Cord Blood Transplantation Using Nonmyeloablative Regimens

Abstract & Commentary

By Andrew Artz, MD, MS, Division of Hematology/Oncology, University of Chicago, Chicago, IL; Dr. Artz reports no financial relationship to this field of study.

Synopsis: Advances such as nonmyeloablative conditioning have contributed to increased utilization of allogeneic transplant in older and less fit individuals. In a prospective protocol, 110 patients having high-risk hematologic disease underwent a nonmyeloablative conditioning regimen followed by unrelated cord blood cell (UCB) transplantation. The median age was 51 years and 85% required two UCB units to meet minimum cell doses. The median time to neutrophil engraftment was 12 days. The cumulative incidence of grades II-IV acute GVHD at 100 days was 59% and transplant related mortality by day 180 was 19%. Three year actuarial survival was 45%. Nonmyeloablative conditioning followed by UCB transplantation represents a promising strategy for transplantation in older and less fit adults lacking an HLA identical adult stem cell donor.

Source: C. Brunstein, et al. Blood. 2007. vol. 110: 3064- 3071.

The traditional notion of restricting hematopoietic cell transplantation to young patients with a human leukocyte antigen (HLA) matched sibling has vanished. Less intensive chemotherapy (ie, conditioning) before the transplant enables adequate immunosuppression for donor engraftment and contributes to reduced toxicity. Increasingly, rather than age or comorbid illnesses, lack of a suitable donor prevents transplantation. For those without an HLA matched sibling, a large registry of volunteer unrelated adult donors exists. Nevertheless, many patients eligible for transplant because of high risk hematologic malignancies do not have an adequately matched unrelated donor. Unrelated cord blood (UCB) cells have emerged as a promising donor source because they appear more permissive across HLA barriers. Thus, additional mismatches for UCB compared to unrelated adult donors are acceptable. UCB cells generally contain lower cell doses than adult stem cell or marrow collections, contributing to a major drawback: slow hematopoietic engraftment (ie, slow recovery of neutrophils) or even graft failure.1,2 In this report, Brunstein and colleagues report on the largest series to date of non-myeloablative conditioning followed UCB transplantation.

Patient eligibility required high-risk hematologic disease and lack of an adequate sibling donor (defined as no more than a 1 antigen HLA mismatch). Further, to receive the non-myeloablative rather than standard ablative conditioning regimen, patients had to be 45 years or greater or have other features increasing the risk of transplant related mortality. UCB units were required to have at least 4/6 HLA matching based upon antigen level matching at HLA-A and HLA-B and allele matching at HLA-DRB1. The minimum total nucleated cell dose (TNC) was 2.0 x 10(7) per recipient weight in kg with a goal of at least 3.0 x 10(7)/kg. When a single UCB unit did not meet the TNC threshold, a second cord matched to the first cord was selected. The conditioning regimen consisted of cyclophosphamide at 50 mg/kg on day - 6, fludarabine 40mg/m2 from day - 6 through day - 2, and a single fraction of TBC at 200 cGy on day - 1. Equine anti-thymocyte globuline was given from day - 3 to day - 1 to those with minimal prior chemotherapy exposure (to promote engraftment of UCB). Post-transplant immunosuppression included cyclosporine A and mycophenolate mofetil. One-hundred ten patients underwent UCB transplantation on this protocol with a median age of 51 years (range 16-79). Approximately half were transplants for AML or MDS. The majority (85%) necessitated two UCB to achieve the minimum cell dose. The median TNC dose was 3.7 x 10(7) /kg. Four of six HLA matched UCB comprised most units (61%); the remainder were 5/6 or 6/6 HLA matched. The median neutrophil recovery occurred 12 days after UCB infusion. Primary and secondary graft failure occurred in 7 and 8 patients, respectively. The cumulative incidence of grades II-IV GVHD was 59% for acute GVHD and 22% for chronic GVHD. Mortality related to the transplant was 19% by day 180. Overall survival was 45% at 3 years but was not stratified for any disease subtypes.

