bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allogeneic hematopoietic stem cell transplantation for cutaneous T-cell lymphoma (CTCL)
Authors: Hosing C. , Donato M. , Khouri I. F. , Chu D. T. , Bethancourt D. L. , Acholonu S. , Giralt S. , Duvic M. , Champlin R. E. 
Published: March 2020

7540 Background: Patients (pts.) with advanced CTCL have a poor prognosis. There has been limited experience with the use of allogeneic hematopoietic stem cell transplantation (HSCT) in these pts. We report the results of 11 pts. with advanced CTCL/Sezary syndrome who underwent allogeneic HSCT at our institution. Patients and Methods: All pts. signed informed consent. Median age at the time of HSCT was 50.5 years (range, 22–63). There were 8 F/3M. All were diagnosed with stage IV disease. The median number of prior treatment regimens was 5.5 (range, 3–11). Treatment regimens included PUVA, TSEB, ECP, topical therapy, retinoids, bexarotene, denileukin diftitox, and multiagent chemotherapy. Seven pts. had a PR to treatment administered prior to transplantation, 2 pts. were in CRu and 2 pts. had SD. The conditioning regimen was fludarabine (125 mg/m2), melphalan 140 mg/m2 in 8 pts., fludarabine (125 mg/m2), cyclophosphamide (3 g/m2) ± rituximab in 2 pts., and fludarabine (120 mg/m2), busulfan (11.2 mg/m2) in 1 pt. Patients who received unrelated or mismatched related stem cells also received ATG. GVHD prophylaxis was with tacrolimus/methotrexate in all patients. Results: Ten of 11 pts. engrafted with a median time to ANC >500 mm3 of 12 days (range, 8–14). One pt. died at 17 days post transplant without engraftment due to sepsis. One pt. developed autologous reconstitution and underwent a 2nd allogeneic HSCT procedure and remains in CR at 3 years post transplant. Of the remaining 9 pts., 7 achieved full donor chimerism and 2 pts. were mixed chimera. At the time of this report 4 of 11 pts. have died. Cause of death was sepsis in 2, fungal pneumonia in 1, and PD in 1 pt. Three pts. relapsed post transplant, all 3 were induced back in to a CR by tapering of immunosuppression (2) or DLI (1). Overall 7 pts. continue to be alive and remission with a median follow up of 2.9 years (range, 3 months to 4.4 years). Four of 7 pts. have cGVHD requiring treatment (Table). Conclusions: Allogeneic HSCT is an effective therapy for refractory CTCL/SS and merits further evaluation. [Table: see text] No significant financial relationships to disclose.
Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple myeloma (MM): Preliminary results
Authors: Farag S. S. , Zhang S. , Miller M. , Buckner M. , Kraut E. , Chan K. , Eng C. , Byrd J. C. , Dancey J. E. , Grever M. R. 
Published: March 2020

