bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and Efficacy of CBV Followed by Autologous PBSC Transplant in Children with Lymphoma after Failed Induction or First Relapse - a Children’s Oncology Group Study.
Authors: Harris Richard E. , Morris Erin , Warkentin Phyllis , Vlachos Adrianna , Chang Myron , Cairo Mitchell S. 
Published: October 2019

Abstract
Purpose: To determine the safety and efficacy of high dose cyclophosphamide, BCNU and etoposide (CBV) chemotherapy followed by autologous non-purged PBSCT in children with Hodgkin’s (HD) and non-Hodgkin’s lymphoma (NHL) who have either failed primary induction therapy or have experienced a first relapse.
Methods: At study entry, patients received 2–4 courses of reinduction therapy as determined by the local institution. When a CR or PR was achieved, G-CSF mobilized PBSCs were harvested and patients underwent autologous PBSCT after a preparative therapy of cyclophosphamide 6000 mg/m2, BCNU 450–300 mg/m2, and etoposide 2400 mg/m2. Patients were to receive a set dose of 5x106 CD34 cells/kg. Patients were followed for disease status and toxicities. 69 patients (38 HD, 31 NHL) were entered onto study between April 1998 and June 2002. Survival statistics were calculated as Kaplan Meier estimates.
Results: 41/69 (27/38 HD, 14/31 NHL) achieved a CR/PR at the conclusion of reinduction; 14 failed due to PD; 7 had SD; 7 were inevaluable. 38 patients (27 HD, 11 NHL) proceeded to autologous PBSCT. Overall 28/38 (20 HD, 8 NHL) of the transplanted patients survive and 21/28 (15 HD, 6 NHL) are progression free. The survival rates at 12 months and 24 months were 88%(±6) (HD 92%(±6), NHL 78%(±14)) and 73%(±10) (HD 76%(±11), NHL 65%(±22)), respectively. The rates of PFS at 12 months and 24 months were 65%(±8)(HD 72%(±9); NHL 46%(±17)) and 53%(±11) (HD 56%(±12); NHL 46%(±19)), respectively. 10 patients died after PBSCT. The causes of death were PD (N=5), infection (N=4), and toxicity (N=1). The first 17 patients received BCNU 450 mg/m2 and 8 of these experienced grade 3 or 4 pulmonary or renal toxicity. The dose was thus dropped to 300 mg/m2 and an additional 21 patients underwent PBSCT and 3 of these patients developed grade 3 or 4 pulmonary or renal toxicity. The incidence of grade 3 or 4 pulmonary of renal toxicity at 300mg/m2 was significantly lower than that at 450 mg/m2 (p=0.04, Fisher’s exact test).
Conclusions: For children with primary resistant or first relapsed lymphoma who achieve a CR or PR after reinduction, CBV preparative therapy followed by PBSCT for children with primarily resistant or relapsed lymphoma results in an acceptable survival but a lower PFS due to a high relapse rate following transplant. A BCNU dose of 300 mg/m2, but not a dose of 450 mg/m2 is well tolerated by these heavily treated patients.
Outcomes of Autologous and Allogeneic BMT for Mantle Cell Lymphoma.
Authors: Kasamon Yvette L. , Jones Richard J. , Diehl Louis F. , Nayer Hassan , Borowitz Michael J. , Garrett-Mayer Elizabeth , Ambinder Richard F. , Abrams Ross A. , Zhang Zhe , Flinn Ian W. 
Published: October 2019

