CBF

Introduction

Perhaps the most critical issue in cord blood transplantation is the effectiveness of cord blood units for transplantation of adults because at least 75% of patients in need of a hematopoietic cell transplant are adults.

Can cord blood units, which require less stringent HLA matching of donor and recipient, satisfy the unmet need for donors for adult patients in need of hematopoietic cell transplants? Guidelines for an adequate cell dose in cord blood transplantation have steadily evolved and the critical importance of cell dose is now firmly established. Selection of a single cord blood unit with adequate cell dose, or the use of more than one cord blood unit are being utilized successfully in a number of transplant centers. In addition, reduced-intensity (nonmyeloablative) conditioning regimens have contributed to successful outcome.

Also, in Annotated Bibliography, see under headings: III. Multi-cord Transplants; IV. Reduced Intensity and Non-Myeloablative Transplants; V. Donor Selection for Unrelated Cord Blood Transplantation; VI. Availability and Time Required to Obtain Cord Blood versus Bone Marrow

(For a commentary regarding the unrealized potential of umbilical cord blood (UCB) units for unrelated donor hematopoietic cell transplantation, go to: Interactive Forum for Medical Professionals on the left hand column of the Home Page of this website.)

  1. Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor. Bautista G, Cabrera JR, Regidor C, Forés R, García-Marco JA, Ojeda E, Sanjuán I, Ruiz E, Krsnik I, Navarro B, Gil S, Magro E, de Laiglesia A, Gonzalo-Daganzo R, Martín-Donaire T, Rico M, Millán I, Fernández MN. Bone Marrow Transplant. 2009;43:365-73.

A number of strategies are being investigated to improve the time to engraftment and rate of engraftment after cord blood transplantation. These include ex vivo expansion of HSC from an aliquot of the transplanted CB, intraosseous infusion, infusion of two CB units, and the co-infusion of third-party donor (TPD) mobilized hematopoietic stem cells (MHSC). This study was done to gather further information about previously reported effectiveness of co-infusion of TPD MHSC in single CB transplants.

Fifty-five adults with high-risk hematological malignancies, median age 34 years, received CBTs (median TNC = 2.39 x 107/kg and 0.11 x 106 CD34+/kg) and TPD-MHSC (median 2.4 X 106 CD34+/kg and 3.2 x 103 CD3+/kg). Results indicated initial predominance of TPD DNA both in granulocytes and mononuclear circulating and in marrow cells, followed by progressive replacement by cells from the CB transplant. Time to ANC >0.5 x 109/l ranged from 9 to 36 days; the estimated time to CB ANC >0.5 x 109/l ranged from 12 to 57 days. Full CB chimerism was achieved by 50 patients. Grades II-IV acute GVHD were seen in 10 patients, and grades III-IV in 6 patients. Relapses occurred in 7 patients resulting in a 5=year cumulative incidence of 0.17 for the overall group. Post-engraftment opportunistic infections were a major cause of morbidity and death of 8 patients. Overall 5-year survival was 56% (41% for patients older than 40 and 63% for younger patients) and DFS was 47% (34% for older patients and 61% for younger patients).

The authors commented that the early recovery of the ANC results from the "bridge" engraftment of the co-infused TPD-MHSC and that this allows the patients to withstand treatments with gancyclovir and other drugs with myelosuppressive side effects. It was pointed out that the cost of obtaining TPD-MHSC is less than one-third the amount charged by CB banks for one unit so that this approach is significantly less expensive than double cord blood transplantation. In summary, results are: (1) short periods of post-transplant neutropenia because of the bridge engraftment of the TPD MSHC, (2) low rates of toxic complications and granulocytopenia-related infections, (3) high rates of CB engraftment and full CB chimerism, (4) incidences of relapses suggestive of valuable GVL effect (5) low incidence of serious GVHD, and (6) slow development of protective immunity against viral and other agents.

In conclusion, the authors indicate that the strategy of co-infusion of MHSC from a TPD can contribute to making CBTs feasible as a first choice option for a large number of patients of wide age range who lack a related HLA compatible donor by reducing the non-hematologic toxic effects of the conditioning regimen as well as the incidence of neutropenia-related infections, thus favoring engraftment.

[Note: Also see Annotated Bibliography, XV, ii, Co-transplantation of cord blood units and mobilized stem cells from a third party donor.]

  1. The intra-bone marrow injection of cord blood cells extends the possibility of transplantation to the majority of patients with malignant hematopoietic diseases. Frassoni F, Varaldo R, Gualandi F, Bacigalupo A, Sambuceti G, Sacchi N, Podestà M. Best Pract Res Clin Haematol. 2010;23:237-244.

