bluuebunny/crossref_metadata_2025_split huggingface dataset:
HLA-C Mismatch Is Associated with Inferior Outcome after Unrelated Donor Non-Myeloablative Hematopoietic Stem Cell Transplantation.
Authors: Ho Vincent T. , Kim Haesook T. , Windawi Sarah , Liney Deborah , Milford Edgar , Gribben John , Cutler Corey , Lee Stephanie J. , Antin Joseph H. , Soiffer Robert J. , Alyea Edwin P. 
Published: April 2020

Abstract
Donor-recipient disparity at HLA-C is an important determinant of clinical outcome after myeloablative unrelated donor (URD) hematopoietic stem cell transplantation, but its importance in URD non-myeloablative stem cell transplantation (NST) is less clear.
Methods: We performed a retrospective analysis of 111 patients who underwent unrelated donor NST for hematologic malignancies from 2000–2004. Of these, 78 were 10/10 matched at HLA-A, B, C, DRB1, DQB1, and 33 were mismatched at one or more HLA-C antigen/allele (21 single C, 3 double C, 9 single C + other HLA locus mismatch). A majority (78%) of the mismatches at HLA-C were detectable at the antigen level. Diseases included AML (24), ALL (3), MDS (17), CML (10), CLL (23), NHL (22), and HD (12). All patients received non-myeloablative conditioning with intravenous busulfan (0.8mg/kg/d x 4 days) and fludarabine (30mg/m2/d x 4 days). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine plus prednisone or tacrolimus plus low-dose methotrexate based regimens. Stem cell source was primarily G-CSF mobilized PBSC.
Results: Median time to neutrophil engraftment (ANC &gt; 500/ul) among patients who nadired was 12 days (range 8–21 days) in both groups. Median unfractionated marrow donor chimerism were ≥ 90% donor at day+30 and day +100 in both groups. There was one late graft failure in the C-mismatched cohort, and one early graft rejection in the 10/10 matched cohort. HLA-C disparity was associated with an increased risk for grade III-IV acute GVHD (33% vs. 12%, p = 0.01) in univariate and multivariate logistic regression analyses (odds ratio 3.6, p = 0.03). This finding remained significant even when baseline differences in GVHD prophylaxis between the 2 cohorts were taken into consideration. Cumulative relapse incidence was not statistically different: 35% in the C-mismatched group, versus 55% in the 10/10 matched cohort, p = 0.09. There was a higher incidence of treatment related mortality in the C-mismatched group: 48% versus 16% (p = 0.001). Overall survival at 2 years was 27% in C-mismatched, vs. 47% in 10/10 matched patients (p = 0.009). In Cox regression model, HLA-C disparity was an independent factor for poor survival (hazard ratio 1.85, p = 0.04).
Conclusions: Donor recipient disparity at HLA-C does not influence engraftment or donor chimerism after URD NST, but is associated with increased acute GVHD and inferior survival. HLA-C is an important transplantation antigen and should be considered in the selection of unrelated donors for NST.
Early Marrow Response in CCG-1952: The Prognostic Impact of Poor Day 14 Marrow Response Is Powerful and Only Partially Reversible with Intensified Therapy.
Authors: Cho Robert , Stork Linda C. , Gaynon Paul S. , Sather Harland N. , La Mei K. , Hutchinson Raymond J. 
Published: April 2020

