bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms in genes of folate metabolism and effects of high-dose methotrexate in patients with primary central nervous system lymphoma
Authors: Knop S. , Guenther M. , Loeffler J. , Meisner C. , Korfel A. , Weller M. , Hebart H. , Herrlinger U.
Published: March 2020

7558

Background: The antifolate methotrexate (MTX) is the single most effective agent in primary central nervous system lymphoma (PCNSL) when given intravenously in high doses. MTX inhibits 5,10-methylentetrahydrofolate reductase (MTHFR) as well as thymidylate synthase (TYMS) in target cells what eventually results in decreased DNA synthesis. Intracellular uptake of folates is mediated by the reduced folate carrier (RFC). Two common MTHFR single nucleotide polymorphisms (SNPs) affect enzyme activity: 677 C→T and 1298A→C. A 28 base pair (bp) tandemly repeated sequence in the TYMS enhancer region (5’-UTR) containing either 2 or 3 repeats alters enzyme activity as does a 6 bp deletion (del) polymorphism in the 3’-UTR of TYMS. An RFC SNP (80G→A) is known to influence folate and MTX transport. We hypothesized that these polymorphisms may be directly linked to toxicity in PCNSL patients receiving high-dose MTX. Methods: Genomic DNA was prospectively collected from patients (pts) who received high-dose (HD) MTX 4 g/m2 every 2 weeks after enrolment onto the German multicenter G-PCNSL-SG1 trial. Genotyping of the two MTHFR and the RFC SNPs was performed by melting point analysis using the Light Cycler technology. Genotyping of the TYMS 28bp polymorphism was performed by conventional PCR followed by agarose gel electrophoresis. The TYMS 6bp del polymorphism was analyzed by PCR, restriction enzyme digest and agarose gel electrophoresis. Response, hematologic (Hb, WBC, ANC, platelets) as well as cumulative incidence of non-hematologic toxicity (renal, pulmonary, mucositis) were assessed prospectively. Results: 123 pts are evaluvable for clinical parameters. Relative risk of any °III/IV toxicity was 26-fold higher for pts with 677TT when compared to CT or CC genotype (p = 0.009). °III/IV non-hematologic toxicity for TT was 10-fold higher than with CT or CC (p = 0.02). Significant differences for hematologic values were restricted to WBC and ANC and found to be associated with RFC 80 GG vs. AG/AA (p = 0.047). Conclusions: Pharmacogenetic studies may identify PCNSL pts who are at risk for severe hematologic and non-hematologic toxicity when treated with HD-MTX.

No significant financial relationships to disclose.
FDG PET for the routine follow-up in NHL: First prospective evaluation
Authors: Jerusalem G. , Silvestre R. , Beguin Y. , Hustinx R. , Fassotte M. , Fillet G.
Published: March 2020

7569

Background: We have shown that FDG PET is able to detect preclinical relapses in patients with Hodgkin’s disease but the high rate of false-positivity (55%) was a problem (Jerusalem et al, Ann Oncol, 2003; 14 : 123–130). The aim of this study was to determine the accuracy of PET during follow-up after treatment in non-Hodgkin’s lymphoma (NHL). Methods: Patients were eligible if they had a positive baseline FDG PET and a negative end of treatment work-up including a negative PET study. They underwent FDG PET every 4–6 months until 3 years after diagnosis. Forty-five aggressive NHL (diffuse large B-cell lymphoma : 34, other : 11) and eighteen low grade NHL (follicular lymphoma : 16, other : 2) were recruited prospectively between 5/94 and 12/01. Results: A total of 197 FDG PET studies were realized. Six patients relapsed (aggressive NHL : 4, low grade NHL : 2) and 3 patients died (aggressive NHL : 2, pancreatic cancer : 1) during the time interval of the study protocol. Four asymptomatic relapses (aggressive NHL : 2, low grade NHL : 2) and one symptomatic relapse (aggressive NHL) was detected by FDG PET. Disease recurrence became symptomatic or clinically detectable a week, 3 months (both aggressive NHL), 12 and 17 months (both low grade NHL) after the first positive PET study. The latter had 4 positive FDG PET studies before biopsy-proven relapse. The time interval between the only false-negative PET and clinical relapse was 5 months in a patient with aggressive NHL. We observed for the whole study population a sensitivity of 89% (8/9), a specificity of 93% (174/188), a positive predictive value of 36% (8/22), a negative predictive value (NPV) of 99% (174/175) and an accuracy of 92% (182/197). In low grade NHL PET had a sensitivity of 100% (5/5), a specificity of 93% (50/54), a PPV of 56% (5/9), a NPV of 100% (50/50) and an accuracy of 93% (55/59). In aggressive NHL, PET had a sensitivity of 75% (3/4), a specificity of 93% (124/134), a PPV 23% (3/13), a NPV of 99% (124/125) and an accuracy of 92% (127/138). Conclusions: In aggressive NHL, routine follow-up by FDG PET is not very useful and we stopped it now in unselected aggressive NHL. In contrast, FDG PET can detect a relapse several months before the development of clinical symptoms in low grade NHL suggesting further evaluation of the role of PET in the routine follow-up of these patients.

