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  • 1
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2507-2507
    Abstract: Introduction Population level data about the survival outcomes of patients with hematologic malignancies occurring as second cancers is limited. We undertook one of the largest analyses of second hematologic malignancies (SHM) using the Surveillance, Epidemiology & End Results (SEER) registry to identify factors associated with survival. Methods SEER 9 & 13 registries were queried to identify adult patients (pts 〉 18 years) diagnosed with SHM that comprised of Acute Myeloid Leukemia (AML), Acute Lymphoid Leukemia (ALL), Myelodysplastic Syndromes (MDS), Chronic Myeloid Leukemia (CML) & Other Acute Leukemias (OAL, biphenotypic leukemias, myeloid sarcomas & leukemias NOS) 〉 1 year (yr) after diagnosis of a primary unrelated cancer, using ICD-O-3 codes over a 40 yr period (1973-2012). Data on demographics, follow up, primary tumor & survival were abstracted. Univariate & multivariate analyses were performed to identify factors influencing survival of SHM & compared with hematologic malignancies occurring as first cancers. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported & significance was set at p 〈 0.01. Results SHM cases included 4665 AML, 3569 MDS, 1140 OAL, 1076 CML & 536 ALL pts. Median age at diagnosis of SHM was 73 yrs (range, 18-100) for AML, 79 yrs (18-100) for MDS, 74 yrs(20-99) for OAL, 74 yrs(18-98) for CML & 70 yrs(19-97) for ALL. Pts 〉 60 yrs comprised 79.2% of AML, 92% of MDS, 88.7% of OAL, 82.9% of CML & 75.2% of ALL cases. Gender distribution was similar across all categories, with females comprising 48.5% of AML, 42.2% of MDS, 45.3% of OAL, 42.8% of CML & 50.2% of ALL cases. More than 85% of pts in each group were Caucasians. While the majority of pts had one primary unrelated cancer (82-89%), 14% of AML pts, 17.8% of MDS pts, 13.8% of OAL, 15.3% of CML pts & 10.6% of ALL pts had 〉 1 primary unrelated cancer. Most common primary sites were prostate (19.1-29.6%), breast (16.1-21.9%) & colorectal (9.3-14.5%). Median survival (range) was as follows: AML 0.2 yrs (0-28.2); MDS 1.5 yrs (0-14); OAL 0.2 yrs (0-29.1); CML 2.5 yrs (0-27.1); & ALL 0.7 yrs (0-28.8). Median latency periods (range) for secondary cancers were as follows: AML 5.2 yrs (1.0-24.2); MDS 7.6 yrs (1.0-35.5); OAL 5.7 yrs (1.0-=34.3); CML 5.2 yrs (1.0-31.6); & ALL 6.2 yrs (1.0-35.5). In univariable analyses, age 〈 60 yrs predicted for better survival (p 〈 0.0001) for all SHM, as did diagnosis in recent yrs (2001-2012) (p 〈 0.0001 for AML, OAL, CML & ALL). Effect of time period on survival for MDS was not done, as it became formally reportable in 2001. Having 〉 2 primaries was associated with an unfavorable outcome for subsequent AML (HR=1.15; 1.08-1.23; p 〈 0.0001), MDS (HR=1.13; 1.05-1.22: p=0.001) & CML (HR=1.30; 1.13-1.48: p=0.0002). In multivariable analyses, advancing age was an independent adverse prognostic factor for all secondary leukemias & MDS, both as a continuous variable & when categorized as 〈 60 yrs vs. 〉 60 yrs (p 〈 0.001). Race & gender did not impact survival. Using breast cancer as a referent primary, AML pts had worse outcomes following colorectal (HR=1.31; 1.14-1.5; p=0.0002) or lung (HR=1.46; 1.22-1.74; p 〈 0.0001) primaries, while MDS pts fared worse with prior lung (HR=1.61; 1.22-2.12; p=0.0007) or Non-Hodgkin lymphoma (HR=1.58; 1.3-1.92: p 〈 0.0001). Of all 2ndCML cases, those after colorectal cancer had worst survival (HR=1.54; 1.12-2.13; p=0.008). Among SHM pts, MDS pts had better survival than those with AML (HR=0.42; 0.4-0.44: p 〈 0.0001), as did pts with CML (HR=0.37; 0.35-0.41: p 〈 0.0001) & ALL (HR=0.64; 0.58-0.70; p 〈 0.0001). Out OAL had similar outcomes compared to AML (HR=0.99; 0.92-1.05; p=0.66). Pts with CML fared better than MDS (HR=0.47; 0.41-0.54; p 〈 0.0001) & OAL (HR=0.37; 0.34-0.41: p 〈 0.0001). Pts with ALL had worse survival than CML (HR=1.8; 1.6-2.03: p 〈 0.0001) & MDS (HR=1.28; 1.11-1.48: p=0.0005), but better than OAL (HR=0.65; 0.58-0.73: p 〈 0.0001). (Figure 1) Patients with all SHM, except CML, had worse outcomes compared to those with primary hematologic cancers (Figure 2). Conclusion The prolonged latencies for SHM in this study suggest that they are likely therapy-related. Our findings show that type & number of primary cancers influence survival of subsequent leukemias & MDS. SHM have worse survival compared to those with primary hematologic malignancies except CML where non-separation of survival curves suggest that CML as SHM does not behave like a therapy-related neoplasm. Disclosures Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: 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: 2015
