Ronald Sobecks

Cleveland Clinic, Cleveland, Ohio, United States

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Publications (123)363.35 Total impact

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    ABSTRACT: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced-intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA-identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA +MTX. Patients receiving MMF+CSA had rapid neutrophil (median 11 versus 19 days with MTX+CSA), and platelet recovery (median 19 versus 25 days), lower incidence of severe mucositis by OMAS (19% versus 53%), and shorter length of hospital stay (median 25 versus 36 days) (p<0.001 for all comparisons). There were no significant differences in incidence of grade 2-4 (MMF+CSA 37% versus MTX+CSA 39%) or 3-4 acute GVHD (17% versus 12%), chronic GVHD (46% versus 56%), relapse (28% versus 27%), non-relapse mortality (20% versus 27%) or overall survival (47% versus 44%) (p=NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3-4 acute GVHD (HR 2.92, 95% CI 1.2-7.15, p=0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed.
    American Journal of Hematology 10/2014; · 4.00 Impact Factor
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    ABSTRACT: Vancomycin-resistant enterococcus (VRE) is a well-known infectious complication among immunocompromised patients. We performed a retrospective analysis to identify risk factors for the development of VRE bacteremia (VRE-B) within 15 months after allogeneic hematopoietic cell transplantation (alloHCT) and to determine its prognostic importance for other post-transplant outcomes. Eight hundred consecutive adult patients who underwent alloHCT for hematologic diseases from 1997 to 2011 were included. Seventy-six (10%) developed VRE-B at a median of 46 days post transplant. Year of transplant, higher HCT comorbidity score, a diagnosis of ALL, unrelated donor and umbilical cord blood donor were all significant risk factors on multivariable analysis for the development of VRE-B. Sixty-seven (88%) died within a median of 1.1 months after VRE-B, but only four (6%) of these deaths were attributable to VRE. VRE-B was significantly associated with worse OS (hazard ratio 4.28, 95% confidence interval 3.23-5.66, P<0.001) in multivariable analysis. We conclude that the incidence of VRE-B after alloHCT has increased over time and is highly associated with mortality, although not usually attributable to VRE infection. Rather than being the cause, this may be a marker for a complicated post-transplant course. Strategies to further enhance immune reconstitution post transplant and strict adherence to infection prevention measures are warranted.Bone Marrow Transplantation advance online publication, 11 August 2014; doi:10.1038/bmt.2014.150.
    Bone marrow transplantation. 08/2014;
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    ABSTRACT: Hematopoietic cell transplantation (HCT) has become an established standard of care for many older patients with hematologic malignancies. The effect of transplantation on the quality of life (QOL) of older patients, however, has not been well studied. We thus analyzed QOL in patients ⩾60 undergoing an allogeneic HCT compared with patients <60 years. Prospective psychometric instruments were administered to 351 patients who underwent HCT from 2003 to 2010. Psychometric data were assessed longitudinally by validated questionnaires: Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), Coping Inventory and the Profile of Mood State-Short Form. Patients ⩾60 reported better social (P=0.006) and functional well-being (P=0.05) with FACT assessment, and had better total scores, (P=0.043) across all time points. When adjusted for baseline QOL scores as a covariate, social well-being remained significantly better, whereas the other scores became non-significant. With a median follow-up of 49 months, there were no significant differences in OS, relapse-free survival, relapse or chronic GVHD. This study provides further evidence that advanced age should not be a barrier in the decision to pursue allogeneic HCT. Older patients achieved comparable QOL when compared with younger patients.Bone Marrow Transplantation advance online publication, 28 July 2014; doi:10.1038/bmt.2014.166.
