bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated Analysis of Allogeneic HSCT after RIC for Hematological Malignancies from the Société Française de Greffe de Moelle Osseuse et de Thérapie Cellulaire (SFGM-TC) Registry.
Authors: Michallet Mauricette , Le Quoc-Hung , Mohty Mohamad , Nicolini Franck E. , Boiron Jean-Michel , Espérou Hélène , Attal Michel , Milpied Noel , Lioure Bernard , Bordigoni Pierre , Yackoub-Agha Ibrahim , Bourhis Jean-Henri , Rio Bernard , Deconninck Eric , Renaud Marc , Sobh Mohamad , Raus Nicole , Blaise Didier 
Published: October 2019

Abstract
This report updates a retrospective study from SFGM-TC registry concerning 1108 patients who underwent allogeneic hematopoeitic stem cell transplantation (HSCT) after reduced intensity conditioning (RIC) from HLA identical siblings (84%) and unrelated donors (16%) for hematological malignancies. At time of conditioning, 442 patients were in CR, 337 in PR, 107 in stable disease (SD) and 222 in progressive disease (PD). As conditioning, 255 patients received fludarabine and TBI (2 grays), 465 patients fludarabine, busulfan and ATG and 388 patients an other regimen. After transplant, 336 patients (30%) developed an acute GVHD ≥ grade II (grade II: 178, III: 80 and IV: 78). A chronic GVHD was present in 388 patients (35%) (185 limited and 203 extensive). With a median follow-up of 30 months, the 3 and 5-year probability of overall survival (OS) were 43.5% (40–47) and 32%(29–35) respectively and the 3 and 5-year probability of event-free survival (EFS) were 35%(31–39) and 28% (24.5–31) respectively. The TRM at 1 year, 2 years and 3 years was 15% (13–17), 18% (15.5–21) and 20% (17–23). A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The probability to be a long-survivor was 24% (17.5–32.5) (Fig.1) and to be a long event-free survivor was 23% (19–28) (Fig. 2). The multivariate analysis has tested recipient and donor age, disease status pre-transplant, number of transplants before RICT, HSC source, sex matching, HLA matching, CMV status and ABO compatibility. The only factor which had a significant impact on long-term survival after RICT was the disease status just prior conditioning: PR versus CR: HR: 3.63 [1.14–9.18] p<0.001 and PD versus CR: HR: 4.35 [2.22–8.51] p<0.0001. In conclusion, these updated data demonstrate that allogeneic HSCT after RIC was able to possibly cure 23% of patients with haematological malignancies and the most important factor to take into account remains to be in CR pre-transplant.
Figure 1 Figure 1. Figure 2 Figure 2.
Allogeneic HSCT for Hematologic Malignancies in 145 Patients - Identical Biologic Prognostic Factors Affect Outcome Despite Different Conditioning Regimen Intensities.
Authors: Rondelli Damiano , Chunduri Sandeep , Dobogai Lisa , Mehta Jayesh 
Published: October 2019

Abstract
Analysis of pre-transplant variables affecting the outcome of allogeneic HSCT after 100 mg/m2 melphalan (± 50 mg/kg cyclophosphamide depending upon prior autograft) in 91 adult patients with hematologic malignancies identified refractory disease, poor performance status (ECOG 2/3), elevated LDH, and donor age >45 years as significant adverse prognostic factors affecting overall survival (OS) (Mehta et al. ASH 2006, BMT 2006). GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched siblings) or tacrolimus-mycophenolate (other donors). The patients were treated at NU. The outcome of 54 patients with hematologic malignancies treated at UIC with more intensive conditioning regimens was studied to see if the prognostic factors identified at NU were applicable to them. The conditioning regimens at UIC comprised 12.8 mg/kg IV busulfan + 120–160 mg/m2 fludarabine (n=36) or 140 mg/m2 melphalan + 150 mg/m2 fludarabine (n=18). Tacrolimus and methotrexate were used for GVHD prophylaxis. While the characteristics of the two patient populations were significantly different (especially diagnosis), transplant-related mortality and relapse rates were not significantly different for the two centers. As the table below shows, chemorefractory disease, poor performance status, and elevated LDH were adverse risk factors for OS in both groups of patients.
