bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remarkable Activity of Bortezomib Combined with Chemotherapy in a Phase I Study of Relapsed Childhood Acute Lymphoblastic Leukemia (ALL). A Report from the Therapeutic Advances in Childhood Leukemia (TACL) Consortium.
Authors: Messinger Yoav H. , Gaynon Paul S. , Raetz Elizabeth , Hutchinson Raymond , DuBois Steven , Bender Julia Glade , Sposto Richard , van der Giessen Jeannette , Eckroth Elena , Bostrom Bruce C. 
Published: April 2020

Abstract
The outcome of relapsed ALL remains very poor, and many re-induction regimens are highly toxic. We report here the Phase I component of a Phase I/II study of bortezomib added to 4-drug induction with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin in children with relapsed ALL. A total of 10 patients were enrolled, 5 in 1st marrow relapse (2 early and 3 late relapses) and 5 in 2nd or subsequent relapse. Four patients were enrolled at dose level 1 (1 mg/m2) to obtain 3 evaluable patients. One patient was inevaluable for toxicity because of an error in dexamethasone doses and was removed after 8 days. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (1.3 mg/m2), the standard single agent dose. One patient had a DLT (hypophosphatemia and rhabdomyolysis) after1 dose of bortezomib, and that patient died from diffuse zygomyces infection by day 17. Five additional patients were enrolled with no further DLT’s. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Only 2 patients had mild peripheral neuropathy (grades 1 and 2). Seven of the10 patients (70%) achieved a CR, and 1/10 had bone marrow CR with persistent central nervous system (CNS) leukemia despite weekly intrathecal (IT) methotrexate, for a total of 80% bone marrow CR rate. In conclusion: the combination of bortezomib with 4 standard drugs is highly active with acceptable toxicity in heavily pretreated relapsed pediatric ALL patients. We are expanding the MTD cohort for a phase II estimate, and intend to report updated results at the ASH meeting.
Day 1 2 4 8 11 14 15 18 22 29 - 35 Bortezomib (1 or 1.3 mg/m2) B B B B Evaluate Vincristine (1.5 mg/m2) V V V V Doxorubicin (60 mg/m2) Dox Dexamethasone (10 mg/m2) x 14 days —— —— —— —— —— —&gt; PEG-Asparaginase (2500 U/ m2) PEG PEG PEG PEG IT Ara-C ITA CNS Negative: IT Methotrexate ITM CNS Positive: IT Triples ITT ITT ITT
The Reduction of Leukemic Blasts In Bone Marrow Aspirate on Day 6 of Remission Induction Treatment Is Predictive for Complete Remission Rate and Survival in Adult Acute Myeloid Leukemia: The Results of Multicenter, Prospective Polish Adult Leukemia Group Study.
Authors: Holowiecki Jerzy , Grosicki Sebastian , Kyrcz-Krzemien Slawomira , Kuliczkowski Kazimierz , Kielbinski Marek , Skotnicki Aleksander B. , Piatkowska-Jakubas Beata , Hellmann Andrzej , Wierzbowska Agnieszka , Seweryn Marek , Stella-Holowiecka Beata , Sadus-Wojciechowska Maria 
Published: April 2020

Abstract
The goal of this study was to pr ove the significance of an early evaluation of leukemic blast reduction based on cytological examination of bone marrow aspirates obtained on day 6 of remission induction treatment.
Patients: 152 adult AML patients aged 18–60 (median 47) registered to the PALG prospective trial evaluating the efficacy of 3 remission induction protocols:
DAF: daunorubicine (DNR) 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 2h inf. iv d 1–5) DAC (like DAF but cladribin is used at 5 mg/m2 instead of fludarabine) and the standard DA 3+7 regimen.
Patients achieving CR received two courses of subsequent intensive consolidation:
HAM (HD AraC, mitoxantrone) HD AraC. In case of partial remission (PR) after the first induction course the same regimen was repeated.
Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Bone marrow aspirates were performed before the treatment and on the 6-th day of the first remission induction course, and the MGG stained marrow smears were evaluated at each centre by two experienced hematologists.
Results: Based on the proportion of blasts in bone marrow specimen on day 6 patients were arranged into 2 groups:
“responders” with &lt;5 % of blasts (n=59) and “non responders” with &gt;5% of blastic cells in bone marrow (n=31).
