Conventional-dose Chemotherapy Research Articles

Virus-mimicking nanodrug active crossing of the blood-brain barrier via transcytosis against central nervous system leukemia

The poor central nervous system leukemia (CNSL) clinical efficacy of conventional doses of chemotherapy is mainly attributed to the limited permeability of chemotherapy agents caused by the blood-brain barrier (BBB). Effectively enhancing the accumulation of drugs across the BBB in the central nervous system is one of the key challenges in improving patient compliance and clinical efficacy of CNSL. Here, we find that the VP1 protein, the functional module of the John Cunningham (JC) virus, can safely penetrate the BBB through a sialic acid receptor-mediated transcytosis mechanism. Based on this, we develop a JC virus-mimicking nanodrug delivery platform based on VP1 protein-conjugated self-assembled nanoparticles (MFHV), which can active target and cross the BBB via a receptor-mediated transcytosis for safe and effective low-dose chemotherapy against CNSL after systemic administration. The results demonstrate that such a platform can penetrate the BBB through the dual mechanism of clathrin-mediated endocytosis and micropinocytosis pathway. When further synergistic with ferroptosis and histamine metabolism, the long-term survivors of low-dose MTX are significantly enhanced by 83.3 % and 56.7 % in two CNSL mice models. Collectively, this study takes a new perspective on natural living materials and molecule targeting of the BBB to present a promising strategy for low-dose chemotherapy against CNSL with safety and efficacy, which might provide a clinically translatable option for the prevention and treatment of CNSL.

Intensified alkylating chemotherapy for patients with oligometastatic breast cancer harboring homologous recombination deficiency: Primary outcomes from the randomized phase III OLIGO study

BackgroundOligometastatic breast cancer (OMBC) is a clinical entity with a prospect of long-term survival, but uncertainty remains on its optimal treatment. We studied whether intensified alkylating chemotherapy (IACT) improves long-term outcome compared to conventional-dose chemotherapy (CDCT) as part of a multimodality approach for patients with OMBC harboring homologous recombination deficiency (HRD). Patients and methodsEligible patients had HER2-negative OMBC, harboring HRD, with ≤ 3 distant metastases, pathologic proof of distant disease and a favorable response to three cycles CDCT. Participants were randomized 1:1 to continue with either CDCT or IACT. IACT consisted of one mobilization course followed by two cycles of mini-CTC (carboplatin, thiotepa and cyclophosphamide) supported by peripheral blood progenitor cell reinfusion. Primary outcome was event-free survival (EFS). Secondary endpoints included overall survival (OS), quality of life and safety. ResultsSeventy-five patients were randomized to either IACT (n = 36) or CDCT (n = 39). Twenty-three (31 %) patients had hormone receptor-positive disease and 52 (69 %) had triple-negative disease. Median EFS in the IACT-group was 28 months (95 % confidence interval [CI] 21-not reached [NR]) versus 25 months (95 %CI 14-NR) in the CDCT-group (hazard ratio [HR] for recurrence or death 0.78, 95 %CI 0.42–1.42). Median OS was 67 months (95 %CI 37-NR) in the IACT-group and 36 (95 %CI 26-NR) in the CDCT-group (HR 0.74, 95 %CI 0.37–1.48). ConclusionsThe entire study population experienced long-term survival, with median OS well over five years. IACT compared to CDCT did not improve outcome in patients with OMBC harboring study-defined HRD. The optimal therapy for patients with OMBC requires further study. Trial RegistrationClinicalTrials.gov: NCT01646034

SEOM-GG clinical guidelines for the management of germ-cell testicular cancer (2023)

