bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Impact of Deletions of Derivative Chromosome 9 on Patients (PTS) with Chronic Myelogenous Leukemia (CML) in Chronic Phase Treated with Nilotinib or Dasatinib.
Authors: Quintas-Cardama Alfonso , Kantarjian Hagop M. , O’Brien Susan , Borthakur Gautam , Verstovsek Srdan , Wierda William , Shan Jenny , Cortes Jorge 
Published: April 2020

Abstract
Background: Submicroscopic deletions of the derivative chromosome 9 [Del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Del der(9) is a powerful prognostic indicator associated with unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by Del der(9).
Methods: We investigated the prognostic impact of Del der(9) in 353 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=161) or dasatinib (n=192). The presence of Del der(9) prior to 2nd generation TKIs was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 245 patients. The median age was 53 years (range, 15–83) and the median follow-up was 24 months (range, 1–53). The primary endpoints evaluated were complete hematologic response (CHR), cytogenetic response, and survival.
Results: Twenty-eight (11%) patients carried Del der(9) and 217 an intact der(9). Among patients with deletions, 22 were in chronic phase (CP), 4 in accelerated phase (AP), and 2 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 122 were in CP, 55 in AP and 40 in BP. Overall, 229 (93%) patients were assessable for response after a median of 25 months (range, 1–53) of therapy. The outcome by CML phase is shown in Table 1.
CML phase Deletion der(9) No. CCyR (%) p EFS (12 mo) p OS (12 mo) p No 122 79 0.77 86 0.05 97 0.04 CP Yes 22 75 60 78 Not done 46 No 55 36 1.0 37 0.47 60 0.95 AP Yes 4 25 67 75 Not done 27 No 40 19 1.0 0 0.85 35 0.39 BP Yes 2 0 0 0 Not done 35
There was no difference in response rates among patients in CP, but those without Del der(9) had an improved EFS and OS at 24 months compared with those carrying Del der(9) (EFS: 86% vs 60%, p=0.05; OS: 97% vs 78%; p=0.04). Notably, whereas a trend towards worse EFS (p=0.05) and OS (p=0.12) was observed in patients in CP with Del der(9) treated with nilotinib, these outcomes were not significantly affected by Del der(9) in patients receiving dasatinib (EFS: p=0.47; OS: p=0.76).
Conclusion: Our results suggest that, in contrast to what has been reported with imatinib therapy, patients with CML-CP carrying Del der(9) who failed imatinib may have a worse survival than their counterparts without deletions after treatment with 2nd generation TKI. This deleterious effect is more apparent among patients treated with nilotinib than among those receiving dasatinib.
A Whole Genome Analysis Identifies SLCO1B1 as a Determinant of Methotrexate Pharmacokinetics and Adverse Effects
Authors: Trevino Lisa R , Shimasaki Noriko , Yang Wenjian , Panetta John C. , Cheng Cheng , Pei Deqing , Chan Diana , Sparreboom Alex , Giacomini Kathleen M , Pui Ching-Hon , Evans William E. , Relling Mary V. 