No significant financial relationships to disclose.
Health related quality of life (HRQOL) evaluated with the EORTC C30 questionnaire in first line therapy of elderly patients with chronic lymphocytic leukemia (CLL): Results of a phase III trial of the German CLL Study Group (GCLLSG)
Authors: Eichhorst B. F. , Busch R. , Hallek M.
Published: March 2020

7572

Background: The GCLLSG evaluated the efficacy of fludarabine (F) versus (vs.) chlorambucil (Clb) in first line therapy of older patients with advanced CLL. HRQOL was evluated by using the EORTC C30 questionnaire. Methods: Pts were randomized to receive 6 courses of F (25 mg/m²/day (d) IV for 5d; 92 pts) or 12 months (mo) of Clb (0.4–0.8 mg/kg/d PO, every 15d; 99 pts). All pts were previously untreated, aged between 65 and 79 years and in advanced stage Binet C or symptomatic Binet B or A. Primary endpoints were overall survival (OS) and progression free survival (PFS), secondary endpoint was HRQOL. The EORTC C30 questionnaire (version 2.0) was sent to all patients at baseline and after 6, 12 and 24 mo. Scores (0–100) for 15 different measures (1 global HRQOL, 5 functional, 3 symptom and 6 single item scales) were evaluated at each time point. Results: F induced significantly higher response rates and prolonged the PFS, while no significant difference in OS was observed. At baseline 130 of 191 pts (68%) completed the questionnaires followed by more than 80% at mo 6 to 24. Compliance rates were similar in both treatment arms. Between pts completing questionnaires or not no statistically significant differences in perfomance status, age, stage or response to treatment were observed. HRQOL differences in comparison to baseline values were significantly improved after F treatment in global HRQOL, role and social functioning after 12 months as shown by the table. Responders had a significantly better global HRQOL and social functioning as well. Except for an impaired physical functioning no differences in HRQOL were observed between different age groups (65–69, 70–74, 75–79). Conclusion: Elderly F treated patients with CLL showed improvement inglobal HRQOL. Elderly age groups had a similar HRQOL as younger age groups.

[Table: see text]

[Table: see text]
The mTOR inhibitor CCI-779 (temsirolimus) downregulates p21 and induces cell cycle arrest and autophagy in mantle cell lymphoma (MCL)
Authors: Yazbeck V. Y. , Georgakis G. V. , Li Y. , Younes A.
Published: March 2020

7573

Background: Mantle cell lymphoma (MCL) is a distinct type of B-cell lymphoma associated with transient response to conventional chemotherapy, continuous relapses and median survival of only 3–4 years. The mammalian target of rapamycin (mTOR) pathway is activated in many human malignancies where it regulates cyclin D1 translation. In a phase II trial, temsirolimus (CCI-779), an inhibitor of mTOR kinase used as single agent achieved an overall response rate of 38% in relapsed MCL patients. Our goal was to determine the activity and the mechanism of action of CCI-779 in MCL cell lines and to examine whether CCI-779 may synergizes with proteasome inhibitors. Methods: The activity of CCI-779 was determined in 3 mantle cell lymphoma cell lines (Jeko 1, Mino, Sp 53). Cell viability was determined by MTS assay, and autophagy by Acridine orange. Analysis of cell cycle was performed by flow cytometry and apoptosis by Annexin-V binding. Molecular changes were determined by western blot . Results: CCI-779 induced cell growth arrest in all cell lines in a time and dose dependent manner. The antiproliferative activity was due to cell cycle arrest in the G0/G1 phase followed by autophagy. CCI-779 decreased S6 phosphorylation in Jeko 1,Sp 53 indicative of mTOR inhibition. Furthermore, CCI-779 downregulated p21 expression in all three cell lines, without altering p 27 expression. Moreover, CCI-779 decreased the expression of the antiapoptotic protein cFLIP and ERK in both Jeko1 and Sp 53, but had no effect on cyclin D1 expression. The proteasome inhibitor bortezomib was also effective in all MCL cell lines, but failed to demonstrate significant synergy with CCI-779. Conclusions: The antiproliferative activity of CCI-779 in MCL is mediated by p21 downregulation and autophagy, without significant effect on cyclin D1 expression. The lack of synergy between bortezomib and CCI-779 should be confirmed using fresh MCL tumor cells.

No significant financial relationships to disclose.
Interleukin-10 promoter gene polymorphism (-819*C) associated with poor treatment outcome in DLBCL patients treated with 8 cycles of R-CHOP as a first line
Authors: Kim Y. K. , Kim H. N. , Lee J. J. , Yang D. H. , Ahn J. S. , Cho S. H. , Chung I. J. , Park M. R. , Kim H. J.
Published: March 2020

7575

Background: IL-10 is an anti-inflammatory cytokine inhibiting Th1 functions, which may facilitate tumor escape from the immune response. Among the various IL-10 promoter genes, the IL-10–1082G, -819C and -592C alleles were reported to be associated with high serum IL-10 level. Methods: In present study, we studied the frequency of these 3 alleles and their influence to the clinical outcome in 50 DLBCL patients treated with 8 cycles of R (Rituximab, 375 mg/m2 on day 1 of each cycle)-CHOP every 3 weeks. Results: 50 patients with newly diagnosed DLBCL were included and all of them represented CD20 positivity. At diagnosis, median age was 60 (19∼85) and 24 (48%), 14 (28%), 8 (16%) and 4 (8%) patients belonged to the low, low-intermediate, high-intermediate and high risk group according to IPI reports, retrospectively. Of 50 patients, 8 (16%), 19 (38%) and 22 (44%) were found to carry IL-10–1082G, -819C and -592C alleles, retrospectively. As compared with -1082AA genotype, -1082G allele (GA/GG) failed to show better outcome (eg. higher CR or longer progression-free survival, PFS) after 8 cycles of R-CHOP. Further, patients with -819C or -592C alleles were not able to affect the response rates (CR or PR) compared with -819TT or -592AA genotype. On the other hand, the PFS was significantly shorter in patients carrying -819C allele than TT genotype (13.9 vs 26.9 ms, p<0.01). PFS also decreased in -592C allele compared with AA genotype (15.2 vs 26.5 ms, p<0.05). Of 30 patients with bcl2 positivity, patients carrying -819C alleles also showed significant lower PFS than TT genotype (12.4 vs 16.1 ms, p<0.05). In multivariate analysis including IPI, stage, IL-10–1082G, -819C and -592C allele frequencies, -819C allele remained as an independent prognostic factor predicting shorter PFS (RR=3.6, p<0.05). In a haplotype analysis, patients carrying ATA/ATA showed significant longer PFS than in other haplotypes (p<0.05). Conclusions: It is still a matter of debate to manage the DLBCL patients with refractory or progressive disease. This study suggests that the detection of IL-10 gene promoter polymorphism such as -819C allele helps us to predict the patients with poor prognosis and to establish a stratified treatment plan in DLBCL patients.

