Citations

Abstract Abstract 680 Cytogenetics play an essential role in determining the prognosis of patients with AML. However, there is still no validated cytogenetics grouping scheme that specifically applies to patients undergoing allogeneic stem cell transplantation, which hampers accurate prognostication and risk stratification. We studied 821 adult patients (median age 41, range 18–74) who underwent SCT between 1999 and 2004 for AML (excluding APL) in CR1 or CR2 and who were reported to the CIBMTR from centers with >20 patients meeting study criteria. 75% of patients received a myeloablative conditioning. 496 patients had a normal karyotype. The primary cytogenetics reports were manually reviewed for 92% of the patients with an abnormal karyotype. We compared the ability of the 6 existing grouping schemes (MRC, CALGB, EORTC/GIMEMA, SWOG/ECOG, DFCI, and Monosomal Karyotype (MK) classifications) to stratify patients, using both the Akaike Information Criterion in multivariable models and the C-statistic. Among all existing schemes, the DFCI system provided a marginally superior stratification for overall and leukemia-free survival. We also built a new classification using individual cytogenetic abnormalities in a Cox model that included other significant covariates (performance status, therapy-related disease, conditioning intensity, graft source, donor match, duration of CR1, and gender match). This CIBMTR scheme (see Table), which is similar to the DFCI scheme except for the inclusion of patients with t(8;21) in the intermediate group, could stratify patients into 3 groups with similar treatment-related mortality but significantly different overall survival, leukemia-free survival, and incidence of relapse. This scheme appeared to apply to both patients in CR1 and in CR2 (see FiguresF2). This transplant-specific scheme could be adopted for prognostication purposes and to stratify patients with karyotypic abnormalities entering transplantation clinical trials. Future studies may clarify the relative outcome of patients with t(8;21) and refine this scheme with the inclusion of molecular abnormalities. Disclosures: No relevant conflicts of interest to declare.

Abstract Higher bone marrow cell dose has been associated with improved survival after allogeneic BMT. Although PBSC provides higher cell dose, it also provides a higher number of T cells which increases the risk of GVHD and may negatively impact the outcome in pediatric patients. A prospective multi-center trial was conducted to evaluate the safety and feasibility of G-CSF primed bone marrow in children receiving HLA-identical sibling bone marrow transplantation (BMT). Thirty eight children at 9 different centers, 17 female and 21 male with a median age of 9.8 years (range 0.8–17) were enrolled between May 2003 and May 2005. Fifteen patients had high risk diseases (ALL ≥CR2=4, AML≥ CR2/refractory=5, Advanced MDS=3, JMML=1, NHL=2) and 23 had standard risk disease (SAA=6, Red Cell Aplasia=1, Sickle cell disease=1, CML-CP=2, AML CR1=9, ALL CR1=2, MDS-RA=2). Five patients had undergone a prior allogeneic transplant. All patients received myeloablative preparative regimens (Cy/TBI±VP-16=12, BU/Cy±other=20 and Cy/ATG=6) and 32 (84%) received CSP/FK506 with MTX as GVHD prophylaxis. Donors were HLA identical siblings except for one who was syngeneic. Donors with median age of 9.2 y (range 1.1–22) received 5 mcg/kg/day of GCSF SQ for 5 consecutive days. Bone marrow was collected on the fifth day with a median volume of 14.5 cc/kg (range 5.2–25). No donor experienced any complications related to G-CSF administration or harvest, up to the time of last follow-up at one month after the harvest. The absolute CD34 cell count at the day of the harvest was measured in 28 patients and it was significantly higher in bone marrow compared to peripheral blood, median of 50/μl (8–247) vs 513/μl (116–156) respectively (p <0.0001). Median nucleated and CD 34 cells infused was 8.4x108/kg (range 2.4–60.9) and 8.7x106/kg (range 2–27.6) respectively. No G-CSF was administered post transplant. All patients had neutrophil engraftment at a median of 19 days (13–28), and all but one patient with early post-transplant relapse had platelet engraftment at a median of 20 days (9–44). Thirteen patients (35%) developed grade 2 GVHD and 4 of 34 evaluable patients (12%) developed chronic GVHD (3 limited and 1 extensive). There was no transplant related mortality. Among 30 patients with malignant disorders 9 (30%) relapsed (6 with high risk and 3 with standard risk disease). The EFS and OS of patients with standard disease at 1 year is 84% (95% CI 68–100%) and 95% (95% CI 87–100) respectively. With a median follow up of 1 year the estimated EFS and OS of all patients at one year is 76% (CI 62–93) and 92% (95% CI 83–100) respectively. We conclude that G-CSF primed bone marrow from pediatric donors is safe and can result in high NC and CD34 cell dose that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD. A prospective randomized trial comparing G-CSF primed bone marrow to unstimulated marrow is planned.

