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  • 1
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 55, No. 1 ( 2014-01), p. 213-216
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2014
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  • 2
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3804-3804
    Abstract: Abstract 3804 Del20q is a commonly detected chromosomal abnormality in myelodysplastic syndromes (MDS) and myelofibrosis (MF). In MDS, del20q is a favorable cytogenetic lesion while in MF it is considered an intermediate risk karyotype. We hypothesized that the heterogeneity observed in del20q patients (pts) stems from the acquisition of various mutations during the pts' disease course. These additional chromosomal and/or new molecular defects may help explain these differences. We studied a total of 127 pts with del20q identified either by MC or single polymorphism array (SNP-A). Most pts are male (N=86) and the median age of the cohort is 70 years. The median follow-up time is 24 months. Most pts have MDS (N=76) while the rest are MDS/MPN (N=10), MPN (N=16), sAML (N=18), and other hematological malignancies (N=7). Hematologic parameters, bone marrow (BM) results and clinical data including IPSS, cytogenetics, transfusion requirements, treatment response, overall survival (OS) and progression free survival (PFS) as defined by IWG criteria were collected. We utilized chi-square and Fischer-exact test to compare descriptive variables. Kaplan-Meier statistics were used to compare survival differences between groups and Cox proportional hazard ratio to determine factors that are predictive of outcomes in these pts. A p-value of ≤0.05 is considered statistically significant. Phenotypically, pts with isolated del20q (iso-del20q) have higher ANC, WBC, less splenomegaly and BM blasts. Survival differences were noted between pts with del20q± additional chromosomal defects with better OS noted in pts with iso-del20q compared to del20q with 1 additional cytogenetic abnormality (del20q+1), and del20q with 2 or more cytogenetic abnormalities (del20q+≥2) (OS: 93 vs 52 vs 64 mos, p=.04; PFS: 24 vs 17 vs 6 mos, p=.005; and EFS: 42 vs 38 vs 12 mos, p=.002). Furthermore, PFS is better in iso-del20q compared to del20q+1 and del20q+≥2 pts (24 vs 17 vs 8 mos, p =.005). After defining key differences in survival in pts with del20q, we sought to investigate the biological rationale for these differences. Whole exome sequencing was performed in 4 pts with del20q. Initial candidate genes, SULF2 and PMEPA1 were WT. Analysis showed involvement of U2AF1 which was further confirmed as somatic. Direct sequencing of U2AF1 in this cohort revealed mutations in 25% of pts. Interestingly, among chromosomal subtypes, U2AF1 mutations are most frequently found in pts with del20q (25% (del 20q) vs 3% (−7/-7q) vs 1.6% (normal) vs 0.5% (+8 and −5q). Moreover, in our cohort, U2AF1 is the most frequently mutated gene in the iso-del20q suggesting a strong correlation between this gene and the pathogenesis of del20q. However, U2AF1 has been associated with poor outcomes. In fact, in our MDS cohort (N=340) (Hasrouni E et al. Abstract # 53469), the median OS of U2AF1 mutants (MUT) vs WT are 7 mos vs 20 mos, p =.010 for the whole cohort and remained poor even in normal karyotype MDS (median OS=4 vs 28 mos; p =.0004). Pts with del20q and U2AF1 mutations have excellent survival (median OS=85 mos) suggesting an alternative mechanism whereby U2AF1 modulates this MDS subtype or the presence of another pathway that suppresses the negative effects of U2AF1 mutations in this karyotypic subtype. These findings are reminiscent of the good outcomes correlated with SF3B1 mutations, which we recently found to be associated with lower levels of DNA damage (Visconte V. et al. Abstract # 55089). Interestingly, U2AF1 MUT del20q have lower gamma-H2AX levels compared to U2AF1 MUT in other choromosmal subtypes (5.17±4.68 vs 34.53±30.51) and this may explain decreased propensity for AML transformation in this group. Also, we performed direct sequencing for genes associated with poor (CBL, IDH1/2, DNMT3A, ASXL1, NRAS/KRAS, TP53, EZH2) and good (SF3B1) prognostic outcomes in MDS and found a lower frequency of poor prognostic molecular defects in iso-del20q compared to del20q + ≥2 (22% vs 81%; p=.004). Elucidation of downstream targets by RNA sequencing in del20q cases particularly those with U2AF1 mutations are underway. In addition, screening for mutations involving genes reported to be important in del20q malignancies, like PTPN1 and L3MBTL1 was negative. In summary, pts with del20q have a characteristic clinical profile associated with low risk disease. Iso-del20q have better OS compared to pts with del20q+1 and del20q+≥2 even in the presence of U2AF1 mutations. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 3
