bluuebunny/crossref_metadata_2025_split huggingface dataset:
Array CGH Analysis at 60kb Resolution of CML Samples at Advanced Stage of Disease.
Authors: Grace Colin , Brazma Diana , Chanalaris Anastasios , Howard Julie , Virgili Anna , Valgañon Mikel , Cross Nick , Apperley Jane F. , Nacheva Elisabeth 
Published: October 2019

Abstract
In spite of the universal presence of the BCR/ABL1 fusion gene, chronic myelogenous leukemia (CML) shows remarkable clinical and genetic diversity. The consequences of der(9)t(9;22) chromosome deletions, associated with poor survival, as well as the mechanism behind their formation remain unclear, as does our understanding of the molecular events driving the disease evolution. The presence of these deletions fuelled the expectations that cryptic genome-wide aberrations may be accountable for the disease progression. Following a comprehensive BAC aCGH analysis of 48 CML samples (Brazma et al., Genes, Chromosomes & Cancer, 2007 in press) we report high-resolution oligo-nucleotide array study of a further 30 CML accelerated/ blast phase samples. We were unable to confirm the high frequency of particular single BAC imbalances (CNVs), reported both by ourselves and others, possibly due to the manufacturer’s array selection strategy. Never-the-less some of the CNVs and a wealth of new imbalances were obtained at 60kb resolution. It was possible to build a precise map of the amplicon affecting the sequences flanking the 3′ ABL1 breakpoint site, which include the LAMC3 and NUP214 genes. The presence of this amplicon was associated with therapy resistance. When assessed, at a resolution of 60 kb, the deletions of the regions flanking the ABL1/BCR breakpoint showed novel features:
the genome loss affects preferentially both flanking sites as seen in 5 of the 6 ‘deleted’ samples and the 120kb deletion identified is the smallest recorded so far.
Most of the major cytogenetic features of the samples were confirmed and a number of cryptic genome imbalances were detected, from 120kb to 10Mb in size, involving regions rich in genes, some already implicated in the pathogenesis of CML. Finally, recurrent micro aberrations of several adjacent oligo-nucleotides affecting non-coding sequences were detected in as many as 2/3 of the samples.
Survival Outcomes for Patients (Pts) with Chronic Myeloid Leukemia (CML) with Clonal Evolution (CE) Treated with 2nd Generation Tyrosine Kinase Inhibitors (TKI) after Imatinib Failure.
Authors: Verma Dushyant , Kantarjian Hagop , Estrov Zeev , Garcia-Manero Guillermo , Koller Charles , Borthakur Gautam , Cortes Jorge 
Published: October 2019

Abstract
Background: CE has been considered a criterion for accelerated phase (AP) CML, particularly when it appears during the course of therapy, when it is associated with a poor prognosis. CE may involve a variety of chromosomal abnormalities and may signal resistance to imatinib. The 2nd generation TKI (2nd TKI) dasatinib and nilotinib are effective in patients with AP after failure to imatinib, including those with CE. However, it is unclear whether different chromosomal abnormalities constituting CE may have the same outcome after therapy with 2nd TKI.
Methods: We analyzed the outcome after 2nd TKI therapy of 61 pts with CML with CE who had failed prior imatinib therapy.
Results: The median age was 55 years (range 23–76); the median follow-up after start of 2nd TKI was 18.9 months (mo) (range 5.3–39.3), and median CML duration 67.9 mo (0.4–206.6). Thirty-five pts had CE alone and 26 had CE with other AP features. At the time of this report 59 patients are evaluable for response: 30 treated with dasatinib and 29 with nilotinib. The accompanying table summarizes the findings.
Conclusion: CE constitutes a heterogeneous entity with variable outcome with 2nd TKI. Regardless of the percentage of metaphases with CE, those with trisomy 8 or with abnormalities in chromosome 17 may have the worse outcome. In all cases, the presence of other features of AP further worsens the outcome. The molecular events behind this worse outcome and potential therapeutic approaches directed at them need to be defined.