No significant financial relationships to disclose.
Helicobacter pylori eradication in gastric MALT lymphoma: Results of 316 patients treated inside and outside of a clinical trial
Authors: Wündisch T. , Günther A. , Mösch C. , Huynh M. , Stolte M. , Neubauer A.
Published: March 2020

7584

Background: Cure of infection induces remissions in most patients with early stage Helicobacter pylori- (Hp-) positive gastric MALT (mucosa-associated lymphoid tissue) lymphoma (GML). We compared the long-term outcome of 120 patients treated within a multicenter trial to that of 196 routinely treated patients. Methods: 120 patients with stage I1E disease from a prospective trial (cohort 1) were compared to 196 patients with GML treated outside a trail by sole Hp-eradication (cohort 2). The latter were evaluated in retrospect and only a minority had a complete staging at diagnosis. Histology was the standard for remission evaluation in all patients and performed by the same pathologist (MS). B-cell-clonality and the t(11;18) were assessed in cohort 1-patients. Results: Median endoscopic follow-up was 79 months (range, 1–121) in cohort 1-patients and 27 months (range, 0–120) in cohort 2-patients. In 41% of the cohort 2-patients no or one control endoscopy was performed after a first CR. Most patients are in continuous complete histological remission in both cohorts. 3 cohort 1- and 5 cohort 2-patients relapsed. 16 cohort 1- and 13 cohort 2-patients exhibited histological residual disease (RD) during follow up after a first CR; a watch-and-wait strategy was applied, and most entered into a second CR. Conclusions: Hp-eradication results in long term CR in the majority of patients with GML in both cohorts. Duration of remission, rate of relapse, and RD were similar, regardless of incomplete staging and follow-up procedures and higher age in the cohort 2-patients.

No significant financial relationships to disclose.
Addition of tumor bulk to the International Prognostic Index (IPI) does not improve prognostication in diffuse large B-cell Lymphoma (DLBCL)
Authors: Panwalkar A. W. , Loberiza F. R. , Vose J. M. , Bociek R. G. , Bierman P. J. , Armitage J. O.
Published: March 2020

7585

Background: Bulky disease in DLBCL has been linked to adverse outcomes. Tumor bulk was not included in the IPI due to lack of uniform data availability. Radiation to sites of bulky disease may result in improved outcomes. We evaluated the impact of tumor bulk as a prognostic factor combined with the IPI in predicting overall survival in DLBCL. Methods: A retrospective review of adult patients with newly diagnosed DLBCL from October 1982 through February 2000 was done, and data pertaining to tumor size, age, Ann Arbor stage, performance status (PS), lactate dehydrogenase level (LDH), extranodal involvement, radiation therapy and overall survival was collected. Surviving patients were followed through December 2005. Bulky disease was defined as largest tumor mass of ≥10 cm. Statistical analysis was performed using Cox proportional hazards regression. Results: Complete data was available on 669 patients. All patients received anthracycline or mitoxantrone based chemotherapy. Bulky disease was found in 27% of patients, while radiation was employed in 22% of patients. There was no significant association between use of radiation and tumor bulk. IPI was calculated as low risk—37%, low-intermediate—28%, high-intermediate—20% and high—14%. Median follow-up of survivors was 100 months (range <1 - 263). In univariate analysis, bulky disease alone was a significant predictor of inferior survival (RR 1.27, p = 0.044), however when combined with the IPI it was not a significant predictor of poorer overall survival as compared with non-bulky disease (RR 1.10, p = 0.36). Radiation therapy was associated with a significant increase in overall survival (RR 0.70, p = 0.005). Conclusions: Bulky disease is an important independent prognostic factor for overall survival in patients with DLBCL, however when combined with IPI it does not result in improved prediction. It is unclear whether this is due to insufficient power or due to possible inter-relation between tumor size, LDH and PS, the latter of which are included in the IPI. Radiation therapy to some patients with bulky disease may also have mitigated the adverse effect. Larger prospective studies may shed light on the utility of tumor bulk combined with IPI and possible alterations in management.

No significant financial relationships to disclose.
High dose 90Yttrium ibritumomab tiuxetan with PBSC support in refractory-resistant NHL patients: Preliminary results of a phase I/II study
Authors: Vanazzi A. , Ferrucci P. , Grana C. , Cremonesi M. , Chinol M. , Papi S. , Calabrese L. , Radice D. , Paganelli G. , Martinelli G.
Published: March 2020

