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Comments about Umbilical Cord Blood Transplantation Meetings and Hematology Meetings including Cord Blood Transplantation in the year 2007.
Note: The increasing number of medical meetings featuring cord blood transplantation is an indication of the growing acceptance of this source of stem cells for hematopoietic cell transplantation (HSCT).
I. The 34th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) which was held in Florence, Italy, March 30-April 2, 2008.
1. The abstract that was given the Van Bekkum Award:
Inhibitory KIR-ligand mismatching is associated with decreased incidence of relapse and improved disease-free survival after unrelated cord blood stem cell transplantation for patients with acute leukaemia. Willemze R, Rodrigues CA, Labopin M, Ionescu, Boudjedir K, Sanz G, Michel G, Socie G, Rio B, Gardia J, Kogler G, Lecchi L, Loiseau P, Gluckman E, Rocha V on behalf of Eurocord-Netcord and acute leukaemia working party of the EBMT, Paris.
HLA class I, killer-cell immunoglobulin-like receptor (KIR) ligands which are missing in the recipient may trigger cytotoxicity of donor NK cells leading to GVHD and/or GvL reactions. It is unknown whether KIR mismatching impacts outcomes in unrelated cord blood stem cell transplantation (UCBTS). The authors studied patients reported to Eurocord Registry with acute Leukemia in complete remission (CR) with available high resolution typing of HLA-B and –C in recipient/donor pairs who received a single UCBT.
Patients and donors were categorized to their KIR-ligand groups by determining whether or not they expressed: HLA-C group1 or 2, HLA-Bw4 and HLA-A3 or –A11. A total of 218 pairs met the eligibility criteria. Conditioning was myeloablative (84%) or reduced intensity (16%), and included ATG in 80%. Sixty-nine patients had a KIR-ligand alloreactive (KIR+) donor and 149 had not (KIR-).
In multivariate analysis, donor KIR-ligand alloreactivity was associated with decreased relapse incidence (RI), increased DFS (HR=2.05, p=0.016) and OS (HR =2, p=0.004) but not with GVHD and non-relapse mortality. In subgroup analysis for AML: neutrophil engraftment for KIR+ vs KIR- was 88%±6% vs 79%±4% (p=0.009), RI 5% vs 36%±7% (p=0.005) and DFS 73%±10% vs 38%±7% (p=0.012): and for ALL: RI was 29%±8% vs 37%±6% (p=0.71) and DFS 44%±9% vs 27%±6% (p=0.10), respectively.
The authors concluded that the use of KIR-ligand alloreactive donors in UCBT resulted in a lower relapse incidence (RI) and increased DFS and OS, especially in AML. Therefore, mismatching for inhibitory KIR-ligand in the GVH direction may be considered in the criteria of donor choice for patients with acute leukemia.
2. Outcomes of CBT in adult patients with hematologic malignancies (2 abstracts).
A. Myeloablation and umbilical cord blood transplantation in 184 patients with leukaemia: analysis of results at a single center. Brunstein C, Weisdorf D, DeFor T, Wagner J for the University of Minnesota Blood and Marrow Transplant Program.
The authors evaluated the outcomes in 184 consecutive patients transplanted with UCB after a myeloablative therapy for the treatment of AML (N=81), ALL (N=84), CML (n=13) and myelodysplastic syndrome (n=6). Conditioning consisted cyclophosphamide, fludarabine and TBI with MMF and cyclosporine immunoprophylaxis or the same CY/TBI with ATG and methylprednisolone immunoprophylaxis. The median age was 16 years (0.5-52), median weight 57.3 kg (8-148). Most were male (57%), cytomegalovirus seropositive (51%). Grafts were composed of two units in 45% and HLA mismatched at one (41%) or two (51%) antigens. Patients were classified as standard risk (n=138) or high risk (46). Median follow-up for survivors is 2.8 years (0.7-9.2).
Engraftment occurred in 164 patients (90%, 95% CI, 86-94%). Incidences of grades II-IV and III-IV acute and chronic GVHD were 43%, 14% and 15%, respectively. The incidence of treatment-related mortality at 2 years was 27%, and the incidence of relapse at 4 years was 27%. LFS was 43% and OS was 45% at 4 years. In multivariate analysis, disease risk group was the only risk factor for poor LFS (RR 2.0; 95%CI 1.3-3.1, p<0.01).
