Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4561-4561
    Abstract: Abstract 4561 Chronic myelomonocytic leukemia (CMML) typically has a dire prognosis with limited treatment options. We retrospectively reviewed the outcomes of 41 patients diagnosed with CMML (n= 35) or MDS/MPD overlap (n=6) who underwent allogeneic stem cell transplantation at three centers (University of Minnesota (n= 19), Johns Hopkins University (n=11), and the Cleveland Clinic (n=11)) between1990-2009. The majority of patients were male (59%) with a mean age of 51. At diagnosis nearly half of the patients had normal cytogenetics (n=20, 49%) with abnormalities of chromosome 7 the most commonly identified clonal finding (n=5, 12%). The majority had 〈 5% blasts (n=22, 54%), and the majority had an MD Anderson Prognostic Score (MDAPS) of 2 (n=16, 39%) or 3 (n=13, 32%) at diagnosis. Fifteen patients (37%) received no pre-transplant therapy while 12 (29%) received hydroxyurea, 11 (27%) induction-type chemotherapy, and 3 (7%) miscellaneous other therapies. Nine patients (22%) had progressed to AML prior to transplant. At the time of transplant, blast percentage was 〈 5% in the majority (n=23, 56%) of patients and more than half of patients now had a MDAPS of 1 (n=13, 32%) or 2 (n=12, 32%). Comorbidity index (HCT-CI) at transplant was retrospectively calculated on 32 patients and was 0 (n=5, 12%), 1–2 (n=13, 32%), or 3+ (n= 15, 37%). Myeloablative conditioning was used in 23 (56%) and stem cell source was bone marrow in 14 (34%), PBSC in 16 (39%), and UCB in 9 (22%). The majority of donors were matched siblings (n=22, 54%) while unrelated donors (URD) (n=16, 39%) and haploidentical donors (n=3, 7%) comprised the remaining. Graft versus host disease (GVHD) prophylaxis consisted of a calcineurin inhibitor (cyclosporine or tacrolimus) + methotrexate or mycophenolate mofetil (MMF) in the majority of patients (n=29, 71%) with the remainder receiving post-transplant cyclophosphamide (n=6, 15%), elutriation (n=2, 5%), or calcineurin inhibitor alone (n=4, 10%). While the median time to follow-up was only 5.8 months (range 0.5–140), 24 patients had died by one year and there was extensive follow-up available in the surviving patients. Overall survival (OS) for the entire cohort at 1 and 3 years was 41% (95% CI, 26–56%) and 16% (95% CI, 6–30%), respectively. No disease or transplant factors significantly impacted survival. Progression free survival (PFS) at 1 and 3 years was 29% (95% CI, 16–43%) and 16% (95% CI, 7–29%), respectively. Sibling donor showed improved PFS at both 1 (45%, 95% CI 24–64%), (p=0.027) and 3 (27%, 95% CI 10–46%), (p=0.04) years. Transplant related mortality (TRM) at Day +100 and 1 year was 27% (95% CI, 13–40%) and 41% (95% CI, 26–57%) respectively. Age at transplant, year transplanted, HCT-CI at transplant, conditioning intensity, donor source, transplant site, or presence of acute graft versus host disease (GVHD) did not impact TRM. Relapse at 1 and 3 years was 29% (95% CI, 15–44%) and 40% (95% CI, 23–56%), respectively. High MDAPS at diagnosis and sibling donor source were the only significant factors impacting relapse. At 1 year, those with an MDAPS of 3–4 had a 53% chance of relapse compared with 29% with a score of 0–1 (p=0.05) and those with a sibling donor had a 9% relapse incidence compared with 50% in the URDs and 67% in the haploidentical setting (p=0.003). Interestingly the presence of acute GVHD at Day +100 was not protective against relapse (40% incidence at 1 year in those with aGVHD versus only 19% for those without). Our data suggest that high MD Anderson Prognostic score at diagnosis predicts for high incidence of relapse post allogeneic stem cell transplantation while a sibling donor source improves rates of relapse and progression free survival. Our data highlight the need for improved CMML treatment paradigms. Augmentation of pre and post transplant therapy including maintenance therapy post transplant are possible approaches to improve outcomes and could be considered for prospective trials. 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: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3886-3886