7587

Background: Therapeutic options are limited in the treatment of relapsing NHL pts not suitable to HDCT. 90Yttrium ibritumomab tiuxetan (Zevalin) is active in DLBCL at 0.4 mCi/kg, but duration of response is usually short. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 11/05, 14 pts were enrolled. Median age was 68ys. 13/14 pts had advanced stage disease (III/IV) at diagnosis. 8 DLBCL, 4 MCL, 1 FL G3, 1 transformed MZL. Median number of prior therapies were 3, including rituximab, RT and HD-CT. Methods: 3 dose levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4 pts received 0.8, 4 pts 1.2 and 6 pts 1.5 mCi/kg. 1wk prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts received PBSC previously harvested. On d28 from reinfusion (+41 from Zevalin) engraftment was considered to be delayed if ANC <1.0×109/L or PLT<20.0×109/L. Results: Dosimetry showed acceptable radiation-absorbed doses to uninvolved organs, reaching max 20Gy. Only 1pt received 30Gy to the liver without developing toxicity. The median radiation-activity delivered was 90 mCi (range 57–150): 8 pts received a dose within 80 and 100 and 6 pts >100 mCi. Mean dose to red marrow: 0.8±0.2 mGy/MBq. All pts but 1 engrafted promptly. PLT/ANC count nadirs were observed 21/17 days after Zevalin (median values: 11×109/L and 0.01×109/L). No statistically significant difference in terms of hematological toxicity exists in PLT-recovering for pts receiving 1.5 mCi/kg and it is probably influenced by PLT count at baseline and by the several treatment previously received. Non-haematologic toxicity: 1 febrile neutropenia and 1HZV at 2nd level; 1 febrile neutropenia, 1 G3 liver toxicity, 1 bacterial pneumonia, 1HZV, 1HCV reactivation (pt died 4 months after treatment) at the 3rd level. 13/14pts are evaluable for response: 6CR, 2PR, 5PD. Conclusions: Zevalin at myeloablative activity with PBSC is feasible. It could be safely delivered in elderly and heavily pretreated pts, including those who previously received HDCT. Efficacy and mild toxicities suggest further investigation. We are continuing enrollment, including pts who previously received no more than 2 lines of CT.

No significant financial relationships to disclose.
Thalidomide increases thrombin generation in multiple myeloma patients
Authors: Candelaria D. , Armijo B. , Montgomery R. , Lee F. , Moll S. , Garcia D. , Liebmann J. , Libby E.
Published: March 2020

7602

Background: Numerous reports have demonstrated that the clinical use of thalidomide (THAL) carries a risk for deep venous thrombosis. Only limited investigations into the causative mechanisms for this complication have been conducted. Thrombin generation is a global measurement of hyper or hypocoagulability that has not been used to examine the hypercoagulable state caused by THAL. The aim of this study was to determine if THAL affects thrombin generation in patients with multiple myeloma (MM). Methods: MM patients on and off THAL were recruited. Patients were considered to be “on THAL” if they had been taking the medication for at least three months and “off THAL” if they had not been taking the medication for at least three months. Coagulation tubes of blood containing 3.2% sodium citrate were drawn from each patient. Platelet poor plasma was prepared from these specimens using standard technique. The samples were snap frozen at -70 C and stored until analysis. Thrombin generation was measured using the Calibrated Automated Thrombogram as described by Hemker(Pathophysiol Haemo Thromb 2003;33:4–15) using a microplate fluorometer, the Fluoroskan Ascent from Thermo Electron and the Thrombinoscope software package. The endogenous thrombin potential or ETP (area under the thrombin generation curve) and peak thrombin generation (the maximum release of thrombin per unit of time) were the variables of interest for this study. Results: Twenty seven patients were recruited. Five were excluded from analysis because they were on warfarin or enoxaparin. The normal ETP in females is 1803 ± 241 nM*min and in males is 1745 ± 259 nM *min. Normal peak thrombin generation in females is 318.5 ± 52.9 nM and in males is 293.4 ± 48.5 nM. The t-test was used to compare subjects to normal values.Peak thrombin generation was significantly increased in the 9 subjects taking THAL, 374 ± 10.6 nM (p<0.001) and in the 13 subjects not taking THAL, 352 ± 14.7 nM (p=0.009) when compared to normal values. The ETP was not significantly increased 1818 ± 10.7 nM*min (p=0.69) in subjects not taking THAL. However, ETP was increased in subjects taking THAL, 1939± 90 nM*min and showed a trend toward statistical significance (p=0.10). Conclusions: Thalidomide therapy increases thrombin generation significantly in patients with MM.

[Table: see text]
In vivo changes in gene expression profiles (GEP) after bortezomib (V) for multiple myeloma (MM): Differential effects on plasma cells (PC) and micro-environment (ME)
Authors: Shaughnessy J. D. , Zhan F. , Huang Y. , Barlogie B.
Published: March 2020

7603

Introduction: V, a proteasome inhibitor with potent anti-myeloma activity, is thought to act through effects on malignant PC and the ME. However, the in vivo effects of this drug have never been examined at the molecular level. Methods: Serial GEP analyses were performed of paired purified PC and bone marrow biopsies from 46 patients, obtained prior to and 48hr following administration of a single V dose at 1mg/m2. RNA was isolated from whole biopsies and purified PCs from each sample, converted to cRNA, and hybridized to Affymetrix U133 Plus2 microarrays. SAM analysis with 5% false discovery rate was employed to identify drug-altered genes. Results: Following V, 36 ME-associated genes (MAGs) were up-regulated, among them the osteoinductive factor osteoglycin (OGN), consistent with a V effect on osteoblastogenesis; CYR61, an angiogenesis inducer, significantly over-expressed in myeloma relative to normal marrow, was one of only 3 significantly down-regulated genes. V is known to induce expression of proteasome genes and PSMA6, PSMA1, and PSMA14 were among 15 genes up-regulated in PC. In contrast, early growth response (EGR1, EGR2, and EGR3), Krupple-like factor (KLR4, KLR5, KLR6, and KLR7) and nuclear receptor (NR4A1, NR4A2, and NR4A3) family members were down-regulated in PC by V. These differential PC and ME expression changes were only noted in low-risk MM, lacking over-expression of CKS1B. Conclusion: We report here, for the first time, on the differential molecular consequences of a single in-vivo dose of V on both tumor cells and cells of the microenvironment. The clinical implications of these findings are being further investigated and will be presented.

