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  • 1
    Online Resource
    Online Resource
    Implications of Saline Water Irrigation for Linseed on Seed Germination, Seedling Survival and Growth Potential
    ResearchersLinks Ltd ; 2019
    In:  Sarhad Journal of Agriculture Vol. 35, No. 4 ( 2019)
    Details
    In: Sarhad Journal of Agriculture, ResearchersLinks Ltd, Vol. 35, No. 4 ( 2019)
    Type of Medium: Online Resource
    ISSN: 1016-4383
    URL: Article
    DOI: 10.17582/journal.sja/2019/35.4.1289.1297
    Language: Unknown
    Publisher: ResearchersLinks Ltd
    Publication Date: 2019
    detail.hit.zdb_id: 3054075-6
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  • 2
    Online Resource
    Online Resource
    Haploidentical Transplantation For Patients With Advanced Hematologic Malignancies With Melphalan-Based Conditioning – Interim Results From a Phase II Clinical Trial
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4523-4523
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4523-4523
    Abstract: T-cell replete haploidentical stem cell transplantation (HaploSCT) using post-transplant cyclophosphamide (PTCY) has been performed primarily with using non-myeloablative conditioning. This approach has been associated with very low non-relapse mortality (NRM); however, a high relapse rate was noted for pts in remission, suggesting that a more intense conditioning could be used to decrease rate of relapse post-transplant. We explored a myeloablative yet reduced-intensity melphalan-based conditioning regimen in an ongoing phase II clinical trial. Patients and Methods Results from the first 57 patients (pts) with advanced hematologic malignancies between 03/2009 and 4/2013 are reported. All pts received a melphalan-based conditioning regimen using fludarabine 160mg/m2, melphalan 140mg/m2 (N=35) or 100mg/m2 (N=22) +/- thiotepa 5-10mg/kg. GVHD prophylaxis was with post transplant cyclophosphamide 50 mg/kg on days +3 and +4 followed by tacrolimus and mycophenolate, for at least 6 and 3 mo post-transplant, respectively. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method and group differences were determined using the log-rank test. Cumulative incidence (CI) of relapse, GVHD, and non-relapse mortality (NRM) were assessed using the competing risks method, where the competing risk for CIR was death, for NRM was relapse, and for GVHD was death and relapse. Group differences were determined using Gray's test. Results 34 (60%) pts were males and the median age was 47 years (range 21-66). Diagnoses were AML/MDS 28 (49.1%), CML 7 (12.3%), ALL 7 (12.3%), and lymphoma/CLL 10 (3 Hodgkin's, 3 NHL, 4 CLL) (17.5%), myelofibrosis/AML 4 (7%) and myeloma 1 pts. Racial distribution was: 18 (31.6%) African-Americans, 16 (28%) Caucasians, 12 (21%) Hispanics, 4 (7%) Asians, 7 (12.3%) Middle-Eastern. All patients except 2 (96.5%) had a bone marrow graft. 20/28 (71.4%) pts with AML/MDS were in complete remission (CR) at transplant (CR1+CR2) and 15/28 pts with AML had poor-risk by cytogenetics (N=12) or FLT3 mutation (N=3). All ALL pts had disease beyond CR1 except 1; 7/10 (70%) lymphoma/CLL pts had advanced disease. All patients with myelofibrosis have progressed to AML. Donors were children (N=26, 46.5%), siblings (N=23, 40.3%), parents (N=7, 12.3%), cousin (N=1), with 3-5 HLA antigen mismatches. The median follow-up of survivors was 14 mo (range: 1.0-48.4 months). One patient had early death due to RSV infection. Primary engraftment was achieved in 54/56 (96.5%) of evaluable patients, with majority (N=51, 90%) achieving full donor chimerism. Of the 6 who had mixed chimerism, 2 relapsed and 4 pts converted to full chimerism. Median time to neutrophil engraftment was 18 days (range 11-43). The CI of gr 2-4 aGVHD and 3-4 aGVHD were 29.7% and 3.7%, respectively, while CI of cGVHD limited+extensive and extensive only were 23.7% and 11.5%. Overall, the NRM was 21.4%, CI of relapse was 25.8% and PFS was 52.8% at the last follow-up (Figure 1A). NRM for myeloid pts transplanted in remission was 9% and PFS 66.8% at 50 mo median follow-up (Table 1, Figure 1B). Conclusions Melphalan-based conditioning for HaploSCT offers good disease control with acceptable NRM for patients in remission at transplant. A low relapse rate was observed in lymphoma/CLL patients despite the fact that most patients were not in remission at transplant. Overall, patients with advanced disease remain a challenge due to higher relapse rate and novel strategies are needed to significantly improve outcomes of these patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4523.4523
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 4533-4533
