Hematologic Adverse Events Research Articles

Real-world analysis of belantamab mafodotin (belamaf): Care patterns in relapsed/refractory multiple myeloma.

e19507 Background: Belamaf is an anti-B cell maturation antigen immunoconjugate for relapsed/refractory multiple myeloma that has shown efficacy and safety in the DREAMM clinical trials. Additional long-term real-world data on its use patterns, efficacy, and tolerability are needed. Methods: This retrospective review (NCT05986682) analyzed adults with multiple myeloma receiving ongoing care at Duke Cancer Institute who began belamaf monotherapy (not in a clinical trial) between 8/5/2020 and 11/22/2022. We abstracted data for 30 patients through 9/18/2023. We described baseline clinical characteristics, disease response (per International Myeloma Working Group [IMWG] criteria, as possible given available marrow biopsy data), belamaf use patterns, and ocular adverse events (AEs) (per the Keratopathy Visual Acuity [KVA] scale). Results: Our sample was 53% (n=16) female, 47% (14) White, and 47% (14) Black; median age was 68 years at the beginning of belamaf therapy. 67% (20) had ≥4 prior lines of therapy (median: 4, min-max: 2-19), 87% (26) were triple-/quad-/penta-refractory, and 23% (7) had high-risk cytogenetics (per IMWG). Overall response rate (ORR) was 67% (11 very good partial response, 9 partial response). Median (min-max) time to best response was 1.5 (0.7-9.9) months. Median (min-max) response duration was 9.8 (1.1-20.2) months. Progression occurred in 73% (22) of patients; median progression-free survival (PFS) was 8.4 months (95% CI 6.6-12.7). Median overall survival was not reached. Median (min-max) number of cycles was 6.5 (2-13). 63% of patients (19) had a dose reduction from 2.5 to 1.9 mg/kg; 65% (13) were due to corneal AEs and 30% (6) due to hematologic AEs. 93% (28) had ≥1 cycle delay, and the median (min-max) number of delays was 5 (1-14); 85% of delays (n=153) were due to corneal AEs. Cycle length changed for 33% (10) from every 3 weeks to every 4 (1) or 6 (9) weeks; 91% (n=10) of cases were due to corneal AEs. 93% (28) had keratopathy (any grade); among all events (n=323), 2% were grade ≥3. Median (min-max) time to resolution of grade ≥2 keratopathies was 6 (2-22) weeks. 90% (27) experienced a visual acuity change; among all events (n=244), 3.3% were grade ≥3. Median (min-max) time to resolution of grade ≥2 visual acuity events was 6 (2.9-53) weeks. The most common ocular symptoms were blurry vision (53% of symptoms), dry eyes (17%), and photophobia (14%). Belamaf was discontinued in 13% (4) due to ocular AEs and 20% (6) to patient/physician choice or other reason. Median (min-max) time to last dose/discontinuation was 9.3 (0.7-21.6) months. Conclusions: In our study, ORR and median PFS were greater than other real-world studies. Corneal AEs were also more common, but severity was consistent with these and DREAMM-3 findings. Despite a higher rate of dose reductions and delays than other real-world studies, our study adds promise to the benefit of belamaf over an extended time with dose modifications.

Efficacy and safety of SHR-2554 in advanced epithelioid sarcoma: A phase 2 trial.

11549 Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. The loss of SMARCB1 (INI1) expression which leads to oncogenic dependence on the transcriptional repressor EZH2 has been observed in over 90% of ES. Patients (pts) with metastatic ES have a poor prognosis. We investigated the efficacy and safety of SHR-2554, an oral selective EZH2 inhibitor, in pts with refractory ES. Methods: To be eligible for inclusion, pts had to fulfill the following criteria: 8 years or older; histologically confirmed advanced or metastatic ES with loss of INI1 or upregulated mRNA level of EZH2; progressive disease after at least one line of doxorubicin-containing chemotherapy; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1. Pts received SHR2554 (350 mg, bid, po) until disease progression or unacceptable toxicity. The primary endpoint was progression-free rate at 12 weeks. A Simon two-stage design was applied. If there were 3 pts remaining progression-free at 12 weeks within the first 9 pts, the cohort would expand to 17 pts and the outcome would be positive if more than 7 pts remained progression-free at 12 weeks. Results: Between Jul 2021 and Dec 2023, a total of 17 pts were enrolled and received at least 1 dose of SHR-2554. The median age was 32 years (range 8-57) and 41.2% were males. 9 (52.9%) pts had received immunotherapy targeting PD-1/L1 and 6 (35.3%) pts had received anti-angiogenesis therapy before enrollment. The median line of previous treatment was 2 (range 1-4). Loss of INI1 was confirmed in 14 (82.4%) pts. Tumor response was evaluated in 14 pts at data cutoff. 9 (64.3%) of 14 pts remained progression-free at 12 weeks. The primary endpoint was met. Based on investigator assessment, 3 (21.4%) of 14 pts achieved partial response and 8 (57.1%) pts had stable disease as best response. Adverse events (AEs) were generally mild. The most common treatment-related hematological AEs were anaemia, platelet count decreased and hyperuricaemia. Conclusions: SHR-2554 showed promising efficacy and an acceptable safety profile in pts with refractory ES, warranting further investigation. Clinical trial information: ChiCTR2100046099.

