bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of Philadelphia Positive Chronic Myeloid Leukemia with Imatinib: Introducing the Concept of Confirmed Molecular Response.
Authors: Palandri Francesca , Rosti Gianantonio , Iacobucci Ilaria , Testoni Nicoletta , Castagnetti Fausto , Breccia Massimo , Abruzzese Elisabetta , Martino Bruno , Cilloni Daniela , Pane Fabrizio , Gobbi Marco , Intermesoli Tamara , Stagno Fabio , Capucci Adele , Martinelli Giovanni , Baccarani Michele 
Published: April 2020

Abstract
Background: Imatinib (IM) is the drug of choice for the treatment of CML, where it was shown that a complete cytogenetic response (CCgR) and a major molecular response (MMolR) at 12 months (mos) were the best surrogate markers of progression-free survival (PFS) (O’Brien et al, NEJM, 2003; Hughes et al, NEJM 2003). The issue of the MolR is particularly sensitive, because the degree of the MolR may fluctuate over time and among different labs, also for methodological reasons (Hughes et al, Blood 2006).
Aim: To evaluate the prognostic value of the MolR based on a retrospective analysis of the patients (pts) who achieved a CCgR with IM 400 mg daily.
Patients and Methods: 130 pts who achieved a CCgR for more than 1 year (confirmed CCgR) and were tested for MolR at least 3 times after achieving the CCgR, were analyzed. Cytogenetic response was assessed every 6 mos by conventional analysis of at least 20 marrow cell metaphases. MolR was assessed every 3 mos by RTQ-PCR (TaqMan) on peripheral blood buffy coat cells and was defined as MMolR when BCR-ABL:ABL&lt;0.05%, corresponding to 0.1% on the International Scale.
Results: In 71/130 pts (55%) MolR was always major (stable MMolR). In 19/130 (15%) pts MolR was sometimes major and sometimes less than major (unstable MMolR). In 40/130 pts (30%) MolR was never major (never MMolR). The proportion of pts remaining in CCgR after 5 years was calculated by the Kaplan-Meyer method (Fig. 1) and was 95% for pts in stable MMolR, 77% for pts with unstable MMolR and 62% for pts without a MMolR during follow-up (p&lt;0.0001, log-rank test).
Conclusions: These data confirm that achieving a MMolR is prognostically important but point out that the prognostic value of achieving a MMolR is greater if the response is confirmed, and introduce the concept of sustained Mol response, alerting from relying on single determinations.
Figure Figure
Relevance of HLA-C Epitopes C1 and C2 for the Survival of Patients with AML and CML after Allogeneic Blood Stem Cell Transplantation.
Authors: Bruns Ingmar , Czibere Akos G. , Uhrberg Markus , Enczmann Jürgen , Kobbe Guido , Neumann Frank , Wernet Peter , Haas Rainer , Fischer Johannes C. 
Published: April 2020

Abstract
BACKGROUND HLA-C epitopes can be grouped in C1C1, C1C2 or C2C2 ligands and mediate NK cell dependent immune response. Especially in haploidentical allogeneic stem cell transplantation a HLA-C ligand mismatch improves event free survival (EFS) in patients with AML known as Velardi effect. Recently, we could show in 109 CML patients that those with a C1C1 phenotype showed better overall survival (OS) and lower rates of treatment related mortality (TRM) (Fischer JC et al. J Immunology. 2007). But, the role of HLA-C ligands in allogeneic transplantations remains controversial.
PATIENTS AND METHODS In this study we retrospectively analyzed a group of 88 patients with AML or CML (n=34), MDS (n=21) or lymphoid malignancies (Non-Hodgkin-Lymphoma or ALL) (n=31) receiving unrelated allogeneic blood stem cell transplantation after myeloablative and non-myeloablative conditioning regimens. HLA-C alleles were determined by DNA-based direct sequencing of all donors and recipients included into this study.
