bluuebunny/crossref_metadata_2025_split huggingface dataset:
Escalating Dose Intravenous Methotrexate without Leucovorin Rescue during Interim Maintenance Is Superior to Oral Methotrexate for Children with Standard Risk Acute Lymphoblastic Leukemia (SR-ALL): Children’s Oncology Group Study 1991
Authors: Matloub Yousif , Bostrom Bruce C. , Hunger Stephen P. , Angiolillo Anne L , Cole Catherine , Thomson Blythe , Devidas Meenakshi , Heerema Nyla A. , La Mei K , Buckley Patrick J. , Carroll William L. , Winick Naomi , Sather Harland , Nachman James B , Gaynon Paul S. 
Published: October 2019

Abstract
A substantial number of relapses derive from the NCI standard risk population. CCG-1991 tested two components of the successful COG augmented “BFM” regimen (N Engl J Med1998; 338:1663) in this subset in a 2 × 2 factorial design. Patients received a 3-drug Induction: vincristine (V), pegylated asparaginase, dexamethasone (D), and intrathecal (IT) cytarabine and methotrexate (M). Patients with an unfavorable early marrow response by morphology (> 25% blasts at day 14, or >25% blasts at day 7 and >5% blasts at day 14) were assigned rescue daunorubicin and “augmented BFM” therapy. Other patients, termed rapid early responders (RER), received Consolidation (daily oral mercaptopurine (MP) and weekly IT M) and were randomized to receive either single or double delayed intensification (DI) phases, and D pulses, oral daily MP, weekly M and monthly V (Reg O) or V and intravenous (IV) escalating dose M with no leukovorin every 10 days for two months preceding and following the DI phase (Reg I).
Induction Consolidation Interim Maintenance Delayed Intensification (DI #1) Interim Maintenance Reg O Oral MP/M/D Reg O Oral 6MP/M/D Maintenance DI #2 Maintenance Reg I V/IV M Reg I V/IV M Maintenance DI #2 Maintenance
CCG-1991 enrolled a total of 3026 patients between 6/1/00 and 1/31/05 with 2078 eligible randomized non-T ALL patients. The overall 5-year event free (EFS) and overall survival (OS) for the randomized patients was 90.5% (SE = 1.0 %), and 96.0% (SE = 1.0%). We previously reported the double DI randomization (Blood2006; 108: abstract #146). Events were 71/1042 patients in Regimen I, and 100/1036 patients in Regimen O. For Reg I and Reg O, 5-year EFS was 92.1% and 88.7% (p = 0.02; RHR = 0.69 respectively. Comparison by type of events: isolated and combined marrow relapse (55 and 54), isolated CNS relapse (10 and 25), testes relapse (0 and 5), death in remission (1 and 5), secondary neoplasm (2 and 6), and other (2 and 4). The benefit was shown in both sexes. The overall survival was 96% on either arm. We therefore conclude that Reg I was superior for children with B-precursor SR-ALL with RER. We saw decreases in CNS and testes relapse with no decrease in marrow relapse. At this time, we find no difference in OS between the two arms.
Predictors of Osteopenia/Osteoporosis in Children with Acute Lymphoblastic Leukemia.
Authors: Athale Uma , Webber Colin , Barr Ronald 
Published: October 2019

Abstract
Background: Loss of bone mineral is a major problem in children with acute lymphoblastic leukemia (ALL), resulting in acute and chronic morbidity. About 30–40% of children with ALL will develop osteopenia/osteoporosis (OP) and about 10–15% will suffer from fractures. Identifying a population at high risk for OP is important to implementing a preventive strategy (e.g. biphosphonate therapy). So far predictors of OP in association with ALL in children are uncertain. Hence we undertook the following study to evaluate predictors of OP in children with ALL treated according to Dana-Farber Cancer Institute protocols.
Aim: To evaluate the relationship between lumbar spine bone mineral density (LS-BMD) Z scores in patients with ALL during maintenance therapy and the variables of age at diagnosis (< 10 vs. ≥ 10-years), risk group [Standard (SR) vs. high-risk (HR)], gender (male vs. female) and LS-BMD at diagnosis.