Efficacy and safety of stem cell transplantation for multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials

Multiple sclerosis (MS) is a common autoimmune neurological disease affecting patients’ motor, sensory, and visual performance. Stem Cell Transplantation (SCT) is a medical intervention where a patient is infused with healthy stem cells with the purpose of resetting their immune system. SCT shows remyelinating and immunomodulatory functions in MS patients, representing a potential therapeutic option. We conducted this systematic review and meta-analysis that included randomized control trials (RCTs) of SCT in MS patients to investigate its clinical efficacy and safety, excluding observational and non-English studies. After systematically searching PubMed, Web of Science, Scopus, and Cochrane Library until January 7, 2024, nine RCTs, including 422 patients, were eligible. We assessed the risk of bias (ROB) in these RCTs using Cochrane ROB Tool 1. Data were synthesized using Review Manager version 5.4 and OpenMeta Analyst software. We also conducted subgroup and sensitivity analyses. SCT significantly improved patients expanded disability status scale after 2 months (N = 39, MD = − 0.57, 95% CI [− 1.08, − 0.06], p = 0.03). SCT also reduced brain lesion volume (N = 136, MD = − 7.05, 95% CI [− 10.69, − 3.4], p = 0.0002). The effect on EDSS at 6 and 12 months, timed 25-foot walk (T25-FW), and brain lesions number was nonsignificant. Significant adverse events (AEs) included local reactions at MSCs infusion site (N = 25, RR = 2.55, 95% CI [1.08, 6.03], p = 0.034) and hematological disorders in patients received immunosuppression and autologous hematopoietic SCT (AHSCT) (N = 16, RR = 2.33, 95% CI [1.23, 4.39], p = 0.009). SCT can improve the disability of MS patients and reduce their brain lesion volume. The transplantation was generally safe and tolerated, with no mortality or significant serious AEs, except for infusion site reactions after mesenchymal SCT and hematological AEs after AHSCT. However, generalizing our results is limited by the sparse number of RCTs conducted on AHSCT. Our protocol was registered on PROSPERO with a registration number: CRD42022324141.

BeEAM vs. BEAM: evaluating conditioning regimens for autologous stem cell transplantation in patients with relapsed or refractory DLBCL.

To evaluate whether BeEAM is an alternative to BEAM for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Data of 60 patients with relapsed or refractory DLBCL who underwent ASCT from January 2018 to June 2023 in our center, including 30 patients in the BeEAM group and 30 patients in the BEAM group, were retrospectively analyzed. The time to hematopoietic reconstitution, treatment-related adverse events, number of hospitalization days, hospitalization cost, and survival benefit were compared between the two groups. The clinical characteristics of the patients did not significantly differ between the two groups. The median number of reinfused CD34 + cells was 5.06 × 106/kg and 5.17 × 106/kg in the BeEAM and BEAM groups, respectively, which did not significantly different (p = 0.8829). In the BeEAM and BEAM groups, the median time to neutrophil implantation was 10.2 and 10.27 days, respectively (p = 0.8253), and the median time to platelet implantation was 13.23 and 12.87 days, respectively (p = 0.7671). In the BeEAM and BEAM groups, the median hospitalization duration was 30.37 and 30.57 days, respectively (p = 0.9060), and the median hospitalization cost was RMB 83,425 and RMB 96,235, respectively (p = 0.0560). The hospitalization cost was lower in the BeEAM group. The most common hematologic adverse events were grade ≥ 3 neutropenia and thrombocytopenia, whose incidences were similar in the two groups. The most common non-hematologic adverse events were ≤ grade 2 and the incidences of these events did not significantly differ between the two groups. Median overall survival was not reached in either group, with predicted 5-year overall survival of 72.5% and 60% in the BeEAM and BEAM groups, respectively (p = 0.5872). Five-year progression-free survival was 25% and 20% in the BeEAM and BEAM groups, respectively (p = 0.6804). As a conditioning regimen for relapsed or refractory DLBCL, BeEAM has a desirable safety profile and is well tolerated, and its hematopoietic reconstitution time, number of hospitalization days, and survival benefit are not inferior to those of BEAM. BeEAM has a lower hospitalization cost and is an alternative to BEAM.

Medium-cumulative dose of cytarabine in consolidation therapy shows the greatest benefit in AML patients

BackgroundHigh-dose cytarabine (HDAC) is commonly used for consolidation therapy in young acute myeloid leukemia (AML) patients, but the dosage of cytarabine is still controversial in the clinic due to its obvious post-chemotherapy adverse effects. The aim of this study was to contrast the efficacy in different dose groups of cytarabine after consolidation therapy in Chinese AML patients.MethodsAML patients treated with cytarabine consolidation at Qilu Hospital, Shandong University from January 2010 to September 2022 were retrospectively analyzed, from which 346 AML patients with relatively complete follow-up data were selected for this study. We compared the patients’ overall survival (OS) rate, relapse-free survival (RFS) rate, and hematologic adverse events in terms of their general characteristics, cytarabine consolidation therapy dose, consolidation course, 2022 European Leukemia Net (ELN) risk stratification, and transplantation.ResultsIn AML patients under 60 years of age, the 5-year RFS rate with high-dose cytarabine consolidation therapy was superior to that of small-dose cytarabine (P = 0.024), while the 5-year RFS rate was comparable in the high-dose and intermediate-dose groups, and there was no obvious difference among the three groups in the 5-year OS rate (P > 0.05). OS and RFS of those given more than 3 courses of cytarabine consolidation therapy were better than those in the 1–2 courses group (P = 0.060, P = 0.040). OS and RFS were better in patients with cumulative dose of cytarabine ≥ 36g than in patients with cumulative dose < 36g (P < 0.05), but cumulative dose ≥ 54g was comparable in OS and RFS with ≥ 36–< 54g group (P > 0.05). There was no significant difference in hematologic adverse effects among the three treatment groups.In the latest ELN risk stratification favorable-risk group, the cumulative dose of cytarabine ≥ 36g had a better 5-year RFS rate than the < 36g group (P = 0.038), and in the intermediate-risk group the 5-year OS rate and RFS rate were better in the ≥ 36g group than the < 36g group (P = 0.012, 0.025). In addition, the prognosis of transplanted patients was better than that of non-transplanted patients, whereas in non-transplanted patients, consolidation therapy with ≥ 36g cytarabine can effectively improve outcomes. Multivariate analysis indicated that age, fibrinogen (FIB) and the cumulative dose of cytarabine of ≥ 36–< 54g were predictors of OS, while age, white blood cell (WBC) and HDAC were predictors of RFS.ConclusionThe results of the study showed that consolidation therapy with cytarabine up to a cumulative dose of ≥ 36–< 54g in AML patients who did not undergo transplantation significantly improved patient prognosis. In the latest ELN risk stratification, cumulative doses of cytarabine ≥ 36g had a better prognosis in favorable and intermediate-risk patients.

