Courses Of High-dose Chemotherapy Research Articles

КЛИНИЧЕСКОЕ ЗНАЧЕНИЕ РЕАКТИВАЦИИ ГЕРПЕСВИРУСНЫХ ИНФЕКЦИЙ У ДЕТЕЙ С ОНКОЛОГИЧЕСКИМИ ЗАБОЛЕВАНИЯМИ

Herpesvirus infection (HVI) reactivation in children with cancer is a common complication during the period of postcytostatic immunosuppression and occurs mostly after courses of high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (HSCT). Clinical manifestations can range from asymptomatic viral reactivation and chemo-induced cytopenia worsening to fatal outcomes of the disease coupled with multiorgan involvement. The purpose of the research was to analyze cases of HVI reactivation in oncological pediatric patients in order to identify the risk factors for HVI development, features of its clinical manifestations and the effectiveness of antiviral therapy. Materials and methods used: a single-center retrospective cohort study was provided. The register of HVI reactivation cases in patients receiving antitumor therapy at the V.A. Almazov National Medical Research Centre of the Ministry of Healthcare of Russia (Saint Petersburg, Russia) in Jan. 2017-Jul. 2021 was analyzed. Routine monitoring of HVI reactivation (CMV, HHV-6A/B, EBV) included determination of viral DNA in patients’ biological materials by PCR using the AmpliSens test system on a Rotor-Gene device (amplifier). Results: 40 cases of HVI reactivation were registered, 22 (55%) were associated with cytomegalovirus infection (CMV), 4 (10%) with human herpes virus 6 (HHV-6A/B), 3 (7.5%) with Epstein-Barr virus (EBV) and 11 (27.5%) mixed. DNAemia was registered in 55%, organ damage in 45%. More often, reactivation of HVI developed after allogeneic HSCT (alloHSCT) (42,5%), autologous HSCT (autoHSCT) (40%). A statistically significant decrease of HVI reactivation cases was observed in patients after alloHSCT without TCRaβ depletion (53% v. 5,5%, p=0.036). Antiviral therapy was carried out in all patients. The first-line drug most often was ganciclovir (60%). Second line antiviral therapy was required in 10% of cases and those were the only CMV infection cases. Conclusion: a statistically significant decrease of HVI reactivation cases was observed in patients without TCRaβ depletion in alloHSCT. The clinical signs usually are not specific and require routine laboratory monitoring. Adequate antiviral therapy allowed achieving infectious control over HVI in most of the cases.

High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Salvage Therapy of Relapsed/Refractory Germ Cell Tumors: A Single-Center Experience

Introduction: The optimal management of relapsed/refractory germ cell tumors remains unsettled. In this study, we aimed to evaluate the efficacy of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as salvage therapy in patients who progressed after at least one line of cisplatin-based chemotherapy. Methods: We retrospectively reported the results of 133 patients who underwent HDCT and ASCT as salvage therapy from 2016 to 2021. Patients received 3 cycles of paclitaxel, ifosfomide and cisplatin (TIP) regimen as induction and 1 cycle of carboplatin 700 mg/m2 on days 1–3 plus etoposide 750 mg/m2 on days 1–3, followed by ASCT. Demographic and clinicopathological features of patients, the International Germ Cell Cancer Collaborative Group (IGCCCG) risk group at diagnosis, serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) levels before HDCT, treatment-related complications and survival outcomes were recorded. Results: The median age of the patients was 31 (range 18–62). The median follow-up was 31.1 months (95% CI, 28.9–33.3 months). During the median follow-up period, 74 of the 133 patients were still alive, and 63 of these were in complete remission. The median progression-free survival (PFS) was 25.8 months (95% CI, 8.1–43.4 months). The 2-year PFS rate was 50.3% and the 2-year overall survival (OS) rate was 60.8%. Variables that remained statistically significant in multivariable analysis and were associated with poor prognosis were mediastinal primary tumor location, presence of brain metastases, and higher AFP and HCG levels at baseline. Conclusion: One course of HDCT and ASCT after induction with TIP is an effective and feasible treatment option for salvage treatment of relapsed/refractory germ cell tumors, with cure rates of up to 60%.

