bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emerging Marrow Fibrosis Is an Early Indicator of Imatinib Failure and Shortened Survival Time in CML Independent of Hematologic, Cytogenetic and Molecular Response.
Authors: Buesche Guntram , Hehlmann Ruediger , Ganser Arnold , Hecker Hartmut , Freund Mathias , Heimpel Hermann , Heinze Barbara , Gadzicki Dorothea , Schlegelberger Brigitte , Fonatsch Christa , Frye Bernd , Tobler Andreas , Georgii Axel , Kreipe Hans H. 
Published: April 2020

Abstract
In chronic myeloid leukemia (CML), imatinib may reverse bone marrow fibrosis (MF) that has occurred before start of therapy. The risk and prognostic relevance of MF evolving during imatinib treatment are unclear as yet. Bone marrow biopsies (n = 1509) taken prospectively from Ph+ CML patients (n = 605) were examined for MF before and during therapy. 107 patients were treated with 400 mg imatinib / day, 208 with interferon-alpha +/− cytosine arabinoside, 154 with hydroxyurea and 136 with busulfan.
Imatinib and interferon-alpha +/− cytosine arabinoside were significantly more effective than the other types of therapy regarding reversal of initial MF (P &lt; 0.000005). During the follow-up period of 3 years, imatinib monotherapy was not superior to interferon-alpha or hydroxyurea in preventing evolution of MF: MF affected more than 20 % of patients and developed from small foci with increased fiber deposition to full-stage fibrosis within 1 – 2 years. Hematologic, cytogenetic and molecular response did not protect against evolution of MF as long as a complete molecular remission (i.e. bcr/abl negativity) was not achieved. Evolving MF was an independent significant predictor of therapy resistance and shortened survival time of patients irrespective of the type of treatment (P &lt; 0.00005).
Conclusion: Although imatinib reverses initial MF in CML, MF may evolve during imatinib monotherapy indicating an unfavorable course of disease independent of hematologic, cytogenetic and molecular response.
A Phase I, Multi-Center, Dose Escalation Study of Atiprimod in Patients with Refractory or Relapsed Multiple Myeloma (MM).
Authors: Wang Michael , Talpaz Moshe , Jagannath Sundar , Chanan-Khan Asher Alban , Alexanian Raymond , Weber Donna M. , Gavino Maria , Estrov Zeev , Harris Pamela J. , Picker Donald , Schlossman Robert L. , Tassone Pierfrancesco , Anderson Kenneth C. , Munshi Nikhil C. 
Published: April 2020

Abstract
Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.
Pulmonary Function Abnormalities 5 Years or More Following Myeloablative and Non-Myeloablative Allogeneic Stem Cell Transplantation for Hematological Disorders - Impact of Chronic GVHD.
Authors: Savani Bipin N. , Srinivasan Ramaprasad , Montero Aldemar , Singh Anurag , Shenoy Aarthi , Kamipour Shervin , Childs Richard , Barrett A. John 
Published: April 2020