7616 Background: Temsirolimus (TEM) is a novel inhibitor of mTOR, a critical molecule in the PI3K/Akt pathway, which is known to play an important role in transducing mitogenic signals induced by the action of cytokines on MM cells. Methods: We performed a phase II trial to investigate the clinical activity and toxicity of TEM in relapsed/refractory MM patients. Patients had Salmon-Durie stage I-IIIA, failed at least one prior therapy, were ≥18 years, had ANC ≥1.2x109/l, platelets ≥75x109/l, serum Cr ≤1.5 mg/dl, fasting cholesterol ≤350 mg/dl, triglycerides ≤400 mg/dl, and ECOG performance status 0–2. TEM was dosed at 25 mg IV on days 1, 8, 15 and 22 of each 28-day cycle. Treatment was continued until progression. Results: 14 patients are evaluable for response and toxicity. Median age was 62.5 (range, 41–75) years; 8 patients were male. 12 patients had stage IIIA and 1 patient had stage IIA and IA each, respectively. Median β2-mg was 3.3 (range, 2.5–7.9) and CRP was 2.2 (range, 0.5–139). Patients had failed a median of 2 (range, 1–5) prior regimens, and 6 had failed autologous stem cell transplant. Overall, 6 (43%) of 14 patients responded, with 5 achieving minor (26–49% decrease in M-protein) responses, and 1 a partial (>50% decrease in M-protein) response using Bladé criteria. 11 patients progressed on treatment. Overall, median time-to-progression was 4.6 months from start of treatment. Grade 3/4 toxicity included neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), nausea (n=1), stomatitis (n=1) and diarrhea (n=1). Response was associated with a maximal reduction in phosphorylated p70S6K (p-p70S6K) and 4EBP1 (p-4EBP1) in peripheral blood mononuclear cells at 48 hours after TEM dosing. The median proportion of p-p70S6K relative to baseline following treatment was 0.38 (range, 0.26–0.84) in responding patients versus 1.65 (range, 0.74–1.66) in non-responders (P=0.0001). Similarly, the median proportion of p-4EBP1 following treatment in responders was 0.49 (range, 0.12–1.25) versus 1.12 (range, 0.73–2.09) in non-responders (P=0.025). Correlation with blood levels of TEM is ongoing. Conclusions: TEM has anti-myeloma activity, and further investigation of TEM as a single agent and in combination therapy is warranted. No significant financial relationships to disclose.
Reduction of murine osteosarcoma lung metastases using the dipeptidyl peptidase inhibitor talabostat
Authors: Kim S. Y. , Cohen S. A. , Epps J. , Smedley J. , Mendoza A. , Khanna C. , Jones B. , Aziz N. , Helman L. J. 
Published: March 2020

9009 Background: Dipeptidyl peptidases comprise a family of serine proteases that includes the genes dipeptidyl peptidase IV (DPP-IV) and fibroblast activation protein (FAP). FAP is expressed in stromal fibroblasts that surround sites of metastatic carcinomas, but not in the tumor cells themselves. Talabostat (valine-proline-boronic acid) is a potent and long-acting inhibitor of dipeptidyl peptidases. It has previously been shown to have anti-tumor activity in preclinical studies. We utilized this compound to determine whether inhibition of dipeptidyl peptidases leads to a decrease in lung metastases using a murine model of osteosarcoma metastasis. Methods: 1×106 K7M3-luciferase murine osteosarcoma cells were injected by tail vein into female Balb/C mice. Mice were then treated by gavage with talabostat (20 ug/dose) twice daily, talabostat once daily, or normal saline twice daily, 5 days on and 2 days off. Half of the mice were analyzed once a week using luminescent imaging. All animals were euthanized on day 24 and the number of lung metastases counted. Results: For the control mice, the average number of surface lung nodules was 75.6 (SD 45.4). Mice treated with talabostat had a ten-fold reduction in the number of nodules (twice daily - average 7.0, SD 6.1, p-value <0.01, once daily - average 3.4, SD 2.4, p-value <0.01). The number of resulting metastatic nodules correlated with luminescent intensity. Conclusions: Mice treated with the dipeptidyl peptidase inhibitor, talabostat, had a ten-fold decrease in the number of visible metastatic lung nodules. Experiments to elucidate the mechanism that links treatment with talabostat and inhibition of metastases are currently being performed. [Table: see text]
A phase I study of 17-AAG in relapsed/refractory pediatric patients with solid tumors: A Children’s Oncology Groups study
Authors: Weigel B. , Blaney S. , Kersey J. , Bagatell R. , Ivy S. P. , Whitesell L. , Krailo M. , Reid J. , Ames M. , Adamson P. 
Published: March 2020

9018 Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m2/dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m2/dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m2/day. Non-DMSO formulations may allow for further dose escalation in children and should be studied. No significant financial relationships to disclose.
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of 17-Allylamino-17-demethoxygeldanamycin (17AAG) in children with solid tumors
Authors: Bagatell R. , Gore L. , Egorin M. , Ho R. , Boucher N. , Heller G. , Trippett T. 
Published: March 2020

