bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal Function Impairment and Outcomes of Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: de Souza Jonas A. , Saliba Rima , Patah Poliana A. , Rondon Gabriela , Qazilbash Muzaffar H. , Hosing Chitra , Popat Uday , Champlin Richard E. , de Lima Marcos 
Published: April 2020

Abstract
Non-relapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We hypothesized that moderate to mild renal function impairment increases NRM in this setting.
Methods: We studied 141 patients diagnosed with AML (n=131) or high-risk MDS (n=10) who underwent allogeneic transplantation with Fludarabine (Flu)/Melphalan (Mel)-based regimens between August 1996, and May 2006 in our institution. Flu dose was 30–40mg/m2 for 4 days and Mel doses were100–180mg/m2. ATG was added for recipients of unrelated donor (UD) HSCT. GVHD prophylaxis was tacrolimus and mini-methotrexate for all but 2 patients. Donors were HLA-compatible siblings (n=69) and matched UD (n=72). Disease status at transplant was complete remission (n=56, 40%) or active disease (n=85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplant on outcomes was analyzed. GFR was calculated by both the Cockcroft Gault (CG) and the Modified Diet in Renal Disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. We considered GFR ≥ 90 as normal and GFR &lt; 90 as decreased. Evaluated outcomes were overall survival, NRM, and regimen-related mortality (RRM) at day 100 and 1-year post transplant.
Results: Median age was 55 years (range, 21–74); 59% of the patients were male. Estimated GFR by CG was normal for 45 patients (32%), and decreased for 96 patients (68%). When estimated by MDRD, 65 patients (46%) had normal and 76 (54%) had reduced GFR. The majority of patients by both estimations had a GFR between 60 and 89 (n= 78 by CG and n= 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR &lt;60 (p&gt;0.05). There was no difference in overall and NRM at day 100 and 1 year post transplant in both groups by any GFR estimation method. There was a small trend towards lower RRM at day-100 for patients with GFR ≥ 90 when using CG, but this was not statistically significant.
Conclusion: A mild to moderate decrease in GFR is not associated with an increase in non-relapse mortality.
Transplant outcomes as a function of GFR at start of conditioning regimen Outcome N 100-Day Mortality HR p 1-year Mortality HR p Abbreviations: NRM: non-relapse mortality; RRM: regimen-related mortality (excludes deaths due to GVHD); GFR: glomerular filtration rate (estimated by CG) Survival- GFR ≥ 90 45 11 (25%) 0.9 0.9 24 (53%) 1.2 0.5 Survival- GFR &lt; 90 96 24 (25%) 44 (46%) NRM* - GFR ≥ 90 45 9 (21%) 0.9 0.9 14 (31%) 0.98 0.9 NRM* - GFR &lt; 90 96 19 (20%) 31 (32%) RRM* - GFR ≥ 90 45 3 (7%) 0.5 0.3 6 (13%) 0.9 0.9 RRM* - GFR &lt; 90 96 12 (13%) 14 (15%)
MabThera (Rituximab) Plus Cyclophosphamide, Vincristine and Prednisone (CVP) Chemotherapy Improves Survival in Previously Untreated Patients with Advanced Follicular Non-Hodgkin’s Lymphoma (NHL).
Authors: Marcus Robert E. , Solal-Celigny Philippe , Imrie Kevin , Catalano John V. , Dmoszynska Anna , Raposo João C. , Offner Fritz C. , Gomez-Codina José 
Published: April 2020

Abstract
Design/methods: Rituximab added to 8 cycles of CVP (R-CVP) chemotherapy improves time to progression and duration of response in previously untreated patients with stage III/IV CD20 positive follicular NHL compared with CVP alone (Marcus et al Blood2005;105:1417–23). A protocol pre-planned analysis of this study with a median follow-up of 53 months has now been performed.
Results: A total of 321 patients (median age 53 years) were recruited. Eighty-three percent of patients in both arms had intermediate to high-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI, score 2–5). Median time to progression or death (TTP) in the R-CVP arm was 34 months compared with 15 months in the CVP arm, p&lt;0.0001 (log rank). This increase in TTP was observed in all FLIPI groups with a risk ratio of 0.40 (95% confidence interval 0.27 to 0.60) for good intermediate risk patients and 0.51 (95% confidence interval 0.34 to 0.76) for poor risk patients; overall the risk ratio was 0.44 (95% confidence interval 0.32 to 0.57). In patients achieving a complete response (CR) or CR unconfirmed (CRu), disease-free survival (DFS) was significantly prolonged (p=0.0001, log rank); the estimated 4-years’ DFS rate was 54% for patients receiving R-CVP compared with 17% for CVP. Nineteen percent (31/162) of patients in the R-CVP group have now died compared with 29% (46/159 patients) in the CVP group. Patients receiving R-CVP had a significant improvement in overall survival compared with CVP (p=0.03, log rank; hazard ratio 0.60 [95% confidence interval 0.38 to 0.96]).