Abstract
Pulmonary function was studied in sixty nine consecutive patients with hematological diseases (65 malignant; 4 benign) 5–12 (median 7.5) years following allogeneic stem cell transplantation from HLA-matched siblings. Fifty-six (81%) patients received total body irradiation-(TBI) based myeloablative bone marrow or peripheral blood stem cell transplantation (MST) for hematological malignancies and 13 (19%) received a fludarabine/cyclophosphamide non-myeloablative peripheral blood stem cell transplantation (NST) for malignant (9) or benign (4) hematological disease. Median age of cohort was 37 years (MST 37, range 10–55; NST 34, range 15–68 years). Thirty nine patients were male. Eleven were smokers. Baseline pulmonary function tests (PFT) showed a median DLCO of 90% predicted (range 59–156%) and FEV1 of 97% predicted (range 64 to132%). Significant pre-transplantation PFT abnormality occurred in 19 (27.5%) patients (DLCO and/or FEV1 &lt;80% of predicted). Twenty five (36%) patients developed acute graft versus host disease (aGVHD) and 43(62%) developed chronic GVHD (cGVHD). At long-term follow-up at a median of 7.5 years after transplant, 32 (42%) patients had PFT abnormalities, 26 with a predominantly restrictive pattern and 6 with a predominantly obstructive pattern. Twenty-two (32%) patients had a mild to moderate decline in PFT (compared with pre-transplant values DLCO/FEV1 value). Of the 32 patients with PFT abnormalities none required supplemental oxygen and only 12 (17.4%) were symptomatic, which included 10 (14.5%) with the most severely depressed pulmonary function (all with predominantly restrictive lung function). In univariate analysis, development of cGVHD (p &lt;0.0001); pre-transplant PFT abnormality (p&lt;0.0001) and a history of smoking (p=0.03); was associated with increased incidence of late PFT abnormality. In multivariate regression analysis, cGVHD (relative risk 36.1; 95% CI 4.1–320) and pre-transplant DLCO/FEV1 of less than 80% of predicted (relative risk 5.5; 95% CI 1.07–29) were independently associated with late decline in PFT. When analyzed for symptomatic PFT abnormality beyond 5 year post-transplant similar results were obtained. The incidence of late PFT abnormality was comparable in both MST (24/56) and NST (5/13) (p=0.51). Our result indicates that a significant proportion of patients developed late PFT abnormality after transplantation, however only a minority are symptomatic. In this series of patients receiving conditioning regimens of different intensity, cGVHD was the only transplant-related risk factor predictive for late pulmonary function defects.
PKC δ Inhibition Restores PTEN Activity in Myeloma Cells and Prolongs Survival of GFP+ Myeloma SCID/NOD Mice In Vivo.
Authors: Bahlis Nizar J. , Starovic Maya , Raedschelders Koen , Gratton Kathy , Bathe Oliver , Belch Andrew 
Published: April 2020

Abstract
PTEN, a cellular phosphatase involved in the regulation of phosphatidylinositol phosphates (PIPs), is often inactivated in myeloma cells either through gene mutation or via phosphorylation of serine and threonine residues in the PTEN C-terminal domain that also results in loss of its activity and stability. The loss of PTEN function results in a failure to de-phosphorylate PIPs with a corresponding increase in Akt kinase activity. We have recently reported that PKCδ inhibition with Rottlerin (3 μM) induces cell death in sensitive and resistant myeloma cell lines (MM1S, MM1R, 8226S and U266) (Blood2002,100,11,393a). In addition Rottlerin blocked constitutive as well as IGF-1 induced phosphorylation of Akt abrogating its kinase activity and suppresses the phosphorylation of FKHR, GSK 3α/β and Bad, downstream substrates of Akt, triggerring activation of the intrinsic apoptotic pathway with loss of the mitochondrial membrane potential (Δψ) and cleavage of caspases 9, 3 and PARP. PKCδ inhibition also suppressed, upstream of Akt, ser 241-PDK1 phosphorylation by PIPs. These findings led us to investigate the PTEN status in human myeloma cell lines (MM1S, 8226S and U266). While normal PTEN expression was detected in these cell lines, PTEN was universally phosphorylated on ser 380 in its C-terminal domain, resulting in loss of its activity. Rottlerin completely suppressed the phosphorylation of this serine residue, restoring PTEN function and dephosphorylating PIPs. In order to verify that Rottlerin exhibited its effects by inhibiting PKCδ, we first stably overexpressed PKCδ in the 8226S cells. PKCδ overexpression partially protected these cells against rotttlerin cytotoxicity and abrogated rottlerin induced AKT inhibition and PTEN activation. Furthermore transfection of 8226S cells with a mammalian PKCδ siRNA expression plasmid (sense strand of shRNA: 5′_AAGAACGCTTCAACATCGACATTCAAGATGCGATGTTGAAGCGTTCTTTTTTTG_3′expression plasmid) reduced PKCδ expression by nearly 90% and more importantly it reduced PTEN, Akt and GSK 3α/β phosphorylation. Finally, we examined the effect of Rottlerin on the viability of GFP+ myeloma SCID/NOD mice in vivo. 4 to 6 weeks old SCID/NOD mice were irradiated (300 rads) and 24 h later received tail vein injections of 5 x 106 RPMI-8226/S-GFP+ cells. Treatment with Rottlerin (3mg/kg ip) every other day was effective in slowing tumor growth as monitored by whole-body real-time fluorescence imaging and prolonged median survival of GFP+ myeloma SCID/NOD mice compared to a non-treated control cohort. In summary, our work provides evidence that PKCδ inhibition restores PTEN function in wild type PTEN expressing myeloma cells and is a valid biological target for the treatment of multiple myeloma.
Allogeneic Transplantation after an Alemtuzumab-Containing Myeloablative Conditioning Regimen for CD52 Positive Acute Lymphoblastic Leukemia (ALL).
Authors: Kebriaei Partow , Saliba Rima M. , Ma Carrie , Ippoliti Cindy , Couriel Daniel R. , de Lima Marcos , Giralt Sergio , Qazilbash Muzaffar H. , Gajewski James L. , Ha Chul S. , Champlin Richard E. , Khouri Issa F. 
Published: April 2020