9022 Background: 17AAG is a benzoquinone ansamycin that binds to heat shock protein 90 (Hsp90) and alters levels of cancer-associated proteins that are regulated by Hsp90. 17AAG has been well-tolerated in adults, but has not previously been administered to children. Methods: A Phase I study of 17AAG was initiated to define the maximally tolerated dose and toxicity profile of this drug in children. PK and PD were also studied. Cohorts of 3–6 patients with recurrent or refractory solid tumors were treated every 21 days with escalating doses of 17AAG twice weekly for two weeks. Plasma PK of 17AAG and its major metabolite, 17AG, were measured on day 1 by HPLC. Changes in levels of the inducible isoform of Hsp70 were assessed by Western blot using peripheral blood mononuclear cells (PBMCs) obtained 24 h after the 17AAG infusion. Actin was measured for comparison. Because 17AAG is a substrate for CYP3A4/5 and MDR1, pharmacogenetic analyses have been undertaken to determine if genotypes including CYP3A4*1B, CYP3A5*3, and MDR1 G2677T/A and C3435T influence 17AAG disposition. Results: 12 pts (median age 11 years, range 5–18) with neuroblastoma (5), osteosarcoma (4), Ewing’s family tumors (2), and desmoplastic small round cell tumor (1) have been treated with 17AAG. An MTD has yet to be defined though one dose limiting toxicity (Grade 3 hypoxia) was observed at Dose Level 4 (360 mg/m2). The AUC of 17AAG increased with dose, with a linear relationship between end of infusion 17AAG plasma concentration and AUC. The AUC of 17AAG increased with dose, with a linear relationship between end of infusion 17AAG plasma concentration and AUC. Clearance ranged between 12.5 and 29.6 l/hr/m2 (median, 21.6 l/h/m2) and did not change with increasing doses. Post-treatment increases in Hsp70 in PBMCs have been observed in pts treated with 17AAG doses at or above 150 mg/m2. Declines in Akt and IGF1R in PBMCs have been seen in some but not all pts following treatment. Conclusions: 17AAG is well tolerated in children at dose levels studied to date. 17AAG dose escalation continues and at the time of the meeting, updated data will be reported. No significant financial relationships to disclose.
Difference in outcome of adolescents (14–17 years) with acute lymphoblastic leukemia (ALL) enrolled in the Italian pediatric (AIEOP) and adult (GIMEMA) multicenter protocols
Authors: Testi A. 
Published: March 2020

9024 Background: Progress in the treatment of acute lymphoblastic leukemia (ALL) has led to better survival rates; however, this benefit has not extended in the same proportion to adolescents who retain a lower cure rate, compared to younger patients. Based on some recent reports, adolescents treated on pediatric ALL trials seem to have a significantly better event free-survival (EFS) than those treated on adult trials. Methods: We retrospectively compared the results obtained in 242 adolescents enrolled either in the national cooperative pediatric (AIEOP; n=150) or adult (GIMEMA; n=92) ALL trials, between 4/1996 and 10/2003. Results: The characteristics of the patients at diagnosis in the two groups under examination were comparable except for age (median age: 15 in the AIEOP vs 16 in the GIMEMA trials). Adolescents in the AIEOP protocols had a better complete remission (CR) rate (97%) compared to those treated with the GIMEMA protocols (89%). Overall treatment results estimated at 2 years were significantly superior for patients treated in the pediatric trials: survival 81% vs 71% and EFS 78% vs 47%. This difference was significant also at the multivariate analysis. Conclusions: Our results support, in keeping with other studies, the concept that adolescents with ALL have a better outcome if treated in pediatric trials. No significant financial relationships to disclose.
Factors affecting event free survival (EFS) after high dose chemotherapy with stem cell rescue (HDC/SCR) in children with brain tumors
Authors: Aguayo J. , Teplick A. , Butturini A. , Erdreich-Epstein A. , Jubran R. , Villablanca J. , Hyder D. , Britt B. , Finlay J. 
Published: March 2020