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    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 92, No. 11 ( 1998-12-01), p. 4336-4343
    Abstract: We report an RNA targeting strategy, which selectively degrades bcr/abl mRNA in chronic myelogenous leukemia (CML) cells. A 2′,5′-tetraadenylate activator (2-5A) of RNase L was chemically linked to oligonucleotide antisense directed against either the fusion site or against the translation start sequence in bcr/abl mRNA. Selective degradation of the targeted RNA sequences was demonstrated in assays with purified RNase L and decreases of p210bcr/abl kinase activity levels were obtained in the CML cell line, K562. Furthermore, the 2-5A-antisense chimeras suppressed growth of K562, while having substantially reduced effects on the promyelocytic leukemia cell line, HL60. Findings were extended to primary CML cells isolated from bone marrow of patients. The 2-5A-antisense treatments both suppressed proliferation of the leukemia cells and selectively depleted levels of bcr/abl mRNA without affecting levels of β-actin mRNA, determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The specificity of this approach was further shown with control oligonucleotides, such as chimeras containing an inactive dimeric form of 2-5A, antisense lacking 2-5A, or chimeras with altered sequences including several mismatched nucleotides. The control oligonucleotides had either reduced or no effect on CML cell growth and bcr/abl mRNA levels. These findings show that CML cell growth can be selectively suppressed by targeting bcr/abl mRNA with 2-5A-antisense for decay by RNase L and suggest that these compounds should be further explored for their potential as ex vivo purging agents of autologous hematopoietic stem cell transplants from CML patients.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1998
    detail.hit.zdb_id: 1468538-3
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1043-1043
    Abstract: Abstract 1043 Poster Board I-65 Background: In older (age 3 60) AML patients (pts) who are induced into complete remission, it is unclear whether post-remission therapy provides additional benefit. Methods: We examined all older AML pts treated with cytarabine-based induction chemotherapy at a single institution between 1997 and 2008. Data on known prognostic factors (age, white blood cell count (WBC) at diagnosis, cytogenetic risk groups (as defined by CALGB 8461) and AML etiology (de novo vs. secondary AML)) were collected. Of 240 pts identified, 25 had unknown post-remission status, leaving 215 pts for analyses: 81 receiving cytarabine-based post-remission therapy (PRT) for 1-2 cycles; 134 received no PRT. A cohort study using a propensity score method was conducted in which pts receiving PRT and those not receiving PRT were matched in a 1:1 ratio to address potential sample selection bias and to better balance patient characteristics. A logistic regression was used to predict the propensities of receiving PRT using individual characteristics: age, gender, race, WBC at presentation, AML cytogenetics, secondary AML, re-induction, FAB classification, and complete remission (CR). Overall survival (OS) was measured from the time of diagnosis; disease-free survival (DFS) from the time of CR. Individual characteristics and survival between groups were assessed by the routines of linear, categorical, and survival analyses. Results: Median age was 68 years (range, 60-81). Patients receiving PRT were more likely to be younger (67 vs 69 years, P=.003), male (67% vs. 52%, p=.04), have de novo AML (75% vs. 