Reduced Intensity Conditioning (RIC) with Fludarabine, Busulfan and Cyclophosphamide for High Risk Patients with Thalassemia Major Undergoing Allogeneic Bone Marrow Transplantation Results in High Rejection Rates.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1998-1998 ◽  
Author(s):  
Mammen Chandy ◽  
Vikram Mathews ◽  
Biju George ◽  
Auro Vishwabandya ◽  
Salamun Desire ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
High Risk ◽  
Graft Rejection ◽  
Thalassemia Major ◽  
Class I ◽  
Class Iii ◽  
High Risk Patients ◽  
Allogeneic Bmt ◽  
Risk Patients

Abstract Usual cytoreductive therapy for bone marrow transplantation (BMT) for thalassemia major consists of busulfan (Bu) 14–16mg/kg and cyclophosphamide(Cy) 160–200mg/kg +/− anti-thymocyte globulin (ATG). In high risk patients, this is associated with significant regimen related toxicity and graft rejection. Fludarabine (Flu) containing conditioning has been used effectively by adding immunosuppression in RIC with reduced doses of myelosuppressive drugs to lower regimen related toxicities and graft rejection. There is also data to suggest that a 24-hour gap between Bu and Cy doses could reduce toxicities associated with this combination. We therefore treated 25 patients (median age: 7 years, range: 3–14), 12 males and 13 females, with beta thalassemia major with a regime of Flu 150mg/m2 (day-15 to -11), Bu 14mg/kg (day-10 to -7) and Cy 160mg/kg (day-5 to day-2). Most of these patients were heavily transfused (median red cell units:100, range: 21–250) and poorly chelated (median serum ferritin: 2510 ng/ml, range: 1039–6740). Their risk stratification (Lucarelli class) was as follows: Class I: 4 (16%), Class II: 8 (32%) Class III: 13 (52%). Allogeneic BMT was performed using a 6/6 matched related donor and bone marrow as the graft. Graft versus host disease (GVHD) prophylaxis consisted of cyclosporine A and mini-methotrexate. The median cell dose was 4.56 × 108 TNC/kg (range: 2.5–14.1). Three (20%) of 20 assessable patients developed grade I-II acute GVHD, 2 (10%) each had hemorrhagic cystitis and veno-occlusive disease. Mortality within the first 100 days were due to graft failure/rejection in 4 patients (16%) and one each of diffuse alveolar hemorrhage, intracranial hemorrhage and sepsis (4% each). With a mean follow-up of 8 months (range 0–11), 18 (72%) of 25 patients are alive. Among the 13 patients in class III, 5 (38.5%) rejected the graft (3 had primary failure and 2 after initial engraftment). In a historical cohort of 47 patients conditioned with Bu16, Cy200 and ATG, the rejection rate was only 8%. The regimen was very well tolerated by all patients and patients in class I had no rejection. Pharmacokinetic data was available on Bu and Cy from 14 of the 25 patients treated with this protocol. The mean values for Bu kinetics were: Cmax-1 (ng/ml): 1069.2±265.8, Cmin-1(ng/ml): 186.8±73.2, Cl-F-1 (l/h/kg): 0.281±0.081, AUC-1 (ng*h/ml): 3648±918 and Css-1 (ng/ml): 608±153. They are not significantly different from patients conditioned Bu16mg/kg without Flu (data not shown). The Cy kinetic data are as follows: Cmax-1(ng/ml): 441.4±188, AUC-1(ng*h/ml): 1431±791, Cl-F-1(l/h/kg): 0.0378±0.027. The Cmax-1 and AUC-1 were significantly lower compared to patients receiving 200mg/kg and dosed without a 24-hour gap between the Bu and Cy. Overall, these data suggest that Flu does not provide adequate immunosuppression for sustained engraftment after allogeneic BMT even when combined with Bu 14 and Cy160 (with a 24-hour gap between Bu and Cy) in high risk patients with thalassemia major (Lucarelli class III) but could be useful in the others (Class I and II). OUTCOME OF ALLOGENEIC BMT CLASS NUMBER (%) OVER ALL SURVIVAL (months) EVENT FREE SURVIVAL (months) REJECTION (%) MORTALITY (%) ALL PATIENTS 25 69±9.8 62.6±10.0 6 (24) 7 (28) CLASS I 4 (16%) 75±21.7 75±21.7 0 1 (25) CLASS II 8 (32%) 83.3±15.2 83.3±15.2 1 (12.5) 1 (12.5) CLASS III 13 (52%) 57.7±14.7 44.9±14.1 5(38.5) 5 (38.5)