    Abstract: Abstract 3886 Poster Board III-822 Introduction A better understanding of multiple myeloma (MM) disease biology has led to the development of targeted agents such as the proteasome inhibitor bortezomib. While bortezomib has provided significant survival advantages for both previously untreated and treated patients with MM, nearly all patients eventually relapse or become refractory to bortezomib therapy. Therefore, there remains a need to develop specific new approaches that are active against MM or enhance the efficacy of existing treatments. Vorinostat (Zolinza®), a potent oral inhibitor of Class I and Class II histone deacetylase (HDAC) enzymes, has demonstrated antiproliferative and proapoptotic activity in preclinical models of MM as a single agent and in combination with bortezomib. Preliminary results from an ongoing open-label, escalating dose, multicenter Phase I trial of vorinostat in combination with bortezomib have shown that the combination is generally well tolerated and effective in heavily pretreated patients with advanced MM (Weber et al. Clinical Lymphoma and Myeloma 2009; 9: S44, abstract A248), including patients refractory to prior bortezomib treatment (Weber et al. Clinical Lymphoma and Myeloma 2009; 9: S42, abstract A242). Here we report the safety and efficacy results for a cohort of patients with relapsed/refractory MM who have received ≥12 cycles of treatment with vorinostat in combination with bortezomib. Methods Patients (aged ≥18 years) with relapsed or refractory MM (ECOG performance status 0-2) were sequentially enrolled on escalating doses of vorinostat combination therapy using a standard 3+3 design for ≤8 cycles. Cycles were repeated every 21 days and consisted of vorinostat 200 mg bid or 400 mg once daily (Days 1-14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on Days 4, 8, 11, and 15; or escalated to 0.9, 1.1, or 1.3 mg/m2 i.v. on Days 1, 4, 8, and 11. The addition of oral dexamethasone 20 mg on Days 1-4 and 9-12 of each cycle was permitted for disease progression (PD). Patients without disease progression at Cycle 8 were allowed to continue on study treatment. Results Of the 34 patients who have entered the study, 9 have received combined vorinostat and bortezomib treatment for ≥12 cycles and are the focus of this report. In this population, drug-related adverse events (AEs) occurred in 9/9 patients; 99% of these AEs were mild to moderate in severity (NCI Grade 1-3) and 6 patients had serious AEs (9 events). One patient experienced Grade 4 neutropenia, and 5 patients experienced Grade 3 drug-related AEs. The most common drug-related toxicities of any grade were diarrhea, nausea, and fatigue. The best responses observed in 9 evaluable patients were 5 partial response (duration 147 to 609 days), 2 minimal response (duration 42 to 161 days), and 2 stable disease (duration 371 to 742 days). Seven of 9 patients have now discontinued treatment; all due to progressive disease (median [range] time to progression was 294 days [42 to 742 days] ). Conclusions These preliminary data indicate that extended treatment with vorinostat in combination with bortezomib (+/- dexamethasone) administered in a 21-day cycle shows significant long-term clinical activity with acceptable tolerability in patients with relapsed/refractory MM. Disclosures: Jagannath: Celgene: Honoraria; Millennium: Ad Board, Honoraria; Merck: Honoraria. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Weber:Millenium: Research Funding, Speakers Bureau; Celgene : Research Funding, Speakers Bureau; Merck : Research Funding, unpaid advisory board. Schiller:Denzyme: Research Funding; Cellegne: Research Funding; Eli Lilly: Research Funding; Centocor: Research Funding; Millennium: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Vion: Research Funding. Lupinacci:Merck: Employment, Equity Ownership. Reiser:Merck: Employment, Equity Ownership. Allen:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 740-740