MEDB-35. Relationship between genetic profile, histology, clinical features and long-term outcome in young children medulloblastoma (YCMB) treated with upfront high dose chemotherapy (HDCT) in Italy

AIMS: We report a cohort of YCMB cases homogeneously treated with HDCT in two Italian institutions, and the prognostic impact of histology and genetics retrospectively evaluated. METHODS: All YCMB (aged≤3 years) treated with upfront HDCT in the period 1998-2019 were included, reclassified according to the WHO2021 classification of CNS tumours. Mutational status ofPTCH1, SUFU, and TP53 was analysed in selected cases. Histology and genetics were correlated with survival, secondary tumours(STs), and cancer predisposition syndromes(CPSs). RESULTS: Fifty-three patients were enrolled (62.3% male), median age 2.2 years. 21 had classic(CMB), 15 desmoplastic/nodular(DMB), 11 MBEN and 6 large-cell/anaplastic(AMB/LCMB) medulloblastoma. Metastases were present in 18. Genomic pattern showed SHH-TP53wt in 29 cases, non-WNT/non-SHH in 22; 2 were SHH-TP53mut. Induction chemotherapy (VCR/HDMTX, HDVP16, VCR/HDCTX and HDCARBO) was followed by 2-3 HDCT courses; irradiation reserved to cases with metastatic disease and/or residual tumours. 22 patients never received irradiation. SHH-TP53wt cases had significantly less metastasis (p=0.002), while non-WNT/non-SHH received more often irradiation (p<0.0001). OS at 5, 10, and 20 yrs was 0.73, 0.70 and 0.57 respectively in the entire cohort; stable at 0.85 (at 5, 10, and 20 yrs) in SHH-TP53wt patients while 0.58, 0.51 and 0.17 in the non-WNT/non-SHH. PFS at 5, 10, 20 yrs was stable at 0.89 in SHH-TP53wt and remained 0.35 in non-WNT/non-SHH. 13/53 patients presented Gorlin Syndrome; 1 had familial MB. 16 STs were reported in 14 cases; life-threatening, irradiation-related STs mainly in non-WNT/non-SHH cases. In SHH-TP53wt benign tumours or related to CPS were reported. CONCLUSIONS: This is one of the first series of YCMB treated with HDCT without stratification for stage and histology. The long follow-up highlights the frequency/types of associated CPS and STs; the latter, in non-WNT/non-SHH, were treatment-related and life-threatening.

IMG-12. Transient atypical brain and spine MRI features after high-dose chemotherapy may represent clumps of CD34+ hematopoietic stem cells

Abstract High-dose chemotherapy is a therapeutic option in selected cases of pediatric high-grade brain tumor (pHGBT). Following high-dose chemotherapy, bone marrow is reconstituted by means of CD34+ peripheral blood stem cell (PBSC) infusion. Intravenously injected PBSCs have been reported to migrate to the Central Nervous System (CNS) and to persist for weeks. We report two cases of pHGBT in which, following PBSC infusion, we observed peculiar brain MRI signal alterations suggestive of clumps of CD34+ cells. A 15-month-old female underwent surgery and chemotherapy for an infratentorial, non-disseminated, Atypical Teratoid Rhabdoid Tumor. Following the second course of high-dose chemotherapy, MRI excluded residual disease, but revealed two contrast-enhancing nodules in the supratentorial ventricular system, with no evidence of diffusion restriction, unlike the primary tumor. Cerebrospinal fluid was collected by means of lumbar puncture and centrifuged: no neoplastic cells were found, while a few cells were positive when immunostained with anti-CD34 antibody. As no disease progression was documented, the patient completed her treatment with focal radiotherapy. Three months after the end of therapy, MRI showed new enhancing nodules with restricted diffusion, in keeping with leptomeningeal spread of disease; these progressively increased in size, despite subsequent lines of treatment, while the above-mentioned ventricular nodules shrank. Similar transient alterations were detected in a 4-year-old boy who had received treatment for high-risk Medulloblastoma, including high-dose chemotherapy. CONCLUSIONS: In the setting of new enhancing brain and spine findings with atypical MRI features, after high-dose chemotherapy to treat pHGBT, the hypothesis of CNS homing of CD34+ hematopoietic stem cells should be considered in the differential diagnosis.

Salvage high-dose chemotherapy (HDCT) for relapsed primary mediastinal nonseminomatous germ-cell tumors (PMNSGCT).