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1200-1200
    Abstract: Consolidative autologous stem cell transplantation (ASCT) is a commonly utilized treatment modality for peripheral T cell lymphomas (PTCL) and has been shown to improve progression free survival. The optimal timing of ASCT for PTCL is not well defined and studies have included upfront ASCT or ASCT at the time of relapse. However, long-term outcomes of ASCT, especially when used as upfront consolidation, have not been well described. Previously published data, including the one from our institution, (Smith S et al BMT. 2007;40:239-243) revealed inferior outcomes following ASCT in relapsed PTCL. We performed a retrospective study to describe our institutional experience in a relatively large cohort of patients with PTCL who were treated with ASCT (N=78) between 1996 and 2013 and had a median follow up of 55 months. Among these, 62% were male, 89% Caucasian and 84% had a Karnofsky performance score ³90. The subtypes included 26 peripheral T cell lymphomas (PTCL) (33%), 19 anaplastic large cell lymphoma (ALCL) alk- (24%), 13 ALCL alk+ (17%) 16 angioimmunoblastic T cell lymphoma (AITL) (21%) and 4 extranodal NK/T cell nasal type (5%). Prominent disease characteristics at diagnosis included stage III-IV in 80%, and IPI score of 0-3 in 73%. Only 26% had bone marrow (BM) involvement. Majority of the patients (76%) received 2 or more prior therapy. 99% of the transplants was performed using Busulfan, Cyclophosphamide, and Etoposide (Bu/Cy/VP16) preparative regimen. While 27 (35%) patients received ASCT as part of their initial treatment, 51 (65%) patients were transplanted after their disease had relapsed. About one third of our cohort (31%) attained a complete response (CR) post ASCT. The 5-year relapse rate (RR) for CR1, CR2 and PR1 were 22%, 53% and 66% (Figure 1) implying that both the disease status and response prior to transplant are key determinant factors for long-term outcome. The RR curve plateaued after 8 years indicating that a proportion of patients had attained a durable remission. At the time of analysis, 42% were alive. Disease relapse was the cause of death in 76% of the cases. Our 10-year RR, relapse free survival (RFS) and overall survival were 64%, 25% and 31% respectively. On univariate analysis disease status, BM involvement and stage were prognostic for RFS and OS, but only disease status (RFS: HR 2.27, p=0.023; OS: HR 4.75, p=0.006) and BM involvement (RFS: HR 3.10, p=0.019; OS: HR 2.94, p=0.018) retained significance on multivariate analysis. Moreover, disease status was also predictive for relapse in both univariate and multivariate analyses (HR 2.12, 95% CI 1.05-4.27, p=0.035). Conclusions: In a relatively large cohort of PTCL patients with long-term follow up after ASCT, upfront consolidative autologous stem cell transplantation in chemo sensitive patients resulted in lower RR and improved RFS and OS. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hill: Millenium: Research Funding; Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4189-4189
    Abstract: Abstract 4189 Methotrexate (MTX) has had a long history of use in graft versus host disease (GVHD) prevention in allogeneic hematopoietic cell transplantation (HCT) and is now most commonly used with a calcineurin inhibitor, such as cyclosporine (CSA) or tacrolimus (Tac). MTX, however, may contribute to severe mucositis and other organ toxicities, which in turn may result in the need to withhold MTX doses. It is not clear whether the omission of doses of MTX has a deleterious effect on relapse, GVHD, and survival. We therefore retrospectively reviewed the experience with MTX at our institution. We identified 109 patients (pts) who underwent a myeloablative HCT with an HLA matched unrelated donor and received MTX in combination with Tac or CSA for GVHD prophylaxis from May 2003 until May 2011. Data was missing on 7 pts, and they were excluded. Of the remaining 102 pts, 70 received all 4 doses of MTX while 32 (31.4%) missed at least 1 dose of MTX. The dose of MTX used was 5mg/m2 on days 1, 3, 6, 11 from May 2003 until July 2009 and was then increased to 15mg/m2 day 1 followed by 10mg/m2 day 3, 6, 11 after July 2009. 