Abstract Background: The association of clinical trial participation with outcomes in cancer patients is controversial, with some studies reporting better outcomes for trial participants while others do not. It is possible that the difference in outcomes is due to differences in baseline characteristics of participants and non-participants. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 trial was a large randomized, multi-center study comparing peripheral blood (PB) with bone marrow (BM) for hematopoietic cell transplantation (HCT) from HLA-matched or 1 allele mismatched unrelated donors (URD) in patients with acute leukemia, chronic myeloid leukemia and myelodysplastic syndromes. The trial reported no significant survival differences between PB and BM; there was decreased risk of graft failure but increased risk of chronic graft-versus-host disease (GVHD) with PB grafts (Anasetti et al NEJM 2012). Methods: We compared characteristics of BMT CTN 0201 study participants (n=494) with HCT recipients who did not participate on the trial (n=1384) but were potentially eligible by virtue of known characteristics. These patients received similar conditioning and GVHD prophylaxis as trial participants at 38 United States trial centers during the study time-period. Centers that had no eligible non-trial participants were excluded. Outcomes between patients on and off trial were compared using Cox proportional hazards regression models. Data were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) that collects patient data on all trial and non-trial allogeneic HCT recipients through its registry function. Results: Approximately 29% [494/1878] of apparently eligible patients were randomized and analyzed as part of the trial. There were no significant differences between study participants and non-participants in age or sex distribution, disease types, HLA or sex matching, comorbidities, or interval from diagnosis to HCT. Higher proportions of non-participants were Hispanic, had a lower performance status and lower disease risk, and received myeloablative conditioning and antithymocyte globulin (ATG) or Campath than the study participants. PB was used more commonly as the graft source in the non-participants as compared to the study participants (65% vs. 50%, p<0.001). In multivariate models, overall mortality (HR 1.09, 95% CI 0.95-1.25, p=0.22), transplant-related mortality (HR 1.08, 95% CI 0.89-1.32, p=0.42) and risks of acute grade II-IV (HR 0.96, 95% CI 0.82-1.12, p=0.57) and chronic GVHD (HR 1.06, 95% CI 0.92-1.23, p=0.41) were comparable between study non-participants and participants. Non-participants were at higher risk for relapse than participants (HR 1.24, 95%CI 1.04-1.49, p=0.02) in the multivariate analysis adjusted for disease risk and other clinical variables. Center effect was examined and was not found to be significant (p=0.10). There was no significant interaction between graft source and trial participation (P=0.22) and the risk of mortality was comparable for BM (HR 0.99, 95% CI 0.80-1.22, p=0.90) and PB recipients (HR 1.17, 95% CI 0.97-1.41, p=0.09) whether on trial or off trial. (Figure) Conclusion: Approximately 29% of patients who appeared eligible and were treated with conditioning and GVHD prophylaxis regimens allowed on the trial were enrolled. Despite some differences in clinical characteristics, most of the outcomes of non-trial participants were comparable to trial participants, suggesting that there is no definitive evidence that the outcomes of patients in a clinical trial are superior to those of the non-participants treated in a similar fashion. The comparable outcomes also indicate that the results of this trial were not seriously affected by selection bias and are therefore representative of the larger population. Figure 1: Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 1:. Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Introduction: Pharmacogenomics is about selecting the “right drug in the right amount for the right patient.” In metastatic colorectal cancer, germline pharmacogenomics testing presents a unique opportunity to improve outcomes, since the genes dihydropyrimidine dehydrogenase and UDP-glucuronosyltransferase metabolizing the chemotherapy drugs, 5-fluorouracil, and irinotecan are already well known. In a retrospective analysis of the landmark TRIBE clinical trial [(TRIBE - TRIplet plus BEvacizumab multicenter, phase III trial by the Italian Cooperative GONO (Gruppo Oncologico Nord Ovest) group (NCT00719797)], the proportion of patients with serious adverse events was higher in those with dihydropyrimidine dehydrogenase/UDP-glucuronosyltransferase aberrations and was dose dependent. We aimed to report on the feasibility and the results of incorporating pharmacogenomics testing into clinical practice. Methods: As a quality improvement initiative and a center of individualized medicine grant, we integrated the use of OneOme RightMed comprehensive test, which reports on 27 genes related to pharmacogenomics and over 300 medications of interest. We limited initial testing to patients with colorectal cancer. Pharmacists provided dosage recommendations based on test results in real-time. Results: At our cancer center, 155 patients underwent pharmacogenomics testing from November 2017 to January 2019. Results were available within 3 to 5 days of testing for most patients and were integrated into treatment decision-making. Of 155 sampled participants, a total of 89 (57.4%) participants had an UGT1A1 variant genotype, NM_000463.2: c.-53_-52[8] *1/*28, n = 74 (47.7%); *28/*28, n = 15 (9.7%). Additionally, 4 (2.6%) participants were heterozygous for dihydropyrimidine dehydrogenase. Two (1.3%) individuals were heterozygous for both UDP-glucuronosyltransferase and dihydropyrimidine dehydrogenase genes. All (100%) the patients had at least 1 actionable aberration related to supportive care medications ( CYP-family) of all the possible medications listed on their pharmacogenomics report. Conclusion: Preemptive comprehensive pharmacogenomics testing can be integrated into clinical practice in real-time for patients with cancer given faster turnaround and low cost. Pharmacist-driven, patient-specific medication management consults add further value given the number of genes/drugs. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients.