RESULTS Looking at the group of 34 patients with AML or CML, the 13 recipients with a C1C1 phenotype showed increased OS compared to those with C1C2 and C2C2 phenotypes (all patients alive with a median follow-up of 154 days, range 90 to 665 days vs. a mean survival of 381 days, respectively; p=0.049). All recipients with a C1C1 phenotype received grafts with matched HLA-C alleles. Within the subgroup of patients with C1C2 or C2C2 phenotypes 6 patients had a HLA-C mismatch which was associated with significantly (p=0.016) increased OS (all patients alive with a median follow-up of 575 days, range 133 to 899) compared to matched HLA-C phenotypes (median survival of 254 days). In recipients with C1C1 phenotype the risk for TRM following HLA-C matched hematopoietic stem cell transplantation was reduced as reflected by an odds ratio of 0.13. In turn, the group receiving HLA-C mismatched grafts had a lower incidence of relapse. This effect was independent from the direction of the mismatch, graft vs. host or host vs. graft. The effects described above were not observed in patients with MDS, ALL or lymphoid malignancy.
CONCLUSION The beneficial effects of a C1C1 HLA-C phenotype could be confirmed for patients with CML and AML in our patient cohort. Our data also suggest that patients with myeloid malignancies and an unfavourable C1C2 or C2C2 HLA-C phenotype benefit from a donor with HLA-C ligand mismatch.
Drug Metabolism Gene Polymorphisms and the Risk of Hepatic Sinusoidal Obstruction Syndrome in Children with Inherited Diseases Receiving Haematopoietic Stem Cell Transplantation.
Authors: Fernandes Juliana F. , Rocha Vanderson , Porcher Raphael , Neven Benedicte , Hue Christophe , Tavela Marli , Fischer Alain , Zago Marco Antonio , Cavazzana-Calvo Marina 
Published: April 2020

Abstract
Hepatic Sinusoidal Obstruction Syndrome (SOS) following high dose cytotoxic therapy remains a serious complication after heamatopoietic stem cell transplantation (HSCT). Genetic polymorphisms that interfere with metabolism of drugs used in conditioning regimens have been associated with SOS after HSCT. In order to study this association in children given a HSCT for inherited diseases of the heamatopoietic system we have analyzed candidate genes in 99 children: 35 who developed SOS and in 64 children who did not develop SOS; both groups were transplanted in the same center and matched for year of transplant (from 1998 to 2004). Four families of candidate genes were analyzed: P450 cytochrome [CYP2B6*2(C64T), *3(C777A), *4(A785G), *5(C1459T), *6(G516T)], Glutathione-S-Transferases [GSTM1 (null), GSTT1 (null), GSTP1 (A313G)], Methylenetetrahydrofolate reductase [MTHFR (C677T)] and Vitamin D receptor [VDR (ApaI, TaqI and BsmI)]. The most frequent diagnosis was severe combined immunodeficiency. The two groups had no statistical differences for gender, diagnosis, type of transplant and source of stem cells. Conditioning regimen consisted in busulfan and cyclophosphamide in 91% of SOS patients and 87% of non-SOS patients (p=ns). There was no statistical difference on the frequency of all gene polymorphisms studied in both groups of patients, except for the gene CYP2B6*2 (C64T). In fact, the mutant allele T (genotypes CT or TT) was present in 31% of SOS patients and 9% of remainders (p=0.01). CYP2B6 is known to play an important role in the metabolism of chemotherapeutic agents such as cyclophosphamide (CY). In conclusion, we found that the polymorphism in CYP2B6*2 allele of the P450 cytochrome family is more frequent in children with inherited diseases who have developed SOS after HSCT than in those who did not develop SOS. This finding may define better surveillance and prophylaxis of SOS for children with the mutant allele of CYP2B6*2 given a HSCT.
Genetic Polymorphisms of Gluthatione-S-Transferases in Two Different Populations of Fanconi Anaemia Patients.