The authors concluded that, clearly, LFS after UCB transplantation, despite HLA mismatch, represents a valuable alternative to BM and PBSC grafting, especially for patients requiring urgent transplant or lacking an HLA matched unrelated adult volunteer donor.
B. Results of umbilical cord blood transplantations in adults with high-risk haematologic malignancies. Zinke-Cerwenka W, Posch U, Zebisch A, Linkesch W, Sill H.
The authors report on 13 patients with a median age of 34.5 years (range: 21-54) and a median weight of 64 kg (range 47-82 kg) who underwent 16 UCB transplantations. All patients had relapsed or resistant disease (8 AML, 2 ALL, 1 AUL, 1 CML with blast crisis, 1 Hodgkin’s disease). Myeloablative conditioning was performed in 7 and reduced intensity conditioning in 6 patients. GVHD prophylaxis consisted of ATG, cyclosporine A, and methotrexate. A second UCB transplantation was performed in 2 patients because of graft failure (only ATG was given before the 2nd graft) and in a third patient because of chemosensitive relapse. A double cord graft was used in one patient. Grafts (total = 17) were matched 6/6 (1), 5/6 (5), 4/6 (9) and 3/6 (2). The median TNC dose was 3.8 X 107/kg (range: 2.5-6.3).
Neutrophil recovery without G-CSF administration occurred at a median of 35 days (range: 25-51). A self-sustained platelet count >20 X 109/L was achieved at a median of 42 days (range 27-62). Graft failure was observed in 2 cases (HLA match 3/6 and 4/6). Six patients died because of infections and 4 because of progression or relapse of disease. Five patients developed aGVHD (grade I, n=1; grade II, n=4). No cGVHD was observed. Three of 13 patients (23%) are disease-free with a follow-up of 72, 17 and 16 months. All of them have a Karnofsky index of 100%.
The authors concluded that the outcome of their patients with advanced stage disease treated with UCB transplantations is comparable with published data using a suitable HLA-matched donor. Therefore, UCB transplantation should be considered if no suitable donor is available in time.
3. Abstracts indicating that GVHD after UCBT is mild and is readily responsive to treatment (2 abstracts). Also see Section 0. The Top Ten Articles on the Cord Blood Forum, VIII Graft-Versus-Host Disease Citation #1.
A. Clinical characteristics of chronic graft-versus-host diseasd following umbilical cord blood transplantation for adults. Sugimoto K, Narimatsu H, Kawase T, et al.
The clinical characteristics of cGVHD following UCB transplantation in adults have not been well described. The authors investigated a total of 77 patients who under went CBT. Of these, 29 survived without graft failure or progression of underlying diseases for at least 100 days after transplantation. The median age of the 29 patients was 42 years (18-67) and primary diseases included AML (12), ALL (n=6), CML (N=5), malignant lymphoma (n=3) and others (n=3). The patients received myeloablative (n=14) and reduced-intensity (n=15) preparative regimens. The median follow-up of surviving patients was 35.3 months (4.2-70.5).
Seven patients developed cGVHD (extensive, n=4; limited, n=3). The cumulative incidence of cGVHD 1 year after day 100 was 24% (95% CI = 11-14%). According to grading proposed by the NIH consensus development project (BBMT 2005;11:945), 6 of these patients were categorized as mild and 1 was categorized as moderate.
In 3 patients cGVHD resolved with supportive care, and the remaining 4 patients were successfully treated with additional immunosuppressive therapy. Overall survival rate of the 29 patients 3 years after day 100 was 53% (95% CI = 32-70%). Overall survival rates of patients with and without cGVHD 3 years after day 100 were 83% and 44%, respectively (p=0.076). Event-free survival rate of the 29 patients 3 years after day 100 was 47%, and event free survival rates with and without cGVHD were 83%and 36%, respectively (p = 0.047).
The authors concluded that these results suggest that cGVHD following CBT is mild and has a graft-versus-malignancy effect.
B. The analysis of chronic GvHD after cord blood transplantation in comparison with bone marrow transplantation. Seo S, Uchida N, Yamamoto H, et al.