To improve the capacity and the speed of engraftment after cord blood transplantation, the authors developed an intra-bone (IB) cord blood transplant technique. 75 patients with hematological malignancies, categorized by disease phase as early (18%), intermediate (20%) and advanced (62%), were transplanted. The median cell dose (TNC) infused was: 2.6 x 107/kg; the HLA disparity was: 12 cases=5/6, 62 cases=4/6 and 1 case=3/6 matched antigens. 72/75 patients engrafted (96%); median day of recovery of neutrophils (PMN) >500×109/L and platelets (PLT) >20 000×109/L was: 23 (14-44) and 35 (16-70) days, respectively. The outcomes at 2 years according to Kaplan-Meier are: OS=46%±5; RI=18%±2; NRM=39%±5. Acute GVHD incidence/severity was: grade 0-I=64%, II=14%, III-IV=0%. The incidence of chronic GVHD was low but in 3 cases was very severe.

The authors commented that intra-bone CBT is associated with high rate of engraftment, early and robust platelet recovery and a low incidence of acute GVHD. A very promising aspect is that the relapse rate is low considering the advanced phase of the disease in two-thirds of patients. A suitable CBU was found for nearly every patient searching for a CBU.

[Note: Another publication regarding this topic is as follows: Unrelated Cord Blood Transplantation: Comparison after single unit cord blood intrabone injection and double units cord blood transplantation in patients with hematological malignant disorders. A Eurocord-EBMT analysis. Rocha V, Labopin M, Ruggeri A et al. Blood 2010 106;104 (Abstract #223).

  1. Cord blood transplantation from unrelated donors in adults with high-risk acute myeloid leukemia. Sanz J, Sanz MA, Saavedra S, Lorenzo I, Montesinos P, Senent L, Planelles D, Larrea L, Martín G, Palau J, Jarque I, Martínez J, de la Rubia J, Moscardó F, Romero M, Luna I, Montava A, Cañabate S, Sanz GF. Biol Blood Marrow Transplant. 2010;16:86-94.

The authors analyzed the outcome and prognostic factors of 49 adults with high-risk acute myelogenous leukemia (AML) receiving single-unit CBT from unrelated donors after myeloablative (MA) conditioning at a single institution. Conditioning regimens were based on the combination of thiotepa, busulfan (Bu), cyclophospamide (Cy), or fludarabine (Flu), and antithymocyte globulin (ATG). Cumulative incidence of myeloid and platelet engraftment was 96% and 73% at a median time of 20 and 62 days, respectively. Engraftment was significantly faster for patients receiving higher doses of CD34+ cells. Confidence Interval (CI) of graft-versus-host disease (GVHD), acute GVHD (aGVHD) grade II-IV, III-IV, and extensive chronic GVHD (cGVHD) were 26%, 15%, and 30%, respectively. Leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse at 2 years were 42%, 39%, and 19%, respectively. A low number of total nucleated cells (TNC) had a negative impact on NRM and LFS. Patients transplanted in first complete remission (CR1) receiving TNC above 2 x 107/kg had a 4-year LFS of 75%. The authors conclude that these results show that CBT from unrelated donors is a curative treatment for a substantial number of patients with high-risk AML, particularly if transplant is performed with highly cellular units in patients in first CR.

  1. Reduced-intensity conditioning hematopoietic stem cell transplantation in patients over 60 years: hematologic malignancy outcomes are not impaired in advanced age. Koreth J, Aldridge J, Kim HT, Alyea EP 3rd, Cutler C, Armand P, Ritz J, Antin JH, Soiffer RJ, Ho VT. Biol Blood Marrow Transplant. 2010;16:792-800.

Reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for older hematologic malignancy patients as well as for younger patients with significant comorbidities who are not candidates for high intensity myeloablative HSCT. Reduced-intensity-conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is markedly underutilized in the elderly, in part because the impact of advanced age on outcomes is poorly understood. For example, at a major U.S. cancer center, despite a protocol mandating that all AML patients aged ≥50 years be evaluated by a HSCT physician with a default plan for RIC HSCT in CR1 if they had a matched related or unrelated donor, only 53 of 99 patients (54%) in CR actually underwent such an evaluation.