50%, p=.0012), favorable- or intermediate-risk cytogenetics (65% vs. 36%, p 〈 .0001), to have M3 AML (5% vs. 0%), and to have achieved a CR (100% vs. 48%, p 〈 .0001). There were no differences between groups in race, WBC at admission, reinduction rates, or comorbid conditions including renal dysfunction, hepatic dysfunction, and cardiac comorbidity. Median DFS and OS for those receiving PRT vs. no PRT were.45 and.34 years, and 1.13 and.69 years (p=.026 and p 〈 .001, respectively, Figure 1). Only 3 patients underwent a bone marrow transplant after relapse, and there was no correlation between the total amount of chemotherapy received during induction for PRT, or OS. After 1:1 propensity score matching (n=88), there were no differences in baseline characteristics, re-induction, or CR rates, yet DFS and OSl remained significantly greater for pts receiving PRT vs. those who did not (Hazard Ratios.48 and.30, p=.05 and p 〈 .0001, respectively). Conclusions: Even after adjusting for patient disease and treatment factors that could influence PRT administration, older AML pts receiving at least one cycle of PRT lived significantly longer than those who did not. PRT should be considered as a standard part of intensive therapy for older AML pts. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 896-896
    Abstract: Follicular lymphoma is generally an indolent disease with a relatively long natural history requiring multiple therapies over many years. The optimal combination and sequence of these therapies continue to evolve. Despite substantial supporting evidence (including a recently published, randomized study), the role of high dose therapy with ASCT in follicular lymphoma has been questioned. Therefore, we reviewed the Cleveland Clinic experience to determine the long-term outcome of follicular lymphoma patients according to histologic grade. Between June 1991 and June 2004, 105 patients with relapsed, grade 1–3, follicular lymphoma (without histologic transformation) received high dose CBV (n=9) or BuCyVP (n=96) and ASCT at the Cleveland Clinic. The median follow-up among survivors is 4.4 (0.1–11.4) years. Table of patient, disease, ASCT characteristics, and outcome Variable Grade 1 (n=45) Grade 2 (n=36) Grade 3 (n=24) p-value Age: median (range) 49(35–62) 51(33–58) 53(42–64) 0.042 Male sex: N (%) 23(51) 20(56) 12(50) 0.89 Years from diagnosis to ASCT: median (range) 3.0(0.4–15.7) 3.0(0.9–17.6) 2.3(0.6–15.2) 0.34 Prior # chemotherapy regimens: 2–3/ 〉 4, N (%) 36(80)/9(20) 32(89)/4(11) 19(79)/5(21) 0.49 Disease status at ASCT: CR/PR, N (%) 6(13)/33(73) 10(28)/22(61) 6(25)/15(63) 0.58 Bone marrow status at ASCT: +/−, N (%) 8(23)/27(77) 4(13)/28(88) 4(18)/18(82) 0.54 Prior radiation therapy: N (%) 14(31) 11(31) 5(21) 0.63 LDH 〉 normal at ASCT: N (%) 28(62) 27(77) 13(54) 0.16 Tumor bulk 〉 10 cm at ASCT: N (%) 8(18) 6(17) 5(21) 0.92 Disease progression: N (%) 20(44) 13(36) 11(46) – Death: N (%) 17(38) 11(31) 10(42) – Kaplan-Meier freedom from progression and overall survival according to histologic grade are shown: Figure Figure By Cox proportional univariate analysis, male sex, ≥4 prior chemotherapy regimens, and elevated LDH predicted a higher risk of progression while prior radiation therapy and bone marrow involvement predicted a higher risk of death. By Cox proportional multivariate analysis, male sex and elevated LDH predicted a higher risk of progression while prior radiation therapy and tumor bulk predicted a higher risk of death. In conclusion, approximately half of all patients that receive high dose therapy and ASCT for relapsed follicular lymphoma of any histologic grade enjoy long-term remissions and survival. ASCT remains one of the most beneficial treatment options for many patients with relapsed follicular lymphoma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 5
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2762-2762