Target trial emulation of carfilzomib safety among patients with relapsed/refractory multiple myeloma using a nationwide observational data in Korea

PurposeCarfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib’s safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database.MethodsThe retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial.ResultsThis study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24–3.35], hypertension [HR 1.58; 95% CI 1.15–2.17]) had the highest risk in the KRd group.ConclusionThe safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events.

Hematological toxicity of cyclin-dependent kinase 4/6 inhibitors in patients with breast cancer: a network meta-analysis and pharmacovigilance study.

We aimed to evaluate and compare the risk of hematological adverse events (AEs) associated with CDK4/6 inhibitors using data from randomized controlled trials (RCTs) and Food and Drug Adverse Event Reporting System (FAERS) database. The PubMed, Embase, and Cochrane Library databases were searched for RCTs related to abemaciclib, palbociclib, and ribociclib. A network meta-analysis (NMA) was conducted to compare the risks of hematological AEs, and a disproportionality analysis was performed to detect signals of hematological AEs. 16 RCTs comprising 16,350 breast cancer patients were included. Palbociclib and ribociclib had similar risks for hematological AEs, except a higher risk of grade 3-4 leukopenia observed with palbociclib (risk ratio [RR]: 7.84, 95% confidence interval [95%CI]: 1.33-41.28). Abemaciclib had a higher risk of anemia than both ribociclib (grade 1-4: RR: 2.23, 95% CI: 1.25 - 3.96; grade 3-4: RR: 3.52, 95% CI: 1.59 - 8.11) and palbociclib (grade 1-4: RR: 1.65, 95%CI: 1.03 - 2.59), but a lower risk of grade 3-4 of both leukopenia (RR: 0.12, 95%CI: 0.02 - 0.49) and neutropenia (RR: 0.15, 95%CI: 0.04 - 0.52) compared with palbociclib. Signals indicating occurrence of leukopenia, neutropenia, anemia, and thrombocytopenia were identified for three CDK4/6 inhibitors. Abemaciclib, palbociclib, and ribociclib showed significant but inconsistent hematological toxicity risks.

High-risk acute myeloid leukemia with DEK-NUP214 rearrangement and eyelid infiltration: a case report

Objective: This study aims to evaluate the safety and effectiveness of gilteritinib (Gilt) -based combination therapy bridging allo-HSCT for FLT3-ITD(+) R/R AML. Additionally, it aims to assess the impact of Gilt maintenance therapy on the prognosis of patients after allo-HSCT. Methods: The clinical data of 26 patients with FLT3-ITD(+) R/R AML treated at the First Affiliated Hospital of Soochow University from August 2019 to January 2023 were retrospectively analyzed. The analysis included an assessment of the composite complete remission rate (CRc), overall survival (OS) time, disease-free survival (DFS) time, and adverse events experienced by all enrolled patients. Results: A total of 26 patients with FLT3-ITD(+) R/R AML were enrolled, including 14 men and 12 women with a median age of 38 (18-65) years. A total of 18 cases were refractory, and eight cases were relapsed. The curative effect evaluation conducted between 14 and 21 days showed that the complete remission (CR) rate was 26.9% (7/26), the CR with hematology incomplete recovery was 57.7% (15/26), and the partial response (PR) rate was 7.7% (2/26). The CRc was 84.6% (22/26), and the minimal residual disease (MRD) negativity rate was 65.4%. The 12 month cumulative OS rate for all patients was 79.0%, and the 24 month cumulative OS rate was 72.0%. The median OS time was not determined. The median follow-up time was 16.0 months. Among the patients who responded to treatment, the 12 month cumulative DFS rate was 78.0%, and the 24 month cumulative DFS rate was 71.0%. The median DFS time was not determined. Patients who received allo-HSCT had a median OS time that was significantly longer than those who did not receive allo-HSCT (3.3 months, 95%CI 2.2-4.3 months, P=0.005). The median OS time of patients with or without Gilt maintenance therapy after allo-HSCT was not determined, but the OS time of patients with Gilt maintenance therapy after allo-HSCT treatment was longer than that of patients without Gilt maintenance therapy after allo-HSCT treatment (P=0.019). The FLT3-ITD mutation clearance rate in this study was 38.5%, and the median OS time of patients with FLT3-ITD mutation clearance was not determined but was significantly longer than the median OS of patients without FLT3-ITD mutation clearance (15.0 months; P=0.018). The most common grade 3 and above hematological adverse events of Gilt-based combination therapy included leukopenia (76.9%), neutropenia (76.9%), febrile neutropenia (61.5%), thrombocytopenia (69.2%), and anemia (57.7%). One patient developed differentiation syndrome during oral Gilt maintenance therapy after allo-HSCT treatment, but his condition improved after treatment. Conclusion: The Gilt-based combination therapy is highly effective in treating FLT3-ITD(+) R/R AML. It demonstrates a high CRc, MRD negativity rate, and rapid onset, leading to a significant improvement in patients' survival. Furthermore, the clearance rate of FLT3-ITD mutation is notably high. Additionally, implementing bridging allo-HSCT and Gilt maintenance therapy after allo-HSCT treatment has considerably enhances patients' survival. Closely monitoring and managing any adverse event that may occur during treatment are crucial.