Commentary

The median age of most leukemias is around 68 years of age and the prognosis is generally worse for older adults. Hematopoietic cell transplantation has historically been reserved for younger adults under the age of 50 years. Increasingly, transplantation is being performed in older and less well adults, in part related to better tolerated transplant conditioning regimens. These so called "nonmyeloablative regimens" lead to minimal or transient marrow ablation. However, reduced extramedullary toxicities (eg, pulmonary, liver) may be the most important determinant of better tolerance. The field of allogeneic transplantation has witnessed large increases in the number of adults over 50 years receiving a transplant. As we move away from age alone as a major limitation to transplant, the lack of an adequately matched HLA identical donor precludes transplant has arisen as a major barrier. Many donor centers require a complete HLA matched unrelated donor and some accept 1 antigen/allele mismatches (ie, 7/8 or 9/10 HLA match). Nevertheless, that leaves a large number of patients without sibling or unrelated HLA matched donors. This is particularly problematic for non-whites, where registry matches are infrequent. Unrelated cord blood (UCB) represents a promising option because of less stringent HLA matching requirements allowing 4/6 antigen match compared to at least a 7/8 HLA allele match required for adult donors. The major limitation to UCB has been lack of adequate cell doses for adults that can lead to either slow engraftment or graft failure. The slow engraftment predisposes to life-threatening neutropenic infections.

In this report, Brunstein and colleagues report on a large series of nonmyeloablative transplants using unrelated UCB as a donor source for those lacking an HLA identical sibling. Eligibility required an increased risk of transplant-related mortality using standard ablative conditioning. The most common indication for using this nonmyeloablative protocol was age > 45 years. Among 110 recipients, 85% required two UCB units to achieve a minimum cell dose of 2 x 10(7) total nucleated cells per recipient weight in kg. The median engraftment of 12 days was highly encouraging and similar to adult stem cell sources (ie, peripheral blood and marrow) and smaller series of myeloablative conditioning followed by double UCB. Single UCB transplant in adults has been reported to lead to a median neutrophil engraftment of 23-28 days. Thus, achieving a minimum cell dose by using two UCB units represents an important advance in reducing the risk of complications from prolonged marrow aplasia and expanding the number of patients eligible to receive UCB transplants. In this group of relatively older adults, reducing neutropenia duration may be especially beneficial. However, primary and secondary graft failure still remains a problem and occurred in 7 and 8 patients respectively.

Acute GVHD occurred in 59%, and transplant related mortality was 19% at day 180. Recipients of two UCB units showed a trend toward more graft-versus-host disease (GVHD) but less relapse. Although statistically non-significant, these results mirror the higher GVHD but lower relapse in single antigen mismatched marrow and blood transplants relative to completely matched donors. For transplant, higher graft-versus-leukemia is almost always offset by more GVHD. The encouraging overall survival mandates confirmatory studies because the small sample size prevents stratifying results by disease subsets (eg, AML in CR1) and thus necessitating comparisons to historical results. Nevertheless, the favorable outcomes appear comparable to nonmyeloablative adult stem cell transplants using unrelated donors.

An important limitation is that donor selection employed in this study differs from most transplant center's donor procurement strategy. Most centers will select an HLA matched unrelated donor when no HLA matched sibling donor exists. Absent an HLA matched unrelated donor, then alternative donor approaches such as UCB, mismatches, or haplo-identical will be entertained. Thus, the ultimate question the report generates is how UCB transplant compares to unrelated adult donor transplants. The long delay in procuring an unrelated adult donor (approximately 3 months) relative to the immediate availability for UCB highlights is a distinct advantage for cord blood.

This large series demonstrates the feasibility of UCB transplantation in older adults and suggests good outcomes. For practicing oncologists, this report should encourage less stringent criteria for transplant referral in patients having high-risk hematologic disease. Ultimately, the decision to proceed with a transplant will remain individualized, and a discrete age maximum can not be stated. Nevertheless, age alone or lack of an HLA identical sibling should not be a barrier for referral for patients in their 50s and possibly 60s who might benefit from a hematopoietic cell transplant.

References

1. Rocha V, et al. N Engl J Med. 2004;351:2276-2285.

2. Barker JN, et al. Blood. 2001;97:2957-2961.