The complete remission rate (CR) in the “responders” group equaling 86% (82/95) was significantly higher in comparison to that found in the “non responders” group 33%(19/57), p=&lt;0,00001. The probability of overall survival (OS) was also higher in the group of “responders” if compared to “non responders” one; 63% versus 33% respectively, p=0,0009. In multivariate analysis including bone marrow examination, cytogenetic risk group, age, leukocyte count at diagnosis and the induction arm, only the persistence of leukemic blasts &gt;5% in bone marrow specimens on 6-th day of induction was associated with higher risk of not achieving CR (HR = 51,1; p=0,00002), and with shorter OS (HR=2,9; p=0,004).
Conclusion: This prospective, multicenter study demonstrates that a simple and commonly accessible evaluation of the leukemic blasts reduction in bone marrow smear on the 6-th day of remission induction treatment is a reliable and independent predictor for achieving CR and for overall survival. This offers a decision point for an early modification of the treatment strategy.
Stem Cell Transplantation in Elderly Patients with Acute Lymphoblastic Leukemia (ALL) in First Complete Remission (CR1).
Authors: Arnold Renate , Beelen Dietrich , Bornhaeuser Martin , Bunjes Donald , Finke Juergen , Kroeger Nikolaus , Stadler Michael , Stelljes Matthias , Goekbuget Nicola , Hoelzer Dieter 
Published: April 2020

Abstract
In the German Multicenter ALL studies (GMALL) patients aged &gt;55 years with high risk (B-lineage ALL with WBC at diagnosis &gt;30000, late CR, t (4; 11), complex aberrant karyotype or prae-T or mature T-ALL) or very high risk (Ph+/BCR-ABL+) ALL are increasingly candidates for allogeneic stem cell transplantation (allogeneic SCT with a HLA identical sibling donor, MRD or a matched unrelated donor, MUD) or autologous SCT. Here, we report on 31 elderly patients transplanted within the GMALL studies 06/99 and 07/03. Median age of the patients was 61 years (56–65). 22 patients belonged to the very high risk group (VHR), 8 patients to the high risk group (HR) and 1 patient from the standard risk group (SR) was transplanted because of detection of minimal residual disease.17/31 patients were transplanted from a matched unrelated donor, 9/31 patients from a HLA identical sibling donor and 5/31 patients underwent autologous SCT. Conditioning regimens for MRD SCT were myeloablative (MAC) in 6 patients (TBI 12 Gy and chemotherapy n=2, radioimmunotherapy + chemotherapy n=2, chemotherapy only n=2) and 3 patients received reduced intensity conditioning (RIC).Conditioning regimens for MUD SCT changed over time with an increasing number of RIC in the study 07/03. In total, 7/17 patients received MAC (TBI 12 Gy and chemotherapy n=5, chemotherapy only n=2) and 10/17 patients received RIC. Conditioning regimens in autologous SCT were myeloablative (MAC) in 5/5 patients.
Results: After allogeneic MRD SCT 4/9 patients (44%) are alive in CCR (d+ 24, d+ 611, d+ 1721, d+ 2321), 3/9 patients died due to leukemia, 2/9 due to transplant related mortality (TRM). After allogeneic MUD SCT 8/17 patients (46%) are alive in CCR (from d+ 165 to d+ 2176). 1 further patient is alive after re- SCT for treatment of relapse. 7/17 patients died due to TRM and 1 patient died due to relapse. After autologous SCT 2/5 patients are alive in CCR (d+ 1703, d+ 1731), 3/5 died due to relapse. Risk factors for TRM: In allo SCT and MAC 8/13 patients died due to TRM in contrast to 1/13 patients with RIC. In auto SCT none of the patients died due to TRM. Risk factors for relapse: In allogeneic MRD SCT 3/9 patients died due to relapse and 2/17 patients relapsed after MUD SCT. Due to the small number of patients, no difference between MAC and RIC could be found. In autologous SCT 3/5 patients died due to relapse.
In conclusion: The study shows that allo MRD but also MUD SCT is very effective in a selected population of elderly ALL patients. Since the survival of elderly patients with chemotherapy only is about 25%, more patients should be encouraged to have a MRD or MUD SCT.
Sym001, the First Recombinant Polyclonal Rhesus-D Specific Antibody Product, Was Safe and Well-Tolerated in a Placebo-Controlled Randomized Phase I Trial.