Abstract
Microscopic assessment of bone marrow response on Day 7 and/or Day 14 of induction therapy remains a powerful predictor of long-term outcome in childhood acute lymphoblastic leukemia (ALL). Between 1996 and 2000, 2175 Rome/NCI standard risk children, i.e., age &gt;1 and &lt;10 years with presenting WBC &lt;50,000/ul, entered CCG-1952 and received induction therapy with vincristine, native asparaginase, prednisone, and intrathecal cytarabine and methotrexate. Bone marrow status was assessed on Day 7 and Day 28. Patients with blasts &gt;5% on Day 7 had an additional evaluation on Day 14. Patients with blasts &gt;25% (M3) on Day 14, adverse cytogenetics (i.e., t(9;22), t(4;11), or severe hypodiploidy (modal chromosome numbers &lt;45) received daunomycin on day 19 of induction and the augmented intensive regimen therafter (Nachman et al, N Eng J Med1998; 338: 1663–71). Early response and event free survival (EFS) data are depicted as follows for 2014 patients who achieved marrow blasts &lt;5% by Day 28.
D7 Response D14 Response n 5-yr. EFS Hazard M1 –––––––––– 970 86.4% 1.0 M2 M1 478 81.9% 1.3 M2 47 79.7% 1.9 M3 0 –––––––––– –––––––––– M3 M1 347 76.7% 1.5 M2 132 54.3% 3.5 M3 40 63.9% 2.9
Day 7 M1 patients had better EFS than Day 7 M2 or M3 patients who did not achieve M1 status until Day 14. Induction daunomycin and stronger post induction intensification therapy may have rescued Day 7 M3/Day 14 M3 patients, who had a better EFS than the more rapidly responding Day 7 M3/Day 14 M2 patients, who received only standard strength intensification. Day 7 M3/Day 14 M2 patients received ‘augmented therapy’ on the subsequent study, CCG-1991. In summary, microscopic assessment of marrow response remains a powerful predictor of long-term outcome. Outcomes may be modified by more effective subsequent therapy.
FLT3 Immunotherapy Can Eliminate Engraftment of ALL Cells in NOD/SCID Mice.
Authors: Piloto Obdulio , Nguyen Bao , Brown Patrick , Kim Kyu-Tae , Huso David , Li Yiwen , Witte Larry , Hicklin Daniel J. , Small Donald 
Published: April 2020

Abstract
The class III receptor tyrosine kinase, FLT3, is expressed by over 90% of B-lineage acute lymphoblastic leukemias (ALL) blasts. In addition, it is expressed at extremely high levels in ALL patients with MLL-rearrangements or hyperdiploidy and sometimes mutated in these same patients. In this report, we investigated the effects of EB10, an anti-human FLT3 monoclonal antibody capable of preventing binding of FLT3 ligand (FL), on ALL cell lines and primary cells. In vitro studies, examining the ability of EB10 to inhibit FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. In some cell lines FLT3 phosphorylation was inhibited and with it, downstream activation of pathways involving MAPK, AKT, and STAT5 phosphorylation. However, several cell lines actually exhibited FLT3 activation upon antibody treatment, possibly because of antibody-mediated receptor dimerization, and subsequent activation of downstream pathways. Nevertheless, through antibody-mediated cellular cytotoxicity (ADCC) such an antibody could still prove efficacious against leukemia cells in vivo. In fact, EB10 treatment significantly prolongs survival and/or reduces engraftment of several ALL cell lines and some primary ALL samples in NOD/SCID mice, even when EB10 treatment results in FLT3 activation of those cell lines in vitro. Moreover, FACS and PCR analysis of EB10 treated NOD/SCID mice surviving 150 days post leukemic cell injection revealed that FLT3 immunotherapy eliminated leukemic engraftment. The leukemic cells surviving EB10 treatment in the mice were characterized by FACS analysis and found to express lower levels of FLT3. To assess for resistance, cells surviving EB10 treatment were injected into NOD/SCID mice and treated with a single dose of EB10. FACS analysis revealed that these cells remain sensitive to EB10 treatment. Taken together, these data demonstrate that EB10 is cytotoxic to ALL blasts in vivo and EB10 treatment did not select for resistant clones. Such an antibody, either naked or conjugated to radioactive isotopes or cytotoxic agents, may prove useful in the therapy of infant ALL as well as childhood and adult ALL patients whose blasts typically express FLT3.
Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.
Authors: Rizzari Carmelo , Valsecchi Maria Grazia , De Lorenzo Paola , Aricò Maurizio , Basso Giuseppe , Locatelli Franco , Lo Nigro Luca , De Rossi Giulio , Masera Giuseppe , Biondi Andrea 
Published: April 2020

Abstract
Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR).
Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants.
Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies.
Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study.
Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.
Acute Lymphoblastic Leukaemia Cells Carrying the t(12;21) Translocation Are Highly Sensitive to Alemtuzumab Mediated Cell Lysis.
Authors: Golay Josee , Cortiana Chiara , Cazzaniga Giovanni , Salvi Anna , Manganini Massimiliano , Spinelli Orietta , Bassan Renato , Barbui Tiziano , Biondi Andrea , Rambaldi Alessandro , Introna Martino 
Published: April 2020

