GOOD RESULTS WITH UNRELATED CORD BLOOD TRANSPLANTATION FOR CLL

June 18, 2010 (Barcelona, Spain) — Unrelated umbilical cord blood (UCB) cells offer a viable source of cells for transplantation in both adults and children with acute leukemia.

Results from a study of adults with acute leukemia are published online June 16 in The Lancet Oncology, to coincide with the presentation of findings from a retrospective study of children with acute lymphoblastic leukemia (ALL) here at the 15th Congress of the European Hematology Association (EHA).

Charles Craddock, MD, director of the Blood and Marrow Transplant Unit, Queen Elizabeth Hospital, Birmingham, and professor of hemato-oncology, University of Birmingham, United Kingdom, commented on both pieces of research in an interview with Medscape Hematology.

"These papers confirm the exciting potential of cord blood as an alternative source for transplantation with curative intent in high-risk hematological malignancies. They represent an important and potential curative strategy for patients, particularly those from ethnic minorities who lack an unrelated donor," he said.

Results Are "Particularly Noteworthy"

In The Lancet Oncology study, investigators found that after 2 years, leukemia-free survival was similar, regardless of whether the graft was from UCB, allele-matched bone marrow, or peripheral blood progenitor cells (PBPC). Unrelated UCB transplants were mismatched for either 1 or 2 human leukocyte antigens (HLAs).

"These results [for survival and rates of graft vs host disease (GvHD)] are particularly noteworthy in view of the fact that 70% of UCB transplants were mismatched at 2 HLA antigens," noted lead study author John Wagner, MD, from the University of Minnesota Blood and Marrow Transplant Program in Minneapolis.

Of the 1525 transplant patients with acute leukemia from whom data were collected, 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at the antigen level, and at HLA-DRB1 at the allele level, or mismatched at 1 or 2 antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1, or mismatched at 1 locus.

Disease status before transplantation affected the leukemia-free survival rate. Patients who were not in complete remission had higher treatment failure rates than those in complete remission.

Transplant-related deaths were significantly higher after UCB transplantation than after fully matched PBPC or bone marrow transplants. However, UCB transplantation was linked to a generally lower rate of acute and chronic GvHD.

"In the absence of a randomized clinical trial, these data support the use of 4–6/6 HLA-matched unrelated UCB or 7/8 HLA-matched unrelated adult donors in the treatment of adults with acute leukemia when an 8/8 HLA-matched unrelated adult donor is not available, and the use of UCB as first-line therapy when a transplant is needed urgently," conclude Dr. Wagner and colleagues.

In a commentary accompanying the study, Paul Szabolcs, MD, from the Pediatric Blood and Marrow Transplantation Division at Duke University Medical Center in Durham, North Carolina, wrote: "Most importantly, transplantation should take place while the patient is in remission. Clinicians should not waste time if it is thought that a patient is in imminent danger of progression, and should move toward cord-blood transplantation as long as a 4-of-6 HLA-matched unit is identified."

In the study presented here at EHA of children with ALL, French researchers found that disease status and age at the time of unrelated UCB transplant are key factors influencing outcome.

Annalisa Ruggeri, MD, from Eurocord-Hôpital Saint-Louis in Paris, France, presented the data. "Results for patients who had experienced first and second remission are very encouraging; however, age at transplant and disease status are the main risk factors. Patients who have received a lot of chemotherapy previously or have refractory disease may not benefit, but for those in remission it is strongly recommended. In children, cord-blood stem cells have a high potential for expansion without risk of rejection and GvHD."

Data for this study come from Eurocord, the European Registry of Cord Blood Transplantation. Dr. Ruggeri and colleagues performed a retrospective analysis of 532 children with primary ALL who were transplanted in European Group for Blood and Marrow Transplantation centers from 2000 to 2009.

Dr. Ruggeri reported that 96% of patients received a myeloablative conditioning regimen and 52% received total body irradiation of more than 6 Gy. All patients received a single nonmanipulated UCB transplant. Patients were then categorized, according to the status of complete remission (CR), as CR1, CR2, or advanced disease.

Other treatment regimens included busulphan with cyclophosphamide, with or without thiotepa or melphalan. Antithymocyte globulin was used in 88% of cases. GvHD prophylaxis was provided by cyclosporine with or without steroids in 75% of recipients.

Retrospective analysis showed that 85% of transplant recipients achieved neutrophil engraftment within a median of 26 days, and 54% of patients showed platelet recovery of more than 20 × 109/L at 180 days (median time, 45 days).

"We saw better engraftments in CR1 and CR2 [patients than in] those with advanced disease. The main factor associated with outcome success was disease status. Those with advanced disease had a poor outcome, even after their transplants. Only 7% of patients with advanced disease showed 2-year leukemia-free survival, whereas approximately 42% and 54% in CR2 and CR1 achieved 2-year leukemia-free survival, respectively," reported Dr. Ruggeri.

"We also found that for patients in the CR1 group, those [younger than 5 years] showed a better outcome in terms of 2-year leukemia-free survival, at 61%, relative to 46% in the group [older than 5 years]," the French researcher told EHA meeting attendees.

Patients in the CR2 group, some of whom were not at high risk for cytogenetic markers but had relapsed early after the first remission, according to the Berlin-Frankfurt-Münster classification, were found to worsen even after transplantation. However, this factor was found to be independent of leukemia-free survival.

"Status of the disease at transplant remains the major risk factor for outcomes in the whole cohort. Other risk factors, such as the role of minimal residual disease before transplant, need to be investigated in clinical protocols," concluded Dr. Ruggeri.

Dr. Wagner reports being a board member of Cord:USE and VidaCord; his coauthors have disclosed no relevant financial relationships. Dr. Craddock and Dr. Ruggeri have disclosed no relevant financial relationships.

Lancet Oncol. Published online June 16, 2010.

15th Congress of the European Hematology Association (EHA): Abstract 1128. Presented June 13, 2010.