bluuebunny/crossref_metadata_2025_split huggingface dataset:
mTOR Activation Is Necessary for Primary AML Cells to Survive Genotoxic Stress.
Authors: Xu Qing , Thompson J. , Carroll Martin 
Published: October 2019

Abstract
The signaling pathways that regulate the survival of AML cells and whether those pathways can be targeted therapeutically are still poorly defined. We have previously demonstrated that AML cells require PI3 kinase activation for survival but clinical targeting of PI3 kinase itself is not currently feasible. Therefore, we have chosen to study the role of the mammalian target of rapamycin or mTOR protein in the survival of leukemic cells. mTOR mediates the effects of PI3 kinase and can be inhibited by the immunosuppressant, rapamycin. For these studies, patient samples were collected from patients seen at the Hospital of the University of Pennsylvania and we selected samples with greater than 75% blast cells for analysis. Here we show that mTOR is activated in over 90% of patient samples examined as shown by constitutive phosphorylation of the mTOR target protein, p70 S6 kinase (p70S6K). A second substrate, 4EBP1, is phosphorylated in the majority of AML samples but less consistently than p70S6K. Inhibition of mTOR with rapamycin caused only a modest 20% decrease in cell survival based on a 48 hour in vitro assay. Strikingly, however, when AML blasts were incubated with a combination of a topoisomerase II inhibitor, etoposide, and rapamycin, the dose response to etoposide was shifted to the left with the ED50 decreased by at least one log in each of 5 tested samples. Rapamycin inhibited mTOR as shown by inhibition of p70S6K phosphorylation and this inhibition was not altered in the presence of etoposide. To determine if combinations of rapamycin and etoposide would have combined effects on leukemic stem cells, AML cells were incubated in etoposide alone or etoposide with rapamycin for 16 hours and then transplanted into NOD/SCID mice for analysis of stem cell survival. Engraftment of AML cells into NOD/SCID animals was decreased by etoposide and this inhibition was increased by the combination of etoposide and rapamycin. These studies suggest that mTOR regulates a critical cell survival pathway in AML stem cells and this pathway is necessary for survival in the presence of a distinct apoptotic signal. Furthermore, these studies suggest that combinations of rapamycin with chemotherapy may enhance the efficacy of chemotherapeutic agents in the treatment of AML and, therefore, we have recently initiated a Phase I trial of rapamycin in combination with MEC chemotherapy for the treatment of relapsed AML.
Lower Relapse Incidence after Non-Cryopreserved Autologous Bone Marrow Transplantation Compared to Peripheral Blood Stem Cell Transplantation for High-Risk Hodgkin’s Lymphoma.
Authors: Holowiecki Jerzy , Giebel Sebastian , Krawczyk-Kulis Malgorzata , Wojnar Jerzy , Kachel Lucja , Sadus-Wojciechowska Maria , Stella-Holowiecka Beata , Grosicki Sebastian , Czerw Tomasz 
Published: October 2019

Abstract
In a number of studies on Hodgkin’s lymphoma (HL), autologous transplantation of peripheral blood hematopoietic stem cells (autoPBSCT) was proved to result in faster hematopoietic recovery compared to bone marrow transplantation (autoBMT), however, no difference regarding long-term outcome has been demonstrated so far. In Katowice transplant centre we developed a new method of autoBMT with bone morrow not-cryopreserved but stored for 3 days in 40C and reinfused 24 hours after completion of CBV conditioning. In this study we analyzed outcome of 40 HL patients treated with this method in comparison with 125 patients given autoPBSCT between 1993–2004. In this setting patients were treated with CBV (n=32), BEAM+/− procarbazine (n=63) or other preparative regimens (n=30). In the autoBMT group patients were transplanted in high-risk CR1 (achieved after >1 line of therapy) (25%), CR>=2 (22.5%), PR1 (35%), PR>=2 (5%), and primary or secondary refractoriness (12.5%). The indications for autoPBSCT were comparable. As well, both groups did not differ in terms of age, histological subtype, disease stage at diagnosis, organ involvement or preceding therapy.
At six years, the overall- and progression-free survival for autoBMT and autoPBSCT group equaled 88% vs. 72% (p=0.1) and 69% vs. 54% (p=0.08), respectively. The relapse incidence was significantly lower for patients given autoBMT compared with autoPBSCT (23% vs. 41%, p=0.03). In a univariate analysis, among other analyzed factors (age, disease stage at diagnosis and at transplantation, organ involvement, histological subtype, conditioning regimen, preceding therapy), the only factor influencing the risk of relapse was disease status at transplantation (CR or PR vs. NR - 32% vs. 62%, p=0.001). In a multivariate analysis the impact of both disease status (p=0.001) and the source of stem cells (p=0.04) remained statistically significant. The 100 days incidence of non-relapse mortality equaled 2.5% for autoBMT and 1% for autoPBSCT (p=NS). The neutrophil >0.5 G/L recovery was faster in the autoPBSCT group compared with autoBMT (14.7 vs. 17 d., p=0.006) whereas the difference regarding platelet >50 G/L recovery was not significant (17.5 vs. 19 d., p=NS). Both procedures did not differ in terms of severe adverse events as well as the need for blood products substitution, iv antibiotic therapy, cytokine tharapy or the time of hospital stay. CONCLUSION: AutoBMT without cryopreservation results in lower relapse rate in high-risk HL patients compared with autoPBSCT. Although the neutrophil recovery is longer by 2.5 days, the toxicity of both procedures as well as the need for supportive treatment is comparable.
A Prospective Phase II Comparison of Stem Cell Source Using Rituximab, Ifosfamide, Carboplatin, Etoposide (RICE) RE—Induction, Then High Dose Fludarabine, Busulfan (FLUBU) and Autologous (ASCT) or Allogeneic (AlloSCT) Hematopoietic Blood Stem Cell Transplantation for Mantle Cell (MCL) and Relapsed Low-Grade B-Cell Non-Hodgkin’s Lymphoma (NHL).
Authors: Stewart Douglas A. , Voralia Michael , Chaudhry Ahsan , Jeje Oluyemi , Morris Donald , Savoie Lynn , Brown Chris , Hasagawa Wanda , Bahlis Nizar , Russell James R. 
Published: October 2019

