bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microvessel Endothelial Cells of Hematological Malignancies Harbor Disease Specific Genetic Aberrations.
Authors: Schwarzinger Ilse , Exner Markus , Esterbauer Harald , Drach Johannes , Jaeger Ulrich , Chott Andreas , Wagner Oswald , Streubel Berthold 
Published: April 2020

Abstract
The growth of most tumors depends on the formation of new blood vessels. In contrast to genetically unstable tumor cells, endothelial cells of tumor vessels are believed to be normal diploid cells that do not acquire mutations. We have recently observed that microvessel endothelial cells of patients with B-cell lymphomas carry lymphoma specific aberrations (NEJM351:250–9, 2004). The aim of this study was to determine whether hematological malignancies other than B-cell lymphomas also carry disease specific genetic aberrations. Using a combined immunohistochemical and fluorescence in situ hybridization assay, we investigated the endothelial cells of 5 multiple myelomas, 6 anaplastic large cell lymphomas, 1 angioimmunoblastic T-cell lymphoma, 4 chronic myeloid leukemias, 3 acute myeloid leukemias and 1 acute lymphoblastic leukemia for cytogenetic alterations that were known to be present in the malignant hematopoietic cells. We found that microvascular endothelial cells of all investigated cases harbored the disease-specific chromosomal aberrations. The percentages of genetically aberrant endothelial cells were highest in chronic myeloid leukemia (median 63%) and multiple myeloma (median 42%) and lowest in anaplastic large cell lymphoma (median 15%). Our findings suggest that the genetic relationship between tumor cells and their endothelium is a common phenomenon of hematological malignancies and reflect a novel aspect of tumor angiogenesis.
Minimal Residual Disease in High and Very High Risk ALL (HR/VHR-ALL) at the End of Induction (EOI) in FRALLE 2000 B and T Protocols.
Authors: Cayuela Jean-Michel , Beldjord Kheira , Grardel Nathalie , Cavé Hélène , Auclerc Marie-Françoise , Auvrignon Anne , Leblanc Thierry , Perel Yves , Mechinaud Françoise , Schmitt Claudine , Gandemer Virginie , Schneider Pascale , Berger Claire , Rialland Xavier , Paillard Catherine , Lejars Odile , Michel Gerard , Leverger Guy , Macintyre Elizabeth A. , Baruchel Andre 
Published: April 2020

Abstract
From January 2000 to July 2006, 580 BCR-ABL negative patients with HR/VHR-ALL (200 T-ALL and 380 BCP-ALL (age≥10 or WBC≥50 or CNS+ or MLL-R) were included in the FRALLE 2000-BT trials. Induction regimen is prednisone (PRED) prephase + IT MTX, VCR, L-Aspa, DNR 120mg/m2 cumulated dose or DNR 160mg/m2 + cyclophosphamide 1g/m2 (T-ALL and D21 M2M3 marrow or MLL-R BCP-ALL). MRD at EOI is quantitatively determined by DNA-based PCR for Ig/TCR rearrangements either competitive PCR with GeneScan analysis or RQ-PCR with clone specific primers (sensitivity ranges 0.5×10−3–10−3, and 10−3–10−5, respectively). MRD status at EOI are available for 425 out of 552 CR (77%). MRD results are reported as negative, positive &lt;10−3, highly positive (10−3≤MRD&lt;10−2), very highly positive (≥10−2). Patients with EOI MRD ≥10−2 were to receive an intensified treatment.
