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.