Testicular germ cell tumors are the most common tumors in adolescent and young men. They are curable malignancies that should be treated with curative intent, minimizing acute and long-term side effects. Inguinal orchiectomy is the main diagnostic procedure, and is also curative for most localized tumors, while patients with unfavorable risk factors for recurrence, or those who are unable or unwilling to undergo close follow-up, may require adjuvant treatment. Patients with persistent markers after orchiectomy or advanced disease at diagnosis should be staged and classified according to the IGCCCG prognostic classification. BEP is the most recommended chemotherapy, but other schedules such as EP or VIP may be used to avoid bleomycin in some patients. Efforts should be made to avoid unnecessary delays and dose reductions wherever possible. Insufficient marker decline after each cycle is associated with poor prognosis. Management of residual masses after chemotherapy differs between patients with seminoma and non-seminoma tumors. Patients at high risk of relapse, those with refractory tumors, or those who relapse after chemotherapy should be managed by multidisciplinary teams in experienced centers. Salvage treatment for these patients includes conventional-dose chemotherapy (TIP) and/or high-dose chemotherapy, although the best regimen and strategy for each subgroup of patients is not yet well established. In late recurrences, early complete surgical resection should be performed when feasible. Given the high cure rate of TGCT, oncologists should work with patients to prevent and identify potential long-term side effects of the treatment. The above recommendations also apply to extragonadal retroperitoneal and mediastinal tumors.

Biomarkers for Salvage Therapy in Testicular Germ Cell Tumors

The outcome of metastatic testicular germ cell tumor patients has been dramatically improved by cisplatin-based chemotherapy combinations. However, up to 30% of patients with advanced disease relapse after first-line therapy and require salvage regimens, which include treatments with conventional-dose chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. For these patients, prognosis estimation represents an essential step in the choice of medical treatment but still remains a complex challenge. The available histological, clinical, and biochemical parameters attempt to define the prognosis, but they do not reflect the tumor’s molecular and pathological features and do not predict who will exhibit resistance to the several treatments. Molecular selection of patients and validated biomarkers are highly needed in order to improve current risk stratification and identify novel therapeutic approaches for patients with recurrent disease. Biomolecular biomarkers, including microRNAs, gene expression profiles, and immune-related biomarkers are currently under investigation in testicular germ cell tumors and could potentially hold a prominent place in the future treatment selection and prognostication of these tumors. The aim of this review is to summarize current scientific data regarding prognostic and predictive biomarkers for salvage therapy in testicular germ cell tumors.

The Use of Salvage Chemotherapy for Patients with Relapsed Testicular Germ Cell Tumor (GCT) in Canada: A National Survey.

Although metastatic germ cell tumor (GCT) is highly curable with initial cisplatin-based chemotherapy (CT), 20-30% of patients relapse. Salvage CT options include conventional (CDCT) and high dose chemotherapy (HDCT), however definitive comparative data remain lacking. We aimed to characterize the contemporary practice patterns of salvage CT across Canada. We conducted a 30-question online survey for Canadian medical and hematological oncologists with experience in treating GCT, assessing treatment availability, patient selection, and management strategies used for relapsed GCT patients. There were 30 respondents from 18 cancer centers across eight provinces. The most common CDCT regimens used were TIP (64%) and VIP (25%). HDCT was available in 13 centers (70%). The HDCT regimen used included carboplatin and etoposide for two cycles (76% in 7 centers), three cycles (6% in 2 centers), and the TICE protocol (11%, in 2 centers). "Bridging" CDCT was used by 65% of respondents. Post-HDCT treatments considered include surgical resection for residual disease (87.5%), maintenance etoposide (6.3%), and surveillance only (6.3%). HDCT is the most commonly used GCT salvage strategy in Canada. Significant differences exist in the treatment availability, selection, and delivery of HDCT, highlighting the need for standardization of care for patients with relapsed testicular GCT.

High dose alkylating chemotherapy for patients with oligometastatic breast cancer harboring homologous recombination deficiency: Results from the randomized phase 3 OLIGO study.