Results:
30% (89/293) of HR/VHR BCP-ALL and 34% (45/132) T-ALL have detectable MRD at EOI, NS. A high or very high MRD is encountered in 16% (47/293) of BCP-ALL and 21% (27/132) of T-ALL (NS). Surprisingly 57% (20/35) of the pts with BCP-ALL and D8 poor PRED response (PPR) and 71% (36/51) of the pts with D8 PPR T-ALL have a negative or slightly positive MRD (&lt;10−3) at EOI, NS. 30% (7/23) of the pts with D21 M2M3 BCP-ALL and 46% (6/13) of the pts with D21 M2M3 T-ALL have also a negative or slightly positive MRD (&lt;10−3) at EOI. By contrast, 11% of good early responders (D8 good PRED response and D21 M1) with BCP-ALL or T-ALL (27/245 and 11/74, respectively) have a high or very high positive MRD. Overall, 20 out of 449 (4.5%) HR/VHR pts in CR have received an intensified treatment due to a very high MRD only. 3y DFS for pts with a highly positive or very highly positive MRD are 65±7% (BCP-ALL) and 64±9% (T-ALL), NS. 3y DFS for pts with a negative or slightly positive MRD (&lt;10−3) are 94±2% (BCP-ALL) and 87±4% (T-ALL), p=.04. There is a statistically significant difference in term of DFS between pts with MRD≥10−3 and MRD &lt; 10−3, p=.001 and p =.05 for BCP- and T-ALL, respectively.
Conclusions:
the incidence of high and very high MRD at EOI is identical in children with HR/VHR-BCP- and T-ALL. High and very high MRD levels are found in good early responders defined by morphology. Conversely, excellent molecular responses can be found in bad early responders. High or very high MRD values are associated to a comparable prognosis between BCP- and T-ALLs.
Minimal Residual Disease Detection by Four-Color Multidimensional Flow Cytometry Identifies Pediatric AML Patients at High Risk of Relapse.
Authors: Meshinchi Soheil , Alonzo Todd , Gerbing Robert B. , Pollard Jessica A. , Gamis Alan S. , Hurwitz Craig A. , Franklin Janet L. , Pardo Laura , Loken Michael 
Published: April 2020

Abstract
We previously demonstrated that the presence of residual leukemic blasts (MRD) in patients in morphologic remission was predictive of subsequent leukemic relapse. More recently, we developed a four-color multidimensional flow cytometric method using standardized rather than patient specific panels, distinguishing the abnormal cells based on “difference from normal”. The feasibility of utilizing this method, which does not require a diagnostic specimen and is applicable even if the phenotype of the leukemic clone changes was tested in a blinded study as part of the recently completed COG AML pilot AAML03P1 that enrolled 341 patients. 302/341 patients in the study consented to participate in the biology portion of the study. 223 (74%) had evaluable specimens at the end of induction I, 191 (87%) of which achieved a morphologic CR at the end of induction I. Of the 191 patients in CR at the end of induction I, 48 (25%) had evidence of MRD. The level of MRD ranged from 0.02% to 3% with 70% of patients having an MRD level between 0.1% to 1%. Relapse risk was assessed in those with and without MRD. Those with evidence of MRD were at significantly higher risk of subsequent relapse, with a relapse-free survival (RFS) from end of induction I of 36% for those with MRD compared to 70% for those without MRD (p &lt; 0.001). The corresponding overall survival at 2 years from induction I was 63% and 86% for those with and without MRD (p=0.003). 181 patients who were in morphologic CR at the end of induction II had evaluable samples for MRD analysis. MRD was detected in 36/181 patients (20%) and presence of MRD was associated with a RFS from end of induction II of 34% compared to that of 70% in those without MRD (p&lt;0.001). Corresponding overall survival at 2 years from induction II was 56% and 83% for those with and without MRD (p=0.009). We determined whether MRD positive patients who clear their disease have an improved outcome. There were 16 patients with detectable MRD at the end of course I with undetectable MRD at the end of course II. Relative risk of relapse for these patients was 40% vs. 30% for those who were MRD negative at both time points. Data from end of induction I and Induction II were combined to maximize our ability to identify those at high risk of relapse. This study demonstrates that flow cytometric based MRD can be utilized in a multi-institutional setting to accurately identify those at high risk of relapse. Multivariate analysis of the prognostic significance of MRD in the context of other prognostic factors including cytogenetics (CBF, etc.) and molecular (FLT3/ITD) prognostic factors will be presented.