Abstract
To evaluate BMT outcomes in patients (pts) with newly diagnosed or relapsed mantle cell lymphoma, 58 consecutive pts were selected through the BMT registry at Johns Hopkins. Flow cytometric and immunohistochemical features were confirmed. Fifty-four pts (88%) had stage III or IV disease and 39 (67%) had documented bone marrow involvement at diagnosis. First-line therapy was CHOP +/− rituximab in 71% and was fludarabine-based in 17%. Thirty-seven pts (64%) were transplanted after first partial or complete remission, 14 pts (24%) after one or more relapses, and 12% after primary induction failure (PIF). Median age at BMT was 55 years. Thirty-eight pts (66%) received autologous (auto) BMT, 19 pts (33%) allogeneic (allo) BMT, and 1 pt syngeneic BMT. Preparative regimens in all but 1 case consisted of cyclophosphamide plus busulfan or total body irradiation. The estimated 3-year event-free survival (EFS) following BMT was 51% (95% CI, 35–65%), probability of relapse 31% (17–51%), and overall survival 59% (42–73%). Median follow-up is 16 months (range < 1 month to 79 months) for all pts and 23 months for surviving pts. Twelve relapses were documented, 8 after auto BMT. Four auto pts and 1 allo pt are alive with relapsed disease, and 3 auto pts developed MDS or AML. Actuarial EFS at 3 years was 57% (CI 35–74%) after auto BMT and 37% (17–57%) after allo BMT. Actuarial relapse rate at 3 years was 34% following auto BMT and 19% following allo BMT. On multiple regression analysis, BMT after one or more relapses (HR 3.0, CI 1.2–7.4, P = 0.02), PIF (HR 5.4, CI 1.9–15.4, P = 0.002), and allo BMT (HR 3.0, CI 1.3–6.8, P = 0.007) predicted an inferior EFS;
Figure Figure
whereas PIF and residual bone marrow involvement independently predicted relapse. Notably, however, EFS curves were not statistically different for auto and allo BMT performed in first remission, with the 3 year EFS approaching or equaling 70%.
Figure Figure
The benefit of BMT for mantle cell lymphoma is thus most apparent when performed in first remission. While the comparative efficacy of auto and allo BMT remains to be determined, allo BMT warrants continued study especially early in the disease course.
KIT Exon 8 Mutations Associated with Core Binding Factor (CBF) - Acute Myeloid Leukemia (AML) Cause Hypersensitivity of KIT to Its Natural Ligand Stem Cell Factor.
Authors: Kohl Tobias M. , Schnittger Susanne , Hiddemann Wolfgang , Spiekermann Karsten 
Published: October 2019

Abstract
Mutations in the extracellular portion of the KIT receptor tyrosine kinase (exon 8 mutations) are strongly associated with core binding factor (CBF) - acute myeloid leukemia (AML), but the functional role of these mutations has not been elucidated. In 93% of cases, codon Asp419 is deleted and exon 8 mutations were reported to confer an impaired prognosis to patients with CBF-AML. In this study, we are the first to report pro-proliferative and antiapoptotic potential of representative KIT exon 8 mutations in a cell culture model and to show a significant difference to KIT wildtype (KIT-WT). Three representative exon 8 mutants including a single deletion of codon 419 were created by in vitro site-directed mutagenesis. The integrity of all constructs was assessed by complete nucleotide sequencing. After stable expression in IL-3 dependent Ba/F3 cells (confirmed by FACS analysis and immunoblotting), exon 8 KIT mutants were characterized by a hypersensitivity to stem cell factor (SCF) stimulation in terms of proliferation and resistance to apoptotic cell death. The differences to KIT-WT occurred in the physiological range of SCF from 1 to 10ng/ml. The proliferative response caused by stimulation with SCF was reversed in KIT-WT and exon 8 mutants in the presence of Imatinib® (Novartis) in contrast to the activation loop mutant D816V which could not be inhibited. These biological effects were confirmed by demonstrating increased phosphorylation of the KIT downstream targets mitogen-activated protein kinase (MAPK) and AKT after SCF stimulation compared to the KIT-WT receptor. Furthermore, the MEK inhibitor PD98059 and the PI3 kinase inhibitor LY294002 resulted in a dose dependent inhibition of SCF induced proliferation in exon 8 mutants. Our data show that KIT exon 8 mutations represent gain-of-function mutations by inducing receptor hypersensitivity to its ligand SCF by activation of MAPK and PI3K and might represent a new molecular target for treatment of CBF leukemias.
High-Dose Chemotherapy with Autologous Stem Cell Support Is Not Superior to Conventional-Dose Chemotherapy in the First-Line Treatment of Aggressive Non-Hodgkin Lymphoma - Results of a Comprehensive Meta-Analysis.
Authors: Greb Alexander , Schiefer Daniel H. , Bohlius Julia , Schwarzer Guido , Engert Andreas 
Published: October 2019