1097 Background: Oligometastatic breast cancer (OMBC) is a clinical entity with favorable prognosis compared to MBC in general, but the optimal treatment for individual patients remains unclear. We compared high dose chemotherapy (HDCT) to conventional dose chemotherapy (CDCT) in patients receiving local ablative therapy (LAT) of all disease sites in HER2-negative OMBC that harbors homologous recombination deficiency (HRD). Methods: In this open-label phase 3 study, we randomly assigned patients with OMBC after 3 cycles of induction CDCT to either continue with CDCT (up to a maximum total of 8 cycles) or switch to HDCT. OMBC was defined as 1-3 distant metastatic lesions, with or without locoregional disease, all amenable to LAT. Main eligibility criteria included pathologic proof of a distant metastatic lesion, HRD (based on either germline BRCA1/2 mutation and/or a BRCA-like profile in the tumor), and a favorable response to induction CDCT. The primary endpoint was event-free survival (EFS), defined as time since randomization to recurrence or death. Overall survival (OS), safety and quality of life (QoL) were key secondary endpoints. Following the advice of the independent data monitoring committee, analyses were performed before the prespecified number of events was reached. Results: Between November 2012 and May 2022, 36 patients were allocated to HDCT and 39 to CDCT. 52 (69%) tumors were triple negative and 23 (31%) were hormone receptor positive; 39 patients (52%) had a solitary metastasis and 43 (57%) had synchronous OMBC. After a median follow-up of 52 months (interquartile range 28-97), 42 EFS-events had occurred. Median EFS in the HDCT-group was 28 months (95% CI 21 – not reached (NR)) compared to 25 months (95% CI 14 – NR) in the CDCT-group (hazard ratio (HR) 0.78 (95% CI 0.42 – 1.42, p = 0.411). Median OS was 67 months (95% CI 37 – NR) in the HDCT-group versus 36 months (95% CI 26 – NR) in the CDCT-group (HR 0.74, 95% CI 0.37 – 1.48, p = 0.398). 5-year EFS was 40% and 30%, and 5-year OS was 51% and 49% in the HDCT- and CDCT-group, respectively. 34 (94%) patients in the HDCT-group experienced grade 3 or higher adverse events, compared to 25 (64%) patients in the CDCT-group; no grade 5 adverse events occurred. QoL was comparable between groups at 12 months. Conclusions: HDCT does not improve outcome compared to CDCT in patients with OMBC harboring HRD and can therefore not be recommended. Survival in this highly selected group of patients with OMBC, all receiving LAT, compares favorably to survival in the overall MBC population. The optimal systemic therapy for patients with OMBC requires further study. Clinical trial information: NCT01646034 .

High-dose chemotherapy with autologous stem cell transplantation for patients with extracranial germ cell tumors – experience of two Brazilian pediatric centers

Malignant extracranial germ cell tumors (GCTs) are rare in pediatric patients and are usually extremely sensitive to chemotherapy. Relapsed or refractory tumors, although rare, established the need for second-line therapies, including high-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT). However, there are few data on its use in children with GCTs. We present a retrospective analysis of all patients diagnosed with extracranial GCTs who received HDCT/ASCT at two Brazilian pediatric cancer centers from May 1999 to December 2019. We identified a total of 34 patients with a median age at diagnosis of 2.8 years (range, 0 to 18.8), who received HDCT/ASCT. Most patients (73%) received carboplatin, etoposide and melphalan (CEM) as a HDCT regimen. Fourteen patients received a second-line conventional dose chemotherapy (CDCT), 14 received a third-line CDCT and five received even a fourth-line CDCT prior to HDCT/ASCT. After a median follow-up of 22.7 months (range, 0.3 to 198.1), 16 patients had died after tumor relapse/progression and 2 patients died from HDCT/ASCT toxicity. We observed a 5-year OS of 47.1% and 5-year EFS of 44.1%. The 5-year OS for patients referred for HDCT/ASCT with progressive disease was 10% compared to 62.5% for those who achieved disease control before HDCT/ASCT (p = 0.001). In our experience, heavily pretreated children and adolescents with extracranial GCTs achieved considerable survival rates with HDCT/ASCT since, at least, partial control of their disease was possible before starting HDCT/ASCT. The role of HDCT/ASCT in pediatric patients with GCTs should be investigated in prospective trials.

High-dose chemotherapy with autologous stem cell transplant (HDCT) for patients (pts) with advanced germ-cell tumors (aGCT): Real-world evidence from a tertiary cancer center in Brazil.

