BACKGROUND Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells. METHODS We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood. RESULTS Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×107 total nucleated cells per kilogram of body weight and 1.81×106 CD34+ cells per kilogram — doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P = 0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001). CONCLUSIONS Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316.)

Background Recurrence is a major cause of treatment failure after allogeneic transplantation for AML and MDS, and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. We hypothesized that low-dose azacitidine administered after transplant would reduce relapse rates, and conducted a study to determine a safe dose/schedule combination. Methods Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was three; 67% were not in remission. Using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, we investigated combinations of five daily azacitidine doses: 8, 16, 24, 32 and 40 mg/m2, and four schedules: 1, 2, 3 or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on day +40. Results Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up is 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation. Conclusions Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pre-treated AML/MDS patients. Our trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit.

Advances in immune assessment, including the development of T-cell receptor excision circle (TREC) assays of thymopoiesis, cytokine-flow cytometry assays of T-cell function, and higher-order phenotyping of T-cell maturation subsets have improved our understanding of T-cell homeostasis. Limited data exist using these methods to characterize immune recovery in adult cord blood (CB) transplant recipients, in whom infection is a leading cause of mortality. We now report the results of a single-center prospective study of T-cell immune recovery after cord blood transplantation (CBT) in a predominantly adult population. Our primary findings include the following: (1) Prolonged T lymphopenia and compensatory expansion of B and natural killer (NK) cells was evident; (2) CB transplant recipients had impaired functional recovery, although we did observe posttransplantation de novo T-cell responses to cytomegalovirus (CMV) in a subset of patients; (3) Thymopoietic failure characterized post-CBT immune reconstitution, in marked contrast to results in other transplant recipients; and (4) Thymopoietic failure was associated with late memory T-cell skewing. Our data suggest that efforts to improve outcomes in adult CB transplant recipients should be aimed at optimizing T-cell immune recovery. Strategies that improve the engraftment of lymphoid precursors, protect the thymus during pretransplant conditioning, and/or augment the recovery of thymopoiesis may improve outcomes after CBT. IntroductionUmbilical cord blood (CB), first demonstrated to have clinical utility by Gluckman et al as a source of hematopoietic stem cells in the setting of Fanconi anemia, 1 was later demonstrated to have utility as a source of unrelated donor stem cells for patients lacking matched-sibling donors. [2][3][4][5] Over the past decade, a large number of studies have demonstrated the clinical utility of CB transplantation (CBT) as a treatment for both malignant and nonmalignant diseases of children and adults. 4,6 The establishment of international cord blood banks, advances in supportive care and donor graft selection, and novel clinical approaches aimed at improving engraftment (eg, ex vivo expansion of CB-derived progenitors 7,8 and the infusion of pooled unrelated units 9 ) have improved outcomes and led to a dramatic increase in the number of CBTs performed worldwide.CB grafts obtained from matched unrelated donors offer advantages over bone marrow or peripheral blood stem cells (PBSC) such as noninvasive procurement, more rapid availability without the need for the more prolonged process of screening and obtaining stem cells from a matched unrelated donor (MUD), and the apparently greater tolerance for incompletely human leukocyte antigen (HLA)-matched products. 10 These advantages are paramount for recipients in historically underrepresented minority groups, for whom the prospect of locating a MUD registry donor remains relatively diminished. At our institution, more than twice the proportion of CB transplant recipients are minorities relati...

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. This portion of the NCCN Guidelines for AML focuses on management and provides recommendations on the workup, diagnostic evaluation, and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients. Please NoteThe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines These guidelines are also available on the Internet. For the latest update, visit NCCN.org.