Published: April 2020

Abstract
Methotrexate is a major component in every treatment protocol for childhood acute lymphoblastic leukemia (ALL). Both beneficial and detrimental effects of methotrexate in ALL have been clearly related to methotrexate plasma pharmacokinetics, which vary substantially among patients. However the genetic basis of such variability remains largely unknown. Herein, we surveyed 600,000 germline single nucleotide polymorphisms (SNPs) to determine how inherited genetic variation affects the disposition of methotrexate among 434 children with ALL who received 3014 courses of methotrexate at 2 to 5 g/m2. Adjusting for age, race, gender and methotrexate regimen, the most significant SNPs associated with methotrexate clearance were annotated to a plausible gene, the organic anion transporter polypeptide, SLCO1B1. The three top SNPs included rs11045879 (P = 1.7 × 10−10), rs4149081 (P = 1.7 × 10−9), and rs2900478 (P = 2.8 × 10−8). Linkage disequilibrium (LD) was observed among these three SLCO1B1 SNPs (r2=1) and with a known functional polymorphism in SLCO1B1, T521C (rs4149056, r2 = 0.86). The top two SLCO1B1 SNPs rs11045879 and rs4149081 were further validated (P = 0.018 and P = 0.017) in an independent cohort of 206 patients with ALL. Additional SNPs annotated to SLCO1B1 were identified and further validated. In a stepwise multiple linear regression analysis, SLCO1B1 genetic variation remained significant and explained clearance variability comparable to that of other non-genetic factors including treatment regimen. SNPs in SLCO1B1 were also associated with methotrexate-related gastrointestinal toxicity (P= 0.03 to 0.0005, odds ratio 8.3 to 16.4). In summary, we have identified a candidate gene, SLCO1B1, which is strongly associated with the pharmacokinetics of methotrexate, an anticancer drug with a low therapeutic index in multiple treatment regimens. Although SLCO1B1 is widely recognized as having a strong impact on the disposition of many drugs in clinical use, based on in vitro data, it was not thought to have a major role in methotrexate transport or disposition. Our study demonstrates proof of principle that genome-wide tools in clinical pharmacologic problems can lead to the discovery of important and novel pharmacogenetic links between inherited genomic variation and drug response in humans.
Efficacy of Imatinib Mesylate in the Treatment of Refractory Sclerodermatous Chronic Graft-Versus-Host Disease.
Authors: YakoubAgha Ibrahim , Magro Leonardo , Catteau Benoit , Willekens Christophe , Coiteux Valerie , Bruno Benedicte , Terriou Louis , Jouet Jean-Pierre 
Published: April 2020

Abstract
Outcomes in the treatment of sclerodermatous chronic graft-versus-host disease (cGVHD) are generally disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) pathways. Recently, the drug’s effects on fibroblasts have been reported in both in vitro and in vivo studies. Inhibiting fibroblast growth (and thus decreasing collagen production in dermal fibroblasts) is thus a logical therapeutic approach. Here, we report on our experience with 12 patients who received imatinib mesylate for refractory sclerodermatous cGVHD following allogeneic stem cell transplantation (allo-SCT). The patients’ characteristics were as follows: median age, 35 years (range: 15–59); 7 male recipients, 6 female donors; 4 cases of CML, 4 MDS, 2 ALL and 2 Hodgkin’s lymphoma. The patients had received either myelo-ablative conditioning with standard GVHD prophylaxis based on cyclosporine and short-course MTX (n=9) or nonmyelo-ablative conditioning with cyclosporine and MMF. Seven patients received a marrow graft and 5 received a peripheral blood graft. All displayed refractory, chronic, sclerodermatous GHVD with at least 3 lines (range 3–6) of prior immunosuppressive therapy. The modified Rodnan skin score was used to assess the extent of skin damage. Glivec was initiated at a dose of 400 mg/day between 16 and 119 months post-transplantation (median: 44). Despite an imatinib dose reduction and the administration of various symptomatic treatments, 4 patients (33%) had to discontinue their treatment soon after its initiation (range: 16–64 days) because of intolerance (especially muscle cramps) and were not evaluable in terms of the efficacy criterion. Other side effects reported were parenthesis, diarrhea and edema. In the remaining patients, the scleroderma symptoms improved within three months of treatment initiation. At the time of this report, all patients were alive and those who tolerated imatinib mesylate have experienced a complete or near-complete response (n=4) or partial response (n=4). All responders (except for one who discontinued the drug 157 days after initiation, due to cramps) were still on the treatment, after a median time period of 216 days (range: 80–2053). This retrospective report shows that when imatinib mesylate is well tolerated, it is effective in patients with refractory sclerodermatous cGVHD and is thus a promising candidate for the treatment of this complication. This study should provide useful background information for building prospective, multicenter studies.