Methods: Children (≤ 18-years) diagnosed with ALL during the period 1995–2006 who were in first clinical remission, were included in the study. LS-BMD was measured using dual-energy X-ray absorptiometry (DEXA) at the time of diagnosis (n=88) and during the maintenance phase of therapy (n=119). The actual values of LS-BMD were expressed as age and gender matched Z-scores based on local population norms. Regression analyses were used to evaluate the risk of osteopenia, defined as LS-BMD Z score < -1.00, and osteoporosis, defined as LS-BMD Z score < -2.00. We evaluated the effect of age at diagnosis, gender, ALL risk category and LS-BMD at diagnosis on the LS-BMD during maintenance phase of therapy.
Results: Of the 119 patients, 19 (16%) were ≥ 10-years of age, 46 (39%) were girls and 41 (34.5%) had HR ALL. At diagnosis 29 of 88 (33%) patients had osteopenia and 6 (6.8%) had osteoporosis whereas, during maintenance therapy, 47/119 patients (39.5%) had osteopenia and 10 (8.4%) patients had osteoporosis. LS-BMD at diagnosis had a positive linear relationship with LS-BMD during maintenance therapy (Pearson correlation coefficient 0.721, p<0.001). Older children and children with HR ALL had a significantly higher risk of osteopenia compared to younger children (p=0.01) and children with SR ALL (p=0.019). Age and risk category were confounding variables since all children ≥ 10 years were classified as HR ALL. Gender by itself had no significant effect. However, the effect of age on the LS-BMD during maintenance phase was gender-dependent with older girls having lower LS-BMD compared to older boys.
Conclusions: Osteopenia and osteoporosis (OP) are common in children with ALL. Age over 10-years, female gender, HR ALL and lower LS-BMD at diagnosis are predictors of lower LS-BMD during the maintenance phase of therapy. Using these variables it is feasible to develop a predictive model to define the risk of OP during the maintenance phase of therapy. Larger prospective studies will better define this risk.
CD20 up-Regulation in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia during Induction Treatment Translates into Higher Rituximab-Sensitivity.
Authors: Attarbaschi Andishe , Schumich Angela , Mann Georg , Haas Oskar A. , Gadner Helmut , Dworzak Michael 
Published: October 2019

Abstract
CD20 is expressed in about one half of childhood acute lymphoblastic leukemia (ALL) cases with B-cell precursor (BCP) origin. We recently observed that this phenotypic marker is further up-regulated in some patients during remission induction treatment containing corticosteroids for up to 5 weeks. To understand the impact of this phenomenon on the potential effectiveness of anti-CD20 immunotherapy (i.e., Rituximab), we studied 237 CD10-positive childhood BCP-ALL patients consecutively enrolled onto the trial AIEOP-BFM-ALL 2000. The analysis included the assessment of CD20 expression changes from diagnosis to the end of induction therapy and complement-induced cytotoxicity by CD20-targeting with Rituximab in-vitro. CD20-positivity significantly increased from diagnosis to the end of induction therapy with respect to the number of positive cases as well as to the levels of expression. After completion of induction therapy, one half of cases showed ≥ 90% CD20pos. leukemic cells, as opposed to 5% at diagnosis and 20% after 2 weeks of chemotherapy. Notably, up-regulation occurred in viable cells sustaining chemotherapy, most probably as a consequence of steroid-induced modulation of gene expression. Rituximab-cytotoxicity was significantly enhanced by CD20 up-regulation and depended on high expression levels. Importantly, CD20 up-regulation was frequent in high-risk patients (mainly poor prednisone responders), patients with high minimal residual disease levels at the end of induction therapy, and patients who suffered later from relapse, but not in TEL/AML1-positive cases. In conclusion, CD20 up-regulation is frequently induced in BCP-ALL during induction therapy and this translates into an acquired state of higher sensitivity to Rituximab.
Acute Erythroleukemia: An Analysis of 108 Patients Treated with Cytarabine-Containing Regimens at the M.D. Anderson Cancer Center.