    Abstract: We have previously demonstrated the value of evaluating patients with NHL undergoing autologous HSCT at 2 years post-transplant; high grade lymphoma patients in CCR 2 years post-transplant are cured, whereas patients with intermediate and low grade histologies are at ongoing risk of relapse. We elected to perform a similar analysis of AHSCT patients. We retrospectively reviewed 161 consecutive AHSCT recipients who had a minimum of 2 years follow-up and who were alive 2 years post AHSCT. Patients received their transplants from 7/1988 to 7/2002. Median age was 36 years; 75% had myeloid malignancies and 25% lymphoid; AML was the most common diagnosis (39%) followed by CML (29%), ALL (14%), NHL (10%), MDS (6%), and myeloma (2%). 98% received bone marrow alone as the hematopoietic stem cell source; 98% received a busulfan/cyclophosphamide-based preparative regimen. 129 (80%) had a matched related donor. Of those patients alive 2 years post AHSCT, 31 patients (19%) have subsequently died, with a median follow up of 6 years. Relapse was the cause of death in 29%; GVHD in 35%; secondary malignancy in 7%; infections in 16%. Patients with myeloid malignancies faired better than those transplanted with lymphoid malignancies, as shown below; (p= 0.04) Figure Figure When we analyzed the pts who developed their first episode of any chronic GVHD or extensive chronic GVHD there were no significant differences between lymphoid and myeloid malignacy patients. Patients receiving a matched sibling donor transplant did not have a plateau in their survival curve, and it continued to inexorably decline. Patients receiving a matched unrelated donor transplant did have a plateau of their survival curve if patients survived at least 3 years (p=0.03). We conclude that the significant majority of patients alive after AHSCT do well with extended follow-up. The graft vs. tumor effect appears to be more robust in myeloid malignancies as compared to lymphoid malignancies. Although most of these patients do well with extended follow-up, the lack of a plateau in the survival curve for patients receiving a matched sibling donor allogeneic BMT warrants additional study.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 843-843
    Abstract: Abstract 843 Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) following reduced intensity conditioning (RIC) compared to myeloablative conditioning (MAC) results in less treatment related morbidity and mortality. RIC permits older and less healthy patients (pts) to undergo Allo-HSCT. Whether RIC is also associated with better quality of life (QOL) and psychosocial functioning (PF) among pts with myeloid malignancies has not been systematically analyzed. We prospectively collected QOL and PF outcomes in 192 consecutive pts with AML (n=130), MDS (n=52), or myeloproliferative neoplasms (n=10) who received MAC (n=154) or RIC (n=38) Allo-HSCT from 2004 to 2010. Psychometric data were assessed longitudinally (at baseline, post-transplant, day100, 180, and 365) by validated questionnaires (Functional Assessment of Cancer Therapy- Bone Marrow Transplant Scale [FACT-BMT], coping inventory [Brief COPE] , and Profile of Mood States Short Form [POMS]). FACT-BMT consisted of individual and summary scores for physical (PWB), social (SWB), emotional (EWB), functional (FWB) well-being along with additional concerns (AC). Brief COPE has 14 components such as use of emotional and instrumental support, venting, positive reframing etc. POMS consisted of 6 components such as depression, vigor, anger etc. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), incidence of acute (aGVHD) and chronic (cGVHD) graft vs. host disease. QOL and PF differences were compared between transplant types over time by repeated measures analysis of variance. Adjustment for baseline differences in QOL and PF was made in mixed linear model analysis. Kaplan-Meier and cumulative incidence methods were used for analyses of secondary endpoints. RIC and MAC patients were comparable (all p 〉 0.1) for gender, race, hematopoietic cell transplantation comorbidity index, number of prior chemotherapies, donor relation, length of follow up. Differences between RIC and MAC groups (all p 〈 0.001) were detected for median age at transplant (61 for RIC vs. 48 yrs for MAC), stem cell (SC) source (95% peripheral SC in RIC vs. 19% in MAC), TBI-containing preparative regimen (95% for RIC vs. 24% for MAC), CD34+ dose (5.2 for