Umbilical Cord Blood Transplantation for the Treatment of Hematologic Malignancies

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1 Umbilical cord blood transplantation is a useful treatment in several types of hematologic malignancies. Gene Elling. St. Lucia. Photograph. Umbilical Cord Blood Transplantation for the Treatment of Hematologic Malignancies Claudio G. Brunstein, MD, PhD Background: The use of unrelated umbilical cord blood (UCB) has grown as an allogeneic source of hematopoietic cells for transplantation of patients with hematologic malignancies. As the number of UCB transplantation procedures has grown, an increasing number of publications have focused on disease-specific outcomes. Methods: This review focuses on the outcome data following UCB transplantation in subsets of hematologic malignancies in which experience with this graft source is greater. Results: Registry and single-institution reports regarding the outcomes of children and adults with acute leukemias after UCB transplantation include many patients, while data on the clinical outcomes of other leukemias are limited due in part to the small number of patients with these diseases. UCB is now routinely used as a source of hematopoietic stem cells (HSCs) in pediatric allogeneic transplantation when a suitable sibling donor is not available. Data also support the use of UCB as an alternative source of HSC for transplantation of patients with hematologic malignancies who lack a more conventional donor. Current data also support UCB for patients who require an allograft in the setting of prospective clinical trials. Conclusions: Along with safety and feasibility in UCB transplantation, continued study is needed that focuses on issues such as accelerating engraftment, extending access, ensuring quality, and examining outcomes in specific subgroups of patients. Introduction Over the last decade we have seen a significant increase in the use of umbilical cord blood (UCB) as a source of hematopoietic stem cells (HSCs) for allogeneic transplan- From the Blood and Marrow Transplant Program and Division of Hematology, Oncology and Transplantation at the University of Minnesota, Minneapolis, Minnesota. Submitted February 8, 2011; accepted May 3, Address correspondence to Claudio G. Brunstein, MD, PhD, Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street, SE, Minneapolis, MN No significant relationship exists between the author and the companies/organizations whose products or services may be referenced in this article. tation. UCB is now used in a growing number of transplant centers worldwide for the treatment of metabolic and deposit diseases, bone failure syndromes, hemoglobinopathies, and malignancies. As the number of UCB transplant procedures has increased, a growing body of evidence has demonstrated that this alternative source of HSCs could, at least in part, close the gap in finding a donor for patients who require a potentially curative allogeneic transplant but lack a suitable related or unrelated adult donor. The use of UCB is standard practice in pediatrics and has become an expanding practice in adults for the treatment of malignant diseases. The advantages of UCB transplantation include rapid availability, low risk of infection transmission, absence of donor risk, and the relatively lower risk of graft-vs-host disease (GVHD) with 222 Cancer Control October 2011, Vol. 18, No. 4

2 preserved graft-vs-malignancy effects. The disadvantages of UCB transplantation are the limited cell dose, delayed engraftment, and lack of additional immune cells if donor lymphocytes are needed. Controversial issues include, but are not limited to, immune reconstitution and risk of infections. While advances have improved results with UCB transplantation, outcomes with matched unrelated transplants have also improved. Determining the optimal source requires further study and is beyond the scope of this manuscript. The field of UCB transplantation has advanced from investigating its safety and feasibility to addressing more specific issues such as accelerating engraftment, extending access, ensuring quality and, importantly, examining outcomes in specific subgroups of patients. This review focuses on our current knowledge about disease-specific outcomes with UCB transplantation. Leukemia Leukemia is currently the disease subset in which the largest amount of data is available regarding UCB transplantation, in particular acute leukemia. Registry and single-institution reports on the outcomes of both children and adults with acute leukemias after UCB transplantation include hundreds of patients. However, data on the clinical outcomes of other leukemias are limited due in part to the small number of patients with these diseases. Although most series on the outcomes of hematologic malignancies after UCB transplantation include a small number of patients with chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), and other myeloproliferative disease, only a few reports address the specific outcomes associated with these diseases. Acute Leukemia in Children Early reports of UCB transplantation tended to reflect the outcomes of pediatric patients, with acute leukemia representing 30% to 50% of patients in most series. 