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  • 1
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 11, No. 9 ( 2005-09), p. 680-687
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2005
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  • 2
    In: American Journal of Hematology, Wiley, Vol. 82, No. 1 ( 2007-01), p. 6-14
    Abstract: Limited data are available for adults undergoing unrelated donor (URD) BMT for AML using chemotherapy‐only preparative regimens. Previous studies incorporated irradiation, included adults and children, and excluded secondary leukemia. Herein we report long‐term outcomes for adults with poor‐prognostic AML receiving a novel regimen of busulfan (16 mg/kg), cytarabine (8,000 mg/m 2 ), and cyclophosphamide (120 mg/kg) (BAC), followed by URD BMT. From June 1995 through October 2001, 45 adults were enrolled. Adverse features included unfavorable cytogenetics (49%), secondary AML (47%), leukemia at transplant (42%), and extramedullary disease (16%). At time of BMT, 23 were in remission (12 CR1) while 22 had leukemia. Four (9%) died early. Acute and chronic GVHD rates were 44 and 67%, respectively. Seventeen (38%) were disease‐free 52 months post‐BMT; 13 were leukemia‐free (eight CR1) at transplant. Eleven relapsed. Three‐year DFS and OS were 42 and 46%, respectively. DFS and OS were longer, and relapses less, for those in CR at time of BMT. Secondary leukemia, cytogenetics, cell dose, and GVHD did not influence outcome. In poor‐risk AML, BAC provided cytoreduction comparable to reported TBI‐containing regimens, when administered for URD BMT. With decreasing treatment‐related mortality, it is justified to proceed early to URD BMT for patients with poor prognostic features. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0361-8609 , 1096-8652
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2007
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2241-2241
    Abstract: Abstract 2241 Poster Board II-218 Introduction: T-LGL has the phenotype characteristics of a post-thymus mature T cell. Expansion of T-LGL has been reported to occur in association with viral infections, autoimmune diseases, lymphoproliferative malignancy and HSCT. The clinical significance of finding T-LGL expansion post HSCT is unclear. We recently reviewed the incidence of T-LGL expansion in patients who underwent allogeneic HSCT in our institution. We specifically asked whether T-LGL expansion was associated with increased viral infections, stable chimerism, graft-versus-host disease (GvHD), recurrence of primary disease, and overall survival. Patients and Methods: A retrospective analysis was done on all adult patients who underwent allogeneic HSCT at the Karmanos Cancer Institute between January 1, 2004 to June 30, 2009. In patients with persistent lymphocytosis ( 〉 3000 cells/mm3) post HSCT, expansion of T-LGL phenotype was identified by flow cytometry (CD2, CD3, CD5, CD7, CD8 and CD57 positive) and clonality was confirmed by T cell receptor beta and/or gamma gene rearrangement (TCR-GR) using southern blot analysis and polymerase chain reaction (PCR). Results: A total of 547 patients underwent allogeneic HSCT during the study period. We identified T-LGL expansion in 24 patients with persistent lymphocytosis using flow cytometry. Median age of patients with T-LGL expansion was 50 years (range 24-68 years). Median time to diagnosis was 275 days post HSCT (range 69-1454 days) and median duration of follow-up was 811 days (range 85-1701 days). All 24 patients achieved full donor chimerism post transplantation by STR analysis. Fourteen out of 24 patients with T-LGL expansion had positive TCR-GR, in 2 patients TCR-GR was not done and the remainder was negative. Twenty out of 24 patients had cytomegalovirus (CMV) viremia confirmed by PCR before the onset of T-LGL expansion; the remainder had no CMV viremia. In all patients with T-LGL expansion there was no subsequent recurrence of CMV viremia or infection. All 24 patients had documented graft versus host disease (GvHD). In the group with T-LGL expansion only 2 patients relapsed with primary disease and only one patient died (due to a cardiac event). The cumulative incidence of T-LGL expansion was 4.4% at the end of the study period. Conclusion: To our knowledge, this is the largest reported