9057 Background: HDC/SCR is a novel approach for treatment of children with brain tumors. Despite several studies suggesting results are better in children with primitive neural ectodermal tumors (PNET) or medulloblastoma (MB), it is controversial whether other factors can predict outcome. Methods: We retrospectively analyzed data from 53 patients who underwent HDC/SCR for brain tumors at Children Hospital Los Angeles between June 1992 and June 2005. Patients were aged 4 months to 15.8 years at diagnosis and 9 months to 18.1 years at transplant. In all cases the conditioning regimen included thiotepa and/or etoposide and/or carboplatin. The variables considered were age at diagnosis, histology, extent of disease, conditioning regimen, radiation therapy, stem cell type and timing of transplant. Results: Diagnoses included 33 PNET/MB, 8 high-grade gliomas, 5 ependymomas, 3 germinomas, 2 choroid plexus carcinomas and 2 rhabdoid tumors. Overall event free survival at 36 months was 53±9.1% in PNET/MB and 40±15.5% in tumors with other histology. Variables associated with better EFS in PNET/MB were no prior progression (p=0.00094), no spread into bone marrow (p=1.2 E-10) and age less than 3 years at diagnosis (p=0.046). There was a trend toward improved outcome if there was gross total resection of the tumor (p=0.11). Patients with PNET transplanted before progression had better EFS if they had localized disease at diagnosis (p=0.00024), and if gross total surgical resection was accomplished (p=0.11). Patients with PNET/MB transplanted after progression had better EFS if there was no spread of disease into blood or bone marrow (p=0.00023), if they were male (p=0.053), had localized disease at relapse (p=0.12) and if radiotherapy was given after transplant (p=0.053). In patients with tumors of other histology, the only variable associated with prolonged EFS was gross total resection (p=0.026). Conclusions: Children most likely to benefit from HDC/SCR for brain tumors are those less than 3 years old who are newly diagnosed with PNET that is locally confined, and those with a non-PNET diagnosis who have gross total resection of tumor. No significant financial relationships to disclose.
Medulloblastoma incidence has not changed over time: A CBTRUS study
Authors: Fisher P. G. , Curran E. K. , Cobb K. L. , Le G. M. , Propp J. M. 
Published: March 2020

9058 Background: Past studies of medulloblastoma (MB) present conflicting claims about declines and rises in MB incidence, possibly due to misclassification. By using a strict classification of the disease and a rigorous analysis of a data registry, we aimed to determine the incidence trends of MB over the last three decades. Methods: 441 MB patients diagnosed between 1985 and 2002 were identified from the Central Brain Tumor Registry of the United States (CBTRUS), a data set representing approximately 5% of the American population (6 registries). MB was strictly defined and non-cerebellar embryonal tumors (primitive neuro-ectodermal tumors [PNETs]) excluded, using histology and site codes. Multiplicative Poisson regression and joinpoint regression were performed (Joinpoint Regression Program, version 3.0, Statistical Research and Applications Branch, National Cancer Institute) to determine the estimated average annual percentage change (EAPC) and sharp (i.e., acute) changes in incidence, respectively. Results: A slight but nonsignificant (p=.18) increase in medulloblastoma was demonstrated (EAPC = 1.1), and no sharp changes in incidence were found (joinpoints = 0). The analysis was repeated with a less strict definition of MB (including non-cerebellar PNETs) and 559 patients were identified. Using this broader classification scheme, there was a statistically significant increase in incidence (p=.02, EAPC = 1.6), but no sharp changes in incidence (joinpoints = 0). Conclusions: MB incidence does not appear to have changed since the 1980s. “Medulloblastoma” incidence increased only when the diagnosis was not strictly defined and misclassified by including non-cerebellar PNETs in the analysis. The observed increase in the combined MB/PNET classification may relate to the PNET hypothesis–a proposal that all brain tumors of apparently undifferentiated neuroepithelial cells be considered a unique diagnostic group–popularized in the 1980s and early 1990s. No significant financial relationships to disclose.
Role of amifostine as a cytoprotectant in children ≥ 3 years with average risk (AR) medulloblastoma (MB) treated with craniospinal irradiation (CSI) and 4 courses of cisplatin (CDDP)-based high dose chemotherapy
Authors: Fouladi M. , Chintagumpala M. , Ashley D. , Kellie S. , Broniscer A. , Merchant T. E. , Kun L. E. , Stewart C. , Wallace D. , Gajjar A. 
Published: March 2020