    Bone marrow transplantation. 07/2014;
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    ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2014; · 3.15 Impact Factor
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    ABSTRACT: In myeloid malignancies, genetic abnormalities in key apoptosis pathway genes (eg., p53) are associated with poor responses to conventional cytotoxic therapy. In pre-clinical models, non-cytotoxic, DNA methyltransferase 1 (DNMT1) depleting regimens of the deoxycytidine analogue decitabine relieve aberrant epigenetic repression of key late-differentiation genes and induce cell cycle exit by p53-independent differentiation pathways (CEBPE, MXD1, p27/CDKN1B) (Ng et al, Leukemia 2011). To translate these observations into practice, a clinical trial is being conducted in MDS, using decitabine at minimum doses required to deplete DNMT1 (0.1-0.2 mg/kg [5-10 mg/m2]), administered by the subcutaneous (SC) route to avoid high peak levels that cause apoptosis, and using a metronomic schedule (1-3X/week for ≥1y) to increase exposure time for S-phase specific depletion of DNMT1. To evaluate mechanism of action, correlative studies include quantification of pH2AX (DNA damage marker) and DNMT1 levels in bone marrow by flow-cytometry, and immunohistochemical evaluation by ImageQuant of p27/CDKN1B and KI67 expression, expected to vary directly and inversely respectively with terminal differentiation. A two-stage Simon design was used, and results from the first stage (n=15, patient characteristics table 1) are reported (median follow-up 330 days, range 142-180). Anti-emetics were not required, and there were no administration related adverse events. Neutropenic fever (NF) occurred in 11 patients, 7 of whom did not have NF prior to therapy (median time to nadir 40 days). By IWG criteria, complete hematologic and cytogenetic remissions (CR) with persistent dysplasia occurred in 2 subjects, hematologic improvement (HI) occurred in 4 subjects (overall response rate, ORR=40%), and stable disease in 7. Median response duration for HI/CR is 243 days, with 5 of 6 responses ongoing (range 74-292). Complete cytogenetic responses occurred even in patients with highly complex chromosome abnormalities (table 1). Bone marrow cell pH2AX expression decreased non-significantly from pre-treatment to week 6 to week 12 (median values 1.2, 0.5 and 0.4% respectively, p=0.27 Wilcoxon test), with a >3-fold reduction in mean percentage of cells expressing DNMT1 in the same period (Turkey-Kramer test p<0.001). Consistent with differentiation-mediated cell cycle exit, median p27/CDKN1B expression increased from 26.8 to 66.2 to 78.7% of bone marrow cells (p<0.001), with a concomitant decrease in median KI67 expression from 65.8 to 46.2 to 28.7% (p<0.001) (table 1). ORR of only 40% despite major p27 and cytogenetic responses and stable disease in almost all subjects (table 1), suggested that relief of cytopenia may require a threshold of normal stem cell reserve and a supportive marrow microenvironment. Accordingly, in HI/CR versus other subjects, median duration of disease was 855 versus 1350 days (p=0.15), and median pre-treatment bone marrow cellularity was 65 versus 30% (p=0.14). In conclusion, this study provides clinical proof of principle that a decitabine regimen rationalized for non-cytotoxic epigenetic-differentiation effects is active in myeloid malignancy, correlates with molecular markers of terminal differentiation, and has potentially important safety and efficacy advantages over cytotoxic therapy that warrant further evaluation and optimization. All subjects: baseline and response characteristics Refer to the abstract for statistics Disclosures: No relevant conflicts of interest to declare.
    ASH Annual Meeting Abstracts. 01/2014; 118:3830.