Abstract Machine learning (ML) offers opportunities to advance pathological diagnosis, especially with increasing trends in digitalizing microscopic images. Diagnosing leukemia is time‐consuming and challenging in many areas globally and there is a growing trend in utilizing ML techniques for its diagnosis. In this review, we aimed to describe the literature of ML utilization in the diagnosis of the four common types of leukemia: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML). Using a strict selection criterion, utilizing MeSH terminology and Boolean logic, an electronic search of MEDLINE and IEEE Xplore Digital Library was performed. The electronic search was complemented by handsearching of references of related studies and the top results of Google Scholar. The full texts of 58 articles were reviewed, out of which, 22 studies were included. The number of studies discussing ALL, AML, CLL, and CML was 12, 8, 3, and 1, respectively. No studies were prospectively applying algorithms in real‐world scenarios. Majority of studies had small and homogenous samples and used supervised learning for classification tasks. 91% of the studies were performed after 2010, and 74% of the included studies applied ML algorithms to microscopic diagnosis of leukemia. The included studies illustrated the need to develop the field of ML research, including the transformation from solely designing algorithms to practically applying them clinically.

Abstract Doublet chemotherapies are the mainstay in the management of metastatic anal cancer. Immunotherapy has been incorporated into guidelines in a refractory setting. Treatment options remain limited with tumor progression beyond immunotherapy. Modified docetaxel, cisplatin, and fluorouracil (mDCF) chemotherapy, after progression postimmunotherapy, has shown a near‐complete response in our patient with metastatic anal cancer. This likely is secondary to the sequence of immunotherapy followed by chemotherapy that is yielding greater than historical responses.

Background and aims: Patient-reported outcomes (PROs) will become increasingly important as primary endpoints in future clinical trials. We aimed to evaluate the relationship between health-related quality of life (HRQoL) and the combination of patient-reported clinical symptoms (ClinPRO2) and Mayo endoscopic subscore (MES) in patients with ulcerative colitis (UC). Methods: We conducted a prospective cross-sectional study of 90 consecutive UC patients who were scheduled for sigmoidoscopy or colonoscopy. All patients completed the following questionnaires: (1) self-rated rectal bleeding and stool frequency (ClinPRO2); (2) Short Inflammatory Bowel Disease Questionnaire (SIBDQ); (3) European Quality of Life 5-Dimensions 3-Level (EQ5D3L); (4) Work Productivity and Activity Impairment questionnaire (WPAI); (5) Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and (6) Hospital Anxiety and Depression Scale (HADS). The endoscopic images were graded according to the MES. “No symptoms” was defined as a symptom score of 0, and “mucosal healing” was defined as MES score of 0–1. Correlations between the combined ClinPRO2 and MES with HRQoL were assessed using Spearman’s correlation coefficients. Results: The combination of the ClinPRO2 and MES was well correlated to SIBDQ (r = −0.70), EQ5D3L (r = −0.51), WPAI (r = 0.62), FACIT-F (r = −0.58), and HADS-depression (r = 0.45). SIBDQ scores had strong correlations with FACIT-F (r = 0.86), WPAI (r = −0.80), and HADS-depression (r = −0.75) (p < 0.05 for all correlations). Patients with no symptoms reported the greatest all HRQoL scores. Conclusions: In patients with ulcerative colitis, the combination of a ClinPRO2 and the MES had good correlation with the SIBDQ. In addition, SIBDQ was well correlated to the various HRQoL.

Abstract Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT). Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research. Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P &lt; 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P &lt; 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P &lt; 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years). Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.