Transplantation of hematopoietic stem cells (HSC) from healthy donors is a curative therapy for a variety of cancers of the blood and bone marrow as well as for an increasing number of nonmalignant disorders. However, major barriers to transplant are both the lack of suitably matched donors, and that searches are too slow. Cryopreserved umbilical cord blood (UCB) from 4-6/6 human leukocyte antigen (HLA)-matched unrelated neonatal donors is a promising alternative HSC source and has the advantages of rapid availability as compared with unrelated volunteers, and a relatively low incidence of graft-versus-host disease despite HLA disparity. The fact that the required HLA-match with UCB is less stringent promises to significantly extend the donor pool. This is of particular importance for Memorial Sloan Kettering Cancer Center patients who come from a wide variety of racial and ethnic backgrounds. For these reasons, Memorial Sloan Kettering has recently created an UCB Transplant Program to treat pediatric and adult patients with hematologic malignancies.
The outcome of conventional myeloablative UCB transplantation in larger adolescent and adult patients has been compromised by the limited cell dose in single UCB units. Therefore, we are investigating the combined transplantation of two or “double” unit grafts to augment UCB graft cell dose (Figure 1). Early experience with this strategy has been associated with improved engraftment and reduced transplant-related mortality as compared with historical controls receiving single units. Furthermore, in 23 adults with advanced hematologic malignancy transplanted in remission the survival rate was promising at 68 percent. Interestingly, while only one unit was responsible for sustained engraftment, both engraftment and survival much exceeded expectations based on the cell dose of the winning unit. Therefore, UCB transplantation using double unit grafts promises to both extend access to allograft for a large number of patients and raises intriguing questions concerning the transplant biology of this approach.
However, some patients will not be fit for myeloablative conditioning due to older age and/or extensive prior therapy. For these patients, we are investigating the transplantation of double unit grafts after reduced-intensity or non-myeloablative conditioning (Figure 1). In a study of 59 adults with advanced hematologic malignancy, non-myeloablative UCB transplant is associated with a cumulative incidence of sustained donor engraftment of 89 percent overall, and 98 percent in patients with a prior autograft or recent combination chemotherapy. Notably, day 180 transplantrelated mortality was relatively low at 14 percent in patients ≥ 45 years of age. The probability of overall and progression-free survival was 44 percent and 35 percent at two years, respectively, with the suggestion of a graft-vs-malignancy effect. Results were particularly promising in B lymphoid malignancies with a probability of one year disease-free survival of 63 percent in 16 patients [median age of 51 years (range 37-67)] with mantle cell non- Hodgkins lymphoma (NHL), advanced or refractory follicular NHL, or chronic lymphocytic leukemia (CLL). Therefore, Memorial Sloan Kettering will now further investigate the efficacy of UCBT after reduced-intensity or non-myeloablative conditioning in diseasespecific protocols (Figure 2). Pretransplant salvage chemotherapy followed by UCB transplant will be delivered as a “treatment package” to both achieve disease debulking to allow sufficient time for the development of a graft-versus-malignancy effect and to aid in recipient immune suppression and thus facilitate donor engraftment.
Memorial Sloan Kettering is also performing correlative laboratory studies on patients undergoing UCB transplant. Despite the promising early experience of double unit UCB transplant, the biology of this approach is not understood. Therefore, on transplant day, small samples from each unit of the patient’s double unit graft are being analyzed (Figures 2 and 3). The scientific questions are: 1) what is the mechanism of unit predominance? and 2) is the non-engrafting unit facilitating the engraftment of the winning unit, and if so by what mechanism? The effect of double unit co-culture on the hematopoietic potential of each unit is being studied in the stem cell biology laboratory of Dr. Malcolm Moore at the Sloan Kettering Institute. Also, the biology of T, NK, and dendritic cells in this setting will be examined in the laboratories of Dr. James Young and Dr. Katharine Hsu.
A significant strength of these studies is that the laboratory results can be correlated with the unit predominance in the patient (Figure 3). An understanding of this biology will facilitate subsequent investigation of other issues such as how the double unit strategy may protect against leukemic relapse as has been suggested by preliminary clinical data. In addition, the immune recovery of patients undergoing UCB transplant will be studied, correlated with infectious complications, and compared with that of patients undergoing unrelated volunteer donor transplants with T cell depletion.
A further research endeavor of Memorial Sloan Kettering ’s UCB Transplant Program is that the data from all patients undergoing unrelated donor HSC searches are being collected and analyzed prospectively (Figure 2). This will measure the extent to which UCB extends access to transplant. This information has not been collected prospectively in a center such as MSKCC, which has a racially diverse patient population and which simultaneously searches for both volunteer donors and UCB units. Identifying to what extent UCB does extend access to transplant, and which patients remain without suitable grafts, is vital as it will assist in addressing the question of how many UCB units may be required in the national inventory so as to guarantee transplants for the vast majority of patients.