B. Outcomes after unrelated cord blood transplantation for children with malignant and non-malignant indications. An Utrecht-Prague collaborative study. Boelens J, Bierings M, Tilanus M, Lie J, Sedlacek P.
The authors analyzed the results of 44 unrelated CBTs in children with malignant (n=21) or non-malignant (n=23) disorders. The diagnoses in patients with malignant diseases were ALL, ALL-Ph+, infant ALL, AML, MDS/AML and JMLL. Diagnoses in the non-malignant group were IEM, SCID, hemophagocytic-lympho-histiocytosis and Fanconi anemia. Median age was 2.9 years (0.2-18.2); median follow-up was 18 months (1-84). The donor was HLA-identical in 8 cases (18%) and incompatible in 36 cases (82%: most with 1 (66%) and 2 (16%) HLA disparities. The median TNC and CD34+ cell doses at collection were 8.8 X 107/kg (2.4-37) and 3.3 X 105/kg (0.7-21.83), respectively. Eight patients received a TBI containing and 36 patients received a chemotherapy based myelo-ablative regimen. All patients received ATG.
Probability of neutrophil engraftment was 97% at a median of 22 days (10-58). Acute GVHD (grade II-IV) was observed in 27% (7% extensive) at two years. The OS at two years and DFS were 71% and 63%, respectively. There was no difference between malignant and non-malignant diseases in OS/EFS. The TNC and CD34+ cell doses did not influence the endpoints.
The authors concluded cord blood appears to be a good alternative stem cell source for malignant as well as for non-malignant disease.
C. Outcomes of second allogeneic transplants for primary graft failure after unrelated cord blood transplantation. Fernandes J, Rocha V, Setubal D, Bierings M, Champagne MA, Pasquini R, Socie G, Gluckman E, on behalf of Eurocord.
The authors retrospectively analyzed 35 patients who received a second UCBT following primary graft failure (PGF) after a first UCBT for hematological diseases. PGF patients were defined as those who did not achieve a neutrophil count >500 X 106/L by day 60 or who received a second transplant for PGF during this period. Patients who relapsed in the first 100 days after UCBT were excluded.
Median age was 11.3 years (range, 1-51). Diagnoses were acute leukemia (n=17), myelodysplasia (n=4) and bone marrow failure syndromes (n=14). Patients received either one (n=31) or two (n=4) unrelated CB units matched 3-6/6 (HLA A and B low resolution and DRB1 allelic typing) as donors for the first transplant. Median time between the first and second transplants was 55 days (22-116) and median follow-up after the second transplant was 18 months. For the second transplants, 3 patients received mismatched unrelated bone marrow grafts, 7 haploidentical related grafts, 15 single UCB and 10 double UCB grafts. T-cell depletion was used in 8 cases. Conditioning regimens were of reduced intensity in the majority of cases (generally fludarabine-based regimens).
Median time to neutrophil recovery was 19 days (10-47) and 19 of 35 patients engrafted (4 of 15 receiving a single CB unit, 7 of 10 receiving double CB units and 7 of 10 other alternative donors). Chimerism analysis for these patients at engraftment showed: 16 = complete donor and 3= mixed chimerism. Twelve patients (34% developed aGVHD grades II-IV and cGVHD was observed 5 of the 18 evaluable patients (28%). At 1 year, TRM was 39%±1% and OS was 41%±8%.
The authors concluded that these results suggest that second transplants in this set of extremely high risk patients are effective and should be considered early following primary graft failure after UCBT.
II. Annotated abstracts from the 2008 BMT Tandem Meetings which were held in San Diego, California February 13-17.
1. Chronic graft-versus-host disease (cGVHD) following sibling donor peripheral blood stem cell transplant (PBSCT) versus bone marrow transplant (BMT): Greater incidence and longer duration of immune-suppression using PBSC. Aurora M, Nagaraj S, DeFor TE, MacMillan ML, Wagner JE, et al.
Chronic GVHD is more frequent following peripheral blood stem cell (PBSC) than BMT. However, the responsiveness of the disease to immune-suppression using either stem cell source has not been well validated. The authors compared the time to discontinuation of immune-suppression between PBSCT and BMT in 184 patients with cGVHD after sibling donor transplantation. Of 717 sibling donor transplants, the cumulative incidence of cGVHD was 25% (95% CI 22-28%) overall and was more frequent after PBSCT [39% (95% CI 32-46%) versus BMT [17% (95% CI 14-20%), P<0.01]. The incidence of discontinuation of immune suppression (DIS) was 9% at 1 year and 67% by 5 years [DIS at 1 year: BMT15% versus PBSCT 5%; and at 2 years: 38% versus 32%. However, both approached 67% by 5 years. The multivariate analysis was restricted to adult patients who received myeloablative conditioning (n=130, 63 BMT, 67 PBSCT).