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4533-4533
    Abstract: Abstract 4533 Purpose: The role of autologous stem-cell transplantation (auto-HCT) in Waldenström macroglobulinemia (WM) is not clearly defined. The aim of this study was to analyze the results of auto–HCT in patients with WM and to determine the prognostic factors that have a significant impact on outcome. Patients and Methods: We analyzed 16 adult patients (10 males and 6 females) with WM who underwent high-dose chemotherapy and auto–HCT at MDACC between 1/89 and 2/11. Median age at diagnosis was 55 years (range 43–74) and median age at auto-HCT was 55.5 years (range 43–75). Concurrent AL amyloidosis was seen in 6 patients (37%). Median interval from diagnosis to time of progression was 3.1 years (range 0.4– 9.5) and patients had received a median of 2 lines of therapy (range: 1–6) prior to auto-HCT. Seven patients (44%) had either primary refractory disease or were in first remission, while 9 patients (56%) had relapsed disease. Median follow-up in the surviving patients was 3.5 years (range, 1.1– 12.2). Preparative regimens were as follows: 9 patients received Melphalan alone; 2 received Melphalan + Rituximab; 1 underwent Melphalan + total body irradiation (TBI); 2 received Thiotepa + Busulfan + Cyclophosphamide; and 2 received BCNU + Etoposide + Cytarabine + Melphalan + Rituximab (BEAM-R). Results: Non-relapse mortality was 6.2% at 1 year. All 15 evaluable patients achieved engraftment with a median time to neutrophil engraftment of 11 days (10–46). Fourteen patients were eligible for response evaluation. One patient died within 30 days and one was lost to follow up. Three (21%) patients achieved a CR, while 9 (64%) achieved a PR. The overall response rate was 85%. Progression-free survival (PFS) and overall survival (OS) at 5 years were 36.7% and 56.4%, respectively. Median PFS and OS from auto-HCT were 2.5 and 8.3 years, respectively. The median OS from diagnosis was 12.3 years. On univariate analyses, disease status at auto-HCT (first remission or primary refractory disease) was the strongest predictor of progression (p=0.05; HR 0.1, 95% CI 0.01–1.04), PFS (p=0.01, HR 0.1, CI: 0.01–0.6) and OS (p=0.01). Similarly, the melphalan-based regimens were associated with a longer OS in patients with relapsed disease at auto-HCT (p=0.002). On univariate analyses, LDH level at auto-HCT, number of prior chemotherapy regimens, use of prior cladribine, concurrent AL amyloidosis or International Staging System score (ISSWM) did not have a significant impact on the outcome. Conclusion: Auto-HCT is a feasible procedure in patients with advanced WM, even when performed later in the course of disease, after a median of 2 lines of therapy. Patients with relapsed disease at auto-HCT have a significantly worse outcome and may require posttransplant therapy. Disclosures: Shah: Celgene: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.4533.4533
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 4
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    Treatment of FLT3-ITD Positive AML Relapsing After Allogeneic Hematopoietic Stem Cell Transplant (HSCT) with Sorafenib.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3471-3471
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3471-3471
    Abstract: Abstract 3471 AML with the internal tandem duplication of the Fms-Like Tyrosine kinase-3 gene (FLT3-ITD) has a poor prognosis, with high relapse rates. Sorafenib is an oral multikinase inhibitor of tyrosine kinases including Flt-3 with activity in AML. We used this drug to treat patients relapsing after allogeneic HSCT and herein present the results. Patients and Methods. We retrospectively evaluated 16 patients with FLT3-ITD AML that received sorafenib for at least a 7-day course either alone (n=8; 50%) or in combination (n=8; 50%) to treat AML relapsing at a median of 3 months (range, 1–7) after HSCT. Median age was 34 years (range, 20–603). Cytogenetics was diploid in 69%, high-risk in 19% and unknown in 12%. Treatment history prior to HSCT included sorafenib in 38% of the cases, and 30% were status post a 2nd HSCT. Donors were related (50%) or unrelated (50%). Seven patients (44%) received and failed other salvage chemotherapy prior to starting sorafenib (median=2 treatments; range, 1–5). At start of sorafenib salvage treatment, median WBC was 22.5 K/mm3 (range, 0.6–119), and median bone marrow blast was 58% (range, 12–88%), while 75% of the patients had circulating blasts. Sorafenib doses were as follows: 400 mg (n=3) or 800 mg daily (n=4) in combination to idarubicin/Ara-C, or 800 mg daily with 5-azacitidine (n=1); single agent: 800 mg (n=6) or 1200 mg (n=2) daily. Median duration of sorafenib single agent therapy was 39.5 days (range, 10–100), and in combination it was 7 days (range, 7–32). Complete remission (CR) rate was zero; 2 patients achieved a PR. Median reduction in bone marrow (n=9) and peripheral blood (n=12) blasts was 0% (range, 0–46), and 50% (range, 0–88), respectively. Two patients were ‘bridged’ to a 2nd HSCT, which led to CR durations of 53 and 106 days. Median survival after sorafenib initiation was 81 days and it was similar with single agent versus combination therapy (Figure 1 and 2). All patients have died. Conclusions. Treatment of overt AML relapse with sorafenib was unsuccessful as described here. It is possible that ‘pre-emptive’ treatment in the presence of minimal residual disease will be more effective, but this remains to be proven. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3471.3471
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
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  • 5
    Online Resource
    Online Resource
    Eltrombopag for Post-Transplant Thrombocytopenia: Results of Phase II Randomized Double Blind Placebo Controlled Trial
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 738-738
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 738-738
    Abstract: Background: Delayed platelet recovery and secondary thrombocytopenia, defined as a drop in platelet count not due to disease relapse after initial platelet recovery, occur in 5-25% of patients after hematopoietic cell transplantation (HCT) and indicate adverse prognosis. Platelet transfusion to prevent bleeding remains a mainstay of therapy and role of thrombopoietic agents is not known. Eltrombopag, a non-peptide small molecule, thrombopoietin receptor agonist, is licensed for use in refractory ITP and aplastic anemia. In this phase II randomized double blind placebo controlled study, we investigated the safety and efficacy of eltrombopag for post HCT thrombocytopenia. Methods: Patients 35 days or more after HCT were eligible for the study if they had 1) platelet count ≤ 20 x 109/l sustained for 7 days or if they were platelet transfusion dependent, and 2) neutrophil count ≥ 1.5 x 109/l with or without G-CSF in the previous 7 days. Patients were excluded if they had abnormal liver function tests (ALT ≥ 2.5 ULN, or Bilirubin 〉 2mg/dl) or had prior venous thrombosis. Patients were randomized to receive placebo or eltrombopag using a Bayesian adaptive algorithm in which the probability of randomization to each arm was based upon the ongoing response rate. Eltrombopag was started at a dose of 50mgs and escalated every 2 weeks to 75mgs, 125 mgs and 150mgs if platelet count was 〈 50 x 109/l. The primary endpoint was platelet count at end of the treatment (8 weeks). A patient was considered responsive if platelet count was ≥ 30 x 109/l. The primary endpoint was evaluated by calculating the Bayesian posterior probability in each arm that the response rate was higher than the other arm. A Beta (0.4, 1.6) prior distribution was assumed for each arm. Given the observed study data, the probability of response in each arm was calculated and the probability that Eltrombopag is superior was computed. Results: Sixty patients were randomized to eltrombopag (n=42) or placebo (n=18) and received at least one dose of drug. 7 patients had an autograft and 53 patients had an allograft. Donor was related for 22 and unrelated for 31 patients. Stem cell source was peripheral blood in 36 patients, bone marrow in 23 patients and cord blood in 1 patient. There were no significant differences in patient characteristics between the 2 treatment arms. The probability that the response rate in the Eltrombopag arm is superior to the response rate in the placebo arm was 0.75, given the observed data. The protocol required this probability to be 〉 0.975 to declare a winner; thus, the results are inconclusive. Fifteen (36%) of patients in eltrombopag arm responded compared to 5 (28%) of patients in placebo arm. A 95% credible interval for response in the Eltrombopag arm is 22% to 50%, and a 95% credible interval for response in the placebo arm is 11% to 48%. 37 patients completed all 8 weeks of therapy; however, all patients (n=60) who received at least one dose of study treatment were included in the intention to treat evaluation of this endpoint. A secondary objective was to compare proportion of patients achieving a platelet count ≥ 50 x 109/l. Response rate was higher in the eltrombopag arm for this endpoint as well: 9 (21.4%) patients achieved success compared with 0 (0%) patients in the placebo arm (p=0.0466; Fisher's exact test). OS, PFS, relapse rate, and non-relapse mortality were similar in two arms. Conclusion: Eltrombopag improves platelet count in patients with post-transplant thrombocytopenia. Disclosures Kim: Eli Lilly: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bayer: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.738.738
