bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNAs 221 and 222 Inhibit Normal Erythropoiesis and Erythroleukemic Cell Growth Via Kit Receptor Downmodulation.
Authors: Felli Nadia , Fontana Laura , Pelosi Elvira , Botta Rosanna , Bonci Desirée , Facchiano Francesco , Liuzzi Francesca , Lulli Valentina , Morsilli Ornella , Santoro Simona , Valtieri Mauro , Liu Chang-Gong , Sorrentino Antonio , Croce Carlo M. , Peschle Cesare
Published: April 2020

MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression primarily through translational repression. In unilineage erythropoietic (E) culture of cord blood (CB) CD34+ progenitor cells, the level of miR 221 and 222 is gradually and sharply downmodulated. Hypothetically, this decline could promote erythropoiesis by unblocking expression of key functional proteins. Our studies indicate that miR 221 and 222 target the Kit receptor: specifically, (a) the luciferase targeting assay showed that miR 221 and 222 directly interact with the 3′UTR of Kit mRNA; (b) in E culture the miR 221 and 222 level is inversely related to Kit protein expression, whereas the abundance of Kit mRNA is relatively stable. Functional studies show that treatment of CD34+ cells with miR 221 and 222, via oligonucleotide transfection or lentiviral vector infection, causes impaired proliferation and accelerated differentiation of E cells, coupled with downmodulation of Kit protein: this phenomenon, observed in E culture releasing endogenous Kit ligand (KL), is magnified in E culture supplemented with KL. Furthermore, transplantation experiments into NOD-SCID mice reveal that miR 221 or 222 treatment of CD34+ cells impairs their engraftment capacity and stem cell activity. Finally, miR 221 and 222 gene transfer impairs proliferation of the TF1 erythroleukemic cell line, expressing the Kit receptor. Altogether, our studies indicate that in human erythropoiesis the decline of miR 221 and 222 unblocks Kit protein production at translational level, thus leading to expansion of early E cells. Furthermore, overexpression of miR 221 and 222 inhibits proliferation of Kit+ erythroleukemic cells, suggesting a potential role of these microRNAs in cancer therapy.
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

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 > 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

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 >1 and <10 years with presenting WBC <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 >5% on Day 7 had an additional evaluation on Day 14. Patients with blasts >25% (M3) on Day 14, adverse cytogenetics (i.e., t(9;22), t(4;11), or severe hypodiploidy (modal chromosome numbers <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 <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

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

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

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<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

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

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

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 < 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

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 < 40 vs. 19/73 non African-Americans. However, since the incidence of arrhythmias in patients age < 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 (> 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.
Should High-Risk Patients with Chronic Atrial Fibrillation and Those with Coronary Artery Disease Receive Combined Aspirin-Oral Anticoagulant Therapy or Oral Anticoagulant Therapy Alone? A Systematic Review and Meta-Analysis.
Authors: Dentali Francesco , Lim Wendy , Douketis James D.
Published: April 2020

Background: Deciding between combined aspirin and oral anticoagulant (OAC) therapy compared to OAC therapy alone in patients with chronic atrial fibrillation who also have coronary artery disease or are at high risk for stroke is a common clinical problem. Individual trials do not address the benefits and risks of these two treatment strategies.

Purpose: To perform a systematic review and meta-analysis of randomized controlled trials comparing combined aspirin-OAC therapy and OAC alone with respect to bleeding complications and overall mortality.

Data Sources: Randomized trials published up to December 2004 in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases.

Study Selection: Included studies satisfied the following criteria: randomized trial involving patients, age ≥18 years, with chronic atrial fibrillation, a mechanical heart valve or coronary artery disease that compared treatment with OAC and aspirin to treatment with OAC alone; OAC therapy was the same in all treatment arms; patient follow-up for at least 3 months; the study documented at least 2 of 3 study outcomes.

Data Extraction: Two reviewers independently extracted data on thromboembolic, major bleeding and mortality outcomes. Authors were contacted if the required information was not available.