PBSC recipients, those with progressive onset of cGVHD and thrombocytopenia (<100,000/µl) at diagnosis of cGVHD had lower rates of DIS than BM recipients. After a median follow-up of 33 months, a trend towards superior overall survival at 5 years was seen in the BMT cohort [5 year survival: BMT 65% (95% CI 53-75%) versus PBSCT 58% (95% CI 45-69%), p=0.07].
Following sibling donor transplantation, cGVHD is more frequent and more resistant to immune-suppression therapy using PBSC vs BM. PBSC recipients were significantly more likely to require prolonged immune-suppression and to have extended morbidity from cGVHD. Careful attention to this serious later morbidity and mortality should guide clinical decisions about the use of either BM or PBSC sources for sibling donor transplantation.
2. Comparison of outcomes in children undergoing a single allogeneic transplant using bone marrow (BM) or umbilical cord (UCB) as stem cell source. The Children’s Memorial Hospital experience. Merchant M, Huang W, Kletzel M.
The authors evaluated 137 transplants with BM and 119 UCB transplants. Bone Marrow: 122 matched related, 15 MUD; 198 patients &8.8%) had malignancies (ALL, AML, others) and 29 (21.2%) had non-malignant conditions (thalassemia, aplastic anemia, SCIDS, others). 67.9% received myeloablative conditioning (fTBI, VP-Cy or Thiotepa); 32.1%had reduced intensity conditioning (RIC) (VP/Cy, Bu/FLU/±ATG). Age 9.2 years (0.2-23); weight 30.4 kg (4-85.1). HLA matching 6/6 (100), 5/6 (28), 4/6 (9). Median TNC dose infused was 1.96 x 108/kg, 1.22 x 108/kg MNC, 7.45 x 106/kg CD34. Umbilical Cord Blood: 82 patients (68.9%) had malignancies (ALL, AML, others); 37 patients (31.1%) had non-malignant conditions (SCIDS, Thalassemia, aplastic anemia, others). 79% received myeloablation (fTBI/VP/Cy for malignancies, fTBI/Cy±Thiotepa for non-malignant); 21% had RIC (VP/Cy or Bu/FLU/±ATG). Age 5.4 years (0.1-20.6), weight 15.7 kg (4-73). HLA matching 6/6 (12), 5/6 (29), 4/6 (70), 3/6 (8). Cell dose infused was 0.8 x 108/kg TNC, 0.55 x 108/kg MNC, 0.78 x 106/kg CD34.
Results in bone marrow transplants: 86.3% achieved ANC (>500 cells/µL), 88.4% achieved platelet (>20,000 cells/µL) at a median of 18.3 days (I10-71) and 32.9 days (4-222), respectively. 23 patients (26.8%) died from transplant related mortality (TRM) (d +100). 20 patients (14.6%) had relapse at 132 days from transplant (6-1097). 55.3% patients developed acute GVHD, 17.5% chronic GVHD. 75 patients (54.7%) are event free survivors with median f/u of 3234 days. Overall survival is 52.9% with f/u of 896 days. Results in umbilical cord blood transplants: 67.6% achieved ANC and 62.1% achieved platelet engraftment at median of 26 days (14-62) and 46 days (14-105), respectively. 26 patients (21.8%) died from TRM. 19 patients (16%) had relapse in 53 days (21-503). 54.6% had acute GVHD, 0.2% had chronic GVHD. 65 (54.6%) are EFS at present with f/u of 1967 days and OS is 52.2% with f/u of 769 days.
The authors concluded that patients undergoing a single allogeneic transplant with BM or UCB show no statistical difference in TRM, relapse, EFS, OS, or acute GVHD. A statistically significant difference was found in age, infused cells dose, time to engraftment and in chronic GVHD. UCB patients were younger, received lower cell dose have less chronic GVHD.
3. Acute graft-versus-host disease (GVHD) in unrelated cord blood transplantation (UCBT): Single institution experience, July 1996-June 2007. Alsultan A, Giller RH, Bathurst J, Hild E, et al.
UCBT has been associated with a lower incidence of GVHD when compared to unrelated transplant using adult donors. However, the characteristics (sites, time to onset, course, and tolerability) of GVHD following UCBT have not been as clearly elucidated.