Bone Marrow Transplantation for β Thalassemia Major: Long Term Experience from a Single Centre in India.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1106-1106 ◽  
Author(s):  
Mammen Chandy ◽  
Vikram Mathews ◽  
Biju George ◽  
Auro Viswabandhya ◽  
M.L. Kavitha ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Thalassemia Major ◽  
Class Ii ◽  
Class I ◽  
Red Cell ◽  
Class Iii ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Bmt

Abstract From October 1991 to December 2006, 218 patients with β thalassemia major underwent allogeneic bone marrow transplant at this center. This represents 45% of all transplants performed here. The median age of this cohort of patients was 7 years (range: 2–24) with 144 males and 74 females. The pre-transplant characteristics were as follows: red cell transfusions: median: 92 units (range: 4–775), median serum ferritin: 2870ng/ml (range: 925 – 13600) with the majority having been on inadequate chelation. Patients were risk stratified by the criteria proposed by Lucarelli: Class I: 15 (6.9%), Class II: 89 (40.8%) Class III: 114 (52.3%). This distribution is a reflection of the poor pre-transplant care that many of these patients receive. Five (2.3%) patients were positive for hepatitis B surface antigen while 28 (13%) were positive for hepatitis C antibody. The donors were HLA AB and DR matched siblings in 202 cases and in 16 patients a HLA identical parent was the donor. One hundred and twenty five (57.3%) of the donors were heterozygous for thalassemia. There was major mismatch of ABO blood group in 25.2%. The bone marrow graft was red cell depleted by sedimentation with hydroxyethyl starch in these cases. There were no donor related complications. Busulfan (Bu) and cyclophosphamide (Cy) with or without ALG was used as the conditioning regime in all but 25 patients in whom Fludarabine was used along with Bu/Cy. Short methotrexate and cyclosporine was used for graft versus host disease prophylaxis. Cyclosporine was initiated on day - 4, continued for 6 months then tapered and stopped at one year in the absence of graft versus host disease (GVHD). Eighty (41%) of 195 assessable patients developed acute GVHD of which 64 (80%) were grade I and II and 16 (20%) were grade III and IV. Twelve (7.2%) of the 166 assessable patients developed chronic graft versus host disease, 10 were limited stage and two were extensive. Forty (18.3%) developed hemorrhagic cystitis which was grade I and II in 60% of the patients. Veno-occlusive disease as defined by the Seattle criteria occurred in 105 [48.2%] patients and this was the most common complication. The important causes of mortality within the first 100 days included: DAH (13), graft failure/ rejection (11), sepsis (10), VOD (9) and GVHD (7). With a mean follow up of 133 months (Range 6–183), 72 (80.8%) of 89 children in class II are alive and well, free off transfusion and off immunosuppression. However, among the 114 patients who were in Class III there was a 34.4% mortality and 19.4% rejection which means that these patients should receive better pre-transplant care and should be taken early for BMT. Allogeneic BMT at US$ 15–20,000 is equivalent to the cost of 3 years of transfusion and chelation and is a good alternative in the developing world. Outcome of Allogeneic BMT for Thalassemia (5 year Kaplan-Meier estimate of OS and EFS) CLASS NUMBER SURVIVAL (%) EVENT FREE SURVIVAL (%) MORTALITY (%) All Patients 218 72.3±3.1 65.3±3.3 14.6 Class I 15 71.8±11.98 71.8±11.98 0 Class II 89 82.6±4.1 78.3±4.4 12.4 Class III 114 64.5±4.6 54.6±4.8 18.4

scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation.