Characteristics (n=59) CCyR n/no. evaluable(%) p EFS % (12mo) p OS % (12mo p CCyR: Complete Cytogenetic Response, EFS: Event Free Survival, OS: Overall Survival, Chr: Chromosome, Ph+: Philadelphia chromosome positive, n: number of patients % Cellls with CE <16 3/12(25) 62 77 16-35 4/10(40) 60 68 36-99 9/15(60) 73 80 100 7/22(32) 0.24 60 0.96 78 0.85 Other AP features No 18/34(53) 80 89 Yes 5/25(20) 0.02 40 <0.001 60 0.005 Double Ph+ No 9/28(32) 55 69 Yes 14/31(45) 0.42 71 0.93 84 0.72 Trisomy 8 No 21/49(43) 72 84 Yes 2/10(20) 0.29 20 <0.001 40 <0.001 Chr 17 Abnormalities No 19/45(42) 74 83 Yes 4/14(29) 0.53 29 0.003 56 0.02 Other Translocations No 20/42(48) 61 75 Yes 3/17(18) 0.04 69 0.71 82 0.81 Other abnormalities No 15/37(41) 62 81 Yes 8/22(36) 0.79 65 0.45 70 0.93
Relationship of Stem Cell Transplant and Risk of Atrial Fibrillation in Multiple Myeloma: A Case-Control Study.
Authors: Gertz Morie Abraham , Fatema Kaniz , Micallef Ivana N. , Eisinger Amy D. , Barnes Marion E. , Cha Stephen S. , Tsang Teresa S. 
Published: October 2019

Abstract
Background: Clinical observations within our tertiary care setting suggested that atrial arrhythmia is common following hematopoietic stem-cell transplant (SCT). Yet little is known with regard to the incidence of such arrhythmia and factors contributing to its development. We assessed the frequency of first atrial fibrillation/flutter (AF/flutter) development in multiple myeloma (MM) patients who underwent SCT at the Mayo Clinic over a 4 year period.
Method: Using a case-control design, we compared 395 consecutive patients who underwent SCT at the Mayo Clinic during the period 2002–2005 to control subjects who did not have SCT (2:1 matched by age, gender, and date of MM diagnosis) in terms of the baseline risk factors and the frequency of new AF/flutter after MM diagnosis. Patients who had a prior history or evidence of atrial arrhythmia were excluded from analyses. Factors predictive of atrial arrhythmia in the cases were also determined.
Results: First AF/Flutter developed in 38 of 395 cases (mean age 58 ± 9 years) and 47 of 790 controls subjects within 5 years of MM diagnosis (P=0.002). The 5-year Kaplan-Meier estimates of the risk of AF/flutter were 17% and 8% for cases and controls, respectively. Amongst the cases who developed new AF/flutter, the onset of the arrhythmia was within 21 days of SCT for the majority (94%). In multivariable analysis, body weight change of ≥3% in the first week post-transplant (HR 2.86; CI 1.13–7.24; P=0.026) and presence of diastolic dysfunction (HR 1.79; CI 0.99–3.23; p=0.054) at MM diagnosis were independent predictors of first AF/flutter in the cases, adjusting for age, sex, and well established clinical risk factors.
Conclusion: The risk for new AF/flutter was remarkably high in the early post- SCT period in MM patients. In addition to established risk factors for atrial arrhythmia, a weight change ≥3% during the first 7 days after SCT, and the presence of diastolic dysfunction at baseline, were independent novel risk factors for new AF/flutter. These findings warrant further investigation, as modification of fluid management and diastolic filling may potentially lower the risk of post-SCT atrial arrhythmia.
Efficacy of Azacytidine (5-AC) Given as Maintenance or Salvage Therapy for Patients (pts) with Acute Leukemia Post Allogeneic Stem Cell Transplantation (HSCT).