1-9 These initial series consisted mostly of pediatric patients, mainly because the cell dose available from a single UCB unit was not sufficient for use with larger adolescent and adult patients. Data on outcomes of children with acute leukemia first became available in the late 1990s. Table 1 summarizes these outcomes from selected publications of the treatment of children with acute leukemia. 7,10-18 These are mostly manuscripts that describe comparisons to other HSC sources. Acute leukemia patients were reported to have engraftment rates of about 80%, with treatment-related mortality (TRM) rates of 44%, relapse rates of approximately 40%, and event-free survival rates at 2 years of 30% to 40%. 10,13 More recently, data on the treatment of acute leukemia from the Cord Blood Transplantation Study (COBLT) were reported. 16,18 The data on infants and young children with acute leukemia showed rates of neutrophil engraftment of only 60%, relapse of 31%, and a probability of survival at 1 year of 47%. 16 In a more recent report from COBLT on children with hematologic malignancies, 84% of whom had acute leukemia, the cumulative incidence of neutrophil engraftment was 80%, the relapse rate at 2 years was 20%, and the 2-year survival rate was 50%. 18 In this later study, children who received better HLA-matched grafts achieved better survival. These studies, however, included mostly patients treated in the 1990s, a time period in which the standard cell dose was lower and UCB grafts with up to 3 HLA mismatches were used more frequently. Moreover, the methodology of HLA typing changed, making it difficult to compare older reports with more recent series. The first studies comparing UCB to unrelated adult donor () bone showed promising results with similar to slightly inferior outcomes after UCB transplantation. 11,12,14 A registry-based landmark analysis by the Center for International Blood and Marrow Transplant Research (CIBMTR) compared UCB to the gold standard of 7 8/8 allele-matched bone grafts. 17 This study of recently treated patients again showed delayed neutrophil engraftment even though patients received UCB grafts that were selected based on modern standards of cell dosage for UCB graft selection. Interestingly, 4 of 6 HLA-matched UCB grafts had a higher TRM but a lower relapse risk, while 5 6/6 HLA-matched UCB grafts had a lower TRM and higher relapse risk. In contrast to prior studies comparing UCB to, this study showed that 6 of 6 HLA-matched UCB grafts had superior leukemia-free survival, compared to less well-matched UCB grafts and to grafts (Fig 1). 17 Thus, considering the substantial body of evidence and experience of UCB transplantation for the treatment of acute leukemia in children, UCB is now routinely used as a source of HSC in pediatric allogeneic transplantation when a suitable sibling donor is not available. Acute Leukemia in Adults The feasibility of UCB transplant in adults with acute leukemia was initially established by a large registry-based study of 68 patients (34 adults with acute leukemia) 6 and by the adult cohort of COBLT, which included mostly acute leukemia patients. 19 These early studies demonstrated that engraftment was poor in the small number of long-term survivors due in part to the nature of the study population, which consisted of many heavily pretreated patients with high-risk disease. More recently, studies comparing the outcomes of adults with leukemia who received either UCB or adult donor HSC sources have become available (Table 2) Two landmark papers in particular advanced the field of UCB transplantation in adults. 20,21 These studies compared the outcomes of adults with leukemia undergoing transplantation with UCB or unrelated donor bone after myeloablative conditioning. In these studies, analysis of HLA-A and -B typing at the antigen level and October 2011, Vol. 18, No. 4 Cancer Control 223

3 Table 1. Umbilical Cord Blood Transplantation for Children With Leukemia a Reference HSC Source With Leukemia Median Age (yrs) Neutrophil Engraftment Platelet Engraftment Acute GVHD II IV Chronic GVHD Relapse Treatment-Related Mortality (% or median days to ANC 500/µL) Survival or Disease-Free Survival Locatelli et al UCB unrelated UCB related days 42 at 1 yr Barker et al UCB at 100 days 53 at 2 yrs at 100 days 41 at 2 yrs P Value NS at 100 days 52 at 2 yrs TCD at 100 days 56 at 2 yrs P Value NS > >.80 Rocha et al UCB at 100 days 35 at 2 ys at 100 days 49 at 2 yrs TCD at 100 days 41 at 2 yrs P Value.0004 <.001 <.001 UCB <.01 TCD.19 UCB.55 TCD.07 Wagner et al UCB at 180 days ALL: high risk 43 standard risk 10 AML: high risk 47 standard risk 1 of 4 patients 30 at 1 yr 58 at 1 yr, 70 at 1 yr if dose > CD34+/kg, 60 at 2 yrs (nonmalignant disease), 38 at 2 yrs (malignant disease) Michel et al UCB days 49 at 2 yrs Continues on page Cancer Control October 2011, Vol. 18, No. 4