Mitomycin C in the treatment of early triple-negative locally advanced BRCA-associated breast cancer

Rationale. BRCA1 associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. At the same time, carcinomas that develop in carriers of BRCA1 mutations are characterized by extremely high sensitivity to DNA-damaging chemotherapy. Mitomycin C alone or in combination with platinum agents has already demonstrated promising results in the treatment of BRCA-associated ovarian cancer (OC) and metastatic breast cancer. In this article, we present the results of a retrospective study aimed at comparing standard neoadjuvant chemotherapy regimens (NACT) with mitomycin-based regimens for primary locally advanced BRCA1-associated TNBC.The aim of the study is to determine the effectiveness of the combination of mitomycin and platinum compounds during neoadjuvant therapy in patients with primary locally advanced BRCA1 – associated TNBC.Materials and methods. The study included 89 patients diagnosed with primary locally advanced BRCA1-associated TNBC. Patients were divided into three groups depending on the therapy: 1) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel (n = 48) (AC + T), 2) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel and carboplatin (n = 27) (AC + TCbP), 3) mitomycin C plus platinum followed by 12 weekly injections of paclitaxel (n = 14) (MR + T). Pathological complete response (pCR) rates were compared.Results. The pCR rate in the MP+T group was 10/14 (71%). In patients with BRCA1-associated breast cancer who received AC + T and AC + TCbP regimens as NACT, the pCR rate was 17/48 (35%) and 19/27 (70%), respectively. The difference in pCR rate between mitomycin-containing therapy and the standard AC + T regimen was statistically significant (p = 0.03); the frequency of regressions was comparable to the frequency in the AC + TCbP group. During the 20-month follow-up period, no relapses were observed in the MR + T group. Relapses were more frequent in the AC + T group compared with the AC + TCbP group (16/48 (33%) vs 1/27 (4%), p = 0.003, Fisher’s exact test). The toxicity profile of the mitomycin-containing regimen included hematologic adverse events, the most common of which were anemia and leukopenia. Compared to standard regimens, nausea was significantly less pronounced. No patients reported alopecia with this regimen.Conclusions. The addition of mitomycin C to neoadjuvant therapy for BRCA1-associated TNBC may be a promising treatment option for this category of patients and merits further study.

Evaluating the clinical efficacy and safety of concurrent chemoradiotherapy with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer

ObjectiveA preclinical study showed that nab-paclitaxel acted as a radiosensitizer and improved tumor radiotherapy in a supra-additive manner. In this study, we aimed to evaluate the clinical efficacy and safety of concurrent chemoradiotherapy (CCRT) with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer with an unfavorable prognosis.MethodsEligible patients with stage IB1-IIA2 (FIGO 2009) cervical carcinoma were recruited retrospectively between August 2018 to May 2021. Patients in both the cisplatin and nab-paclitaxel groups received postoperative radiotherapy and weekly intravenous cisplatin 40 mg/m2 or nab-paclitaxel 100 mg concurrently. An analysis of overall survival, progression-free survival, and adverse reactions was conducted.ResultsA total of 105 early-stage cervical cancer patients were included into our study. The median follow-up time was 38.7 months. The 3-year overall survival and progression-free survival in both group was similar. The cycles of chemotherapy in the cisplatin group were less than those in the nab-paclitaxel group (4.5 vs. 5.0; p = 0.001). Patients in the cisplatin group had a significantly higher frequency of hematological adverse events than patients in the nab-paclitaxel group (P < 0.05). Patients in the cisplatin group had a significantly higher frequency of grade 3–4 leukopenia (46.1% vs. 18.9%; P = 0.03), grade 1–2 thrombocytopenia (32.7% vs. 9.5%; P = 0.014) than patients in the nab-paclitaxel group. Gastrointestinal reactions, such as vomiting, nausea, and anorexia were significantly reduced in the nab-paclitaxel group compared with those in the cisplatin group. Regarding the effects on alopecia, the incidence rate of the nab-paclitaxel group was higher than that of the cisplatin group (P = 0.001). There were no differences between the groups in terms of other adverse reactions.ConclusionThe results of this study indicate that nab-paclitaxel-based concurrent radiotherapy is tolerable and effective, and can be considered an alternative to cisplatin chemotherapy.