Data Synthesis: Fifteen studies were included, totalling 8984 patients with a mechanical heart valve, chronic atrial fibrillation or coronary artery disease. The risk for thromboembolic outcomes was significantly lower in patients receiving aspirin-OAC therapy compared to OAC therapy alone (OR = 0.62; 95% CI: 0.51, 0.77; P <0.001). In patients receiving aspirin-OAC therapy or OAC therapy alone, there was no difference in the risk for major bleeding (OR = 1.14; 95% CI: 0.90, 1.45; P = 0.27), intracranial bleeding (OR = 0.84; 95% CI: 0.51, 1.39), or fatal bleeding (OR = 1.36; 95% CI: 0.71, 2.61). There was no significant difference in all-cause mortality in patients receiving aspirin-OAC therapy compared to OAC therapy alone (OR = 0.93; 95% CI: 0.78, 1.10; P = 0.38). In patients receiving aspirin-OAC therapy compared to OAC therapy alone, there was no significant difference in the case-fatality rate for thromboembolism (12.1% vs. 12.2%; P = 0.99), or major bleeding (13.2% vs. 11.5%; P = 0.66).

Conclusions: Aspirin may be added to OAC in patients at high risk of thromboembolic complications since it appears to be effective with a similar bleeding risk as therapy with OAC alone. However, does not appear to reduce the risk of death.
Does Thromboprophylaxis Reduce Mortality in Medical Patients? A Systematic Review and Meta-Analysis of Randomized Cntrolled Tials.
Authors: Dentali Francesco , Gianni Monica , Lim Wendy , Douketis James D.
Published: April 2020

Background: Despite good evidence that anticoagulants are effective in preventing venous thromboembolism in medical patients at risk for this disease, only one-third of such patients are receiving thromboprophylaxis. Underutilization of thromboprophylaxis in medical patients may be due to lack of evidence that thromboprophylaxis reduces mortality, concerns about anticoagulant-related bleeding, and questions about the clinical significance of surrogate (venographic) outcomes to assess efficacy in these trials. We performed a meta-analysis of randomized, placebo-controlled trials of anticoagulant thromboprophylaxis in medical patients to assess effects on mortality and bleeding.

Methods: The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases were searched until June 2005. Studies were included that were randomized, placebo-controlled trials investigated a prophylactic dose of unfractionated heparin, low-molecular-weight heparin, or fondaparinux in medical patients. Meta-analysis was done to obtain pooled estimates of the effects of anticoagulant thromboprophylaxis on mortality and clinically important (major) bleeding. The effect of treatment on venous thromboembolism was not pooled because of across-study difference in methods used to diagnose this, and use of asymptomatic (venographic) outcomes in some studies.

Results: There were 8 studies of 20,631 patients in the assessment of mortality and 4 studies of 5,428 patients in the assessment of major bleeding. Death occurred in 536 of 10,321 (5.2%) patients who received thromboprophylaxis, and in 608 of 10,510 (5.8%) who received placebo. Thromboprophylaxis was associated with 10% decreased risk for all-cause mortality, although this effect was not quite statistically significant (odds ratio [OR] = 0.90; 95% confidence interval [CI]: 0.81, 1.01). Major bleeding occurred in 22 of 2,726 (0.8%) patients who received thromboprophylaxis, and in 11 of 2,702 (0.4%) patients who received placebo. Thromboprophylaxis was associated with 2-fold increased risk for major bleeding, although this effect was not quite statistically significant (OR = 2.04; 95% CI: 0.98, 4.23).

Conclusion: In medical patients who are at increased risk for venous thromboembolism, anticoagulant thromboprophylaxis appears to confer a small reduction in mortality; this benefit should be balanced against an increased risk for major bleeding.
Anti-Xa Levels and Renal Function: Analysis of the First 32 Patients in the Tinzaparin in Renal Insufficiency for Venous Thromboembolism Study.
Authors: Lim Wendy , Douketis James , Wang Luqi , Woods Karen , Schnurr Terri , Kinnon Krystyna , Cruickshank Rebecca , Clase Catherine M. , Rabbat Christian , Crowther Mark A.
Published: April 2020

Background: Low-molecular-weight heparin (LMWH) is renally eliminated; its use in patients with renal insufficiency may be associated with accumulation and an increased bleeding risk. Due to its higher molecular weight and greater negative charge, tinzaparin may be less dependent on renal elimination compared to other LMWHs. As a result, tinzaparin may be less prone to accumulate in patients with renal insufficiency.

Purpose: To measure the anticoagulant effect of a 5-day course of therapeutic-dose tinzaparin used for the initial treatment of venous thromboembolism (VTE) in patients with varying degrees of renal insufficiency. We present the anti-Xa results of the first 32 patients enrolled in the study, correlated with renal function.

Design: Prospective cohort study.