4 Table 1. Umbilical Cord Blood Transplantation for Children With Leukemia a Reference HSC Source With Leukemia Median Age (yrs) Neutrophil Engraftment Platelet Engraftment Acute GVHD II IV Chronic GVHD Relapse Treatment-Related Mortality (% or median days to ANC 500/µL) Survival or Disease-Free Survival Jacobsohn et al UCB at 3 yrs at 3 yrs P Value.0004 <.001 < Gluckman et al UCB at 60 days at 3 yrs Wall et al UCB (infant) CINC 59 KM 69 CINC 53 KM 82 CINC 41 KM 44 CINC 26 KM 33 CINC 31 KM of 32 patients 47 at 1 yr Eapen et al b < HLA mismatched < ( ) UCB < 16 6/ ( ) 5/6 high ( ) 5/6 low ( ) 4/ ( ) 1.62 ( ) 0.76 ( ) 0.60 ( ) 0.98 ( ) 0.72 ( ) 0.77 ( ) 0.8 ( ) 0.67 ( ) 0.72 ( ) 0.54 ( ) 1.42 ( ) 0.26 ( ) 1.48 ( ) 1.88 ( ) 2.31 ( ) 0.99 ( ) 0.54 ( ) 0.94 ( ) 1.12 ( ) 1.17 ( ) Kurtzberg et al UCB at 180 days at 100 days 57 at 1 yr a Unless otherwise specifi ed, clinical outcomes described are for the whole cohort. b 6/6 = HLA-matched UCB, 5/6 high = 1-locus HLA-mismatched UCB with high cell dose, 5/6 low = 1-locus HLA-mismatched UCB with low cell dose, 4/6 = 2-loci HLA-mismatched UCB. Results for acute and chronic GVHD, TRM, relapse, and time to treatment failure (shown in the survival column) are relative risks using the allele-matched unrelated groups as the reference (RR 1.0). HSC = hematopoietic stem cells, GVHD = graft-vs-host disease, UCB = umbilical cord blood, = unrelated volunteer donor, REL = related, TCD = T-cell depleted, ALL = acute lymphoblastic leukemia, AML = acute myeloid leukemia, CINC = cumulative incidence, KM = Kaplan-Meier, NS = not signifi cant, = not available. October 2011, Vol. 18, No. 4 Cancer Control 225

5 DRB1 at the allele level was performed, and leukemia-free survival was similar for recipients of UCB and unrelated donor bone. Despite some methodological differences, these studies reported that leukemia-free survival for UCB was similar to mismatched and similar to slightly inferior to matched. These studies set the stage for an increase in the utilization of UCB as a source of HSC for adult transplantation worldwide. More recently, two additional registry-based studies revisited the issue of the efficacy of UCB relative to grafts. 26,27 A study from the Japan Cord Blood Bank Network and the Japan Marrow Donor Program examined the outcomes of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) who received 4 6/6 HLA-matched UCB grafts to 8/8 allele-matched bone. 26 Both ALL and AML patients were found to have significantly lower rates of neutrophil engraftment. Relapse rates were similar for both graft sources. Notably, while outcomes for ALL patients were similar for both graft sources, UCB recipients with AML had a higher rate of TRM and a lower rate of leukemiafree survival compared to bone transplantation (Table 2). The authors attributed these findings not only to delayed engraftment after UCB transplantation but also to the relative risk of acute and chronic GVHD among bone recipients. A collaboration between the CIBMTR and Eurocord registries led to an updated study in adult patients with leukemia comparing UCB to grafts. 27 In contrast to prior registry studies, this analysis compared the outcomes of 4 6/6 HLA-matched UCB grafts with a cryopreserved nucleated cell dose of /kg to 7 8/8 allele-matched grafts from bone and/or peripheral blood. While TRM was higher among recipients of UCB, the leukemia-free survival was similar for all graft types, thus further supporting the utilization of UCB as an alternative source of HSC for patients with low-risk and high-risk leukemia (Fig 2) with no HLA-matched unrelated donor. Single institutions have also compared UCB with adult donor stem cell sources in cohorts that largely consisted of patients with leukemia Takahashi et al 22 studied 113 patients with hematologic malignancies (70% with acute leukemia) who received either 3 6/6 HLA-matched UCB or 5 6/6 HLA-matched grafts. In contrast to registry-based studies, they observed a lower risk of TRM and better disease-free survival after UCB transplantation. Another report by Takahashi et al 23 compared 171 patients with hematologic malignancies (70% with acute leukemia) who received either UCB or related donor grafts (peripheral blood and bone ). While the incidence of severe acute and extensive chronic GVHD was lower in recipients of UCB grafts, the incidences of grade II IV GVHD, TRM, relapse, and disease-free survival were similar for both HSC sources. As the number of adults receiving UCB transplantation is still relatively small, most series have not provided outcomes for specific leukemia subtypes. Reports on the outcomes of patients with AML are promising, with factors that influence these outcomes ranging from graft selection to disease stage at transplantation Ooi et al 29 reported on 18 patients with de novo AML who received single UCB grafts after myeloablative condition- 100 Adjusted Probability Number at Risk Time After Transplantation (Years) HLA-matched cord blood HLA-matched bone One-mismatched cord blood (high cell dose) HLA-mismatched bone One-mismatched cord blood (low cell dose) Two-mismatched cord blood Fig 1. Leukemia-free survival of children with acute leukemia after myeloablative single umbilical cord blood or unrelated donor bone transplantation. From Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone in children with acute leukaemia: a comparison study. Lancet. 2007;369(9577): Reproduced with permission from Elsevier. 226 Cancer Control October 2011, Vol. 18, No. 4

