prospective study (COG AREN0534).

An objective of the Children's Oncology Group AREN0534 Study was to improve the survival of patients with bilateral Wilms tumors (BWT) by using preoperative chemotherapy of limited duration and tailoring postoperative therapy based on histopathologic response. The authors report outcomes based on postoperative histopathologic responses. Patients with BWT received treatment with vincristine, dactinomycin, and doxorubicin for 6 or 12 weeks followed by surgery. Postoperative therapy was prescribed based on the highest risk tumor according to the International Society of Pediatric Oncology classification and the Children's Oncology Group staging system. Analyses were performed on data from 180 evaluable children. The 4-year event-free survival (EFS) and overall survival (OS) rates were 81% (95% CI, 74%-87%) and 95% (95% CI, 91%-99%), respectively. Seven patients who had completely necrotic tumors had a 4-year EFS rate of 100%. Of 118 patients who had tumors with intermediate-risk histopathology, the 4-year EFS and OS rates were 82% (95% CI, 74%-90%) and 97% (95% CI, 94%-100%), respectively. Fourteen patients who had blastemal-type tumors had 4-year EFS and OS rates of 79% (95% CI, 56%-100%) and 93% (95% CI, 79%-100%), respectively. Eighteen patients who had diffuse anaplasia had 4-year EFS and OS rates of 61% (95% CI, 35%-88%) and 72% (95% CI, 47%-97%), respectively; and the 4-year EFS and OS rates of 7 patients who had focal anaplasia were 71% (95% CI, 38%-100%) and 100%, respectively. There was no difference in the outcomes of patients who had different histopathologic subtypes within the intermediate-risk group (P = .54). A risk-adapted treatment approach for BWT results in excellent outcomes. This approach was not successful in improving the outcome of patients who had diffuse anaplasia.

The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a novel prognostic factor for patients with diffuse large B-cell lymphoma.

The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a prognostic marker in several types of malignant tumors. The prognostic value of HALP score in diffuse large B-cell lymphoma (DLBCL) remains unknown. We aimed to determine the prognostic value of baseline HALP score in DLBCL patients. We retrospectively analyzed data from 153 newly diagnosed DLBCL patients treated with R-CHOP or R-CHOP-like regimens at our university hospital center. We evaluated the significance of HALP score as a predictor of response to treatment, overall survival (OS), and event-free survival (EFS). The median follow-up time for all patients was 40 months. Lower HALP score was found in patients with advanced stages of disease (P = 0.005) and in those with poor response to therapy (P = 0.004). Patients with a HALP score ≤20.8 had significantly worse 5-year OS (47.3% vs. 79.5%, P < 0.001) and 5-year EFS (40.6% vs. 76.7%, P < 0.001). These observations remained statistically significant in the multivariate Cox regression models independently of International Prognostic Index (IPI) and age. Lower HALP is associated with unfavorable clinicopathological characteristics of DLBCL and seems to be an IPI independent negative prognostic factor. HALP score can be easily and inexpensively applied to timely recognize DLBCL patients under higher risk of unwanted outcomes in everyday clinical practice.

A Nomogram for Predicting Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study.

ObjectiveEven though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL.MethodChildren with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China children’s leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 7:3 ratio (training set, n=1187; validation set, n=506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram.ResultThe parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1/TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 [95% confidence interval (CI) = 0.792-0.830] and 0.797 (95% CI = 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan–Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated.ConclusionThe nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making.

Discovery of Pre-Treatment FDG PET/CT-Derived Radiomics-Based Models for Predicting Outcome in Diffuse Large B-Cell Lymphoma.

Simple SummaryDiffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. Even with the improvements in the treatment of DLBCL, around a quarter of patients will experience recurrence. The aim of this single centre retrospective study was to predict which patients would have recurrence within 2 years of their treatment using machine learning techniques based on radiomics extracted from the staging PET/CT images. Our study demonstrated that in our dataset of 229 patients (training data = 183, test data = 46) that a combined radiomic and clinical based model performed better than a simple model based on metabolic tumour volume, and that it had a good predictive ability which was maintained when tested on an unseen test set.Background: Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) will have recurrence. The aim of this study was to develop a radiomic based model derived from baseline PET/CT to predict 2-year event free survival (2-EFS). Methods: Patients with DLBCL treated with R-CHOP chemotherapy undergoing pre-treatment PET/CT between January 2008 and January 2018 were included. The dataset was split into training and internal unseen test sets (ratio 80:20). A logistic regression model using metabolic tumour volume (MTV) and six different machine learning classifiers created from clinical and radiomic features derived from the baseline PET/CT were trained and tuned using four-fold cross validation. The model with the highest mean validation receiver operator characteristic (ROC) curve area under the curve (AUC) was tested on the unseen test set. Results: 229 DLBCL patients met the inclusion criteria with 62 (27%) having 2-EFS events. The training cohort had 183 patients with 46 patients in the unseen test cohort. The model with the highest mean validation AUC combined clinical and radiomic features in a ridge regression model with a mean validation AUC of 0.75 ± 0.06 and a test AUC of 0.73. Conclusions: Radiomics based models demonstrate promise in predicting outcomes in DLBCL patients.

Treatment and outcome of pediatric intracranial ependymoma after first relapse.

Almost 50% of children with intracranial ependymoma experience disease relapse, and their outcomes areextremely poor. The aim of this study was to investigate optimal salvage treatment for pediatric intracranial ependymoma after the first relapse and to identify prognostic factors affecting survival. We conducted a retrospective analysis of 159 children who underwent initial treatment for intracranial ependymoma at Beijing Tiantan Hospital from 2013 to 2017. Relapse was observed in 73 patients (73/159;45.9%), with a median age of 7.2 ± 3.5years old. Molecular subgrouping analysis identified H3K27me3-negative PF-EPNs in 74% of patients, ST-RELA EPNs in 21% of patients, and H3K27me3-positive PF-EPNs in 5% of patients. The 5-year event-free survival(EFS) and overall survival(OS) rates after first relapse were 21.1% (95% CI 16.0-26.2) and 30.5% (95% CI 19.8-30.8), respectively. Patients with GTR at first relapse had higher 5-year EFS and 5-year OS than those with STR (P = 0.031 and P = 0.003) or no surgery (P = 0.007 and P = 0.001). Radiotherapy or re-radiotherapy at first relapse significantly prolonged 5-year EFS and OS (both P < 0.001). Patients with H3K27me3-negative PF-EPN had worse 5-year EFS and OS than those with ST-RELA EPN (P = 0.001 and P = 0.002). Multivariate analysis showed that both tumor resection and radiotherapy at first relapse had independent prognostic significance for survival (all P < 0.05). Children with recurrent intracranial EPN have poor outcomes, andsurgery and radiotherapy at first relapse should be encouraged to improve their prognosis.

Prognostic Significance of Comprehensive Gene Mutations and Clinical Characteristics in Adult T-Cell Acute Lymphoblastic Leukemia Based on Next-Generation Sequencing.

BackgroundAdult T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignant tumor with poor prognosis. However, accurate prognostic stratification factors are still unclear.MethodsData from 90 adult T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients were collected. The association of gene mutations detected by next-generation sequencing and clinical characteristics with the outcomes of T-ALL/LBL patients were retrospectively analyzed to build three novel risk stratification models through Cox proportional hazards model.ResultsForty-seven mutated genes were identified. Here, 73.3% of patients had at least one mutation, and 36.7% had ≥3 mutations. The genes with higher mutation frequency were NOTCH1, FBXW7, and DNMT3A. The most frequently altered signaling pathways were NOTCH pathway, transcriptional regulation pathway, and DNA methylation pathway. Age (45 years old), platelet (PLT) (50 G/L), actate dehydrogenase (LDH) (600 U/L), response in D19-BMR detection, TP53 and cell cycle signaling pathway alterations, and hematopoietic stem cell transplantation (HSCT) were integrated into a risk stratification model of event-free survival (EFS). Age (45 years old), white blood cell (WBC) count (30 G/L), response in D19-BMR detection, TP53 and cell cycle signaling pathway alterations, and HSCT were integrated into a risk stratification model of overall survival (OS). According to our risk stratification models, the 1-year EFS and OS rates in the low-risk group were significantly higher than those in the high-risk group.ConclusionsOur risk stratification models exhibited good prognostic roles in adult T-ALL/LBL patients and might guide individualized treatment and ultimately improve their outcomes.