5032 Background: Patients with PMNSGCT have high relapse rates after first-line therapy. Historical outcomes in this subset with standard-dose salvage chemotherapy or HDCT+bone marrow transplant (BMT) have been poor. The use of peripheral-blood stem-cell transplant (PBSCT) has allowed for more rapid engraftment and the ability to start the 2nd course 3-4 weeks after the 1st course of HDCT. We report survival outcomes of salvage HDCT+PBSCT in relapsed PMNSGCT. Methods: Between 2004-January 2021, 32 pts with relapsed PMNSGCT were treated with HDCT+PBSCTx2 utilizing our institutional regimen: carboplatin 700 mg/m2 + etoposide 750 mg/m2, for 3 consecutive days, followed by PBSCT. Median time between cycle1 day1 to cycle2 day1 was 3.2 wks (range, 2.6-4.6). Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) analysis. Results: Median age was 30. At the start of HDCT, median AFP was 192 (range, 4-17130) and hCG 1.5 (range, 0.6-15711). First-line therapy was standard germ cell tumor chemotherapy such as bleomycin-etoposide-cisplatin (BEP) or etoposide-ifosfamide-cisplatin (VIP). HDCT was 2nd line in (26, 81.3%) and 3rd line in (6, 18.8%). Eighteen (56.3%) pts had platinum-refractory disease defined as progression within 4 weeks of 1st line chemo. Twenty-three (72%) patients had extra mediastinal metastases (mets) at the start of HDCT. Metastatic sites included pulmonary (17), lymph nodes (2), liver (3), bone (2), brain (1). Median follow-up time from start of HDCT was 1 yr (range, 0.02-14.1). Twenty-six (81%) pts completed both cycles, while 6 (19%) completed only one cycle due to toxicity or progression. The estimated 2-yr PFS was 30.7 (95% CI, 15.8-46.9) and 2-yr OS was 35.2 (95% CI, 18.9-51.9). At the most recent follow-up, 9 (28%) pts were continuously no evidence of disease (NED), including 2 pts who had surgical resection of teratoma following HDCT. Median follow-up from the start of HDCT for the NED pts was 4.6 yrs (range, 1-14.1). Five of the NED pts had extra mediastinal mets, and 2 had platinum-refractory disease. Among the 9 NED pts, HDCT was 2nd line in 7 (77.8%) and 3rd line in 2 (22.2%). These results compare favorably to historical data with standard-dose chemotherapy or HDCT+BMT in relapsed primary mediastinal GCT with salvage rates &lt; 10% (Hartmann et al., JCO 19:1641-1648, 2001). Grade ≥3 toxicity, as previously described in our study (Adra et al., JCO 35:1096-1102, 2017), occurred in 8 (25%) pts. There were two treatment-related deaths. Conclusions: HDCT+PBSCT is a safe and effective salvage therapy in pts with relapsed PMNSGCT with curative potential. In our opinion, these complicated patients are best managed at tertiary centers with expertise in medical oncology, stem cell transplantation, and thoracic surgical oncology.

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

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

Long-Term Outcome and Role of Biology within Risk-Adapted Treatment Strategies: The Austrian Neuroblastoma Trial A-NB94.

Simple SummaryNeuroblastoma, the most common extracranial malignancy of childhood, shows a highly variable course of disease ranging from spontaneous regression or maturation into a benign tumor to an aggressive and intractable cancer in up to 60% of patients. To adapt treatment intensity, risk staging at diagnosis is of utmost importance. The A-NB94 trial was the first in Austria to stratify therapy intensity according to tumor staging, patient’s age, and MYCN amplification status, the latter being a biologic marker turning otherwise low-risk tumors into high-risk disease. Recent publications showed a prognostic impact of various genomic features including segmental chromosomal aberrations (SCAs). We retrospectively investigated the relevance of SCAs within this risk-adapted treatment strategy. The A-NB94 approach resulted in an excellent long-term survival for the majority of patients with acceptable long-term morbidity. An age- and stage-dependent frequency of SCAs was confirmed and SCAs should always be considered in future treatment decision making processes.We evaluated long-term outcome and genomic profiles in the Austrian Neuroblastoma Trial A-NB94 which applied a risk-adapted strategy of treatment (RAST) using stage, age and MYCN amplification (MNA) status for stratification. RAST ranged from surgery only to intensity-adjusted chemotherapy, single or multiple courses of high-dose chemotherapy (HDT) followed by autologous stem cell rescue depending on response to induction chemotherapy, and irradiation to the primary tumor site. Segmental chromosomal alterations (SCAs) were investigated retrospectively using multi- and pan-genomic techniques. The A-NB94 trial enrolled 163 patients. Patients with localized disease had an excellent ten-year (10y) event free survival (EFS) and overall survival (OS) of 99 ± 1% and 93 ± 2% whilst it was 80 ± 13% and 90 ± 9% for infants with stage 4S and for infants with stage 4 non-MNA disease both 83 ± 15%. Stage 4 patients either >12 months or ≤12 months but with MNA had a 10y-EFS and OS of 45 ± 8% and 47 ± 8%, respectively. SCAs were present in increasing frequencies according to stage and age: in 29% of localized tumors but in 92% of stage 4 tumors (p < 0.001), and in 39% of patients ≤ 12 months but in 63% of patients > 12 months (p < 0.001). RAST successfully reduced chemotherapy exposure in low- and intermediate-risk patients with excellent long-term results while the outcome of high-risk disease met contemporary trials.