6 Table 2. Studies Comparing Umbilical Cord Blood to Other Types of Donors for Transplantation of Adults With Leukemia Reference Leukemias Included HSC Source Median Age (Range) Median Time to ANC 500/µL Median Time to Platelet Count > /L Acute GVHD II IV Chronic GVHD Relapse Treatment- Related Mortality Disease-Free Survival Laughlin et al AML ALL MDS UCB 150 (16 60) d a MM ( ) 0.66 b ( ( ) 1.12 ( ) 0.73 ( ) 0.85 ( ) 1.89 ( ) 0.99 ( ) 367 (16 60) d a 1.0 a 1.0 a 1.0 a 1.0 a 83 (16 60) d b 1.0 b 1.0 b 1.0 b 1.0 b P Value <.001 < a 1.48 ( ) 0.94 ( ).04 b.02 a.69 b.16 a.65 b <.001 a.001 a.96 b.69 b Rocha et al AML ALL UCB (15 55) ( ) 0.64 ( ) 1.02 ( ) 1.13 ( ) 0.95 ( ) (15 59) P Value Takahashi et al AML ALL MDS CML UCB (16 53) (16 50) ( ) 0.60 ( ) 0.75 ( ) 0.32 ( ) 0.27 ( ) P Value <.01 Takahashi et al AML ALL MDS CML UCB ( ) 0.49 ( ) 0.72 ( ) 0.49 ( ) REL P Value.83 <.01 < ( ) Continues on page 228 October 2011, Vol. 18, No. 4 Cancer Control 227

7 Table 2. Studies Comparing Umbilical Cord Blood to Other Types of Donors for Transplantation of Adults With Leukemia Reference Leukemias Included HSC Source Median Age (Range) Median Time to ANC 500/µL Median Time to Platelet Count > /L Acute GVHD II IV Chronic GVHD Relapse Treatment- Related Mortality Disease-Free Survival Kumar et al 24 ALL UCB e MRD e e MM e P Value e <.01 <.01 Tomblyn et al ALL UCB ( ) MM ( ) pm ( ) wm ( ) AUTO a ( ) REL P Value <.01 a <.01 b NS.05 c 1.5 ( ) 2.2 b ( ) 1.4 ( ) 0.9 ( ) 0.6 c ( ) 0.9 ( ) 1.4 ( ) 1.1 ( ) 0.8 ( ) 1.4 ( ) Atsuta et al 26 AML UCB P Value <.001 ALL UCB ALL ALL P Value Continues on page Cancer Control October 2011, Vol. 18, No. 4

8 Table 2. Studies Comparing Umbilical Cord Blood to Other Types of Donors for Transplantation of Adults With Leukemia Reference Leukemias Included HSC Source Median Age (Range) Median Time to ANC 500/µL Median Time to Platelet Count > /L Acute GVHD II IV Chronic GVHD Relapse Treatment- Related Mortality Disease-Free Survival Eapen et al AML ALL UCB MM ( ) ( ) PB ( ) PB MM ( ) 0.63 ( ) 0.59 ( ) 0.38 ( ) 0.46 ( ) 0.85 ( ) 0.84 ( ) 0.85 ( ) 0.91 ( ) 1.69 ( ) 1.06 ( ) 1.62 ( ) 0.95 ( ) P Value <.0001 < < < ( ) 0.93 ( ) 1.12 ( ) 0.91 ( ) Brunstein et al AML ALL MDS CML ducb MRD ( ) 1.58 a ( ) 3.67 a ( ) 0.31 a ( ) a 1.71 b 3.05 a 0.61 ( ) ( ) ( ) ( ) MM a 2.07 b 2.50 a 0.38 a ( ) ( ) ( ) ( ) P Value <.01 <.01 <.01 < a <.01 <.01 NS.01 b 1.09 ( ) 0.85 ( ) 1.12 ( ) a Indicates relation between percentage or RR results in the specifi c table column and the P values for that column within the same study. b RR applies to comparison between UCB compared to matched. c RR applies to comparison between UCB compared to mismatched. d Age reported by intervals of 16 20, 21 30, 31 40, 41 50, and No median available. e Refers to grade III IV acute GVHD. Data on grade II IV were not available. HSC = hematopoietic stem cell, ANC = absolute neutrophil count, GVHD = graft-vs-host disease, AML = acute myeloid leukemia, ALL = acute lymphoblastic leukemia, MDS = myelodysplastic syndrome, UCB = umbilical cord blood, = unrelated donor, MM = HLA-mismatched unrelated donor, CML = chronic myeloid leukemia, REL = related donor with no reference to HLA-matching, MRD = matched unrelated donors, pm = partially HLA-matched unrelated donor, wm = well HLA-matched unrelated donor, AUTO = autologous donor, ducb = double umbilical cord blood, CI = confi dence interval, NS = not signifi cant. October 2011, Vol. 18, No. 4 Cancer Control 229

9 ing. Seventeen of the 18 patients achieved neutrophil recovery, and 16 achieved sustained platelet recovery. Half of the 6 patients died of AML relapse. One patient died of treatment-related causes. At the time of the report, 14 patients were alive and disease-free, resulting in a disease-free survival rate of 77% at 2 years. In a more recent report, Sanz et al 30 evaluated 49 adults with AML treated with myeloablative UCB transplantation. In this study, UCB selection took into consideration both the nucleated and CD34+ cell doses. The cumulative incidence rates of neutrophil and platelet engraftment were 96% and 73%, respectively. The incidence of TRM was 39%, with a relapse rate of 19% at 2 years. The overall leukemia-free survival rate in this cohort was 37% at 4 years, which was influenced by the infused nucleated cell dose. A preliminary study describing the outcomes of AML after reduced-intensity conditioning was presented at the 2006 American Society of Hematology meeting. 