Variable Mel100 (NU) BuFlu/Mel140 (UIC) (OS) RR (95% CI) P RR (95% CI) P *Note the disparity - unfavorable in the NU group and favorable in the UIC group Refractory disease 3.0 (1.7–5.0) 0.0001 4.5 (1.8–11.4) 0.002 Performance status 2/3 3.9 (2.2–6.8) <0.0001 6.0 (2.0–17.8) 0.001 Elevated LDH 2.1 (1.3–3.5) 0.004 4.2 (1.7–10.8) 0.003 Donor age >45 1.9 (1.2–3.2) * 0.009 0.24 (0.06–1.03) * 0.06
However, donor age >45, an adverse risk factor in the NU population, appeared to be a borderline favorable factor in the UIC population. HLA mismatch was found to be an additional significant adverse risk factor in the combined population when it did not reach statistical significance in either group individually. The figures below shows the effect of the number of adverse risk factors (excluding donor age) on DFS and OS in the entire group of 145 patients (P<0.0001 for each). We conclude that biologic disease-related risk factors such as chemorefractoriness and elevated LDH, and patient-related risk factors such as poor performance status appear to be applicable to allograft recipients irrespective of the intensity of the underlying transplant procedure. The reason for the disparate effect of donor age in the two groups of patients is unclear, and needs to be studied further.
Figure Figure Figure Figure
Reduced Intensity (RI) Allogeneic Hematopoietic Cell Transplantation (HCT) Improves Outcomes for Older (≥ 60 Yrs) Patients (Pts) with Acute Myeloid Leukemia (AML).
Authors: O’Donnell Margaret R. , Stein Anthony S. , Nakamura Ryotaro , Slovak Marilyn L. , Tsai Nicole , Palmer Joycelynne , Rodriguez Roberto , Spielberger Ricardo , Smith Eileen P. , Snyder David S. , Parker Pablo M. , Popplewell Leslie , Pullarkat Vinod , Karanes Chatchada , Kogut Neil , Somlo George , Forman Stephen J. 
Published: October 2019

Abstract
The current paradigm of cytarabine-based induction chemotherapy followed by repetitive cycles of similar consolidation has yielded 2-year disease-free survival (DFS) of no more than 20% in older pts (≥60 yrs) who achieve remission. Induction failure (IF) is also high in this population (20–35%), depending on cytogenetic risk. Regimen-related toxicities have been a barrier to allogeneic HCT in older pts. RI conditioning provides a means to harness graft vs. leukemia in this group. Between 2/2000 and 3/1/2007, 46 pts ≥ 60 yrs (median 63 yr, range 60–71) received RI HCT from either related (26) or unrelated (20) HLA matched donors. In 23 pts, RI HCT was used as consolidation of remission (CR1 [19 pts] + CR2 [4 pts]) while 23 had active disease, including 10 IF. Karyotype was favorable in 9%, intermediate in 48% and poor in 41%. The median % marrow blasts for non-remission pts was 31% (6–80%) and peripheral blood blast was 5% (0–78%). The majority (41 pts) received fludarabine (FLU)/melphalan (MEL) for conditioning. Four pts received FLU with either 200G total body irradiation (TBI) (3 pts) or busulfan (1 pt) and one received TBI alone. Graft vs. host disease (GVHD) prophylaxis was based on either cyclosporine/mycophenolate mofetil alone or with methotrexate (MTX) (20/10) or tacrolimus/sirolimus +/− MTX (2/14 pts). The graft source was peripheral blood in 43 pts and marrow in 3 pts. Engraftment occurred at a median of 15 days (0–27 days) in 98% of recipients; graft failure occurred in one sibling HCT. Donor engraftment based on DNA analysis ranged from 30–100% at 4–6 wks post-HCT (median 100%) in the 33 analyzed pts. Mortality at day 100 was 10.8%. Acute GVHD (Grade 2–4) occurred in 61% of recipients and chronic GVHD has occurred in 23/33 evaluable pts. With a median follow-up of 24.5 months (m) for surviving pts (4–83 m), 25/46 (64.5%) pts are alive. For remission pts, the 2 yr DFS is 65% (CI 51–76%). For pts who received RI HCT as “salvage”, 34% are DF at 2 yrs. (CI 27–41%). Relapse rates were 11% for remission pts and 60% for non-remission pts. Deaths post HCT were attributed to relapse in 12 pts and treatment related mortality due to GVHD (6 pts) or infection (3 pts).