80 pts received the lower dose of MTX, with 26 (32%) having missed a dose and 22 pts received the higher dose MTX after July 2009, with 6 (27%) having missed a dose. Severe mucositis or organ dysfunction were the primary reasons for dose omission in all pts and was based on physician discretion. Pts underwent HCT for acute myeloid leukemia (n=42), myelodysplastic syndrome (n=25), acute lymphoblastic leukemia (n=19), non Hodgkin lymphoma (n=6), chronic myeloid leukemia (n=6), myeloproliferative neoplasms (n=2), biphenotypic leukemia (n=1), and plasma cell leukemia (n=1). The two groups did not differ significantly in age, gender, disease, disease status, CMV status, or hematopoietic cell source, but did differ in the number of prior chemotherapy regimens to which the patient had been exposed. 43.8% of pts in the missed MTX group had received 3 or more prior chemotherapy regimens compared with 24.3% in the 4-dose group, (p=0.047). The conditioning regimen most commonly used was cyclophosphamide (Cy) with busulfan (Bu), n=56; but other preparative regimens included Bu/Cy and etoposide (VP-16), n=14; Cy in combination with total body irradiation (TBI), n=3; TBI/VP-16, n=20; and Cy/TBI in combination with ATG or ECP, n=9. There were no statistically significant differences in the preparative regimen or use of TBI between the two groups. Outcomes were compared between full and missed dose groups using the log-rank test or Pepe-Mori test. With the omission of doses of MTX due to toxicities, there was no difference in time to hematopoietic recovery or length of hospital stay. Median time to neutrophil recovery for full dose MTX was 18 days, (range 9–75) compared to 16, (range 10–27) in the missed dose group, (p=0.55). Median time to platelet recovery was 25 days, range (13–51) for the 4 dose group compared to 21 (range 12–75, p=0.36). There was no significant difference in acute GVHD between full and missed dose groups (6 month incidence 38.6% versus 53.1% grade 2–4, p=0.35; 20.0% versus 9.4% grade 3–4, p=0.16). There was also no difference in chronic GVHD (2 year incidence 30.4% versus 41.8% any chronic, p=0.43; 20.0% versus 26.1% extensive chronic, p=0.74). Full dose and missed dose also did not differ with respect to relapse (5-year incidence 31.3% versus 37.7%, p=0.65), overall survival (OS) (5-year 41.3% versus 26.6%, p=0.14), or non-relapse mortality (NRM) (5-year incidence 32.6% versus 57.6%, p=0.13). We have previously shown that severe mucositis is associated with inferior survival (Fanning et al, BJH 2006, 135:374). While the differences in GVHD, NRM and OS did not reach statistical significance, it did appear that those who missed a dose of MTX did worse than those who received all 4 doses; and one can speculate this may be related to the toxicity of severe mucositis. Even with the dose change in our cohort, there was interestingly no difference in the incidence of missed does between the groups assigned to receive low or standard dose MTX. This initial analysis provokes many additional questions, including whether a fourth dose of MTX is needed in all pts. Single nucleotide polymorphisms of the enzymes which MTX inhibits induce differential effects on MTX metabolism which may lead to increased toxicity and a potential protective effect for GVHD for a given dose. Further prospective study of dosing of MTX in GVHD prophylaxis is warranted. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2637-2637
    Abstract: Patient-reported outcomes and quality of life (QOL) are becoming increasingly recognized as important factors in cancer clinical trials and patient care. Many studies have described the predictive value of QOL in cancer survival beyond the standard clinical measures. Allogeneic hematopoietic cell transplant (HCT) is the only curative option for many hematologic malignancies, however is often complicated by a high incidence of treatment related morbidity and mortality. While the HCT comorbidity index (HCT-CI) has been developed to assess the impact of co-morbidities and risk of death in patients undergoing allogeneic HCT, we hypothesized that QOL prior to transplant may also add to the assessment of patient risk for post-transplant survival. We thus undertook an analysis to determine the prognostic impact of pre-transplant QOL scores, as captured by the FACT-BMT, on post-HCT non-relapse (NRM) and overall mortality. From 2003-2012, 512 adult patients underwent a first allogeneic transplant at our institution. Prospective psychometric instruments (FACT-BMT) were administered to 409 patients. No significant differences were found between the study cohort and the 103 patients who did not participate in a baseline assessment during the same time period in regards to transplant outcomes or baseline characteristics, except for year of transplant, higher proportion of females, and a shorter time from diagnosis to transplant in the study cohort. Patients with QOL assessments underwent HCT for malignant (n=395) and non-malignant (n=14) diseases. Most patients (n=314, 77%) underwent a myeloablative HCT, while the remaining received a reduced-intensity (RIC) preparative regimen (n=95, 23%). At the time of analysis, median time to follow up was 49 months, range (1.2-128). 