series of T-LGL expansion post allogeneic HSCT. T-LGL expansion was associated with an interesting sequence of CMV viremia preceding T-LGL expansion and subsequent lack of recurrence of CMV viremia or infection. We also observed a very low number of relapse of primary disease or death in patients with T-LGL expansion. One hypothesis is that T-LGL expansion may be a result of specific stimulation with CMV antigens post allogeneic HSCT. An alternate hypothesis is that T-LGL expansion is a surrogate marker for accelerated immune reconstitution. At present, it is also unclear if T-LGL expansion is a marker of ‘graft-versus-leukemia' effect with respect to relapse of primary disease warranting further research. Disclosures: Lum: Transtarget Corporation: Founder
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 5461-5461
    Abstract: We report here the long-term outcome of 95 patients with myelodysplastic syndromes (MDS) who underwent allogeneic stem cell transplantation (SCT) following busulfan-containing regimens. The median age was 43 (range:3–62) and 55 patients were male. Eighty-four patients had primary MDS, 11 had secondary MDS. Twenty patients received induction therapy for leukemic transformation prior to SCT. Pre-transplantation cytogenetic studies were available in 82 patients, and were categorized according to the international prognostic scoring system (IPSS) karyotype groups. The bone marrow biopsies/aspirates were reviewed and classified according to WHO classification (Table 1). Sixty one patients received related donor transplant (54 patients were 6/6 HLA-matched), and 34 patients received unrelated donor transplant (26 patients were 6/6 HLA-matched). Ninty patients received consecutive administration of busulfan 4 mg/kg/day orally for 4 days, cytosine arabinoside 2 g/m2 IV every 12 hours for 4 doses, and cyclophosphamide 60 mg/kg IV daily for 2 days (BAC); and 5 received other busulfan-containing regimens. GHVD prophylaxes were either cyclosporine (75 patients) or tacrolimus (12 patients) regimens, and 8 patients received other regimens. The median duration of transplant hospitalization was 34 days (range:13–121 days). Grade I–IV regimen-related toxicities (RRT) included GI (diarrhea, 32; stomatitis, 38), liver (28), cardiac (19), kidney (15), lung (25), neurological (7) and skin (5). Acute and chronic GHVD occurred in 48 (50%) and 21 (22%) patients, respectively. With a median follow up of survivors of 6.7 years, the Kaplan-Meier estimates for overall survival were 45%±5% (±SE), 35%±6% and 34%±6% at five, ten and fifteen years, respectively (Figure 1). Fifty-four patients died. The causes of death were GHVD (14 patients), relapse (12), infection (11), pulmonary toxicity (3), multiorgan failure (3), hepatic (2), renal (1), cardiac (1) and other causes (7). Non-relapse mortality at 100 days and three years was 22% and 40% respectively. The long-term follow up of patients receiving high-dose busulfan-based regimens for allogeneic SCT in this study indicated durable overall survival with acceptable toxicity. Patient Characteristics BAC: Busulfan/Ara-C/Cyclophosphamide, BU: Busulfan, CY: Cyclophosphamide, TLI: Total lymphoid irradiation, FLU: Fludarabine, ATG: Antithymocyte globulin, CS: Cyclosporin # of Patients 95 Median Age (range) 43 (3–62) Male/Female 55/40 Cytogenetic risk (IPSS)     Good/Intermediate/Poor 38/14/30     Not available 13 Disease Duration Median (range) 182 (40–1944) Etiology     Denovo/Secondary 84/11 Donor     HLA-identical sibling 54     HLA-nonidentical sibling 7     Unrelated HLA-identical 26     Unrelated HLA-nonidentical 6 WHO Classification     RA 5     RARS 2     RAEB-1 4     RAEB-2 16     RCMD 14     CMML 4     AML 20     MDS-U 6     Not available 24 Source of stem cells     BM/PBSC 69/26 GVHD prophylaxis     CSA/Methylprednisolone 32     CSA/Methotrexate 43     Tacrolimus/Mycelophenolate 7     Tacrolimus/Methotrexate 5 Busulfan regimen     BAC 90     BU/ATG/CS/TLI 2     BU/CY 1     BU/FLU/TLI 2 Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 5
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3346-3346