Authors: Jabbour Elias , Giralt Sergio , Kantarjian Hagop , Garcia-Manero Guillermo , Shpall Elizabeth , Kebriaei Patrow , de Padua Leandro , Champlin Richard , de Lima Marcos 
Published: October 2019

Abstract
Background. Relapse is the most frequent cause of treatment failure in pts with refractory acute leukemia undergoing HSCT. Modifications of the preparative regimen using multiple combinations of chemotherapy and physical agents have failed to reduce the risk of relapse without an increase in non relapse mortality. 5-AC is a DNA hypomethylating agent that may induce leukemic cell differentiation and increased immunogenicity, therefore potentially increasing the graft-versus-leukemia effect. 5-AC, at low doses, through its hypomethylation effect has shown significant activity in pts with myelodysplastic syndromes. Furthermore, low doses are likely to be better tolerated after ASCT. Patients 5-AC was given as salvage therapy for post HSCT relapse in 7 pts with acute myeloid leukemia (AML) and as maintenance therapy in 5 (4 AML, 1 acute lymphocytic leukemia) with high-risk disease. Median age was 52 years (range, 29–67 years). At the time of HSCT, 8 pts were refractory and 4 pts (AML) were in second (n=2) and third complete remission (CR) (n=2). Four pts received and failed previous HSCT following ablative regimen. Donors were HLA-compatible related (n=2), unrelated (n=7; cord blood, n=2), or syngeneic (n=1). Conditioning regimen was gemtuzumab ozogamicin 2 mg/m2, fludarabine and melphalan 140 mg/m2 in 3 pts, fludarabine and melphalan 140 mg/m2 in 6, cyclophosphamide, fludarabine and low dose TBI in 2, and busulfan and cyclophosphamide in 1.GVHD prophylaxis was tacrolimus and mini-methotrexate. ATG was administered to recipients of unrelated donor transplants.
Results. After HSCT all pts were in CR. 5-AC was administered at the time of relapse that occurred at a median of 11 months (range, 5–26), and at a median of 4 months (range, 1–12) post HSCT as a maintenance therapy. 5-AC was given at the dose of 16 mg/m2 daily × 5 repeated every 4 weeks (n=3) and 25 mg/m2 daily × 5 (n=9). A median of 7 cycles (range, 2–18 cycles) were delivered. Among 7 pts with relapsed disease [medullary relapse in 4 (median percentage of blasts, 39), extramedullary relapse in 3], 3 achieved a sustained CR for 7+ months, 2 had sustained partial remission for 3+ months, and 2 pts did not respond. All pts receiving 5 AC as maintenance therapy remain in CR for a median of 14+ months (4–28). There was no significant increase in the rates of GVHD. After a median follow-up of 14 months (range, 3–20 months) from the start of 5-AC therapy,11 out of 12 pts are alive, 9 in CR. The 12-month actuarial survival from HSCT is 91%. There were no extra-medullary toxicities and only grade I/II hematologic toxicities were noted.
Conclusion. Low dose 5-AC may be effective in the post HSCT setting. Further follow-up and larger number of patients will be necessary to confirm these observations.
Administration of Rituximab Is Feasible and Does Not Affect Engraftment of Allograft Recipients with Advanced CD20+ Malignancies.