Long Term Outcomes for Patient with Diffuse Large B-Cell (DLBCL) or Hodgkin’s Lymphoma (HL) following Autologous Stem Cell Transplant (ASCT) Who Are Disease Free at Five Years Post Transplant.
Authors: Vose Julie M. , Loberiza Fausto , Bierman Philip , Bociek Robert , Armitage James 
Published: April 2020

Abstract
From 1984–2002, 294 patients (pts) with DLCL and 436 pts with HL (total 730) received high dose chemotherapy and ASCT at the University of Nebraska Medical Center. This analysis evaluates the long term outcome for pts in those cohorts who survived for five years and remained progression-free (PFS) during that interval with no further therapy. There were 92 pts with DLCL and 121 with HL who were alive and disease-free at 5 years post-transplant. The median age for pts with DLBL was 44 yrs (range 17–70) and 32 yrs (range 15–62) for pts with HL at the time of transplant. The median time to transplant from the time of diagnosis was 11 months (mo) for the DLCL group and 32 mos for HL pts. The majority of pts were chemo sensitive at the time of transplant – 80% for DLCL and 70% for HL. The median follow-up among survivors was 98 mo (range 61–222) for DLCL pts and 127 mo (range 63 – 272) for HL pts. The outcomes are as follows:
Variables DLCL HL p-value PFS @ 10 yrs 89% 82% 0.26 OS @ 10 yrs 91% 90% 0.72 Secondary Malignancies 11 (12%) 21 (17%) 0.26
Figure Figure
Cox regression analysis showed only age (&gt; 60 yrs) at the time of transplant was associated with an increased relative risk (RR) of death; 7.64 (2.61–22.35) compared to pts &lt; 40 yrs. Pts with DLCL had a RR of progression 0.12 (0.02–0.89) as compared to those with HL. Causes of death are as follows:
Secondary malignancy 14 (41%) Disease progression 7 (20%) Organ dysfunction 8 (24%) Infection 2 (6%) Unknown 3 (9%)
Conclusions: Patients with DLCL and HL who are progression-free at five years post-transplant have a low risk of relapse of their lymphoma. However, secondary malignancies and organ dysfunction are a long term risk from ASCT and survivors should be carefully followed for these complications.
Similar 5-Year Survival after Peripheral Blood Autotransplants (AutoPB) Versus HLA Matched Sibling Myeloablative Transplants (AlloBMT) for Acute Myeloid Leukemia (AML) in First Complete Remission (CR1).
Authors: Keating Armand , Kukreja Manisha , Silva Gisela Tunes da , Gupta Vikas , Cutler Corey , Tallman Martin S. , Sierra Jorge , DiPersio John F. , Horowitz Mary M. , Weisdorf Daniel J. 
Published: April 2020

Abstract
Optimum post-remission strategies for AML CR1 remain uncertain. Previous studies comparing autotransplants with alloBMT favored the latter because of less relapse despite treatment-related mortality (TRM) rates of 20–30%. In those studies, the autotransplants were exclusively with bone marrow (BM) and reported TRM of 12–20%. We were interested in determining the effect of lower TRM with AutoPB shown in many series to be 5–10%. We compared TRM, relapse, leukemia-free survival (LFS), and overall survival (OS) of 1133 patients 19–60 years of age in CR1 who underwent HLA-identical myeloablative BM or peripheral blood (PB) allogeneic transplants or AutoPB for AML reported to the CIBMTR from 1995–2004. For alloBM, alloPB and autoPB, median ages were 36, 40 and 44 yrs; cytogenetics were missing/unknown in 26%, 12% and 17%; proportion with poor risk cytogenetics was 6%, 9% and 7%; and median follow-up of survivors was 82 (6–149), 60 (4–144), and 62 (1–139) mo., respectively. Outcomes were evaluated in univariate and by multivariate analyses using the pseudo-value technique.