Abstract
We have investigated CD52 expression and alemtuzumab (Campath-1H®) mediated lysis in acute lymphoblastic leukaemia (ALL) cell lines and freshly isolated samples. CD52 was expressed in 4 out of 9 ALL cell lines studied (44%), only two of which expressed it at high levels: the preB ALL REH carrying a t(12;21) translocation and the B-ALL Silti with rearranged c-myc (both with MFI of about 270). In contrast, of 57 freshly isolated ALL samples analysed, 86% of cases expressed CD52, albeit at varying levels. CD52 expression was generally more frequent and more intense on more mature ALL along either the B or T lineage. In particular none of the 4 proB-ALL carrying a t(4;11) translocation expressed CD52 (0%), whereas 100% of B linage ALL with a t(12;21), t(9;22) or t(1;19) translocations (total 19 cases analysed) stained positive for CD52 at varying levels (100%). We next analysed alemtuzumab and complement mediated lysis (CDC) and ADCC. ADCC was equivalent in different CD52+ lines, reaching 50% lysis at a 60:1 effector:target ratio. In contrast complement dependent cytotoxicity was variable in different cell lines, since the REH cell line bearing the t(12;21) translocation showed 47% lysis at 10 μg/ml alemtuzumab compared to 0–6% for the other cell lines (Silti and the B lymphoma EsIII), expressing equivalent amounts of CD52. Interestingly amongst freshly isolated ALL, 10/10 t(12;21) ALL samples showed very high CDC (mean 96% lysis) in presence of 10 μg/ml alemtuzumab and human serum, compared to the other 15 CD52+ cases tested in the same conditions which showed a mean of 19% lysis (p&lt;0.0001). Furthermore in t(12;21) samples, near maximal CDC was obtained with as low as 1 μg/ml alemtuzumab whereas other ALL cases required 10 to 100 μg/ml alemtuzumab for significant lysis to be observed. CDC correlated only in part with CD52 levels, suggesting that CD52 expression as well as other yet undefined factors contribute to the particular sensitivity of t(12;21) cells. In non t(12;21) ALL cases showing low lysis, CDC could be increased 2 to 3 fold by increasing alemtuzumab concentration to 100 μg/ml, or by blocking the CD55 and CD59 complement inhibitors. Furthermore, increased cytotoxicity (up to 100%) could be obtained in several non t(12;21) ALL cases by combining alemtuzumab with fludarabine or mafosfamide, with an approximately additive effect observed between the antibody and these chemotherapeutic drugs. We conclude that the cytotoxic activity of alemtuzumab against CD52+ ALL is variable and its effectivenes can be improved by the combination with cytotoxic drugs.
Curcumin Induces Apoptosis by Inhibiting the Expression of IAPs in Human Precursor B-Acute Lymphoblastic Leukemic (PreB-ALL) Cells.
Authors: Hussain Azhar R. , Siraj Abdul K. , Manogaran Pulicat S. , Al-Kuraya Khawla S. , Uddin Shahab 
Published: April 2020

Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood resulting from the clonal proliferation of lymphoid precursors with arrested maturation. Chemotherapy can induce complete remission in more than 95% of cases of childhood ALL and achieve long-term survival in 70–80% of cases. However, ALL with the t(9:22) BCR-ABL translocation or Philadelphia chromosome (Ph1) are still highly resistant to chemotherapy from the onset. Thus, new therapeutic approaches are required to improve their prognosis. Characterization of the growth requirement of ALL cells suggest that these cancers are dependent on various cytokines via paracrine and/or autocrine mechanism in which the JAK family of proteins are closely implicated. Accordingly, tyrosine kinase inhibitors against JAKs are expected to become a new class of anti-tumor agents against these cancers. Curcumin has been shown to inhibit JAK-STAT pathway in a variety of hematological malignancies including multiple myeloma and primary effusion lymphomas. We therefore sought to determine whether curcumin suppresses the growth of acute lymphoblastic leukemia. We tested a panel of preB-ALL cell lines with various translocations after treatment with different doses of curcumin. The cell lines included REH (t12:21), RS4:11 (t4:11), 697 (t1:19) and SupB15(t9:22). Cell viability decreased in a concentration-dependent manner in 697, REH and RS4:11 with curcumin (0–40mM) whereas only minimal changes in viability was detected in SupB15. Curcumin induced apoptosis in all preB-ALL cell lines except SupB15 that was found to be refractory to curcumin treatment. Curcumin induced apoptosis via truncation of BID, loss of mitochondrial potential as determined by JC1 staining with subsequent release of cytochrome c from the mitochondria, and activation of caspase 3 and PARP. Curcumin treatment also caused the down-regulation of the IAPs, cIAP1 and XIAP. All these events occured in the sensitive cell lines 697, REH and RS4:11, however, in SupB15, curcumin failed to inhibit the expression of cIAP1 and XIAP and remained refractory to treatment. These results suggest that the IAPs may play an important role in curcumin induced apoptosis in preB-ALL cells. Altogether, our findings suggests a novel function for curcumin, acting as a growth suppressor of most preB-ALL cells and inducing apoptosis via down-regulation of IAPs. Therefore, curcumin may have a future therapeutic role in preB-ALL and possibly other malignancies.
A New Recurrent 9q34 Duplication in Pediatric T-Cell Acute Lymphoblastic Leukemia.
Authors: Van Vlierberghe Pieter , Meijerink Jules P.P. , Lee Charles , Ferrando Adolfo A. , Look A. Thomas , van Wering Elisabeth R. , Beverloo H. Berna , Aster Jon C. , Pieters Rob 
Published: April 2020