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    ABSTRACT: The clinical relevance of mismatches at the major histocompatibility complex class I-related chain A (MICA) in hematopoietic stem cell transplantation (HSCT) remains unclear. We investigated the association of MICA donor/recipient mismatch and whether there is an interaction between these and HLA-DPB1 mismatch on clinical outcomes following unrelated donor HSCT. Our study included 227 patients who underwent unrelated donor allogeneic HSCT at our institution between 2000 and 2010. Among these, 177 (78%) received HSCT from a 10/10 HLA-matched donor. MICA genotyping was performed using commercially available kits. In univariable analysis, the risk of grade II-IV acute GvHD was greater for patients with MICA mismatch (hazard ratio (HR) 1.73, p=0.02) than for HLA-DPB1 mismatch (HR 1.62, p=0.07). When MICA and HLA-DPB1 were assessed simultaneously, patients mismatched at both loci had the greatest risk (HR 2.51, p<0.01) and those mismatched at only one locus had somewhat greater risk (HR 1.53, p=0.12) than patients matched at both loci; this remained significant in multivariable analysis. 100-day incidence was 66%, 45%, and 31% (p=0.03). Results were similar for grade III-IV acute GvHD, with 100-day incidence 34%, 16%, and 8% (p=0.01). These results are clinically pertinent to donor selection strategies and indicate that patients with mismatch at both MICA and HLA-DPB1 are at increased risk for acute GvHD.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 01/2014;
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    ABSTRACT: An allogeneic hematopoietic cell transplant (HCT) from an HLA-identical donor after high-dose (myeloablative) pre-transplant conditioning, is an effective therapy for some people with chronic lymphocytic leukemia (CLL). Because CLL is a highly radiosensitive cancer, we hypothesized total body irradiation (TBI) conditioning regimens may be associated with better outcomes than those without TBI. To answer this we analyzed data from 180 subjects with CLL receiving myeloablative doses of TBI (N=126) or not (N=54), transplanted from an HLA-identical sibling donor, between 1995 and 2007 and reported to the Center for International Blood & Marrow Transplant Research (CIBMTR). At 5 years, treatment-related mortality was 48% (95% CI, 39-57%) vs. 50% (95% CI, 36-64%); p=NS. Relapse rates were 17% (95% CI, 11-25%) vs. 22% (95% CI, 11-35%); p=NS. Five-year progression-free survival and overall survival was 34% (95% CI, 26-43%) vs. 28% (95% CI, 15-42%); p=NS and 42% (95% CI, 33-51%) vs. 33% (95% CI, 19-48%); p=NS, respectively. The single most common cause of death in both cohorts was recurrent/progressive CLL. No variable tested in the multivariate analysis was found to significantly affect these outcomes including having failed fludarabine. Within the limitations of this study we found no difference in HLA-identical sibling transplant outcomes between myeloablative TBI and chemotherapy pre-transplant conditioning in persons with CLL.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; · 3.15 Impact Factor
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    ABSTRACT: A previous interim report of MM-011, the first study that combined lenalidomide with anthracycline-based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long-term outcomes of all 76 treated patients with follow-up ≥5 years. This single-center phase I/II study administered lenalidomide (10 mg on days 1-21 of every 28-day cycle), intravenous liposomal doxorubicin (40 mg/m(2) on day 8), dexamethasone (40 mg on days 8-11), and intravenous vincristine (2 mg on day 8). After 4-6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1-7); 49 (64.5%) patients had refractory disease. Forty-three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment-related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression-free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline-based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM. (ClinicalTrials.gov number, NCT00091624).
    American Journal of Hematology 11/2013; · 4.00 Impact Factor
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    ABSTRACT: Cytomegalovirus (CMV) is a common infection after myeloablative allogeneic hematopoietic stem cell transplant (M-alloHSCT). Achievement of complete donor T-cell chimerism (CDC-T) post transplant is a measure of immune reconstitution. We investigated the association between CDC-T post M-alloHSCT and the incidence of CMV viremia. We retrospectively reviewed all CMV and chimerism results of 47 patients for the first 6 months post M-alloHSCT. CDC-T was analyzed as a time-varying covariate for association with post M-alloHSCT CMV viremia. CMV viremia occurred in 15 (32%) and CDC-T was achieved in 38 (81%) recipients within the first 6 months post M-alloHSCT. On univariable analysis, increased CMV viremia was seen among patients with CDC-T (hazard ratio 2.81 [P = 0.07, 95% confidence interval = 0.93-8.52]). A 30-day landmark analysis showed that the incidence of CMV viremia at 6 months (regardless of recipient CMV serostatus) was 50% among those who had achieved CDC-T by day 30, and 23% among those who had not (P = 0.06). We conclude that shorter time to CDC-T may be associated with higher risk of CMV viremia. If confirmed in a larger cohort, this might be a marker for risk stratification in the management of CMV in this population.