Abstract
Introduction: A “genetically-randomized” prospective phase II study was designed to compare stem cell source following novel, uniform, and expected low toxicity re-induction and high dose chemotherapy for indolent B-cell NHL.
Patients and Methods: Pts with MCL in 1st remission or 1st relapse, or other indolent B-cell lymphoma in 1st or 2nd relapse were eligible providing adequate organ function and age <65 years. Pts received RICE (Rituximab 375mg/m2 d1,8,15,22, Ifosfamide 1.67g/m2 d16-18, Carboplatin AUC=5 d17, Etoposide 100mg/m2 d16-18), with G-CSF d22-30, and apheresis d29-31 if ASCT, then FluBu (Fludarabine 50mg/m² d-6to-2, Busulfan 3.2 mg/kg IV daily d-5to-2) and SCT d0. GVHD prophylaxis for AlloSCT involved ATG 4.5mg/kg, MTX and CSA.
Results: The initial 43 pts accrued from 06/2001-03/2004 included Follicular=30, MCL=7, SLL=4, other histology=2. Disease status was 1st remission=2, 1st relapse=18, 2nd relapse=12, 10 refractory=11. The median EFS following most recent prior chemotherapy was 7 mos. RICE resulted in an overall RR of 72%. Blood stem cell source was ASCT=27, donor SCT=16 (related=14, unrelated=1, syngeneic=1). For ASCT, a median of 5.9 (1–14.5) x106 CD34+ cells/kg were collected from 1 (n=17) or 2 (n=10) 15-25L aphereses. Three pts required a second mobilization procedure. 16/24 pts converted from positive to negative marrow biopsies post-RICE. Two pts had NHL detected in the autograft. FluBu resulted in no acute Bearman grade 3-4 RRT(overall 100d non-relapse mortality (NRM)=0% for both ASCT and donor SCT). Median engraftment times were slightly longer post AlloSCT than ASCT (ANC>0.5 = 15 vs 11d, and platelets>20 = 12 vs 9d, respectively). Of 15 AlloSCT pts, grade 3–4 aGVHD occurred in 5 (33%), cGVHD occurred in 64%, and death from extensive cGVHD + infection occurred in 5 pts from 7-13mo post-AlloSCT (overall NRM=33% for AlloSCT). With a median follow-up of 22mo, the 2 year projected outcome of ASCT vs Allo/Syngeneic-SCT for relapse-free survival (RFS) was 64% vs 87% (logrank p=0.48), event-free survival (EFS) 63% vs 52% (logrank p=0.38), and overall survival (OS) 86% vs 46% (logrank p=0.0018), respectively. For relapsed follicular lymphoma only, the 2yr EFS was 61% vs 59% (logrank p=0.49) and OS 100% vs 51% (logrank p=0.0009) for ASCT (n=19) vs Allo/Syngeneic SCT (n=11), respectively.
Conclusion: These preliminary results suggest that RICE can "in-vivo" purge autografts but mobilizes blood stem cells only moderately well. RICE-FluBu/ASCT may result in prolonged EFS with significantly less NRM than AlloSCT.
Comparison of the Sequential High-Dose Chemotherapy Followed by Autologous Stem Cell Support with and without Rituximab in Relapsed and Refractory Aggressive Non-Hodgkin’s Lymphoma.
Authors: Sieniawski Michal , Staak Jan Oliver , Scheuss Helena , Glossmann Jan Peter , Diehl Volker , Engert Andreas , Josting Andreas 
Published: October 2019