Use of High-Dose Chemotherapy in Front-Line Therapy of Infants Aged Less Than 12 Months Treated for Aggressive Brain Tumors.

Introduction: Malignant brain tumors in infants less than 12 months of age are extremely rare, and they have poor prognosis. We evaluated genetic characteristics and response rates of infants with congenital brain tumors subjected to high-dose chemotherapy and autologous stem cell transplant after gross total tumor resection.Materials and Methods: In total, 10 infants, aged less than 12 months, were enrolled in this study. The median age was 56 days (range: 1–279 days). Pathological examination demonstrated the following: four anaplastic astrocytomas, two glioblastomas, two central nervous system (CNS) embryonal tumors, not otherwise specified (NOS), and two atypical teratoid/rhabdoid tumors.Results: All patients were exposed to induction chemotherapy regimen, two high-dose chemotherapy courses, and autologous stem cell transplant after maximal surgery. At 1–3–5 years, the global overall survival (OS) was 90, 70, and 70% and the progression-free survival (PFS) was 80–60 and 60%. In all the patients, the copy number variants (CNVs) profile was analyzed using the SNP/CGH array approach. To investigate the clinical relevance of germline SMARCB1 mutation in AT/RT patients, we performed sequence analysis of the coding regions. The two patients with AT/RT were found to have germline SMARCB1 mutations. No BRAF mutations were found, and only NTRK gene fusion was present in one patient. We also have examined the association with OS and PFS and different histological subtypes of infant CNS proving that high-grade astrocytoma has better overall survival than other tumor types (p: 0.007 and p: 0.0590).Conclusion: High-dose chemotherapy regimen represents a valid therapeutic approach for congenital brain tumors with a high rate of response. The molecular analysis has to be analyzed in all infants' brain tumor types. High-grade gliomas are characterized by a better prognosis than other histologies of infant CNS.

Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333.

Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.

Prognostic significance of rate of tumor marker (TM) decline during high-dose chemotherapy (HDCT) for relapsed germ cell tumors (rGCT).

403 Background: Rate of serum TM decline is prognostic in patients (pts) with GCT receiving first-line chemotherapy. We investigated the prognostic value of TM decline in rGCT treated with HDCT+peripheral-blood stem-cell transplant (PBSCT). Methods: 462 consecutive pts with rGCT treated with HDCT+PBSCT at Indiana University between 1/2004-1/2019. All pts were planned for 2 consecutive HDCT courses with carboplatin+etoposide per protocol (N Engl J Med 2007;357:340-8). Pts with elevated AFP and/or hCG were included (N=347). Slope and half-life (T1/2) were calculated for weekly AFP+hCG during HDCT starting with peak value at days 1-7 to avoid interference from lysis. T1/2 AFP≤7 days and hCG≤3 days were categorized satisfactory (SAT). Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier. Uni- and multivariable analysis using Cox regression model was performed. Results: 347 pts had elevated TM: 312 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (292), mediastinum (26), retroperitoneum/other (29). Metastatic sites included retroperitoneum (277), lung (233), liver (83), brain (77), and bone (21). At initiation of HDCT, 77 pts had elevated AFP, 222 elevated hCG, and 48 elevated both AFP+hCG. Median AFP 9 (1-21,347) and hCG 113 (1-178,140). 314 pts (91%) completed 2 planned cycles of HDCT. Overall, 46/347 pts had SAT decline (13 for AFP; 30 for hCG; 3 for both). Pts with SAT TM decline had superior outcomes compared to UNSAT: 2-yr PFS 69% vs 45% (p=0.006) and 2-yr OS 75% vs 51% (p=0.006). When evaluating each TM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 74% vs 47% (p=0.002). There was statistically non-significant difference for AFP: 2-yr PFS 48% vs 42% (p=0.65). In univariable analysis, UNSAT decline of hCG, but not AFP, was an adverse prognostic factor for PFS: HR=2.51 (95% CI, 1.40-4.51); p=0.002. Multivariable analysis will be presented. Conclusions: SAT rate of TM decline, particularly in hCG, predicts superior outcomes in rGCT undergoing HDCT+PBSCT. Pts with UNSAT TM decline are at higher risk for relapse and death.

Risk Factors for Acute Kidney Injury During High-dose Chemotherapy and Outcomes for Patients With Relapsed Germ Cell Tumors.

