bluuebunny/crossref_metadata_2025_split huggingface dataset:
PML-RARα isoform at diagnosis is associated with disease-free survival (DFS) in patients enrolled in the intergroup trial (C-9710) for treatment of acute promyelocytic leukemia (APL)
Authors: Stock W. , Moser B. , Sher D. A. , Schachter-Tokarz E. , Myers M. , Powell B. L. , Bloomfield C. D. , Bucci D. , Tallman M. S. , Larson R. A. , Gallagher R. E. 
Published: March 2020

6504 Background: Refinement of prognostic groups using molecular genetic features of the disease may facilitate the design of future risk-adapted trials for APL. Previous analyses of the prognostic value of PML-RARα transcript levels and isoform type have generated conflicting results. We sought to determine the clinical significance of measuring PML-RARα transcript level at the time of diagnosis using real-time quantitative RT-PCR (RQ-PCR) of the long (L) and short (S) isoforms of the fusion gene. Methods: PML-RARα transcript levels were measured in pretreatment bone marrow (BM) and/or paired blood (B) samples of 139 patients (pts) with newly diagnosed APL registered to C-9710, the intergroup phase III randomized study of concurrent tretinoin and chemotherapy with or without arsenic trioxide as initial consolidation therapy. Transcript levels were expressed as the normalized quotient (NQ) of PML-RARα/ABL or PML-RARα/GAPDH. Correlations between pre-treatment NQ values and other pre-treatment characteristics including age, presenting WBC and platelet count, and L or S isoform were explored. Results: Pre-treatment NQ values using ABL vs. GAPDH showed significant correlation (p < 0.0001). Pre-treatment transcript levels in B and BM for 57 pts with S-form were significantly higher than 82 L-form patients (p = 0.02) when NQ was determined using GAPDH as the control gene (but not with ABL). With a median follow-up of 24.3 months for all patients, there have been 19 events. Median DFS for either isoform has not been reached, however, DFS was significantly shorter for patients with S-isoform compared to those with L-isoform (p = 0.017) with an estimated hazard ratio of 3.28. Using a multivariate proportional hazard model, no other significant relationships were found between DFS and NQ level at diagnosis, age, presenting WBC or platelet count. Conclusions: The S-isoform of the PML-RARa fusion gene was associated with shorter DFS in a subset of patients entered onto C-9710. If confirmed in a larger cohort of C-9710 pts, presence of the S-isoform should be considered as a high-risk feature in the design of future risk-adapted treatment strategies for APL. No significant financial relationships to disclose.
Preliminary phase III efficacy and safety of alemtuzumab vs chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphocytic leukemia (BCLL)
Authors: Hillmen P. , Skotnicki A. , Robak T. , Jaksic B. , Dmoszynska A. , Sirard C. , Mayer J. 
Published: March 2020

6511 Background: Phase 3, open-label, randomized comparative trial, enrolled Rai stage I-IV BCLL patients with previously untreated, progressive disease requiring treatment. Objectives: Compare efficacy and safety of alemtuzumab (CAMPATH [(CAM]) to chlorambucil (CHLO) as front-line therapy. Methods:Patients were randomized 1:1 to CAM 30 mg IV 3x/week for a maximum of 12 weeks (wks) or CHLO 40 mg/m2 PO once every 28 days, to a maximum of 12 cycles. All CAM patients received prophylactic antibiotic (trimethoprim/sulfamethoxazole DS) and antiviral (famciclovir) treatment during therapy and until CD4+ counts were ≥200 cells/μL. The primary endpoint was progression free survival; secondary endpoints included safety, response rate and overall survival. Results: Accrual completed in July 2004 with 297 patients enrolled (213 males, 84 females; median age 60 years); CAM n=149 and CHLO n=148. Treatment arms were balanced for key prognostic factors analyzed to date. Most patients had performance status 0–1 (96%) and maximum lymph nodes <5cm (70%). Median length of treatment with CAM = 11.7 wks, CHLO = 24.4 wks. The design provided for investigator assessment and an independent review of response (IRR). Preliminary data from the IRR are presented. Response rate for CHLO was consistent with historical data. Safety data indicate 34.7% of CAM patients and 19.7% of CHLO patients experienced a serious adverse event, with 21.1% and 4.1% considered drug related, respectively. The incidence of grade 3/4 thrombocytopenia and anemia were comparable in both treatment arms. Grade 3/4 neutropenia (42.2% vs 23.1%), infections (excluding CMV) (14.3% vs 6.8%), and CMV infections (6.8% vs 0%) were more frequent in the CAM arm. One treatment related death occurred in the CHLO arm. Conclusions: Preliminary efficacy and safety data confirm therapy naïve BCLL patients treated with single agent CAM have an excellent response rate with a manageable toxicity profile. [Table: see text] [Table: see text]
Cloretazine is an effective induction therapy in elderly patients (pts) with poor-risk de novo AML
Authors: Karp J. E. , Rizzieri D. , Vey N. , Mufti G. , Geller R. , O’Brien S. , Giles F. 
Published: March 2020