Authors: Fernandes Juliana F. , Rocha Vanderson , Porcher Raphael , Bittencourt Marco , Santos Moema N. , Skvortsova Yulia , Bonfim Carmen , Tavela Marli , Socie Gerard , Gluckman Eliane , Pasquini Ricardo , Zago Marco Antonio 
Published: April 2020

Abstract
Fanconi anaemia (FA) patients are known to have a markedly increased toxicity of chemotherapeutic agents, due to impairment in various important cellular processes, such as DNA repair. This toxicity had led to several alterations in preparative regimens in the setting of haematopoietic stem cell transplantation (HSCT). Several polymorphisms in genes coding for metabolising enzymes and drug transporters have been described and are now being associated with predisposition to efficacy or toxicity to different drugs. We have driven the hypothesis that FA patients may have a different frequency of those gene polymorphisms. For this purpose we have studied two different FA populations and their controls. The following of genes were analyzed: P450 cytochrome [CYP2B6*2(C64T), *3(C777A), *4(A785G), *5(C1459T), *6(G516T)], Glutathione-S-Transferases [GSTM1 (null), GSTT1 (null), GSTP1 (A313G)], Methylenetetrahydrofolate reductase [MTHFR (C677T)] and Vitamin D receptor [VDR (ApaI, TaqI and BsmI)]. The first groupt consisted of 57 FA patients, from Saint Louis Hospital in Paris compared with 107 samples of a normal control population (healthy marrow donors) of the same ethnic group. The second group of patients consisted of 72 FA patients treated in the Hospital de Clinicas in Curitiba (Brazil) compared to a control population of 72 healthy blood donors matched to age, sex and ethnicity.
Results: in both groups, the frequency of CYP2B6 alleles, MTHFR, VDR and GSTP1 polymorphisms was not statistically different between patients and controls. For GSTT1, gene deletions were found in 5 (9%) of 57 FA patients and in 27 (25%) of the 107 controls from the first group, which revealed a significant difference (p=0.013). This result was also found in the second group of patients. In fact, GSTT1 null genotype was present in 8 (11%) of the 72 FA patients and in 19 (26%) of the normal controls (p=0.016). For GSTM1, the first group had no statistical difference in the frequency of gene deletions between FA patients and their controls. However, in the second group, GSTM1 null phenotype was found in 38 (53%) patients and in 26 (36%) controls (p=0.05). In conclusion, we found in two ethnically different groups, that FA patients may have a lower frequency of GSTT1 null genotype, compared to a normal population. GSTM1 null phenotype had a higher incidence in FA patients in the Brazilian group, but was not reproducible in the French group. This finding should be further analyzed to explain if it can be related to the disease itself and/or if it translates in increased toxicity of drugs in FA patients.
Comorbidity Indexes and Allogeneic Stem Cell Transplantation (SCT).
Authors: Xhaard Alienor , Porcher Raphael , Chien Jason , de Latour Regis Peffault , Robin Marie , Ribaud Patricia , Martin Paul J. , Socié Gérard 
Published: April 2020

Abstract
Despite recent advances, mortality rates after allogeneic hematopoietic cell transplantation remain high and cannot be accurately predicted. During the last years several reports from the Seattle group suggest the use of comorbidity indexes (CI) to provide valid and reliable scoring of pre-transplant comorbidities that predicted non-relapse mortality (NRM) and survival [Blood 2004 (CCI), 2005 (HCT-CI) & Ann Int Med 2006 (PAM)). However whether such indexes could be applied by other groups, and if one index better predicts NRM than another, is unknown yet. Patients undergoing their first allogeneic SCT at Saint-Louis between April 2004 and December 2005 were considered. A total of 183 patients were first included in the study (median age 31, range [4–64], 41% from unrelated donors, 87% intermediate or high-risk diseases). Survival curves were estimated using Kaplan-Meier estimator, and cumulative incidence curves of NRM, treating relapse as competing event. The likelihood ratio statistics in proportional hazards models was computed for each index, with its associated P-value, as a measure of association between the comorbidity indexes collapsed into risk groups and the outcomes. Discriminative performance of comorbidity indexes was then evaluated by the c-index. Standard errors of c-indexes were computed from that of Somers’ Dxy rank correlation coefficient. P-values for comparison of c-indexes were obtained using a nonparametric bootstrap procedure. Using CCI, 21% of our patients had indexes of 1 or more; median HCT-CI was 1; and median PAM score was 24. The discriminative properties of the 3 CI were rather low in our patient population with c-index of 0.54, 0.49 and 0.57 for the CCI, HCT-CI and PAM indexes, respectively. Comparisons of patients- and transplant-characteristics between our and Seattle group’s cohorts however reveal significant differences with more cord blood HCT and HCT for Fanconi anemia in St Louis. Finally direct comparison of scoring items revealed that, unrelated HCT, renal function, and lung function (PFTs) had however similar impact on NRM and OS in our cohort. Additional analyses including patients transplanted in 2006 are underway.
Therapeutic Drug Monitoring (TDM) of IV Busulfan in Patients with Severe Obesity.