The authors reviewed GVHD in 81 consecutive UCBT [treated on a single therapeutic trial with consistent GVHD prophylaxis. 13 patients were unevaluable based on death prior to UCB infusion (1), death prior to engraftment (7) or graft rejection (4). Thus, 68 patients were evaluable (median age 6.8 years (0.3-24.4); median weight 22 kg (5.35-82.9). Diagnoses included leukemia in 75%, MDS 3%, lymphoma 1%, metabolic disorders 6%, immune/genetic disorders l9%, and aplastic anemia 6%. The median TNC infused was 4.06 x 107/kg (range 0.73-28 x 107/kg), median CD34 cells infused 2.3 x 105/kg (range 0.3-31.7 x 105/kg). HLA matching was 6/6 (23), 5/6 (31) and 4/6 (14). Conditioning was TBI –based in 66 % and non-TBI-based in 34%. GVHD prophylaxis was cyclosporine and steroids in 91%, cyclosporine and methotrexate +/- steroids in 7% and other in 2%.
Median engraftment times were 23.5 days for neutrophils and 65 days for platelets. Acute GVHD had a median day of onset of 25 days (10-93) with grade II-IV seen in 49% and grade III-IV in 25% of patients. Event free survival at 1 and 2 years were 62% and 58% for patients without acute GVHD, 75% and 56% for grade II only, and 53% and 47% for grade III-IV acute GVHD. Survival with higher grade GVHD may be related to both the more delayed onset of GVHD and more manageable course of GVHD after UCBT.
4. Unrelated cord blood transplantation in adults with lymphoid malignancies. A Eurocord/EBMT-lymphoma working party study. Rodrigues CA, Sanz G, Brunstein C, Renaud M, et al.
Little is known about the outcome of UCBT in patients with advanced lymphoid malignancies. The authors evaluated 104 adult patients (median age 41 years, range 16-65) who received a single (n=81) or double (n=23) unrelated UCBT for advanced lymphoid malignancy. Sixty-three patients had a non-Hodgkin lymphoma, 28 had Hodgkin lymphoma, and 13 had B-cell lymphomas. The majority of patients had advanced disease and 54% had a prior autologous transplant. Based on antigen-level HLA-A and B and allele-level HLA-DRB1 grouping, cord blood units were matched (9%) or mismatched at 1 (26%), 2(59%) or 3 (6%) antigens. The median number of cellos 8in fused was 2.4 x 107 TNC/kg for single transplants and 3.1 x 107 TNC/kg for double transplants. Conditioning regimen varied according to the transplant center, but 62% received a reduced-intensity conditioning (RIC). GVHD prophylaxis was achieved with cyclosporine and MMF in 48% of cases. Median follow-up time for survivors was 14 months.
The probability of engraftment at day 60 was 86%, with a median time to engraft of 20 days (3-54). In a multivariate analysis, a higher cell dose (2.5 x 107 TNC/kg) was significantly associated with the neutrophil engraftment (p=0.04). Grade II-IV acute GVHD was observed in 24% of the patients. TRM was 34% at 6 months. In a multivariate analysis, TRM was significantly lower for patients with B-cell malignancies as compared to those with Hodgkin or T-cell lymphomas (21% vs 49%, p=0.005), patients who received TBI (25% vs 49%; p=0.04). DFS at 1 year was 40%. In a multivariate analysis, DFS was significantly better for patients with B-cell malignancies (54% vs 21%, p=0.006) and patients who received TBI (48% vs 23%; p=0.001).
The authors concluded that UCBVT is a valuable alternative for patients with advanced non-Hodgkin lymphoma and CLL. B-cell malignancies and the use of TBI are associated with a significantly better outcome.
5. Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis. Cutler C, Kao G, Ho V, Alyea E, et al.
The authors studied double umbilical cord blood transplantation (DUCBT) using sirlolimus and tacrolimus to improve GVHD outcomes.
Conditioning consisted of fludarabine (30 mg/m2 x 6), melphalan (100 mg/m2 x 1), and rabbit ATG (1.5 mg/kg x 4). UCB units were >4/6 HLA-A, B, DR allele-matched with each other and the recipient, and contained a minimum combined dose of 3.7 x 107 TNC/kg pre-cryopreservation. GHVD prophylaxis was tacrolimus and sirolimus.
The authors report on 29 patients (median age 49 years (range 19-67) with >100 day follow-up. Diagnoses include AML, NHL, HD, MDS, CLL/PLL, ALL, MPD, and CML. Median total cell doses prior to cryopreservation were 5.2 x 107 TNC/kg (range 3.7-7.6) and 12.5 x 106 CD34+ cells (range 1.5-29.0). Neutrophil engraftment occurred at a median of 21 days (range 13-70) and platelet engraftment occurred at a median of 42 days (range 25-162) after DUCBT.