41% of patients remained alive, 23% of patients died from relapse and 36% from NRM. We examined the association of overall mortality and NRM with: (1) individual QOL domains captured by the FACT-BMT instrument (physical wellbeing (PWB) functional wellbeing (FWB), social wellbeing (SWB), emotional wellbeing (EWB) and additional concerns (AC), (2) trial outcome index (TOI; PWB+FWB+AC), and (3) total score. In univariable analysis, poor performance status, high risk disease, and high (≥3) HCT-CI score were found to be significant factors for overall mortality but not NRM; umbilical cord, unrelated and mismatched donor transplants were risk factors for both overall mortality and NRM. Additionally, worse FACT-BMT PWB scores (HR 0.97, 95% CI 0.94-0.99, p=0.004), TOI score (HR 0.94, 95% CI 0.88-0.99, p=0.043), and total score (HR 0.95, 95% CI 0.90-0.99, p=0.043) were significant variables associated with overall mortality, but not NRM. In multivariable analyses evaluating individual FACT-BMT QOL domains and adjusted for patient and disease factors, including HCT-CI score, only PWB score was associated with overall mortality, but not NRM (Table). TOI scores which is representative of changes in physical and functional outcomes were associated with overall mortality but not NRM (Table). Total score was not associated with overall or NRM (Table). High (≥3) HCT-CI score remained prognostic for adverse overall mortality but not NRM in all multivariable models. In summary, QOL assessments, particularly PWB and the TOI, may provide independent prognostic information beyond standard clinical measures. While the magnitude of difference of these measures is small, further study on how QOL may be reflected by disease burden or co-morbidities and how patient-reported outcomes and behaviors may further impact survival is warranted. Table: Results of multivariable analysis (separate models were built for each QOL domain) Variable Overall Mortality Non-relapse mortality HR 95% CI P-value HR 95% CI P-value PWB* 0.97 0.94-0.99 0.03 0.97 0.94-1.01 0.20 SWB* 1.00 0.97-1.04 0.76 0.99 0.95-1.03 0.57 EWB* 1.00 0.96-1.04 0.95 0.99 0.94-1.04 0.57 FWB* 0.95 0.95-1.01 0.16 1.00 0.96-1.05 0.80 AC† 1.04 0.95-1.14 0.38 1.03 0.91-1.17 0.60 TOI‡ 0.93 0.87-0.99 0.04 0.97 0.89-1.07 0.56 Total score‡ 0.95 0.90-1.00 0.06 0.97 0.90-1.05 0.46 Abbreviations: PWB- physical well-being; SWB- social well-being; EWB- emotional wellbeing; FWB- functional well-being; AC- additional concerns; TOI- total outcome index *per 1 point increase †per 5 point increase ‡per 10 point increase Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 6
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 978-978
    Abstract: MEC (mitoxantrone, etoposide, cytarabine) is a standard regimen for relapsed/ refractory (R/R) acute myeloid leukemia (AML), but outcomes remain poor. The overexpression of proteasomes and constitutive activation of NF-KB in AML cells suggest that proteasome inhibitors (PI) such as bortezomib (Bz) may be effective anti-leukemia therapy. PI or a decoy NF-KB oligonucleotide increase chemosensitivity to both anthracyclines and cytarabine. To test the hypothesis that PI may improve the efficacy of MEC, we conducted a phase 1 trial of Bz in combination with MEC. Here, we present final results of this trial: response rate, toxicity, and correlation of outcomes with mutation analysis. As CD74 expression may identify a subset NF-KB-dependent AML with predicted increased sensitivity to PI (Clin Can Res 2008; 14: 1446-54), we also explored this correlation. Methods: All pts were treated at the Cleveland Clinic from Aug 2010-Mar 2014. This protocol was approved by the institution’s review board. Eligibility included: age 18-70 yrs, R/R AML, cardiac ejection fraction ≥ 45%. CD74 was assessed by flow cytometry using CD45 PE (BD Biosciences San Jose, CA) and CD74-Alexa 488 (AbD Serotec Raleigh, NC). A myeloid panel mutational analysis was performed on extracted DNA in pts with banked samples (n=26). All pts received 1 cycle of MEC: mitoxantrone (6 mg/m2/d), etoposide (80 mg/ m2), and