31 This study included patients with high-risk AML who received either a 4 6/6 HLA-matched UCB graft (n = 43) or an HLA-matched sibling peripheral blood stem cell (PBSC) graft (n = 21). Most of the UCB grafts (n = 28) consisted of two UCB units. In this limited number of patients, the proportion of engraftment was not significantly lower after UCB (88% vs 100%, P =.10). When comparing UCB and PBSC recipients, there were similar incidence rates of TRM at 1 year (28% vs 38%, P =.43) and relapse rates at 2 years (35% vs 35%, P =.72), resulting A Leukemia-Free Survival 100 Number at Risk 8/8 matched bone 7/8 matched bone 8/8 matched PBPC 7/8 matched PBPC 4/6 6/6 matched UCB Months Bone matched Bone mismatched PBPC matched PBPC mismatched UCB B Leukemia-Free Survival 100 Number at Risk 8/8 matched bone 7/8 matched bone 8/8 matched PBPC 7/8 matched PBPC 4/6 6/6 matched UCB Months Bone matched Bone mismatched PBPC matched PBPC mismatched UCB Fig 2. Leukemia-free survival of adults with acute leukemia after myeloablative transplantation comparing single umbilical cord blood to unrelated donor 7 8/8 allele level HLA-matched bone and peripheral blood with low- (A) and high-risk disease (B). PBPC = peripheral blood progenitor cells, UCB = umbilical cord blood. From Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11(7): Reproduced with permission from Elsevier. 230 Cancer Control October 2011, Vol. 18, No. 4

10 in similar survival rates at 2 years (31% vs 32%, P =.62). In multivariate analysis, only the disease-risk group was associated with an increased relative risk (RR) of relapse (RR = 2.9, 95% confidence interval [CI], , P <.01) and death (RR = 2.6, 95% CI, , P =.02). Investigators at the University of Minnesota compared the outcomes of UCB to other graft sources after myeloablative conditioning for the treatment of ALL. 24,25 Significant differences were reported among the stem cell sources regarding year of transplantation, time from diagnosis to transplantation and, as expected, cell doses infused. The worst outcomes were observed after autologous transplantation 25 and mismatched graft. 24,25 While other graft sources including UCB had similar leukemiafree survival, other factors that were predictors of poorer outcome were advanced disease ( CR3), white blood cell count /L at diagnosis, a cytomegalovirus seropositive recipient or donor, and 2 induction cycles to achieve a complete response. In patients transplanted in CR1 2, independent predictors of poorer outcomes were older age, white blood cell count /L at diagnosis, and mismatched graft. Cell dose is well recognized as a factor that influences outcomes following UCB transplantation. This is a particular problem for adults for whom finding a single unit with an adequate cell dose to proceed to transplantation can be difficult. A recent collaboration between the University of Minnesota and the Fred Hutchinson Cancer Research Center compared the outcomes of leukemia patients after double UCB transplantation to adult-related and adult donor grafts after cyclophosphamide/total body irradiation (TBI)-based myeloablative conditioning 28 (Table 2). Double UCB transplantation has been shown to overcome, at least in part, the cell dose limitation imposed by single UCB grafts. While the combination of 2 UCB units provides a graft suitable to proceed to transplantation, neutrophil engraftment was still delayed following double UCB compared to adult donor grafts Cumulative Proportion Double umbilical cord blood Matched related donor Matched unrelated donor Mismatched unrelated donor Years Post-Transplantation Fig 3. Leukemia-free survival of adults with leukemia after myeloablative transplantation comparing double umbilical cord blood to matched related donor and 7-8/8 allele level HLA-matched unrelated donors. From Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefi ts of double umbilical cord blood. Blood. 2010;116(22): Reproduced with permission from American Society of Hematology (ASH). as previously observed in single UCB transplants. The TRM rate was significantly higher after double UCB and was largely influenced by delayed engraftment. For patients who recovered neutrophil counts before 26 days, which was the median time to neutrophil recovery among double UCB recipients, TRM was similar to other donor types. In contrast, patients recovering neutrophil counts after 26 days had substantially higher TRM. The higher TRM among double UCB recipients was offset by a significantly lower relapse risk in this group. While the mechanism behind the lower relapse rate is poorly understood and requires confirmation in prospective trials, the net result was that leukemia-free survival was equivalent for all donor types (Fig 3). 28 A large proportion of patients with acute leukemia are older and not candidates for treatment with conventional myeloablative conditioning regimens. Similar to the myeloablative setting, early studies in the nonmyeloablative setting included a significant proportion of patients with acute leukemia. 