414 Background: HDCT is a potentially curative treatment for pts with aGCT after conventional-dose chemotherapy (CDC). There is scarce evidence of outcomes from aGCT pts treated with HDCT in low and middle-income countries. Methods: We reviewed our institutional database to identify pts with progressive aGCT referred for HDCT following tumor boards. Medical charts were analyzed to extract clinical data. Log-rank was used to compare survival estimates and Cox proportional hazard to determine effects on overall survival (OS). Exploratory correlation and survival trend analysis used synthetic minority oversampling and Spearman’s rho estimated correlations. Results: From 1/2013 to 8/2022, 35 aGCT pts were referred for HDCT. Median age was 28 years (IQR 25-30). Most pts had testicular primary (84%), non-seminoma histology (87%), 1 prior treatment line (62%), poor-risk by IGCCCG (78%), and intermediate to very high-risk by IPFSG (45%). Of these, 32 pts were deemed eligible after initial evaluation, 25 had mobilization chemotherapy, and 21 received ≥1 cycle of HDCT. Reasons for treatment non-fulfillment included progressive disease and/or performance deterioration due to toxicity. HDCT regimen varied, with most pts receiving TI-CE (62%). Most pts had delays ≥1 month (85%) and ≥2 months (52%) in the scheduled treatment. The 1-year and 2-year OS rates were 42% and 38% in the eligible population, while 70% and 62% among those who had ≥ 1 cycle HDCT. No risk factors correlated with OS in the univariate analysis (Table). Exploratory analysis of oversampled pts treated with ≥1 cycle of HDCT showed correlation of poor IGCCCG (p<0.01) and IPFSG (p=0.03) with OS. Time to mobilization (TTM) was larger in poor-risk IGCCCG pts (0.4 vs. 1.7 months, p<0.01). Four deaths were attributed to HDCT. Conclusions: HDCT was feasible at our tertiary center in Brazil, despite some treatment-related deaths. For pts who had at least 1 HDCT cycle, survival outcomes were similar to the established literature. Significant delays in protocol were noted and correlated with prognostic group risk. [Table: see text]

A case report of desmoid tumor involving the head and neck region: challenges in diagnosis and treatment

Desmoid tumor, or aggressive fibromatosis, is a rare condition affecting young adults. Diagnosis is challenging asit has to be established histopathologically by experienced oncopathological experts. Treatment options includesurgery, radiation, and other forms of noninvasive modalities like hormonal therapy, low-dose and conventional-dose chemotherapy, non-steroidal anti-inflammatory drugs, tyrosine kinase inhibitors, etc. Each treatment modalityhas its own advantages and disadvantages. Also, there is a lack of clear guidelines for the management of suchtumors, so the treatment-related decisions also become more challenging. Here, we are presenting such a casethat was successfully treated using radiation alone with minimal side effects and achieved a good outcome interms of tumor control, functional preservation, and cosmesis. Hopefully, it will help the medical community indeciding the treatment options and acting as a base for future studies.

A case report of desmoid tumor involving the head and neck region: challenges in diagnosis and treatment

Desmoid tumor, or aggressive fibromatosis, is a rare condition affecting young adults. Diagnosis is challenging as it has to be established histopathologically by experienced oncopathological experts. Treatment options include surgery, radiation, and other forms of noninvasive modalities like hormonal therapy, low-dose and conventionaldose chemotherapy, non-steroidal anti-inflammatory drugs, tyrosine kinase inhibitors, etc. Each treatment modality has its own advantages and disadvantages. Also, there is a lack of clear guidelines for the management of such tumors, so the treatment-related decisions also become more challenging. Here, we are presenting such a case that was successfully treated using radiation alone with minimal side effects and achieved a good outcome in terms of tumor control, functional preservation, and cosmesis. Hopefully, it will help the medical community in deciding the treatment options and acting as a base for future studies.

High-dose chemotherapy for relapsed testicular germ cell tumours.

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

High Efficacy of the PARP Inhibitor Olaparib Combined with High-Dose Chemotherapy and Autologous Stem-Cell Transplant for Refractory Lymphomas