Results: 5 year transplant outcomes by univariate analysis are as follows:
Allo BM Allo PB Auto PB Outcomes@5years N Prob (95%CI) N Prob (95%CI) N Prob (95%CI) P-value Relapse 473 20 (17–24) 425 26 (21–30) 227 45 (38–52) &lt;0.001 TRM 473 19 (16–23) 425 20 (17–24) 227 8 (5–12) &lt;0.001 LFS 473 61 (56–65) 425 54 (49–59) 227 47 (40–54) 0.13 Survival 475 64 (59–68) 428 59 (54–64) 230 54 (47–60) 0.19
All analyses showed that risks associated with alloBM and AlloPB were identical, hence relative risk (RR) was modeled for any allotransplant (alloBMT) vs autoPB. Multivariate analysis of alloBMT vs autoPB cohorts revealed that age &gt;40 yrs was associated with increased RR for TRM, LFS and OS at 5yrs:1.39 (1.05–1.84;n=518;p=0.019);1.25(1.04– 1.51;n=521;p=0.015);1.28(1.05–1.56;n=521;p= 0.012), respectively. For relapse at 5 yrs, the presence of extramedullary disease was a poor prognostic factor: [RR: 1.60 (1.13– 2.27); for no n=1036; yes n=88]. Cytogenetics risk category was not a significant covariate for TRM (p=0.84), relapse (p=0.13), LFS (p=0.27) or OS (p=0.062) at 5 yrs.
Conclusions: AutoPB may provide acceptable alternative post-remission therapy for AML CR1 in the absence of a matched sibling donor, and its role in this regard should be reinvestigated prospectively.
The Role of FDG-PET in Hodgkin Lymphoma S/P Autologous Hematopoietic Cell Transplant (HCT) as a Predictor of Outcome.
Authors: Shah Neel B. , Farhat Mohamed , Lakhani Arti , Mcfarland Daniel , Venugopal Parameswaran , Gregory Stephanie A , Shammo Jamile , Maciejewski John , Tuncer Hande , Fung Henry C 
Published: April 2020

Abstract
The role of PET scans in Hodgkin Lymphoma (HL), especially after autologous HCT, is undefined. Positron emission tomographic (PET) scanning has increasingly become a promising non-invasive modality for the monitoring of patients with HL. Whole body PET scans have been reported to have increased sensitivity and accuracy as compared to conventional staging methods for the initial staging of HL. The sensitivity of PET is reported as 86% compared to 37% for CT, while the specificity has been reported as 96.5% compared to 99.7% for CT. The purpose of this study was to investigate the utility of PET scanning in relapsed HL s/p autologous HCT as a prognostic indicator of transplant outcome. Here, we describe a single institution retrospective analysis of 55 patients with HL who had FDG-PET scans after stem cell transplantation.
Patients/Methods: Between 1/94 and 12/06, 55 patients with refractory or relapsed Hodgkin Lymphoma underwent an autologous HCT at our institution. They each had a FDG-PET approximately one month following stem cell transplant to evaluate for response following HCT. Patients were placed into two separate categories depending on results of the PET scan. The incidence and timing of relapse, disease free survival, and overall survival were assessed.
Results: A total of 55 patients were evaluated post autologous HCT with a median age of 32 years (ranging from 15–66) with a median follow-up of 26 months. The patients were divided into two groups based on FDG-PET activity. Twenty-nine patients had no evidence of activity post transplant, while twenty-six patients had evidence of activity. The median DFS and OS of the PET negative group were 35.8 months and 35.8 months, respectively. The median DFS and OS of the PET positive group were 18.1 months and 10.1 months, respectively. There were statistically significant differences between the two groups when comparing their DFS and OS (p=0.0035 and p=0.004), in favor of the PET negative group. There were 2 relapses in the PET negative group and 9 relapses in the PET positive group (see figures).