32,33 While preliminary reports suggest similar outcomes for AML patients when comparing UCB and related donor grafts in the nonmyeloablative setting, 31 additional study is needed. An ongoing analysis by CIBMTR is comparing acute leukemia outcomes after reduced-intensity conditioning between UCB and peripheral blood grafts, and initial results are expected soon. Taken together, these data support the utilization of UCB as an alternative source of HSC for transplantation of patients with acute leukemia who lack a suitable related donor. Chronic Myeloid Leukemia Since tyrosine kinase inhibitors became the first line of therapy for CML, this type of leukemia went from being the most common indication of allogeneic transplantation 38 to one of the least frequent ones. The introduction of tyrosine kinase inhibitors also coincided with the increased interest in UCB as a source of HSCs. Considering the efficacy of donor lymphocyte infusion for the treatment of relapsed hematologic malignancies, CML is by far the leukemia with the highest response rates As there are no donor lymphocytes available from UCB, grafts are a more desirable HSC source for patients with CML. Still, a substantial number of patients with CML may not be able to find a suitable adult donor and would require an alternative HSC graft source. Limited data on the outcomes of CML patients after UCB transplantation have been described in case reports 42,43 and small case series Initial reports suggested that engraftment was reduced in patients with CML compared to those with other leukemias. However, this effect was likely due to small cell dose since most CML patients were adults receiving what would now be considered a suboptimal cell dose for UCB grafts. 5 Sanz et al 46 initially reported on 9 adults who received a UCB transplant in chronic phase (CP1, n October 2011, Vol. 18, No. 4 Cancer Control 231

11 = 5; CP2, n = 1), accelerated phase (n = 1) or blast crisis (n = 2). All had failed more conventional treatments and autologous transplantation (n = 3) and lacked a suitable unrelated or related donor. were conditioned with a myeloablative regimen using a combination of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin (ATG). Four of the 9 patients, all transplanted in chronic phase, had prolonged remissions. This group recently updated their experience, reporting outcomes for 26 patients who received the same conditioning regimen. 47 Most patients were in chronic phase (CP1, n = 7; CP2, n = 11). All patients in accelerated phase or blast crisis died of transplant-related causes. For the whole cohort, the disease-free survival rate at 8 years was 41% for all patients and 59% for only chronic phase patients. In another report, 20 patients with CML (CP1, n = 6; accelerated phase, n = 14) received UCB transplants after myeloablative (n = 12) or nonmyeloablative (n = 8) conditioning. 45 With the exception of time to neutrophil engraftment, which was longer for myeloablation (21 vs 13 days), both conditioning regimens resulted in similar rates of acute GVHD, TRM, relapse, and survival. Notably, the relapse rate was approximately 10% and the overall survival rate was 50%. Although a large proportion of patients were transplanted with advanced disease, relapse rates were low, suggesting a potent graft-vs-leukemia effect of UCB in CML. 5,44-47 Myelodysplastic Syndrome MDS is a relatively uncommon hematologic malignancy, and the only potentially curative therapy for MDS is allogeneic HSC transplantation. Ooi et al 48 initially reported on 13 adults with MDS and AML secondary to MDS who received single UCB grafts after myeloablative conditioning. Notably, neutrophil recovery occurred in 12 of 13 patients, with 10 patients being alive and disease-free at the time of their report. In an update of this cohort that included 33 patients, they continue to observe a high incidence of neutrophil engraftment (90%), low TRM (14%), low relapse risk (16%), and an encouraging event-free survival rate at 5 years of 70%. 49 A Eurocord study of 171 adult recipients of UCB transplants, including 16 patients (9%) with MDS, reported a 30% relapse rate. 44 An analysis of a larger number of MDS patients should be available soon. A report from the University of Minnesota 50 described the outcomes of 84 adults with MDS undergoing myeloablative (62%) and nonmyeloablative (38%) transplantation, of whom 26 patients (31%) received UCB grafts. Although engraftment was delayed after UCB transplant, the cumulative incidence of engraftment did not significantly differ from other donor types. Relapse and disease-free survival rates were similar across donor types. The main determinant of outcome seemed to be the percentage of blasts at the time of transplantation, in which patients with < 5% blasts had a lower risk of relapse (16% vs 35%, P =.06) and a better disease-free survival at 5 years (42% vs 19%, P =.12). Investigators at Duke University recently published a pediatric series involving 23 patients with MDS who received 4 6/6 HLA-matched UCB grafts and TBI-based myeloablative conditioning. Outcomes for this cohort were comparable to previous studies, with a neutrophil engraftment rate of 80%, a relapse risk of 13%, a TRM rate of 27%, and an event-free survival rate at 3 years of 61%. Taken together, these limited data suggest that MDS patients who lack a suitable, more conventional donor can be considered for UCB transplantation, preferably in prospective studies. Lymphoid Malignancies UCB has recently been evaluated for the treatment of lymphomas and multiple myeloma. Although data on multiple myeloma are limited to a few cases in larger series or case reports, several studies on patients with lymphomas treated with UCB transplantation suggest that UCB may be a valuable alternative for patients with this diagnosis who require an allogeneic transplant (Table 3) Yuji et al 56 reported the outcomes of 20 patients with Hodgkin and non-hodgkin lymphomas after reduced-intensity conditioning and UCB transplantation. The conditioning regimen consisted of fludarabine, melphalan, and 4 Gy of TBI. Although 8 patients died of transplant-related causes, 15 achieved primary neutrophil recovery and 10 were alive and progression-free at the time of the report. An updated analysis by this same group on 110 patients with low-, intermediate-, and high-grade lymphoma/leukemia was presented at a meeting of the American Society of Hematology. 