1991 ◽  
Vol 9 (7) ◽  
pp. 1224-1232 ◽  
Author(s):  
T J Nevill ◽  
M J Barnett ◽  
H G Klingemann ◽  
D E Reece ◽  
J D Shepherd ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
High Risk ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Conditioning Regimen ◽  
Allogeneic Bone ◽  
Risk Patients ◽  
Standard Risk

The regimen-related toxicity (RRT) of a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) conditioning regimen (BuCy) was evaluated in 70 consecutive patients undergoing allogeneic bone marrow transplantation for hematologic malignancies. Patients were given toxicity gradings retrospectively in each of eight organ systems (cardiac, bladder, renal, pulmonary, hepatic, CNS, stomatic, and gastrointestinal) according to a recently developed RRT scale. A set of patient, disease, and treatment parameters (age, sex, diagnosis, Eastern Cooperative Oncology Group [ECOG] score, preconditioning liver function tests [LFT], prior chemotherapy exposure, disease status, graft-versus-host disease [GVHD] prophylaxis, antimicrobial agent use, hematologic recovery, and severity of acute GVHD) was statistically analyzed to determine significant predictors of RRT. The most common significant organ toxicities were stomatic (87% of patients; 63% grades II to IV) and hepatic (83% of patients; 44% grades II to IV). Renal and gastrointestinal toxicities were not uncommon (35% and 27%, respectively) but were rarely serious (9% and 1% grades II to IV, respectively). Twelve patients developed grade III toxicities of the following systems: hepatic (seven), pulmonary (two), bladder (two), and CNS (one). Females had more frequent stomatitis (P = .04) and hepatic RRT (P = .004). Patients receiving methotrexate in their GVHD prophylactic regimen experienced more grade II to IV stomatitis (P = .04) and hepatic RRT (P = .04). The use of amphotericin B (P = .01) or prolonged antibiotic courses (P = .04) was associated with more grades II to IV hepatic RRT. In a multivariate analysis, only amphotericin B administration predicted grades II to IV hepatic RRT (P = .01). The incidence of acute GVHD was 49%, with 31% having grades II to IV GVHD. The estimated 2-year event-free survival (EFS) for the entire study group was 44%. The estimated 2-year EFS was 63% for standard-risk patients (acute leukemia in first remission and chronic myelogenous leukemia [CML] in first stable phase) and 24% for all others (high-risk patients). High-risk patients were at increased risk of disease recurrence and RRT. BuCy is an efficacious bone marrow transplant conditioning regimen for standard-risk patients with leukemia but has significant associated hepatic RRT.

OUTCOME of Unrelated DONOR BONE MARROW TRANSPLANTATION for THALASSEMIA MAJOR PATIENTS

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 149-149 ◽  
Author(s):  
Franco Locatelli ◽  
Roberto Littera ◽  
Daria Pagliara ◽  
Benedetta Contoli ◽  
Giovanna Giorgiani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Thalassemia Major ◽  
Unrelated Donor ◽  
Class Iii ◽  
Patients At Risk ◽  
Grade Iii