[Table: see text]
Phase 1 first-in-human dose escalation study of cp-751,871, a specific monoclonal antibody against the insulin like growth factor 1 receptor
Authors: Lacy M. , Alsina M. , Melvin C. L. , Roberts L. , Yin D. , Petersen J. F. , Birgin A. , Poutney S. , Sharma A. , Gualberto A.
Published: March 2020

7609

Background: Multiple lines of evidence indicate that the Insulin Like Growth Factor 1 Receptor (IGF-1R) plays a key role in the progression of multiple myeloma (MM). IGF-1 is a growth factor for MM cells. It promotes survival to the cytotoxic effects of chemotherapy in animal models of MM and its blood levels has been shown to correlate with those of paraprotein in MM patients. CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of the autophosphorylation of IGF-1R. Methods: Based on its mechanism of action and the potential relevance of IGF-1R in MM, a Phase 1 First-in-Human dose escalation study was initiated with the objective to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic properties of CP-751,871 in this patient population. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase and/or less than complete remission following autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 10 dose-escalation cohorts of patients received from 0.025 to 10 mg/kg of CP-751,871 by iv infusion on Day 1 of 4-week cycles. In patients with a suboptimal response to CP-751,871 alone, oral dexamethasone was added to the treatment regimen. Patients received up to 14 cycles of CP-751,871 therapy, alone or in combination with dexamethasone. No dose limiting toxicities have been identified to date. Plasma CP-751,871 exposure increases with dose, and the pharmacokinetic characteristics are consistent with target-mediated disposition. Pharmacodynamic measurements indicate complete target saturation by CP-751,871 for the complete length of the dosing period. One near CR and 2 PR in combination with dexamethasone have been reported. Conclusions: These data indicate that CP-751,871 is well tolerated and may constitute a therapeutic approach for patients with multiple myeloma.

[Table: see text]
Percutaneous vertebroplasty and/or kyphoplasty is an effective and safe treatment for painful vertebral compression fractures in multiple myeloma (MM)
Authors: Thomas S. K. , Wang M. L. , Yao K. , Villareal H. , Fukshansky M. , Suki D. , Mendel E. , Weber D. M. , Alexanian R. , Burton A.
Published: March 2020

7610

Background: Painful vertebral compression fractures are a major source of morbidity in MM. Vertebroplasty involves percutaneous injection of polymethylmethacrylate (PMMA) into a vertebral body, while kyphoplasty involves inflation of a balloon for painful kyphotic deformity prior to stabilization with PMMA. Methods: We assessed safety and efficacy of 100 vertebroplasties and/or kyphoplasties in 81 consecutive myeloma patients between 12/2000 and 2/2005. Results: Median age was 63 (range 32–84), with 29% having prior radiotherapy to the vertebra treated. Contraindications included epidural compression of neural elements and failure to localize a symptomatic level. Kyphoplasty was preferred if kyphosis of > 20 degrees contributed to pain, or if the posterior vertebral cortex was disrupted so that controlled delivery of bone cement was difficult. Vertebroplasty was performed when vertebral collapse was either slight or so severe that insertion of balloon device was not possible, or if patient could not tolerate the general anesthesia required for kyphoplasty. The median preoperative visual analog pain score (0–10) was 8(range 2–10); the median postoperative pain score was 3 (range 0–10) (p < 0.01). There were no significant complications . Conclusions: Percutaneous vertebroplasty and kyphoplasty provided rapid and marked pain relief. These procedures are safe and feasible and represent the treatment of choice in selected MM patients with severe refractory pain due to pathologic compression fractures.

No significant financial relationships to disclose.
Randomised, placebo-controlled, trial comparing low dose versus standard dose Lenograstim (L) following myeloablative chemotherapy (HDT) and peripheral blood progenitor cell rescue (PBPCR) for lymphoma
Authors: Nolan L. , Chilton S. , Lorigan P. , Else R. , Smith P. , Sweetenham J. W. , Johnson P. W.
Published: March 2020

7624

Background: This trial was performed to determine whether low-dose or standard dose L would influence recovery of haematopoiesis following HDT and PBPCR. Methods: 61 patients (pts) with non-Hodgkin lymphoma (40) or Hodgkin’s disease (21) undergoing HDT were randomised. Pts had normal peripheral blood counts prior to HDT (Hb ≥100g/L, total white cell count ≥ 3.0, neutrophils (N) ≥ 1.0 and platelets ≥ 50, and had a minimum 2.5 million CD34+ cells/kg PBPC previously collected following mobilisation with Cyclophosphamide 3g/m2 and G-CSF. All received HDT with BCNU 300mg/m2 d-7, Etoposide 200mg/m2 od d-5-d-2, Cytosine arabinoside 200mg/m2 bd d-5-d-2 and Melphalan 140mg/m2 d-1 before return of PBPC on D0. Pts were allocated standard dose L 263mcg daily (20 pts), low dose L 105mcg daily (21 pts) or placebo injections (20 pts). These commenced on day +5 following PBPCR and continued until N≥0.5. Pts received standard supportive care including prophylactic Fluconazole and Acyclovir, but not routine antibacterial prophylaxis, until haemopoietic recovery. Results: L at any dose resulted in a significantly shorter median time to N recovery ≥0.1 (10.0 vs 11.0 days, P=0.02) and ≥0.5 (11.0 vs 14.0 days, p=0.0003) compared to placebo. The only significant difference between standard- and low-dose L was in hospital stay (21.0 vs 22.0 days, p=0.04), however L at any dose showed a significant reduction over placebo (22.0 vs 23.0 days, p=0.01). Conclusions: Short course low dose L is as effective as standard dose in reducing neutrophil engraftment time following HDT and PBSCR. L at any dose reduces hospital stay when compared to placebo. This approach should be considered for those patients in whom growth factor support is indicated. Long-term follow-up data will be presented.