Authors: Hjelmström Peter , Hallén Bengt , Lindenstroem Ewa , Gyaw Shwe 
Published: April 2020

Abstract
Sym001 is the first compound in a new class of biopharmaceuticals in clinical development for the treatment of Immune Thrombocytopenic Purpura (ITP), and the prevention of hemolytic disease of the newborn by anti-D prophylaxis (ADP). Sym001 is a recombinant polyclonal antibody product consisting of 25 different anti-Rhesus D specific (RhD) antibodies. The primary objective of this clinical study was to assess the safety of Sym001 following a single intravenous (iv) dose in RhD+ and RhD− healthy male volunteers. Secondary objectives were to assess the potential immunogenicity and pharmacokinetic (PK) profile of Sym001. Fifty-nine RhD+ subjects and 18 RhD− subjects were randomized to receive up to 12.5 μg/kg or 75 μg/kg, respectively, in seven dose cohorts as shown below:
Number of Subjects Cohort Dose (μg/kg) RhD+ Sym001 RhD+ Placebo RhD− Sym001 RhD− Placebo 1 0.25 5 2 0 0 2 1.0 5 2 0 0 3 4.0 7 2 7 2 4 12.5 7 2 7 2 5 25 7 2 0 0 6 50 7 2 0 0 7 75 7 2 0 0
Treatment with Sym001 was well tolerated and there were no serious adverse events (SAEs), no AEs of severe intensity and no AEs that resulted in discontinuation of the study in either the RhD+ or RhD− population. The frequencies of treatment-emergent AEs (TEAE), i.e. AEs occurring after drug administration, were similar among Sym001 and placebo treated subjects and there was no dose-dependent pattern of TEAEs. No significant decrease in mean hemoglobin level compared to baseline was observed at any dose level during the study, and no decrease in hemoglobin &gt; 2 g/dL in any subject was seen. No other laboratory findings were suggestive of clinically significant hemolysis. In addition, no clinically significant changes in vital signs or electrocardiograms (ECGs) were observed, and there were no significant changes in clinical chemistry variables that did translate into SAEs or were assessed as being related to study medication. No immunogenicity to Sym001 was detected and analysis of PK is in progress. In conclusion, Sym001 was found to be safe and well-tolerated in healthy volunteers in doses up to 75 μg/ kg. Sym001 is now being evaluated in a red blood cell (RBC) challenge trial for the ADP indication and in a Phase II trial for treatment of patients with ITP.
Alemtuzumab-CHOP for Aggressive T Cell Lymphoma. A Phase II HOVON 69 Trial.
Authors: Kluin-Nelemans J.C. , Van Marwijk Kooij Marinus , Lugtenburg P.J. , Wijermans Pierre W , Van Putten Willem JL , van Imhoff Gustaaf W 
Published: April 2020

Abstract
The prognosis of patients with aggressive mature T cell lymphoma is very poor. We wondered whether the addition of the anti-CD52 monoclonal antibody alemtuzumab to 2-weekly CHOP chemotherapy as 1st line treatment would result in acceptable toxicity, improved response, and outcome. In a multicenter phase II design, 20 patients were to receive 8 cycles of CHOP14 (d 1: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, 2 mg max, and day 1–5 prednisone 100 mg; repeat at day 15). Alemtuzumab 30 mg subcutaneously was added at day 1, 5 and 10 of each cycle (total of 24 administrations). Valaciclovir, cotrimoxazol and fluconazol were given as prophylaxis for herpes viral, PCP and fungal infections, respectively; G-CSF was given to enhance neutrophil recovery. Blood products were irradiated. Monitoring for CMV (re)activation by PCR or pp65 antigenemia was mandatory. Between Nov 2005 and Oct 2007, 20 patients with newly diagnosed T-NHL were included by 10 different centers (55% male; median age 50, range 20 to 65 years; 19 stage III/IV; 11 IPI high/high-intermediate). T-NHL histologies were: peripheral T cell lymphoma NOS (n=10), angioimmunoblastic lymphoma (n=6), subcutaneous panniculitis-like lymphoma (n=3), enteropathy-associated T cell lymphoma (n=1). Patients received a median of 8 CHOP cycles, 85% received 6 or more. Response to treatment was: 12 CR, 6 PR (ORR 85%) and 2 NR. At a median follow-up of 18 months, 11 patients are still alive, 9 patients have relapsed; the median FFS is 20 months (range 2–25) and median OS is 23 months (5–29). Toxicity was considerable, with CMV reactivation in 7/20 patients; one patient developed CMV disease; hospital admissions because of (mostly neutropenic) fever occurred in 8 patients. However, none of these patients died from these adverse events. One patient died in CR, 5 months after treatment due to sepsis complicating an extensive varicella zoster infection. Three patients (two with peripheral T cell lymphoma, one with angioimmunoblastic lymphoma without initial EBV activity) developed an EBV-related lymphoproliferative disorder. These patients ultimately died of relapse T-NHL.