Conclusion: When added to first-line chemotherapy in patients with follicular NHL, rituximab not only improves TTP and DFS, but also has a favorable effect on overall survival.
Activity of ABL Kinase Inhibitors in Two Distinct Models of Imatinib Resistance.
Authors: Donato Nicholas J. , Wu Ji , Bornmann William , Talpaz Moshe 
Published: April 2020

Abstract
The tyrosine kinase inhibitor imatinib mesylate (Gleevec) is effective in controlling BCR-ABL expressing leukemias but resistance occurs in a small subset of early stage patients and is very common in advanced stage patients. Resistance is associated with overexpression and/or mutations in the BCR-ABL gene but patients are also increasingly reported to fail imatinib therapy while retaining wild-type BCR-ABL expression. To circumvent or overcome resistance novel kinase inhibitors have been synthesized and tested clinically. However, while investigators have designed models to measure and predict activity of novel compounds in mutation-mediated imatinib resistance, other mechanisms of resistance have not been modeled or shown clinical relevance. In this report, the activity of four novel kinase inhibitors (norlotinib, dasatinib, SKI-606, ON012380) was compared in two distinct models of imatinib resistance. These models include cell lines established from natural resistant variant clones selected from imatinib sensitive cell lines and associated with a T315I BCR-ABL mutation (BV-173R) or overexpressed Lyn kinase (K562R). Kinase inhibitory activity in these models was compared to transfectant-based resistance models including BaF3 cells expressing the T315I mutant form of BCR-ABL and overexpression of Lyn kinase in K562 cells. K562R cells were completely resistant to imatinib and norlotinib but highly sensitive to Src/Abl inhibitors (dasatinib, SKI-606) but only partially sensitive to ON012380. Overexpression of Lyn in K562 cells reduced imatinib and norlotinib sensitivity (3-fold) but did not affect sensitivity to the other kinase inhibitors. BV-173R cells expressing the T315I mutant form of BCR-ABL were completely resistant to Abl-selective kinase inhibitors (imatinib, norlotinib) and ~100-fold less sensitive (IC50 ~ 2 microM) to Src/Abl-directed inhibitors (dasatinib, SKI-606) while the non-ATP competitive kinase inhibitor, ON012380, was equally effective against both BV-173 and BV-173R cells. Expression of the T315I mutant form of BCR-ABL in BaF3 cells completely blocked kinase inhibitory activity of all inhibitors except ON012380. IL-3 dependent BaF3 cells were not inhibited by imatinib, norlotinib or SKI-606 but were equally sensitive to ON012380 when compared to IL-3 independent BCR-ABL transfectants. Cellular sensitivity was associated with reduced phosphorylation of BCR-ABL, CrkL and Lyn kinase with all inhibitors except ON012380, which mediated apoptosis in the absence of alterations in tyrosine phosphorylation. Together, our results suggest that imatinib resistant cell models are useful in evaluating the activity of novel kinase inhibitors but need to be carefully interpreted and mechanistically tested. Additional mediators of imatinib resistance need to be defined and modeled so that an appropriate individualized therapy can be applied to most effectively overcome resistant disease.
Therapeutic Drug Monitoring of Imatinib and Impact on Clinical Decision Making.
Authors: Blasdel Carolyn , Wang Yanfeng , Lagattuta Theodore , Druker Brian , Letvak Laurie , Egorin Merrill 
Published: April 2020

Abstract
OBJECTIVES: Imatinib (IM) has demonstrated durable clinical efficacy in the majority of chronic myeloid leukemia (CML) patients. Optimal response may be influenced by multiple innate and external factors, some of which may be controlled by monitoring plasma concentrations of the drug. This abstract reports 6 cases where analyzing plasma IM trough concentrations (Cmin) in patients treated with three commonly used IM doses (400, 600, and 800 mg daily) influenced clinical decision making.