The authors of this publication retrospectively analyzed outcomes in 158 consecutive hematologic malignancy patients aged ≥60 years (median, 63 years; range: 60-71 years) undergoing fludarabine/busulfan-based RIC, with a median-follow-up of 34 months (range: 12.0-85.7). Multivariate analysis was undertaken for factors having an impact on outcome. For the patients aged ≥60 years, 2-year nonrelapse mortality (NRM) and relapse was 10% and 54.6%, respectively. Two-year overall and progression-free survival (OS, PFS) was 46% and 35%, respectively. Grade II-IV acute and chronic graft-versus-host disease (aGVHD, cGVHD) incidence was 19.6% and 45.9%, respectively. Comparing 110 patients aged 60-64 years versus 48 patients aged ≥65 years, 2-year NRM and relapse was 10.5% versus 8.3% (P = .84) and 53.5% versus 56.3% (P = .31), respectively. Grade II-IV aGVHD and cGVHD incidence was 19.1% versus 22.9% (P = .52) and 51.8% versus 32.5% (P = .01), respectively. Two-year OS and PFS was 49% versus 41% (P = .11) and 36% versus 35% (P = .24), respectively. In a multivariate Cox-model, high-risk disease was associated with poorer progression free survival (hazard ratio [HR] = 2.1, P = .01) and OS (HR = 1.84, P = .03). RIC HSCT is well tolerated, with reasonable survival in elderly patients. Age is not associated with impaired outcomes. Specifically, with regard to the impact of advanced age, patients ≥65 years did not experience impaired engraftment or greater treatment-related toxicity (NRM, GVHD), and their survival was comparable to patients aged 60-64 years. The authors conclude that "advanced age should not be the basis for excluding hematologic malignancy patients from potentially curative RIC HSCT".

  1. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Bachanova V, Verneris MR, DeFor T, Brunstein CG, Weisdorf DJ. Blood 2009;113:2902-5.

Twenty-two adult acute lymphoblastic leukemia (ALL) patients (21 of 22 in complete remission [CR]) received reduced-intensity conditioning followed by allogeneic transplantation. All patients were high risk. After a uniform preparative regimen (fludarabine 40 mg/m2 x 5, cyclophosphamide 50 mg/kg, 200 cGy total body irradiation), patients received either matched related (n=4) or umbilical cord (n=18) donor grafts.

All patients reached neutrophil engraftment and 100% donor chimerism (median, days 10 and 23, respectively). Overall survival, treatment-related mortality (TRM) and relapse were 50%, 27% and 36% at 3 years, respectively. There were no relapses beyond 2 years. The cumulative incidence of acute and chronic GVHD was 55% and 45%. Hematopoietic cell transplantation in CR1 (n=14) led to significantly less TRM (8%, P<.04) and improved overall survival (81%, P<.01).

The authors concluded that for adults with ALL in CR, reduced intensity conditioning allografting results in modest TRM, limited risk of relapse, and promising leukemia-free survival.

  1. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Brunstein CG, Cantero S, Cao Q, Majhail N, McClune B, Burns LJ, Tomblyn M, Miller JS, Blazar BR, McGlave PB, Weisdorf DJ, Wagner JE. Biol Blood Marrow Transplant. 2009;15:214-222.

The authors point out that nonmyeloablative hematopoietic cell transplantation (HCT) has been used to treat patients with advanced or high-risk lymphoid malignancies. Here, the authors report the outcomes of patients with low- or intermediate-grade lymphoid malignancies. Depending on the ethnic background of patients, 40-80% will not be able to find an acceptable adult stem cell donor. As a result, umbilical cord blood (UCB) has been increasingly used as a source of stem cells for hematopoietic cell transplantation.

The authors studied 65 patients (median age 46 years and median weight 81 kg) receiving an umbilical cord blood (UCB) graft after a single conditioning regimen consisting of cyclophosphamide (50 mg/kg) on day -6, fludarabine (40 mg/m2) daily on days -6 to -2, as well as a single fraction of total-body irradiation (TBI) (200 cGy) along with cyclosporine mycophenolate mofetil immunosuppression.

The incidence of neutrophil recovery was 89% at a median time of 7.5 days (range: 0-32). The cumulative incidence of platelet recovery was 82% with a median time to platelet recovery ≥50,000/µL of 46 days (range: 8-111). Cumulative incidences of grade II-IV, grade III-IV acute, and chronic graft-versus-host disease (aGVHD, cGVHD) were 57%, 25%, and 19%, respectively. Transplant-related mortality at 3 years was 15% (95% CI: 5%-26%). Median follow-up was 23 months. The progression free-survival (PFS), current PFS and overall survival (OS) were 34%, 49%, and 55% at 3 years.