Little is known about graft versus leukemia/lymphoma (GVL) effect in cord blood transplantation (CBT). The authors analyzed cGVHD in CBT compared with that in BMT and evaluated the relevance between cGVHD and GVL. The retrospectively studied 162 patients who had been free from disease progression for more than 100 days after either unrelated BMT (n=75) or CBT (n=87). Median age of the patients was 52 years (BMT vs CBT: 49 vs 53). Underlying diseases were acute leukemia (n=88), myelodysplastic syndrome (n=17), lymphoma (n=39) and others (n=18). Conditioning regimens were mainly composed of fludarabine with several combinations of melphalan, busulfan and/or TBI.
The median observation period after transplantation was 612 days (109-1944). The cumulative incidence of cGVHD was 84% in BMT and 62% in CBT (p=0.09). The severity of cGVHD was analyzed based on its type; limited or extensive. In CBT, the percentage of limited was 34% vs 25% in BMT, and extensive was 23% in CBT and 48% in BMT. Multivariate analysis showed that cGVHD increased over-all survival (p<0.01) and suppressed recurrence of the disease (p<0.01). During the observation period, no patients died of cGVHD.
The authors concluded that their data demonstrated that cGVHD in CBT is tolerable compared with that in BMT and that the occurrence of cGVHD could result in a good prognosis. The analysis also suggested that CBT could have a GVL effect as well as BMT.
4. Double cord blood transplants (3 abstracts).
A. Umbilical cord blood transplantation in adult patients using double cord blood units. Somers JAE, Meijer E, Braakman E, Sintnicolaas, K, et al.
The authors explored the feasibility of double UCBT in adult patients lacking a suitable matched unrelated donor. Fourteen double UCBTs were performed. Conditioning regimens were myeloablative in 2 patients and non-myeloablative in 12 patients. A high-risk hematological malignancy was diagnosed in 13 patients and aplastic anemia in 1 patient. Median age of recipients was 48 years (17-61). Eleven UCBs were mismatched at 1 antigen and 16 were mismatched at 2 antigens. The median number of TNCs infused was 5.3 X 107/kg (3.7-7.0). The median follow-up of survivors is 20 months (4-18). Nine of 14 patients are alive and well, 1 patient has died due to relapse and 4 patients (29%) have died due to TRM. Cumulative incidence of neutrophil recovery in 12 evaluable patients is 75% with a median time to neutrophil recovery of 26 days. After hematopoietic recovery, hematopoiesis was derived from a single unit (5 patients) or from both units (5 patients). Acute GVHD grade II-IV developed in 3 patients and, among 9 patients who survived beyond 90 days after UCBT, cGVHD developed in 2 patients.
The authors concluded that their results suggest that double UCBT is feasible and may lead to sustained engraftment in the majority of patients transplanted for high-risk hematological malignancy.
B. Successful engraftment with double umbilical cord blood transplantation in adult patients with high-risk acute leukaemia. Baltadakis I, Karakasis D, Balotis C-G, et al.
Among the methods to increase cell dose, the combined transplantation of 2 partially HLA-matched UCB units has proven to be feasible and can extend he applicability of UCBT to virtually all adult patients who do not have a timely available HLA-matched donor.
The authors report on 10 patients who received a double UCB transplant for high-risk acute leukemia (AML, n=8; ALL (n=2). The median age was 33.5 years (16-57) and the median weight was 60 kg (53-94). At the time of transplant, 3 patients were in 1st CR, 4 in 2nd CR, 1 in 3rd CR and 2 in resistant relapse. The conditioning regimen was myeloablative in 8 and non-myeloablative in 2 patients. The majority of UCB units (19/20) were 4/6 antigen matched to recipient for HLA-A, -B, -C, -DRB1 and –DQB1. The median doses of nucleated and CD34+ cells at infusion were 4.4 x 107/kg (range: 2.9-5.4) and 1.27 X 105 (range: 0.6-2.0), respectively.
All patients achieved sustained neutrophil recovery at a median of 18.5 days (range 6-41). Engraftment of both units was observed in 5 of 10 patients on day 28 but, in all cases, one unit finally predominated. The cumulative incidence of platelet recovery (>50,000/µL) was 70% by day 150, and occurred at a median of 96 days (range: 33-117). All patients developed aGVHD (grade II:9, grade III:1) which was responsive to treatment with steroids. Two of 5 evaluable patients have developed cGVHD. Three patients died due to TRM. Seven are alive and in CR, 3-17 months after UCBT.
The authors concluded that double UCBT resulted in stable donor engraftment with acceptable TRM in this high-risk adult patient group. Further improvement is anticipated with the application of the method at earlier disease phases.