RIC vs. 2.2 ×106/kg for MAC), GVHD prophylaxis. RIC pts had shorter median time-to-neutrophil (11 vs. 15 days, p 〈 0.001) and -platelet (12 vs. 21 days, p 〈 0.001) recovery. There was no baseline QOL difference between RIC and MAC according to FACT-BMT. RIC pts had better baseline scores for anger, emotional support use, venting, and positive reframing (all p 〈 0.05). As compared to MAC, pts with RIC had superior QOL scores post-transplant, i.e FWB (up to day 180, p 〈 0.01), AC (up to day 100, p 〈 0.05), and summary (up to day 100, p 〈 0.05) despite the absence of baseline differences. FWB advantage of RIC remained significant up to half a year (p 〈 0.05) in mixed linear model analysis adjusted for baseline differences. RIC pts had better depression (p 〈 0.01) and anger (p 〈 0.01) scores post-discharge after controlling for baseline differences. In adjusted analysis of COPE, RIC pts had better positive reframing (p=0.02) and use of instrumental support (p=0.02) during early post-transplant follow up. All QOL and PF metrics equalized between RIC and MAC by post-transplant day365 (all p 〉 0.1). With a median follow up of 34 months, there were no differences between RIC and MAC in incidence of aGVHD or cGVHD, RFS, or OS (all p 〉 0.3). In conclusion, our prospective study provides further evidence on overall comparable clinical, QOL and PF outcomes between RIC and MAC and it is the first to demonstrate significant early advantage of RIC in certain QOL and PF metrics up to 180 days post-transplant across all three psychometric instruments. 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: 2011
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  • 7
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2652-2652
    Abstract: Background Prostate cancer is the most common cancer diagnosis in men, and one of the leading indications for radiation therapy. The risk of resultant secondary leukemias has not been consistently established. We investigated the risk of all leukemias in a population-based cohort of patients (pts) with locoregional prostate cancer definitively treated with radiotherapy. Methods We queried the Surveillance, Epidemiology, and End Results (SEER) 17 registries to identify a cohort of men 〉 20 years old (n = 183,268) with locoregional prostate adenocarcinoma newly diagnosed between January 1973 and December 2008. Pts who underwent initial treatment with radical prostatectomy (RP) were compared to pts receiving RP with external beam radiotherapy (RP w/EBRT) to investigate the risk of radiation-induced leukemias. These cohorts tend to be well matched regarding age, medical comorbidities and disease characteristics. All new leukemias occurring as a second primary cancer at least one year after the first diagnosis of prostate cancer were identified in SEER using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) morphology codes. Secondary leukemias included acute myeloid leukemia (AML); chronic myelogenous leukemia (CML); acute and chronic lymphocytic leukemia (ALL & CLL) and other categories as reported in SEER. Pts were observed from date of prostate cancer diagnosis until leukemia occurrence, death, or last date of follow-up. Univariate and multivariate analyses were performed using the Fine and Gray competing risk regression analysis with leukemia as a time-dependent endpoint and death from any cause or the diagnosis of any other second cancer as competing events. RP w/ EBRT group was compared with the RP cohort as the reference group, controlling for age. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Results Median age was 67 years (yrs, range 22 – 105) at prostate cancer diagnosis: 67 yrs in RP and 68 yrs in RP w/ EBRT pts (p 〈 0.0001); 158,913 (86.7%) were treated with RP and 24,355 (13.3%) with RP w/EBRT. Median follow-up was 7.6 yrs [(range, 1 – 35.5): 7.5 yrs in the RP group and 8.3 yrs in the RP w/ EBRT group, (p 〈 0.0001)]. In total, 949 (0.5%) leukemia cases were identified: 336 (0.2%) acute leukemias [266 (0.2%) in the RP group and 70 (0.3%) in the RP w/ EBRT]; 538 (0.3%) chronic leukemias [462 (0.3%) in the RP group and 76 (0.3%) in the RP w/ EBRT] and 75 (0.04%) of unspecified