More active HDC are needed for ASCT for refractory/poor-risk relapsed lymphomas. Enhancement of the activity of HDC through combination with DNA damage repair (DDR) inhibitors is a promising but unexplored avenue. The enzyme poly(ADP-ribose) polymerase (PARP) catalyzes PARylation at the DNA damage site, which initiates DDR. Olaparib, the first FDA-approved PARP inhibitor for use in selected solid tumors, has shown synergy with conventional-dose chemotherapy, albeit with increased myelotoxicity. We studied in vitro the interaction of olaparib, epigenetically potentiated with the histone deacetylase (HDAC) inhibitor vorinostat, with a combination of gemcitabine/busulfan/melphalan (GemBuMel), which we had developed previously. We observed a markedly increased cytotoxicity of vorinostat/GemBuMel when combined with olaparib in refractory B- and T-cell lymphoma lines (Valdez et al., Leuk Lymphoma 2017;58:2705-16). Our preclinical work led us to design and clinically study olaparib plus vorinostat/GemBuMel with ASCT in refractory lymphomas. PATIENTS AND METHODS: Patients ages 15-65 with refractory lymphomas and adequate end-organ function were eligible for this phase I trial (NCT03259503). Olaparib was given from day -11 to -3, at 7 dose levels (DL1-DL7), ranging from 25 to 300 mg PO twice daily. Vorinostat was given at 1,000 mg PO daily (days -10 to -3). Gemcitabine was administered at 2,475 mg/m2/day IV (days -8 and -3), infused as a loading dose of 75 mg/m2 followed by continuous infusion at 10 mg/m2/min over 4 hours. Busulfan dosing targeted 4,000 μM.min-1/day IV (days -8 to -5). Melphalan was infused at 60 mg/m2/day IV (days -3 and -2). Patients with CD20+ tumors received rituximab (375 mg/m2) IV on day -10. ASCT was on day 0. The trial goals were to identify the recommended phase 2 dose (RP2D) of olaparib, and estimate the overall (ORR), and complete response (CR) rates, event-free (EFS) and overall survival (OS) rates of the regimen. RESULTS: Between 10/19 and 06/22 we enrolled 30 patients: 18 Hodgkin, 6 DLBCL and 6 T-NHL, median age 34 (20-61), median prior lines of therapy 3 (range, 2-7), 8 prior CAR-T or other cellular immunotherapies. Eleven patients had PET+ tumors at HDC (3 of them in PD). An olaparib dose of 150 mg PO BID (DL4) was identified as the RP2D. There was 1 TRM (sepsis) at DL5. The toxicity profile was similar to that of vorinostat/GemBuMel without olaparib and included mucositis (17 grade 3, 11 grade 2), asymptomatic elevation of transaminases (10 grade 3, 7 grade 2), hyperbilirubinemia (7 grade 3, 2 grade 2, with no cases of VOD/SOS), colitis (2 grade 3, 3 grade 2), diarrhea (3 grade 3, 3 grade 2), and asymptomatic bradycardia during the HDC regimen (6 grade 1). Neutrophils and platelets engrafted promptly. The ORR and CR rates were both 100%. At median follow-up of 16 (range, 2-34) months, the EFS and OS rates are both 90%. There were only two relapses at 4 and 7 months, respectively, both in patients treated at DL1. Olaparib markedly inhibited PAR levels (measured by ELISA in PBMNC), which decreased significantly from baseline to day -5 (and became undetectable in those patients treated at the RP2D), with rapid PARylation recovery on day -2 (around 12 hours after the last dose of olaparib). CONCLUSION: In this first trial combining a PARP inhibitor and an HDAC inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and highly active in refractory relapsed lymphomas, including post-CAR-T relapses. Olaparib, in combination with HDAC inhibition, strongly potentiates HDC through inhibition of PARylation and DDR during treatment. The clinical data are encouraging and this approach warrants further evaluation.

The efficacy and safety of low-dose chemotherapy combined with tyrosine kinase inhibitors in the treatment of Philadelphia-chromosomal-positive acute lymphoblastic leukemia

目的探讨低剂量化疗联合酪氨酸激酶抑制剂（TKI）作为Ph染色体阳性急性淋巴细胞白血病（Ph+ ALL）诱导治疗方案的有效性与安全性。方法回顾性分析2008年1月1日至2021年7月31日北京大学人民医院收治的217例初诊Ph+ ALL患者的临床资料，通过logistics回归和Cox回归分析，比较低剂量化疗与常规剂量化疗的疗效及不良反应。结果研究纳入217例患者，中位年龄38（10～69）岁，低剂量化疗组78例，常规剂量化疗组139例。低剂量化疗组与常规剂量化疗组相比，4周完全缓解（CR）率（98.7％对97.0％，P＝0.766）及总CR率（100％对100％，P＝1.000）差异均无统计学意义。多因素分析显示，化疗剂量对无病生存率、总生存率无显著影响。而两组诱导化疗期间感染发生率（OR＝0.444，95％ CI 0.227～0.866，P＝0.017）、粒细胞缺乏持续时间（OR＝0.272，95％ CI 0.128～0.576，P＝0.001）、PLT<20×109/L持续时间（OR＝0.487，95％ CI 0.232～1.022，P＝0.057）及红细胞悬液输注量（OR＝0.309，95％ CI 0.147～0.651，P＝0.002）差异有统计学意义，低剂量组均显著低或短于常规剂量化疗组。结论对于Ph+ ALL患者，低剂量化疗联合TKI作为一线诱导治疗的疗效与常规剂量化疗相当，且安全性好。