C. Double cord blood transplantation in patients with high-risk haematological diseases. Ruggeri A, Peffault de Latour R, Rocha V, et al.
Double cord blood transplantation has extended cord blood use to adults with hematological disease. The authors report 35 double UCBTs, 23 had high-risk malignant disorders (ALL =6, AML+MDS=8, secondary AL=5, CML=2, Hodgkin disease=2 and 12 with high risk of rejection (SAA =5, PNH=1 and Fanconi anemia=6). Median age was 35 years (6-55), median weight was 59 kg (17-90) and median follow-up was 15 months (4-37). The conditioning regimen varied according to disease (myeloablative) or second transplant (reduced intensity) and 22 patients received ATG. GVHD prophylaxis consisted of cyclosporine-steroids in 21 patients and associated with MMF in 14
Twenty-four patients (71%) engrafted at a median time of 25 days (11-42). Before day 100, among 29 evaluable patients, 18 showed full donor chimerism and 6 mixed chimerism (5 autologous recovery). After day 100, 16 of 19 evaluable patients maintained a complete donor chimerism and 3 had evidence of engraftments of both CB units. Acute GVHD was observed in 18 patients (43%) (grade III-IV, n=6) and cGVHD in 15 out of 26 patients at risk. Delayed immune reconstitution was observed in all patients. At 12 months overall survival was 56%±8 and event-free survival was 48%±9. Sixteen patients died, 2 of relapse and 7 from infections. Five of 9 patients have been rescued of previous non-engraftment and are alive and well (5-37 months).
The authors concluded that double UCBT is an option to treat patients with high risk diseases lacking a suitable HLA matched donor despite a long lasting immune deficiency.
5. Comparisons of outcomes following UCBT and BMT (2 abstracts).
A. Unrelated cord blood or mismatched unrelated volunteer donor transplants in patients who lack an HLA-identical donor. Okas M, Ringden O, Uhlin M, Uzunel, M, Remberger M, Mattsson J.
The aim of this study was to compare the use of HLA-A, -B , or –DRB1 mismatched unrelated donors (MM URD) (n=14) with UCB transplants (n=27). Diagnosis, disease stage and age were similar in the two groups. Eleven MM URD transplants were T-cell depleted.
Graft failure occurred in two patients in the UCB group and three in the MM URD group. Time to ANC >0.5 X 109/l was a median of 30 days in the UCB group and 17 days in the MM URD group (p=0.002). Platelet engraftment was also significantly delayed in the UCB group (p=0.03). At 100 days, complete donor engraftment in the UCB/MM URD patients was 63%/44% for CD3, 71%/44% for CD19 and 63%/56% for CD33. Probability of aGVHD grades II-IV was 30% in the UCB group, compared to 21% in the MM URD group. Corresponding figures for cGVHD were 9% and 20% in the two groups, respectively. TRM was 30% in the UCB patients and 50% in the MM URD patients. Three year survival was 66% in the UCB group vs 14% in the MM URD group (p=0.006).
The authors concluded that although engraftment was delayed, leukocyte chimerism was not significantly different and survival was superior using UCB compared to MM URD transplants.
B. Disease-specific analyses of unrelated cord blood transplants compared with unrelated bone marrow transplants in adult patients with acute leukaemia. Atsuta Y. Kato S, Suzuki R, et al. on behalf of the Japan Marrow Donor Program (JMDP) and the Japan cord Blood Bank Network (JCBBN).
The authors made a disease-specific comparison of the outcomes of unrelated CB recipients and unrelated BM recipients among 649 adult patients 16 years old or older with AML (CB vs. BM = 261 vs 388) and 460 adult patients with ALL (CB vs BM = 178 vs 282). The subjects were limited to those that received myeloablative transplants during the years 2000 through 2005.
CB recipients were more likely to have advanced leukemia at conditioning. HLA was serologically mismatched in 93% of patients with ALL among CB recipients, while HLA A, B, and DR were all matched genotypically for BM recipients.
In controlled comparisons using multivariate analyses, among patients with AML, higher rate of treatment-related mortality (TRM) (hazard ratio=1.51, 95% confidence interval (CI) 1.11-2.05, p=0.008) was observed in recipients of CB, which contributed to decreased OS (HR=1.45, p=0.003). Relapse rate did not differ between the two groups of AML patients. In patients with ALL, the relapse rate was higher with marginal significance among CB recipients. There was no significant difference between these groups for TRM, or overall mortality for patients with ALL There was no increase in the incidence of aGVHD in CB recipients among patients with either AML or ALL despite HLA disparity.