Methods: In- and out-patients requiring therapeutic dose anticoagulation were enrolled and stratified into 4 groups based on creatinine clearance (CrCl): > 60 ml/min, 30–60 ml/min, ≤ 30 ml/min and hemodialysis-dependent. Tinzaparin 175 IU/kg was administered once daily for 5 days or until the INR was ≥ 2.0 with warfarin therapy. Trough anti-Xa levels were measured prior to the 3rd (day 3) and 5th (day 5) tinzaparin doses. Patients with an anti-Xa level > 0.5 IU/mL received tinzaparin dose adjustment using a standardized nomogram.

Results: The relationship between anti-Xa levels and CrCl is shown in figure 1. One patient with a CrCl of 47 ml/min had a day 3 anti-Xa level of 0.62 IU/ml and required dose adjustment, resulting in a day 5 anti-Xa of 0.22 IU/ml. There has been one minor bleeding event (hematoma) following a traumatic intravenous catheter insertion. No major bleeding or recurrent VTE events have occurred.

Conclusions: In a cohort of 32 patients with differing degrees of renal function including patients requiring hemodialysis, use of therapeutic-dose tinzaparin for 5 days does not appear to result in accumulation of the anticoagulant effects. There is no apparent correlation between anti-Xa level and renal function. Our results support ongoing evaluation of tinzaparin in patients with severe renal insufficiency.

Figure 1. Anti-Xa levels an renal function Figure 1. Anti-Xa levels an renal function
Estimated Annual Number of Incident and Recurrent, Non-Fatal and Fatal Venous Thromboembolism (VTE) Events in the US.
Authors: Heit John A. , Cohen Alexander T. , Anderson Frederick A. ,   on Behalf of the VTE Impact Assessment Group
Published: April 2020

Background The total annual number of VTE events and related deaths in the US is unknown, largely because the complete spectrum of disease (including asymptomatic events and sudden deaths) occurring in the community is under-recognized.

Objective To estimate the total annual number of non-fatal and fatal deep vein thrombosis (DVT) and pulmonary embolism (PE) events (incident and recurrent) in the US.

Methods We developed an incidence-based model that included both hospital- and community-acquired VTE events as well as death from recognized and unrecognized VTE. We estimated the annual number of community-acquired events using the average age-, sex-, and event-specific incidence rates in Olmsted County, MN (1966–1990) and Y2000 US census data. We estimated the annual number of hospital-acquired events using patient age and Y2002 International Classification of Disease (ICD-9) discharge diagnosis codes for major surgery types or acute medical illnesses within the Healthcare Utilization and Cost Database, which includes major discharge diagnoses from all US acute-care hospitals. Patients were included in the hospital model if they were deemed at risk of VTE according to current American College of Chest Physicians definitions. The hospital at-risk population was divided into categories according to type of surgery or medical diagnosis on admission. We estimated the annual number of VTE events based on the published probability of VTE with and without prophylaxis, and US prophylaxis rates, by risk group. Fatal and recurrent events were estimated based on published data. The effects of VTE and prophylaxis rate uncertainty on our estimates were tested using sensitivity analyses.

Results The estimated total annual number of symptomatic VTE events in the US exceeded 600,000, (DVT, n=376,365; PE, n=237,058. Table).

Table. Annual Number of Non-Fatal and Fatal, Community- and Hospital-Acquired Symptomatic VTE Events in the US Event Type Community Hospital Total Non-Fatal ---------n---------- DVT 108,240 268,125 376,365 PE 85,358 151,700 237,058 Total 193,598 419,825 613,423 Fatal DVT 649 1,609 2,258 PE 105,902 188,210 294,112 Total 106,550 189,819 296,370

VTE-related deaths were estimated at 296,370 annually. Of these deaths, 21,223 (7%) patients were diagnosed with VTE and treated, 101,032 (34%) were sudden fatal PE and 174,115 (59%) followed undetected PE. Approximately two-thirds of symptomatic VTE events were hospital-acquired and one-third were community-acquired.