cytarabine (1000 mg/ m2) Days 1-6. Bz was administered IV on Days 1, 4, 8, and 11. Dose was escalated using a standard 3 x 3 design. Dose levels (DL) were: -1 (0.40 mg/ m2), 1 (0.70 mg/ m2), 2 (1.0 mg/ m2), and 3 (1.3 mg/m2). Response was defined by IWG criteria (Cheson, 2006). The maximum tolerated dose (MTD) of Bz with MEC was 1.0 mg/m2 (Advani et al, ASH 2012, Abstract 3595). Results: Of 35 pts enrolled, the median age was 55 yrs (range 33-69), 13 (38%) were male, and median baseline WBC was 4.0 K/ µL (range 0.82-84.7). The median time from initial diagnosis of AML to enrollment was 8.4 months (range 1.1-88.2) and 6 pts (17%) had an antecedent hematologic disorder. Salvage status (S) at enrollment: S1 (24 pts, 69%), S2 (7 pts, 20%), S4 (4 pts, 11%). Nine pts (26%) were refractory to all prior therapies, and 3 pts (9%) had received prior allogeneic hematopoietic cell transplant (AHCT). Adverse cytogenetics per CALGB/ Alliance 8461 criteria occurred in 19% of pts at study entry and 15 of 26 pts (58%) had poor-risk molecular mutations (RUNX1, ASXL1, TET2, p53, IDH1, MECOM, FLT3 ITD). Ten pts were enrolled on DL1, 13 pts on DL2, 11 pts on DL3, and 1 pt died prior to treatment. Overall, 3 pts (9%) died during induction. In addition to febrile neutropenia and Gr 4 hematologic toxicity, the most commonly reported adverse events (AEs) were metabolic, constitutional, gastrointestinal (GI), and dermatologic, with the majority of these being Gr 1 or 2. GI toxicity was the only reported AE attributable to Bz: 12 pts had constipation or ileus (10: Gr 1 or 2; 2: Gr 3 or 4). Seventeen of the 33 evaluable pts (52%) have achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi); with 1 pt inevaluable due to donor lymphocyte infusion. The estimated median overall survival was 7.2 months; median duration of response was 10.3 months. DL did not correlate with response. Eleven pts (32%) went on to receive AHCT. Among pts with poor-risk molecular mutations, 64% achieved CR/ CRi. Inhibition of NF-KB signaling in leukemia cells with mutated RUNX1 efficiently blocks growth and development of leukemia (Blood 2011; 118: 6626-37). Of the 5 pts with RUNX1 mutations, 3 (60%) achieved CR/ CRi, suggesting that Bz may have promising clinical benefit in this difficult subset of pts. Among the 17 pts with CD74 expression testing who were evaluable for response, the mean CD74 expression trended higher in non-responding pts (32.6%) than in responders (11.1%) (p=0.14). Conclusions: The combination of MEC/Bz was well-tolerated and resulted in high response rates, even within a molecularly-defined poor risk population of pts with R/R AML. Our data do not confirm the expectation that higher CD74 expression would correlate with response in this R/ R AML cohort, but larger pt numbers are needed. These results, especially in pts with poor-risk mutations, support development of a randomized study to address the benefit of adding Bz to MEC in the treatment of R/R AML. Disclosures Advani: Takeda: Research Funding. Carew:Takeda: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 7
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2566-2566
    Abstract: Although outcomes after allogeneic hematopoietic cell transplantation (alloHCT) for AML have improved, this has mainly been attributed to a reduction in transplant-related mortality rather than reduced leukemia relapse. NK cell alloreactivity is regulated by inhibitory and activating signals mediated through cell-surface receptors including the killer immunoglobulin-like receptors (KIRs). Group A and B KIR haplotypes have distinct centromeric (Cen) and telomeric (Tel) gene-content motifs and donor Cen group B KIR haplotypes have been reported to be associated with decreased relapse and improved survival in AML patients undergoing unrelated donor alloHCT. We hypothesized that donor KIR genotype may also be predictive of outcomes after matched related donor (MRD) alloHCT. We evaluated 93 AML patients in CR1/CR2 who underwent T-cell replete alloHCT using HLA- matched related donors at our institution from 1/2000-3/2013. Sixty-six had myeloablative conditioning (MAC) that that was busulfan/cyclophosphamide-based and 27 had reduced-intensity conditioning (RIC) with fludarabine/total body irradiation or busulfan/fludarabine. Donors were KIR genotyped to assign haplotypes A/A vs. B/X and the distinctive Cen and Tel gene-content motifs of group A and B KIR haplotypes according to the presence or absence of one or more B haplotype-defining KIR genes. KIR B–content score for each KIR genotype was defined as the number of Cen and Tel