Abstract
Background: High-dose chemotherapy with autologous stem cell support (HDT) has been proven effective in relapsed aggressive Non-Hodgkin lymphoma (NHL). However, conflicting results of HDT as part of first-line treatment have been reported in randomized controlled trials (RCTs). Here, we report our updated meta-analysis to better define the role of HDT in these patients.
Methods: RCTs were identified by computerized search and handsearching of conference proceedings. Data extraction and quality assessment was performed independently by two reviewers. First authors were contacted to request individual patient data. Eight investigators provided us with individual patient data, for five trials data were extracted from survival curves. The hazard ratio (HR) was used as a measure of treatment effect; the inverse variance method (fixed effect model) was used for pooling. The relative risk was determined for binary data.
Results: 15 RCTs including 3079 patients were eligible for this meta-analysis. Overall treatment-related mortality was 6.0% in the HDT group and not significantly different compared to conventional chemotherapy (RR 1.33, p=0.59). Analysis of 13 studies including 2018 patients showed significantly higher CR rates in the group receiving HDT (RR 1.10, p=0.004). However, HDT did not have an effect on OS, when compared to conventional chemotherapy. The pooled HR was 1.04 (p=0.58). There was no statistical heterogeneity among the trials and sensitivity analyses underscored the robustness of these results. Subgroup analysis of prognostic groups according to IPI did not show any survival difference between HDT and controls in 12 trials (low and low-intermediate risk IPI: HR 1.41, high-intermediate and high risk IPI: HR 0.97). Event-free survival (EFS) also showed no significant difference between HDT and CT (HR 0.93, p=0.31). We incorporated several additional variables to possibly identify other risk factors such as the proportions of diffuse large cell lymphoma, protocol adherence, the HDT strategy used, response status of patients before HDT, the conditioning regimen used, and methodological issues. However, our analyses demonstrate that the results described here are not related on either of these factors.
Conclusion: Despite higher CR rates, there is no benefit for HDT in patients with aggressive NHL when incorporated in first-line treatment.
Successful Treatment of AL Amyloidosis Patients over Age 65 with High-Dose Melphalan and Autologous Stem Cell Transplantation (HDM/SCT).
Authors: Seldin David Cary , Anderson Jennifer J. , Skinner Martha , Malek Karim , Wright Daniel G. , Quillen Karen , Sanchorawala Vaishali 
Published: October 2019

Abstract
Over the past 10 years, HDM/SCT has been employed for treatment of patients with AL amyloidosis. Although peri-transplant mortality is greater than for other hematologic diseases, HDM/SCT leads to durable hematologic complete responses (CR), improvements in organ function, and extended survival in a substantial proportion of patients (Skinner et al., Ann. Int. Med. 2004). In that study, the proportion of patients eligible for HDM/SCT was lower for patients >65 years of age than for younger patients (34.3% vs. 68.4%), but the hematologic complete response (CR) rate and survival appeared to be no different. Here, we update these results and present a detailed analysis of outcomes in patients >65 vs. those <65. Data were collected with IRB approval. Through 07/01/04, 349 patients began G-CSF mobilization, of which 66 (19%) were >65. The median age of the 66 patients was 68, range 65–80; 73% male; 18% ? and 82% ?, while for the 283 patients <65, the median age was 55, range 29–64; 57% male; 16% ? and 84% ?. The median number of involved organs was no different in the two groups, nor was the type of organ involvement or performance status. There was also no difference in the rate of serious complications during stem cell collection, as a similar fraction of patients in both groups did not proceed to transplant, 12.1% of patients >65 versus 10.3% of patients <65 (p=.659). Based on treatment protocol, only 19% of patients >65 received an IV dose of melphalan of 200 mg/m2 (the remainder being treated with 140 mg/m2 or less), vs. 64% of those <65 (p <.001). There was no difference in early transplant-related mortality (10.3% in patients >65 vs. 13.4% in patients <65, p=.665). There was also no difference in one year mortality (22.4% for those >65 vs. 20.9% for those <65, p=.859). There was a non-significant trend towards a lower rate of hematologic CR in the older patients (32% vs. 44%, p=0.155). However, the median survival after HDM/SCT was no different (see fig; 4.9 years for patients >65 vs. 4.6 years for those <65, p=0.42 by log-rank test). Thus, while fewer patients >65 meet eligibility requirements for HDM/SCT, for those who do, treatment-related mortality, hematologic CR rate, and survival are no different than for younger patients. These data strongly support the use of HDM/SCT for suitable patients with AL amyloidosis who are >65 years old.
Figure. Figure.
Follow up Analysis for MRC Myeloma VII Trial.
Authors: Morgan Gareth J. , Davies Faith E. , Hawkins Kim , Bell Susan E. , Brown Julia M. , Owen Roger G. , Drayson Mark T. , Selby Peter J. , Child Anthony J. ,   for the Medical Research Council Adult Leukaemia Working Party
Published: October 2019