The authors concluded that matched or mismatched CB is a favorable alternative stem cell source for patients without a suitable donor. The pointed out that there were different outcomes between patients with AML and ALL, which indicates the importance of disease-specific analyses in alternative donor studies.
6. Reduced-intensity (RI) UCBT, including RI double cord transplants (2 abstracts).
A. Double umbilical cord blood transplantation using reduced-intensity conditioning: a single-centre experience. Cutler C, Yeap B, Kao G, Ho V, Alyea E, Koreth J, Armand P, Dey B, Spitzer T, Soiffer R, Antin J, Ballen K.
Fifty-one patients were treated on 2 sequential protocols between 2003-2007. All patients received fludarabine, rabbit ATG, and melphalan as conditioning. GVHD prophylaxis was administered day-3 through day 100, and the tapered. Cyclosporine/MMF (Cy/MMF) was given to the first 21 patients, and sirolimus/tacrolimus (Sero/Tac) was given to the remaining 30 patients. The median age was 49 years (19-67) and 30 patients (59%) were male. Malignant diagnoses were similar although there was a higher proportion of advanced lymphoid malignancy in the Siro/Tac group.
Subjects received a combined total of 4.4 X 107 TNC/kg and 1.9 X 105 CD34 cells/kg, without cohort differences. Neutrophil engraftment (ANC of 500) occurred at a median of 21 days (13-70) and platelet engraftment (20,000/µL) at a median of 42 days (21-185). Five patients experienced graft loss between days 35 and 102. Grade II-IV aGVHD occurred in 20% (33% Cy/MMF, 10% Siro/Tac), p=0.05). Chronic GVHD occurred in 24% without cohort differences. 100 day TRM was 12% and the risk of relapse at 1 year was 19% (Cy/MMF 5%, Siro/Tac 32%, p=0.03). With a median follow-up of 20 months, relapse-free survival and OS at 1 year are 59 and 74% without cohort differences.
The authors concluded that double UCBT following reduced intensity conditioning results in early engraftment and low 100-day treatment related mortality. The use of Siro/Tac is associated with less GVHD than Cy/MMF. This approach may lead to a higher relapse incidence, although this may be explained by differences in subject baseline characteristics. Double UCBT should be considered for all adults in whom a suitable adult donor does not exist.
B. Graft-versus host disease and infectious complications following reduced intensity conditioning umbilical cord blood transplantation in adults. Furst S, Mohty M, Faucher C, et al.
The aim of this study was to assess the outcome of 27 high risk adult patients (AML, n=15; ALL, n=7; NHL, n=3; CML, n=1; and HD, N=1) who underwent reduced intensity UCBT (RI UCBT) with a special focus on GVHD and infectious complications.
The median age and weight was 43 years (17-59) and 62 kg (47-125), respectively. The RIC regimen included fludarabine, cyclophosphamide and low dose TBI. CSA and MMF were given for GVHD prophylaxis. 11 patients received a single CB unit whereas 16 patients received 2 CB units. The median cryopreserved and infused cell doses were 4.9 X 107 TNC/Kg (3.3-7.0) and 3.7 X 107/Kg (1.9-5.5), respectively. Neutrophil engraftment occurred in 26 patients (96%) at a median of 19 days (6-45). Sustained platelet recovery (>50,000/µL) was observed in 19 patients (70%) at a median of 48 days (29-131). The overall incidence of grade II-IV aGVHD was 58% (95% CI=39-77%); 16 patients were evaluable for cGVHD for an overall incidence of 41% (7 limited and 4 extensive).
Sixteen patients (59%; 95% CI=40-77%) experienced at least one episode of a “serious” infectious complication (virus other than CMV reactivation, n=8; bacteria, n=8; fungal, n=4), requiring long-term hospitalization, and of whom 7 patients were in grade III-IV aGVHD. Six patients (22%) experienced severe interstitial pneumonia, with 4 patients (15%) developing ARDS. With a median follow-up of 385 days (111-903), 5 patients (18%) had relapsed with this being significantly lower in those patients transplanted in CR (p=0.01), but without significant difference between single and double CB recipients. The KM estimate of OS and EFS was 73% and 58% at 2 years, respectively, with no significant differences between single and double CBT recipients.