Abstract
Over the last decade, genetic characterization of pediatric T cell acute lymphoblastic leukemia (T-ALL) has led to the identification of a variety of chromosomal abnormalities, including translocations, deletions and amplifications. In this study, we used array-comparative genome hybridization (array-CGH) to identify a novel recurrent 9q34 amplification in 33 percent (12/36) of pediatric T-ALL samples, which is therefore one of the most frequent cytogenetic abnormalities observed in T-ALL thus far. The exact size of the amplified region differed slightly among patients, but the critical region involved VAV2, TRAF2 and NOTCH1. FISH analysis revealed that this 9q34 amplification was the result of a 9q34 duplication on one chromosome and could be identified in 17 to 39 percent of the leukemic cells at diagnosis. Although the presence of this leukemic subclone did not predict for poor clinical outcome in our small patient cohort, leukemic cells carrying this duplication were still present at times of relapse, indicating that these cells effectively survived intensive chemotherapeutic treatment. Episomal NUP214-ABL1 amplification and activating mutations in NOTCH1, two other recently identified 9q34 abnormalities in T-ALL, were also detected in our pediatric patient cohort. We showed that both genetic abnormalities are independent from this newly identified 9q34 duplication.
Phase III Trial of All-Trans Retinoic Acid (ATRA) vs Daunorubicin (D) and Cytosine Arabinoside (A) as Induction Therapy and ATRA vs Observation as Maintenance Therapy for Children with Newly Diagnosed Acute Promyelocytic Leukemia (APL).
Authors: Gregory John , Kim Haesook , Alonzo Todd , Gerbing Rob , Ogden Angela , Woods William , Weinstein Howard , Shepherd Lois , Schiffer Charles , Appelbaum Frederick , Willman Cheryl , Wiernik Peter , Rowe Jacob , Tallman Martin , Feusner James 
Published: April 2020