    Transplant Infectious Disease 11/2013; · 1.98 Impact Factor
  • Bone marrow transplantation 06/2013; · 3.00 Impact Factor
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    ABSTRACT: Central line-associated blood stream infections (CLABSI) commonly complicate the care of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients following allogeneic stem cell transplantation (HCT). We developed a modified CLABSI (MCLABSI) definition which attempts to exclude pathogens usually acquired due to disruption of mucosal barriers during the vulnerable neutropenic period following HCT that are generally included under the original definition (OCLABSI). We conducted a retrospective study of all AML and MDS patients undergoing HCT between August 2009 and December 2011 at the Cleveland Clinic (n=73), identifying both OCLABSI and MCLABSI incidence. The median age at transplantation was 52 years (range, 16-70); 34 had a high (≥3) HCT comorbidity index (HCT-CI); 34 received bone marrow (BM), 24 received peripheral stem cells (PSC), and 15 received umbilical cord blood cells (UCB). Among these 73 patients, 23 (31.5%) developed OCLABSI, of whom 16 (69.6%) died, and 8 (11%) developed MCLABSI, of whom 7 (87.5%) died. OCLABSI was diagnosed a median of 9 days from HCT: 5 days (range, 2-12) for UCB and 78 days (range, 7-211) for BM/PSC (p<.001). MCLABSI occurred a median of 12 days from HCT, with similar earlier UCB and later BM/PSC diagnosis (p=.030). Risk factors for OCLABSI in univariate analysis included CBC (p<.001), HLA-mismatch (p=.005), low CD34+ count (p=.007), low total nucleated cell dose (p=.016), and non-Caucasian race (p=.017). Risk factors for OCLABSI in multivariable analysis were UCB (p<.001) and high HCT-CI (p=.002). There was a significant increase in mortality for both OCLABSI (HR 7.14, CI 3.31 - 15.37, p<.001) and MCLABSI (HR 6.44, CI 2.28-18.18, p<.001). CLABSI is common and associated with high mortality in AML and MDS patients undergoing HCT, especially in UCB recipients and those with high HCT-CI. We propose the MCLABSI definition to replace the OCLABSI definition given its greater precision for identifying preventable infection in HCT patients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2013; · 3.15 Impact Factor
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    ABSTRACT: Abstract 1696 The standard treatment concept and approach in MDS aims for apoptosis-induction in expanding malignant clones in the hope that this will permit recovery by functionally normal hematopoietic stem cells (HSC). This concept is fundamentally undermined, however, by frequent genetic deletion in MDS/AML cells of key apoptosis genes. Hence, therapy selects for relapse with the most apoptosis-resistant malignant subclones (e.g., p53-null) while destroying crucial normal HSC (which have intact apoptosis-pathways). Observations regarding biology of sustained proliferation (MYC activity) in MDS/AML suggested an alternative approach: key late-differentiation MYC-antagonist genes (e.g., CEBPE) are repressed epigenetically even though lineage-specifying transcription factors (TF) (e.g., CEBPA) that drive expression of these genes are highly expressed. The basis for this paradox has been exposed: MDS/AML associated genetic abnormalities (e.g., RUNX1 mutation) favor recruitment of corepressors (e.g., DNMT1) instead of coactivators to lineage-specifying TF, thereby repressing differentiation target genes. Thus, in pre-clinical MDS/AML models, depleting DNMT1 by non-cytotoxic methods triggers MYC-antagonist expression