Conclusions Our study confirms that VTE is a major US health problem. Given that effective VTE prophylaxis and expert consensus prophylaxis guidelines are widely available, these data suggest that universal, safe and effective prophylaxis could significantly reduce US VTE incidence and related deaths. Future studies should address the impact of universal VTE prophylaxis on VTE incidence and survival.
Bendamustine HCl (TREANDATM) Treatment in Combination with Rituximab Results in Objective Responses in Patients with Refractory/Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin’s Lymphoma: Results from Phase II Multicenter Study (SDX-105-02).
Authors: Robinson Katherine Sue , Williams Michael E. , Cohen Philip , Tulpule Anil , van der Jagt Richard H. , Herst Jordan A. , Joyce Robin M. , Bessudo Alberto , Lemieux Bernard , Schwartzberg Lee S. , Oliver Jennifer , Benaim Ely
Published: April 2020

Background: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agent with a purine-like ring system and novel mechanisms of action that exhibits impressive single-agent activity in multiple hematologic and solid tumors. In vitro data indicate that bendamustine induces cell death as a result of both apoptosis and mitotic catastrophe, resulting in potent cell-killing activity in cancer cells that are resistant to traditional chemotherapy (alkylating and fludarabine-containing regimens). In vitro data have also demonstrated a synergistic effect with rituximab for the treatment of non-Hodgkin’s lymphomas (NHL). A Phase II multicenter study (SDX-105-02) was conducted to determine the efficacy and toxicity of the combination of bendamustine with rituximab in relapsed NHL patients.

Methods: The intent-to-treat (ITT) population consists of 54 patients with relapsed indolent CD20-positive B-cell or mantle cell NHL, enrolled from 22 sites in the US and Canada. Median age of the patients was 60 years (range 40–84); 59% had follicular NHL, 6% had small lymphocytic lymphoma, 4% had lymphoplasmacytoid lymphoma, 4% had marginal zone lymphoma, and 17% had mantle cell lymphoma; and 72% of all patients had Stage III/IV disease. Patients relapsed from a median of 1 prior therapy. Patients received rituximab, 375 mg/m2 IV on day 1, and bendamustine, 90 mg/m2 on days 2 and 3, every 28 days for 4–6 cycles. All patients received an additional dose of rituximab 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle.

Results: Of the 54 ITT patients, 37% had prior treatment with rituximab. Forty-three patients are currently evaluable for response, as defined by the International Working Group. The overall response rate was 84%, with complete response in 21% and partial response in 63% of patients. The median duration of response has not yet been reached after a median follow up of 3.6 months. Minimal toxicity was observed. The most common nonhematologic toxicities included grade 1/2 gastrointestinal complications. The primary grade 3/4 hematologic toxicity was neutropenia (with no neutropenic fever), observed in 22% of patients. Grade 3/4 anemia and thrombocytopenia were observed in only 1 patient. No alopecia was observed.

Conclusions: Bendamustine, administered in combination with rituximab, produced high objective response rates with minimal toxicity in patients with refractory indolent and mantle cell NHL, including patients that previously failed alkylating and fludarabine-containing regimens. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.
Outcome of Patients > Age 40 with Burkitt Lymphoma (BL) Treated with Aggressive Chemotherapuetic Regimens: Results from the International Burkitt Lymphoma Collaborative Group.
Authors: Friedberg Jonathan W. , Ciminello Lauren , Kelly Jennifer , Clawson Simon , Hoelzer Dieter , Holte Harald , LaCasce Ann S. , Mead Graham , Thomas Deborah , van Imhoff Gustaaf W. , Cheson Bruce , Magrath Ian T. , Fisher Richard I.
Published: April 2020