Authors: Santos Fabio P.S. , Faderl Stefan , Garcia-Manero Guillermo , Koller Charles A. , Beran Miloslav , Borthakur Gautam , Bueso-Ramos Carlos , Keating Michael , Cortes Jorge , Kantarjian Hagop M. , Ravandi Farhad 
Published: October 2019

Abstract
Acute erythrocytic leukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML). It usually presents as a proliferation of dysplastic erythroid elements mixed with blasts of myeloid origin, although there are some rare cases of pure erythroid proliferation (DiGuglielmo’s disease). It has previously been associated with a poor prognosis. Here, we report the experience at the M.D. Anderson Cancer Center. From January, 1980 to May, 2006 there were 2992 patients with newly diagnosed AML (excluding APL), and 108 (4%) had the diagnosis of AML-M6. Diagnosis was based on morphological features according to the FAB classification, PAS-positivity by cytochemistry and immunophenotypical positivity for glycophorin A when available. Seventy (65%) were males; median age was 60 years (range 17 – 85). Antecedent hematological disorder (AHD) and/or MDS was present in 54 patients (50%) compared to 40% in other AML patients (p=0.056), and 27 (25%) patients had previously received treatment for other malignancies. The median white blood cell count at diagnosis was 2.5x109/L (0.3–45.1), hemoglobin 7.8 g/dL (2.5–12.6) and platelet count 40x109/L (3–22). Information about bone marrow dysplasia was available in 80 patients. Significant morphological dysplasia of erythroid lineage was found in 66 (83%), of myeloid lineage in 38 (48%) and of megakaryocytic lineage in 36 (45%) cases. Cytogenetic analysis was available in 106 (98%) cases, and was abnormal in 77 (71%) patients. The most common abnormalities were: Monosomy 5/Monosomy 7 in 50 (46.3%) and Trisomy 8 in 9 (8.3%). Poor risk cytogenetics were found in 46% of patients with AML-M6, comparing to 19% of the control group (other AML patients excluding APL) (p<0.001). All patients received induction chemotherapy containing cytarabine. Complete remission rates were 63% for AML-M6 patients, comparing to 58% for the control group (p = 0.285). Seventeen patients (15.7%) were refractory and 23 (21.3%) had induction death. Median disease free survival of AML-M6 patients was 31 weeks, compared to 49 weeks for the control group (p = 0.03). Median overall survival of AML-M6 patients was 33 weeks, compared to 42 weeks for the control group (p = 0.190). A total of 24 patients underwent allogeneic stem cell transplantation. Their median survival after transplantation was 32 weeks. We conclude that acute erythrocytic leukemia is a rare subtype of AML. It is commonly associated with a previous diagnosis of MDS and often presents with dysplastic features at diagnosis. It is frequently associated with poor-risk cytogenetics and a poor outcome.
NDRG1 Expression Is Inhibited in AML and Its Knockdown Attenuates Neutrophil Differentiation.
Authors: Tschan Mario P. , Shan Deborah , Laedrach Judith , Eyholzer Marianne , Leibundgut Elisabeth Oppliger , Baerlocher Gabriela , Tobler Andreas , Stroka Deborah , Fey Martin F. 
Published: October 2019

Abstract
The N-myc down-regulated gene 1 (NDRG1) is a stressed induced protein whose expression is associated with growth arrest and differentiation of tumor cells. Although the exact function of NDRG1 protein remains unknown, various studies support its role as a suppressor of tumor metastasis. In prostate, colon and breast cancer its expression is associated with a better disease prognosis and patient survival. In hematopoietic cells, NDRG1 was identified in a differential display screen for differentiation-related genes in human myelomonocytic U937 cells. In the present study, we sought to investigate the role of NDRG1 in myeloid differentiation. To this end we first evaluated NDRG1 mRNA expression in acute myeloid leukemia (AML; n=82) patient samples as well as in CD34+ progenitor cells (n=5) and neutrophils (n=6) of healthy donors using quantitative real-time RT-PCR. We found significantly higher NDRG1 mRNA levels in granulocytes as compared to CD34+ (p=0.0043) or AML blast cells (p<0.0001), whereas no significant difference between CD34+ progenitor and AML blast cells was seen (Figure A). Moreover, we found that NDRG1 mRNA levels were increased in 4/5 APL patients upon ATRA therapy. In contrast, the closest relative of NDRG1, NDRG2, did not show significantly different expression in these primary cells, thus indicating a unique role for NDRG1 in granulocyte differentiation. Next we examined NDRG1 expression using quantitative RT-PCR and Western blotting in two different cell line models for ATRA-induced neutrophil differentiation. ATRA treatment of NB4 and HT93 acute promyelocytic leukemia (APL) cells induced NDRG1 mRNA 2.3- and 14.3- fold, respectively. Increased NDRG1 mRNA expression was paralleled by an increase of NDRG1 protein as well as a decrease in c-myc protein. Earlier reports described that NDRG1 is also suppressed by c-myc suggesting that down-regulation of c-myc in our cell line models allowed for an increase of NDRG1. In line with these observations, lentivirus-driven short hairpin (sh)RNA-mediated silencing of NDRG1 diminished ATRA-induced neutrophil differentiation of NB4 and U937 cells as measured by CD11b, CD11c and CD18 surface expression. In NB4 NDRG1 knockdown versus non-targeting shRNA expressing cells mean fluorescent intensities (MFI) for CD11b, CD11c and CD18 upon six days of ATRA-treatment were 99±17 vs 146±7, 20±2 vs 32±10 and 19±2 vs 45±6, respectively (Figure B). Similarly, U937 NDRG1 knockdown versus control cells displayed the following MFIs for CD11b and CD18 upon neutrophil differentiation: 61±1 vs 102±2 and 11±4 vs 33±13, respectively. In conclusion, we report here for the first time an association of low NDRG1 levels with an immature hematopoietic cell phenotype. Using RNAi technology we further provide evidence that NDRG1 is functionally involved in neutrophil maturation.