Abstract Abstract 149 At present, allogeneic bone marrow transplantation (BMT) is still recognized as the only treatment potentially able to cure a large proportion of patients with thalassemia major. For many years, the only donor employed was an HLA-identical sibling. Unfortunately, at least 70% of patients who might benefit from BMT lack a compatible sibling. With the establishment of bone marrow donor registries, including now more than 15 million volunteers world-wide, many patients are able to locate a suitable unrelated donor. Aim of this study was to evaluate the outcome of patients transplanted from an unrelated volunteer, selected using stringent criteria of compatibility after high-resolution molecular typing of HLA loci, and to identify factors with a prognostic relevance. We analyzed 122 thalassemia patients (96 children and 26 adults, age range at time of BMT 1–35 years, median 10,5) given the allograft in one of 4 Italian Centers participating to this study. Seventy-one patients were males and 51 females; 13 patients had positive Hepatitis C Virus (HCV) serology. Prior to transplantation, all patients underwent a complete check-up and children were assigned to one of 3 classes of risk according to the criteria proposed the Pesaro group. In detail, 39 pediatric patients belonged to the class I, 41 to the class II (23) and 16 to the class III of the Pesaro classification. In 105 donor/recipient pairs were matched for the HLA-A, -B, -C, -DRB1 loci; 17 donor/recipient pairs had a disparity at the HLA-C locus, but both HLA-C molecules pertained to the same HLA-C ligand group. The patients were prepared for the allograft using a myeloablative conditioning regimen based on the combination of busulfan/treosulfan (BU/TREO), thiotepa (TT) and either cyclophosphamide (CY, 54 patients), or fludarabine (FLU, 68 patients). All patients received fresh, unmanipulated bone marrow cells, the median dose of nucleated cells infused being 5×108/Kg recipient b.w. (range 1.4–15). Graft-versus-host disease (GvHD) prophylaxis was homogeneous in all patients and consisted of cyclosporine-A, short-term methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6 and + 11) and anti-thymocyte globulin (ATG, 2.5 mg/Kg from day –4 to –2). Twenty patients died and 16 patients had either primary (11 patients) or secondary (5 patients) graft failure, the 5-year probability of overall survival (OS), and thalassemia-free survival (TFS) being 84% (95% Confidence Interval, CI, 76–90) and 75% (95% CI, 66–81) respectively. Acute and chronic GvHD were the main causes of death accounting for 6 and 4 fatal events respectively. Thirty-four patients at risk (28%) developed grade II-IV acute GvHD with 16 of them (13%) experiencing grade III-IV acute GvHD. Fourteen patients at risk (13%) had chronic GvHD, which was limited in 8 cases and extensive in 6. The probability of survival was not influenced by the occurrence of graft failure which was responsible of only 2 of the 20 fatal events. The chance of being alive for children belonging to class I, II and III of the Pesaro classification was 97% (95% CI, 83–100), 85% (95% CI, 70–93) and 78% (95% CI, 51–93), respectively, while that of adults was 65% (95% CI, 44–80) (p<0.01). Occurrence of both grade III-IV acute and chronic GvHD, older patient's age, positive HCV serology and adult/class III group of risk predicted a poor survival in univariate analysis; however, in multivariate analysis, only occurrence of grade III-IV acute GvHD was associated with a poor outcome (Hazard ratio, 10.4, 95% CI 3.19 – 34.06, P=0.001). Altogether, these data indicate that, provided that selection of the donor is based on stringent criteria of HLA-compatibility, transplantation from unrelated volunteers is able to cure a large proportion of patients with patients with thalassemia major, the results being comparable to those obtained when the donor is an HLA-compatible sibling. Prevention of severe acute GvHD is able to optimize the outcome of patients with thalassemia major transplanted from an unrelated volunteer. Disclosures: No relevant conflicts of interest to declare.

The Mean Fluorescence Intensities of Anti-HLA Antibodies Detected Using Micro-Bead Flow Cytometry Predict the Risk of Platelet Transfusion Refractoriness.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2285-2285
Author(s):  
Ashanka M Beligaswatte ◽  
Eleni Tsiopelas ◽  
Ian Humphreys ◽  
Greg Bennett ◽  
Kathryn Robinson ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Platelet Transfusion ◽  
Blood Product ◽  
Class I ◽  
Cell Transplant ◽  
Hla Antibodies ◽  
High Risk Patients ◽  
Risk Patients ◽  
Antibody Titers

Abstract Abstract 2285 Background: HLA allo-immunized patients often receive matched platelets only after demonstrating platelet transfusion refractoriness (PTR). If further risk stratification was possible, high risk patients could be considered for pre-emptive HLA-matched platelets, cryopreserved autologous platelets, or possibly thrombopoietin analogues. Micro-bead flow cytometry is widely used to detect anti-HLA antibodies, and mean fluorescence intensities (MFI) obtained from these assays correlate with antibody titers. We asked whether MFIs could be used to stratify the risk of PTR among allo-immunized patients. Study design: We retrospectively identified 387 patients who received an autologous stem cell transplant or induction therapy for acute leukemia, between January 2005 and March 2012. All patients had a serum sample taken for HLA antibody assay within 6 weeks of commencing cellular blood product transfusions. No patient was scheduled to receive prophylactic HLA matched platelets. The primary endpoint was the development of PTR. To minimize the influence of sensitization occurring after screening, only outcomes during the first 2 weeks from commencing cellular blood product transfusions were considered. PTR was defined as having received ≥ 2 consecutive RDPLT transfusions associated with an 18–24h corrected count increment of < 2.5 at 18 – 24 hours. Antibody testing was performed using a micro-bead flow cytometry assay (Lifecodes LifeScreen Deluxe, with positive results confirmed by Lifecodes Class I ID assay, Gen-Probe Transplant Diagnostics, Stamford, CT) either during the treatment period, or on serum samples stored at −30°C. Mean fluorescence intensities (MFI) were acquired using a Luminex 100 analyzer (Luminex Corporation, Austin, TX), and analyzed using Lifecodes Quicktype v2.5.5 (Gen-Probe Transplant Diagnostics, Stamford, CT). We defined the predictor variable avgMFI to be the average MFI of the 7 individual beads in the assay, weighted by whether the presence of antibodies was confirmed or not: where w = 1 if the presence of antibodies is confirmed, and 0 otherwise; and subscript i refers to the ith class I bead. Results: Antibodies were detected in 57 (14.7%) patients of whom 45 (78.9%) were female. A total of 1443 random donor platelet (RDPLT) transfusions (mean platelet count 2.4×1011/unit) were studied. Sixty six (17%) patients developed PTR, of whom 28 had detectable antibodies; 29 of 321 patients who did not develop PTR also tested positive. Among antibody positive patients, median avgMFI for refractory patients was 4589 versus 349 for patients who were not, Wilcoxon rank sum test P< 0.0001. (Figure 1). The area under the receiver operating characteristic curve for avgMFI as a predictor of PTR was 0.8633 (95% confidence interval: 0.7664 – 0.9602). Higher avgMFIs also correlated with a broader range of target antigens, likely due to increasingly avid binding to cross-reactive epitopes. (Spearman's r = 0.7736 for correlation between avgMFI and panel reactive antibody percentages (cPRA), calculated in reference to the general American population, and used here as a surrogate for the range of antibody specificities). cPRA was >80% in 25/27 patients with avgMFI>1000, suggesting poor ability to discriminate among patients with moderate to high antibody titers, and was not an independent predictor of PTR. Hence, while the increased probability of encountering a cognate antigen on a RDPLT may partly explain the correlation between avgMFI and PTR, the avidity of binding, represented in vitro by the MFIs, appears to be a more significant determinant of risk. In conclusion, we provide evidence for the concept that PTR risk due to HLA allo-immunization is usefully predicted by the MFIs of antibodies detected using micro-bead flow cytometry. Our model allows cut-offs for identifying high risk patients to be based on the degree of risk acceptable in a given clinical situation. This should enable hematology units to develop risk-adapted strategies for supporting allo-immunized thrombocytopenic patients. Disclosures: No relevant conflicts of interest to declare.

Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia.

1997 ◽  
Vol 15 (1) ◽  
pp. 44-51 ◽  
Author(s):  
K Seiter ◽  
E J Feldman ◽  
H D Halicka ◽  
F Traganos ◽  
Z Darzynkiewicz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Leukemia ◽  
S Phase ◽  
Low Risk ◽  
Myelogenous Leukemia ◽  
Laboratory Evaluation ◽  
Apoptotic Cells ◽  
High Risk Patients ◽  
Risk Patients

PURPOSE To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients. PATIENTS AND METHODS Fifty-three patients with acute leukemia not responsive to standard therapy were treated at eight dose levels of topotecan (2.5 mg/m2/d to 7.75 mg/m2/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m2/d, both for 5 days. Using a flow-cytometric technique, the percent apoptotic cells in blood and bone marrow samples was determined, and the cell cycle distribution of the leukemic cells studied. RESULTS Oropharyngeal mucositis was dose-limiting. The MTD of topotecan was 4.75 mg/m2/d for 5 days in high-risk patients and 7.0 mg/m2/d for 5 days in low-risk patients. The mean percent apoptotic cells in the peripheral blood reached a peak of 18.8%, a median of 48 hours following the first dose of topotecan. Patients with higher S-phase fractions, either before treatment or following cytarabine, were more likely to achieve bone marrow aplasia than those with lower S-phase fractions (P = .01 and P < .05, respectively). Clinical responses were seen in four of 39 patients with acute myelogenous leukemia (AML; of whom 32 had received prior high-dose cytarabine), three of six with acute lymphoblastic leukemia (ALL), and one of eight with chronic myelogenous leukemia in blast phase (CML-BP). CONCLUSION The recommended phase II dose of topotecan with intermediate-dose cytarabine is 4.75 mg/m2/d for high-risk patients and 7.0 mg/m2/d for low-risk patients. The percentage of cells in S phase was important in determining response to treatment.

Abstract 13513: MitraClip ® for Functional Mitral Regurgitation: Outcomes in Over 600 Patients

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Gorav Ailawadi ◽  
D. Scott Lim ◽  
Irving L Kron ◽  
Alfredo Trento ◽  
Saibal Kar ◽  
...  
Keyword(s):  
Coronary Artery ◽  
High Risk ◽  
Mitral Regurgitation ◽  
Nyha Class ◽  
Class I ◽  
Symptom Improvement ◽  
Surgical Risk ◽  
High Risk Patients ◽  
High Surgical Risk ◽  
Risk Patients

Background: The treatment options for degenerative or primary mitral regurgitation (DMR) include mitral surgery and transcatheter edge-to-edge repair (MitraClip). However, the optimal therapy for patients with functional or secondary MR (FMR) remains unclear. The purpose of this study was to evaluate the 1 year outcomes of all patients with FMR undergoing MitraClip in the United States as part of the EVEREST (Endovascular Valve Edge-to-Edge Repair STudy) II study. Methods: Patients treated in the EVEREST II trial (randomized trial and continued access registries) with severe FMR were evaluated. Outcomes at 30 days and 1 year were analyzed and adjudicated by an independent core laboratory. Patients were further stratified by surgical risk (High risk= STS mortality score ≥12% or pre-specified risk factors). Results: A total of 619 patients (mean age=73.4 years) with FMR were treated with MitraClip. Comorbidities were common including coronary artery disease (81.1%), NYHA functional class III/IV (80.3%), and previous coronary artery bypass grafting (55.7%). Device implantation was achieved in 96.4% with a mean hospital stay of 3.3 days and an 87.2% discharge to home. At 30 days, mortality was 3.6% with a major adverse event rate of 9.2%. At 1 year, the survival was 78.3%, while the majority of survivors had MR≤2+ (84.5%) and significantly improved symptoms (83.2% NYHA Class I/II). The left ventricular end diastolic volume (LVEDV) improved from 162.5ml to 152.6ml (P<.001). When comparing high surgical risk patients (n=485; mean STS score=10.6±6.9%) to non-high risk patients (n=134), the 30 day mortality was similar (4.1% vs. 1.5%, P=.19), but the 1 year mortality was worse (22.7% vs. 13.4%, P=.02). Nevertheless, at 1 year, there were similar rates of MR reduction (MR≤2+: 83.9% vs. 87.3%) and improvement in LVEDV (-9.0ml vs -12.6ml). The non-high risk cases had greater symptom improvement (NYHA Class I/II: 91.2% vs. 80.2%, P=.001). Conclusions: MitraClip in patients with severe FMR is associated with excellent safety, positive ventricular remodeling, symptom improvement, and stable MR reduction at 1 year independent of surgical risk. Compared to high surgical risk patients, non-high risk patients may derive the greatest survival and symptom benefit.

Effect of Circulating CCL3, Which Is Produced by Malignant Cells of Waldenström's Macroglobulinemia, on Patients' Survival

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2894-2894
Author(s):  
Evangelos Terpos ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Efstathios Kastritis ◽  
Anna Tasidou ◽  
Dimitrios Christoulas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Median Survival ◽  
Plasma Cells ◽  
Malignant Cells ◽  
Santa Cruz ◽  
Minor Response ◽  
High Risk Patients ◽  
Probability Of Survival ◽  
Risk Patients

Abstract Abstract 2894 C-C motif ligand 3 (CCL3) chemokine, previously known as macrophage inflammatory protein-1 alpha, is a member of the C-C chemokine family. CCL3 has chemotactic function against monocytes, macrophages, mast cells, T-lymphocytes, dendritic cells, eosinophils and natural killer cells. Circulating CCL3 is elevated in hematopoietic malignancies, including multiple myeloma and chronic lymphocytic leukemia (CLL). CLL cells produce CCL3 and a recent study has shown that circulating CCL3 is an independent prognostic factor for survival in CLL patients (Sivina et al, Blood 2011;117 :1662–9). Waldenström's macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration along with an IgM monoclonal gammopathy. Our group has previously shown that malignant cells of WM patients express CCL3 (Terpos et al, Clin Lymphoma Myeloma Leuk 2011;11 :115–7). However, there is no information for the prognostic significance of CCL3 in WM. To address this issue, we studied 41 newly-diagnosed patients with symptomatic WM who required therapy. Fifty-eight per cent were males and their median age was 66 years (range: 39–82 years). According to ISSWM, 22% were low risk, 60% were interemediate risk and 18% were high risk patients. Circulating CCL3 was evaluated using an ELISA methodology (R&D Systems, Minneapolis, MN, USA) in all patients and in 40 healthy, age- and gender-matched, individuals who served as controls. Bone marrow biopsy sections of all patients at diagnosis were immunochemically tested for the expression of CCL3 (using an anti-CCL3 monoclonal antibody by Santa Cruz Biotechnology, Santa Cruz, CA, USA), CD20, CD79a, CD138, MUM-1, as well as for mu, gamma, alpha heavy and kappa and lambda light immunoglobulin chains. The immunoreactivity of CCL3 was examined on the basis of positive lymphoplasmacytic and/or plasma cells with a cut-off value of >20% positive cells to be defined as positive expression. Median circulating CCL3 levels were higher in WM patients 66 pg/ml (range 10.6–1627 pg/ml) compared to healthy controls (median 15.4 pg/ml, range: 1.4–54 pg/ml; p=0.01). In all WM cases, the whole number of the neoplastic cells, including CD20(+)/CD138(-)/MUM-1(-)/CIgM(kappa)(+) B-lymphocytes (small lymphocytes, lymphoplasmacytoid lymphocytes and rare immunoblasts) as well as CD20(-)/ CD138(+)/MUM-1(+)/CIgM(kappa)(+) plasma cells revealed strong cytoplasmic positivity for CCL3. Elevated circulating CCL3 correlated with high serum beta2-microglobulin levels (r=0.385, p=0.019), but there were no strong correlations between CCL3 levels and ISSWM stage, serum LDH, serum albumin, serum IgM levels or age. All patients received rituximab-based regimens as first line therapy and 67% of them achieved at least a minor response. The median survival of all patients has not been reached yet, while the 3-year probability of survival was 77%. The 3-year probability of survival for low-, intermediate- and high-risk patients per ISSWM was 100%, 77% and 38%, respectively (p=0.018). We then evaluated the effect of circulating CCL-3 on patients' survival using as a cut-off value the level of 54 pg/ml, which was the highest CCL3 value of our control group. The median survival for WM patients with CCL3 levels ≥54 pg/ml was 67 months, while it has not been reached for patients with CCL3 levels <54 pg/ml (Figure; p=0.093). In conclusion our results suggest that CCL3 is produced by WM cells and its high circulating levers are associated with a clear trend for inferior survival. These observations support a role of CCL3 in WM biology through interactions of the malignant clone with the marrow microenvironment and reveals CCL3 as a potential target for developing novel drugs against WM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Abstract Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

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