9. Unrelated CB allogeneic stem cell transplantation for MDS. A commentary on the paper of Ooi (see citation 8) Laughlin, MJ. Leuk Lymphoma. 2006; 47:569-570.

With conventional HLA matched grafting after administration of reduced intensity conditioning, disease free survival (DFS) rates are only 35-40%, with disease relapse the most common cause of treatment failure. The patients reported by Ooi were treated with fully ablative conditioning and single unit non-expanded allogeneic unrelated cord blood transplantation. In the 21 patients demonstrating myeloid reconstitution, chimerism analyses confirmed full donor engraftment. Only 4 patients relapsed despite the majority of patients having advanced disease at the time of transplant. The probability of DFS at four years was an impressive 76%.

The report by Ooi identifies the use of banked unrelated cord blood as a suitable alternative allogeneic graft source that results in durable remissions for adults with MDS and emerging AML, with low rates of GVHD, and excellent survival rates. Further studies are warranted to determine the impact of improved HLA matching and higher graft cell dose threshold (>2.5 x 10⁷/kg).

10. Unrelated umbilical cord blood transplantation for adults with haematological malignancies: results from a single Australian centre. Bradstock KF, Hertzberg MS, Kerridge IH, Svennilson J, McGurgan M, Huang G, Antonenas V, Gottlieb DJ. Intern Med J. 2006;36:355-61.

Favorable results are reported in this small study from Australia. Nine adult patients (median age 32 years, median weight 68 kg) with haematological malignancies (five with acute myeloid leukaemia, one with acute lymphoblastic leukaemia, one with Hodgkin lymphoma and two with non-Hodgkin lymphomas) received transplants of cryopreserved cord blood after conditioning therapy with high-dose cyclophosphamide, total body irradiation and antithymocyte globulin. Cord units contained a median 2.6 x 10(7) nucleated cells/kg recipient bodyweight and were matched for four (seven cases) or five (two cases) major histocompatibility complex class 1 and 2 antigens. Patients were given post-transplant immunosuppression with cyclosporin and methylprednisolone.

Neutrophil recovery to 0.5 x 10(9)/L was seen by median day 30 after transplant in all seven patients who survived more than 1 month post-transplant. Platelet recovery to 50 x 10(9)/L occurred by median day 81 in five evaluable patients. Acute graft versus host disease (GVHD) grades II-IV was seen in four of seven evaluable patients and limited chronic GVHD was seen in four of five. Infection was the most common complication. Four patients died before day 100 of infection (methicillin-resistant Staphylococcus aureus septicaemia, respiratory syncitial virus pneumonia), GVHD and multi-organ failure, and intracranial bleeding. Five patients survived 7-69 months post-transplant, without evidence of relapse of the underlying malignancy. The authors concluded that transplantation of unrelated cord blood is a feasible strategy for adult patients with poor-risk haematological malignancies, with infection relating to immunocompromise being the major limitation.

11. Phase II study of unrelated cord blood transplantation for adults with high-risk hematologic malignancies. Lekakis L, Giralt S, Couriel D, Shpall EJ, Hosing C, Khouri IF, Anderlini P, Korbling M, Martin T, Champlin RE, de Lima M. Bone Marrow Transplant. 2006; 38:421-6.

The authors investigated a strategy in which CB units should contain at least 2 x 10⁷ total nucleated cells/kg of recipient weight, otherwise a second unit had to be added.

Patients with advanced hematologic malignancies without a human leukocyte antigen-matched sibling or unrelated donor were eligible. Conditioning regimen consisted of fludarabine and 12 Gy of total body irradiation (n=11), or melphalan (n=4), with antithymocyte globulin. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Fifteen patients with acute leukemia (n=9), chronic myelogenous leukemia (n=2), multiple myeloma (n=2) and lymphoma (n=2) were treated; 60% had relapsed disease at transplantation. Three patients received double CB transplants. The 100-day and 1-year treatment-related mortality rates were 40 and 53%, respectively. Median time to neutrophil and platelet engraftment was 22 days (n=10) and 37 days (n=10), respectively. One patient had secondary graft failure and five patients failed to engraft. Two patients are alive and disease free; 4-year actuarial survival is 33 versus 0% for patients transplanted in remission versus in relapse.

The early mortality and engraftment failure rates were deemed excessive and led to premature trial discontinuation. Explanations for these results include the following: The most important variable was disease status at transplantation, associated with extensive prior treatment and poor tolerance to transplant-associated toxicities, factors that likely increased TRM. It is possible that a diagnosis of CML was an added risk factor in two of the cases.

The 100 day mortality rate of 40% was similar to that observed in two other studies published in 2001 and 2005 with data collected throughout the earlier experience of CB transplants. Lower 100 day mortality has since been reported by several single-center studies. This may indicate the influence of growing experience using CB units, but one cannot underestimate the effect of patient selection on outcomes. At the time the authors' trial was initiated, they allowed the use of units with three HLA mismatches (3 patients were so treated). Other factors of possible significance was the GVHD prophylaxis regimen that employed "mini" methotrexate, the use of fludarabine and melphalan in the preparative regimen in 4 cases, and high dose ATG.

The authors concluded that CB carries the potential to extend hematopoietic transplantation to a variety of patients otherwise not eligible for this form of treatment but high-risk patients have an increased probability of TRM even with the use of units containing higher TNC counts. Thus, treatment of relapsed patients should only be pursued under controlled clinical trials.

12. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR et al. N Engl J Med 1998; 339:1565-1577.

In this landmark article reporting outcomes among 562 recipients of placental blood transplants from unrelated donors, 18% of the patients were over the age of 18 years and 17% were over 60 kg in weight. The authors concluded that placental blood transplantations from unrelated donors regularly engraft, cause GVHD at a relatively low rate, and produce survival rates similar to those with transplantation of bone marrow from unrelated donors. In multivariate analysis age was not independently predictive of engraftment.

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