and irreversible cell cycle exit by p53/p16-independent differentiation pathways (CEBPE-p27). The same treatment spares normal HSC, which unlike AML stem cells, do not express high levels of lineage-specifying TF. To translate these observations, this NIH-supported clinical trial (NCT01165996) incorporated the following novelty: (i) Lower dose of the cytidine analogue decitabine (DAC, Eisai) than in any previous trials (3.5–7 mg/m2) since hemoglobinopathy clinical trials demonstrated that these low doses deplete DNMT1 in normal HSC without cytotoxicity/apoptosis; (ii) SC instead of IV administration to avoid high peak levels that cause apoptosis; (iii) Use of the lack of toxicity to administer drug frequently 1–3X/week, to catch more MDS cells in S-phase via greater exposure times and distribution than in previous MDS trials (FDA-approved schedules only treat MDS cells entering S-phase in the first few days of multi-week cycles); (iv) Scientific correlates to measure non-cytotoxic, epigenetic-differentiation mechanism of action. Sample size = 25 as planned, 10/25 (40%) were relapsed/refractory after 5-azacytidine and/or lenalidomide, median age = 72y (range 46–85y), median disease duration = 900d (range 60–4680d). Anti-emetics were not needed, and cytotoxic side-effects e.g., hair loss did not occur. Neutropenic fever (NF) occurred in 11 subjects (5 had NF and 8 had ANC<500 prior to therapy). There was one treatment-associated fatality from sepsis. Though non-cytotoxic, suppression of clonal hematopoiesis is intended: nadir preceded complete remission (CR) 4/25 (16%) or hematologic improvement (HI) 7/25 (28%) (CR + HI = 47%) and 10/25 stable disease (SD) (CR+HI+SD = 84%) (IWG criteria). In transfusion dependent patients durations of transfusion independence for platelets (n=5) were median 343d (range 186–707d), 3/5 ongoing; for RBC (n=10) median 399d (range 290–696d), 5/10 ongoing. Complete cytogenetic remissions (CyR) occurred in 6/12 (50%) and partial CyR in 2/12 (17%) (overall CyR = 67%). Consistent with a p53-independent mechanism, CyR occurred even in poor risk cytogenetics, and increasing DAC frequency salvaged loss of response. Higher marrow cellularity was the best predictor of CR/HI, and CyR was substantially higher than CR/HI, underscoring that despite efficacious clone suppression, marrow HSC reserve is crucial to relief of cytopenia. Non-cytotoxic epigenetic-differentiation mechanism was confirmed by marrow IHC and FCM measurement of DNMT1, g-H2AX, p27/CDKN1B, MYC, and KI67 (3rd party quantification). Differentiation therapy transformed the outlook for M3 AML. Not surprisingly, a worthy goal has been to extend this paradigm. Biology of sustained MYC activity in MDS/AML guided logical repurposing of DAC for non-cytotoxic differentiation therapy even in MDS/AML with complex cytogenetics. Tolerance permits ready application despite age or comorbidities. Treatment exposure time and surrogates of normal HSC reserve are more important predictors of CR/HI than disease-mutations, and some patients may require separate measures (e.g., cytokines) to boost normal HSC diminished by age and previous insults. Disclosures: Reu: Celgene: Research Funding. Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Saunthararajah: Cleveland Clinic Innovation: patent application for oral THU-decitabine., patent application for oral THU-decitabine. Patents & Royalties. Off Label Use: lower dose of decitabine, subcutaneous administration, metronomic administration. Footnotes * Asterisk with author names denotes non-ASH members.