6512 Background: The incidence of AML increases with age with a median of 68 years in the US. The treatment of elderly pts (≥60 years) with AML poses challenges related to pt characteristics (age, performance status (PS), comorbidities) and adverse biological features. The majority of elderly pts are not considered for standard induction therapies that incorporate araC + anthracycline, and complete remission rates (CR+CRp), leukemia-free (LFS) and overall survival (OS) are significantly lower than in younger pts. As a result, NCCN guidelines recommend investigational therapy for this population. Cloretazine (C) is a novel DNA alkylating agent that selectively targets the O-6 position in guanine and has been developed in AML, based on phase I data demonstrating activity in refractory hematologic malignancies with acceptable toxicity. Methods: A multi-center trial in elderly pts with untreated poor-risk AML and high risk MDS was performed. Pts received C (600 mg/m2) as a single 30–60 minute infusion. Retreatment for induction was permitted for pts who showed improvement. A consolidation course of C at 400 mg/m2 was an option for pts who achieved a CR. Results: 105 pts were treated, of whom 45 pts (median age 72, range 60–84) had de novo AML, 44 had secondary AML, and 16 had high-risk MDS. Considering only de novo AML pts, pt characteristics are the following: M/F=25/20; favorable/intermediate/poor/NA cytogenetics =0/28(62%)/15(33%)/2; and PS 0/1/2=8(18%)/21(47%)/16(36%). The CR rate was 49% (N=22). CR was 50% for pts with intermediate cytogenetics and 53% for pts with poor risk cytogenetics. CR remained consistent despite increasing PS (PS0=50%, PS1=48%, PS2=50%). For responders, the median time for ANC≥1000 cells/dl was 31 days (range 27–44) and for plt≥20,000/dl was 22 days (range 14–29). There was no significant non-hematologic toxicity; the early death rate was 20%. Of the 22 pts who achieved CR, 8 remain alive and disease-free at a median of 337 days (range 137–546). At one year, the LFS is 27% and the OS is 22%. Conclusion: C is very well tolerated and has demonstrated impressive response results as a single agent in an elderly pt population with poor risk AML. [Table: see text]
Expression signature of p53 status (p53 signature) for the prediction of TP53 mutation and prognosis in breast cancer
Authors: Ishioka C. , Takahashi S. , Ishida T. , Moriya T. , Ohuchi N. 
Published: March 2020

652 Background: The current risk evaluation criteria, such as the St. Gallen and NIH, are not sufficient for predicting which BC patients are at high risk for recurrence and mortality. The TP53 mutations are associated with worse RFS and OS, independent other risk factors in BC, but the p53 status is not simply determined and often determined incorrectly (Soussi et al. Nat Rev Cancer 2006). Our purpose was to identify the gene sets that determine expression signature of the p53 status and to correlate the gene expression profile (GEP) with clinical outcome. Methods: Comprehensive expression analysis (Agilent 41K human genome oligo microarray) and DNA sequencing of the TP53 gene in 38 Japanese BC (30 Stage I-II, 8 stage III-IV; 20 TP53 wt, 20 TP53 mt) were performed using RNA and DNA obtained from the microdissected frozen tumor samples. We determined a gene set consisted of 33 genes from differentially expressed genes depending on the p53 status in the 26 BC (training set) and validated the ability to predict p53 status in the remaining 12 BC (test set). Prognostic value of the gene set was analyzed in 29 BC (stage I or II), and were validated using publicly available dataset of the independent 295 BC (stage I or II), van de Vijver et al. NEJM 2002). Results: The GEP using the 33 genes, many of which related in cell cycle and cell division, predicted the p53 status (wt or mt p53 signature) accurately in the test set (accuracy: 83%, overall accuracy: 95%). The p53 signature has the ability to predict RFS of the 29 early BC (Log Rank, P=0.032). It divided the 295 early BC into 176 wt and 119 mt group, and also has the ability to predict both RFS and OS (Log Rank, both P<0.0001). This was also true when the cohort were stratified by ER status, LN status, St. Gallen criteria and NIH criteria, and retained the predicted value in ER+, LN+, LN-, St. Gallen (intermediate/high) and NIH (high) subgroups (Log Rank, P<0.0001). Conclusions: The p53 signature is a powerful and independent predictor of the outcome of disease in early breast cancer than standard systems based on clinical and histologic criteria. No significant financial relationships to disclose.
An international multi-center study to assess the clinical accuracy of the molecular subclassification of leukemia by gene expression profiling
Authors: Haferlach T. , Mills K. , Kern W. , Hofmann W. , Te Kronnie T. , Hernandez Rivas J. , Downing J. , De Vos J. , Kipps T. , Foa R. 
Published: March 2020