[Table: see text]

No significant financial relationships to disclose.
Polymorphisms in candidate genes in patients with congestive heart failure (CHF) after childhood cancer: A Report from the Childhood Cancer Survivor Study (CCSS)
Authors: Aplenc R. , Blanco J. , Leisenring W. , Davies S. , Relling M. , Robison L. , Sklar C. , Stovall M. , Bhatia S.
Published: March 2020

9004

Background: In cancer survivors, CHF associated with the use of anthracyclines is an important clinical complication. Risk factors for anthracycline associated cardiac toxicity, including cumulative dose, gender, and age, have been described. However, these risk factors do not fully explain the observed clinical variability. Notably, the potential role of genetic risk factors has not been studied. A recent “unifying hypothesis” postulates that the early cardiac damage is mediated mostly by oxidative stress while the more chronic type of toxicity is induced by anthracycline alcohol metabolites synthesized by carbonyl reductases (CBRs). Therefore we hypothesized that genetic polymorphisms in genes encoding for enzymes involved in oxidative stress pathways, and the metabolism of anthracyclines may impact on the risk of anthracycline-related cardiotoxicity. Methods: We conducted a nested case-control study within a cohort of 5,739 patients enrolled in the CCSS. Forty-seven cases with CHF and 195 matched controls (matched for demographics, follow-up and treatment) were genotyped for 10 genetic polymorphisms in 7 genes: catalase (CAT), GSTP, GSTT, GSTM, superoxide dismutase (SOD 1), NQO1, and CBR3. Results: In the subjects who received anthracyclines, multivariable analyses of CHF risk, adjusted for gender, smoking history, recurrence, and family history of heart disease, showed the GSTP +313A>G polymorphism was a significant risk factor, HR = 5.0, p = 0.01 for the A/G genotype vs. A/A; HR = 3.3, p = 0.19 for the G/G genotype vs. A/A. In addition, a suggested association between CBR3 V244M polymorphism and the risk of CHF after treatment with anthracyclines, HR=10.2, p=0.06 for G/G vs. A/A; HR = 4.0, p=0.18 for G/A vs. A/A was seen in an identical multivariable analysis. Conclusions: These data suggest that specific polymorphic genetic variants on a panel of candidate genes relevant to the anthracycline pharmacodynamics may modify the risk of CHF in childhood cancer survivors. Future studies to further refine the role of these novel genetic risk factors affecting a large population are warranted.

No significant financial relationships to disclose.
Gender affects survival from medulloblastoma only as a function of age: A SEER registry study
Authors: Curran E. K. , Le G. M. , Propp J. M. , Cobb K. L. , Fisher P. G.
Published: March 2020

9005

Background: Males have a higher incidence of medulloblastoma (MB) than females, but studies examining whether gender affects survival are conflicting and limited. We aimed to determine the effect of gender on outcome in MB, via rigorous analysis of a large data set, comprised solely of MB patients. Methods: 1,226 subjects–763 males and 463 females–were identified from 1973 to 2002, using the Surveillance Epidemiology End Results (SEER-9) registry. MB was strictly defined, using histology and site codes, to exclude non-cerebellar embryonal tumors (primitive neuro-ectodermal tumors [PNETs]). Kaplan-Meier analysis and logrank tests were performed using SPSS 12.0. Because children <3 years (yr) of age are known to have worse survival, patients were stratified by age <3 yr at diagnosis (95 male, 82 female) and ≥3 yr (668 male, 381 female). Results: There was no significant difference in overall survival between males and females (logrank p= 0.22; median survival: males 90 months [mo], females 152 mo). Among subjects ≥3 yr, females had significantly greater survival than males (logrank p=.02; median survival: males 93 mo, females 211 mo). In children <3 yr, there was a trend toward worse survival in females (median survival: males 27 mo, females 13 mo), although this was not significant (logrank p=0.24). Females <3 yr comprised a significantly greater proportion of patients with medulloblastoma, compared to individuals ≥3 yr (chi-squared test p=.01). Conclusions: Females with MB have a survival advantage only in subjects ≥3 yr. In children <3 yr, females no longer possess this survival advantage and possibly have a worse outcome. The effect of gender on survival and incidence in MB warrants additional biologic investigation, and may differ in very young children with MB.

No significant financial relationships to disclose.
Temozolomide phase II study in children with relapsing refractory high-risk neuroblastoma
Authors: Rubie H. , Chishlom J. , Defachelles A. , Morland B. , Munzer C. , Valteau Couanet D. , Hargrave D. , Bergeron C. , Coze C. , Djafari L. , Vassal G.
Published: March 2020

9012

Background: To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population. Methods: A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m2 on 5 consecutive days and repeated every 28 days) was undertaken in children with a refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Evidence of activity was defined by radiologic or MIBG scan evidence of sustained reduction in lesion size or activity whenever it occurs. Methodology included a two-step study using Fleming’s method with a first step of 15 patients and a second of 10 additional patients if 2 to 4 responses had been observed in the first cohort. All data were centrally reviewed by a panel. Results: Among 34 registered patients over a 14 month period in 14 centres, twenty five are finally evaluable and received 94 cycles of chemotherapy. Disease status was metastatic NB (n=23) either refractory (n=9) or in relapse (n=14). Grade ¾ thrombocytopenia was the most frequent toxic event (16% of the cycles). Myelosuppression resulted in significant treatment delays and dose reductions (24% and 21% of cycles respectively). Out of 25 patients, response (CR, VGPR or PR) was observed in 5 (RR=20 ± 8%) with a median duration of 6 months. Furthermore a mixed response or an objective effect was observed in respectively 2 and 3 additional patients. Conclusions: Temozolomide is effective in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug

No significant financial relationships to disclose.
Phase I study of concurrent motexafin gadolinium (MGd) with radiation therapy for children with newly diagnosed brain stem gliomas (BSG): A Children’s Oncology Group study
Authors: Bradley K. , Mehta M. , Adamson P. , Ames M. , Jakacki R. , Vezina G. , Ingle A. , Ivy P. , Blaney S. , Pollack I.
Published: March 2020

9014

Background: MGd, a radiosensitizer that selectively accumulates in tumors, generates reactive oxygen species intracellularly. In preclinical experiments, MGd enhances RT-induced apoptosis. Methods: A multi-institutional Phase I dose escalation and pharmacokinetic (PK) study was performed in children with newly diagnosed BSG to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of MGd administered i.v. 2 to 5 hours prior to involved field radiotherapy (RT) (1.8 Gy/day, total 54 Gy). Cohort 1 received MGd, 1.7 mg/kg/dose M-F × 3 wks and cohort 2 received the same dose M, W and F × 6 wks. The 6 subsequent cohorts of 3 to 6 pts received MGd M-F × 6 weeks at doses of 1.9, 3.4, 4.4, 5.5, 7.1 and 9.2 mg/kg/dose. Serum for PK analysis, and MRI scans (MGd is detectable by MR), were obtained for analysis of drug accumulation and responses. Results: 44 pts (42 fully evaluable for toxicity) with a median age of 6 years (range 2–20) were enrolled. At the 9.2 mg/kg/dose, 2/2 pts experienced DLT. During subsequent expansion of the 7.1 and 5.5 mg/kg/dose cohorts, DLTs, including transaminitis, hypertension and urticaria, were observed in 2/5 and 2/6 pts. At the MTD of 4.4 mg/kg/dose, 1/6 pts had reversible grade 3 serum transaminase elevations. PK analysis showed biphasic elimination with a terminal t 1/2 of 6.4 h. At the MTD, serum MGd concentrations were >250 ng/ml for 24 h. Serum clearance and steady-state volume of distribution were 0.0243 L/h/kg and 0.162 L/kg. MRI for intra-tumoral MGd distribution is ongoing. One patient had a CR and 4 had a PR. The estimated median survival is 10.3 months (95% confidence interval: 8.1 months-11.5 months). Conclusions: The recommended phase II dose of MGd for children with BSG is 4.4 mg/kg/d administered M-F × 6 weeks with involved field RT. A COG phase II trial is planned.

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A phase I study of bortezomib (PS-341) in pediatric patients with relapsed or refractory leukemia: A Children’s Oncology Group study
Authors: Horton T. M. , Thompson P. A. , Bomgaars L. R. , Adamson P. C. , Krailo M. , Ingle A. , Blaney S. M.
Published: March 2020

9021

Background: Bortezomib is a 26S proteasome inhibitor that is effective as a single agent for the treatment of multiple myeloma in adults. Bortezomib at a dose of 1.2 mg/m2 is well tolerated as a single agent in pediatric patients with solid tumors. This phase 1 study examined the tolerability and efficacy of bortezomib in pediatric patients with relapsed/refractory leukemia. Methods: Cohorts of 3–6 patients received bortezomib administered twice weekly (days 1, 4, 8 and 11) for two weeks every 21 days. Pharmacokinetics and NF-κB activation status were examined in peripheral blood mononuclear cells (PBMC) at 6, 12, and 24 hours following the first dose of bortezomib, and from bone marrow leukemic cells before treatment and on days 8 and 18 of the first treatment cycle. Results: Twelve patients (4 female, 8 male) (ALL=9, AML=3), median age 11y (range 1–18y), were enrolled at the 1.3 mg/m2 (6 enrolled, 3 evaluable) or 1.7 mg/m2 (6 enrolled, 2 evaluable) dose levels. Patients not fully evaluable for toxicity experienced disease progression prior to completing the first 21-day cycle of therapy. Two DLTs occurred at the 1.7 mg/m2 dose level. One patient had altered mental status and the other patient had febrile neutropenia associated with Grade 3 hypotension, Grade 4 renal insufficiency and hypoxia, followed by death on day 9 of cycle 1. No CRs or PRs were observed in the 10 patients evaluable for response. One patient had SD for 2 cycles. PK analysis (n= 5) revealed a Cl of 0.62 L/min/m2, Vd of 13 L/m2, and a terminal T1/2 of 12.6 h. NF-κB activation was inhibited in the leukemic blasts of 2 patients examined to date. Conclusions: Bortezomib was tolerated at 1.3 mg/m2 in children with relapsed/refractory leukemia. Although bortezomib appeared to inhibit NF-κB activation, it was ineffective as a single agent for pediatric leukemia treatment.