    54th ASH Annual Meeting and Exposition, Atlanta, GA; 12/2012
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    ABSTRACT: The standard treatment concept and approach in MDS aims for apoptosis-induction in expanding malignant clones in the hope that this will permit recovery by functionally normal hematopoietic stem cells (HSC). This concept is fundamentally undermined, however, by frequent genetic deletion in MDS/AML cells of key apoptosis genes. Hence, therapy selects for relapse with the most apoptosis-resistant malignant subclones (e.g., p53-null) while destroying crucial normal HSC (which have intact apoptosis-pathways). Observations regarding biology of sustained proliferation (MYC activity) in MDS/AML suggested an alternative approach: key late-differentiation MYC-antagonist genes (e.g., CEBPE) are repressed epigenetically even though lineage-specifying transcription factors (TF) (e.g., CEBPA) that drive expression of these genes are highly expressed. The basis for this paradox has been exposed: MDS/AML associated genetic abnormalities (e.g., RUNX1 mutation) favor recruitment of corepressors (e.g., DNMT1) instead of coactivators to lineage-specifying TF, thereby repressing differentiation target genes. Thus, in pre-clinical MDS/AML models, depleting DNMT1 by non-cytotoxic methods triggers MYC-antagonist expression and irreversible cell cycle exit by p53/p16-independent differentiation pathways (CEBPE-p27). The same treatment spares normal HSC, which unlike AML stem cells, do not express high levels of lineage-specifying TF. To translate these observations, this NIH-supported clinical trial (NCT01165996) incorporated the following novelty: (i) Lower dose of the cytidine analogue decitabine (DAC, Eisai) than in any previous trials (3.5–7 mg/m2) since hemoglobinopathy clinical trials demonstrated that these low doses deplete DNMT1 in normal HSC without cytotoxicity/apoptosis; (ii) SC instead of IV administration to avoid high peak levels that cause apoptosis; (iii) Use of the lack of toxicity to administer drug frequently 1–3X/week, to catch more MDS cells in S-phase via greater exposure times and distribution than in previous MDS trials (FDA-approved schedules only treat MDS cells entering S-phase in the first few days of multi-week cycles); (iv) Scientific correlates to measure non-cytotoxic, epigenetic-differentiation mechanism of action. Sample size = 25 as planned, 10/25 (40%) were relapsed/refractory after 5-azacytidine and/or lenalidomide, median age = 72y (range 46–85y), median disease duration = 900d (range 60–4680d). Anti-emetics were not needed, and cytotoxic side-effects e.g., hair loss did not occur. Neutropenic fever (NF) occurred in 11 subjects (5 had NF and 8 had ANC<500 prior to therapy). There was one treatment-associated fatality from sepsis. Though non-cytotoxic, suppression of clonal hematopoiesis is intended: nadir preceded complete remission (CR) 4/25 (16%) or hematologic improvement (HI) 7/25 (28%) (CR + HI = 47%) and 10/25 stable disease (SD) (CR+HI+SD = 84%) (IWG criteria). In transfusion dependent patients durations of transfusion independence for platelets (n=5) were median 343d (range 186–707d), 3/5 ongoing; for RBC (n=10) median 399d (range 290–696d), 5/10 ongoing. Complete cytogenetic remissions (CyR) occurred in 6/12 (50%) and partial CyR in 2/12 (17%) (overall CyR = 67%). Consistent with a p53-independent mechanism, CyR occurred even in poor risk cytogenetics, and increasing DAC frequency salvaged loss of response. Higher marrow cellularity was the best predictor of CR/HI, and CyR was substantially higher than CR/HI, underscoring that despite efficacious clone suppression, marrow HSC reserve is crucial to relief of cytopenia. Non-cytotoxic epigenetic-differentiation mechanism was confirmed by marrow IHC and FCM measurement of DNMT1, g-H2AX, p27/CDKN1B, MYC, and KI67 (3rd party quantification). Differentiation therapy transformed the outlook for M3 AML. Not surprisingly, a worthy goal has been to extend this paradigm. Biology of sustained MYC activity in MDS/AML guided logical repurposing of DAC for non-cytotoxic differentiation therapy even in MDS/AML with complex cytogenetics. Tolerance permits ready application despite age or comorbidities. Treatment exposure time and surrogates of normal HSC reserve are more important predictors of CR/HI than disease- mutations, and some patients may require separate measures (e.g., cytokines) to boost normal HSC diminished by age and previous insults. Disclosures: Reu: Celgene: Research Funding. Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Saunthararajah: Cleveland Clinic Innovation: patent application for oral THU-decitabine., patent application for oral THU-decitabine. Patents & Royalties. Off Label Use: lower dose of decitabine, subcutaneous administration, metronomic administration. Footnotes * Asterisk with author names denotes non-ASH members.
    54th ASH Annual Meeting and Exposition, Atlanta, GA; 11/2012
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    ABSTRACT: Development of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination. Patients ≥ 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses. All patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug-related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization. Vorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy.
    Clinical lymphoma, myeloma & leukemia 10/2012; 12(5):319-24.