Abstract
Alemtuzumab is an effective agent in the treatment of various B- and T-cell malignancies that express CD52. Patients with advanced or refractory ALL have poor outcome after allogeneic stem cell transplantation (SCT). We investigated whether the addition of alemtuzumab to a standard myeloablative conditioning regimen would have any additional therapeutic effect and improve outcome after SCT in CD52+ ALL.
Patients and Methods: Patients were eligible if their disease expressed CD52 in &gt;20% blasts by flow cytometry. The conditioning regimen consisted of cyclophosphamide (Cy, 60 mg/kg daily x 2 doses) and total body irradiation (TBI, 12 Gy in four daily fractions). Alemtuzumab at 10 mg was intravenously administered daily on days -6 to -2 prior to day of stem cell infusion. Patients received additional graft versus host disease (GVHD) prophylaxis with tacrolimus and methotrexate.
Results: Fifteen patients (9 M/6 F) with median age 33 years (range 22–57) were studied. Twelve patients had B-lineage and 3 had T-lineage disease. Cytogenetic data were available for 12 patients; all had high-risk cytogenetics, including 5 with Ph+ disease. The median number of prior chemotherapy regimens was 3 (range 1–6). At time of study entry, 3 patients were in CR1, 3 were in ≥ CR1, and 9 were in primary or refractory relapse. Five patients received a matched related donor transplant and 10 received an unrelated donor graft. The source of stem cells was bone marrow (n=7) or peripheral blood (n=8). The median CD34+ cell dose infused was 4.67 x 106/kg (range 1.85–6.43). Median time to ANC ≥ 0.5 x 109/L was 15 days (range 11–20). Median time to platelet count ≥ 20 x 109/L was 19 days (range 13–34). The cumulative incidence of non-relapse mortality at 2 years was 13% (95% CI, 4%–43%). The incidence of grade II-IV acute GVHD was 7% (95% CI, 1%–38%); no grade III/IV acute GVHD was observed. The incidence of chronic extensive GVHD was 20%. Overall survival at 2 years was 16% (95% CI, 3%–40%). Failure was related mainly to progression; thirteen of 15 patients had disease progression at a median time of 4 months (range 1–22).
Conclusion: These data suggest that alemtuzumab can be safely added to the standard transplant conditioning regimen for ALL without delayed engraftment or increased regimen-related toxicity. However, any potential direct antileukemia effect in CD52+ ALL patients with advanced disease appears to be negated by in-vivo T-cell depletion of the donor graft. Strategies to restore the graft-versus-leukemia effect in this setting are needed.
Comparison of HLA-Identical Sibling Hematopoietic Stem Cell Transplant (HCT) Versus Chemotherapy as Postremission Therapy in t(8;21) Acute Myeloid Leukemia (AML).
Authors: Pasquini Marcelo C. , Perez Waleska , Zhang Mei-Jie , Schlenk Richard F. , Ganser Arnold 
Published: April 2020