In conclusion, an intensive alemtuzumab-CHOP14 regimen is feasible and effective in aggressive T-NHL as far as response and early outcome are concerned. Toxicity, especially the high percentage of herpes viral reactivation including EBV-related lymphoproliferation requires careful monitoring.
Chemical Genomic Screen Identifies Ionophores as Modulators of Notch1 in T-ALL
Authors: Roti Giovanni , Ross Kenneth N. , Mecucci Cristina , Ferrando Adolfo A. , Aster Jon C. , Stegmaier Kimberly 
Published: April 2020

Abstract
Although in recent years intensive chemotherapy regimens have improved outcome for patients with T-cell acute lymphoblastic leukemia (T-ALL), side effects and relapse-rates remain high. An alternative therapeutic approach would be to target constitutively active mutated Notch1. Notch1, a trans-membrane receptor that acts as a transcription factor following proteolytic activation by the γ-secretase complex, harbors gain of function mutations in over 50% of T-ALL. Early clinical trials attempting to modulate Notch1 with γ-secretase inhibitors (GSI) were closed secondary to gastrointestinal toxicity, suggesting that alternative approaches to inhibiting Notch1 signaling are needed. Transcription factor complexes are difficult to target pharmacologically with conventional high-throughput screening approaches. We therefore sought to target Notch1 with a new gene expressionbased approach to small molecule library screening. Signatures for the Notch1 on versus off states were defined using microarray expression profiling of 7 different Notch1 mutant T-ALL cell lines treated with vehicle (Notch1 on) versus a GSI (Notch1 off). We adapted this 32-gene signature to our gene expression-based high-throughput screening (GE-HTS) assay, which uses ligation-mediated amplification (LMA) and a Luminex bead-based detection system. As proof of principle, we confirmed that an shRNA against Notch1 induced the Notch1 off signature in DND41 cells (a T-ALL cell line bearing a mutated Notch1 allele). In order to facilitate future clinical translation, we screened a collection of 4,500 bioactive compounds highly enriched for FDA-approved drugs in DND41 cells. Twenty-eight compounds that induced the Notch1 off signature were identified as top hits. These compounds were tested in a secondary screen in a 2-fold dilution series in two GSI sensitive cell lines, DND41 and KOPTK1, and one GSI resistant cell line, PF382. Ion channel modulators emerged as the top class of compounds confirmed to induce the Notch1 off signature across all cell lines. We next focused on two representative compounds, the ionophores salinomycin and ionomycin. Similar to GSI, both of these molecules induced cell cycle arrest and markedly decreased levels of the activated intracellular portion of Notch (ICN). Both salinomycin and ionomycin, as well as numerous other ionophores that scored as inhibitors in the screen, are known to increase cytosolic calcium. These studies are consistent with a role for calcium in the activation of oncogenic forms of Notch1 and suggest a potential role for ion channel modulators in the treatment of T-ALL.
Comparing Standard IPI with Revised-IPI in Patients with Diffuse Large B-Cell Lymphoma: Which Has a More Differential Potential for Predicting the Outcomes after R-CHOP Chemotherapy.
Authors: Yang Deok-Hwan , Ahn Jae Sook , Kim Yeo-Kyeoung , Lee Je-Jung , Choi Young Jin , Shin Ho Jin , Chung Joo-Seop , Moon Joon Ho , Chae Yee Soo , Kim Jong Gwang , Sohn Sang Kyun , Kim Hyeoung-Joon 
Published: April 2020

Abstract
The utility of International Prognostic index (IPI) in the era of immunochemotherapy could not be determined by the available randomized trials. Recently, the study of British Columbia group suggested that a revised IPI (R-IPI) which redistributed the IPI factors into 3 distinct prognostic groups provided a more clinically useful prediction of outcome for patients with diffuse large B-cell lymphoma (DLBCL). We investigated the clinical outcomes of R-CHOP chemotherapy in patients with DLBCL for determining which has a more differential potential of predicting the prognosis among R-IPI or standard IPI.
Patients and Methods: We analyzed a total of 348 patients with newly diagnosed DLBCL from National University Hospitals of Southern Korea (NUHSK) between September 2002 and July 2008. R-CHOP conducted standard doses of chemotherapy and rituximab (375 mg/m2) administered a 21-day interval. The limited-stage patients were treated with 3rd or 4th chemotherapy followed by involved field radiation therapy (IFRT) and the advanced-stage patients were treated with six to eight cycles of chemotherapy.