No significant financial relationships to disclose.
Increase of creatine kinase value (CK) correlates with muscoloskeletal complaints (MSC) in GIST patients during imatinib therapy
Authors: Allione P. , Grignani G. , Aliberti S. , Rota Scalabrini D. , Carnevale Schianca F. , Capaldi A. , Vormola R. , Caravelli D. , Galla A. , Aglietta M.
Published: March 2020

9509

Background: MSC-pain, muscle cramps, myalgias, arthralgias-are commonly associated with imatinib therapy, affecting 25% to 50% of patients. The cause is still unknown. MSC is usually mild to moderate and manageable without reduction of imatinib dose. Calcium and magnesium supplements have occasionally provided some relief. It is rather difficult to quantify MSC and patients who deserve interruption or analgesia on the base of symptoms alone. Since CK values are commonly elevated during imatinib therapy, we evaluate CK as a surrogate marker of MSC. Methods: Since 2002, 40 patients (pts) affected by advanced GIST were treated with imatinib 400 mg/day until progressive disease when dosage would be increased to 800 mg/day. Toxicity (CTC 2.0) and blood chemical values were prospectively collected on a monthly basis. Results: G1–2 MSC was observed in 22 pts (55%). We had to stop therapy in one patient only for one week because of uncontrolled MSC. CK was abnormal in 23 pts (57%). 13 pts (32%) had CK values up to twice upper normal value (UNV); 8 pts (20%) above thrice the UNV and 2 pts (5%) above 5 times the UNV. Among 10 pts having MSC G2, seven had CK above thrice UNV. The 2 pts experiencing MSC G3 had also CK above 5 times UNV. Conclusions: CK increase reflects MSC in a great majority of the patients who experienced this rather common imatinib side effect. To consider CK into standard clinical chemistry work up of patients on imatinib allows clinicians to add an objective measure of MSC.

No significant financial relationships to disclose.
A SARC phase II multicenter trial of imatinib mesylate (IM) in patients with aggressive fibromatosis
Authors: Chugh R. , Maki R. G. , Thomas D. G. , Reinke D. , Wathen J. K. , Patel S. , Priebat D. A. , Meyers P. A. , Benjamin R. S. , Baker L. H.
Published: March 2020

9515

Background: Aggressive fibromatosis (desmoid tumors, AF) are uncommon, locally aggressive, connective tissue neoplasms. Existing literature on systemic treatment of AF is sparse and consists mostly of case reports and small case-series. Based on previous observation of regression of AF treated with IM and tumoral expression of IM targets, SARC (Sarcoma Alliance for Research through Collaboration) included the treatment of AF onto a multi-institution phase II trial of IM in sarcoma. Here we report early clinical and laboratory results of the AF group. Methods: Eligible patients had histologically proven AF, unresectable or difficult to resect without considerable functional impairment. Patients were treated with IM 300 mg po BID (BSA≥1.5m2). The primary endpoint was complete (CR) or partial response(PR) at two months or stable disease (SD) or better at four months. Tumor DNA was extracted from available formalin fixed paraffin embedded tissue specimens and analyzed via allelic PCR and genomic DNA sequence analysis for specific point mutations in PDGFRα exons 12/14/18, PDGFRβ exons 12/18, KIT exons 9/11/13/17, and bRAF. Results: 51 patients were enrolled from 10/02 to 12/05 at 5 institutions, with 45 patients currently evaluable. The median age is 37 (range 14–67), and median number of prior therapies is 1 (range 0–3). 36 patients (80%) reached the primary endpoint of CR/PR at 2 months or SD or better at 4 months. The median time to treatment failure is 6.8 months (95% C.I. 5.8–17.1). Thus far, the maximum change in the largest dimension of the tumor ranged from a 21% increase to a 45% decrease. In 22 available tumor specimens, deletions within PDGFRαE12 and E18 were noted in 1 and 3 patients, respectively, while a wildtype genotype was found in other regions. Conclusions: IM has activity in AF, the mechanism of which remains unclear. While this is the largest reported phase II trial of AF, further improvement in evaluating clinical efficacy in this disease is clearly necessary. We plan an analysis of the maximum change in largest tumor dimension for each patient, which will be particularly beneficial in AF as responses often occur late. We have not as yet identified a laboratory predictor of clinical benefit. Further investigation of other potential targets in fresh tissue is warranted.

[Table: see text]
Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate
Authors: Blanke C. D. , Demetri G. D. , Von Mehren M. , Heinrich M. C. , Eisenberg B. L. , Fletcher J. , Corless C. L. , Wehrle E. , Sandau K. B. , Joensuu H.
Published: March 2020

9528

Background: Imatinib achieves tumor control in most pts with advanced GIST, but the durability of remissions has not been well described. We now present an updated long-term analysis of a randomized phase II trial first presented in 2001, with a median follow-up of 52 months. Methods: 147 pts with unresectable or metastatic malignant GIST were randomized to treatment with daily dosing of imatinib, 400 or 600 mg po. Results: Two pts (1%) achieved a complete response, 98 (67%) achieved a partial response (PR), and 23 (16%) exhibited stable disease (SD) as their best response. Median time-to-response was 13 weeks (95% CI; 12–23 weeks), but one quarter of pts responded after 23 weeks. No significant response differences were seen between the two dose levels tested. The median duration of response was 27 months, and median overall survival was 58 months. Pts with SD or PR had similar 4-year survival rates (64% versus 62%). KIT and/or PDGFRA mutational analyses were obtained in 87% of patients, and the mutational status was highly significant in predicting outcome. GISTs harboring KIT mutations in exon 11, exon 9, and with no detectable mutations in KIT or PDGFRA demonstrated PR rates of 87%, 48%, and 0%, respectively. The median survival for pts with exon 11 KIT mutations has not yet been reached, and it was 45 months for those with exon 9 mutations. Conclusions: While late progression can be seen in GIST pts treated with imatinib, the majority of pts derive benefit. Survival in those achieving SD parallels those with PRs. Late responses are often seen in pts with initial SD, and responses in general are of lasting duration. In particular, pts with KIT mutations in exon 11 (the most common exon affected) have very high response rates and favorable long term survival.

[Table: see text]