Three patients developed grade II-IV aGVHD (2 grade II and 1 grade III, median 21 days). Acute GVHD was less frequent when compared with a prior DUCBT cohort that received cyclosporine and MMF as GVHD prophylaxis (10.3% vs 36.9%, p=0.04). Only 2 patients developed chronic GVHD after DUCBT.
The median follow-up is 13.5 months (15.2 months among survivors, range 4.1-22.3 months). 100 day treatment-related mortality was 10.3%, without any VOD or TMA. One and two year relapse-free survival is 56.9% and 45.6% and overall survival is 74.8% and 69.8% at 1 and 2 years. Chimerism analysis at day 100 (n=23) revealed complete single cord chimerism in 13 subjects with mixed chimerism in 10. The first unit infused was the predominant unit at day 100 in 15/23 subjects. There was no correlation between cord dominance and HLA match, TNC/kg or CD34+ cell count.
The authors concluded that their study demonstrates excellent engraftment after DUCBT using a reduced-intensity conditioning regimen. The risk of acute and chronic GVHD are low when sirolimus and tacrolimus are used as GVHD prophylaxis, and survival is comparable to historical unrelated donor cohorts.
6. The feasibility of using CCR5Δ32/Δ32 hematopoietic stem cell transplants for immune reconstitution in HIV-infected children. Chen TK, Moore TB, Territo M, Chow R, Tonai R, Petz L, et al.
Studies demonstrate that homozygosity for a 32 bp deletion in the HIV-1 CCR5 co-receptor gene (CCR5Δ32) is associated with protection against R5 HIV infection, while CCR5Δ32 heterozygosity is associated with slower disease progression. Thus, T-cells developing after a transplant with HSC homozygous for the CCR5Δ32 mutation should be resistant to R5 HIV infection. The authors evaluated the feasibility of HSC transplantation using CCR5Δ32/Δ32 stem cells for the immune reconstitution of HIV-infected children who are imunocompromised despite HAART.
StemCyte, an international cord blood bank, has been actively screening their cord blood units for the CCR5Δ32 allele. To date, StemCyte has identified 30 homozygotes and 754 heterozygotes for the CCR5Δ32 mutation among 10,488 CBUs screened. 44 patients were randomly selected from a cohort of HIV-infected children and adolescents and HLA typing was performed to identify patients with potential HLA matched CBUs. Seven (15.0%) of patients had a 4/6 HLA match to the identified homozygous CBUs and 20 (45%) had a 3/6 match. Two of 7 patients have cord bloods with sufficient cell count for transplant.
Thus, the authors have identified and characterized 7 potential HIV-positive patients who could benefit from a transplant of HLA-matched, CCR5Δ32/Δ32 umbilical cord blood stem cells.
7. A multicentric comparative analysis of outcomes of HLA identical related cord blood and bone marrow transplantation in patients with beta-thalassemia or sickle cell disease. Kabbara N, Locatelli F, Rocha V, Ghavamzadeh A, Bernaudin F, Li C-K, et al.
[Note: this was one of three abstracts chosen for a CIBMTR Best Abstract Award for Clinical Research.]
The authors cpmpared outcomes after HSCT in 402 patients with β-thalassemia (TM) or sickle cell disease (SCD) who received HLA identical sibling cord blood (CB) (n=72) or bone marrow (BM) (n=330). Only centers that performed both types of HSCT during the same period were included.
Compared to BM, CB recipients were significantly younger (median age 5.5 years vs 7.6 years), smaller (18 kg vs 26 kg) and were transplanted more recently (in 2000 vs 1998). More TM patients belonging to Pesaro II-III risk classes received BM (64%) compared to CB (36%) ( p=0.04). There were also differences in the conditioning regimen and GVHD lprophylaxis. Moreover, the TNC was 10 times higher in BM compared to CB.
After HSCT for TM, the 5 year DFS rates were 88% and 83% for BM and CB recipients, respectively, and after HSCT for SCD, 94% and 96%, respectively. In a multivariate analysis adjusted for age and type of hemoglobinopathy, DFS ws not statistiscally different between CB and BM recipients (RR=1.64, p=0.20).
The authors concluded that patients with TM or SCD had excellent outcomes after HSCT whether they received CB or BM from an HLA identical sibling. These results strongly suggest that CB transplantation from HLA identical siblings should be pursued when possible to avoid the discomfort and risks of a BM harvest.
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