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    ABSTRACT: Constitutive activation of STAT5 (by phosphorylation) has been identified in a number of malignancies, including acute myeloid leukemia (AML). We investigated whether the level of phosphorylated STAT5 (pSTAT5) expression correlates with clinical outcome in AML. Adult patients with newly diagnosed AML receiving induction chemotherapy and with an available diagnostic bone marrow were evaluated. Forty-two percent of patients had pSTAT5 expression >0 on immunohistochemical analysis of fixed bone marrow core biopsies. In multivariable analyses, controlling for age, history of antecedent hematologic disorder, cytogenetic risk, and WBC at diagnosis, pSTAT5 expression was significantly associated with an increased risk of death (HR 1.96, 95% CI 1.19-3.23, P = 0.008) and of relapse after achieving complete remission (HR 2.31, 95% CI 1.16-4.63, P = 0.018). Validation of pSTAT5's prognostic value requires additional study in a larger group of uniformly treated patients. However, our data suggests that targeting this signaling pathway in AML may improve the outcome of patients.
    European Journal Of Haematology 06/2012; 89(4):288-93. · 2.55 Impact Factor
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    ABSTRACT: We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ≥350 cells/μL at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/μL (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ≥350 cells/μL on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/μL (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/μL vs. ≥350 cells/μL, P ≤ .0004 for OS and EFS) along with WBC at diagnosis (≤6.0 or >30.0 K/μL vs. >6.0-30.0 K/μL, P ≤ 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL. Am. J.Hematol. © 2012 Wiley Periodicals, Inc.
    American Journal of Hematology 06/2012; 87(10):957-60. · 4.00 Impact Factor
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    ABSTRACT: Patient readmission within 30 days from discharge has been perceived by the Centers for Medicare and Medical Services as an indicator of poor healthcare quality for specific high-cost medical conditions. Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are often being readmitted. Our study identified the risk factors for 30-day readmission among 618 adult recipients of myeloablative allo-HCT from 1990 to 2009. Two hundred forty-two (39%) of 618 patients (median age = 42 years [range: 18-66]) were readmitted a median of 10 days (range: 1-30) from their hospital discharge. Median duration of readmission was 8 days (range: 0-103). Infections (n = 68), fever with or without identified source of infection (n = 63), gastrointestinal complications (n = 44), graft-versus-host disease (GVHD) (n = 38), and other reasons (n = 29) accounted for 28%, 26%, 18%, 16%, and 12% of readmissions, respectively. During their index admission, patients who were subsequently readmitted had more documented infections (P < .001), higher hematopoietic cell transplantation comorbidity index (HCT-CI) (P < .01), total body irridiation (TBI)-based conditioning (P < .001), unrelated donor (P < .001), and peripheral stem cell (P = .014) transplantation. In multivariable analysis, HCT-CI (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.25-2.52), TBI-based preparative regimen (OR = 2.63; 95% CI, 1.67-4.13), and infection during admission for allo-HSCT (OR = 2.00; 95% CI, 1.37-2.92) predicted 30-day readmission. Thirty-day readmission itself was an independent predictor of all-cause mortality (hazard ratio [HR](Adj) = 1.66; 95% CI, 1.36-2.10). Our data emphasize the importance of a risk-standardized approach to 30-day hospital readmission if it is used as a quality-of-care metric for bone marrow transplantation.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2011; 18(6):874-80. · 3.15 Impact Factor
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    ABSTRACT: BU and CY is a common conditioning regimen for allogeneic hematopoietic progenitor cell transplantation (HPCT). I.v. BU is increasingly used in place of the oral formulation for conditioning. We compared the outcomes of 135 consecutively treated AML and myelodysplastic syndrome patients who underwent allogeneic HPCT at our institution with BUCY2 using oral (n=93) or i.v. (n=42) BU, without dose adjustment. The i.v. BU patients had a lower incidence of any severity of oral mucositis (3 versus 55%, P=0.002) and severe mucositis (3 versus 24%, P=0.005). Other post transplant outcomes were comparable between the groups. In all 26 i.v. BU and 33 oral BU patients are alive; however, the median follow-up was significantly longer for the oral BU group. One- and two-year non-relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 23% and 29%, respectively. One- and two-year relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 24% and 29%, respectively. Substituting i.v. for oral BU reduces variability in drug exposure and potentially improves toxicity as suggested by our finding of significantly less oral mucositis and decreased severity with i.v. BU.