LTBK-05. Outcomes of Infants and Young Children with Newly Diagnosed Localized (M0) SHH Medulloblastoma Treated on The NEXT Consortium “Head Start” 4 Protocol

Advances in RNA and DNA profiling have identified four core molecular subgroups of medulloblastoma of prognostic significance: Sonic Hedgehog (SHH) subtype, WNT subtype, Group 3, and Group 4. Infants and young children with SHH medulloblastoma have demonstrated a favorable outcome in clinical trials utilizing either high-dose chemotherapy (“Head Start”) or a combination of intravenous and intraventricular methotrexate (HIT-SKK). Two recently conducted clinical trials (COG ACNS1221 and St. Jude – SJYC07) failed to demonstrate similar survival advantage with conventional dose chemotherapy and without intraventricular methotrexate. “Head Start” 4 (HS 4) is a prospective randomized clinical trial that tailors treatment based on medulloblastoma molecular subgroups and response to induction chemotherapy to compare the efficacy of one versus versus three (tandem) cycles of myeloablative therapy. Eligibility includes newly diagnosed children less than six years of age with localized medulloblastoma. Eligible patients with SHH medulloblastoma were considered “low-risk” and non-randomly assigned to receive three cycles of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate) followed by consolidation with single cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and autologous hematopoietic progenitor cell rescue. Patients with less than a complete response after three induction cycles received two additional cycles prior to consolidation therapy. Only children between 6 -10 years old, or those with confirmed residual tumor post-consolidation, were meant to receive irradiation after consolidation. Twenty-eight children with localized SHH medulloblastoma were enrolled on the trial with a median age of 2.1 years (range: 0.3-5.9 years). Median follow-up for this cohort is 29.6 months (range: 7.0-58.6 months). The estimated 3-year event-free (EFS) and overall survival (OS) is 96% (CI: 89-100%) and 100%, respectively. The estimated 3-year EFS for SHH subtype 1 and 2 patients is 100% and 95%, respectively (p=0.65). None of the M0 SHH medulloblastoma patients received irradiation.

Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature.

We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

Current Status of Stem Cell Transplant in Treatment of Testicular Germ Cell Tumors.

We aim to discuss the history of high-dose chemotherapy with autologous stem-cell transplant in testicular germ cell tumors, prognostic factors to consider prior to transplant, and issues both during and after transplant while also touching on the use of conventional-dose vs. high-dose chemotherapy for initial salvage treatment in patients with relapsed disease. The advancements in the treatment of testicular cancer have led to the majority of patients even with distant metastases being cured of their malignancy. Despite this, around 20% of patients with metastatic disease will relapse after first-line therapy, and the majority of these patients will go on to need further salvage chemotherapy, either with conventional-dose chemotherapy or high-dose chemotherapy. High-dose chemotherapy with autologous stem-cell transplant is an effective salvage therapy and will still remarkably result in cures for the majority of patients with relapsed disease. While patients receiving it as even third-line salvage therapy may achieve cures, earlier administration likely results in greater efficacy.

Current Management of Refractory Germ Cell Tumors.

Germ cell tumors (GCTs) are the most common solid tumors affecting men between ages of 20 and 34 years. Most of the cases, even in advanced disease, will have good prognosis. However, around 20-30% of advanced disease will be refractory or develop relapse after treatment. Herein, we review the current management of refractory/relapsed GCTs. Salvage treatment of GCTs has been a controversial topic for the last few decades. Conventional dose chemotherapy (CDCT), high-dose chemotherapy (HDCT) with stem cell infusion, and surgical salvage were proven to be effective and curative options in some cases. The international randomized trial (TIGER) will ultimately answer which chemotherapy approach may be optimal. Furthermore, the usage of immunotherapy is still under investigation with limited data so far in the setting of relapsed/refractory GCTs. Curative paradigms including with CDCT and HDCT are possible, although novel approaches beyond HDCT are still needed to eliminate mortality from this disease.