    Abstract: Abstract 3346 Poster Board III-234 Background: Patients who receive high-dose chemotherapy with or without radiation preparative regimens prior to allogeneic hematopoietic stem cell transplant (AHSCT) have high incidence of mucositis. The mucositis is usually seen at the nadir of neutropenia and improves with engraftment. At our center we observed late onset mucositis in patients received intravenous IV Busulfan/Fludarabine (IV-BU/FLU) preparative regimen. The onset was within 5 days of engraftment and resolved 5 days after engraftment (peri-engraftment mucositis, PEM). Upon review of literature, no reports were found that detailed this phenomenon. We attempted to determine the incidence of PEM in our patient population, as well as possible risk factors and consequences. Methods: This retrospective chart review was designed as a cohort study. It included 382 patients who received AHSCT at Karmanos Cancer Center between 2004 and 2009; out of these were 207 patients received IV-BU/FLU; 103 patients received myeloablative dose of BU 130mg/m2 daily x 4 doses starting at day -6 and FLU 30mg/m2 daily x five doses starting at day -6. 104 patients received reduced intensity regimen of IV BU 130mg/m2 daily x 2 doses starting day -6, FLU 30mg/ m2 daily x 5 doses starting day -6, and 200 rad total body irradiation TBI (IV-BU/FLU/TBI). All patients received tacrolimus and mycophenolate for GVHD prophylaxis starting at day -3, with no methotrexate. We attempt to define this entity by examining the clinical course and correlations of diagnosis, preparative regimen, patient characteristics (age, race, weight, height, grade and duration of mucositis, opiate use, and engraftment associated acute leukocytosis) and patient outcomes (hospitalization duration, incidence of acute GvHD, survival). Results: A total of 207 patients received IV- BU/FLU and 175 patients received other preparative regimens. The incidence of peri-engraftment mucositis was 19% (39/207), in the group receiving IV-BU/FLU, while with other regimens it was 1 % (2/174). There was no difference in the distributions of the diagnosis, patient characteristics or patient outcomes among those who received IV-BU/FLU versus those who received other preparative regimen. Due to high incidence of this phenomenon observed in patients who received BU/FLU, this patient group was further studied. On evaluation of these patients (n=207), 9 (4%) patients were not assessable for mucositis, 62 (30%) had no mucositis and 136 (66%) developed mucositis. Of the 136 pts with mucositis, 39 (29%) met predefined criteria for peri-engraftment mucositis (PEM). PEM (N=39) group characteristics: Mean age is 50 (20-67). 34 patients had IV-BU/FLU and 5 IV-BU/FLU/TBI. Diagnosis: 22 AML, 6 MDS, 4 CML, 2 NHL, 2 CLL, 1each with CMML, HD, ALL. 16 patients had related AHSCT and 23 had unrelated AHSCT. All PEM patients were tested and found negative for herpes simplex virus infection at the time of PEM. The median engraftment day for both mucositis group (MG) and peri-engraftment mucositis (PEMG) group was day +11. The median duration of mucositis (6 vs. 11 days, p 〈 0.001), incidence of intravenous (iv) opiate usage (62% vs. 82%, p 0.023), median duration of iv opiate usage (5 vs. 7 days, p 〈 0.001), Mucositis grade 3 (21% vs. 43 % p 〈 0.001 value) and median duration of hospitalization (24 vs. 31 days, p 〈 0.001) were different in MG (N=97) vs. PEMG(N=39) group, respectively. The p values were calculated using wilcoxan rank sum test. No significant differences in other patient characteristics or other patient outcomes were observed in the MG vs. PEMG. Conclusion: BU/FLU regimen has been in use for less than a decade. Peri-engraftment mucositis has not been described previously with this regimen. PEM is a unique phenomenon, with features including; longer duration (Fig1), more incidence of grade 3 mucositis, higher incidence and longer duration of iv opiate use and longer hospitalization. Although the pathophysiology of PEM remains unclear and no specific risk factors have been identified for it, this phenomenon increases patients' morbidity and cost of transplant. Disclosures: Lum: Transtarget Corporation: Founder. Abidi:Merck Pharmaceuticals: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2239-2239