Abstract
The t(8;21) is associated with high complete remission (CR) rates and high survival rates after cytarabine-containing postremission therapy for AML. However, patients with leukocytosis and additional cytogenetic abnormalities, such as loss of sex chromosome (LOS), have worse outcomes. We compared patients ages 16 to 60 years with t(8;21) AML in first CR, comparing 132 patients receiving postremission chemotherapy (chemo) with 118 receiving HLA-identical sibling HCT. The chemo cohort included patients treated with double induction followed by cytarabine-containing regimens in one of eight different German AML Intergroup clinical trials (SHG-Hannover-AML-2/95, SHG-Hannover-AML-1/99, SHG-Dresden-AML-96, AMLHD93, AMLHD98A, AMLCG92, AMLCG99, OSHO-AML-96) between 1993 and 2002. HCT recipients were registered with the CIBMTR from 1990 to 2000. To adjust for potential bias caused by delayed entry in the transplant cohort, left-truncated univariate analysis and Cox multivariate models were used. The median age of patients undergoing chemo and HCT were 42 and 32 years of age, respectively (p&lt;0.001). The table below shows five-year outcomes in months, including relapse rate, treatment related mortality (TRM), adjusted leukemia free survival (LFS) and adjusted overall survival (OS) according to multivariate analysis (Table). WBC &gt; 25.4×109/L was associated with higher relapse risk (RR=2.09, P=0.03), shorter LFS (RR=1.9, P=0.008) and shorter survival (RR=1.91, P=0.012), independent of postremission treatment. Neither year of treatment nor specific chemotherapy protocols were significantly associated with outcomes. HCT and chemotherapy had similar overall survival in patients with LOS and leukocytosis; in those without LOS, survival was significantly higher with chemotherapy. In this cohort of patients with t(8;21) treated in the 1990s, high transplant related mortality offset the antileukemia benefit of HCT, suggesting that HCT be reserved for patients who fail postremission chemotherapy.
TRM (95% CI) Relapse (95% CI) LFS (95% CI) OS (95% CI) LOS No LOS *From multivariate models Chemo 6 (2–11) 29 (21–37) 64 (55–73) 55 (41–69) 84 (74–92) HCT 32 (22–44) 14 (8–21) 55 (45–65) 64 (50–77) 53 (39–67) P-value* &lt; 0.001 0.01 0.24 0.74 0.002
Total Therapy 1 (TT1): Status Report of the First Tandem Autotransplant (TAT) Trial for Multiple Myeloma (MM) - 15 Years Later.
Authors: Barlogie Bart , Tricot Guido , Fassas Athanasios , Desikan Raman , Anaissie Elias , Jagannath Sundar , Crowley John 
Published: April 2020

Abstract
Background: Melphalan-based high-dose therapy (HDT) with autologous peripheral blood stem cell support has become the standard of care for newly diagnosed patients with MM, based on IMF90 and MRC7 trial results of single HDT vs. standard-dose therapy and on IMF94 data demonstrating superior EFS and OS with TAT over single HDT. The aim of this report is to provide a detailed account of the long-term outcome of all 231 patients originally enrolled in TT1 between 8/1990 and 6/1995 of whom 63 remain alive.
Patients and Methods: Outcome data on TT1 have been reported previously (Blood93, 1999; 101, 2003). Here we give final account of patient status with a median follow-up of 12 years (range, 9–15).
Results: Of 231 patients, 195 had received at least 1 and 165 the 2 scheduled transplants; 7 without insurance coverage were given intermediate dose melphalan 70mg/sqm. Of 87 (38%) initially achieving CR (median, 27 mo), 17 (20%) remain in uninterrupted 1st CR. The median EFS duration was 31mo, and 32 (14%) remain continuously event-free. The median OS duration is 68 mo with a 12-yr estimate of almost 30%. Of all 63 survivors, 19% had cytogenetic abnormalities (CA) prior to therapy, and 38% had CA intermittently. Of the 17 patients in continuous CR, 10 never had CA at any time, 4 developed CA subsequently with resolution in 3; of 3 with baseline CA, 2 normalized and 1 persisted. A detailed account of CA type and frequency as well as salvage therapies such as thalidomide, bortezomib and further auto- or allotransplants will be provided.
Conclusion: TT1 was the first tandem autotransplant protocol applied to 231 newly diagnosed patients MM that yielded an unprecedented positive outcome with 12-yr rates of CCR, EFS and OS of 20%, 14%, and 30%, respectively. The Figure displays a 3-phasic relapse pattern: an initial steep slope spanning years 1-3, a more shallow slope between years 4 to 10, merging into a cure-consistent “hockey-stick”.
Event-Free Survival- TT1 Patients Event-Free Survival- TT1 Patients Overall Survival- TT1 Patients Overall Survival- TT1 Patients
Molecular Pathogenesis of Polycythemia Induced in Mice by JAK2 V617F.
Authors: Zaleskas Virginia M. , Krause Daniela S. , Lazarides Katherine , Patel Nihal , Hu Yiguo , Li Shaoguang , Van Etten Richard A. 
Published: April 2020