Patients with relapsed germ cell tumors (GCTs) can be cured with salvage chemotherapy. We evaluated the risk factors and outcomes of patients who had developed acute kidney injury (AKI) during high-dose chemotherapy (HDCT) for relapsed GCT. All patients were scheduled to receive 2 consecutive courses of HDCT per our standard protocol. The characteristics and outcomes of the patients with stage≥ 3 AKI were analyzed and compared with those without stage≥ 3 AKI. Of 462 patients, 21 (4.5%) developed stage≥ 3 AKI. Of these 21 patients, 18 had required hemodialysis during HDCT and 6 had died during HDCT. Of the 15 patients who had survived HDCT, 10 experienced recovery of renal function to baseline. AKI had occurred in the first cycle of HDCT in 18 patients. These patients were also more likely to have received HDCT in a third-line setting or further, to have Eastern Cooperative Oncology Group performance status of 1 or 2, and to have experienced gastrointestinal, hepatic, pulmonary, and infectious grade≥ 3 toxicities. At a median follow-up of 10 months after HDCT, 5 patients had no evidence of disease, 3 were alive with disease, 6 had died of disease, 6 had died of complications from HDCT, and 1 had been lost to follow-up. Irreversible AKI during HDCT for relapsed GCT is uncommon but is associated with greater rates of infectious, gastrointestinal, hepatic, and pulmonary complications and treatment-related death. These patients were also more heavily pretreated and had a lower baseline performance status. However, most surviving patients had recovered their renal function and 5 of 21 were alive with no evidence of disease.

High-dose chemotherapy plus peripheral blood stem cell transplantation for patients with relapsed germ cell tumors and active brain metastases.

The optimal management of progressive brain metastases in patients with germ cell tumors (GCTs) remains unsettled. This study reports the management of 25 consecutive patients with relapsed GCTs and progressive brain metastases undergoing high-dose chemotherapy (HDCT) with peripheral blood stem cell transplantation (PBSCT) at Indiana University from 2006 to 2016. All patients were planned to undergo HDCT, which consisted of carboplatin at 700mg/m2 on days 1 to 3 plus etoposide at 750mg/m2 on days 1 to 3, followed by PBSCT on day 5 for 2 cycles. Patients were treated with brain metastectomy, stereotactic radiotherapy or whole-brain radiotherapy, HDCT alone, or a combination thereof. All 25 patients had progressive brain metastases at the time of initiating HDCT. Patient and disease characteristics, management of brain metastases, and outcomes were measured. Platelet transfusions were given to maintain platelet counts > 30,000/µL; the goal was >50,000/µL when there were signs of prior or active hemorrhaging. Twenty-two of 25 patients completed both courses of HDCT. The median α-fetoprotein level was 7.5ng/mL (range, 1.6-1130ng/mL), and the human chorionic gonadotropin level was 31.3IU/mL (range, 0.5-25,601IU/mL). At a median follow-up of 24.5months (range, 0.4-117months), 11 patients (44%) were alive with no evidence of disease, 2 patients were alive with relapsed disease, and 12 patients had died of disease progression or complications from HDCT. Fifteen patients developed progressive brain metastases despite radiation and/or craniotomy before HDCT, and 8 of these patients were alive without evidence of disease. There were no intracranial hemorrhagic events leading to death. Patients with relapsed GCTs and progressive brain metastases are curable with multimodality therapy that includes HDCT and peripheral blood stem cell transplantation.

Risk factors for renal failure (RF) during high-dose chemotherapy (HDCT) and outcomes for patients (pts) with relapsed germ-cell tumors (rGCT).