Conclusion: We conclude that FDG-PET scan performed after autologous HCT for patients with relapsed or refractory Hodgkin lymphoma strongly predicted transplant outcome. Patients with any significant PET uptake are at high risk of treatment failure and should be considered for additional treatment with strong contemplation for participation in clinical trials.
Figure Figure
Impact of Autologous Stem Cell Transplantation and/or Rituximab on Outcome of Patients with Relapsed Follicular Lymphoma- Retrospective Analysis of 2 Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Weigert Oliver , Uysal Atakan , Metzner Bernd , Pfreundschuh Michael , Schmitz Norbert , Wandt Hannes , Peschel Christian , Hoster Eva , Unterhalt Michael , Hiddemann Wolfgang , Dreyling Martin 
Published: April 2020

Abstract
Background: There is no standard therapeutic approach for patients (pts) with relapsed advanced stage follicular lymphoma (FL). The impact of high-dose therapy followed by autologous blood stem cell transplantation (ASCT) with or without addition of rituximab (R) to salvage regimens was evaluated.
Methods: Patients with advanced stage FL from 2 successive prospective randomized trials of the GLSG (MCP vs. CHOP and CHOP vs. R-CHOP, both followed by randomization for IFN maintenance vs. ASCT) were eligible for retrospective analysis of subsequent therapy if they had progressive, relapsed or refractory disease following 1st line treatment, were &lt;65 years, had no prior ASCT and required treatment according to our established criteria.
Results: 222 patients were identified of whom 167 data sets were available for analysis (n=36 lost to follow-up, n=6 dead before initiation of salvage therapy, n=13 no indication for treatment). Median age was 50 years (range 19–64), 97 pts (58%) were male, 20 pts (12%) had previously received R (R-CHOP 1st line). 87 pts (53%) were treated with a R-containing salvage regimen. Most commonly used chemotherapy protocols were purin-analogue based (26%), followed by alkylator (22%) and anthracycline (13%) based regimens. Overall response rate (ORR) for chemotherapy with or without R 2nd line was 86% (CR 39%, PR 47%) and 78% (CR 26%, PR 52%), respectively. Median PFS for pts treated with or without Rituximab 2nd line was 3.4 and 2.8 years (yrs), median OS 8.3 and 7.2 yrs, respectively. Adequate numbers of peripheral blood stem cells could be harvested in 92% of evaluable patients. 66 pts received ASCT (40%) of whom 31 were also treated with R. 26 pts (39%) received a TBI-containing conditioning therapy. Most common non-hematologic grade 3/4 toxicity of ASCT were mucositis (43%) and infectious complications (30%). 4 pts died within 3 months after ASCT (6%). ORR before and after ASCT was 79% (CR 19%, PR 60%) and 95% (CR 60%, PR 35%), respectively. Median PFS for pts receiving ASCT or not was 5.5 and 2.3 yrs (p=0.038), median OS 7.2 yrs and not reached yet, respectively.
Conclusion: This retrospective analysis of two prospective multicenter trials suggests that patients with relapsed FL qualifying for ASCT may profit from that approach in terms of improved response rates and prolonged remission duration, albeit with more toxicity and an early death rate of 6%. Subgroup analysis revealed that the addition of R to salvage therapy primarily benefited patients not receiving ASCT 2nd line. Comparison of these results with ASCT in 1st remission with or without R is ongoing and will be presented at the meeting.
Significantly Reduce Acute Graft-Versus-Host Disease in Haploidentical Stem Cell Transplantation by Using Cord Blood as the Third Party Cells.