Abstract
The results of the MRC Myeloma VII trial and overview analysis of comparable trials have suggested that VAD-like induction chemotherapy followed by high dose therapy (HDT) with autologous transplantation may be regarded as a new standard treatment for multiple myeloma. However, there is a need for data from the extended follow up of patients in such trials to provide confirmatory evidence of the benefit of treatment incorporating HDT compared with conventional dose treatment, in particular to determine the long term difference in survival and the impact of attaining a complete response (CR) following intensive treatment. We present an updated analysis of Myeloma VII with median follow up of 5.5 years. Myeloma VII is the largest trial of its type in which patients with previously untreated multiple myeloma, age <65 years, were randomized to receive either standard conventional-dose combination chemotherapy (ABCM) or a sequence of treatment, C-VAMP followed by high dose therapy (HDT), typically melphalan 200g/m2 with autologous stem cell transplant. The planned maintenance in both arms was interferon α-2a. The trial, initiated in 1993 and closed to entry in 2000 and was conducted to MRC guidelines for good clinical practice in clinical trials. In the 401 evaluable patients the CR rate was 44% in the intensive therapy group, 8% in the standard therapy group (p<0.001). Intention to treat analysis showed a survival benefit of 14.1 months in the intensive arm (Figure 1); median 56.3 months (95% CI 46.0–74.6) vs. 42.2 months (95% CI 33.1–48.9), p=0.004 (log rank test). Progression free survival was also improved in the intensive group, median 31.2 months (95% CI 27.1–37.5) compared with 19.5 months (95% CI 16.2–21.6) in the standard group (p=<0.001). This analysis provides confirmatory evidence that treatment including high dose therapy is superior to conventional dose chemotherapy. Long term follow up of this study shows that the benefits of intensive treatment are maintained long term and that an important therapeutic aim is the achievement of CR. For the patients receiving the full protocol, the differences are accentuated, implying that maximising numbers of patients getting to transplant is an important therapeutic aim. These results would also support the continuing development of peri-HDT strategies to further improve outcomes.
Figure Figure
Hsp90 Inhibitors Induce Apoptosis in Human Leukemia Cells.
Authors: Campos Lydia , Flandrin Pascale , Olaru Daniela , Guyotat Denis 
Published: October 2019

Abstract
The 90-Kda heat shock protein (Hsp90), together with a number of other chaperones are involved in normal cellular differentiation and cancerogenesis. Hsp90 is implicated in the conformational maturation of a large variety of protein kinases. We have shown its overexpression in a series of 116 acute myeloid leukemias (AML). Geldanamycin and its analogue 17-AAG selectively block the activities of Hsp90, but do not interact with other members of the Hsp family. The objective of the study was to test the effect of 17-AAG on cell lines (Jurkat, U-937, HL60, HL60R : resistant to daunorubicin (DNR), and KG1a) and on 24 AML samples tested positive for Hsp90 (14 strongly positive and 10 moderately positive). CD34+ cells from bone marrow donors were used as controls. Cells were maintained in liquid culture in the presence or absence of 17-AAG. Moreover hematopoietic and leukemic progenitor assays were performed in semi-solid media containing or not 17-AAG. CD34+ cells were non affected by 17-AAG. Jurkat, U937, HL60 were partially sensitive to 17-AAG. Addition of low dose DNR to 17-AAG induced an apoptotic death in 48 hours in all samples, including HL60R. KG1a (exhibiting high HSP90 levels) was more sensitive to 17-AAG alone with a death rate of 100% at higher doses. A similar effect was observed in AML samples : 17-AAG induced cell death in all 14 cases highly positive for HSP90, but a partial death in 5 cases, and no death in 5 cases mildly positive for HSP90. DNR increased apoptosis in only 5/10 of these cases. The other 5 patients were also positive for bcl-2. When they were first incubated with 17-AAG and then treated with bcl-2 antisens oligodeoxynucleotides (bcl-2AS), a complete apoptosis was obtained. So, in the 10 samples with moderate HSP90 expression a synergystic effect was found when a combination of 17-AAG with either chemotherapy or bcl -2AS was used. While normal progenitors were not affected by 17-AAG, leukemic progenitors were completed inhibited in the 14 patients who responded to 17-AAG in liquid culture. This apoptosis was caspase -3 dependant. Finally, we investigated the implication of the ERK signal pathway in Jurkat line and in 14/24 17-AAG responder samples using an ERK inhibitor (PD98059). When this inhibitor was added prior to 17-AAD and DNR, the apoptotic effect was completely inhibited. So, ERK signal pathway may interfere with the Hsp90 function. In conclusion, these results raise the possibility that Hsp90 antagonists represent a novel antileukemic strategy in sequential addition to conventional chemotherapy
Safety of Total Therapy III for Newly Diagnosed Multiple Myeloma: Preliminary Analysis of 62 Consecutive Patients.
Authors: Anaissie Elias J. , Miceli Marisa H. , Dong Li , Saghafifar Fariba , Talamo Giampaolo , Hollmig Klaus A. , Tricot Guido , Barlogie Bart 
Published: October 2019