e16042 Background: Pts with rGCT can be cured with salvage chemotherapy (CT). We evaluated risk factors and outcomes of pts who developed RF during HDCT for rGCT. Methods: All pts were planned to receive 2 consecutive courses of HDCT per protocol (N Engl J Med 2007;357:340-8). Characteristics and outcomes of pts sustaining grade ≥3 RF were analyzed and compared with those not sustaining grade ≥3 RF. Results: 21 (4%) of 473 pts had grade ≥3 RF: median age 38 (range 25-70), median creatinine 1.2 (0.6-1.8), median creatinine clearance (CrCl) 94 (48-216), median body mass index 27.1 (19.9-34.2). Median # prior standard-dose cisplatin-based CT cycles 5 (4-8) and median total dose of cisplatin 1000mg (600-1976). 10/21 pts had history of renal disease prior to HDCT, 4 had hypertension, 2 had diabetes, 2 had solitary kidney and 5 had stent or nephrostomy tube for obstruction. 20/21 pts developed neutropenic fever. 5 required total parenteral nutrition and 18 required hemodialysis (HD) during HDCT. 6 of 21 died during HDCT. 10 of 15 pts who survived HDCT had renal function recover to baseline, 2 came off HD but renal function was not restored to baseline, and 3 continued to be on HD at most recent f/u. In comparison to pts (n = 452) who did not experience grade ≥3 RF, pts (n = 21) who did experience grade ≥3 RF were more likely treated with HDCT ≥ 3rd line setting (38% vs 15%), had ECOG PS 1/2 (53% vs 18%), less likely to receive both courses of HDCT (33% vs 94%), more likely to experience GI (62% vs 11%), hepatic (43% vs 3%), pulmonary (38% vs 2%), and infectious (95% vs 1%) grade ≥ 3 toxicities; treatment-related death was also higher in this group (29% vs 2%). With a median f/u of 10 months after HDCT, 5 pts had no evidence of disease (NED), 3 were alive with disease, 6 died of disease, 6 died from complications of HDCT, and 1 lost to follow up. Conclusions: Irreversible RF during HDCT for rGCT is uncommon, but is associated with higher rates of infectious, GI, hepatic, pulmonary complications and treatment-related death. These pts are more heavily pre-treated, have lower baseline PS, and are likely to have history of renal disease prior to HDCT. However, most surviving pts recovered their renal function and 5/21 remain alive with NED.

Prognostic value of serum tumor marker (STM) rate of decline during high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) for relapsed germ-cell tumors (rGCT).

e16044 Background: Rate of STM decline is prognostic in patients (pts) with metastatic GCT receiving first-line chemotherapy. We investigated the prognostic value of STM decline in pts with rGCT treated with HDCT and PBSCT. Methods: 444 consecutive pts with rGCT were treated with HDCT and PBSCT at Indiana University between 2004-2018. All pts were planned for 2 consecutive HDCT courses. Pts with elevated STM (AFP &gt; 25 and/or hCG &gt; 4.9) were included in this analysis. Slope and half-life (T1/2) were calculated for weekly AFP and hCG values during HDCT starting with peak value during days 1-7 to avoid interference from lysis. T1/2 AFP≤7 days and hCG≤3 days were categorized as satisfactory (SAT); normalization within 7 days was also considered SAT regardless of T1/2. Pts with elevated AFP and hCG must have adequate decline in both to be SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier methods. Results: 2-yr PFS for pts with elevated STM at initiation of HDCT (N = 335) was inferior to pts with normal STM (N = 109) [49% vs. 89%; p &lt; 0.001]. Among the 335 pts with elevated STM, 300 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (285), mediastinum (25), and retroperitoneum/other (25). Metastatic sites included retroperitoneum (267), lung (226), liver (81), brain (76), and bone (21). At initiation of HDCT, 73 pts had elevated AFP only, 215 had elevated hCG only, and 47 had elevated both AFP and hCG. Median AFP 9 (1-21,347) and hCG 115 (1-178,140). 307 pts (92%) completed 2 planned cycles of HDCT. Overall, 45/335 pts had SAT decline (13 for AFP; 29 for hCG; 3 for both). Pts with SAT STM decline had superior outcomes compared to UNSAT: 2-yr PFS 71% vs 46% (p = 0.004) and 2-yr OS 77% vs 52% (p = 0.004). When evaluating each STM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 76% vs 47% (p = 0.002). There was statistically non-significant difference in outcomes for AFP: 2-yr PFS 50% vs 43% (p = 0.55). Conclusions: SAT rate of STM decline predicts superior outcomes in pts with rGCT undergoing HDCT and PBSCT. Although UNSAT STM decline does not preclude long-term remissions, these pts are at higher risk of relapse and death.

Abstract P1-17-08: High-dose chemotherapy and immunotherapy in premenopausal breast cancer patients with more than 10 axillary nodes (PBC+10N). Long-term follow-up of a phase II study