BL is considered a highly curable tumor when treated with dose-intensive, multiagent chemotherapy including central nervous system prophylaxis. 60–90% of pediatric and young adult patients (pts) with BL achieve durable remission if treated appropriately. However, the outcome of older adults with BL is more uncertain. We first investigated the SEER database and determined that 57% of reported pts with BL are > age 40. We then performed a systematic review of published manuscripts describing outcome of adult pts (> age 15) with confirmed de novo BL (REAL/WHO defined and confirmed) treated in the modern therapeutic era. Of 33 manuscripts, 17 were excluded due to small sample size (< 10 pts), inclusion of pts with HIV, inclusion of pts with alternate histologies, or utilization of CHOP-like therapy. Corresponding authors of the remaining 16 manuscripts were contacted to provide details on outcome of pts > age 40 for inclusion in a database, and full data is available from 12 manuscripts (10 prospective; 2 retrospective). 470 total adult BL pts ages 15–79 were treated, and 183 (39%) were > age 40. Pts > age 40 had significantly inferior outcomes in 10 of the 12 series. Treatment regimens included intensive short duration therapy (4 series; total N=212; > 40 N=93); ALL-like therapy (6 series; total N=182; > 40 N=62) and ASCT as part of induction therapy (2 series, total N=76; > 40 N=28). The median overall survival at 2 years (OS) for all pts treated with short duration therapy was 71%, and for pts > age 40 was 39%. The OS for all pts treated with ALL-like therapy was 51%, and for pts > age 40 was 40%. Pts > age 40 treated with ASCT as part of induction regimens had somewhat better outcomes (median OS 62%), however this represents a small number of pts who may have been subject to more rigorous selection criteria. We conclude that pts > age 40 with BL are significantly underrepresented in the published clinical trials. Even when these pts are treated with appropriate intensive chemotherapy, the OS is inferior compared to published outcomes in younger pts, and is similar to OS survival historically observed with CHOP chemotherapy alone (40%). Future efforts should evaluate whether BL in older adults has unique biological features. Novel therapeutic regimens, with decreased toxicity, targeting the older majority pts with BL are required.
Primary Mediastinal Large B-Cell Lymphoma (PMBL) Outcome Is Significantly Improved by the Addition of Rituximab to Dose Adjusted (DA)-EPOCH and Overcomes the Need for Radiation.
Authors: Dunleavy Kieron , Pittaluga Stefania , Janik John , Grant Nicole , Steinberg Seth , Staudt Louis , Jaffe Elaine , Wilson Wyndham H.
Published: April 2020

Gene expression profiling has revealed that over one third of genes more highly expressed in PMBL than other DLBCLs are characteristically expressed in classical Hodgkin Lymphoma (HL) suggesting a biological relationship (J Exp Med198:851, 2003). PMBL and HL also share mediastinal presentation, young age, female predominance, prominent sclerosis and CD30 expression. Although some cases lie in a pathological “grey zone” between HL and PMBL, the latter is distinguished by robust CD20 expression. Like HL, local mediastinal failure after doxorubicin-based regimens has led to routine mediastinal xRT, which is associated with secondary malignancies and coronary disease. We analyzed the outcome of DA-EPOCH in 36 untreated PMBLs. No pts received xRT except for CNS PMBL. DA-EPOCH was administered with G-CSF for 2 cycles beyond CR for 6 to 8 cycles as described (Blood99:2685, 2002). The first 14 pts were on a DA-EPOCH study and the last 22 on a DA-EPOCH-Rituximab study. Most pts had adverse prognostic features with bulky disease, elevated LDH and extranodal sites, which were balanced among the 2 series. IHC in 34 cases was consistent with gene expression profiling of PMBL with frequent CD20+ 33/33 (100%), infrequent CD10+ 1/26 (4%) and variable BCL-6+ 17/24 (71%) and MUM-1+ 8/22 (36%) expression. Tumor proliferation by MIB-1 was high with a median (range) of 82% (54–98). IHC markers were similar among the 2 series. EFS and OS are shown below with a median follow-up of 8.6 and 3.4 yrs, respectively, for pts receiving DA-EPOCH −/+ R. Rituximab was associated with a significantly improved EFS (p=0.036) and trend in improved OS (p=0.10) by 2-tailed exact log-rank test. In conclusion, pt characteristics were consistent with the clinical-pathological and molecular definition of PMBL and prognostic features were similar to other series (Haematologica87:1258, 2002). These results suggest for the first time that rituximab significantly improves the outcome of PMBL and that DA-EPOCH-R obviates routine mediastinal xRT. DA-EPOCH-R may be more effective than CHOP-based treatment because it overcomes high tumor proliferation and employs pharmacodynamic dosing. Although needing confirmation, our results suggest DA-EPOCH-R without xRT is highly effective for PMBL. Patient Characteristics

Patient Characteristics Characteristics All Patients DA-EPOCH DA-EPOCH-R Total Patients 36 14 22 Gender (F/M) 23/13 (1.77) 9/5 (1.8) 14/8 (1.75) Median age, y (range) 33 (12–70) 34 (20–62) 33 (12–70) Median Mass cm (range) 8.9 (3–16) 8.4 (5.1–15.7) 10 (3–16) Bulky mass > 6 cm 29 (83%) 11 (85%) 18 (82%) ECOG PS > 1 4 (11%) 2 (14%) 2 (9%) Stage III or IV 15 (42%) 7 (50%) 8 (36%) LDH > Normal 26 (72%) 12 (86%) 14 (64%) Extranodal sites 20 (56%) 7 (50%) 13 (59%) Pleural effusion 9 (25%) 3 (21%) 6 (27%) Figure Figure