histology. Histologic subtypes (per ICD-O-3 codes) were: AML (n=249), acute monocytic leukemia (n=18), ALL (n=24), other acute leukemias (n=45), other myeloid/monocytic/lymphocytic leukemias (n=48), aleukemic/subleukemic/NOS (n=27), CML (n=131) and CLL (n=407). Median age at acute leukemia diagnosis was 77 yrs [(range, 50 – 101): 78 yrs in the RP group and 76 yrs in RP w/EBRT pts, (p=0.0271)] and for chronic leukemias was 76 yrs [(range, 47 – 101): 76 yrs in the RP group and 77 yrs in the RP w/EBRT pts, (p=0.50)] .The median time to develop acute leukemias was 6.0 yrs [(range, 1 – 28.2): 6.1 yrs in the RP group and 5.7 yrs in the RP w/EBRT pts, (p=0.20)] and chronic leukemias was 6.9 yrs [(range, 1 – 29.8): 6.7 yrs in the RP group and 8.6 yrs in the RP w/EBRT pts, (p=0.0020)] . The cumulative incidence rate (CIR) at 20 years for acute leukemias was 0.24% for the RP pts vs. 0.32% for the RP w/EBRT pts (p=0.0196). The CIR at 20 years for chronic leukemias was 0.47% for the RP pts vs. 0.36% for the RP w/EBRT pts (p=0.10). In univariate analyses, age 〉 70 yrs (HR=1.40; CI, 1.13 – 1.74; p=0.0023), and those who received RP w/ EBRT (HR=1.49; CI, 1.14 – 1.94; p=0.0033) were significantly more likely to develop acute leukemias. In multivariate analysis, both advanced age (HR=1.40; CI, 1.13 – 1.74; p = 0.0023) and RP w/ EBRT (HR=1.49; CI, 1.14 – 1.94; p=0.0032), remained significantly associated with increased risk of acute leukemias. Radiation treatment was not significantly associated with the risk of developing chronic leukemias among pts treated with RP w/EBRT vs. RP [HR=0.91; CI, 0.72 – 1.16; p=0.45). Conclusions Among the best matched prostate cancer treatment cohorts, those who underwent EBRT following RP had a 49% increased risk of subsequent acute leukemias, although the absolute number of cases was low. Risk assessment in this cohort spans a time frame where radiation technologies have rapidly advanced and hence treatment period effects need to be considered in interpretation of results 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: 2013
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  • 8
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2117-2117
    Abstract: Umbilical cord blood transplantation (UCBT) is often complicated by delayed engraftment and higher rates of engraftment failure. We sought to investigate the outcomes of patients undergoing UCBT2 after engraftment failure compared to those who had autologous hematopoietic recovery and did not receive UCBT2. Methods We reviewed the medical records of 186 patients who received UCBT between 2001 and 2011 at the Case Comprehensive Cancer Center [Seidman Cancer Center, University Hospitals Case Medical Center and Taussig Cancer Institute, Cleveland Clinic]. Standard definitions of engraftment were used. Patients who died or had progressive disease before day 30 were excluded (n=9), as they were considered inevaluable for engraftment. Results Twenty-seven patients (15%) had primary engraftment failure; twelve had autologous hematopoietic recovery and 15 presented no recovery (Table). The median total nucleated cell dose for the first UCBT was 2.56x107 cells/kg (range 1.23 x107 - 5.69x107), not statistically different from patients achieving engraftment (p = 0.29). The cause of engraftment failure could not be identified in 22 patients. Among patients with engraftment failure without autologous recovery, 2 patients did not receive further salvage and died at 40 and 48 days after first UCBT; 2 others received backup autologous hematopoietic cell infusions and 11 received UCBT2. In patients with autologous hematopoietic recovery, 8 did not receive a UCBT2 because disease remission had been attained (n=4), active infection (n=1), relapsed disease beyond 40 days after UCBT (n=1) or absence of compatible donor (n=1). Fifteen patients (engraftment failure [n=11]); autologous recovery, [n=4] ) underwent UCBT2, at a median of 43 days (range 33-244) from first to second UCBT. All patients received non–myeloablative second conditioning regimens. Four patients received one UCB unit and 11 received two units. Neutrophil engraftment after UCBT2 was