Authors: Hutcherson Donald A. , Sessions Jolynn K. , Mihelic Ronald A. , Sanvidge Katherine , Stricker Stephen R. , Langston Amelia , Flowers Christopher , Lechowicz Mary Jo , Waller Ned , Lonial Sagar 
Published: April 2020

Abstract
It has been previously reported that increases in relapse and graft rejection can be associated with a low busulfan area under the curve (AUC) and hepatic toxicities are associated with a high AUC. This has lead to strategies to adjust busulfan dosing to achieve a target AUC. A retrospective analysis was performed in patients with severe obesity, defined as a Body Mass Index (BMI) greater than 40, to evaluate the reliability of IV busulfan dosed using the package insert dosing strategy to reach a targeted AUC. The study included 11 females and 8 males who received IV busulfan as part of their hematopoietic progenitor cell transplant preparative regimen. There were 11 autologous and 8 allogeneic transplants for lymphoma (10) and leukemia (9). The mean and median ages were 38 and 41 years (range 19–51). The mean and median BMIs for this population were 47.8 and 46.2 (range 40.4–62.7). The mean and median weights were 139.5 kg and 142.5 kg (range 107–192.3). TDM was performed with the first dose of busulfan along with subsequent dosage adjustments to achieve a target AUC of 1150–1350 micromol X min/L. Busulfex package insert dosing recommendations are for 16 doses of 0.8 mg/kg (12.8 mg/kg) using an adjusted ideal body weight (AIBW) for obese patients. AIBW = 0.25 × (actual weight − ideal body weight) + ideal body weight. Using the AIBW dosing, the mean starting dose to actual body weight ratio was 0.48 mg/kg (range 0.40–0.55 mg/kg). Based on the AUC analysis, the predicted mean AUC using the AIBW dosing was 972 (range 702–1356). Six AUCs were below 900, 10 AUCs were above 900 but below 1150, 2 AUCs were within the target range and 1 AUC was greater than 1350. Thirteen of the patients had repeat AUC analyses following a subsequent dose to confirm that the dose adjustments achieved the targeted AUCs. Seven of these patients had further dose adjustments following the repeat AUC analysis. Five patients with a busulfan mean half-life of 235 minutes (range 218–247 minutes) had higher AUCs than the rest of the group. The mean and median AUCs for these 5 patients were 1177 and 1223 (range 997–1357). The remaining 14 patients with a mean busulfan half-life of 177 minutes (range 151–201) had mean and median AUCs of 899 and 903 (range 702–1105). The total therapy delivered ranged from 12.7 to 21.4 mg/kg based on the AIBW. When calculated on actual weight, the range was 6.9 to 11.24 mg/kg.
Conclusion: The AIBW dosing strategy of IV busulfan is inadequate to achieve the targeted AUC of 1150–1350 in severely obese patients. Severely obese patients require dose increases in the majority of cases, while those with delayed clearance could be overdosed if higher doses are administered without TDM. Severely obese patients require TDM and the majority will require dosage adjustments to administer IV busulfan in the targeted therapeutic range.
Reduced Fibrinolysis in the Hepatic Venous Occlusive Disease: Effect of Defibrotide on Plasmin Activity.
Authors: Echart Cinara , Repice Cinzia , Ferro Laura , Anderson Kenneth , Richardson Paul , Falanga Anna , Fareed Jawed , Iacobelli Massimo 
Published: April 2020

Abstract
Introduction: The fibrinolytic activity has been shown to be reduced in many vascular diseases, including hepatic veno-occlusive disease (VOD) after stem cells transplantation (SCT). Defibrotide (DF) is a polydisperse oligonucleotide with antithrombotic, profibrinolytic, anti-ischemic, and anti-adhesive properties. Numerous clinical studies have shown promising results with DF in the treatment of VOD, with minimal toxicity. In laboratory studies, DF has been shown to decrease plasminogen activator inhibitor-1 (PAI-1), increase tissue plasminogen activator (t-PA) levels and increase the overall plasma fibrinolytic activity in patients with VOD. Similar results have been observed in pre-clinical studies with endothelial cells stimulated by lipopolysaccharide. Plasmin is a potent and nonspecific serine protease, generated from the proenzyme plasminogen by plasminogen activators. Plasmin plays a pivotal role in fibrinolysis by virtue of its ability to effectively degrade fibrin clots. The purpose of this study was to investigate whether DF is capable of modulating the activity of plasmin in different in vitro studies.