Conclusion: DFS can be improved for older patients with the use of RI HCT as remission consolidation. RIC also provides a meaningful salvage option for pts with IF or early relapse. Evaluation of donor options including both siblings and unrelated donors should be considered during induction for patients with good performance status.
Expression of CD38 and High Levels of CD5 Identifies Members of CLL Clones That Have Progressed beyond G1 and Proliferated.
Authors: Calissano Carlo , Damle Rajendra N. , Hellerstein Marc , Murphy Elisabeth J. , Hayes Gregory M. , Matthew Kaufman , Allen Steven , Rai Kanti , Chiorazzi Nicholas 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the monoclonal expansion of CD5+ B cells with the morphology of small mature lymphocytes. Although the great majority of circulating CLL B cells appears as quiescent/non-proliferating lymphocytes, a small percentage of cells in peripheral blood appear to be cycling. Furthermore, within these clones, the CD38+ subset is enriched in those cells that entered G1, as evidenced by a larger number of Ki67-expressing cells. In an attempt to further identify submembers of CLL clones with different proliferative capacities, we measured, by flow cytometry, expression of Ki67 along with mcm6 and Cyclin D1, expressed from G1 to M, and Cyclin B1, expressed in G2-M. Since the expression of CD5 is characteristic of CLL cells and increases in vitro upon cellular activation, the intensity of CD5 expression was used to further divide CD38+ and CD38− cells into CD5bright and CD5dim fractions. The leukemic clones of eighteen IgVH unmutated CLL (U-CLL) and 16 IgVH mutated CLL (M-CLL) patients were analyzed. A similar pattern of expression for each cell cycle related marker studied was found. The presence of CD38 and high expression of CD5 was correlated with increased percent of cells expressing the various cell cycle markers (CD38−CD5dim<CD38−CD5bright; CD38+CD5dim<CD38+CD5bright). Strikingly, significant differences characterized the intraclonal comparisons between the 4 subpopulations (Table). To confirm these findings, the cells of 4 CLL patients involved in a deuterated “heavy” water protocol were sorted using CD38 and CD5 expression. In two of these cases, because of limiting cell numbers, CD5bright and CD5dim cells could be obtained only among CD38− cells. CD38−CD5bright cells contained more deuterium in their DNA than CD38−CD5dim cells indicating that more CD38−CD5bright cells had divided than CD38−CD5dim cells. A similar pattern was found in two patients for whom all four subfractions could be sorted. Thus, lowest deuterium enrichment in DNA was found in CD38−CD5dim cells and highest in CD38+CD5bright cells. The combined use of surface and intracellular markers, together with the 2H labeling, effectively further subdivides the proliferative leukemic compartment in CLL.
Expression of Cell Cycle related markers in CLL B cells defined by surface expression of CD38 and CD5 N=34 mcm6 % CyclinD1 % Ki67 % CyclinB1 % For every marker studied: all intraclonal comparisons (1 vs. 2, 1 vs. 3 etc.) are statistically significant (P<0.05) with the exception of 2 vs. 3 and, for cyclinB1, 3 vs. 4 CD38−CD5dim (1) 4.0±0.8 9.9±2.6 3.8±0.8 0.8±0.2 CD38−CD5bright (2) 9.8±1.9 17±4.2 10.2±1.9 2.1±0.5 CD38+CD5dim (3) 8.5±1.4 13.7±2.8 7.8±1.1 2.3±0.6 CD38+CD5bright (4) 19.5±2.3 24.3±4.0 15.2±1.8 2.8±0.6
Constitutively Serine Phosphorylated STAT3 Provides Chronic Lymphocytic Leukemia (CLL) Cells with Survival Advantage and Promotes Their Proliferation.