9063 Background: Therapy for MB (CSI and CDDP-based chemotherapy) results in hearing loss before completion of therapy in 30%-50% of patients, who consequently require a reduced cisplatin dose. Cytoprotection against cisplatin-induced ototoxicity may be provided by amifostine, a thiol prodrug that protects many normal tissues against therapy-induced damage without diminishing antitumor effects. Method: This study was designed to detect a 20% decrease (80% power) in CDDP induced ototoxicity (defined as needing hearing aids) in AR MB patients with the use of amifostine (n=62) compared to historical controls (n=35) one year from diagnosis. An interim analysis was conducted after accrual of 32 pts on the experimental arm. A total of 67 AR MB patients received CSI (23.4 Gy) followed by 3-dimensional conformal boost to the tumor bed (total 55.8 Gy) and 4 cycles of high-dose cyclophsophamide (4,000 mg/m2 per cycle), cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5 mg/m2 doses per cycle). When used, amifostine (600 mg/m2 per cycle) was given before and 3 hours into the cisplatin infusion. Results: The median age of the 40 male, 27 female patients was 8.7 (range, 3.2–20.2) yrs. The 2 groups had similar median ages (amifostine, 9.1; control, 7.8 years) and gender (male: amifostine, 66%; control, 54%). One year after the start of treatment, the objective criteria for needing a hearing aid in at least 1 ear were met by 13 (37%) of control-group patients and 6 (18.8%) of those who received amifostine. Conclusion: The interim analysis has demonstrated that the need for hearing aids in AR MB children treated with the above-described regimen is halved by using amifostine during CDDP administration. No significant financial relationships to disclose.
Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial?
Authors: Le Cesne A. , Van Glabbeke M. , Verweij J. , Casali P. , Zalcberg J. , Reichardt P. , Issels R. D. , Judson I. R. , Blay J. Y. 
Published: March 2020

9510 Background: From 2/2001 to 2/2002, 946 patients (pts) with advanced GIST were randomized to IM at two dose levels within a controlled EORTC/ISG/AGITG trial. This analysis investigates whether achievement of an objective response, according to the RECIST criteria, has any predictive value for time to progression (TTP) and overall survival (OS). Methods: According to the protocol, the 3 first disease measurements were foreseen at 2, 4, and 6 months (m). Results of those measurements were classified in 6 categories: PR (>30% reduction of the tumor load), MR (10–30% reduction), NC- (0–10% reduction), NC+ (0–20% increase), PD (> 20% increase or new lesions), and subjective PD (clinical PD, no measurements). Pts included the analyses were those still followed at the measurement point, who had not previously progressed. Results: A total of 906 pts had measurable disease at entry; from those, 852 were evaluable at 2 m, 681 at 4 m and 642 at 6 m. At all measurement time points, PR and MR resulted in similar TTP and OS; this was also true for NC- and NC+, and for PD and subjective PD. As an example, for the evaluation at 4 m, the median TTP was respectively 2.50, 2.55, 1.86, 1.65, 0.31 and 0.30 years in the 6 groups of pts, while the 3 years OS estimate were 71%, 72%, 57%, 56%, 32% and 0%. Pts were subsequently classified as responders (more than 10% reduction of the tumor load), no change (less than 10% reduction and less than 20% increase) and PD (> 20% increase, new lesions or clinical PD). This new response category is highly predictive of further progression or survival, for the 2 first measurements points, and in both therapeutic arms, but pts stable at 6 m had the same survival as responders at 6 m. In addition, RECIST response documented at 2, 4 and 6 m resulted in similar TTP and OS. Conclusions: The RECIST criteria are only optimal for identifying IM-resistant GISTs (PD > 20%) and not adequate for the evaluation of IM efficacy. All pts exhibiting at least a 10% reduction (until complete response) of the tumor load have to be considered as responders to IM (IM-sensitive GISTs). A real stabilisation of the disease consisting in a less than 10% tumor reduction and a less than 20% tumor increase identifies pts who have an intermediate sensitivity to IM. [Table: see text]