Results: The median age was 61 years (range, 18–85) with 51.6% of patients aged above 60. After a median follow-up of 25 months (range, 2-66.8), 280 patients (80.5%) were alive and 76 patients (21.8%) had relapsed or progressed. 16 patients (4.6%) underwent autologous stem cell transplantation (ASCT). The 4-year probability of overall survival (OS) and progression-free survival (PFS) were 73.7 ± 3.4 % and 69.1 ± 3.6 %, respectively (Fig. 1A). The distribution of patients and 4-year OS rates according to IPI factors were followings; 16.7% patients had zero risk factor with 95.4%, 33.9% patients had 1 factor with 90.0%, 19.3% patients had 2 factors with 69.9%, 19.0% patients had 3 factors with 55.7%, 10.3% patients had 4 factors with 28.4% and 0.9% patients had 5 factors without reached 4-year OS rates (Fig. 1B). Both standard IPI and revised IPI showed a significant potential as prognostic variable in OS and PFS. However, the standard IPI distinguished clinical outcomes between patients with 3 risk factors and patients with 4–5 risk factors. In addition, there was no survival difference between patients with zero risk factor and patients with 1 risk factor (Fig. 2).
Conclusion: The standard IPI had more differentiation potency in predicting prognosis than R-IPI in patients with DLBCL treated with R-CHOP chemotherapy.
Fig. 1 Overall outcomes (A) and outcomes according to the number of IPI factors (B) Fig. 1. Overall outcomes (A) and outcomes according to the number of IPI factors (B) Fig. 2 Comparison of OS and PFS according to the standard IPI and revised IPI Fig. 2. Comparison of OS and PFS according to the standard IPI and revised IPI
First-Line Treatment with Rituximab Combined with Intravenous or Oral Fludarabine for Patients with Extranodal Mucosa Associated Lymphoid Tissue (MALT) Lymphoma.
Authors: Salar Antonio , Domingo-Domènech Eva , Estany Cristina , Canales Miguel , Servitge Octavio , Gallardo Fernando , Fraile Guadalupe , Montalbán Carlos 
Published: April 2020

Abstract
Backgroud: Synergistic antitumor effect with combination of fludarabine and rituximab has been demostrated on MALT cells. Addition of rituximab to other drugs has improved outcomes in several types of NHL without a significant addition of toxicity. Our aim was to evaluate the safety and efficacy of rituximab combined with fludarabine (RF) in first-line therapy for extranodal MALT lymphoma.
Patients and methods: Adult patients with untreated extranodal MALT lymphoma who were included and received rituximab 375 mg/m intravenously (IV) on day 1 and fludarabine 25 mg/m (IV) given on days 1–5 (days 1–3 in &gt; 60 years), every 4 weeks; after the first cycle, oral fludarabine was permitted. After 3 cycles, a work-up was done. Patients in complete remission (CR) received an additional cycle and, if partial remission (PR), a total of 6 cycles.
Results: 22 patients were included. Characteristics: median age: 60 years (32–83); 45% male; PS 0–1 (100%); site of lymphoma origin: gastric (61%) and extragastric (39%); stage: I (45%), II1 (23%), II2 (5%) and IV (27%). A total of 101 cycles of RF were administered and 21 pts were evaluable for response. After the third cycle, 13 pts (62%) achieved CR and 8 pts (38%) PR. At the end of therapy, 19 pts (90%) achieved CR and 2 pts (10%) PR. Univariate analysis identified primary extragastric disease as an adverse factor to reach CR after 3 cycles of RF (HR 23.3 (95% CI, 2.0–273.3)). The median follow-up time was 23 months (95% CI, 18–27 months). Progression free survival (PFS) at 24 months was 88 % (95% CI, 80–100%). PFS at 24 months in gastric and extragastric MALT lymphoma were 100% and 79%, respectively. Tolerance to oral fludarabine was excellent. Mild neutropenia was the most common toxicity, usually presenting after the third cycle and 2 pts had prolonged mild thrombocytopenia. No grade 3–4 infections were observed.
Conclusions: Immunochemotherapy with RF, either with intravenous or oral fludarabine, achieves a high CR rate in both gastric and extragastric MALT lymphoma, although the firsts responded faster. With only four cycles of RF, two thirds of patients achieves CR. RF is associated with a good safety profile being mild granulocytopenia and thrombocytopenia the main adverse events. The long-term benefit of this therapy will require prolonged follow-up.