gene-content motifs containing B haplotype–defining genes (range, 0-4). As compared to those with haplotypes B/X (n=40; B content scores of 1-4) those with haplotype A/A (n=25; B content score of 0) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (8% vs. 0%, 13% vs. 0%, 15% vs. 0%, 25% vs. 0%, respectively, Figure 1) which was confirmed on multivariable analysis (HR 9.19, p=0.03). There were no differences between these groups regarding patient and transplant-related characteristics, or for acute or chronic GVHD, relapse, or survival. The causes of death in the group with haplotypes B/X were most commonly attributed to infection and then GVHD. However, within the group with B/X haplotypes, the B motif content score (1-4) was not associated with significant differences in NRM (HR 0.79, p=0.56). No difference in outcomes was observed for those undergoing RIC. The number of donor activating KIR genes (2SD1, 2DS2, 2DS3, 2DS4, 2DS5, and 3DS1) was then assessed. As compared to those with 3-6 activating KIR genes (n=20) those with 0-2 (n=41) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (15% vs. 0%, 15% vs. 5%, 15% vs. 5%, 29% vs. 8%, respectively, Figure 2) which was confirmed on multivariable analysis (HR 4.07, p=0.01). There were no differences in other post-transplant outcomes when comparing these groups or when considering those undergoing RIC. An increase of 1 donor activating KIR also was highly associated with NRM (HR 1.37, p=0.008). Overall, these results suggest that in the MRD MAC alloHCT setting donor KIR genotype may be predictive of increased NRM risk, particularly for those with B/X haplotypes and greater numbers donor activating KIRs. No comparable effects were observed in the RIC setting. Future strategies to further enhance immune reconstitution post-transplant may be appropriate to pursue for these higher risk patients. These results may have potential implications to improve donor selection for those AML patients with multiple HLA-matched related donors and need to be validated in larger cohorts. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 8
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1973-1973
    Abstract: Abstract 1973 Mutations in the spliceosome machinery have recently been identified in myeloid neoplasms including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and MDS/MPN overlap syndromes. Somatic alterations in SF3B1, U2AF1 and SRSF2 are the most frequently affected spliceosome genes in myeloid malignancies with the frequencies of any of the 3 genes being 39% in low risk MDS, 11% in high risk MDS/AML (primarily U2AF1), and 24% in MDS/MPN, (primarily SRSF2). While SF3B1 mutations as well as ring sideroblasts (RS) appear to be associated with improved survival and lower risk of leukemic evolution, mutations of U2AF1 and SRSF2 appear to be associated with poorer outcomes. Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for many myeloid malignancies, however, the prognostic role of SF3B1, U2AF1 or SRSF2 mutations in patients (pts) undergoing high intensity chemotherapy (HIC) and HCT has yet to be investigated. We evaluated 404 pts with the diagnosis of AML (n=96), MDS and MDS/MPN (n=294), MPN (n=13), and congenital sideroblastic anemia (n=1). 35 pts received HIC defined as treatment with 7+3, high dose cytarabine, clofarabine, or other comparable chemotherapy in the context of a clinical trial. 97 pts underwent a myeloablative (n=69) or reduced intensity (n=28) allogeneic HCT from an HLA matched related (n=39), unrelated (n=50) or cord blood (n=8) donor from April 2003 until August 2011. Median age of the whole cohort was 69 and those who underwent BMT at time of transplant was 52 (range 19–70). We performed direct sequencing for the three most commonly mutated spliceosome genes, SF3B1 (exon 13–16), SRSF2 (exon 1 and 2) and U2AF1 (exon 2–6). Given the close association between SF3B1 mutations and RS, we analyzed the impact of the presence or absence of RS on the outcomes associated with the type of therapy received. We found a total of 24 SF3B1 mutations in MDS and MDS/MPN (primarily in pts with RS), 37 SRSF2 mutations in MDS and MDS/MPN (primarily CMML), and 13 U2AF1 mutations in MDS, MDS/MPN and secondary AML. Among pts with MDS and MDS/MPN, significant overall survival (OS) differences were found between SF3B1 mutant and wild type (WT), (83 vs. 31 months, p=0.001) and U2AF1 or SRSF2 mutant (18 vs. 37 months, p=0.007). The U2AF1 mutation by itself was more strongly associated with poor outcome (8 vs. 37 months, p 〈 0.0001), compared to an SRSF2 mutation (26 vs. 36 months, p=0.16). Analysis