METHODS: IM trough blood samples were collected at a time before that day’s IM dosing. Plasma concentrations of IM were determined by a validated LC/MS/MS method.
RESULTS: In large population studies of CML patients enrolled in Phase I, II, and III clinical trials, the mean Cmin levels of IM at 400 mg qd, 600 mg qd, and 400 mg bid doses were: 981 (±543, 55%, n=394), 1572 (±1032, 66%, n=14), and 3479 (±1264, 36%, n=14) ng/mL, respectively. Large inter-patient variability was shown at all three doses. Of the 6 cases detailed in the table below, 4 (ID 1, 3, 4, and 5) had dose reduction due to tolerability concerns with subsequent improvement of symptoms following dose adjustment. One patient (ID 2) had a dose increase because of a poor qRT-PCR response. Another (ID 6) had a dose increase due to low plasma IM exposure resulting from drug-drug interaction with phenytoin, a known inducer of CYP3A4 (the major metabolizing isozyme for IM). After dose adjustment, all six patients showed good clinical response to IM treatment. The new mean Cmin value in these patients was 2000 (±471) ng/mL, representing a 24% coefficient of variability.
CONCLUSIONS: Although the data is limited, IM drug monitoring proved useful in managing tolerability, lack of efficacy, adherence or potential drug interactions that modulate imatinib drug concentrations. More prospective studies are needed to demonstrate the value of IM drug monitoring in routine clinical practice.
Patient ID Age, Sex CML Stage IM Daily Dose 1st Cmin (ng/mL) Reason for Dose Change New Dosing Regimen New Cmin (ng/mL) CP, chronic phase1 1 54, f CP 200 mg bid, Jan 03 3048, Sep 05 transfusion-dependent, anemia, Sep 05 300 mg, Oct 05 2130, Jan 06 2 9, f CP 300 mg, Jan 05 not done qRT-PCR 0.016, Jan 06 400 mg, Jan 06 2341, Jul 06 3 13, f CP 300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 05 1966, Feb 06 nausea, fatigue, arthralgias, myalgia, ongoing 400 mg, Mar 06 1222, May 06 4 67, f CP 400 mg, Feb 05 not done myelosuppression, Mar 05 200 mg, Mar 05 1928, May 06 5 53, f CP 400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04 not done inflammatory pulmonary reaction with shortness of breath; dose held, Mar 05 400 mg, Oct 05 2378, May 06 6 73, m CP 350 mg, on phenytoin, Apr 99 35, Jun 99 stopped phenytoin, Jul 99 500 mg, Jul 99 not done; qRT-PCR negative, Jul 06
Prognostic Significance of Serial Determinations of LDH Levels in Primary (De Novo) Myelodysplastic Syndromes.
Authors: Wimazal Friedrich , Sperr Wolfgang R. , Vales Anja , Kundi Michael , Boehm Alexandra , Thalhammer Renate , Schwarzinger Ilse , Valent Peter 
Published: April 2020

Abstract
An increased lactate dehydrogenase (LDH) level at diagnosis is associated with a reduced probability of survival and an enhanced risk of AML development in primary (de novo) myelodysplastic syndromes (MDS). However, so far, little is known about the prognostic value of an increase in LDH levels during the follow up in these patients. We have serially determined LDH levels in 221 patients (102 males, 119 females) with de novo MDS (median age 70 years; FAB-types: RA, n=62; RARS, n=46; RAEB, n=48; RAEBT, n=36; CMML, n=29), and examined the prognostic value of LDH as a follow-up parameter. Confirming previous data, an elevated LDH level at diagnosis was found to be associated with a significantly increased probability of AML evolution and a significantly decreased probability of survival (p&lt;0.05). In the follow up, an increase in LDH (from normal to elevated) was found to be associated with progression of MDS and AML evolution in most cases. Moreover, in those patients who progressed to AML, LDH levels were found to be significantly higher in the two three-months-periods preceding progression compared to the two initial three-months-periods examined (p&lt;0.005). In most patients, the increase in LDH was accompanied or followed by other signs of disease progression, such as the occurrence of thrombocytopenia or an increase in blasts. Together, our data show that LDH can be employed as a prognostic follow-up variable in patients with MDS. In those patients in whom an increase in LDH is noted, a thorough re-evaluation of the progression-status of the disease including a bone marrow examination should be considered.