Long Term Results of the AIEOP-All-95 Trial for Childhood Acute Lymphoblastic Leukemia. An Insight on the Prognostic Value of Dna Index in the Frame of BFM-Based Chemotherapy.
Authors: Arico Maurizio , Valsecchi Maria Grazia , Rizzari Carmelo , Barisone Elena , Biondi Andrea , Casale Fiorina , Locatelli Franco , Nigro Luca Lo , Luciani Matteo , Messina Chiara , Micalizzi Concetta , Parasole Rosanna , Pession Andrea , Santoro Nicola , Testi Anna Maria , Silvestri Daniela , Basso Giuseppe , Masera Giuseppe , Conter Valentino 
Published: April 2020

Abstract
Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) conducted the ALL-95 study for risk-directed, BFM-oriented therapy of childhood acute lymphoblastic leukemia (ALL), aimed at exploring treatment reduction in standard risk (SR) and intensification during continuation therapy in intermediate risk (IR) as randomized questions and treatment intensification in high risk (HR). The prognostic value of DNA index was explored in this setting. 1,744 patients were enrolled, 115 SR, 1,385 IR, and 244 HR risk. SR patients (DNA index ≥1.16 and &lt;1.60, age 1–5 and WBC&lt;20K, non-T, no high risk features), received a reduced induction therapy (no anthracyclines); IR patients were randomized to receive or not vincristine-dexamethasone (VCR-DEXA) pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by double reinduction phase. The event-free-survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE 1.3) and 83.6% (0.9); 85.0% (3.4) and 95.5% (2.0) in SR, 75.1% (1.5) and 87.5% (0.9) in IR, 51.0% (3.2) and 57.2% (3.3) in HR patients, respectively. Patients with favorable DNA index had superior EFS in both IR [83.8(2.7) versus 73.9(1.7)] and in HR [67.8(9.4) and 49.6(3.5)]. Of the 6 patients with DNA index. &lt;0.8 only 1 remained in remission. As for treatment burden there was no difference between SR patients, receiving only 3 drugs, and others in Induction IA. Highest treatment burden was reported during consolidation in HR patients. In reinduction, first protocol II had figures similar to those reported during protocol II given to non-HR patients, while second protocol II in HR patients was associated with higher treatment burden Treatment reduction, although appealing, should be applied with great caution not to endanger outstanding cure rate achieved with over 80% of patients in Italy during the second half of the 90s having been cured. Contribution of HSCT in front-line therapy remains limited. In this study, favorable DNA index was associated with better prognosis in IR and HR patients defined by clinical criteria and treated with BFM-oriented chemotherapy. Continuous effort put in the genetic studies could provide novel insights for treatment of subsets of childhood ALL refractory to modern chemotherapy.
Preliminary Results of a Phase II Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults with Myelodysplastic Syndrome (MDS).
Authors: Steensma David P. , Baer Maria R. , Slack James L. , Buckstein Rena , Godley Lucy , Larsen Julie S. , Cullen Michael T. , Kantarjian Hagop M. 