Method: Plasmin activity was measured in the presence and absence of DF, at different concentrations, by following the cleavage of the chromogenic substrate S-2251. S-2251 contains the preferential cleavage site for plasmin and mimics the fibrin polymer substrate present in fibrin clots. In addition, we evaluated the activity of plasmin generated by t-PA and urokinase-plasminogen activation as well as the plasmin activity in plasma in the presence and absence of DF. Further, plasmin activity generated in fibrin clot plate was measured in the presence and absence of DF. Finally, the inhibition of plasmin by aminocaproic acid was tested in these systems.
Results: DF increased the activity of plasmin, to hydrolyze its substrate, in a dose dependent manner. Similar concentration-dependent effects of DF were observed when plasmin was generated by t-PA or urokinase activation of plasminogen and on plasmin in plasma samples (p&lt;0.001). In contrast, DF had no direct effect in activation of plasminogen to plasmin. We also showed that DF was able to enhance the activity of plasmin to degrade the fibrin clot formed from fibrinogen, plasminogen and thrombin (p&lt;0.001). This effect was concentration dependent and directly correlated with the enzymatic activity of plasmin.
Conclusion: The present study demonstrates that DF is capable of enhancing the activity of plasmin. The stimulation of plasmin by DF was concentration-dependent. These findings can, in part, explain the fibrinolytic activity of DF and support its effect in restoring the fibrinolytic vascular phenotype in conditions such as VOD.
Gemtuzumab Ozogamicin as Part of Reduced-Intensity Conditioning in Patients with Relapsed or Refractory Acute Myeloid Leukemia - Results of a Phase I/II Trial.
Authors: Bornhaeuser Martin , Illmer Thomas , Uwe Platzbecker , Rainer Ordemann , Johannes Schetelig , Markus Schaich , Alexander Kiani , Ulrich Schuler , Gerhard Ehninger 
Published: April 2020

Abstract
Gemtuzumab ozogamicin (GO) has been associated with an increased risk of liver sinusoidal obstruction syndrome (SOS) when applied within three months before or after allogeneic stem cell transplantation. In addition, excess of liver toxicity has been observed when GO was used directly before conventional intensive preparative regimens. We hypothesized that GO might be safe and effective as part of a fludarabine-based reduced-intensity conditioning regimen. 30 patients relapsing after conventional induction chemotherapy (n=17) or after previous transplantation (autologous n=3; allogeneic n=10) have been included in a prospective phase I/II trial. Per protocol the preparative regimen contained 6 mg/sqm and 3 mg/sqm GO on day-21 and day-14 followed by fludarabine 120 mg/sqm, 200 or 800 cGy total-body irradiation (TBI; depending on age and pretreatment) and stem cell infusion during GO-induced aplasia. Five patients who had previously undergone TBI received melphalan 140 mg/sqm. GvHD prophylaxis was performed with tacrolimus (starting day-1) and mycophenolate mofetil (1.5g BID from day 0). Four patients with progressive disease after GO did not proceed to conditioning therapy and went off study. A reduction of marrow blast counts after GO monotherapy was achieved in 15/30 patients (50%). In 11 cases without response to GO, an additional salvage regimen containing anthracyclines and high-dose cytarabine was administered before conditioning therapy and transplantation. 26 patients received G-CSF mobilized peripheral blood progenitor cells from matched-sibling (n=6) or unrelated donors (n=20). Primary engraftment was observed in all cases. With a median follow-up of 20 months (range 6–55) only one patient experienced sinusoidal obstruction syndrome which was reversible after treatment with defibrotide. Grade II-IV acute GvHD occurred in 15 patients (54%). Nine patients are alive in complete remission. Reasons for death in the other patients were relapse/progression (n=10) and GvHD/Infection (n=7). The probability of overall and disease-free survival at two years for patients having received a transplant is 38% and 32%, respectively. Blast reduction after GO was associated with a superior disease-free survival (48%, p=0.1). These data suggest that GO can be integrated into reduced-intensity conditioning therapy before allogeneic stem cell transplantation in patients with relapsed AML. Refractory patients with no response to GO monotherapy have a low chance of cure and should probably receive other combination therapies.