6522 Background: Microarray analysis can identify differentially expressed genes of pediatric and adult leukemias. Recently, the MILE (Microarray Innovations in Leukemia) study has started in 11 centers (European Leukemia Network: 7, USA: 3, Singapore: 1). MILE compares the accuracy of gene expression profiles of 16 acute and chronic leukemia subclasses, MDS, and non-leukemia as control group to routine diagnostic workup. Methods: In a pre-phase each center was trained on the identical microarray protocol (HG-U133 Plus 2.0 microarrays). 2 cell lines (MCF-7, HEPG2) and cell lysates of three leukemia patients (AML t(8;21), CML, CLL) were tested. After proficiency testing, centers started to analyze 2000 leukemia samples. Results: The pre-phase demonstrated a very high intra- and inter-laboratory comparability among centers. Using principal component analysis each sample type was clustered with no observable sub-grouping of the different centers. Replicates of leukemia samples demonstrated squared correlation coefficients between 0.930–0.997 for CML, 0.936–0.998 for CLL, and 0.940–0.999 for AML t(8;21).Here we present classification results of the first series of 607 pts. that were included prospectively in a training data set (total n=1,049) to form linear classifiers for all 153 class pairs. The average cross-validation accuracy is 89.4%. In first independent cohort (HG-U133 Plus 2.0, n=105) 89.5% classification accuracy were achieved. In a second independent cohort (n=1,094), analyzed previously in two centers on HG-U133A/B microarrays, 83.5% classification accuracy were achieved. In detail, 136 out of 139 (97.8%) chronic leukemia samples (CML or CLL) were classified fully in agreement with standard diagnostic procedures. For acute leukemia subtypes 767 out of 904 (84.8%) were classified correctly. Interestingly, an AML-like signature can be found in MDS samples with IPSS >1.5. Conclusions: This international multi-center study demonstrates a very high inter- and intralaboratory reproducibility of microarray analyses. Data will be used to design a new custom format microarray dedicated to further develop the application of gene expression profiling for diagnosis and subclassification of leukemia. No significant financial relationships to disclose.
Targeted immune depletion prior to reduced-intensity allogeneic stem cell transplantation results in rapid and complete donor chimerism with low treatment-related mortality
Authors: Dean R. M. , Fowler D. H. , Steinberg S. M. , Odom J. , Gea-Banacloche J. , Sportes C. , Hardy N. , Pavletic S. , Gress R. E. , Bishop M. R. 
Published: March 2020