58 The conditioning regimen was the same except that the TBI dose was 0 8 Gy. The higher dose of TBI was given to patients with high-grade disease. Notably, one-third of patients had an Eastern Cooperative Oncology Group (ECOG) performance score 3. This ECOG score was a primary influence on outcomes, as seen in a PFS rate of 23% at 3 years, a TRM rate of 42%, and a relapse rate of 29%. with high-grade lymphoma/leukemia who received higher TBI doses had a better PFS. Interestingly, in the subgroup of patients with mature lymphoid malignancies (n = 84), low levels of lactate dehydrogenase (LDH) was the only independent predictor of a better PFS. Eurocord reported the results of a study that included patients with lymphoid malignancies who received UCB transplant after reduced-intensity conditioning (n = 64) or myeloablative conditioning (n = 36). 60 Neutrophil recovery was achieved in 84% of patients, with a slightly shorter interval to recovery for recipients of reduced-intensity conditioning (17 days vs 22 days) and a higher engraftment rate for patients who received a conditioning regimen that included TBI and a higher CD34+ cell dose but did not receive antilymphocyte globulin/atg (ALG/ATG). The TRM rate was 28% at 1 year and the relapse/progression rate was 35% at 2 years. The PFS rate was 36% at 2 years and was better 232 Cancer Control October 2011, Vol. 18, No. 4

12 Table 3. Umbilical Cord Blood Transplantation for Adults With Lymphoid Malignancies Reference Lymphoid Malignancies Included HSC Source Median Age (yrs) Median Time to ANC > 500/µL Median Time to Platelet Count > /L Acute GVHD II IV Chronic GVHD Relapse/ Progression Treatment- Related Mortality PFS Yuji et al NHL HL UCB of 15 2 of Majhail et al 57 HL UCB REL P Value Wake et al NHL HL MM ATL LBL UCB at 3 yrs Brunstein et al NHL HL CLL UCB at 3 yrs Current PFS: 49 at 3 yrs Rodrigues et al NHL HL CLL UCB at 2 yrs Rodrigues et al NHL HL CLL UCB at 2 yrs 34 at 2 yrs P Value NS.05 NS NS NS HSC = hematopoietic stem cell, ANC = absolute neutrophil count, GVHD = graft-vs-host disease, PFS = progression-free survival, NHL = non-hodgkin lymphoma, HL = Hodgkin lymphoma, UCB = umbilical cord blood, = not available, REL = related donor, MM = multiple myeloma, ATL = acute T-cell leukemia/lymphoma, LBL = lymphoblastic lymphoma, CLL = chronic lymphocytic leukemia, = unrelated donor, NS = not signifi cant. October 2011, Vol. 18, No. 4 Cancer Control 233

13 for patients with chemotherapy-sensitive disease who received a higher nucleated cell dose and a conditioning regimen that included low-dose TBI. Intermediate- and low-grade lymphoid malignancies are more frequently diagnosed in older patients, and often patients have received an autologous transplant by the time they are referred for allogeneic transplantation. Thus, the number of reduced-intensity conditioning UCB transplantations for lymphomas is likely to be greater than that of myeloablative conditioning transplantation as many institutions would consider recipients of prior autologous transplantation heavily pretreated to withstand a second myeloablation. A study of 65 adults with high-, intermediate-, and low-grade lymphoid malignancies with a median of 4 previous treatments was reported by the University of Minnesota (Table 3). 59 All patients received a conditioning regimen consisting of cyclophosphamide, fludarabine, and 2 Gy of TBI. Median time to neutrophil recovery was only 8 days. A large proportion (86%) received double UCB grafts, resulting in 57% of patients developing grade II IV acute GVHD. TRM was relatively low (15%), the relapse/progression rate was 42%, and the PFS rate was 34%. However, of 26 patients who had disease relapse/ progression, 15 patients, of whom 9 achieved a complete response, had immunosuppression removed or received some form of additional antilymphoma therapy, which generally included rituximab. Thus, the current PFS rate was 49% and the overall survival rate was 55%. with low-grade disease had a particularly improved current PFS rate of 68% (Fig 4). 59 Preliminary data from the same institution suggested that outcomes of Hodgkin lymphoma patients are similar, regardless of whether they receive a UCB or related-donor graft (Table 3). 56 More recently, the Eurocord presented a study comparing the outcomes of lymphoid malignancy patients after 4 6/6 HLA-matched UCB transplantation (n = 75) or 6/6 or 8/8 Cumulative Proportion follicular lymphoma/cll large-cell/mantle-cell lymphoma Hodgkin lymphoma Months Post-UCBT Fig 4. Current progression-free survival of patients with lymphoid malignancies after reduced-intensity umbilical cord blood transplantation. Brunstein CG, Cantero S, Cao Q, et al. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2009;15(2): Reproduced with permission from Elsevier. HLA-matched peripheral blood (n = 284) transplantation in the setting of reduced-intensity conditioning. 61 As part of the conditioning regimen, it was more common for UCB patients to receive TBI and for patients to receive ATG/ALG or alemtuzumab. Neutrophil engraftment was higher after transplantation (98% vs 85%, P <.0001). Acute GVHD, TRM, and relapse risks were similar between the two groups, but there was slightly less chronic GVHD after UCB transplantation (37% vs 48%, P =.05). The PFS at 2 years was 34%, the same for both UCB and. A final analysis based on this presentation should be available soon. While the outcomes of UCB transplantation need to be evaluated in larger numbers of patients with specific subtypes of lymphoid malignancy, current data support the utilization of UCB for patients who require an allograft in the setting of prospective clinical trials. Conclusions Supported by a rapidly growing body of evidence demonstrating the safety and efficacy of UCB transplantation, this HSC source has been used more frequently for the treatment of patients with hematologic malignancies. After an initially limited utilization among adults in contrast to routine utilization in children who lack a suitable sibling donor, UCB transplantation for older and larger patients is also increasing. Factors that specifically contributed to the expanded use of UCB in adults include, but are not limited to, results of outcomes utilizing a higher minimum nucleated cell dose to select grafts that yielded results similar to other donor types, the utilization of double UCB grafts for adult patients who do not have a single unit large enough to proceed to transplantation, and the use of reduced-intensity conditioning regimens in UCB transplantation. The field of UCB transplantation is still relatively young, and several areas of this field require additional research to further improve outcomes. One example is the reduced rate and cumulative incidence of engraftment in UCB recipients that could potentially impact the risk of TRM. Efforts in improving engraftment are ongoing and include expanding the inventory of highquality UCB units, utilizing double UCB grafts, 28 coadministering third-party CD34+ progenitors, 62 improving ex vivo expansion, 63 activating homing receptors (such as CXCR4), 64 and utilizing intra-bone injection. 65,66 Others have been investigating how to reduce the risk of GVHD and potentially improve immune reconstitution and reduce the risk of infections. 67 As with unrelated donor transplantation, outcomes in specific patient subgroups could also be improved by refining donor selection such as considering killer immunoglobulinlike receptor (KIR) ligand matching. 68,69 The results of ongoing multicenter prospective clinical trials in both Europe and the United States will improve understanding of the indications and applicability of double UCB grafts 234 Cancer Control October 2011, Vol. 18, No. 4

14 (eg, CTN-0501) and reduced-intensity conditioning (eg, CTN-0604) UCB transplantation. Appreciation is expressed to Michael J. Franklin, MS, of the University of Minnesota for assistance in editing and to Carol Taubert for assistance in preparing this manuscript. References 1. Wagner JE, Kernan, Steinbuch M, et al. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet. 1995;346(8969): Wagner JE, Rosenthal J, Sweetman R, et al. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood. 1996;88(3): Kurtzberg J, Graham M, Casey J, et al. The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation. Blood Cells. 1994;20(2-3): ; discussion Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cordblood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337(6): Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med. 1998;339(22): Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001;344(24): Wagner JE, Barker JN, De For TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: infl uence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100(5): Ohnuma K, Isoyama K, Ikuta K, et al. Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies. Br J Haematol. 2001;112(4): Isoyama K, Ohnuma K, Kato K, et al. Cord blood transplantation from unrelated donors: a preliminary report from the Japanese Cord Blood Bank Network. Leuk Lymphoma. 2003;44(3): Locatelli F, Rocha V, Chastang C, et al. Factors associated with outcome after cord blood transplantation in children with acute leukemia. Blood. 1999;93(11): Barker JN, Davies SM, De For T, et al. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone : results of a matched-pair analysis. Blood. 2001;97(10): Rocha V, Cornish J, Sievers EL, et al. Comparison of outcomes of unrelated bone and umbilical cord blood transplants in children with acute leukemia. Blood. 2001;97(10): Michel G, Rocha V, Chevret S, et al. Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis. Blood. 2003;102(13): Jacobsohn DA, Hewlett B, Ranalli M, et al. 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