Figure Figure
Survival after Complete Response to Treatment with Laromustine (CLORETAZINE®) in Elderly Patients with De Novo Poor Risk Acute Myelogenous Leukemia (AML).
Authors: O’Brien Susan , Schiller Gary , Stuart Robert Kenneth , Hudak Diana , Giles Francis 
Published: October 2019

Abstract
Background: Treatment options for patients with AML are limited. Poor outcomes are associated with increasing age, decreasing performance status, unfavorable cytogenetics, and the presence of comorbid conditions. Elderly patients ³ 65 years with AML have a short survival (median 2.4 months) (Lang 2005), and for older patients who receive treatment, 1-year survival is 5–25% (Menzin 2002, Kantarjian 2006, Burnett 2007). CR/CRp is a desired outcome from induction treatment and a requisite for meaningful survival. Laromustine (Cloretazine) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Results of two sequential Phase II multi-center studies of single agent laromustine (CLI-033 and CLI-043) conducted in elderly untreated AML patients have been reported (Giles 2007, Schiller 2008). The purpose of this analysis is to assess survival for a combined group of patients from the two studies who achieved a response to laromustine (CR/CRp by IWG criteria [Cheson 2003]).
Methods: Eighty-five patients in study CLI-043 and 55 patients from a retrospectively identified de novo subset of CLI-033 who reasonably met the eligibility criteria for CLI- 043, received laromustine 600 mg/m2 as induction therapy (N=140). Poor risk was defined as the presence of at least one risk factor: age ³ 70 yrs, unfavorable cytogenetics, PS2, or pulmonary, cardiac, or hepatic comorbidity. 86% (120/140) pts had 2 or more risk factors. 16% (22/140) pts received a second induction of laromustine 600 mg/m2. 24% (34/140) patients received a consolidation cycle; per individual protocol, 15 pts received consolidation with laromustine 400 mg/m2 and 19 pts received cytarabine 400 mg/ m2. Kaplan-Meier analysis of survival was used to better understand the clinical benefit of CR/CRp.
Results: 52/140 (37%) pts achieved a CR/CRp; 44/140 (31%) pts survived ³ 30 days following CR/CRp. All but one patient achieved CR/CRp following first induction. Estimated Kaplan-Meier survival from time of response for these 44 patients is shown below. Six and 12 month survival for this subset is 58% and 44%, respectively. The 30-day mortality for the entire group is 14% (20/140).
Figure Figure
Conclusions: Early mortality, progressive disease, and short CR/CRp duration account for short median survival rates in leukemia studies. The 30-day mortality for this group compares favorably with published data of early death rates in older patients with multiple risk factors who receive induction chemotherapy (Appelbaum 2006, Kantarjian 2006). Relatively long survival in a subset of older patients with multiple risk factors who achieve a response to laromustine implies clinical benefit, and confirms the concept that obtaining a CR/CRp is in itself a benefit.
Late Relapses in Acute Myelogenous Leukemia: Analysis of Characteristics and Outcome.