Published: April 2020

Abstract
Decitabine (Dacogen®), a hypomethylating agent, is FDA-approved for treatment of patients (pts) with all FAB subtypes of MDS. The approved regimen of 15 mg/m2 intravenously (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days repeating q 6 wks demonstrated an overall improvement rate (CR+PR+HI) of 30% in MDS pts. An alternative regimen, in which decitabine is administered 20 mg/m2 IV over 1 hr once daily for 5 consecutive days repeating q 4 wks not only permits outpatient therapy, but also showed promising efficacy in a pilot study (Blood2007:109:52). This alternate regimen was evaluated in a multicenter study and preliminary results from this open-label single-arm Phase 2 study are reported. Eligible pts were ≥18 years (yrs) of age with MDS (de novo or secondary) of any FAB subtype (including chronic myelomonocytic leukemia with white count &lt;12,000/μL) and International Prognostic Scoring System (IPSS) score ≥ 0.5 (Intermediate-1 (Int-1), Intermediate-2 (Int-2) and High-risk groups) as determined by complete blood counts, bone marrow assessment, and cytogenetics within 28 days of enrollment. Responses, the primary endpoint of the study, were assessed using International Working Group (IWG) criteria (Blood2000;96:3671), which existed at study initiation and also used in the Phase 3 trial with the FDA-approved 3-day regimen. Secondary objectives included evaluation of hematologic improvement, cytogenetic response, overall survival, time to acute myeloid leukemia progression or death, transfusion requirements, and toxicity. Ninety-nine pts enrolled: median age 72 yrs, 72% male, 89% de novo MDS, median time from diagnosis 153 days, and 29% with prior therapy for MDS. The distribution of IPSS risk groups was as follows: Low, 1%; Int-1, 53%; Int-2, 23%; and High, 23%. Pts have thus far been followed for one year after enrollment of the last pt, and the preliminary data are reported here. Investigator assessments of response, using pathology results at the individual study sites along with laboratory findings, demonstrated an overall improvement rate of 43%; central confirmation of results is ongoing. Pts received a median of 5 cycles of decitabine (range 1–17). Median survival has not been reached; a total of 62 pts continue to be followed. The most frequent adverse events were fatigue, fever, constipation, nausea, and neutropenia. Decitabine administered daily for 5 days in the outpatient setting demonstrated clinical activity with manageable toxicity profile in Int-1 to High risk MDS, suggesting that both the 3- and 5-day regimens provide meaningful clinical benefit to patients.
Preliminary Results from a Phase I Study of Revlimid® (Lenalidomide) in Combination with Vidaza® (Azacitidine) in Patients with Advanced Myelodysplastic Syndromes (MDS).
Authors: Sekeres Mikkael A. , List Alan , Cuthbertson David , Paquette Ronald , Loughran Thomas , Maciejewski Jaroslaw P. 
Published: April 2020

Abstract
Background: Early MDS becomes more advanced as immature myeloid cells proliferate, angiogenesis increases, genetic lesions accumulate, and tumor suppressor genes become inactivated through hypermethylation. Progression to acute myeloid leukemia (AML) may be prevented by targeting these defects through combination therapy, using an immunomodulatory, anti-angiogenic agent, lenalidomide (LEN), and a hypomethylating drug, azacitidine (AZA).
Methods: We conducted a multicenter, Phase I trial in patients (pts) with advanced MDS (IPSS score ≥1.5, or FAB or WHO classification with ≥5% myeloblasts) starting in 6/06, with results reported through 7/07. Pts were enrolled using a “3+3” design (See Table), and could not receive LEN or AZA previously. Cycles lasted 28 days, to a maximum of 7 cycles of therapy. The primary endpoint was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs, defined as Grade 3/4 non-hematologic toxicity or &gt;50% neutrophil (ANC) or platelet (plt) drop without recovery by Day 56) of the combination. A secondary endpoint was response as defined by the Modified International Working Group.
Dose Level AZA Schedule LEN Schedule 1 75 mg/m2 SC days 1–5 5 mg PO days 1–14 2 75 mg/m2 SC days 1–5 5 mg PO days 1–21 3 75 mg/m2 SC days 1–5 10 mg PO days 1–21 4 50 mg/m2 SC days 1–5, 8–12 5 mg PO days 1–14 5 50 mg/m2 SC days 1–5, 8–12 5 mg PO days 1–21 6 50 mg/m2 SC days 1–5, 8–12 10 mg PO days 1–21
Results: Seven patients have been enrolled, 6 are evaluable for toxicity data. Median age was 64 years (range 52–70), 1 pt was female, and median follow-up is 5.5 months (range 1.5–13). All pts had RAEB-2; IPSS scores were 1.5 (4), 2.0 (2), and 3.0 (1), with IPSS cytogenetic risk categories of poor (1), intermediate (1), and good (5). No pt had a del (5q) lesion. Median time from MDS diagnosis was 3.5 wks (range 2–106). No DLTs occurred in Dose Levels 1 or 2, and MTD has not yet been reached. Grade 1/2 non-hematologic toxicities (n=6) included fatigue (4), injection site reaction (6), rash (3), pruritis (3), constipation or diarrhea (6), dizziness (1), and mucositis (1). Grade 3/4 non-hematologic toxicities included febrile neutropenia (1). Median ANC drop was 16.4% and plt drop was 10.4%. Although one patient was delayed 1 week in starting cycle 2 for neutropenia, there were no dose-reductions for toxicities. Four pts are evaluable for response: 2 had a complete response, 1 an erythroid response, and 1 progressive disease.