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4569-4569
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4569-4569
    Abstract: Abstract 4569 Background: Allogeneic hematopoietic cell transplantation (allo HCT) is a potentially curative therapy for multiple myeloma (MM), but has high treatment-mortality (TRM). In addition, disease relapse occurs in a significant number of patients. We sought to evaluate if the recent advances in the field of HCT and MM have impacted the results of allo HCT for MM. We present the results of allo HCT performed at a single center over last 25 years. Methods: 149 patients with MM who underwent allo HCT between 11/1985 and 6/2010 using myeloablative (MA) N= 52, or reduced intensity conditioning (RIC) N=97 at our institution were retrospectively analyzed. Results: Patient characteristics and pertinent outcomes are summarized in the Table. 62 (42%) were female. Median age was 50 (28-70) years. Median follow up is 2.4 years [11.3 years for the patients who received allo HCT prior to year 2000( 〈 2000); 2 years for the patients who received allo HCT in the year 2000 and onwards (≥2000)]. TRM at 2 year was 37%. TRM was significantly lower for year ≥2000, recipients of RIC regimens, recipients of peripheral blood stem cells (HPC-A), and disease status at transplant PR or better. There was no difference between TRM for patients above or below age 50 years (p 0.08). Grade II-IV acute and limited or extensive chronic graft-versus host disease was seen in 31%, and 37% patients, respectively. Progression free survival (PFS) at 2 year and 5 year was 23% (95% CI: 16–30) and 15% (95% CI: 9–21), respectively. Overall survival (OS) at 2 year and 5 year was 40% (95% CI: 32–48) and 21% (95% CI: 13–29), respectively. At the time of last follow up 40 patients are still alive and 28 are in remissionn, longest for 166 months. On univariate analysis the OS was significantly better for year ≥2000 versus year 〈 2000; recipients of HPC-A versus HPC-M; primary responsive disease versus relapse or primary refractory disease at HCT; disease status at HCT PR or better; and patients without poor risk cytogenetic features at diagnosis. OS was longer in patients who received maintenance therapy post allo HCT (N=12) versus the patients who did not, although it did not reach statistical significance (2.9 years versus 8.4 months; p 0.06). Conclusion: Allo HCT for MM can offer long term disease control in a subset of MM patients. TRM has declined and outcomes have significantly improved over the last decade. Maintenance therapy may have a role post allo HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Qazilbash:Celgene: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4569.4569
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
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  • 7
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    Influence of Overlapping Genetic Abnormalities on Treatment Outcomes of Multiple Myeloma
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 3314-3314
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3314-3314
    Abstract: Introduction Numerous genetic abnormalities (including chromosomal translocations, deletions or amplifications, mutations) affect treatment outcomes in multiple myeloma (MM) and explain the heterogeneity in prognosis of MM patients with similar disease and host factors. Hyperdiploidy is associated with favorable outcomes, in contrast to del 17p, del 13, t(4;14), and gain of 1q2, which are associated with unfavorable outcomes. There is conflicting data about the role of overlap in cytogenetic and molecular abnormalities and their impact on prognosis. We sought from our study to determine the influence of overlapping genetic abnormalities in MM patients who received frontline autologous stem cell transplantation (ASCT) consolidation therapy. Methods Between January 2009 and January 2016, we included all consecutive newly diagnosed MM patients who underwent frontline ASCT at The University of Texas MD Anderson Cancer Center. All adult patients (≥18 years) who received high-dose melphalan conditioning regimen and had available conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) studies at diagnosis were eligible. Patients with primary refractory and relapsed disease were excluded. Hyperdiploidy was defined as any extra copy of one or more of the odd chromosomes. High-risk genetic abnormalities are defined presence of del 17p, del 13, t(4;14), and/or 1q21 gain (detected by FISH and/or conventional cytogenetics). Primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Survival estimates were calculated by Kaplan-Meir method, and Cox proportional hazards regression analysis was used to assess the predictors of PFS on univariate and multivariate analysis. Results A total of 494 patients (57% males, 43% females) with a median age of 61 years (range, 33-80) were eligible and included in final analysis. 