Authors: Lu Dao-Pei , Wu Tong , Gao Zhi-Yong , Wang Jing-Bo , Cao Xing-Yu , Zhao Yan-Li , Dong Lujia , Yin Yu-Ming , Ji Shu-Quan , Da Wan-Ming 
Published: April 2020

Abstract
More alternative donor stem cell transplantation (SCT) has been performed in recent years in China due to lack of HLA identical siblings. Higher risk for developing acute graft-versus-host disease (aGVHD) has been seen in patients who receive haploidentical stem cell transplantation (haplo-SCT) compared with identical sibling SCT patients (Lu DP et al, Blood2006; 107: 3065). In a murine model, we have first demonstrated that the animals transplanted with three mixed bone marrow (A+B+C to A) were survived longer due to milder aGVHD compared with the mice transplanted with single allogeneic bone marrow (B to A). In current clinical trial, we examine whether cord blood (CB) as the third party cells could reduce aGVHD in haplo-SCT setting under the same principle investigator in two hospitals. Between January 2006 and April 2008, total 133 haplo-SCT patients with hematological malignancies were enrolled. The patients with advanced diseases were excluded. All patients received unmanipulated blood and marrow transplant after BUCy2 or CyTBI plus antithymocyte globulin (ATG, Genzyme 10mg/kg) as preconditioning. Cyclosporine, short-term Methotrexate, and Mycophenolate mofetil were employed for GVHD prophylaxis. Fifty-six patients received one unit of HLA 3–6/6 matched CB one day before SCT as CB group, and 77 cases did not receive CB as control group. The main clinical characteristics in both groups are comparable. All patients in both groups achieved full donor chimerism. Low levels of CB chimerism were detected in a few patients at early stage after SCT. No long-term CB engraftment was found. The cumulative incidences of grade II to IV aGVHD were 16.4% versus 38.4% (p=0.008) in CB group, control group respectively. The cumulative incidences of grades III to IV aGVHD for CB group versus control group were 9.2% versus 22.4% with p=0.043. The incidences of 100-day treatment-related mortality were 1.8% versus 10.4% (p=0.053) for CB group, control group respectively. Our preliminary clinical study has shown that CB as the third party cells could significantly reduce the incidences of aGVHD, especially for severe aGVHD, and also treatment-related mortality in haplo-SCT. The mechanism of this strategy need to be further investigated.
Clinical Outcome of Aspergillus-Specific Cytotoxic T Lymphocytes for Refractory Invasive Aspergillosis in Patients with Hematological Malignancies.
Authors: Wu Tong , Tong Chun-Rong , Cao Xing-Yu , Wang Jing-Bo , Chang Lung-Ji , Liang Yin , Lu Dao-Pei 
Published: April 2020

Abstract
Invasive aspergillosis has high mortality in patients with hematological malignancies after chemotherapy or allogeneic stem cell transplantation (SCT) due to usually low response rate to current antifungal agents and relatively poor tolerance to the toxicities of the antifungal medicines. In this pilot clinical study, we explore to manage the patients with refractory invasive aspergillosis with aspergillus-specific cytotoxic T lymphocytes (aspergillus CTL). Ten patients who were either no longer response to antifungal medicines or have to stop antifungal agents due to severe toxicities were included in this clinical study. Diagnosis are ALL (2 cases), AML (5 cases), and CML (3 cases). The median age was 37 (10 to 62) years old. Seven of them received allogeneic SCT (unrelated 3 cases, haploidentical 3 cases, identical sibling 1 case), and 3 patients were after chemotherapy. Aspergillus CTLs were either donor origin (5 cases) or patient origin (5 cases) if original donor was not available. Patients received 1 to 3 infusions of aspergillus CTLs. The median CTLs infused were 3.61 (0.28–40.00) x 105/kg. No infusion-related reactions were noted. No pre-existed graft-versus-host disease deteriorated. With aspergillus CTL therapy, one of them (10%) achieved complete response, 6 patients (60%) improved significantly, 1 case was stable, and 2 patients became worse. Our preliminary data has shown that aspergillus-specific cytotoxic T lymphocyte is a safe and promising mean to manage refractory invasive aspergillosis in patients with hematological malignancies.