Conclusions: The combination of LEN and AZA is well-tolerated and early results suggest efficacy in advanced MDS. Responses and toxicity data from higher Dose Levels will be presented.
Risk Factors for Disease Progression in del(5q) MDS Patients Treated with Lenalidomide.
Authors: Giagounidis Aristoteles A. , Haase Sabine , Platzbecker Uwe , Germing Ulrich , Lohrbacher Vera , Ehninger Gerhard , Aul Carlo 
Published: April 2020

Abstract
Introduction: Lenalidomide is a novel immunomodulatory drug that is highly effective in patients with transfusion-dependent MDS with del(5q.31) chromosomal abnormality. In the recent MDS-003 study of lenalidomide, there was a 76% erythroid response rate, including 67% transfusion independence. Cytogenetic complexity or bone marrow blast percentage did not affect this response rate. A number of patients experienced disease progression to higher FAB subtypes or AML. We questioned whether lenalidomide might promote disease progression in del(5q) MDS and performed a retrospective analysis to identify risk profiles.
Methods: Fifty patients from three institutions were included in this analysis. They were partly treated within the Lenalidomide-MDS003-study. Patients were treated with an initial lenalidomide dose of 10 mg po daily. In case of grade &gt;2 neutropenia, G-CSF and antibiotics were administered.
Results: The median age was 71 years; 31 patients were female and 20 were male. Disease progression to a higher FAB subtype or to AML occurred in 13 patients (29.5%). 7 of the 13 patients had RAEB at the first lenalidomide dose. In addition, 3 of these had additional chromosomal aberrations (2, trisomy 21; 1, complex karyotype). Of the remaining 6 patients, 2 had a complex karyotype at the first lenalidomide dose, 1 had an additional inv(9)(p11q12), and 1 had hypocellular bone marrow so no FAB subtype could be assigned. Only 2 of 50 patients (4.3%) with 5q-syndrome progressed to AML; both patients developed acute erythroid leukemia (FAB M6).
Conclusion: Within the del(5q) MDS subgroup, patients with an isolated del(5q) chromosomal aberration and a bone marrow blast count of &lt;5% have the longest overall survival. Patients with additional chromosomal abnormalities or a higher blast percentage have a much shorter overall survival and a higher risk for progressing to AML. Our data show that progression to higher MDS subtypes or AML occurs almost exclusively in patients with additional risk factors such as &gt;5% bone marrow blasts or additional chromosomal anomalies. Lenalidomide does not seem to increase the risk of transition of del(5q) MDS to higher stages of disease.
Therapy of Early Stage Myelodysplastic Syndrome (MDS) with Anti-Thymocyte Globulin (ATG) and Etanercept.