Abstract
Between April 1992 and February 1995, 71 children with locally diagnosed APL were enrolled on the national trial (ECOG E2491) to test ATRA during induction and maintenance (MAINT). Induction consisted of either ATRA, 45 mg/m2/d orally, or 1–2 cycles of D, 45 mg/m2/d IV bolus days 1–3, plus A, 100 mg/m2/day by continuous intravenous (IV) infusion days 1–7. All patients (pts) achieving complete remission (CR) were scheduled to receive two cycles of consolidation chemotherapy consisting of one cycle the same as induction followed by A, 2 gm/m2 IV over one hour every 12 hours days 1–4, plus D, 45 mg/m2/d IV bolus days 1–2. Pts on both arms were then randomized to receive either MAINT ATRA, 45 mg/m2/d orally for one year, or observation (OBS). Fifty-three children with the (15;17) translocation or centrally reviewed M3 FAB APL are the subject of this report. These patients were aged 1–18 years (median 12 years; only 2 &lt; 2 yrs). A female predominance was noted (60% female). The distribution by race was: White 35, African American 7, Hispanic 8, Asian 2, and Filipino 1 patient. No extramedullary disease was proven at diagnosis. Twenty-seven patients were reported to have bleeding symptoms at diagnosis. The median WBC at study entry was 3.2 (4.2 for the DA arm, 2.6 for the ATRA arm). Only one patient was noted to have the M3v subtype. Twenty-seven pts were treated on the ATRA induction arm and 26 on the DA induction arm. A CR rate of 70% was obtained (ATRA CR 81%, DA CR 58%, P=0.08) after Induction and 3 additional patients achieved a CR after cross-over to DA (overall CR=75%). The 3 year DFS from achieving CR was 49% (DA 46%, ATRA 51%, P=0.33). Thirty-three patients reached maintenance therapy after CR- 16 in the OBS arm and 17 in the MAINT ATRA arm. The 3 year DFS from the start of MAINT was 48%( MAINT ATRA 75%, OBS 19%, P=0.0001). The 5 year OS was 68% (DA 62%, ATRA 73%, P=0.33). Induction toxicity data for 53 patients treated on this study included: four patients had a Grade III/IV hemorrhage during induction (DA 3, ATRA 1), intracranial hemorrhage(ICH) in 3, retinoic acid syndrome (RAS) in 2, pseudotumor cerebri definite in 2 and probable in 6, typhlitis in 2, and pancreatitis in 1. Four lethal toxicities occurred including two from ICH and one each from infection and RAS. (DA 3, ATRA 1) In conclusion, 1) the outcome for children with APL is excellent when treated with ATRA and anthracycline-based induction; 2) ATRA as maintenance resulted in a statistically significant advantage in DFS; 3) the salvage rate for relapsed patients appeared promising.
Use of Arsenic Trioxide in Acute Promyelocytic Leukemia Leads to Cardiotoxicity in African-American Patients.
Authors: Patel Sandip P. , Estey Elihu H. 
Published: April 2020

Abstract
Arsenic trioxide (ATO) is an effective therapy for acute promyelocytic leukemia (APL), but cardiac side effects have been described. We reviewed the charts of all 77 patients given ATO at M.D. Anderson from 1998 to present. Our objectives were to: (1) identify patients at relatively high risk of developing arrhythmias after receiving ATO and (2) evaluate the sensitivity and specificity of the electrocardiographic QTc interval in predicting subsequent arrhythmias. The median age of the patients was 54 years. 5% were African-American. 70% received ATO for treatment of APL, 18% for myelodysplastic syndrome, and 12% for other hematological malignancies. The dose of ATO was 0.15 mg/kg daily for 60 days. If, after this time, response was observed ATO was given for an additional 6 months, on a 2 weeks on, 2 weeks off schedule. The dose was lowered from 0.15 mg/kg in the event of acute toxicity, however the African-American patients discussed below were on the standard 0.15 mg/kg dose when they experienced arrhythmias.
Arrhythmias were observed in 4 of the 77 patients (5%, exact 95% CI 1– 13%). Of these 4 patients, 2 developed ventricular tachycardia and 2 atrial tachycardia. In 3 of the 4 patients, these arrhythmias led to discontinuation of ATO and its replacement by mylotarg. Three of the 4 African-Americans given ATO developed arrhythmias vs. only 1/73 non African-Americans (Fisher exact p value, 0.002). The patients who developed arrhythmias were younger (median age = 32) than those who did not (median age = 57) and had no history of cardiac disease, electrolyte abnormalities, or use of medications that would alter their response to ATO relative to the other patients. African-Americans tended to be younger than non African-Americans: 3/4 were age &lt; 40 vs. 19/73 non African-Americans. However, since the incidence of arrhythmias in patients age &lt; 40 was 3/3 for African-Americans vs. 0/19 for others (p= 0.0006), it seems that race, not age, is the principal predictor of arrhythmias. Similarly, although all 4 African-Americans had APL vs. 50/73 others, the respective incidence of arrhythmias in African-American APL patients was 3/4 vs. 1/50 in non African-American APL patients (p = 0.0006). Furthermore, arrhythmias were seen on average 8 days after ATO induction in the 3 African-Americans, while the Caucasian patient did not develop arrhythmias until 45 days after ATO induction. Although all patients were on weekly to bimonthly ECG monitoring, QTc interval prolongation (&gt; 430 ms) was not observed in the patients who developed serious cardiac arrhythmias. None of the 3 patients with QTc prolongation had a documented arrhythmia. Thus, QTc monitoring had zero sensitivity and zero specificity for eventual arrhythmia development. Despite uncertainty as to mechanism, physicians should be aware that ATO may cause arrhythmias in young African Americans. Our data also calls into question the value of QTc monitoring, at least in patients given ATO.