Authors: Kharfan-Dabaja Mohamed A. , Tate Cheryl , Perkins Janelle , Fernandez Hugo F. , Field Teresa , Ayala Ernesto , Perez Lia , Raychaudhuri Jyotishankar , Alsina Melissa , Sullivan Dan , Brand Linda , Poling William , Anasetti Claudio 
Published: October 2019

Abstract
Rituximab is a chimeric murine/human IgG1 kappa anti-CD20 monoclonal antibody that has revolutionized treatment of patients with CD20+ malignancies because of its non-cross resistance with chemotherapy and favorable toxicity profile. There is limited data evaluating the feasibility of combining rituximab with conditioning chemotherapy (or chemo-radiotherapy) for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for advanced CD20+ expressing malignancies. Twelve patients (M= 7; F=5), with a median age of 54.5 (41–66) years, underwent allo-HCT for the following diagnoses (disease status at time of transplantation) [chronic lymphocytic leukemia (CLL)= 7 (CR2=2; PR2= 3; ≥PR3=2); mantle cell lymphoma (MCL)= 3 (CR1=1; ≥PR2= 2); follicular NHL=1 (CR3=1), diffuse large B-cell (DLBC)=1 (>PR3=1)]. Donors were as follows: matched-related donors (MRD) = 7; matched-unrelated donors (MUD) =3; mismatched unrelated donor (MMUD)= 2. Fludarabine-based conditioning regimens comprised fludarabine plus targeted doses of intravenous busulfan (FLU-BU=8), or total-body irradiation (FLU-TBI=3), or cyclophosphamide (FLU-CY=1). Anti-thymocyte globulin (ATG) was administered in two cases of MMUDs. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil= 8, or methotrexate = 4. Nine (75%) of 12 patients received rituximab 375 mg/m2 on day +1 (±3 days) and all (100%) patients received rituximab 375 mg/m2 on day +8 (± 3 days) without serious infusion reactions. All patients engrafted. Median time to neutrophil engraftment for the entire cohort was 15.5 (12–27) days. Median time to platelet engraftment in nine patients was 14.5 (10–17) days. Three patients never dropped their platelet counts below 20,000/uL. Median donor chimerism at day +90 (±10 days) for unsorted BM, CD3 and CD33 by PCR/STR method were 94% (70–100%), 86% (59–100%) and 100%, respectively. At a median follow up of 5 (0.6–30.3) months, the 100-day non-relapse mortality (NRM) in 11 evaluable patients was 10%. Acute GVHD, grades II, III, and IV, developed in 50%, 8.3% and 8.3%, respectively, at a median time of 27 (16–77) days. These findings demonstrate that administration of rituximab as part of conditioning chemotherapy is feasible and does not affect timely hematopoietic engraftment of allograft recipients with advanced CD20+ malignancies.
Graft-Versus-Leukemia Effect Is Equivalent in Recipients of Matched Sibling and Matched Unrelated Donor Conventional Hematopoietic Cell Transplant.
Authors: Arora Mukta , Pavletic Steven , Anasetti Claudio , Barrett John , Wang Tao , Antin Joseph H. , Di Bartolomeo Paolo , Bolwell Brian J. , Bredeson Christopher , Cairo Mitchell , Gale Robert P. , Giralt Sergio , Hahn Theresa , Hale Gregory , Halter Joerg , Jagasia Madan , Litzow Mark R. , Locatelli Franco , McCarthy Phillip L. , Mort Cowan , Petersdorf Effie W. , Russel James , Schiller Gary , Schouten Harry S. , Tallman Martin , Verdonck Leo F. , Wiley Joseph , Wingard John R. , Horowitz Mary M. , Ringden Olle 
Published: October 2019

Abstract
Anti-leukemia effects of allotransplants are largely mediated by immune mechanisms collectively termed graft-versus-leukemia (GvL). We postulated that allotransplants from HLA-matched unrelated donors (URD) have greater GvL activity than similar transplants from HLA-identical siblings because of greater genetic-disparity between donor and recipient. We tested this hypothesis in 4099 adult recipients of HLA-matched sibling (N= 3158) or 8/8 HLA-allele-matched URD (N= 941) transplants for acute leukemia (AML and ALL) and chronic myeloid leukemia (CML) receiving conventional transplants between 1995–2004 and reported to CIBMTR. Relapse, transplant-related mortality (TRM) and leukemia-free survival (LFS) were compared between the cohorts. Contrary to our hypothesis, relapse rates at 5 y were similar in patients receiving sibling and URD transplants. More TRM was seen in URD cohort in early AML [sibs 24% (20–27%) versus URD 40% (31–50%), p=0.001], advanced ALL or AML [sibs 31% (25–36%) versus URD 44% (35–53%), p= 0.01] and early CML [sibs 31% (28–33%) versus 38% (32–44%), p=0.02]. LFS was superior with sibling donors in early- and advanced- AML and CML. These data indicate comparable GvL-activity of HLA matched URD and HLA-identical sibling transplants in AML, ALL and CML receiving conventional transplants despite greater genetic disparity.