Abstract
Introduction: Combination chemotherapy can cure patients (pts) with Non-Hodgkin’s lymphoma (NHL), but those with relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell support (ASCT) can improve the outcome of these pts. Rituximab demonstrated encouraging activity in aggressive NHL and showed low toxicity in the setting of combined immunochemotherapy. To investigate the influence of addition of rituximab to the intensified salvage program followed by a final myeloablative course with stem cell reinfusion we compared the group of patients treated with this program - immuntherapy group (IT) with the standard therapy group (ST) of patients treated with the same program without rituximab.
Patients and methods: Eligibility criteria for both groups were as follows: age 18–67 years, eligibility for HDCT, histologically proven CD20+ relapsed or progressive NHL. Treatment program starts with two cycles DHAP (dexamethasone, cytarabine, cisplatin); pts with PR or CR receive cyclophosphamide (4g/m2) followed by PBSC harvest; methotrexate 8g/m2 and vincristine 1,4mg/m2; and etoposide 2g/m2. The final myeloablative course is BEAM followed by ASCT. Pts in IT received additionally rituximab (375mg/m²) to the each chemotherapy cycle.
Results: In the immuntherapy and standard therapy group were enrolled 23 and 57 pts, respectively. There were 18 (78%) IT and 34 (60%) ST pts with relapsed and 5 (22%) IT and 23 (40%) ST pts with refractory disease. The majority of pts in both groups received CHOP-like regimens as first line treatment (91% IT vs. 79% ST). The response rate at the final evaluation for all patients was in IT 61% (52% CR and 9% PR) and in ST 43% (32% CR and 11% PR). The overall response rate (OR) for patients who responded to 2 cycles DHAP was in IT 83% (71% CR and 12% PR) and in ST 59% (44% CR and 15% PR). The therapy toxicity was tolerable and comparable in both groups.
Conclusion: The preliminary results suggest better therapy outcome in patient with sequential high-dose chemotherapy with rituximab compared to pts treated with the same therapy regimen without additional antibody. The combination regimen allows effective mobilization of stem cells. The tolerability of the final myeloablative BEAM was in both groups not affected by rapid sequential administration of DHAP and high doses of cyclophosphamide, methotrexate, etoposide and rituximab. The toxicity was tolerable in both groups. The full results of match pair and multivariate analysis as well as OS and FF2F will be presented.
Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM).
Authors: Goodman Mark , Bensinger William I. , Giralt Sergio , Salzman Donna , Ruffner Katherine L. , Breitz Hazel B. 
Published: October 2019

Abstract
Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented.
Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months.
Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials.
Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis.
Recovery of Polyclonal Immunoglobulin Synthesis after Autologous Stem Cell Transplantation in Multiple Myeloma Patients as a Prognostic Factor for Event-Free Survival.
Authors: Höfer Annette , Benner Axel , Klaus Jens , Breitkreutz Iris , Herrmann Doris , Cremer Friedrich W. , Gerull Sabine , Moehler Thomas , Egerer Gerlinde , Hegenbart Ute , Ho Anthony D. , Goldschmidt Hartmut 
Published: October 2019

Abstract
Suppression of polyclonal immunoglobulin (Ig) synthesis is one feature of multiple myeloma (MM). To evaluate if recovery of polyclonal Ig synthesis after autologous stem cell transplantation (ABSCT) influences prognosis, we have retrospectively analyzed the prognostic value of clinical and laboratory variables of 348 multiple myeloma patients who underwent their first autologous stem cell transplantation between 06.1992 and 10.2002 at the University Hospital of Heidelberg. The median follow-up was 34 months (range, 3 to 136 months). The median number of chemotherapy courses prior to first ABSCT was 5 (range, 3 to 30). Twenty-two of 348 patients underwent altogether three ABSCTs (including 18 patients with tandem transplantations), 141 had two ABSCTs (including 87 tandem transplantations) and 29 patients were treated with allogeneic transplantation as second line treatment. Recovery of polyclonal Ig synthesis was studied by serumelectrophoresis on day 100 after first ABSCT (±30 days). Full polyclonal Ig recovery was observed in 93 of 348 patients (28%), partial recovery (reduced polyclonal Ig, no monoclonal Ig) in 58 (17%), no recovery (almost no polyclonal Ig and no monoclonal Ig) in 16 (5%), polyclonal Ig recovery associated with monoclonal Ig in 95 (27%) and monoclonal Ig without polyclonal Ig in 72 patients (21%) (data missing in 14 patients (4%)). On multivariate analysis (333 patients), using Cox proportional hazards regression model stratified with respect to tandem transplantation, superior event-free survival was observed with recovery of polyclonal Ig synthesis, low beta2-microglobulin at diagnosis (<2.5mg/L) and a high haemoglobin at diagnosis, whereas MM type IgA and a high number of chemotherapy courses prior to first ABSCT were identified as adverse prognostic factors. Regarding polyclonal recovery, patients with polyclonal Ig recovery associated with monoclonal Ig had a superior event-free survival compared to patients with only monoclonal Ig without any polyclonal Ig recovery. Overall survival was superior in patients with a low β2-microglobulin at diagnosis (<2.5mg/L) and a high haemoglobin at diagnosis, and worse in patients with a high number of chemotherapy courses prior to first ABSCT. We conclude that any recovery of polyclonal Ig synthesis even when associated with monoclonal Ig, improves event-free survival, and therefore can be used as a predictor of prognosis in the follow-up of multiple myeloma patients who underwent ABSCT.
Serum Free Light Chain Responses after High-Dose Intravenous Melphalan and Autologous Stem Cell Transplantation for AL (Primary) Amyloidosis.
Authors: Sanchorawala Vaishali , Wright Daniel G. , Magnani Barbarajean , Skinner Martha , Seldin David C. 
Published: October 2019