Authors: Verma Dushyant , Faderl Stefan , O’Brien Susan , Pierce Sherry , Cortes Jorge , Vu Khanh , Freireich Emil , Keating Michael J. , Kantarjian Hagop M. , Ravandi Farhad 
Published: October 2019

Abstract
The majority of patients with acute myelogenous leukemia (AML) who achieve complete remission (CR) with initial chemotherapy will eventually relapse. Most relapses occur in the first three years and rare patients relapse after being in CR for more than 5 years. We have reviewed retrospectively 2347 patients with AML treated at M D Anderson Cancer Center from January 1980 to July 2008. Of the total cohort, 1366 patients achieved CR and among these 942 patients relapsed. We identified 11 patients (1.16%) who relapsed after being in CR >5 years; these patients are the focus of this analysis. There were 4 females and 7 males. Their median age was 66 years (range 37–79), and their median presentation white blood cell (WBC) count was 2.3 x109/L (range, 1.1–92.3). The FAB classification was M2 in 5 patients, M1, M4, M5, M6 in 1 patient each, and unknown in 2 patients. Initial cytogenetics were diploid in 6, del(7q) in one, miscellaneous in 1, and unavailable in 3 patients. Initial therapy was with combination of idarubicin (Ida) and cytarabine (Ara-C) in 4 patients (1 with additional fludarabine), amsacrine based in 3, daunorubicin (Dauno) single agent in 2 and other agents in 2 patients. All patients except one achieved CR after the first induction course; one patient needed 2 cycles of induction to achieve CR. None underwent an allogeneic stem cell transplant in first CR. The median duration of CR was 81 months (range, 60–137).
At the time of relapse, median WBC count was 4.4 x109/L (range 1.7–48.8). Karyotype at relapse was diploid in 2, del(5)del(7) in 1, del(6)del(7) in 1, trisomy 8 in 1, hyperdiploid in 2, add(2q) and add(6q) in 1 each and unavailable in 2 patients. The karyotype at relapse was different from the initial finding in 8 of 8 patients with available data at both time points. Treatment for relapse included Ida (or Dauno) with Ara-C in 8 patients (1 with additional fludarabine), and other agents in 3 patients. The response to treatment was CR in 4, partial remission in 2, resistant in 4 and unknown in 1. No patient underwent an allogeneic stem cell transplant in second CR. The median duration of the second CR was 2 months (range 0–37). The median survival after relapse was 6.4 months (range 1–39). Median survival from initial diagnosis of AML was 107 months (range 68–143). We conclude that late relapses in AML (>5 years after CR) are infrequent (1.16% of all relapses) and response to their subsequent therapy is poor; best responses occur with a regimen similar to the initial induction regimen. The karyotype at relapse is frequently different raising the question of a second AML versus relapse with the original clone.
Clinical and Serologic Interleukin 2 Receptor α Response to Interleukin-2 in CCG-2961, a Ranomized Phase 3 Trial for Pediatric Acute Myeloid Leukemia.
Authors: Lange Beverly , Yang Richard K , Gan Jacek , Hank Jaqueline A , Sievers Eric , Gerbing Robert , Alonzo Todd , Sondel Paul M 
Published: October 2019

Abstract
The Children’s Cancer Group conducted a randomized comparison of interleukin-2 (IL-2) to no further therapy (control) in pediatric patients with acute myeloid leukemia in first remission after 3 courses of dose intensive chemotherapy. To assess biologic activity of IL-2, serum samples for soluble IL-2 receptor alpha concentration (sIL-2rα) were collected before induction chemotherapy, and after completing chemotherapy but before (day 0), during (day 4) and after IL-2 (day 18) in those randomized to receive IL-2 and before chemotherapy and at the end of chemotherapy (day 0) and 28 days later in the controls. Of 385 eligible patients, 289 consented to participation in the randomization, and 172 submitted specimens. Patients randomized to IL-2 received IL-2 9 x 106 IU/m²/day by continuous infusion (CI) days 0–3 and 1.6 x 106 IU/m²/day CI days 8–17. At five years disease-free survival (DFS) is 51% + 9% in the IL-2 group and 58% + 8% in the controls (p =0.489), and respective overall survivals are 70% + 8% and 73% + 8% (p= 0.727). At diagnosis, median sIL-2rα concentration was 3342 pg/ml in the IL-2 group (N=34) and 3778 pg/ml in the controls (N=41) (p=0.947). In both groups there was a significant reduction in sIL-2rα concentration between the start and day 0 after chemotherapy. In the IL-2 group median sIL-2rα increased significantly from 1462 pg/ml on day zero to 13659 pg/ml on day 4 (p<0.001) and 8435 pg/ml on day 18 (p<0.001). In the control group day sIL-2rα was 1424 pg/ml on day zero and 1559 pg/ml on day 28. Despite evidence of substantial biologic activity as measured by significant increases in sIL-2rα concentration during IL-2 administration, IL-2 in this dose and schedule had no significant effects on DFS or survival. Furthermore, sIL2αr levels (the pretreatment sIL2rα level, the sIL2rα level obtained after chemotherapy or the level achieved after IL2 treatment) did not correlate with DFS or survival, or treatment-related toxicity.