of survival according to treatment type revealed that no pts who underwent HIC or HCT carried an SF3B1 mutation. The presence of RS was also associated with improved survival (38 vs. 25 months, p=0.04), and this benefit remained if pts received HIC (18 vs. 9 months, p=0.04). However, this benefit became non-significant if pts underwent HCT. There were 19 pts who had either an U2AF1 or SRSF2 mutation that underwent HIC. Although it appeared that having either mutation was associated with worse survival, (9 vs. 21 months), it did not reach statistical significance (p=0.46). Among pts who underwent HCT, there were 10 pts who carried either an U2AF1 or SRSF2 mutation. Those pts with mutations appeared to have superior survival with HCT compared to WT, (53 vs. 34 months), but this did not reach statistical significance (p=0.54). Among pts with either an U2AF1 or SRSF2 mutation, those who underwent HCT had a superior survival (53 vs. 17 months, p=0.05) compared to those who received conventional chemotherapy, defined as HIC or low intensity chemotherapy (LIC), such as hypomethylating agents. There was no difference in survival between receiving HCT or conventional chemotherapy in pts who were WT for U2AF1 or SRSF2 (34 vs. 31 months, p=0.08). Consistent with previous findings of improved survival and loss of SF3B1 with leukemic progression in MDS and MDS/MPN pts, we found no SF3B1 mutations in our cohort of pts receiving HIC or HCT. In contrast, we found poorer outcomes with SRSF2 or U2AF1 mutations. Although the incidence of these mutations was rare in our cohort of pts, we found statistically significant survival benefit for pts with these mutations if they underwent HCT compared to conventional chemotherapy. This is the first study evaluating the impact of spliceosomal mutations on the survival outcomes of pts undergoing HCT. Our preliminary findings of improved survival with HCT in poorer-risk spliceosome mutations is provoking and further molecular analysis is ongoing. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia & MDS International Foundation: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1201-1201
    Abstract: Background: The role of autologous stem cell transplantation (ASCT) in follicular lymphoma (FL) in the rituximab era remains undefined. Although ASCT has demonstrated to improve outcomes in relapsed/refractory (R/R) FL, there are very few studies addressing this issue in patients who had prior exposure to rituximab. Our aim was thus to assess the outcome of ASCT in FL patients in the modern era. Methods and Patients: We conducted a single center retrospective analysis of patients who underwent ASCT for follicular lymphoma at the Cleveland Clinic. Patient and disease characteristics were examined and prognostic factors for survival were determined using univariate and multivariate Cox analysis. Results: Total of 127 patients with a confirmed diagnosis of FL underwent ASCT at our institution between March 2000 and October 2013. Study population was predominantly male (61%) and Caucasian (92%). Median age at transplant was 55 years. Majority of the patients had FL grade of 1-2 (88%), International Prognostic Index (IPI) 0-2 (81%), and stage IV disease (60%) at the time of diagnosis. All, but 9 patients (93%) received rituximab as part of their prior treatment and 53% had received ³3 prior therapies. Disease status prior to transplant was 1st partial response (PR1) (9%), 2nd complete remission (CR2) (24%), 2nd PR (PR2) (60%), and R/R (8%); no patients received transplant in the 1st CR (CR1). An uniform preparative regimen consisting of Busulfan, Cyclophosphamide and Etoposide (Bu/Cy/VP16) was used in all patients. Median CD34+ cell dose was 7.49 x 106/kg. Median days to neutrophil engraftment were 10 days and platelet engraftment was 14 days. In our cohort, 10-year progression free survival (PFS) and overall survival (OS) were 33.2% and 52.4% respectively. Disease relapsed in 58/127 (46%) of the patients and 67% were alive at the time of last follow up. Age at transplant (Figure 1) and number of prior therapies, 〉 3 vs 1-3 (Figure 2) were significant prognostic factors for OS, in both univariate and multivariate analyses. Higher age (HR 1.76, 95% CI 1.23-2.52, p=0.002) and 〉 3 prior therapies (HR 2.58, 95% CI 1.31-5.12, p=0.006) were predictive for inferior OS. Disease status at transplant, IPI, and stage had no impact on survival. Disease relapse (67%) and secondary malignancies (7.1%) were the leading causes of death. Conclusions: In our analysis, a durable PFS, median of 49 months, was observed in patients with R/R FL who underwent an ASCT in the rituximab era. Age at transplant and number of prior therapies were identified as poor prognostic factors for OS. These data suggest that ASCT should be considered in young patients with R/R FL early in their disease course. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hill: Millenium: Research Funding; Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 10