observed in 10 of 15 patients at a median of 30 days (range, 13-35). The median survival for the entire cohort was 272 days (range 40–2130); one year overall survival was 36%. Engraftment and overall survival were not statistically different between those receiving 1 or 2 UCB units for UCBT2. Overall survival was not statistically different between patients who underwent UCBT2 and those who had autologous recovery or backup autologous infusions without further salvage. The proportion of patients in remission was similar in the 2 subgroups (UCBT2, 53%; autologous recovery, 50%). Relapse occurred in 2/15 patients who underwent UCBT2 and 8/10 patients who had autologous recovery or backup infusions. Forty months after transplantation, the cumulative incidence of relapse was 92% after autologous recovery vs. 50% after UCBT2 (Figure). Non–relapse mortality after UCBT2 was 73%. Conclusion Engraftment failure after UCBT frequently has no identifiable cause, and is associated with high morbidity and mortality. UCBT2 is feasible and can result in engraftment in the majority of patients, but is limited by patient condition after transplant as well as the availability of compatible grafts. UCBT2 is associated with significantly better disease control than continued autologous hematopoiesis, but additional efforts are necessary to reduce the high risk of non-relapse mortality in this group of patients. Disclosures: Hill: Celgene: Honoraria, 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: 2013
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  • 9
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 622-622
    Abstract: The reactivity of NK cells and some T cell populations is regulated by the interaction of KIRs with target cell HLA class I molecules. KIR interactions have been suggested to influence outcomes of haploidentical and HLA-identical allogeneic hematopoietic stem cell transplants, particularly for AML patients. We analyzed the KIR ligand phenotypes of 60 AML patients who received HLA-identical sibling myeloablative ABMT from 4/9/97-11/5/03. The median age was 45 yrs (range 8–62). At the time of transplant 24 patients (40%) were in CR. All patients received a busulfan/cyclophosphamide-based preparative regimen and all received bone marrow (T-cell replete) as their stem cell source. Patient HLA KIR ligands were categorized as: 1) HLA-Cw groups C1/C1, C2/C2, C1/C2; 2) HLA-Bw4 (+ or −); 3) HLA-A3 or A11 (+ or −) (as reviewed in Farag et al Blood100:1935,2002). Recursive partitioning analysis for post-transplant time-related outcomes (acute GVHD, grade 3/4 acute GVHD, chronic GVHD, extensive chronic GVHD, freedom from relapse and survival) was performed for each KIR ligand group. Patients with C1/C1 or C2/C2 (n=26) had improved survival compared to the C1/C2 group (n=34) (median survival 43.5 months vs. 5.8 months, respectively, p=0.018), as shown below: Figure Figure This survival difference was associated with more relapse in the C1/C2 group (p=0.048), but not with incidence or severity of acute or chronic GVHD, age, infection or pretransplant disease status. There were 26/34 (76%) deaths in the C1/C2 group with 15 (58%) due to relapse as compared to 13/26 (50%) deaths in the C1/C1 + C2/C2 group where 4/13 (31%) were due to relapse. The median follow up of survivors was 36.3 mos (range 7.8–72.4 mos). No significant differences in outcomes were observed when patients were analyzed for the presence or absence of HLA-Bw4 or A3/11. The majority of patients had KIR genotyping performed for those KIRs with established HLA ligands. Among those tested there were no cases in which the donor did not have at least one inhibitory KIR gene specific for a Cw ligand present in the patient or donor. This may suggest that KIR expression at the cellular level rather than KIR genotype alone should be investigated. In conclusion, AML patients undergoing matched sibling donor ABMT who were heterozygous for HLA-Cw KIR ligand groups (C1/C2) had reduced survival compared to patients homozygous for these groups. The higher relapse rate observed in the heterozygous ligand group may suggest a less effective graft-versus-leukemia (GVL) response. Since C1/C2 heterozygotes have a greater opportunity to engage inhibitory KIRs than do C1 or C2 homozygotes, they may more effectively inhibit KIR-positive NK and T cell populations involved in GVL responses.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 612-612