Secondary Myelodysplastic Syndrome after Hydroxychloroquine Therapy.
Authors: Muslimani Alaa , Spiro Timothy , Chaudhry Asif , Hamed Daw 
Published: April 2020

Abstract
Introduction: The myelodysplastic syndromes (MDSs) include a group of marrow disorders united by the common feature of ineffective hematopoiesis. Primary MDS is defined as occurring in the absence of exposure to ionizing radiation, chemotherapeutic agents or myelotoxic drugs. Secondary MDS occurs in the presence of such exposure. The reported hematological side effects of hydroxychloroquine include aplastic anemia, agranulocytosis, thrombocytopenia, and hemolytic anemia in individuals with G-6-PD deficiency. However the frequency of secondary MDS after treatment with hydroxychloroquine is unknown. We report four patients who developed MDS after hydroxychloroquine therapy, a previously unrecognized association.
Methods: We did a retrospective chart analysis of 217 patients on hydroxychloroquine for rhematological conditions in 2005. None of these patients had exposure to myelosuppressive drugs including methotrexate, radiation, chemotherapeutic agents, or benzene. Amongst these patients, 4 had been diagnosed with MDS in 2005. The demographics, type of MDS, karyotypic abnormalities, dose and duration of treatment with hydroxychloroquine were reviewed.
Results: Two patients were male (M) and two female (F); the median age was 69.75 years, (range 65–76). There was no personal or family history of hematopoietic cancer. The dose of hydroxychloroquine for all patients was 400 mg daily, with median treatment duration of 10.5 years and a range of 6–16. All patients had bone marrow biopsy confirmation of the diagnosis of MDS, and two had karyotype abnormalities.
Conclusion: The incidence of MDS in a group older than 70 years ranges from 15 to 50/100,000 persons/year. The diagnosis of four cases of MDS among 217 patients in one year is approximately 123–37 fold higher than the risk of MDS in the general population aged more than 70 years (P &lt; 0.001) and suggest that long-term treatment with hydroxychloroquine is associated with an increased risk of developing secondary MDS.
Age (years)/sex Dose (daily) / duration of hydroxychloroquine treatment MDS subtype Cytogenetic studies. Two (or more) cytogenetically different populations of cells are indicated by a slanted line (/) between their karyotype notations.The number in brackets [ ] indicates the number of cells seen with the preceding karyotype.del (deletion): loss of part of a chromosome. q: the long arm of the chromosome. +: extra copy of the chromosome. −: random loss of chromosomes. Case 1 65/M 400 mg/6 years Refractory anemia without ringed sideroblasts. 45 XY case 2 73/F 400 mg/7 years Refractory anemia without ringed sideroblasts. 46 XX case 3 76/M 400 mg/16 years Refractory anemia with excess blasts 49,XY,+4,+8,+12[5]/46,idem,−5, −6,−13[1]/46,XY[15] case 4 65/F 400mg/13 years Refractory anemia with ringed sideroblasts 46 XX, del (20) (q11.2q13.3)[2]/46 XX[18]
Phase II Study of Thymglobulin, Cyclosporin, and G-CSF for the Initial Treatment of Aplastic Anemia and Low Risk Myelodysplastic Syndrome.
Authors: Ravandi-Kashani Farhad , Estrov Zeev , Ferrajoli Alessandra , Borthakur Gautam , Beran Miloslav , Pierce Sherry , Koller Charles A. , Cortes Jorge , Faderl Stefan , Kantarjian Hagop M. 