Abstract PO3-18-12: Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269

Abstract Background: Topoisomerase I inhibitors (Topo I) have been shown to be highly effective across a broad range of tumors including breast cancer. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been shown to be effective in BRCAm breast cancers. The combination of Topo I plus PARPi is known to be synergistic beyond the BRCAm subtype but overlapping myelotoxicities have prohibited successful clinical combinations. DAN-222 is a novel therapeutic HDC (High-capacity drug conjugate) whose payload is the topoisomerase 1 inhibitor camptothecin (CPT). Our previously published preclinical data demonstrates synergy of DAN-222 plus a PARPi regardless of BRCA or HRD status. Furthermore, DAN-222 demonstrates reduced bone marrow exposure enabling clinical combinations. Herein we present data for the first-in-human study of DAN-222 as mono- and combination therapy with a PARPi. The expectation is clinical benefit with this complimentary combination for patients with HRD+ and HRD- tumors, and not restricted to BRCAm, while minimizing overlapping myelotoxicities. Methods: A phase 1 study of DAN-222 as monotherapy and in combination with niraparib is being conducted in heavily pretreated patients with metastatic breast cancer. The objectives are to evaluate the safety, tolerability, and pharmacokinetics of DAN-222, and initial clinical activity based on RECIST v1.1 criteria to determine the recommended phase 2 dose. PK will be characterized for the total conjugated and the unconjugated CPT. Adults (≥18 years) with HER2-negative metastatic breast cancer that progressed on standard therapies were enrolled, without restriction on BRCA or HRD status. Results: As of June 2023, 30 patients had enrolled in dose escalation of monotherapy (2-16 mg/m2) or combination therapy with niraparib (100 mg). The median age was 61.5 years old (range, 36-75). The median number of prior treatment lines was 6. All patients were PARPi naïve and BRCAwt. In the monotherapy cohorts, the hematological adverse events (AEs) were neutropenia (28%; grade [Gr] ≥3: 17%), thrombocytopenia (22%; Gr ≥3: 6%) anemia (17%; Gr ≥3: 0%), and lymphopenia (11%; Gr ≥3: 0%), the non-hematologic adverse events Gr ≥3 was one case of cystitis. In the combination cohorts, the hematological AEs were anemia (25%; Gr ≥3: 17%), thrombocytopenia (17%; Gr ≥3: 8%), neutropenia (8%; grade Gr ≥3: 8%), and lymphopenia 8%; Gr ≥3: 0%) and there was no Gr ≥3 non-hematologic adverse events. The exposure of DAN-222 was linear and increased in a dose-proportional manner. The mean half-life ranged from 25.2 to 33.5 hours across all cohorts. Clinical activity during dose escalation was demonstrated with stable disease in 28% of patients with monotherapy and 67% of patients with combination therapy across all dose levels. Conclusions: No DLTs were observed in monotherapy or combination therapy in the dose escalation phase of this study. This study demonstrates the feasibility for DAN-222 to be combined with a PARPi at clinically relevant doses. The reduced myelotoxicity of DAN-222 will also enable combination with other therapies to treat patients with other types of cancer. The promising antitumor activity seen with DAN-222 in combination with PARPi in BRCAwt, supports continued clinical development. Citation Format: Sara Hurvitz, Erika Hamilton, Timothy Pluard, Aki Morikawa, Hatem Soliman, Kay Yeung, Adam Brufsky, Amy Tiersten, Wajeeha Razaq, Kristen Foye, Timothy Hagerty. Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269] [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-12.

Abstract PO1-12-06: Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia?

Abstract Background: Febrile neutropenia (FN), a major hematologic adverse event in perioperative chemotherapy for breast cancer, is more prevalent among Asians than in Caucasian populations. Four main guidelines, i.e., ASCO, EORTC, NCCN, and ESMO, provide recommendations regarding the appropriate use of hematopoietic growth factors. These guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) based on the estimated incidence of FN, primarily defined by the chemotherapy regimen. G-CSF administration is recommended when the incidence of FN is ≥20% or 10–20% with risk(s). However, the incidence of FN varies depending on the trial and design, and patient-specific risk factors for FN remain unclear. We previously performed a multicenter prospective cohort study in Japan, the CSPOR-BC FN study, evaluating the incidence of FN during perioperative chemotherapy for breast cancer. Herein, we conducted an additional analysis to explore thresholds of patient-specific risk factors for FN that could be evaluated before chemotherapy. We analyzed the risk factors for FN and verified the appropriateness of patient selection for prophylactic G-CSF administration. Methods: The previously reported CSPOR-BC FN study (PubMed ID=33631458) consecutively enrolled 1005 patients with stage I–III breast cancer between August 2015 and July 2017. In the current additional analysis, we intended to have 477 patients in the visiting group that evaluated true-FN, defined as ≥37.5℃ and grade 4 neutropenia. Multivariate analysis of risk factors for FN was performed, followed by the determination of cutoff values for age and pretreatment absolute neutrophil count (ANC) as risk factors. Results: Chemotherapy regimens administered were FEC (fluorouracil, epirubicin, and cyclophosphamide) in 170 patients (36%), E(A)C (epirubicin (doxorubicin) + cyclophosphamide) in 165 patients (35%), and TC (docetaxel + cyclophosphamide) in 142 patients (30%). The incidence of FN was 28.7% (N = 137). To evaluate the risk factors for FN, we predefined regimens, age, performance status (PS), stage, chemotherapy or radiotherapy history, infectious wounds, open wounds, ANC, and renal and liver dysfunction as potential risk factors. Multivariate analysis of risk factors for FN identified regimen (TC), age (≥65), low pretreatment ANC, treatment setting, and no primary pegfilgrastim prophylaxis as significant risk factors. Two patient-specific risk factors (age and pretreatment ANC) were analyzed. Logistic regression analysis revealed that age≥65 years was a significant risk factor (odds ratio=2.24, 95% confidence interval: 1.34–3.75). Applying a cutoff of 65 years (age) to predict FN, the sensitivity and specificity were 28.4 and 83.8%, respectively, which were inaccurate. Despite applying a cutoff of 67 years optimized from the receiver operating characteristic (ROC) curve, the sensitivity (22.4%), specificity (90.7%), and area under the curve (0.519) indicated low discrimination for predicting FN. The incidence of FN by age group was as follows: &amp;lt; 45 years, 30.8%; 45–55 years, 26.4%; 55–64 years, 20.9%; ≥65 years, 39.6%. Additionally, applying a cutoff of 2436/µL (pretreatment ANC) optimized from the ROC curve, the observed sensitivity (27.6%) and specificity (83.8%), and area under the curve (0.558) also indicated low discrimination for predicting FN. The incidence of FN by stratum of pretreatment ANC was as follows: &amp;lt; 2000, 33.3%; 2000–3000, 30.7%; 3000–4000, 29.9%; and &amp;gt;4000, 24.6. Accordingly, setting a cutoff value to predict FN incidence using age and/or pretreatment ANC was deemed inappropriate. Conclusion: Selecting patients for primary prophylactic G-CSF based on the existing FN risk can be challenging. Primary prophylactic G-CSF would be considered for every patient undergoing perioperative chemotherapy for breast cancer, especially Asians. ROC curve for FN and age. The AUC was 0.519. ROC curve for FN and neutrophil count. The AUC was 0.558. Citation Format: Kazutaka Narui, Takashi Ishikawa, Ikumi Takashima, Kosuke Kashiwabara, Yukari Uemura, Yuichiro Kikawa, Naruto Taira, Hirofumi Mukai. Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-06.