    Abstract: AML and MDS are heterogeneous myeloid neoplasms with variable biologic and clinical outcomes. Although allogeneic HCT is the only potentially curative therapy for high risk AML and MDS, survival after transplant remains poor, and identifying who benefits is challenging. We hypothesized that next-generation sequencing (NGS) mutational analyses can predict outcome in MDS and AML patients undergoing allogeneic HCT. We performed multi-amplicon targeted pre-HCT NGS using a somatic panel of the 60 most commonly mutated genes in myeloid neoplasias as previously determined by whole exome sequencing, on 123 patients with AML (N=64, 52%) and MDS (N=59, 48%) who subsequently underwent HCT. Median age at transplant was 53 years (range, 20-73). 21 (17%) patients had complex karyotype, 10 (8%) with monosomy 7, 48 (39%) normal, and 48 (39%) with other or unknown cytogenetic abnormalities. 45 (37%) patients were in a complete remission (CR) prior to transplant, while 78 (63%) were in less than a CR; with CR as defined by International Working Group criteria for MDS, or 〈 5% blasts for AML. The majority of patients received myeloablative conditioning (N=83, 68%), and 40 (33%) received a reduced-intensity preparative regimen. Donor source was matched sibling (N=52, 42%), matched unrelated (N=56, 46%), cord-blood (N=12, 10%), and haplo-identical (N=3, 2%). Median follow up was 35 months (range 5-178). Mutations were analyzed individually and by molecular pathway. 88 (72%) patients had at least one mutation, most frequently in STAG2 (10.2%), TET2 (9.8%), ASXL1 (8.1%), and RUNX1 (8.1%). TP53 mutations were more common in MDS patients compared to AML (10% versus 1.6%, P=0.05). NRAS (P=0.019) and TP53 (P=0.022)mutations were more commonly associated with complex karyotype. Mutations in BCOR (P=0.048) and TP53 (P=0.047)were associated with less than CR, while TET2 (P=0.03)mutations were associated with CR prior to HCT. In univariable analyses, the presence of complex karyotype was associated with shorter overall (OS) and relapse-free survival (RFS) (hazard ratio [HR] 2.4; P=0.002 and HR 3.1; P 〈 0.001). Mutations in TET2 (HR 2.1; P=0.042) and EZH2 (HR 2.3; P=0.048), or presence of any mutation in the histone modification pathway (ASXL1, EZH2, KDM6A, SUZ12); (HR 1.7; P=0.039) was associated with poor OS. The presence of any mutation in the DEAD box RNA-helicase family genes (DHX29, DDX54, DDX41) was associated with poor RFS (HR 3.1; P=0.009). Nothing except complex karyotype was specifically associated with higher relapse. Unlike in previous reports, TP53 mutations were not found to be significantly associated with poor OS or RFS, though these cases (N=7) were limited. In multivariable analyses, adjusting for clinical variables, complex karyotype remained significantly associated with poor OS (HR 2.7; P 〈 0.001) and RFS (HR 3.9; P 〈 0.001). TET2 also remained independently associated with poor OS (HR 2.4; P=0.022). Presence of any of the DNA methylation mutations (TET2, DNMT3A, IDH1, IDH2) was associated with poor RFS (HR 1.7; P=0.05). 3-year OS was 23% in patients with a complex karyotype versus 48% in patients without (P=0.002); and 14% in patients with a TET2 mutation and 46% without (P=0.042) (Figure 1). Molecular abnormalities are important variables in determining outcome after allogeneic HCT. We demonstrate that TET2 mutations in AML and MDS predict for poor survival after HCT. Ongoing serial mutational analyses in an extended cohort of patients will enhance our understanding of the role of NGS in informing care decisions for patients undergoing allogeneic HCT for AML and MDS. Figure 1. Overall Survival by TET2 mutation status Figure 1. Overall Survival by TET2 mutation status Disclosures Majhail: Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy. Sekeres:Celgene Corporation: 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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 678-678