6540 Background: Significant variation in host immune status may influence outcomes after reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT). We have investigated a strategy of targeted immune depletion (TID) with conventional chemotherapy to deplete host T cells and achieve a minimal disease state prior to RI alloSCT. The aim of TID is to rapidly establish complete donor chimerism after RI alloSCT in order to potentiate a graft-versus-tumor (GVT) effect. In a prospective phase II trial (NIH 03-C-0077), we evaluated the effect of TID on donor chimerism, acute graft-versus-host disease (GVHD), and clinical outcome. Methods: Thirty-one patients (pts) with relapsed and refractory hematologic malignancies (NHL = 16; HL = 4; CLL/PLL = 4; MDS/AML = 3; other = 4) were enrolled. Median age was 57 years (range: 31–71). All pts received EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine) ± rituximab (R) as TID to deplete host CD4+ cells <100/μL. All pts then received a RI conditioning regimen consisting of fludarabine and cyclophosphamide followed by a T-cell replete allograft from HLA-matched siblings. GVHD prophylaxis consisted of cyclosporine plus short-course mini-methotrexate. Results: EPOCH-F(R) achieved the target host T-cell level in 74% of pts. All 31 pts engrafted after RI alloSCT. Complete donor chimerism (> 95%) was observed in 74% and 81% of pts at day +14 and +28 post-transplant, respectively. The incidence of grade II-III acute GVHD was 42% with no cases of grade IV acute GVHD. The median potential follow-up from transplant is 25 months. Actuarial treatment-related mortality at 1 and 2 years was 3% and 8%, respectively. Event-free survival probabilities at 1 and 2 years post-transplant are 65% and 49%, respectively. Ten pts are alive and event-free >24 months post-transplant. The overall survival probabilities at 1 and 2 years are 84% and 64%, respectively. Conclusions: TID prior to RI alloSCT results in rapid, complete donor engraftment and may potentiate GVT effects. This treatment strategy was associated with very low TRM and favorable outcomes in an older patient population with advanced hematologic malignancies. No significant financial relationships to disclose.
Reduced intensity allogeneic stem cell transplantation in patients with myelodysplastic syndrome: Does the conditioning matter? A retrospective study of the SFGM-TC on 61 patients
Authors: Terriou L. , Chir Z. , Esperou H. , Boiron J. , Gratecos N. , Vernant J. , Michallet M. , Milpied N. , Jouet J. , Yakoub-Agha I. 
Published: March 2020

6547 Background: Reduced-intensity allogeneic stem cell transplantation (RIT) has emerged as an alternative to myeloablative transplantation in pts with myelodysplastic syndrome (MDS). Given the uncertainty regarding the appropriate conditioning, SFGM-TC conducted a retrospective multicenter study with the attempt to evaluate the impact of conditioning on pts’ outcome. Methods: The record of 61 pts (37 males) with MDS who received a RIT between 1998 and 2003, from 22 French transplantation centres, were reviewed. According to the FAB classification, 11 pts had RA at diagnosis, of whom one had progressed to REAB and one to AML before transplantation. Thirty-two pts had REAB, of whom 2 had progressed to REAB-T and 7 to AML. Twelve pts had REAB-T and 6 CMML, of whom 8 progressed to AML. The median time from diagnosis to RIT was 12 months (6–129). Conditioning regimen consisted of fludarabin (Flu) plus busulfan ( n=29), Flu plus 2-Gy TBI ( n=20) and idarubicin plus aracytine and Flu (n=12). Donors were HLA-identical siblings (n=52) and HLA-matched unrelated (n=9). All pts received peripheral blood stem cells. The median of CD34+ infused cell dose was 5 × 106/kg (0.5–17.3). Results: At the reference date of 1 July 2005, median follow-up was 44.7 months (21–85). Estimated 3-year overall survival (OS), progression free survival (PFS), relapse and transplant-relapse mortality (TRM) were 35%, 27%, 66% and 30%, respectively. Neither of the 3 conditioning regimens used had impact on pts’ outcome. In multivariable analyses, while acute III/IV grade GVHD development was the only factor found to adversely influencing OS (HR=3.6; 95% CI: 1.1–12.2), chronic GVHD development was the only favourably influencing PFS and relapse ratios (HR=0.3; 95% CI: 0.1–0.7 and HR=0.2; 95% CI: 0.1–0.6, respectively). TRM was adversely influenced by male sex of pt (HR=9.2; 95% CI: 1.5–66.6). Conclusions: RIT seems to be an effective treatment in MDS pts irrespective of conditioning type. While acute III/IV grade GVHD appeared to be detrimental, the benefit effect of chronic GVHD was to be bound to GVL effect. New approaches with focus on immunosuppressive treatment are needed to enhance the GVL effect with an acceptable risk of GVHD. No significant financial relationships to disclose.
Human leukocyte antigen (HLA) DR4 is not associated with differences in overall survival (OS), progression free survival (PFS), or graft-vs-host-disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo HSCT) for myeloid malignancies
Authors: Gupta S. , Aggarwal C. , Hahn T. , Padmanabhan S. , McCarthy P. , Battiwalla M. 
Published: March 2020

6552 Background: HLA DR4 is associated with autoimmune disorders and with response to cyclosporine immunosuppression in T-cell Large Granular Lymphoproliferative Disorder (BJH 2003;123(3)). We have earlier reported association of DR 15 positivity with decreased acute GVHD (aGVHD) in patients undergoing allo HSCT for myeloid malignancies (Blood, 2005 Nov 10;Epub). Therefore we investigated the role of HLA DR4 on graft-versus-leukemia effect and GVHD in HLA-matched allo HSCT performed for myeloid malignancies. Methods: A retrospective review of 119 consecutive related and 48 consecutive unrelated allo HSCT patients (pts) treated between 1992 and 2003 at RPCI was performed to investigate the influence of HLA DR4 on OS, PFS and the incidence of grade 2–4 aGVHD and chronic GVHD (cGVHD). HLA DR B1 locus typing was determined by either molecular (n=108) or serologic (n=59) methods. The proportion of patients with one or two HLA DR4 antigens was 26% (43/167) which is similar to the range seen in general Caucasian population. Pt characteristics included: AML (n=84), CML (n=63), and MDS (n=20); median age 43 years (range 11–66); Male (n=104), Female (n=63); Caucasian (>95%); Total Body Irradiation (TBI) conditioning regimens (n=124); Busulfan (Bu)/Cyclophosphamide (Cy) (n=22), Bu/TBI (n=27), Cy/TBI (n=13), Etoposide/Cy/TBI (n=84), or other combinations (n=21). Results: There was no difference in OS and the PFS between the HLA DR4 positive vs negative groups in any disease or donor subgroups (p=0.4 and 0.6). GVHD prophylaxis was similar in the two groups but aGVHD and cGVHD incidence was not different in the two groups (p=0.8 and 0.9) Conclusions: HLA DR 4 is not associated with differences in GVHD or outcomes unlike the previous finding that HLA DR15 is associated with decreased acute GVHD in myeloid malignancies. These results suggest that there are differential effects of HLA DR antigens on the incidence of GVHD and outcomes in myeloid and lymphoid malignancies. Understanding these differences may facilitate the design of pt specific GVHD prophylaxis following allo HSCT. No significant financial relationships to disclose.
Fatigue in older adults with acute myeloid leukemia (AML): Predictors and impact on quality of life (QOL) and functional status
Authors: Alibhai S. M. , Leach M. , Brandwein J. , Minden M. D. 
Published: March 2020

6565 Background: Fatigue is one of the most common and important symptoms in patients with cancer, yet little is known about predictors of fatigue or its impact on either QOL or functional status in older adults with AML. Methods: Patients aged 60 or older presenting with AML to an AML referral centre were enrolled at diagnosis. Fatigue and QOL were evaluated at baseline and at 1, 4, and 6 months. Questionnaires included the Functional Assessment of Cancer Therapy Anemia and Fatigue subscale (FACT-An) and the European Organization for the Research and Treatment of Cancer QLQ-C30. Correlations between FACT-An scores, predictor variables, and QOL domains were examined with Pearson correlation. Mixed effects modeling was used to examine changes in fatigue over time. Results: Between June 2003 and December 2005, 63 patients (mean age 72) were enrolled. Fatigue was the most common symptom and was of moderate severity in the majority of patients. Fatigue scores at baseline did not correlate with age, hemoglobin level, white blood cell count, or bone marrow blast percentage but correlated positively with depression scores. There were strong correlations (r=0.56 to 0.70, p<0.01) between fatigue scores and depression scores over time, and moderate to strong correlations (r=0.36 to 0.67, p<0.01) with both global QOL and all 5 QOL domains of the QLQ-C30 over time. Correlations were slightly weaker with functional status measures (r=0.25 to 0.76). There was a weak but inconsistent relationship between fatigue scores and change in hemoglobin over time. Fatigue scores did not improve over time regardless of treatment intent and were not better by 6 months among those achieving complete remission. Conclusions: Fatigue is the most common symptom in older adults with AML and is negatively correlated with QOL and functional status. There is a weak relationship with anemia but not with other markers of disease severity. Fatigue does not improve by 6 months even in those who achieve remission. Further studies are needed to identify potential intervention targets to improve fatigue in this population. No significant financial relationships to disclose.