Abstract Background: PBC+10N have a high risk of relapse. Experimental studies suggest that high expression of vascular endothelial growth factor (VEGF) promotes tumor progression through neoangiogenesis and that natural killer (NK) cells mediate lytic activity against cancer cell lines. In a phase I-II study, we have shown that low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) increased NK cells and decreased VEGF, in patients with advanced cancer and a clinical benefit from chemotherapy (Clin Cancer Res 7: 1251, 2001). We assumed that IL-2 and RA, increasing NK and decreasing VEGF, could improve disease-free survival (DFS) and overall survival (OS) in PBC+10N. Primary endpoint was the evaluation of NK cells and VEGF; secondary endpoints were DFS, OS and toxicity. Methods: 34 patients with PBC+10N, after high-dose chemotherapy and peripheral blood progenitor cell transplantation were entered into the study. They were given hormonal therapy if needed and subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week, 3 weeks/month, until progression. NK cells, VEGF, response and toxicity were assessed every 4 months. Results: After a median follow-up of 120 months (range 69-209), a total of 41 courses of high-dose chemotherapy and 60 courses of immunotherapy were delivered. A statistically significant improvement of NK cells [from a mean of 302 ± 75/mm3 to a mean of 582 ± 72/mm3 (p &amp;lt; 0.001)] and a decrease of VEGF [from a mean of 525 ± 68 pg/mm3 to a mean of 155 ± 13 pg/mm3, (p &amp;lt; 0.001)], were observed. 18-years DFS and OS were 29% and 32%, respectively. A significant improvement, with respect to NCI SEER data (*), was observed in the 5-year OS rate: 55% vs. 6% No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: Our data show that immunotherapy with IL-2/RA, may determine, with an acceptable toxicity profile, a statistically significant improvement of NK cells, a decrease of VEGF, and better 5-year survival rates with respect to NCI SEER data. Citation Format: Recchia F, Candeloro G, Rea S. High-dose chemotherapy and immunotherapy in premenopausal breast cancer patients with more than 10 axillary nodes (PBC+10N). Long-term follow-up of a phase II study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-08.

High Dose Thiotepa with Autologous Stem Cell Transplantation in Children over 3 Years with High-Risk Medulloblastoma: Retrospective Cohort Study

Background. Despite current treatment regimens prognosis for high-risk medulloblastoma (MB) is still unfavorable. High dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) may improve results.Objective. Our aim was to evaluate the outcomes in children over 3 years with high-risk MB who underwent high dose chemotherapy with thiotepa and ASCT.Methods. We investigated the therapy results in 23 children older than 3 years who received treatment at Russian Cancer Research Centre (Moscow) between January 2013 and December 2017. At consolidation stage they received tandem thiotepa at a dose 300 mg/m2 days -4, -3 and carboplatin at a dose 510 mg/m2 days -4, -3 followed by ASCT. 3 patients failed to undergo the second HDCT course for severe toxic complications.Results. As a result of treatment, 14 patients (60.9%) achieved complete remission, 9 patients (39.2%) had partial response. Treatment mortality rate was 8.6%. The level of 4-year survival was achieved: event-free survival (EFS), overall survival (OS), and disease free survival (DFS) rates were 59%±14%, 68.9%±12.3%, and 69.2%±15.6%, respectively. The worst results were registered in patients with metastatic tumor: 4-year EFS was 64.3%±12% versus patients with M0 stage - 80%±8.9%. Conclusion: Presented intensive treatment with moderate toxicity improves outcomes in poor prognosis patients over 3 years.

THE EFFICACY OF HIGH-DOSE CONSOLIDATION AND AUTOLOGOUS BONE MARROW TRANSPLANTATION IN FIRST REMISSION OF ACUTE MYELOID LEUKEMIA

Introduction. The question of the most adequate treatment strategy of AML in cases when it is impossible to perform allogeneic HSCT because of any reason still remains open. The aim of this study was to assess the long-term survival of patients with AML who received chemotherapy (CT) or autologous HSCT as consolidation in the first remission of the disease. It was included 135 patients aged 18 to 67 years, with a verified diagnosis of AML (except FAB M3) in the study. Of these, 100 patients received only CT, 35 patients received consolidation with autologous bone marrow transplantation. Patients who achieved remission after completion of induction CT courses received one of three treatment options as consolidation: 1) chemotherapy of standard-intensity (sCT), 2) high-dose chemotherapy (HDCT), 3) autologous HSCT (autoHSCT) conducted after 1–2 courses of high-dose CT. Adverse prognostic factors were identified as: age over 40 years, hyperleucocytosis more than 50,0 × 10 9/L and unfavorable cytogenetic and molecular-biological risk group. Materials and methods. Depending on the number of prognostic factors at the onset of disease relapse-free survival (RFS) was 47 % in their absence, 45 % in the presence of 1 factor, in the presence of 2 factors – 14 % (p = 0,000), regardless of the variant of consolidation therapy (sCT, HDCT, autoHSCT). A high level of white blood cells adversely affects OS (38 % vs. 22 %) and increases the frequency of relapse (52 % vs. 69 %) when performing only CT (sCT and HDCT). At initial white blood cells level more than 50,0 × 10 9/L the 5-year OS was 60 % when performing both autoHSCT and HDCT. Performance of autoHSCT at failure to achieve remission after the 1st induction course CT is associated with the best 2-year OS (62 % vs. 35 %, p = 0,05), EFS (50 % vs. 22 %, p = 0,05) and RFS (50 % vs. 37 %, p = 0,05) in comparison with HDCT and sCT. In favorable cytogenetic risk group 5-year RFS was 80 % when performing autoHSCT and 67 % when performing HDCT; the 5-year OS was 80 % regardless of consolidation therapy option. Conclusion. AutoHSCT is the preferred consolidation option in favorable risk group patients, and after failure to achieve remission after the 1st CT course.