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3068-3068
    Abstract: Abstract 3068 Advanced age is becoming less of a barrier to allogeneic hematopoietic cell transplantation (HCT) and transplantation has become an established standard of care for many older patients (pts) with hematologic malignancies. We previously reported superior quality of life (QOL) scores in pts age 60 and over undergoing high dose chemotherapy and autologous stem cell transplant compared with pts less than 60 (Dabney J et al, Blood 2008 112: Abstract 2381). These data prompted us to evaluate QOL assessments in pts≥60 undergoing allogeneic HCT compared to pts 〈 60 years. 435 adult pts underwent allogeneic HCT from June 2003 to December 2010. Prospective psychometric instruments were administered to 304 pts 〈 60 years of age (median 47, range 18–59) and 47 pts≥60 years of age (median 62, range 60–70) with acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, non-Hodgkins lymphoma, Hodgkins disease, myeloproliferative neoplasms, aplastic anemia, and plasma cell neoplasms. Psychometric data was assessed longitudinally (at baseline, first post-discharge visit, day 100, 180, and 365) by validated questionnaires: Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), coping inventory (Brief COPE), and the Profile of Mood State- Short Form (POMS). The FACT-BMT measures five components of QOL: physical well being (PWB), social well being (SWB), emotional well being (EWB), functional well being (FWB), and additional concerns (AC). The POMS measures depression, vigor, anger, tension, confusion and fatigue. Brief COPE has 14 coping skills, such as use of emotional and instrumental support, venting, and positive reframing. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), incidence of acute and chronic graft versus host disease (GVHD), and relapse. Imbalances between the two groups (p 〈 0.01 for all) included comorbidity index (HCT-CI), (62% of pts 〈 60 with a comorbid score of 〉 1 compared to 74% in pts≥60), preparative regimen, (84% myeloablative in pts 〈 60, 21% in pts ≥60%), and source of hematopoietic cells, (29% peripheral stem cells in pts 〈 60 versus 72% in pts≥60), with a higher median CD34+ cell dose (4.51×106/kg in pts≥60) compared with pts 〈 60 (2.51×106/kg). Psychosocial functioning and QOL differences were compared between age groups over time by repeated measures analysis of variance, using intensity of transplant as a variable given the imbalance. On FACT, pts≥60 reported better social (p=0.006) and functional well being (p=0.05), and had better total FACT scores, (p=0.043) across all time points. On POMS, pts≥60 reported less fatigue than patients 〈 60 (p=0.01), while COPE assessment indicated that older pts reported worse use of planning (p=0.012) and humor (p=0.041) compared with younger pts. Pts≥60 years also reported worse scores for active coping, but only at day 365 (p=0.019), and scored worse on behavioral disengagement at the first post-transplant time point (p=0.016), but this difference became non-significant by day 100 (p=0.81). With a median follow up of 49 months, there were no significant differences in OS, RFS, relapse, or chronic GVHD. There was a lower incidence of grade 3–4 acute GVHD in pts≥60 compared to pts 〈 60, (6.4% versus 15.8% at 6 months, p=0.016). This study provides further evidence that advanced age should not be a barrier in the decision to pursue allogeneic HCT. Older pts achieved better total scores in QOL assessments when compared to younger pts. One can hypothesize that older pts are more likely to have experienced adversity or family and personal health related problems, making them better able to endure symptoms than younger pts. In addition, younger pts may be more affected due to non-health related concerns including the adverse effect of transplantation on their careers, family, and finances. While our older population has proven to have similar medical outcomes and improved QOL, younger pts may benefit from social work interventions that focus on adapting to changes in functioning and social well-being. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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