Authors: Scott Bart L. , Holsinger Aaron L. , Ramakrishnan Aaravind , Storer Barry , Becker Pamela S. , Petersdorf Stephen , Deeg H. Joachim 
Published: April 2020

Abstract
Immunosuppressive therapies have proven valuable in treating ineffective hematopoiesis in patients with Myelodysplastic Syndrome (MDS). Following an encouraging pilot trial, we evaluated the combination of equine anti-thymocyte globulin (ATGAM) and the soluble TNF receptor etanercept in a phase 2 trial. So far 23 patients with MDS (6-RA, 4-RARS, 12-RCMD, 1-RAEB-1) in IPSS risk groups low (n=8) or intermediate-1 (n=15) have been enrolled. All patients were platelet or red blood cell transfusion dependent. Nineteen patients completed therapy with I.V. ATGAM at 40mg/kg/day for four consecutive days, followed by etanercept, 25mg s.c. twice a week for 2 weeks every month for 4 months. The regimen was well tolerated and the majority of adverse events were anticipated infusional reactions related to ATGAM administration. Responses were assessed by modified International Working Group criteria. Twelve patients had hematological improvement (HI)-erythroid, 2 HI-neutrophil, and 3 HI-platelet. Five patients achieved red blood cell and one patient platelet transfusion independence. There was one complete remission in a patient with a co-existing diagnosis of multiple sclerosis. Thus, the overall response rate by intent to treat analysis among the 23 patients was 61%. Four patients did not complete their first course of therapy due to anaphylactic reaction, thrombosis of a pre-existing femoral graft, myocardial infarction, and patient preference. Among patients who completed treatment 74% had a hematological response, with duration of at least 5 months. Combination therapy with ATG and etanercept was active and safe in unselected patients with low and intermediate-1 risk MDS.
Alemtuzumab Treatment for Aplastic Anemia (AA) and Low-Risk Myelodysplastic Syndrome (MDS): Preliminary Results.
Authors: Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Seol Miee , Lee Young-Shin , Sim Soo-Kyung , Ryu Seong-Gil , Kang Young-Ah , Lee Kyoo-Hyung 
Published: April 2020

Abstract
We investigated the effectiveness of systemic immunosuppressive treatment using alemtuzumab (MabCampath®, Schering, Berilin, Germany) in adult patients with AA and low-risk MDS. This prospective study began on September 2005 and 11 patients, 7 severe AA and 4 MDS (RA 2, RCMD 1, RCMD-RS 1), have been enrolled onto the study. Patients received a total of 101 mg of alemtuzumab for 11 days: a test dose of 1 mg on the first day and a daily dose of 10 mg for the next 10 consecutive days. Anti-infective prophylaxis including ciprofloxacin, acyclovir, and bactrim was given for 8 weeks. One patient died of cerebral hemorrhage on 22 days after alemtuzumab treatment and another patient was lost to follow-up 123 days after the treatment. Nine patients are surviving with a median follow-up duration of 366 days. Non-hematologic toxicities were mild and transient: infusional fever/chill in 5 (grade I in all), skin rash in 2 (grade I in both), and increase of liver enzymes in 4 (grade I in all). Patients experienced transient aggravation of pancytopenia. One patient showed severe thrombocytopenia that was refractory to platelet transfusion leading to fatal cerebral hemorrhage. Lymphocyte subset analyses showed that B cells and natural killer cells recovered by 6 months, but CD4+ or CD8+ T cells remained at low levels for more than 6 months. There was no serious opportunistic infection requiring hospitalization. Three patients (27.3%) showed hematologic response to alemtuzumab treatment: partial response in 2 and complete response in one. Two partial responses occurred on 50 days (in an 18 year-old female with AA) and 157 days (in a 50 year-old male with RCMD-RS) after alemtuzumab treatment, but response duration was short in both patients (231 days and 51 days, respectively). In a 25 year-old male with RA, hematologic response occurred on 83 days after alemtuzumab treatment and complete response was attained on 237 days after the treatment. He remained in complete hematologic response on 370 days after the treatment. Our preliminary results showed that alemtuzumab treatment might be effective in some patients with AA and low-risk MDS, but hematologic response rate seemed low. This study will continue with the patients who are unresponsive to standard immunosuppressive treatment with ATG plus cyclosporine and are ineligible for allogeneic hematopoietic cell transplantation.