Authors: Hazan-Halevy Inbal , Ferrajoli Alessandra , Harris David , Mandal Pijus K. , McMurray John S. , Keating Michael , Estrov Zeev 
Published: October 2019

Abstract
Because signal transducer and activator of transcription (STAT) 3 is constitutively phosphorylated in several malignant disorders and plays a role in the pathophysiology of lymphoid malignancies we sought to investigate the activity of STAT3 in CLL. Using Western immunoblotting we studied peripheral blood (PB) cells from 40 patients with CLL and found that in all patients, regardless of disease stage or PB cell count, STAT3 is constitutively phosphorylated (p) on serine 727, but not on tyrosine, residues. Because it is thought that phosphorylation of tyrosine residues is requires for activation of STAT3 we asked whether the serine phosphoryalted form of STAT3 is biologically active in CLL. First we explored whether serine pSTAT3 translocates to the nucleus. Using confocal microscopy and Western blot analysis of cytoplasmic and nuclear cellular fractions we demonstrated that serine pSTAT3 is present both in the cytoplasm and nucleus of CLL cells. Then we asked whether serine pSTAT3 binds to DNA. Using the electrophoretic mobility shift assay (EMSA) we identified both a ‘shift’ and a ‘super-shift’ with anti-STAT3 and anti-serine 727 pSTAT3 antibodies, indicating that serine pSTAT3 binds to DNA. To further elucidate the role of serine pSTAT3 in CLL we inhibited its activity. We used PM, an analog of the STAT3 inhibitor Ac-Tyr(PO3H2)-Leu-Pro-Gly-Thr-Val-NH2 (Coleman DR et al., J Med Chem48:6661, 2005). Previous studies demonstrated that PM binds to the SH2 domain of STAT3 (but not to that of STAT5) and specifically inhibits STAT3 activity. Therefore, we incubated CLL cells with increasing concentrations of PM and found that PM inhibited the phosphorylation of STAT3 on serine 727 residues and downregulated Bcl-2 protein levels in a dose-dependent fashion. Because the Bcl-2 gene is activated by STAT3 it is conceivable that serine pSTAT3 activates its transcription in CLL cells. Furthermore, PM suppressed CLL colony-forming cell proliferation and induced apoptosis of CLL cells as determined by Annexin V, suggesting that constitutive serine phosphorylation of STAT3 induces both proliferative and antiapoptotic effects in CLL cells. Taken together, our data suggest that STAT3 is constitutively phosphorylated on serine 727 residues and is biologically active in CLL. Therefore, the activity of STAT3 inhibitors should be investigated in this disease.
Regulation and Function of NOTCH2 in B-CLL Cells.
Authors: Hubmann Rainer , Hilgarth Martin , Schnabl Susanne , Demirtas Dita , Schwarzmeier Josef D. , Jaeger Ulrich , Shehata Medhat 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) represents a clonal expansion of self-reactive CD5+ B-lymphocytes which seems to be resistant to apoptosis in vivo. One of the characteristics of B-CLL lymphocytes is the high expression of the B-cell differentiation/activation marker CD23 which we recently identified as a target gene for NOTCH2 signaling. NOTCH2 is implicated in the development/homeostasis of murine CD5+ (B-1a) B-cells, suggesting a function for human NOTCH2 in B-CLL leukemogenesis. Here we show that peripheral B-CLL lymphocytes overexpress a transcriptionally active form of NOTCH2 (N2IC) irrespective of their prognostic marker profile (ie. IgVH mutational status, CD38 expression, and cytogenetics). Although the majority of unstimulated B-CLL samples downregulate their N2IC activity in vitro, DNA-bound N2IC complexes could be maintained by the protein kinase C (PKC) activator TPA (12-O-tetradecanoylphorbol 13-acetate) accompanied by an upregulation of the NOTCH2 target gene CD23 and increased B-CLL cell viability. These effects are sensitive to the PKC-δ selective inhibitor Rottlerin. In 80% of B-CLL cases, NOTCH2 signaling was found to be resistant to the γ-secretase inhibitors (GSI’s) Dapt and compound E, indicative for the expression of truncated forms of NOTCH2 which do not require γ-secretase for processing and function. Inhibition of NOTCH2 either by Dapt in GSI sensitive B-CLL cases or, more specifically, by RNA interference downregulates CD23 expression on the mRNA and protein level and sensitizes B-CLL cells for apoptosis. Since self-reactive B-cells are normally eliminated either by chronic (anergy) or apoptotic (negative selection) B-cell receptor (BCR) signaling, we asked whether NOTCH2 modulates B-cell fate decisions triggered by the BCR. For this reason, we stably transduced the human B-cell line BL41 with constitutive active forms of NOTCH2 and found that NOTCH2 inhibits BCR mediated apoptosis induced by surface-IgM cross-linking. In summary, the data demonstrate that NOTCH2 signaling is deregulated in B-CLL cells and might be critically involved in the PKC-dependent maintenance of their malignant phenotype.