Abstract
A somatic mutation (V617F) in the JH2 pseudokinase domain of the JAK2 tyrosine kinase is found in the majority of patients with polycythemia vera (PV), and some patients with essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF). The JAK2 V617F mutant is constitutively active and induces polycythemia in mice after retroviral expression in transplanted bone marrow (James et al., Nature2005; 434:1144). We expressed murine JAK2 wild-type (WT) or a JAK2 V617F mutant in bone marrow (BM) using retroviral transduction and transplantation in two different strains of inbred mice, C57Bl/6 (B6) and Balb/c. In both B6 and Balb/c mice, JAK2 V671F induced non-fatal polycythemia characterized by increased hematocrit and hemoglobin, reticulocytosis, and splenomegaly that were manifest by 3 weeks post-transplantation and were sustained for months. JAK2 V617F also induced significant leukocytosis and neutrophilia that was much more pronounced in Balb/c mice than in B6. Platelet counts were not significantly increased in either strain, despite expression of the mutant JAK2 kinase in megakaryocytes. By contrast, peripheral blood counts in recipients of BM transduced with JAK2 WT were normal and not significantly different from recipients of vector-transduced BM. We also employed BM from donor mice with mutations in erythropoiesis signaling pathways to analyze the pathogenesis of PV. Mice lacking the Src family kinase Lyn or with deficiency of both Stat5a and Stat5b have normal hematopoiesis as adults, but exhibit defects in stress and fetal erythropoiesis. JAK2 V617F efficiently induced polycythemia in BM from mice lacking the Src kinases Lyn, Hck and Fgr. By contrast, deficiency of both Stat5a and Stat5b in the donor BM attenuated the polycythemia and reticulocytosis induced by JAK2 V617F. These results demonstrate that the principal effect of expression of JAK2 V617F in hematopoietic stem/progenitor cells is expansion of the erythroid lineage through a Stat5-dependent, Src kinase-independent pathway. The strain-dependent leukocytosis suggests that genetic modifiers affect the hematopoietic phenotype of this activated JAK2 mutation. The lack of thrombocytosis implies that additional events may be required for JAK2 V617F to cause essential thrombocythemia.
Cyclophosphamide Mobilization Does Not Improve Outcome in Patients Transplanted for Multiple Myeloma.
Authors: Dingli David , Nowakowski Grzegorz S. , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne , Litzow Mark R. , Gastineau Dennis A. , Gertz Morie A. 
Published: April 2020

Abstract
Patients with multiple myeloma (MM) who undergo high dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) and achieve a complete response (CR) have a superior overall survival (OS) and time to progression (TTP). Thus achieving a CR is an important goal of therapy with ASCT. Cyclophosphamide has significant activity against MM and is often used in high doses prior to ASCT for mobilization of hematopoietic stem cells. We hypothesized that high dose cyclophosphamide (HDC) may further improve CR rates in patients undergoing ASCT.
Methods: The Mayo Clinic myeloma transplant database was searched for patients without circulating myeloma cells who had stem cell mobilization with hematopoietic growth factor (HGF) alone or HDC followed by HGF. Relevant demographic, clinical and laboratory characteristics were abstracted. The main outcome studied was the impact of HDC on CR rates and time to progression (TTP) to myeloma.
Results: We identified 201 patients without circulating myeloma cells. Of these, 127 were mobilized with HDC and HGF and 74 with HGF alone. The two cohorts were similar with respect to age, gender, isotype, B2M, plasma cell labeling index, cytogenetics, conditioning regimen, disease status at time of transplant with no statistically significant differences between the two cohorts. CR rates were 37.4 and 41.3% (p=0.6115) for patients mobilized with HDC/HGF and HGF respectively. TTP was 19.9 and 17.6 months (p=0.6039) respectively. The median number of collection sessions for patients mobilized with HDC/HGF was 2 (1–10) and those mobilized with HGF was 4 (1–10) (p&lt;0.0001). In a multivariate analysis for TTP, cytogenetics and achieving a CR were the only independent variables (p=0.0012 and p&lt;0.0001).
Conclusion: HDC for autologous hematopoietic stem cell collection reduces the number of collections necessary to support HDT/ASCT. However, HDC does not increase CR rates or improve on TTP for patients undergoing ASCT.