    Abstract: Only 5-azacytidine (5Aza) and decitabine (Dec), both DNA methyltransferase (DNMT1) depleting drugs, are FDA-approved to treat all myelodysplastic syndrome (MDS) subtypes. Neither agent is curative. What are the mechanisms of resistance? MDS is genetically heterogeneous, thus, this question has been approached by attempting to correlate MDS genetics with response, or by examining genetics at relapse. Unfortunately, results have been contradictory/inconclusive. Another approach is to consider that achievement of the intended molecular pharmacodynamic (PD) effect of DNMT1-depletion is a minimum requirement for response, superceding other biological considerations including genetics/susceptibility to apoptosis or differentiation. As such, a logical first-step is to examine whether relapse is driven by sub-clones thriving despite DNMT1-depletion, or from failure to deplete DNMT1 in the first place. In both murine and clinical studies, relapse was from failure to deplete DNMT1 (Leukemia 2011;25(11):1739-50; Oncotarget 2012;3(10):1137-45; J Clin Invest 2015;125(3):1043-55). Thus, the question can be reframed as: Why is molecular PD not achieved, and can mechanisms be identified to extend response? Achievement of molecular PD by 5Aza/Dec depends on intra-cellular exposure/half-life (t½). Intra-cellular t½ depends in turn on extra-cellular exposure time (plasma t½) and pyrimidine metabolism enzymes that phosphorylate 5Aza/Dec, trapping these drugs in cells. There is controversy regarding the identify of the enzymes that phosphorylate and trap 5Aza: UCK1, UCK2 or both. To answer this question, we correlated UCK1, UCK2 and DCK expression with sensitivity of NCI60 cancer cell lines (n=60) to 5Aza or Dec. 5Aza sensitivity correlated strongly with UCK2 expression but not UCK1 or DCK (corr. coeff.: 5AzaGI50 vs UCK2-0.28, p=0.03; vs UCK1 0.22, p=0.1; vs DCK -0.07, p=0.5). Dec sensitivity correlated with DCK expression but not UCK2 or UCK1 (corr. coeff.: DecGI50 versus DCK-0.27, p=0.04; vs UCK1-0.01, p=0.9; vs UCK2-0.19, p=0.2). There was greater than 2-fold variation of UCK2/DCK expression in primary MDS CD34+ bone marrow cells, not linked with WHO-subtypes or genetics, suggesting flexible use of one or the other enzyme for pyrimidine salvage, although a trend for higher DCK expression was noted in MDS containing mutated TP53 (GSE58831). Does treatment select for sub-clones utilizing salvage enzymes that avoid drug? DCK and UCK2 expression was serially measured by QRT-PCR in bone marrow from MDS patients treated with a Dec regimen rationalized for non-cytotoxic DNMT1-depletion (0.1-0.2 mg/kg SC 1-3X/week, n=12) or with conventional 5Aza (n=6). UCK2 consistently increased (up to 100-fold) and DCK consistently decreased at relapse on Dec, with vice-versa for 5Aza (Fig. 1). Mechanism-based solutions to such resistance were evaluated in xenotransplant models of human MDS-AML that phenocopy human disease with bone marrow infiltration and death by cytopenia. Candidate solutions investigated were (i) Dec + thymidine, or HU, or methotrexate, to increase DCK (by inhibition of ribonucleotide reductase [RNR]); (ii) 5Aza or Dec at lower dose to decrease Cmax and avoid cytotoxicity + tetrahydrouridine (THU) to increase plasma t½/Tmax for DNMT1-depletion (THU inhibits the enzyme cytidine deaminase that rapidly inactivates 5Aza and Dec in vivo); (iii) 5Aza alternating or combined with Dec, since 5Aza-mediated increases in DCK are expected to increase sensitivity to Dec, while Dec-mediated increases in UCK2 are expected to increase sensitivity to 5Aza; Of these interventions, reduced dosage 5Aza or Dec + THU, and alternating THU-5Aza with THU-Dec, but not simultaneous THU-5Aza+THU-Dec, nor the RNR inhibitors, increased response and survival to striking extents (approaching 1 year)(Fig. 2). Bone marrow gH2AX and DNMT1-expression by flow-cytometry and preservation of murine hematopoiesis confirmed the non-cytotoxic, epigenetic mechanism of action (Fig. 2). We show that straightforward shifts in pyrimidine metabolism demonstrably account for much of the resistance to 5Aza or Dec. Fortunately, such resistance is amenable to logical, non-toxic, clinically applicable solutions, validated in pre-clinical in vivo models. Clinical trials of non-cytotoxic THU-Dec (IND#112914) and alternating THU-Dec/THU-5Aza, incorporating companion PD/metabolism biomarkers, are planned. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Saunthararajah:Not applicable: Other: patent applications around decitabine, 5-azacytidine and tetrahydrouridine. Off Label Use: decitabine used by route of administration and dosages other than FDA approved regimens.
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages