Multiple Transplant-Related Risk Factors for Hemolysis Including Major Kidd-Group Incompatibility Did Not Influence the Favourable Course of Unrelated Donor Bone Marrow Transplantation for Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5444-5444
Author(s):  
Miroslaw Markiewicz ◽  
Iwona Wylezol ◽  
Sebastian Giebel ◽  
Malgorzata Krawczyk-Kulis ◽  
Jerzy Wojnar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Effective Treatment Option ◽  
Single Donor ◽  
Related Risk ◽  
Severe Pancytopenia ◽  
Nasal Septum Perforation ◽  
Cmv Reactivation

Abstract The significance of additional transplant-related risk factors for hemolysis, including potentially severe hemolysis due to Kidd group incompatibility, is unknown in BMT from matched unrelated donors (MUD). We report MUD BMT for 35y old male PNH patient (pt) diagnosed 1,5y before, with CD59 defect on 95% of erythrocytes (Er), with refractory hemolysis (LDH 1886 U/l, haptoglobin 0.08 g/l) and IgG autoantibodies on Er, previously treated with steroids and multiple transfusions with increasing frequency. BMT-related risk factors for hemolysis were: major Kidd incompatibility (Jk(b)+ donor and detectable anti-Jk(b) alloantibodies in titer 2 in pt), minor AB0 incompatibility (pt B, donor 0 with anti-B titer 1:16) and different Rh (pt−, donor+). Other risk factors included CMV seronegativity of the donor and seropositivity of the pt, arterial hypertension, steroid-related diabetes mellitus and probable former thrombotic episode leading to nasal septum perforation. MUD was ten alleles HLA-matched 38y old male. Myeloablative conditioning consisted of Treosulfan, Fludarabine and Thymoglobulin. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin-A and methotrexate. Gancyclovir and IgG were used for CMV-reactivation prophylaxis. Transplanted bone marrow was depleted of Er on Fenwall CS3000 plus and contained 0.5x10(8) NC/kg, 2.1x10(6) CD34+ cells/kg and 12.5x10(6) CD3+ cells/kg. No serious complications were observed during the treatment and post-transplant aplasia. Filtered washed Er 0Rh-Jk(b)- were transfused 7x and single-donor platelets 7x. Following 11 days of absolute agranulocytosis full reconstitution of haematopoiesis was achieved with granulocyte count of 1.0x10(9)/l and platelets 50x10(9)/l on day +22, Hb 10 g/dl on day +26. Acute GVHD grade II was transiently present since day +21 and responded well to low-dose methylprednisolone. No chronic GVHD was observed. CMV reactivation with transient severe pancytopenia developed after day +70 and was overcome with ganciclovir, foscarnet and immunoglobulins. Hemolysis gradually decreased (LDH less than 400 U/L since day +5, normal haptoglobin >0.7 g/l since day +38). Anti-Jk(b) alloantibodies titer reached 0 on day +31 and since then they were detectable only with use of a micro-method. Full 100% donor chimerism was achieved on day +28 and was re-confirmed on days +71 and +99. Recipient-type population of erythrocytes gradually decreased (24%, 7% and 1% on days +30, +70 and +98, respectively). Complete eradication of PNH clone was confirmed by absence of complement inhibitor CD55 (DAF) and CD59 (MIRL) defects on 100% of erythrocytes and granulocytes in flow-cytometric evaluation performed on day +160. The patient stays at home without any signs of GVHD, hemolysis nor PNH over 9 months following BMT. We conclude that MUD BMT can be offered as an effective treatment option despite multiple transplant-related risk factors for hemolysis including Kidd group incompatibility.

Higher Rate of Thrombotic Thrombocytopenic Pupura (TTP) Associated with Graft Versus Host Disease (GVHD) and Unrelated Donor Bone Marrow Transplantation (BMT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1111-1111
Author(s):  
B. Oran ◽  
A. Aleman ◽  
E. J. Shpall ◽  
C. Hosing ◽  
M. Korbling ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Stem Cell ◽  
Median Time ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Lymphoid Malignancies ◽  
Gvhd Prophylaxis

Abstract TTP is one of the complications of allogeneic hematopoietic stem cell transplantation (HSCT). In contrast to idiopathic cases, post-transplantation TTP may not be associated with severe von Willebrand factor-cleaving protease deficiency but rather a diffuse endothelial injury. Our aim was to define incidence, risk factors and mortality of TTP following allogeneic HSCT. 1312 patients with lymphoid malignancies (n=605), myeloid malignancies (n=688) or aplastic anemia (AA, n=18) who were treated with ablative preparative regimens (n=614) or reduced intensity regimens (n=697) followed by HSCT from an HLA matched related (MRD, n=694) or unrelated donor (MUD; n=461) and 1–3 antigen mismatched related (MMR, n=99) or unrelated donor (MMUD, n=57) between December 1997 and December 2004 were studied. Patients with prior allogeneic HSCT or graft failure were excluded. GVHD prophylaxis was tacrolimus-based in 1276 (97.3%) and cyclosporine based in 15 (1.1%) patients. Twenty patients did not receive GVHD prophylaxis per protocol. Anti-thymocyte-globulin (ATG) was added in 350 patients. Stem cell sources were bone marrow (n=626), peripheral blood (n=635) or cord blood (n=50). The following variables were evaluated: age, gender, primary diagnosis, disease status before HSCT, intensity of preparative regimen, stem cell source and acute GVHD(aGVHD) grade ≥2 (time dependent variable). Of the 1312 patients with a median follow-up from transplantation of 11.4 months (range, 5 days-7.2 years), 77 developed TTP (6%). The actuarial risk of developing TTP was 6.5% at 1 year. The median time of the onset of TTP was 67 days post HSCT (range, 11–1812) with 27 cases (35%) presenting after day 100. Female gender, lymphoid malignancies, unrelated or antigen mismatched related donor and aGVHD grade ≥2 were found to be independent risk factors. (Table1). Among the patients who had aGVHD grade≥2, the median time of interval between the onsets of two events was 25 days (range, 2–335 days). All patients were treated with therapeutic plasma exchange (PE). Of the 77 patients only 1 died of TTP (intracranial hemorrhage). The overall one-year survival after TTP was 29% and the most common cause of death were acute or chronic GVHD (n=35, 55%) and primary disease progression (n=10, 16%). Stem cell donors other than MRD, lymphoid malignancies and aGVHD≥2 have been established as risk factors associated with development of TTP and therapeutic PE has been shown to decrease TTP related mortality. Risk factors for TTP after allogeneic HSCT Variables sample size events HR 95% CI p Male 793 33 1.0 Female 518 44 2.2 1.3–3.6 0.002 Myleoid malignancy 688 33 1.0 Lymphoid malignancy 605 42 1.9 1.1–3.3 0.03 AA 18 2 1.3 0.2–8.0 0.75 MRD 694 28 1.0 MUD 461 40 2.9 1.6–5.1 <0.001 MMR 99 7 2.4 0.9–6.0 0.06 MMUD 57 2 1.7 0.4–7.6 0.5 aGVHD ≥2 370 39 3.3 2.0–5.5 <0.001

Unrelated Donor Marrow Transplantation for B-Cell Chronic Lymphocytic Leukemia After Using Myeloablative Conditioning: Results From the Center for International Blood and Marrow Transplant Research

2005 ◽  
Vol 23 (24) ◽  
pp. 5788-5794 ◽  
Author(s):  
Steven Z. Pavletic ◽  
Issa F. Khouri ◽  
Michael Haagenson ◽  
Roberta J. King ◽  
Philip J. Bierman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Cell Chronic Lymphocytic Leukemia

Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

scholarly journals Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2354-2363 ◽  
Author(s):  
J Casper ◽  
B Camitta ◽  
R Truitt ◽  
LA Baxter-Lowe ◽  
N Bunin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Significant Difference ◽  
Matched Sibling

Allogeneic bone marrow transplantation is the treatment of choice for many childhood leukemias. The donor of choice-an HLA matched sibling-is only available about 30% of the time. Unrelated donors are an alternative choice. In this report, we describe the results of unrelated donor bone marrow transplants (BMT) in 50 children with leukemia (25 acute lymphoblastic leukemia [ALL], 3 acute myeloid leukemia [AML], 3 juvenile chronic myelogenous leukemia [JCML], 10 chronic myeloid leukemia [CML]) or myelodysplastic syndrome (MDS; 9). The median age of the 31 male and 19 female patients was 9 years (range 2 to 18). Only 13 patients were serologically matched at HLA-A, B, DR, and DQ with their donors; 6 of these were reactive in mixed lymphocyte culture. The other 37 patients were mismatched for one (36 patients) or more (1 patient) HLA antigens. Pretransplant conditioning included cytosine arabinoside, cyclophosphamide, fractionated total body irradiation (TBI) (with lung, liver, and more recently, kidney shielding), and methylprednisolone. High-risk patients also received busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of T- cell depletion with IgM monoclonal antibody T10B9 plus complement and posttransplant cyclosporine-A. Forty-nine patients (98%) engrafted. Median times to greater than 500 polymorphonuclear leukocytes (PMN)/microL and greater than 25,000 platelets/microL were 18 and 20 days, respectively. Acute GVHD > or = grade II occurred in 16 patients (33%); 13 (81%) of these died. Chronic GVHD developed in 30 of 40 patients at risk, but was extensive in only 5. Event-free survival (EFS) for all patients was 44% +/- 7% (median follow-up was 49 months), and overall survival was 50 +/- 7%. Patients with low-risk disease (ALL or AML in first or second remission and CML in chronic phase) had a better EFS than children with high-risk disease (60% v 34%, P = .07). There was no significant difference in EFS between patients who were serologically matched with their donors (46%) and those who were partially mismatched (43%) (P = .97). These data compare favorably with published reports for children transplanted with HLA-matched sibling donors and should encourage earlier consideration of unrelated donor BMT in children with leukemia or myelodysplasia.

scholarly journals Predictors of death from chronic graft-versus-host disease after bone marrow transplantation

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1428-1435 ◽  
Author(s):  
JR Wingard ◽  
S Piantadosi ◽  
GB Vogelsang ◽  
ER Farmer ◽  
DA Jabs ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Actuarial Survival ◽  
Host Disease ◽  
Late Morbidity

Abstract Chronic graft-v-host disease (chronic GVHD) is a frequent cause of late morbidity and death after bone marrow transplantation (BMT). The actuarial survival after onset of chronic GVHD in 85 patients was 42% (95%Cl = 29%, 54%) at 10 years. Baseline characteristics present at the onset of chronic GVHD (before therapy) in 85 patients were reviewed to determine which were risk factors for death. In a multivariate proportional hazards analysis, three baseline factors emerged as independent predictors of death: progressive presentation (chronic GVHD following acute GVHD without resolution of acute GVHD; hazard ratio of 4.1, 95% Cl = 2.1 to 7.8), lichenoid changes on skin histology (hazard ratio of 2.2, 95% Cl = 1.1 to 4.3), and elevation of serum bilirubin greater than 1.2 mg/dL (hazard ratio = 2.1, 95% Cl = 1.1 to 4.1). Actuarial survival of 23 chronic GVHD patients with none of these risk factors was 70% at 6 years (95% Cl = 38%, 88%). Thirty-eight patients with one of these risk factors had a projected 6-year survival of 43% (95% Cl = 21%, 63%). The 29 patients with any combination of two or more of these factors had a projected 6-year survival of only 20% (95% Cl = 8%, 37%). Identification of baseline risk factors should facilitate design of trials of chronic GVHD therapies and assignment of high-risk patients to more aggressive innovative therapeutic regimens.

Alemtuzumab (Campath 1-H) Exposure Correlates with Risk of Chronic Graft vs Host Disease and CMV Viremia after Allogeneic Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1818-1818
Author(s):  
Justin P. Kline ◽  
Rajiv Swamy ◽  
Dezheng Huo ◽  
Laura Michaelis ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
At Risk ◽  
Half Life ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Absolute Lymphocyte Count ◽  
Enzyme Linked Immunosorbent Assay ◽  
Unrelated Donor ◽  
Increased Risk ◽  
Cmv Reactivation

Abstract Conditioning regimens using in vivo alemtuzumab (Campath-1H, humanized anti-CD52) are characterized by low rates of acute and chronic GVHD, but may also result in delayed immune reconstitution. Optimization of such regimens will depend on an understanding of the relation between alemtuzumab exposure, immune reconstitution and GVHD. We have conducted a prospective study of fludarabine 30 mg/m2/d x 5 days, melphalan 140 mg/m2 x 1 day and alemtuzumab 20 mg/d x 5 days as conditioning for related and unrelated allografts. Using an enzyme-linked immunosorbent assay (ELISA), we determined serum free and total Campath levels in 46 patients with hematologic malignancies (45) or sickle cell disease (1) on day 0, day 7, day 14, day 28, day 50, day 75, day 100, day 150 and at one year after transplant (HSCT). 26 (57%) had a matched sibling donor, 16 (35%) a matched unrelated donor (MUD) and 4 (9%) a mismatched related or unrelated donor. 44 pts engrafted and are included in the analysis. Median follow up for survivors was 2.8 years. Grade II–IV aGVHD occurred in 8 pts after a median of 42 days (range 22 to 60). Eight pts developed cGVHD after a median of 107 days (range 89–140). 15/41 (37%) at risk pts developed CMV reactivation. The half-life of free alemtuzumab (fA) was 26 days after HSCT with wide interpatient variation in fA pharmacokinetics (e.g. Coefficient of variation was 138% on day 0). On day 0, 1 patient had an undetectable level of fA. By day 28, 50, and 100, there were 6 (14.6%), 12 (35.3%), and 13 (52%) pts with undetectable fA, respectively. Figure 1 shows the fitted means and 95% confidence intervals of fA over time. Using log-rank and Cox proportional hazard models, there was no association between fA on day 0, day 28, or the last available fA, and development of acute GVHD. However, pts with higher average free and total Campath levels in the first month had a lower risk of developing cGVHD (p=0.02). The median fA concentration in the first month for pts with cGVHD was 0.32 (inter-quarter range IQR: 0.22–0.41), as compared with 0.97 (IQR: 0.23–3.31) in those without cGVHD. No significant association between absolute lymphocyte count and fA concentration was found after adjusting for time (p=0.28). Finally, among pts at risk, a higher fA concentration on day 0 (p=0.002), and in the first month (p=0.003) was significantly associated with CMV viremia. In summary, the estimated half-life of serum fA is 26 days after HSCT, but with considerable interpatient variability. Higher concentrations of fA were associated with a decreased incidence of cGVHD, but an increased risk of CMV reactivation. In contrast to a previous preliminary analysis, no association existed between fA and lymphocyte reconstitution. Variation in alemtuzumab pharmacokinetics may predict important clinical outcomes, such as cGVHD and CMV reactivation. Future studies are warranted to determine an optimal alemtuzumab exposure that hastens immune reconstitution while minimizing chronic GVHD. Fig 1. Fitted Mean Free Campath and 95% CI Fig 1. Fitted Mean Free Campath and 95% CI

Primary Graft Failure (GF) after Unrelated Donor Cord Blood Transplants (UCBT): Risk Factors and Management.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 44-44 ◽  
Author(s):  
Ka Wah Chan ◽  
Michael S. Grimley ◽  
Candace Taylor ◽  
Donna A. Wall
Keyword(s):  
Risk Factors ◽  
Cord Blood ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Viral Reactivation ◽  
Unrelated Donor ◽  
Cell Dose

Abstract Primary GF is recognized as a major risk in UCBT. Both graft (cell dose and quality of the cord blood unit) and recipient (diagnosis of aplastic anemia, prior chemotherapy exposure) characteristics have been reported as being associated with non-engraftment. Here we present a large series of UCBT patients from a single institution and analyze the risk factors and management of this complication. Between 3/2001 and 7/2006, 106 consecutive patients (pts), of median age 5.3 (range 0.1–18.4) years and weight median 22 (range 4–85) kg, received UCBT at Texas Transplant Institute. 13 did not achieve donor engraftment as documented by recovery of ANC< 500/μl by day + 42, and lack of donor cells on ≥2 RFLP analysis of the bone marrow. Failure to attain engraftment occurred in 5/27 with a non-malignant disorders, and 8/79 with hematologic malignancies (p< 033). Non-engraftment was less common in better HLA matched transplants (≥5/6 HLA match: 1/45 vs ≤ 4/6 HLA : 12/61; p< 0.02). Preliminary analysis showed no difference in cord blood TNC/kg, CD34/kg and pre thaw CFU/kg in pts who had primary GF compared to the rest of the cohort. A post thaw CFU/pre-freeze ratio of <20% was more common in primary GF. Among the 79 pts with hematologic malignancies (HM), 8 did not engraft. 4 died early; 1 from persistent leukemia, and 3 from transplant-related complications (TRM). Of the remaining 4 pts with HM, 2 were ALL children in CR1. The other primary GF occurred in 2/5 children with HLH (both with active disease at UCBT), 2/8 the children transplanted for aplastic anemia, and one pt with CD40L deficiency who had primary GF. The 9 pts who had not relapsed or died of TRM went on to second (2nd) UCBT 33 to 95 (median 55) days after first transplant (1st UCBT). Conditioning regimen for 2nd UCBT was fludarabine 175mg/m2, cyclophosphamide 50mg/kg, TBI 2 Gy, ± ATG in 7/9 patients. Median cell dose for 2nd UCBT were 3.6 × 107/kg. HLA matching was similar to 1st UCBT. There was one TRM (respiratory failure) but the rest (8/8) engrafted; with ANC >500/μl at a median of 15 (range 5–64) days, and platelets > 20000/μl at a median of 92 (range 24 to 137) days. All became transfusion-independent, and as of 8/1/2006, 7 of 9 pts are alive. All have complete donor chimerism 164–1616 (median 672) days after 2nd UDCBT. EBV-lymphoproliferatve disorders developed in 2 patients and it was fatal in one. Other viral infections encountered were BKV(1), HHV-6(1), CMV(3) in the blood; adenovirus(1) and enterovirus(1) in the stool; and BKV (1) in the urine. Acute graft-versus-host disease (GVHD) was diagnosed in 2/8 pts. 7/8 pts surviving >100 days had chronic GVHD, and it was extensive in 5 pts. It is important that primary GF be recognized as a risk of UDCBT and a back-up donor source be identified prior to transplant. Children with intact/active immune systems prior to transplant are at greater risk. Early 2nd UCBT, before patient’s condition deteriorates, is a feasible treatment alternative. This immunosuppressive preparative regimen is well tolerated early post first UCBT and can result in reliable engraftment, albeit a greater risk of chronic GVHD and viral reactivation post transplant.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

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.

Allogeneic Bone Marrow Transplantation From Unrelated Donors in Multiple Myeloma: A Study from the Italian Bone Marrow Transplantation Donor Registry

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2009-2009
Author(s):  
Benedetto Bruno ◽  
Roberto Passera ◽  
Francesca Patriarca ◽  
Francesca Bonifazi ◽  
Vittorio Montefusco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Stem Cell Source ◽  
Cell Source ◽  
Reduced Intensity

Abstract Abstract 2009 To evaluate the role of allografting from unrelated donors in the treatment of myeloma we conducted a retrospective study through the Italian Bone Marrow Transplantation Donor Registry. Overall, from 2000 through 2009, 196 myeloma patients, median age 51 years (32–67), for a total of 199 allografts, were transplanted from an unrelated donor at 34 Centers in Italy. Fifty-two (28.1%%), 69 (37.3%), and 64 (34.6%) patients were prepared for transplant with a myeloablative, a reduced-intensity and a non-myeloablative conditioning respectively. Patient characteristics of the 3 cohorts are reported in Table 1.ConditioningMyeloablativeReduced-intensityNon-myeloablativePatient number (%)52/185 (28)69/185 (37)64/185 (35)Median Age455355Previous therapy lines < 2 (%)23 (27)33 (38)30 (35)Previous therapy lines ≥ 2 (%)29 (29)36 (37)34 (34)Stem Cell Source BM (%)24 (57)18 (43)0 (0)Stem Cell Source PBSC (%)28 (19)51 (36)64 (45) Cumulative incidence of acute grade II-IV graft-versus-host-disease (GVHD) was 46.4% whereas chronic GVHD was 45.1%. There was no difference in GVHD incidence among the 3 cohorts defined by type of conditioning. Complete and partial remissions in patients who survived at least 3 months post-transplant were 27% and 28% for an overall response rate of 55%. At a median follow up of 32 (0–118) months post-transplant, in the entire study population, median OS from diagnosis was 70.6 months while OS and EFS from the allograft were 18.9 and 14.9 months. Overall, the cumulative incidence of transplant related mortality (TRM) was 29.6% at 1 year and 32.4% at 5 years post-transplant. OS from diagnosis and EFS from transplant were 70.6 and 28.2 months; 66.8 and 9.1 months; and 111.9 and 22.4 months in patients who respectively underwent a myeloablative, a reduced-intensity and a non-myeloablative transplant. One-year and 5-year TRM was 33.3% and 35.7%, 32.2% and 34.4%, and 22.1% and 26.5% respectively. Univariate and multivariate analyses, assessed by multivariate Cox proportional hazards models, were performed for the following variables: number of previous chemotherapy lines (1,2 vs. ≥3), disease status at transplant, HLA- matched antigens (10/10 vs. 9/10 vs. ≤8/10), recipient/donor gender combinations, hematopoietic cell source (peripheral blood vs. bone marrow), conditioning (myeloablative vs. reduced-intensity vs. non-myeloablative), use of anti-thymoglobulin in the conditioning, acute GVHD, chronic GVHD, best response post-transplant, year of transplant (2000–02 vs. 2003–05vs. 2006–09). By univariate analysis, lower number of chemotherapy lines before the allograft, disease status at transplant, a fully HLA-identical donor, the use of peripheral hematopoietic cells rather than bone marrow were statistically significant variables for better OS whereas disease status at transplant, a fully HLA-identical donor, chronic GVHD (either limited or extensive) were statistically significant for better EFS. However, by multivariate analysis, only the development of chronic GVHD (HR 0.50; p<0.001) and a better response post-transplant (HR 2.11; p<0.03) were significantly associated with longer OS whereas chronic GVHD was the only variable associated with better EFS (HR 0.32; p<0.001). Acute GVHD was associated with both poorer OS (HR 2.35; p<0.001)) and EFS (HR 3.19; p<0.001). In conclusion, with a degree of caution given the retrospective nature of this study, there appears to be a strong association between both limited and extensive chronic GVHD and graft-vs.-myeloma effects. However, long term disease control remains an issue independent of the conditioning employed. Prospective trials may allow to define which patient category may most benefit from an unrelated donor allograft. Disclosures: Patriarca: Roche: Honoraria; Celgene: Honoraria; Schering-Plough: Honoraria; Janssen: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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