The authors concluded that RIC UCBT is an efficient therapy for high risk hematological malignancies. However, GVHD and serious infections are still a matter of concern warranting prospective efforts to define optimal prophylactic approaches.
7. Intra bone marrow injection of UCB blood (2 abstracts).
A. Direct intra-bone injection of unrelated cord blood cells overcomes the problem of delayed/failure to engraft and improves the feasibility of haematopoietic transplant in adult patients. Frassoni F, Gualandi F, Podesta M, Ibatici A, Raiola AM, Piaggio G, Gobbi M, Bacigalupo A.
The authors hypothesized that direct intrabone transplant of cord blood cells could improve hematologic recovery. Unrelated CB cells were selected for 37 consecutive patients (25 patients 4/6 HLA match, 11 patients 5/5 HLA match and one patient 3/6 antigen matched). CB cells were concentrated in 4 syringes of 5 ml each and infused in the supero-posterior iliac crest (11 patients bilaterally; 26 patients monolaterally) under rapid general anesthesia (10 min. with propofol).
The infusion of cells was uneventful. Six patients are not evaluable because they died of multiorgan failure within 14 days from transplant. One patient did not engraft and was re-transplanted. All the other patients that survived more than 14 days engrafted. Median for PMN engraftment (>0.5 X 109/l) was day 25 (14-44), whereas for platelets (>20 X 109/l) it was day 40 (22-64). Four patients died of infection; one patient died of PTLD on day +140. Four patients relapsed and died. Twenty-two patients are alive in remission at a median follow up of 9 months (2-21). Only 4 patients experienced aGVHD grade II and 2 grade I; 4 patients have moderate cGVHD and one patient extensive cGVHD.
The authors concluded that direct intrabone transplant of CB cells overcomes the problem of graft failure even when low numbers of HLA mismatched CB cells are transplanted.
B. Intra-bone marrow injection of umbilical cord blood: no impact on rate of haematopoietic recovery. Brunstein C, Barker J, Weisdorf D, DeFor T, Wagner J.
The authors evaluated the safety and potential efficacy of UCB intra-bone marrow injection (IBMI). Based on the authors’ prior experience with two partially HLA matched UCB units, the median time to neutrophil engraftment was 23 days (range 15-41). Twenty-nine patients received cyclosporine, fludarabine and TBI with MMF and cyclosporine A immunoprophylaxis. Median recipient age was 35 years (20-44) and median weight 73.6 kg (56-92). All patients received 2 UCB units randomly assigned to either IV infusion or IBMI. The IBMI unit was volume reduced to ~20 mL with ~10 mL infused into each posterior superior iliac crest under local anesthesia at the patients’ bedside.
Ten patients were evaluable. No adverse events were reported with the IBMI procedure. Nine of 10 engrafted. Median time to neutrophil (ANC>500/mcL) and platelet recovery (>50,000/mcL) was 21 days (17-49) and 69 days (30-272), respectively. Complete chimerism was observed with one unit engrafting long term (IBMI unit in 4 and IV unit in 5). Seven of 8 evaluable patients had aGVHD (grade II in 5 and grade III in 2). With a median follow up of 10 months, the probability of survival is 47% (95% CI= 14-80%) at 1 year.
Based on this interim analysis, the study was prematurely discontinued based on the fact that a predetermined required rate of neutrophil recovery (median 18 days) was unlikely with a high degree of certainty. While technically easy and safe, neither neutrophil nor platelet recovery after IBMI warranted additional patient accrual.
8. UCBT for thalassemia, for children with malignant and non-malignant indications, and for graft failure.
A. 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, Grafakos, S, et al.
Most patients with beta thalassemia major or sickle cell disease (SCD) can be cured by hematopoietic stem cell transplantation (HSCT) from either cord blood (CB) or bone marrow (BM). To compare outcomes after HSCT with CB or BM, the authors studied 388 patients with TM or SCD who received HLA identical sibling CB (n= 72) or BM (n=316) allografts between 1994 and 2005.
Compared to BM, CB recipients were significantly younger (median of 6.2 yrs versus 7.2 yrs), smaller (19 vs 24 kg), and were transplanted more recently (2001 vs 1998). More TM patients belonging to Pesaro II-III risk classes received BM (65%) compared to CB (36%) p=0.004).There were also differences in the conditioning regimens and GVHD prophylaxis and, in addition, the nucleated cell content was 10 times higher in BM compared to CB.