Early Disease (1stremission or 1st chronic phase) Outcome at 5 years Sibling donor URD P AML (N= 878) 760 118 Relapse 15 (13–18)% 22 (15–30)% 0.1 LFS 61 (57–65)% 38 (28–48)% <0.001 ALL (N= 333) 271 62 Relapse 23 (18–29)% 15 (7–25)% 0.13 LFS 46 (39–53)% 42 (29–55)% 0.6 CML (N=1443) 1152 291 Relapse 6 (5–8)% 5 (3–8)% 0.5 LFS 63 (60–66)% 57 (51–63)% 0.06 Intermediate Disease (2nd or subsequent remission or accelerated phase) AML (N= 268) 180 88 Relapse 22 (16–29)% 21 (13–30)% 0.8 LFS 48 (40–56)% 41 (30–52)% 0.3 ALL (N= 172) 111 61 Relapse 32 (24–42)% 36 (24–48)% 0.7 LFS 27 (18–36)% 24 (14–37)% 0.8 CML (N=263) 173 90 Relapse 22 (15–28)% 16 (9–24)% 0.5 LFS 36 (29–44)% 35 (26–46)% 0.9 Advanced Disease (Not in remission or blast phase) AML (N= 423) 294 129 Relapse 46 (40–52)% 43 (34–51)% 0.6 LFS 23 (18–29)% 13 (8–20)% 0.01 ALL (N= 152) 88 64 Relapse 52 (42–63)% 48 (35–60)% 0.6 LFS 10 (4–18)% 5 (1–12)% 0.2 CML (N=76) 49 27 Relapse 35 (23–49)% 39 (20–60)% 0.8 LFS 21 (11–35)% 0 <0.001
The Clinical Usefulness of Novel Prognostic Factors in CLL: A Study of 477 Patients with Low-Risk (Non-11q, Non-17p) FISH and Known IGVH Mutation Status.
Authors: Tam Constantine S. , Keating Michael J. , Tsimberidou Apostolia M. , O’Brien Susan , Tsimberidou Alessandra , Lerner Susan , Abruzzo Lynne , Schlette Ellen , Kantarjian Hagop , Wierda William 
Published: October 2019

Abstract
In order to develop integrated models utilizing commonly available prognostic factors, we studied the clinical signficance of IGVH mutation, CD38 and ZAP-70 in 477 CLL patients (pts) with low-risk (non-11q, non-17p) FISH findings. All pts were untreated at the time of FISH assessment, and were collected prospectively in the MD Anderson CLL database. Two hundred & fifteen pts (45%) had mono- (n=160) or bi-alleleic (n=55) deletion of 13q {DEL13Q}, 162 pts (34%) had a negative FISH panel {NEG}, and 100 pts (21%) had trisomy 12 as sole FISH abnormality (n=78) or in association with deletion 13q (n=22) {T12}. Compared to other FISH groups, DEL13Q pts had lower B2m (median 2.2 v 2.6mg/L, p=0.01) and were less likely to be IGVH unmutated (33% v 48%, p=0.001). In contrast, T12 pts were more likely to present with advanced stage disease (Rai≥2 36% v 23%, p=0.01), be CD38 positive (44% v 13%, p<0.001), and have karyotypic abnormalities (48% v 7%, p<0.001). One hundred and twenty-three pts had active disease requiring immediate therapy and 354 pts had stable disease, of whom 291 were evaluable for disease progression. At a median follow-up of 20 months, 73 pts had developed active disease with NCI-WG indication(s) for treatment. Actuarial 2 year time to treatment (TTT) was 26%, with no significant difference between 13q, NEG and T12 pts (p=0.27). TTT was associated with elevated B2m (≥1.5ULN), IGVH mutation status and ZAP-70 in DEL13Q and NEG pts, but not in T12 patients (Table). For DEL13Q/NEG pts, a simple model using IGVH mutation and B2m separated high risk pts (unmutated or high B2m, 2yr TTT 43%) from standard risk pts (mutated and low B2m, 2yr TTT 11%, p<0.0001). For T12 pts, a model based on CD38 positivity and karyotypic abnormalities separated high risk pts (2 factors, 2yr TTT 75%) from standard risk pts (0 or 1 factor, 2yr TTT 15%, p=0.008). These results show that the impact of prognostic factors on TTT is dependent on the underlying FISH karyotype, and underscores the need for future studies in CLL prognostic factors to take into account the complete risk profile of the pt.
NEGATIVE FISH DELETION 13Q TRISOMY 12 p-value hazard ratio p-value hazard ratio p-value hazard ratio IGVH Mutation <0.001 8.0 0.003 2.9 0.97 0.98 B2m ≥1.5ULN <0.001 4.5 0.07 2.2 0.54 0.68 CD38 Positivity 0.05 2.5 0.05 2.4 0.06 7.4 Abn Cytogenetics <0.001 11.0 0.27 2.2 0.09 2.8 ZAP-70 0.02 2.9 0.007 3.1 0.70 1.3
Figure Figure Figure Figure
ZAP70 Expression by Immunohistochemistry Correlates with IgVH Mutation Status in Chronic Lymphocytic Leukemia and Predicts Time to Progression, but Survival Is Decreased in p53-Positive CLL, Regardless of ZAP70 Expression.
Authors: Schlette Ellen J. , Tam Constantine , Admirand Joan , Wierda William , O’Brien Susan , Lerner Susan , Keating Michael J. 
Published: October 2019

Abstract
Background: IgVH mutation status (IgVH MS) in chronic lymphocytic leukemia (CLL) is accepted as a powerful prognostic indicator, however, this test is not widely available. Therefore, ZAP70 expression, first described as a surrogate for IgVH MS, but also described as an independent prognostic marker, is more commonly used. ZAP70 expression can by detected by flow cytometry or immunohistochemical staining (IHC) methods, but the optimal detection method is controversial. Though cytogenetic abnormalities of 17p in CLL have been reported as a poor prognostic indicator when compared to other abnormalities, the prognostic effect of p53 expression by CLL has not been well described, nor has it’s utility in combination with ZAP70 expression been reported.
Methods: The bone marrow specimens from 2 cohorts of CLL patients (pts), specifically 208 pts uniformly treated with FCR between 11/99–01/04 and 349 CLL pts entered in the Low Risk FISH (LRF) study (no 11q or 17p FISH abnormalities) between 1/04 - 05/07, were evaluated for ZAP70 expression by IHC. IgVH MS was available for 61/208 FCR pts and all LRF study pts. The FCR group was evaluable for complete response (CR) and CR duration. 215 LRF study pts were evaluable for time to first treatment and 114 pts were evaluable for response to either FCR-type therapy (74pts) or rituximab-based therapy (40pts). 193 BM specimens from the FCR cohort were also studied for p53 expression by IHC staining.
Results: IgVH MS showed good concordance (80%) with ZAP70 IHC expression(table 1). The time to first therapy for the LRF cohort was 18% v 43% at 18 months for ZAP70+ versus ZAP70− CLL pts (p=0.0001). However ZAP70 IHC did not predict response in either the FCR cohort (n= 208) or the LRF cohort (n=114). In 193 FCR pts, a significant correlation between p53 expression and overall survival, regardless of ZAP70 expression, was seen (p<0.001) (Figure 1). ZAP70 IHC expression correlated with the time to progression for 165 FCR pts who had achieved complete response (p=0.0009)(Figure 2).
Conclusions: ZAP70 IHC expression shows good correlation with IgVH MS for the pooled cohorts. ZAP70 IHC expression has additional value in predicting time to first therapy and time to progression, but does not have an impact on CR rate. The decreased CR duration is due to the ZAP70 relationship with IgVH MS. When ZAP70 and p53 expression are combined, decreased survival is seen in pts with p53+ CLL, regardless of ZAP70 expression.
SH status in combined cohorts (N=410) versus ZAP70 expression by IHC Combined cohorts N=410 IHC ZAP− IHC ZAP+ Sensitivity 78%; Specificity 82% IgVH MS Mutated 178 39 Unmutated 42 151 Figure Figure Figure Figure