Histone H1.2 Releasing under Different Apoptotic Stimuli in Chronic Lymphocytic Leukemia (CLL).
Authors: Gine Eva , Crespo Marta , Muntañola Ana , Calpe Eva , Gomes Maria Joao , Villamor Neus , Montserrat Emili , Bosch Francesc 
Published: October 2019

Abstract
Cytosolic release of histone H1.2 has been described as a new apoptogenic mechanism induced by DNA damage that results in cytochrome C release and activation of the apoptotic mitochondrial pathway. Primary tumoral CLL cells from 25 patients were investigated for histone H1.2 cytosolic release after treatment with genotoxic (fludarabine, mitoxantrone, etoposide, or X-ray radiation) and non-genotoxic (dexamethasone) agents. Cases were analyzed for the presence of poor-risk genetic alterations, particularly deletions at 17p13 and 11q22. Histone H1.2 release was correlated with the presence of genetic abnormalities and with the best clinical response obtained with standard treatments. FISH analysis, cell viability measured by annexin V binding, Western Blot studies and inmunofluorescence techniques with confocal spectral microscopy were also employed. DNA-damaging agents induced H1.2 release in a p53-dependent manner, which was confirmed by the lack of H1.2 release in p53-deleted cases. Non DNA-damaging agents induced release of H1.2 in both p53-deleted and non-deleted CLL cases. Moreover, nuclear H1.2 release was observed after genotoxic and non-genotoxic treatment independently of ATM function. From the clinical standpoint, the lack of histone H1.2 release correlated with resistance to genotoxic treatment. In CLL cells, histone H1.2 traffic was dependent on the p53-status after genotoxic treatment, but was also inducible after treatments acting independently of p53. In contrast, histone H1.2 release seemed not to be dependent on ATM function. Nuclear histone H1.2 release appears to be an important element in apoptosis induction in CLL, particularly in cases with abnormal p53 function resistant to conventional treatment.
Survival and Efficacy of Decitabine in Myelodysplastic Syndromes (MDS), Analysis of the 5-Day IV Dosing Regimen.