In TM patients, the 5-year DFS rates were 87% and 83% for BM and CB recipients, respectively, and in SCD patients, 92% and 85%, respectively. In a multivariate analysis adjusted for age and type of hemoglobinopathy, DFS was not statistically different between CB and BM recipients (RR=1.4, p=0.34).
The authors concluded that patients with TM or SCD had excellent outcomes after HSCT whether they received stem cells of CB or of BM from an HLA identical sibling. These results strongly suggest that CB transplantation from HLA siblings should be pursued when possible to avoid the discomfort and risks of a bone marrow harvest.
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. The 5th Annual International Umbilical Cord Blood Transplantation Symposium was held in Los Angeles, California on May 11-12, 2007. The faculty consisted of 38 scientists and clinicians from North America, Europe, Japan and Australia. The 8 sections of the program included discussions of (1) Risk factors affecting survival in recipients of cord blood, (2) Strategies to improve engraftment after UCBT, (3) Cord blood banking, manipulation and unit selection, (4) Conditioning regimens, (5) Non-hematopoietic stem cells, (6) The graft versus tumor effect and (8) Governmental affairs.
The Summary and Abstracts of the Fifth Annual International Umbilical Cord Blood Transplantation Symposium have now been published: Biology of Blood and Marrow Transplantation 2007;13(11):1380-92. Reprints are still available. To receive a reprint, send your postal mailing address to: symposiumreprint@cordbloodforum.org.
[Note: the Sixth Annual International Umbilical Cord Blood Transplantation Symposium will be held at the Los Angeles Marriott Hotel June 6-7, 2008. For details, go to cordbloodforum.org – “Upcoming Conferences.”]
III. Conference on Biology and Clinical Applications of Cord Blood Cells, Paris, France, October 19-21, 2007. This inaugural European conference on umbilical cord blood transplantation had a faculty consisting of 45 scientists and clinicians from Europe, North America, Israel and Japan. Topics included (1) Stem cells from cord blood, (2) Mesenchymal cells, (3) Non-hematopoietic stem cells, (4) Immunological properties, (5) Clinical results, (6) Ex-vivo expansion, (7) Graft facilitation/homing, and (8) Cord blood banking, organization, and regulatory issues.
IV. The First Latin American Symposium on Hematology, Stem Cell Transplantation, Regenerative Medicine and Cellular Therapy was held in Buenos Aires, Argentina on November 26-27, 2007. Although the meeting was not exclusively related to umbilical cord blood transplantation, there were a number of presentations relating to this topic by scientists from Peru, Argentina, Brazil, Israel, France and the United States.
V. The 49th Annual meeting of American Society of Hematology was held in Atlanta, Georgia, December 8-11, 2007. Although this is a very large meeting and there are a generous number of presentations on Cord Blood Transplantation, these tend to be diffused among the more than 3,700 abstracts, multiple simultaneous sessions, special lectures, educational programs, scientific committee reports, and other activities. Nevertheless, cord blood was front and center on a number of occasions:
(A.) The E. Donnall Thomas Lecture was presented by Dr. Hal Broxmeyer, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN. The title of his presentation was, “The Road to and Future of Cord Blood Transplantation.” Dr. Broxmeyer reviewed the history of CB transplantation with discussion of the basic biology that formed the scientific basis for the first CB transplant in 1988, the current status of CB transplantation and his expectations regarding its future.
(B.) An Educational Program on Hematopoietic Stem cell Transplantation included a lecture, “Umbilical Cord Blood (UCB) Transplantation: An alternative to the Use of Unrelated Volunteer Donors?” by Dr. Juliet Barker of Memorial Sloan-Kettering Cancer Center. This is a succinct and authoritative review of the field. The complete text is available in the Educational Program of the ASH Meeting (pages 55-61).
(C.) The abstracts submitted for the program included at least 75 that were related to CBT. A number of these were devoted to the topic of double cord blood transplants, reduced-intensity conditioning in CBT, transplantation for specific disorders (e.g., marrow failure, hematologic malignancies, juvenile myelomonocytic leukemia, MDS), experimental transplantation, basic biology, and immune reconstitution. For a rather complete listing of pertinent abstracts, see the Annotated Bibliography, XXIII American Society of Hematology Abstracts 2007.
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