154 patients (31%) were identified to have any hyperdiploidy and 189 patients (38%) to have any high-risk abnormality. A total of 84 patients (17%) had hyperdiploidy without any high-risk feature and 121 patients (25%) had a high-risk cytogenetic abnormality without hyperdiploidy. With a median follow up of 27 months (range, 1-76) the 2-year PFS and OS of all study group were 71% and 90%, respectively. Among patients with any hyperdiploidy, the 2-year PFS and OS were 72% and 92%. In contrast, for patients with any high-risk genetic feature, the 2-year PFS and OS were 56%and 81%. Acquisition of any high-risk genetic abnormality, age 〉 55 years, and international staging system (ISS) stage III were associated with worse PFS in univariate analysis. Further stratification of patients according to overlapping genetic abnormalities showed that the co-existence of hyperdiploidy with any high-risk genetic abnormalities was associated with significantly worse PFS compared to hyperdiploidy without co-exisiting genetic abnormalities (2-year PFS 59% vs 80%, HR 2.9, p=0.003) (Figure). PFS in patients with co-existing hyperdiploidy and high-risk genetic abnormalities was comparable to that in patients with high-risk genetic abnormalities without hyperdiploidy (59% vs. 55%, HR 0.9, 95%CI: 0.6-1.7; p=0.9) (Figure). The effect of high-risk abnormalities on PFS persisted on multivariate analysis, and was reflected on OS as well (Figure). Conclusions Our findings confirm that the co-existence of hyperdiploidy and high-risk genetic features does not abrogate the poor prognosis of MM patients with associated high-risk genetic abnormalities at diagnosis. Patients with hyperdiploidy and high-risk genetic abnormalities have similar outcomes to high-risk MM patients without hyperdiploidy, and should be considered as high-risk patients to guide future risk-adaptive treatment prospective clinical trials. Figure Figure. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.3314.3314
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 8
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    Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 33-33
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 33-33
    Abstract: Background: Induction therapy prior to consolidation with autologous stem cell transplantation (ASCT) continues to improve with the use of proteasome inhibitors and imids and combination regimens such as RVD. Bortezomib-based induction therapy has improved overall response rates (ORR) prior to transplant, which has translated to improvements in ORR and progression free survival post ASCT. However, complete remission (CR) rates with RVD remain low (10-15%) after 4 cycles of induction therapy. Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib/dexamethasone, has demonstrated a significant improvement in depth of response and progression free survival in patients (pts) with relapsed myeloma as seen in PANORMA I. Preclinical data demonstrate synergy between the combination of bortezomib and panobinostat. We undertook a phase I/Ib trial in pts with newly diagnosed myeloma (NDMM) of RVD + Panobinostat to establish the safety of the combination and goal of improving the depth of response with induction therapy prior to ASCT. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and safety/tolerability of RVD + panobinostat in NDMM. Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival. Pts had to have NDMM with indication for therapy, candidates for ASCT with and had adequate organ function. Panobinostat was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m2 was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle. Dose-escalation of panobinostat used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Three dose levels were studied with Panobinostat escalated from 10 to 20 mg. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: 22 pts were enrolled; 12 pts in the completed phase 1 dose escalation portion of the study and 10/20 in the ongoing dose expansion. The median age was 61 (range 53-79); ISS stage I 12; stage II 7/20; stage III in 3/20 pts. No DLTs were observed in 3 pts dosed in cohort 1, with Panobinostat at 10 mg. In cohort 2, panobinostat was dosed at 15 mg, 2/6 pts encountered a DLT. One patient experienced Grade 4 (G4) thrombocytopenia, and the second patient had G3 diarrhea without supportive measures, for 〈 12 hours and resolved with supportive measures. In cohort 1, 3 additional patients were enrolled and no DLTs were encountered in the remaining 3 pts. The final recommended dose was Panobinostat 10 mg in combination with RVD in NDMM. Treatment emergent SAEs related to therapy observed in 5 pts with 2 incidences of G3 diarrhea; 2 pts with atrial fibrillation; and other events included G4 thrombocytopenia; G3 bacteremia, G3 cellulitis, G3 myocardial infarction (MI), G3 pulmonary emboli; G3 pneumonia. Hematologic adverse events G3/4 included anemia 3/22; neutropenia 4/22; thrombocytopenia 7/22. G3/4 nonhematologic toxicities included ALT elevation (n=2); AST elevation (n=1); constipation (n=2); diarrhea (n=2); fatigue/muscle weakness (n=2); MI (n=1); pneumonia (n=3). Among 18/22 pts who have completed 4 cycles of therapy and are evaluable for efficacy, the ORR (≥PR) was 100%: including nCR/CR in 5/18 (28%), VGPR in 5/18 (28%), PR in 8/18 (44%). Conclusions: MTD has been established at level 1, with panobinostat 10 mg and full dose RVD in NDMM. The DLTs were diarrhea (irrespective of supportive care) and thrombocytopenia. This is the first experience with panobinostat and subcutaneous bortezomib and first experience in combination with RVD. The combination is well tolerated with limited toxicity and side effects can be managed with supportive care. The preliminary activity after 4 cycles of therapy demonstrated a high ORR of 100% and a promising depth of response with a nCR/CR of 27%. Enrollment in a dose expansion cohort is near completion and full data will be presented at ASH. Disclosures Shah: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Weber:OncPep: Research Funding. Thomas:Novartis, Celgene, Millenium, Idera Pharmaceuticals: Consultancy, Research Funding. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.33.33
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 9
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    EBMT Risk Score for Pre Transplant Risk Assessment in Patients with Multiple Myeloma.
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3094-3094
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    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3094-3094
    Abstract: Abstract 3094 Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for patients with multiple myeloma (MM) but its use is limited by high non-relapse mortality (NRM). European Group for Bone Marrow transplant (EBMT) risk score is a validated predictor of outcome for patients undergoing allo-HCT for hematological malignancies. It takes into consideration patient's age, donor's gender and type, disease status and the interval from diagnosis to allo-HCT, with the score ranging from 0 to 7. We assessed the impact of EBMT risk score in MM patients undergoing allo-HCT. Methods: A total of 189 patients with MM who underwent HSCT between November 1985 and June 2010 at MD Anderson Cancer Center were included in the analysis. Results: Patient characteristics are summarized in Table 1. There were 110 males (58%) and 79 females (42%) with a mean age of 50 years (range 28–70). Donors were related in 146 patients (HLA-identical=131, 1 antigen mismatched (AGMM) = 5, 2 AGMM =1, 3AGMM=1, syngeneic=8) and unrelated in 43 patients (HLA identical= 37, 1AGMM=4, 2AGMM=1, unknown=1). One-hundred and twelve patients had prior autologous transplants (auto-HCT). Of these 83 had 1, 28 had 2 and 1 had 3 prior auto-HCT, respectively. Median time from diagnosis to allo-HCT was 24.7 months (range 3.3–232) and median overall follow up was 13 months (0.2–266). Overall 94 patients (49%) had progressed before last follow-up. Incidence of all-cause mortality was 138 (73.4%) with 69 (36%) of all deaths attributed to NRM. KM estimates of 2-year PFS and OS were 25% and 42%, and 5-year PFS and OS were 16% and 27%, respectively. Cumulative incidence (CI) of grade 2–4 and grade 3–4 acute graft versus host disease (aGVHD) was 33% and 13%, respectively. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 47% and 17%, respectively. EBMT risk score was, 0–3 for 41 (21.7%), 4 for 72 (38.1%) 4 and 5–7 for 76 (40.2%) patients. EBMT risk score was higher for males, African-Americans and older allo-HCT recipients, patients with higher LDH levels ( 〉 618mg/dl), ß2-microglobulin 〉 3.5mg/dl and patients with bone marrow plasmacytosis. Median PFS in patients with EBMT scores 0–3, 4 and 5–7 were 10.1, 8.4 and 6.4 months, respectively (P=0.0036). Median OS in patients with EBMT scores 0–3, 4 and 5–7 were 39, 15.8 and 9.6 months, respectively (p=0.001). Cumulative NRM in patients with EBMT scores 0–3, 4 and 5–7 were 37% (15/41), 36.1% (26/72) and 37.3% (28/75), respectively (p= 0.234). Cumulative incidence of progression in patients with EBMT scores 0–3, 4 and 5–7 were 36.5% (15/41), 50% (36/72) and 56.5% (43/76), p=0.119. Compared to those with EBMT risk score (0–3), individuals with EBMT risk scores 〉 5 had a higher risk of all-cause mortality (HR 2.34, 95% CI 1.44–3.80), and disease progression (HR 3.06, 95% CI 1.67–5.61). Addition of ß2-microglobulin, BM plasma cells or prior response status alone or in combination with EBMT risk score significantly improved the discrimination properties of the model containing EBMT score alone (p 〈 0.05). Conclusions: EBMT risk score is an independent predictor of survival in MM patients undergoing allo-HCT. Addition of myeloma-specific factors predictors (ß2-microglobulin, plasma cell infiltration and prior response status) to EBMT score significantly improves its prognostic impact. Disclosures: Giralt: Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3094.3094
    RVK:
    XA 33000
    RVK:
    XA 10000
    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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    Transplant Outcomes of 9/10 HLA Matched Unrelated Donors (MUD) Treated with Post-Transplant Cyclophosphamide for Prevention of Graft Versus Host Disease
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2486-2486
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2486-2486
    Abstract: Background: Graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (ASCT). The incidence of GVHD with conventional GVHD prevention is higher with HLA mismatched compared to matched donors, with 69% of patients (pts) developing grade 2-4 and 16% grade 3-4 acute (aGVHD) and more than half the pts developing chronic (cGVHD), as previously reported by us(Ciurea SO abstract ASH 2010). Here we report preliminary results of 9/10 MUD transplant pts receiving GVHD prophylaxis with post-transplantation cyclophosphamide (PTCY), in addition to tacrolimus and mycophanolate mofetil (MMF). Methods: Patients were treated prospectively using a 9/10 MUD on a separate arm of a phase II clinical trial (2009-0266). Conditioning regimen consisted of Melphalan 140 mg/m2 on day −8 (100mg/m2 for pts ≥55 years or with comorbidities), Thiotepa 5-10 mg/kg on day −7 and Fludarabine 40 mg/m2/day on days −6, −5, −4, and −3. All patients received T-cell replete bone marrow graft. GVHD prophylaxis included PTCY 50mg/kg on days +3 and +4, MMF was given until day 100 and Tacrolimus until day 180 if no GVHD. Primary objectives were to determine the incidence of acute and chronic GVHD and non-relapse mortality (NRM), while secondary objectives included progression free survival (PFS) and overall survival (OS). Results: 39 patients with median age of 50 years (range 20-64) received a 9/10 MUD with PTCY GVHD prophylaxis. 20 patients (51%) were women and AML/MDS was the most common indication for transplantation in 13(33%), NHL 8(21%), ALL 7(18%), AA in 4(10%) and CLL, CML/MPD, HL and MM constituted rest of the patients. Poor, intermediate and low risk cytogenetics were seen in 6, 8 and 4 patients with leukemia, respectively. 22 patients (56%) were not in complete remission at the time of transplantation. Median follow-up time for survivors was 35.9 months (range: 2.6–123.5). All patients engrafted the donor cells. Day 100 NRM for all pts was 18%.The cumulative incidence (CI) of grade II-IV aGVHD and gr III-IV aGVHD was 42% and 17%, respectively. CI of all cGVHD was only 20% and extensive only cGVHD was 13%. NRM for all pts was 36% at 1 year and 40% at 3 years. OS for all pts at 1 and 3 yr was 57% and 44%, while PFS at 1 and 3 yr was 43% and 39%, respectively. Conclusions: Post-transplant cyclophosphamide for prevention of GVHD which has been successfully used in haploidentical transplantation, resulted in a modest improvement in the rates of grade 2-3 and 3-4 acute GVHD compared to reports of standard GVHD prophylaxis for 9/10 MUD transplants. However, a promising low rate of chronic GVHD was observed. This approach can produce durable remissions for patients with hematologic malignancies who lack an HLA matched donor. Figure 1 Figure 1. Disclosures Andersson: Otsuka Pharmeceuticals: Research Funding, Research funding from Otsuka Pharmeceuticals Other.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2486.2486
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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