Abstract PO5-20-10: Treatment with CDK4/6 Inhibitor in a Patient with Metastatic Breast Cancer Causing Myelophthisis

Abstract Background: Symptomatic bone marrow metastasis causing myelophthisis is a rare manifestation of metastatic breast cancer, indicating a poor prognosis due to significant cytopenias. CDK4/6 inhibitors are first-line therapies for metastatic hormone-positive breast cancer but remain an unclear choice in breast cancer patients with significant cytopenias due to associated hematological adverse effects. We present a case of biopsy-proven hormone-positive breast cancer with bone marrow infiltration causing profound pancytopenia. CDK4/6 inhibitors were safely administered despite their cytopenic effects. Case Presentation: A 59-year-old female presented after an abnormal annual mammogram and biopsy showed calcifications stromal fibrosis, cyst formation, and usual ductal hyperplasia in the right upper outer quadrant. One month later, she presented to an outside hospital with gingival bleeding, epistaxis, progressive dyspnea on exertion, and generalized weakness. Labs showed severe anemia with a hemoglobin of 4.8 g/dL (baseline 12.1 g/dL), thrombocytopenia with platelets of 5 K/mm (baseline 215 K/mm), LDH of 879, reticulocyte count of 5%, and negative direct Coombs test. Peripheral smear showed no schistocytes, but showed nucleated RBCs, severely reduced platelets, and occasional giant platelets. The patient was treated for presumed ITP, and the presence of nucleated RBCs prompted bone marrow biopsy which confirmed metastatic invasive lobular carcinoma breast cancer (ER 90-95%, PR 90-95%, HER2 1+). She was discharged on letrozole 2.5 mg daily with close outpatient oncologic follow-up. One week later, she presented to our institution with persistent symptomatic anemia and thrombocytopenia. Inpatient systemic therapy was begun using dose-reduced Palbociclib (75mg) and letrozole with close CBC monitoring while also receiving packed red blood cells (goal &amp;gt;6.5) and platelet transfusions (goal &amp;gt;10). Repeat bone marrow biopsy showed extensive marrow fibrosis, but no significant hematopoietic elements. ADAMTS13 was 134%, ruling out TTP, and she was treated again for presumed ITP with dexamethasone and IVIG, Throughout the 4-week admission, her right breast mass decreased in size and she was discharged after completing 3 weeks of Palbociclib with biweekly outpatient transfusions. During follow-up, the patient’s hemoglobin and platelets slowly started to respond allowing her to become transfusion-independent and allowing dose escalation. Restaging scans 2 months after hospitalization showed an overall improvement of disease burden. The patient continued to do well for almost 18 months, however, later redeveloped visceral crisis and is responding to chemotherapy. Discussion: There is limited data on the management of breast cancer with bone marrow infiltration at presentation. A wide range of survival data in different case reports exists, ranging from 5 to 44 months. However, chemotherapy was used in these studies rather than CDK4/6 inhibitors. By far, cytopenias are the most concerning grade 3 and 4 side effect of Palbociclib. Data from the PALOMA-1 trial suggest that hematologic toxicities, specifically neutropenia, were different from those associated with cytotoxic chemotherapies and are more transient and reversible in nature. Studies have examined the in vitro mechanism of bone marrow suppression in Palbociclib versus cytotoxic chemotherapy, and its cytostatic effect on neutrophil precursors allows for hematological toxicities to be transient. With strong supportive care measures, patients in bone marrow visceral crisis can be safely treated with cytopenic CDK4/6 inhibitors. Citation Format: Nikita Dahake, Jordan Senchak, Jalil Nasibli, Jason Incorvati. Treatment with CDK4/6 Inhibitor in a Patient with Metastatic Breast Cancer Causing Myelophthisis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-10.

Pembrolizumab-Induced Pancytopenia: A Case Report

Introduction: Immunotherapy is increasingly acknowledged as an effective treatment for metastatic melanoma. Hematological immune-mediated adverse events are rarely reported. In this article, we report a case of a patient who developed pancytopenia following administration of pembrolizumab. Case Report: A 63 -year-old woman, followed for a scalp melanoma with pulmonary metastasis developed severe pancytopenia after receiving 4 cycles of pembrolizumab. Outcome and Management: Following the appearance of the adverse effect, Pembrolizumab was stopped. A series of blood tests were performed in order to get the reasons of this event. The patient received high-dose of corticosteroids with tapering the dose over 6 weeks, and blood transfusion was required. Discussion: Checkpoint inhibitors (ICI) stimulate both humoral and cellular immune responses against tumor antigens, potentially resulting in immune-related adverse effects, including hematological issues like pancytopenia. Due to the substantial morbidity and mortality linked to ICI-induced pancytopenia, further data is essential to formulate evidence-based management guidelines.

Efficacy and safety of flumatinib in the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase: A real-world single-center retrospective study, with a focus on premature drug discontinuation

PurposeTo assess the real-world efficacy and safety of flumatinib as first-line and post-line treatments for chronic myeloid leukemia in the chronic phase (CML-CP). ResultsAmong 141 patients receiving flumatinib as first-line and post-line treatment, the 12-month major molecular response (MMR) rates were 69.4% and 67.6%, respectively. The median time to response was 6 and 10.5 months, respectively. In post-line treatment, the early molecular response (EMR) of flumatinib as second-line is significantly superior to that of third-line treatment (3-month EMR rate: 79.2% vs. 39.3%, P<0.001; 3-month MMR rate: 45.8% vs. 21.4%, P=0.033). Contrastively, patients who switched to flumatinib due to intolerance had significantly higher MMR rates at 3, 6, and 12 months compared to patients who switched due to inadequate response (60.6% vs. 24.2%, P=0.003; 66.7% vs. 36.0%, P=0.027; 84.2% vs. 50.0%, P=0.038). Premature drug discontinuation was observed in 28.4% of the patients. Grades 3–4 hematologic adverse events (AEs) were identified as independent risk factors for premature drug discontinuation. Patients who discontinued treatment and those who previously received only imatinib therapy had a poorer molecular response and failure-free survival. ConclusionsFlumatinib demonstrates favorable efficacy and safety. Treatment discontinuation can result in a poorer molecular response and long-term prognosis.

Safety and efficacy of multiple-dose versus single-dose MIBG therapy in patients with refractory pheochromocytoma and paraganglioma: a single-center retrospective analysis.

To investigate the incidence of adverse events (AEs) following single and multiple administrations of I-131 metaiodobenzylguanidine (MIBG) therapy for inoperable pheochromocytomas and paragangliomas (PPGLs). A single-center retrospective study was conducted on patients with inoperable PPGLs who underwent I-131 MIBG therapy between January 2000 and December 2020. A total of 28 patients with available electronic medical records were included. The treatment consisted of a single intravenous administration of 150mCi (5.55GBq) of I-131 MIBG. We evaluated the first MIBG treatment and repeated MIBG treatments performed within 200days of the previous treatment. AEs for each treatment were evaluated using CTCAE version 4.0, and the statistical analysis was conducted at a significance level of p < 0.05. Objective response based on RECIST 1.1 criteria and biochemical response based on urinary catecholamines were assessed. The study included a total of 63 administrations, consisting of 28 single administrations (SAs), including the first administration for all 28 cases, and 35 multiple administrations (MAs), which included the second or later administrations. Hematological AEs were evaluable for 23 SAs and 29 MAs. Grade 3 or higher leukopenia occurred in 9.8% of all administrations, and Grade 3 or higher lymphopenia in 23.5%; both were manageable through observation. There were no significant differences in clinical AE Grades 1-2 (p = 0.32), hematological AE Grades 1-2 (p = 0.22), or hematological AE Grades 3-4 (p = 0.12) between MAs and SAs. Statistical analysis for each type of AE revealed significant increases in leukopenia (p < 0.01) and lymphopenia (p = 0.04). No significant difference in anemia, thrombocytopenia, or neutropenia was observed between MAs and SAs. There was no significant increase in the incidence rate of Grade 3 or higher hematological AEs for any of the parameters. The objective response rate was 0% for SAs and 36% for MAs. Biochemical response rates were 18% for SAs and 67% for MAs. In I-131 MIBG therapy for PPGLs, multiple administrations significantly increased only Grade 1 or 2 lymphopenia and leukopenia compared to single administration.

Chinese expert consensus on the management of clinical pathway and adverse events of trastuzumab deruxtecan (2024 edition)

Trastuzumab deruxtecan (T-DXd) is one of the new generation antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER-2) with bystander effect. T-DXd can not only significantly improve the survival of HER-2-positive advanced breast cancer patients, but also enable advanced breast cancer patients with low HER-2 expression to benefit from HER-2-targeted therapy. T-DXd has been approved by the National Medical Products Administration (NMPA) for the treatment of HER-2-positive or HER-2-low breast cancer patients. It is foreseeable that T-DXd will be widely used in clinical practice in the future. However, T-DXd has also shown different safety characteristics compared to previous HER-2 targeted drugs in clinical trials. How to manage T-DXd adverse events more reasonably and fully utilize the efficacy of T-DXd is an urgent clinical problem. Based on the existing clinical evidence and guideline consensus, combined with clinical practice experience, the expert group finally reached the consensus of clinical care pathway and adverse reaction management of trastuzumab deruxtecan after many discussions. This consensus content includes the clinical use method of T-DXd, pre-treatment patient education, and management of common or noteworthy adverse events of T-DXd. The adverse events include infusion related adverse events, digestive system adverse events (nausea/vomiting, constipation, diarrhea, and decreased appetite), hematological adverse events (neutropenia, febrile neutropenia, anemia, thrombocytopenia), respiratory adverse events (interstitial lung disease/pneumonia), cardiovascular adverse events (decreased left ventricular ejection fraction), adverse events in liver function (elevated transaminases) and other common adverse events (alopecia, fatigue, etc). This consensus focuses on the prevention of adverse events, dose adjustment and treatment when adverse events occur, and recommendations for patients' lifestyle, aiming to improve clinicians' understanding of T-DXd and provide practical guidance for clinical oncologists on T-DXd clinical management.

Abstract LB268: Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797

Abstract First-generation PARP1/2 inhibitors are approved for the treatment of cancers, such as ovarian, prostate, pancreas, and breast cancers, with maximal activity against tumors harboring BRCA1/2 mutation or homologous recombination deficiency (HRD). However, PARP1/2 inhibitors in clinical use have severe hematological toxicities due to the inhibition of PARP2, which has been shown to play an important role in the survival of hematopoietic progenitor cells. Furthermore, the current data indicate that synthetic lethality with BRCA mutations is primarily caused by PARP1 inhibition and trapping, whereas PARP2 inhibition and trapping are not critical for anticancer activity. Therefore, the development of selective PARP1 inhibitors is expected to reduce the hematological adverse effects associated with PARP2 inhibition while maintaining the required efficacy. XZP-7797 is a potent, selective, and brain-penetrating PARP1 inhibitor with trapping ability. In biochemical assays, XZP-7797 is more than 1000-fold selective for PARP1 over PARP2 and other members of the PARP family, including PARP3, PARP5a, PARP5b, and PARP6. XZP-7797 can significantly inhibit MDA-MB-436 cell proliferation in vitro (IC50=2.4nM). In MDA-MB-436 tumor cells, XZP-7797 inhibits PARylation and increases γH2AX level in a concentration-dependent manner. XZP-7797 demonstrates rapid tumor regression in a dose-dependent manner in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. In a pancreatic cancer xenograft model, XZP-7797 can also significantly inhibit tumor growth. To evaluate the ability of XZP-7797 to cross the blood-brain barrier, an intracranial xenograft model of breast cancer is used. The results show that XZP-7797 can significantly inhibit the growth of intracranial tumors in mice at a dose of 10 mg/kg, demonstrating the brain-penetrating ability of XZP-7797. Additionally, XZP-7797 has great PK profiles in preclinical species after oral dosing and good ADME properties. In a 14-day toxicology study of XZP-7797 in SD Rats, XZP-7797 has no hematological adverse effects at the exposure that is 10 times higher than the exposure required to achieve superior efficacy. Citation Format: Yeqing Gao, Yuqian Lu, Bo Chen, Benke Jiang, Feng Wang, Genyan Zhang, Xifeng Ma, Dapeng Zhou, Chunmin Shi, Yunling Wang, Zhipeng Liu, Jun Sun, Huimin Zhou, Mei Xu, Jiakui Li, Bin Liu. Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB268.

Abstract LB277: Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2)

Abstract Osimertinib (Osi) is a potent, CNS-active irreversible inhibitor of epidermal growth factor receptor-mutate (EGFRm) and T790M mutations. It is currently approved as the standard of care in patients with locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR-TKI therapy and as the first-line agent in patients with locally advanced or metastatic EGFRm NSCLC. FLAURA2 is a global, randomized, open-label, multi-center phase III clinical study to investigate the safety and efficacy of Osi 80 mg once daily in combination with platinum-pemetrexed chemotherapy compared to Osi monotherapy, as a first-line treatment in patients with locally advanced or metastatic EGFRm NSCLC. This study is ongoing and an sNDA has been submitted for approval. The objectives of this current analyses were to 1) assess the exposure-efficacy relationship between population PK model-derived Osi exposure metrics (AUCss, Cmaxss, Cminss), and PFS in patients from the investigational arm (Osi + chemotherapy arm, n=244) of FLAURA2 study and 2) assess the relationship between Osi exposure metrics and key safety endpoints. The exposure response (ER) relationship between Osi and progression free survival (PFS) in patients enrolled in the investigational arm of FLAURA2 was assessed. Kaplan Meier plots with patients stratified by quartile exposure of Osi in the investigational arm indicated no clear ER relationship, though there appears to be a trend of lower PFS with highest AUCss quartile. A stepwise Cox proportional hazard analysis indicated that the effect of Osi exposure metrics were not statistically significant associated with PFS; however, the number of pemetrexed cycles appeared to be a significant covariate on PFS. The relationship between Osi exposure metrics and AEs CTCAE Grade 3 and above causally related to Osi, as well as AESIs from the investigational arm of FLAURA2 study were explored. The graphical exploration and logistic regression analysis did not identify statistically significant relationship of Osi exposures on CTCAE ≥ Grade 3 adverse events (AEs) causally related to Osi, AEs leading to Osi dose interruptions/reductions/discontinuations, and AESIs including ≥ Grade 3 haematological AEs, cardiac effects, left ventricular ejection fraction decrease and ≥ Grade 1 interstitial lung disease causally related to Osi. In conclusions, no statistically significant relationships between exposure of Osi and response were observed, supporting the recommended dose of Osi of 80 mg daily in the FLAURA2 patient population. Overall, the recommended dose of Osi as monotherapy or in combination with chemotherapy is 80 mg once daily, with a dose reduction to 40 mg daily if unacceptable toxicity is observed. Citation Format: Jincheng Yang, Damilola Olabode, Aarti Sawant, Karthick Vishwanathan, Srinivas Bachina, Alexandar Todd, Dana Ghiorghiu, Yuri Rukazenkov, Alex Phipps, Diansong Zhou, Azar Shahraz. Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB277.

A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n=8; stage 4, n=56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.