Authors: Kantarjian Hagop , Garcia-Manero Guillermo , O’Brien Susan , Estrov Zeev , Ravandi Farhad , Cortes Jorge , Shan Jianqin , Davisson Jan , Issa Jean-Pierre 
Published: October 2019

Abstract
An optimized dosing regimen for decitabine, an epigenetic therapy approved for the treatment of MDS, has been described recently based on the results of a single center, Phase II three arm adaptive randomization study (Kantarjian et al, Cancer2007;109:265–273). The results of this trial have been described in the context of a pooled data set from all three treatment arms; only a limited set of data specific to the 5-day IV dosing arm has been presented. Here, we provide an in-depth update of important efficacy and toxicity endpoints specific to the 93 patients treated within this trial with the 5-day schedule. 39/93 patients were not categorized (N/C) by IPSS due to exclusion from IPSS (extensive prior therapy, secondary MDS). Distribution by IPSS in the 54 categorized patients was: Intermediate-1 (INT-1) 26%, Intermediate-2 (INT-2) 50%, and High risk (HR) 24%. The median age was 65 years (range 37–83). Abnormal chromosomes were observed in 62%, 47% had >10% bone marrow blasts; 96% had various degrees of cytopenias. Secondary MDS was documented in 28 patients (30%). The median duration of MDS was 2.5 months. Prior therapy for MDS was given to 52 pts (56%): growth factors only in 34; chemotherapy ± growth factors 18. Overall 36 pts (39%) pts achieved CR, and 75 (81%) had a response by IWG criteria. The response rates by IWG criteria with IPSS subsets were: INT-1 71% (9 CR, 1 marrow CR); INT-2 70% (9 CR, 6 hematologic improvement [HI], 4 marrow CR); HR 62% (4 CR, 3 HI, 1 marrow CR); and N/C 72% (14 CR, 1 PR, 6 HI, 7 marrow CR). The median number of cycles was 8+. The median time to response was 2.3 months. The median duration of CR was 14 months (range 3 to 16+ months). The median time to acute myeloid leukemia (AML) transformation or death was 15 months. The median time to AML (censoring for death without AML) was 30 months. The median survival was 20 months, with 1- and 2-year survival rates of 61% and 41%, respectively. The side effect profile for the 5-day IV regimen was consistent with what has been previously reported, with Grade 3–4 drug-related extramedullary side effects being uncommon. The encouraging survival and response rates of the 5-day dosing regimen of decitabine in this poor-prognosis population, coupled with its manageable side effect profile, provide a beneficial therapeutic option and a foundation for further advances for patients with MDS.
Thrombin Generation in Severe Hemophiliacs with Different Clinical Phenotype.
Authors: Santagostino Elena , Mancuso Maria E. , Tripodi Armando , Chantarangkul Veena , Clerici Mariagrazia , Siboni Simona M. , Mannucci Pier M. 
Published: October 2019

Abstract
Introduction: Some severe hemophiliacs (FVIII/FIX<1%) exhibit a mild bleeding tendency, but the basis for this heterogeneous clinical expression is poorly understood. This study investigated the relationship between the values of endogenous thrombin potential (ETP) and clinical phenotype in severe hemophiliacs. The impact of FVIII/FIX gene mutations and thrombophilic polymorphisms into the modulation of the phenotype was also evaluated.
Methods: severe hemophiliacs older than 18 years without inhibitor history and treated on demand were eligible for inclusion in the study. Mild bleeders (MB) and severe bleeders (SB), representing the extremes of the clinical spectrum, were defined according to the following criteria: spontaneous bleeding episodes per year ≤2 (MB) or ≥25 (SB) and concentrate consumption <500 (MB) or >2000 (SB) IU/Kg/year. Patients who did not fit these criteria were considered as intermediate bleeders (IB). Plasma samples were obtained after a minimum wash-out period of 5 days. FVIII was measured by chromogenic assay. ETP was measured in platelet-rich plasma after addition of tissue factor.
Results: 22MB, 22SB and 28IB were enrolled. MB showed an older age at first bleed compared to SB (p < 0.005) and p for trend among the 3 groups was also significant (p < 0.05). The prevalence of severe FVIII/FIX gene defects (null mutations) was extremely low in MB (6%). ETP values were higher in MB compared with both IB and SB (p<0.05); p for trend among the 3 groups was also significant (p <0.05).
Conclusions: this study shows that the measurement of thrombin generation in platelet-rich plasma may allow to identify patients with mild bleeding diathesis among severe hemophiliacs, in contrast with the features of conventional functional assays.
SB (#22) IB (#28) MB (#22) P Age (yr) 38 (21–76) 38 (23–62) 32 (22–73) NS Age 1st bleed (yr) 1 (0–4) 2 (0–6) 3 (1–10) < 0.005 Bleeding episodes/yr 36 (25–60) 10 (3–20) 0 (0–2) < 0.0005 Factor use (IU/Kg/yr) 2207 (2040–8696) 1068 (207–2400) 60 (25–487) < 0.0005 Null mutations (%) 59 70 6 < 0.005 PTG20210A (%) 0 7 5 NS FV Leiden (%) 5 7 0 NS Median ETP (nM) 414 478 850 < 0.05