Abstract
AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses of plasma cell dyscrasias underlying AL amyloidosis following HDM/SCT and other forms of treatment. The definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic response as a ≥ 50% reduction in free light chain (FLC) measurements. Hematologic responses by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a retrospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which hematologic CR, by our standard criteria, correlates with FLC response. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 67 patients with AL amyloidosis before and after treatment with HDM/SCT. After treatment with HDM/SCT, 27 patients (40%) achieved a CR by standard criteria. Of these 27 patients, 63% (n=17) demonstrated normalization of FLC levels and an improvement of ≥50% in FLC occurred in 100%. Of the 40 patients who did not achieve a CR, 25% (n=10) experienced normalization of FLC levels, and an improvement of ≥50% occurred in 78% (n=31), while only 5 patients (13%) experienced no significant change in FLC. The average improvement in FLC was 94% for patients who achieved a CR by standard criteria and 72% for those who did not (p=0.0001, t-test). Thus, HDM/SCT was found to induce improvements in FLC levels of ≥50% in the vast majority of AL amyloidosis patients treated with HDM/SCT (87%, or 58/67). These data indicate that a decrease in FLC of ≥50% is a substantially less stringent indicator of hematologic response than is CR, as defined by standard criteria. Nonetheless, these measures of hematologic response are complementary, since decreases in FLC can be detected earlier following treatment than changes in IFE and marrow studies required to determine CR.
CD56 as Prognostic Factor in Patients with Multiple Myeloma Treated by High-Dose Chemotherapy and Autologous Stem Cell Transplantation.
Authors: Hundemer Michael , Klein Ulrike , Hose Dirk , Cremer Friedrich , Raab Marc , Moos Marion , Ho Anthony D. , Goldschmidt Hartmut 
Published: October 2019

Abstract
Neuronal cell adhesion molecule (NCAM, CD56) is expressed by approximately 75% of multiple myeloma (MM) clones. The lack of CD56 expression on MM cells is described to be associated with a higher frequency of extramedullary involvement (Pellat-Deceunynck et al. 1998) and a lower overall survival in patients treated by conventional chemotherapy (Sahara et al. 2002). We analyzed the CD56 expression of myeloma cells by flowcytometry in 52 newly diagnosed patients to determine its prognostic and clinical relevance. Seventeen of 52 patients were NCAM-negative and 35 patients NCAM positive. The CD56 expression did not correlate with elevated beta2-microglobulin levels or deletions of chromosome 13q14 as investigated by interphase FISH. All patients were scheduled for treatment according to the GMMG-HD3 protocol and received 3 cycles of VAD or TAD induction chemotherapy, followed by CAD chemotherapy, stem cell collection and high dose chemotherapy with melphalan and autologous stem cell transplantation (ASCT). We analyzed the response rate (EBMT/IBMTR criteria) 3 months after the first ASCT and the event free survival (EFS) (median 479 days, range 29–911 days). Three months after the first ASCT, 6/17 of the CD56 negative patients were in CR, 7/17 in PR, 1/17 in MR and 3/17 had PD. Of the CD56 positive patients evaluated for clinical outcome 5/35 showed CR, 20/35 a PR and 10/35 a PD. In an intention-to-treat analysis, EFS showed no significant difference between these two groups. With only 13 events out of 52 cases, a longer follow up in terms of EFS and OS is required. We conclude that in patients treated by high-dose melphalan and autologous stem cell transplantation, the lack of CD56 did not correlate with a poor response rate 3 month after transplantation. Our preliminary results indicate that high-dose therapy followed by ABSCT is able to overcome the poor prognosis of CD56 negative patients treated with conventional chemotherapy.