Abstract
Background: Total therapy III (TT-III) is designed to improve the outcome of newly diagnosed myeloma (MM) patients (pts), especially those presenting with unfavorable cytogenetics. Induction employs 2 cycles of V-DTPACE (Velade™, dexamethasone, thalidomide, cisplatin, adryamycin®, cytoxan®, etoposide) followed by tandem melphalan 200 mg/m2 autologous stem cell transplants (ASCT).
Objective: to evaluate the safety outcome of TT-III pts. Materials and
Methods: Prospective evaluation of the toxicities occurring throughout treatment in 62 TT-III pts enrolled between February and July 2004.
Results: Median age was 59 years (range: 23–74) and 41 pts (66 %) were males. The 1st and 2nd induction cycles were completed in 42 (68%) and 22 (35%) pts respectively, whereas 19 pts (31%) underwent their 1st ASCT. Infections and/or Grades III–IV gastrointestinal tract (GIT) toxicities (NCI Common Toxicity Criteria) were observed throughout treatment in 32 (76%) patients (table). One treatment-related death occurred in an 80 y.o. male with significant pre-existing comorbidities.
Conclusion: Gastrointestinal tract toxicities and pneumonia were the most frequent complications following TT-III. Studies are ongoing to identify the risk factors for and interventions to decrease their incidence and severity.
Infections and Grade III -IV GIT toxicities throughout TT-III
Toxicity Cycle 1 (n=42) Cycle 2 (n=22) 1st ASCT (n=19) Pneumonia 7 (17%) 1 (5%) 2 (11%) Bacteremia 2 (5%) 4 (18%) 2 (11%) Septic Shock 1 (2%) - - C. difficile colitis 2 (5%) - - Febrile neutropenia 2 (5%) 2 (10%) 5 (26%) Sinusitis 2 (5%) - - Cellulitis 1 (2%) - - Mucositis 5 (12%) - 7 (37%) Nausea/vomiting 15 (36%) 4 (18%) 12 (63%) Diarrhea 3 (7%) - 4 (21%)
Rapid Response to Treatment of Multiple Myeloma Detected with FDG PET Scanning in Multiple Myeloma - Early Results from Total Therapy III.
Authors: Walker Ronald , Jones-Jackson L. , Rasmussen Eric , Miceli M. , Anaissie Elias , Epstein Joshua , Tricot Guido , Shaughnessy John , Barlogie Bart 
Published: October 2019

Abstract
Fluorodeoxyglucose Positron Emission Tomography (PET) scanning can rapidly detect and quantify changes in tumor metabolism. We present early results from the first 47 patients enrolled in Total Therapy III for multiple myeloma using PET scanning and correlating with serum M protein. Since we have previously demonstrated that diffuse uptake patterns do not have prognostic significance, we have limited our assessment of these 47 patients to those with one or more PET-defined focal lesions (FL) at baseline who have had at least one follow-up PET scan (25 patients). Of this group of 25, 10 have had a second follow-up scan. These whole body PET scans were performed at baseline and at time points corresponding to immediately after two cycles of VDT-PACE, landmarks LMK1 and LMK2. Patients with complete resolution of FL on PET are considered to be in PET-CR. We find that 17/25 (68%) had a decrease in number of FL from baseline to LMK1 and 8/10 (80%) had a decrease in number of FL from baseline to LMK2. In addition, 6/25 (24%) were in PET-CR by LMK1 and 3/10 (30%) in PET-CR by LMK2. Similarly, a decrease in serum M-protein was seen in 16/25 (64%) from baseline to LMK1 and in 8/10 (80%) from baseline to LMK2.
At baseline, 10 patients had serum M protein levels of 0.01 g/dl or less. Of these, 8 (80%) had PET-defined focal lesions, demonstrating PET’s ability to monitor tumor metabolism in the face of hypo- or non-secretory disease. Of these, 7 have been enrolled sufficient time to have a second PET scan, with 6/7 (86%) demonstrating a continuing decrease in number of FL in response to treatment. At baseline, PET detected 5 of 47 patients with extramedullary disease (EMD), a finding of severe adverse prognostic significance at baseline. Of these patients, all had FL at baseline PET and all had decreasing number of FL on first follow-up PET scan (two have had a second follow-up scan, one improving and one PET-CR). One of these patients with EMD is nonsecretory.
From these data, we conclude that functional imaging with PET scanning offers important and unique information about early tumor response that improves patient management by demonstrating rapid change in response to treatment that not only parallels serum M-protein response but which also is reliable in hypo- or non-secretory disease as well as in detection and monitoring of extramedullary tumor, an ominous condition that is particularly difficult to detect in the hypo- or non-secretory patient.