    Abstract: Abstract 2239 Poster Board II-216 Background: Acute graft versus host disease aGVHD continues to affect approximately 60% or more of patients undergoing UHSCT, with significant mortality and morbidity. Furthermore viral infections such as Cytomegalo virus (CMV) affect approximately two thirds of these patients. Methods: In a phase II trial, we prospectively evaluated whether adding Thymo (4.5 mg/kg divided doses on days -1,-2, and -3) to Tacrolimus and Sirolimus combination for aGVHD prophylaxis in recipients of UHSCT would decrease the rate of aGVHD. The primary endpoint is aGVHD, which is calculated as cumulative incidence. Since infections are a concern after T cell depletion, the incidence of infections and adverse events were monitored closely. Results: There were 25 patients (pts) with median age of 51(20-70) years enrolled in the protocol, 10 females and 15 males. There were 10 AML (5CR1, 5CR2), 7 MDS (untreated), 2 ALL (CR1), 1 ALL/AML (uCR1), 1 CML (CP), 1 CMML (untreated), 1 granulocytic Sarcoma (CR1), 1 NKT cell lymphoma (CR3), and 1 DLBCL(CR2). Preparative regimens included Bu/Flu (21 pts), VP16/TBI (2 pts) R-BEAM (1 pt), and Flu/MEL (1 pt). All patients received peripheral blood hematopoietic stem cells (PBHSC) mobilized with granulocyte colony stimulating factor G-CSF with an average CD34+ dose of 8.24×10 6/kg (3.7-14.3). All patients received daily G-CSF starting day +6 till engraftment. After molecular typing, 11 of 25 patients received HLA fully matched graft, 11 of 25 received a 1 antigen (Ag) mismatched graft, and 3 of 25 received a 2 Ag mismatched unrelated PBHSC graft. All patients' engrafted. Median engraftment day is 12 (9,13). Eighteen patients had passed the day 100 time point; seven pts did not reach day 100. Three deaths occurred, due to: relapse (1), multi organ failure (1), and pneumonia (1). Two patients experienced disease relapse. Both went into complete remission once immune suppression was withdrawn, demonstrating clear graft versus Leukemia (GVL) effect, before day 100. Seven of 25 pts developed aGVHD, 1 developed aGVHD after relapse. Three developed grade 1 aGVHD, 3 pts developed grade 2 aGVHD. One pt developed grade 4 aGVHD after immune suppression withdrawal due to disease relapse. Five patients needed systemic steroids, maximum duration 36 days. All aGVHD cases have responded to therapy. The cumulative incidence rate for aGVHD at 100 days is 0.258 ( 0.101, 0.448); the cumulative incidence rates of competing events: relapse is 0.146 (0.034, 0.334) and death without GVHD or relapse 0.050 (0.003, 0.212). Patients tolerated Thymo well. Two patients developed thrombotic thrombocytopenic purpura (TTP), one patient after day 100 that required discontinuation of tacrolimus and sirolimus. Four patients developed CMV PCR sub-clinical activation 16% (95% CI 5.7-33.6%), which resolved with treatment. Six patients developed PCR sub-clinical Epstien-barr virus (EBV) activation 20% (95% CI 8.2-38.4), 5/6 needed Rituximab. Three patients developed Herpese simplex virus (HSV) stomatitis, two rhinovirus upper respiratory tract infections, and 3 BK viral cystitis. 14 patients had a documented bacterial infection all resolved. Apart from 2 oral candidiasis, no fungal infections observed. All infections have resolved. Conclusion: These early results suggest that the combination of Tacrolimus/Sirolimus and Thymo in pts undergoing unrelated HSCT is well tolerated and is associated with a low rate and severity of acute GVHD, and early GVL effect as demonstrated in two patients. Low rates of CMV viral infections were seen. Further accrual and a longer follow-up will be needed to confirm these encouraging results. Disclosures: Al-Kadhimi: Genzyme pharmacutical: Research Funding. Off Label Use: Thymoglobulin is used to prevent graft versus host disease in unrelated transplant in this protocol. That is an off lable drug use.. Abidi:Merck Pharmaceuticals: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 7
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4659-4659