Administration of high-dose chemotherapy (HDCT) with stem-cell support in patients (pts) with advanced germ cell tumors (GCT) 40 years of age or older: A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.

415 Background: The administration of HDCT in GCT pts ≥ 40 years may raise concerns, owing to the limited data on safety outcomes. Yet HDCT strategy may be the optimal one to achieve a cure in many cases. Consequently, understanding more on the outcomes of these pts and on safety of HDCT delivery has relevant clinical impact. Methods: Criteria for patient selection consisted of: GCT diagnosis, male gender, age ≥ 40 at the time of first HDCT course. Summary statistics were used to describe patient characteristics and outcomes. Probabilities for overall survival (OS) and transplant-related mortality (TRM) were calculated using the Kaplan-Meier method. TRM was defined as mortality from any cause other than disease progression within 100 days of HDCT. Results: From 11/1981 to 12/2015, 1,179 pts aged ≥ 40 have been registered, from 236 centers, in the EBMT database after having received single (n = 578) or multiple (n = 601) HDCT courses. Age distribution was: 917 pts 40-49, 236 pts 50-59, 26 pts 60-71. 56 had extragonadal GCT. Bone marrow was used as stem cell source in 85 pts (7.2%). Median follow-up was 38.6 months. Overall 74 TR deaths were found. Significant decrease of TRM was observed during the decades: 1981-1990 (8.3%), 1991-2000 (6.8%), 2001-2015 (4,1%, p = 0.024). Focusing on 2001-2015 period, no differences were found according to age: 40-49y (n = 673): 4.7%, 50-59y (n = 174): 1.8%, 60-71y (n = 23): 4,3% (p = 0.419). TRM for HD-carboplatin-etoposide regimen only (all pts &gt; 1990) was as follows: 40-49y (n = 289): 2.9%, 50-71y (n = 90): 1.1% (p = 0.713). 2-y OS was consistent across all age subgroups. Causes of death were: infection/sepsis (46/74, 62.2%), organ failure (11/74, 14.9%), and cardiac toxicity (8/10.8%), other (9 pts). The retrospective nature of the data is a major limitation. Conclusions: The administration of HD-carboplatin-etoposide in GCT pts ≥ 40 and ≥ 50 years is feasible and is supported by adequate safety data. Collecting additional information on non-severe long-term sequelae is needed. These results may add important information to improve patient counselling.

High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience.

Purpose Patients with relapsed metastatic germ cell tumor (GCT) can be cured with second-line and even third-line regimens. We report survival outcomes of patients treated with high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplantation (PBSCT) at Indiana University between 2004 and 2014. Patients and Methods We conducted a retrospective analysis of 364 consecutive patients with GCT who progressed after cisplatin-based combination chemotherapy and were subsequently treated with HDCT and PBSCT. Three hundred forty-one patients received two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. Twenty-three patients received only a single course of HDCT because of progressive disease or toxicity. Cox proportional hazards models were used to test predictors of disease progression. Results The median age was 32 years (range, 17 to 70 years). With a median follow-up of 3.3 years, the 2-year progression-free survival (PFS) was 60% (95% CI, 55% to 65%) and the 2-year overall survival was 66% (95% CI, 60% to 70%). Three hundred three patients received HDCT as second-line therapy with a 2-year PFS of 63% (95% CI, 57% to 68%), and 61 patients received HDCT as third-line or later therapy with a 2-year PFS of 49% (95% CI, 36% to 61%). In a multivariable analysis, factors associated with disease progression included use of HDCT as third-line or later therapy, platinum-refractory disease, mediastinal primary tumor site, nonseminoma histology, intermediate- or poor-risk disease at the time of GCT diagnosis, and human chorionic gonadotropin ≥ 1,000 mIU/mL at initiation of HDCT. There were nine treatment-related deaths. Secondary leukemia developed in five patients. Conclusion This large single-institution study demonstrates that patients with relapsed metastatic GCT are curable by HDCT plus PBSCT even when used in third-line or later therapy.