Published: April 2020

Abstract
Standard therapy of aplastic anemia (AA) involves the use of equine anti-thymocyte globulin (ATG) in combination with cyclosporine. Hematological responses occur in 40% to 50% of patients treated with ATG alone. The addition of cyclosporine to ATG has improved response and survival; response rates have been up to 65%, and the 5-year survival rate in the responding patients has been over 80%. Several lines of observation have also implicated an autoimmune mechanism in at least a subset of patients with myelodysplastic syndrome (MDS) whose disease process may overlap AA. The rationale for treating refractory or relapsing patients with ATG from a different animal has been the lower risk of potentially life-threatening allergic reactions. In a recent study, most patients who received rabbit ATG (Thymoglobulin) after unsuccessful treatment with ATG became transfusion independent (Di bonna E, Br J Haematol, 1999). Another study has reported high responses to Thymoglobulin in patients with relapsed AA (Scheinberg P, Br J Haematol, 2006). We are conducting a clinical trial of Thymoglobulin in combination with cyclosporin and GCSF in the first line therapy of patients with AA or low-risk MDS. Patients receive Thymoglobulin 3.5 or 2.5 (if they were 55 years or older) mg/kg/day IV for 4 days, methyl prednisone 1 mg/kg/day IV for 4 days followed by a tapering dose of oral prednisone, cyclosporine 5 mg/kg orally, and G-CSF 5 μg/kg daily for up to 3 months at the discretion of the treating physician. All patients receive prophylactic broad-spectrum antibiotics. We have enrolled 13 patients in the study including 7 patients with AA and 6 patients with MDS. The median age for AA patients was 61 years (range 45 – 73 years), and for MDS patients 60 years (range, 41 – 71 years). The median absolute neutrophil count (ANC) for AA patients was 0.74 × 109/L (range, 0.1 – 1.0 × 109/L) and for MDS patients 2.0 × 109/L (range, 1.1 – 8.1 × 109/L). The median Hgb for AA patients was 6.9 g/dL (range, 3.9 – 7.9 g/dL) and for MDS patients 8.1 g/dL (range 6.4 – 10.7 g/dL). The median platelet count for AA patients was 8 × 109/L (range, 0 – 153 × 109/L) and for MDS patients 10 × 109/L (range, 6 – 16 × 109/L). Flow cytometry for a PNH clone was negative in all patients. Seven patients (4 AA, 3 MDS) were positive for HLA-DR15. So far, 6 patients with AA have responded including 3 CRs, 2 PRs and 1 HI. One patient with MDS had a PR. Toxicity has been acceptable with no grade 3 or 4 side effects. Other side effects (grade 1 and 2) included infusion-related reactions, hypomagnesemia, elevation of serum creatinine, and hyperbilirubinemia. We conclude that Thymoglobulin can be administered safely in combination with cyclosporin and GCSF to treat patients with untreated AA and MDS.
Analysis of the Incidence of Treatment-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Registration and Compassionate-Use Trials of Ibritumomab Tiuxetan Radioimmunotherapy (RIT).
Authors: Czuczman Myron S. , Emmanouilides Christos , Darif Mohamed , Witzig Thomas E. , Gordon Leo I. , Revell Steven , Vo Katie , Molina Arturo 
Published: April 2020

Abstract
Radioimmunotherapy (RIT) is a therapeutic modality indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed non-Hodgkin’s lymphoma (NHL), where the mechanism of action involves the intrinsic activity of the monoclonal antibody and the cytotoxic effects of radiation. The primary toxicity is a late-occurring, transient, and reversible myelosuppression. Because of concerns regarding the long-term effects of radiation on the bone marrow, we investigated the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after ibritumomab tiuxetan RIT. A total of 746 patients with NHL were treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Patients had a median age of 61 years (range, 24–87) and had received a median of 3 prior therapies (range, 0–9+). The crude incidence of t-MDS or t-AML was 2.3% (17/746), with an incidence of 4.7% (10/211) in patients enrolled in registration trials and of only 1.3% (7/535) in patients included in the compassionate-use trial, with a median follow-up of 5.7 and 3.5 years, respectively. These malignancies were documented at a median of 5.6 years (range, 1.2–13.9) after the diagnosis of NHL and 1.5 years (range, 0.1–5.8) after RIT. The annualized rates were 0.3% (95% CI, 0.2%–0.4%) a year after the diagnosis of NHL and 0.7% (95% CI, 0.4%–1.0%) a year after RIT. Cox multivariate regression analysis found that previous treatment with a purine nucleoside analog was a significant risk factor for t-MDS or t-AML (hazard ratio, 3.9 [95% CI, 1.5–10.4]; P = .006). All patients in whom t-MDS or t-AML developed and in whom cytogenetic data were available (n = 15) had multiple cytogenetic aberrations, commonly of chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. There were documented bone marrow cytogenetic abnormalities before treatment in 2 patients who developed t-MDS or t-AML. These data suggest that the annualized incidence of t-MDS or t-AML following ibritumomab tiuxetan RIT is consistent with that expected on the basis of the patients’ history of treatment for NHL. Cytogenetic testing before administration of RIT may identify existing chromosomal abnormalities in previously treated patients, particularly in those who have been treated with alkylating agents and/or purine nucleoside analogs and who are thereby at a higher risk for t-MDS or t-AML.