    Abstract: Abstract 4659 Introduction Large pericardial effusion (LPE) as a manifestation of polyserositis is a known complication of GVHD. Due to its rarity, the incidence and natural history of LPEs are lacking in adult stem cell transplant recipients and current evidence is based on published case reports. Methods We retrospectively evaluated the incidence post-transplant LPE development for all adult patients who underwent transplants at our institution from 2005 to 2008. Results During this period, 858 transplants were performed, 512 autologous and 346 allogeneic (148 related and 198 unrelated). No LPEs were documented in post-autologous transplant patients. One patient developed polyserositis with LPE after allogeneic transplant on imatinib therapy and was excluded from this analysis. Seven patients (2%) who received unrelated transplant developed LPEs a median 229 days (range 42-525 days) post-transplant (Table 1). Only two patients developed large LPEs less than 100 days post-transplant, however in both cases LPEs developed after the second transplant. Six patients (86%) developed biopsy proven GVHD prior to the detection of LPEs; among them 5 (83%) had skin and GI tract involvement and 1 (17%) had GVHD of the liver. Six patients (86%) had concomitant pleural effusions (PEs). No patients had active manifestations of GVHD besides polyserositis at the time of LPE detection. Six patients (86%) required pericardial window (PW) placement with a pericardial biopsy; none had evidence of a malignant or infectious process involving the pericardium. Four patients were alive a median of 172 days (range 20-274 days) post LPE detection and all 4 had PW placed. Out of 4 survived patients, 3 had steroids initiated or increased with a clinical improvement of polyserositis on subsequent follow up in 2 patients and 1 patient had persistent pleural effusions. One patient had a systemic relapse shortly after LPE detection. Three patients died, among them 2 had PW placed and died less than 100 days after LPE detection; the first patient died at day 93 from MRSA pneumonia and the second one died at day 7 from polymicrobial sepsis and multiorgan failure. Both these patients had undergone a second transplant when the LPE occurred. The third patient, who did not receive a PW, died of progressive bronchiolitis obliterans, 542 days after LPE detection, her polyserositis symptoms resolved while on cyclosporine therapy. Conclusion LPE is a rare complication after allogeneic transplant in adults and in our study developed only after unrelated transplant. PW can be safely performed in these patients and polyserositis can be successfully treated with systemic steroids, although patients might continue having polyserositis despite aggressive immunosupression. Abbreviations MUD= matched unrelated donor, S=skin, L=liver, GI=gastrointestinal tract, Bu= busulfan, Flu= fludarabine, TBI= total body irradiation, CVB= cyclophosphamide, etoposide and BCNU Disclosures: Abidi: Merck Pharmaceuticals: Research Funding. Lum:Transtarget Corporation: Founder.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 8
    In: Journal of Oncology Pharmacy Practice, SAGE Publications, Vol. 14, No. 3 ( 2008-09), p. 113-121
    Abstract: Aprepitant (AP) is a known inhibitor of cytochrome P450 3A4 which may affect tacrolimus metabolism. We retrospectively examined the effect of oral AP on intravenous tacrolimus concentrations in 26 patients undergoing reduced intensity transplantation from 09/2005 to 09/2006. Oral AP 125 mg daily was administered on transplant day +1 and 80 mg on days +2 and +3. Intravenous tacrolimus was administered as a 0.03 mg/kg/day continuous infusion on day -6 through day +1 (pre-AP), during-AP (days +2 to +7), and post-AP starting on day +8. Tacrolimus doses were adjusted to achieve concentrations of 5—20 ng/mL. Dose-corrected tacrolimus concentrations (ng/mL/mg per dose) in the pre-AP, during-AP, and post-AP time periods were: 8.12 (95% CI: 7.3—9.1), 11.63 (95% CI: 9.63—13.63), and 11.42 (95% CI: 8.12—14.7), respectively (P 〈 0.01 between pre-AP and during-AP, P 〈 0.01 between during-AP and post-AP, P = 0.01 between pre-AP and post-AP time periods). Although statistically significant, the observed rise was not clinically significant between during-AP and post-AP time periods. Previous work has shown that AP is not expected to exert an inhibitory effect within 48 h of AP discontinuation. Collectively, these data suggest that AP effect on tacrolimus metabolism is of minor clinical significance. A controlled trial is needed to confirm these findings. J Oncol Pharm Practice (2008) 14: 113—121.
    Type of Medium: Online Resource
    ISSN: 1078-1552 , 1477-092X
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2008
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