    Bone marrow transplantation 08/2011; 47(5):633-8. · 3.00 Impact Factor
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    ABSTRACT: Suppression of apoptosis by TP53 mutation contributes to resistance of acute myeloid leukemia (AML) to conventional cytotoxic treatment. Using differentiation to induce irreversible cell cycle exit in AML cells could be a p53-independent treatment alternative, however, this possibility requires evaluation. In vitro and in vivo regimens of the deoxycytidine analogue decitabine that deplete the chromatin-modifying enzyme DNA methyl-transferase 1 without phosphorylating p53 or inducing early apoptosis were determined. These decitabine regimens but not equimolar DNA-damaging cytarabine upregulated the key late differentiation factors CCAAT enhancer-binding protein ɛ and p27/cyclin dependent kinase inhibitor 1B (CDKN1B), induced cellular differentiation and terminated AML cell cycle, even in cytarabine-resistant p53- and p16/CDKN2A-null AML cells. Leukemia initiation by xenotransplanted AML cells was abrogated but normal hematopoietic stem cell engraftment was preserved. In vivo, the low toxicity allowed frequent drug administration to increase exposure, an important consideration for S phase specific decitabine therapy. In xenotransplant models of p53-null and relapsed/refractory AML, the non-cytotoxic regimen significantly extended survival compared with conventional cytotoxic cytarabine. Modifying in vivo dose and schedule to emphasize this pathway of decitabine action can bypass a mechanism of resistance to standard therapy.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2011; 25(11):1739-50. · 10.16 Impact Factor
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    ABSTRACT: Fludarabine is an effective treatment for follicular lymphoma (FL), but exposure to it negatively impacts stem cell mobilization and may increase the risk of subsequent myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML). We hypothesized that the risk that fludarabine imparts to stem cell mobilization and t-MDS/AML would be affected by dose or timing. All patients with FL treated at Cleveland Clinic from 1991 to 2007 with autologous hematopoietic cell transplantation were evaluated. Recursive partitioning analysis was used to explore associations of fludarabine and mitoxantrone dose and timing with poor stem cell harvest and t-MDS/AML. We identified 171 patients, of whom 52 previously received fludarabine. Patients exposed to fludarabine prior to auto-HCT were more likely to require >5 days of leukapheresis (P<0.001) and second stem cell mobilization (P<0.001), especially at a cumulative dose >150 mg/m(2). Univariable risk factors for t-MDS/AML included the number of chemotherapy regimens before auto-HCT, the need for >5 days of leukapheresis to collect CD34+ cells and fludarabine exposure in a dose-dependent manner, particularly when >500 mg/m(2). A cumulative dose of fludarabine >150 mg/m(2) increases the risk for poor stem cell harvests and any exposure increases the risk of t-MDS/AML, with the greatest risk being at doses >500 mg/m(2).
    Bone marrow transplantation 05/2011; 47(4):488-93. · 3.00 Impact Factor

Publication Stats

966 Citations
363.35 Total Impact Points

Institutions

  • 2004–2014
    • Cleveland Clinic
      • Department of Hematologic Oncology and Blood Disorders
      Cleveland, Ohio, United States
  • 2011
    • Massachusetts General Hospital
      • Division of Hematology and Medical Oncology
      Boston, MA, United States
  • 2010
    • Fairbanks Memorial Hospital
      Fairbanks, Alaska, United States
  • 2005–2009
    • The Ohio State University
      • Division of Hematology
      Columbus, OH, United States
  • 2007
    • University of Miami Miller School of Medicine
      • Division of Hematology and Oncology
      Miami, FL, United States
  • 2003–2005
    • Michiana Hematology Oncology
      Indiana, Pennsylvania, United States