Definition of Organ Involvement and Treatment Response in Primary Systemic Amyloidosis (AL): A Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis.

Introduction Previously, specific criteria for recognizing organ involvement and defining response in amyloid (AL) had minimal utility. However, new therapies directed at the plasma cell, including conventional dose chemotherapy, myeloablative chemotherapy, and agents directed at disruption of fibril structure are regularly being used to treat patients. Currently criteria for response and organ involvement differ from institution to institution, making it difficult to directly compare outcomes. Outcomes are directly related to the number of organs involved with amyloid and accurate definition as to what constitutes organ involvement are more than an academic exercise. Thirteen leaders in the field were invited to submit institutional criteria from which the current guidelines were developed.Results The panel drew up consensus guidelines for the following questions: What is required for a diagnosis of amyloidosis?, differentiating systemic from localized amyloidosis, How is amyloidosis characterized as AL type?, Definitions of organ involvement, Criteria for organ response (heart, kidney, liver, nerve and soft tissue) and organ progression, hematologic response criteria (including utilization of the newly developed immunoglobulin nephelometric free light chain assay) and Definitions for progressive disease both hematologic and organ based.Conclusion Defining organ involvement and response criteria, both hematologic and organ-based for amyloidosis AL has always been challenging. The thirteen members of the consensus panel have defined criteria proposed to be used worldwide by physicians who treat patients with this disease and to permit uniform reporting criteria of treatment-related outcomes. In the future integration of new imaging techniques, as well as serum biomarkers such as serum troponin and brain naturetic peptide will further define the definitions of organ involvement and response.

Nonhematologic neoplasia in biallelic BRCA2 mutated Fanconi anemia.

10041 Background: Fanconi anemia (FA) is a cancer predisposition disorder. Affected individuals do not tolerate conventional doses of chemotherapy or radiation well. Biallelic BRCA2 mutations cause a rare (̃3%) form of FA. Most patients with this subtype have a family history of breast cancer and die in early childhood. Optimal management remains uncertain. Herein, we report the world’s largest single center cohort of biallelic BRCA2 patients, with a focus on non-hematologic malignancies. Methods: The University of Minnesota’s prospectively maintained FA database was analyzed for data on biallelic BRCA2 mutated FA patients. IRB-approved consent was obtained for all subjects. Results: Twenty patients with biallelic BRCA2 were identified. Median age of FA diagnosis was 1.5 years (range: 0-16.2 years). All patients had a significant history of cancer in the family with breast cancer being particularly frequent (65%). Eight (40%) patients developed non-hematologic neoplasia before 18 years of age. These included 10 malignant tumors and 4 benign neoplastic lesions; 3 patients had more than one solid tumor (see Table). Surgical resection was attempted in all malignant tumors, dose reduced adjuvant chemotherapy was utilized in 5 cases and radiation in one case. Thirteen (65%) patients developed hematologic malignancies (AML=6, ALL=3, MDS=4), all without preceding marrow failure. Fourteen patients underwent allogeneic HCT. Eleven patients have died, 3 from solid tumors and 5 from leukemias. Nine patients are currently alive, of whom 3 are post-HCT. Only 4 (age range: 6.5-16.3 years) patients in the cohort remain free of any oncologic diagnoses. Conclusions: Patients with FA due to biallelic BRCA2 mutations have a unique phenotype with an extraordinarily high risk of early-onset de-novo acute leukemia and solid tumors, often both diagnosed in the same patient. They require extensive, lifelong cancer surveillance from an early age to optimize outcomes. Therapy for malignant diagnoses should aim to minimise exposure to genotoxic / crosslinking agents and radiation. BRCA2 mutation testing in family members and appropriate genetic counselling is essential. Additionally, a family history of BRCA2 mutated cancers should prompt FA testing in offspring with any relevant FA-related clinical findings. Nonhematologic neoplasia and therapy.[Table: see text]