    Abstract: Background: The incidence of thyroid cancers has been rising in the United States primarily due to the increased detection of well differentiated thyroid cancers (WDTC). Radioactive iodine (RAI), which is frequently used to treat WDTC, can be considered a circulating radiation emitter with the potential for mutagenic effects on hematopoietic stem cells. With a growing number of WDTC patients (pts) surviving long term following RAI therapy, establishing the risk of developing a myelodysplastic syndrome (MDS) in this cohort has important clinical implications. Methods: A novel R program, SEERaBomb (Radiat Environ Biophys. 2014;53(1):55-63) was used to query all 18 Surveillance Epidemiology and End Results (SEER) registries to identify WDTC cases treated with RAI and MDS as second cancers. SEERaBomb allows merging of all 18 SEER registries - a function not permitted by the SEER*Stat MP-SIR that limits researchers to use to one of two datasets (SEER 9 or SEER 13), thereby significantly increasing the capture of MDS cases (Figure 1). WDTC includes papillary and follicular thyroid histologies. WDTC survivor person-years at risk for developing MDS was based on age at diagnosis of WDTC, survival time, and age at diagnosis of MDS. Relative risks (RR) for developing MDS were then based on observed/expected cases between the cohorts receiving surgery alone (control), surgery combined with RAI as well as those receiving external beam radiation therapy (EBRT) and surgery with or without (+/-) RAI. Mean radiation exposure to bone marrow was compared between RAI and prostate cancer (as example) treated with other radiation modalities - brachytherapy (seeds), EBRT (3D, IMRT and VMRT). Results: In total 132,157 WDTC patients were identified from 1973-2011, of whom 69,975 (53%) received surgery alone, 59,015 (45%) underwent surgery + RAI and 3167 (2%) underwent EBRT [combined with surgery+/- adjuvant RAI]. Mean age at the time of WDTC diagnosis was: 49.4 years (yrs, range, 2-105) in the surgery group; 46.7 yrs (2-99) in the surgery + RAI group and 55.1 yrs (10-101) in the EBRT group. Median person years of follow up after WDTC diagnosis was: 6.1 yrs (2.5-11.6) in pts undergoing thyroidectomy; 5.4 yrs (2.4-9.7) in the surgery + RAI group and 5.9 yrs (1.7-11) in the EBRT group. A total of 55 patients developed MDS; 24 had surgery alone, 27 received surgery + RAI and 4 had EBRT. Median time to development of MDS after WDTM diagnosis (25-75 interquartile range) was: 6.4 yrs (4-15) in pts receiving surgery alone; 4 yrs (1.7-6.7) in the surgery + RAI group and 3.6 yrs (2.4-7.9) in the EBRT group. MDS cases were classified as RA (n=11), RARS (n=2), RCMD (n=3), RAEB (n=9), MDS with 5q deletion syndrome (n=1), and MDS-U (n=29). Compared to patients definitively treated with surgery, those who additionally received RAI (+/- EBRT) had a statistically significantly increased risk of developing MDS within the first two years of exposure (RR=1.9; 95% CI, 0.43-5.61 vs. RR=5.8; 95% CI, 2.84-12.22). Beyond 2 years, the risk for MDS drops to baseline rates, and a trend observed beyond 12 years, which did not reach statistical significance (Figure 2). Conclusion: WDTC pts undergoing RAI treatment appear to have an increased risk of developing MDS within the first two years of exposure to RAI. It is difficult to determine whether this early excess risk is true risk or an effect of ascertainment bias (RAI pts followed more closely), as the kinetics of RAI indicate a lower magnitude of bone marrow exposure compared to other radiation modalities (Figure 3). Considering the long latency of MDS seen in atomic bomb cohorts, relative young age of WDTC pts, current trend towards overdiagnosis and overtreatment of WDTCÕs, MDS rates are likely to continue to rise. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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