The authors comment that the reason for the relatively rapid neutrophil and platelet recovery in this study is the nonmyeloablative intensity of the conditioning regimen which allows transient autologous reconstitution and a period of mixed chimerism. Also, 90% of the patients had received chemotherapy within a few weeks of undergoing nonmyeloablative conditioning and 40% and received a prior autologous transplant; both of these factors are associated with a decreased risk of graft failure.

Interestingly, in spite of the unavailability of DLI, the authors found that it is still possible to salvage a significant portion of patients and provide long-term remission by manipulating immunosuppression and/or additional systemic or local therapy. Indeed, 9 of 26 patients who had disease progression or relapse were so salvaged. Moreover, every CR achieved in this setting resulted in a durable outcome.

Based on their data, the authors concluded that a nonmyeloablative conditioning regimen followed by UCB transplantation is an effective treatment for patients with advanced lymphoid malignancies who lack a suitable sibling donor.

Further, the authors point out that UCB is an attractive source of hematopoietic stem cells for transplantation because it is rapidly available, has the ability to cross HLA barriers, and has a relatively low incidence of GVHD if considered that most UCB transplants are mismatched. They indicate that UCB blood has been the preferred source of unrelated hematopoietic stem cells for transplantation at their institution since the early 2000s.

  1. Cord blood transplantation for adults. Brunstein CG, Wagner JE. Vox Sang. 2006; 91:195-205.

Advantages and disadvantages of umbilical cord blood (UCB) over donations from unrelated adults: Advantages are (1) that UCB units are immediately available for transplantation, (2) there is no risk to the donor, (3) there is a low risk of viral transmission of CMV, hepatitis and HIV, and (4) a higher degree of HLA mismatch appears to be acceptable with a comparatively lower risk of acute and chronic GVHD. Disadvantages are (1) there are a limited number of hematopoietic progenitor cells in a single UCB unit and cell dose has been shown to be a major determinant of engraftment and survival. (2) there is no access to donor lymphocytes in the event of relapse after UCB transplantation, and (3) there is significantly less experience with UCB than with unrelated donors, especially in adults.

COMPARISONS OF UCB AND OTHER HSC SOURCES:

The results of two reported studies that compared related donor HSC vs. unrelated UCB transplantation are summarized in the text and in a detailed table. The first study compared unrelated UCB to HLA- and partially HLA-matched related donors after a myeloablative preparative regimen. Time to neutrophil and platelet recovery were longer in the UCB cohort, but overall donor-derived engraftment was comparable by day 42. The rate of aGVHD grades II-IV was the same but grade III-IV aGVHD was significantly more frequent among recipients of a related donor graft (8% vs. 19%, p=0.04). The incidences of cGVHD and TRM, and the 3-year relapse rate, as well as probability of 3-year survival were comparable between the two groups. The second study compared outcomes in patients transplanted with unrelated UCB and haploidentical T-cell depleted marrow grafts for the treatment of AML and ALL. Once again, median time to neutrophil recovery was longer in the UCB cohort. The incidence of grades II-IV aGVHD was higher for the UCB group. Other than GVHD, patients with AML had similar outcomes, regardless of graft source. However, patients with ALL had a higher probability of 2-year-leukemia-free survival if the received a UCB graft.

At least three retrospective studies have been reported that compared UCB with unrelated donor transplantation in adults after a myeloablative preparative regimen. Again the tie to neutrophil and platelet recovery was significantly delayed, and graft failure was higher after UCB transplantation. The incidence of grades II-IV aGVHD after UCB transplantation was similar or lower. Relapse rates were similar between UCB and unrelated donor grafts in all studies. The impact of graft source on TRM and survival has been more controversial. One study showed TRM after UCB transplantation to be significantly higher than after HLA-matched unrelated marrow (although similar to HLA-mismatched unrelated marrow), another study showed similar TRM rates for UCB and unrelated marrow grafts, while the third study observed lower TRREM for the UCB group compared with unrelated marrow. Overall, these studies suggest that UCB transplantation is an acceptable alternative for all patients who do not have a suitable related and unrelated donor. The question, at present, is the relative place of UCB – first-line or second-line therapy.

MULTIPLE UCB UNITS

It is unequivocally clear that cell dose and HLA match are central factors in predicting the risk of TRM. Furthermore it is clear that low cell dose amplifies the deleterious effect of HLA mismatch. The use of "double" UCB transplantation is based on the rationale that if a single unit does not provide an adequate cell dose for an adult patient, perhaps the combined cell dose of two partially HLA-matched units could improve the outcome.

Double UCB transplantation after a myeloablative preparative regimen: In a study comparing outcomes after single or double UCB transplantation for acute leukemia patients, sustained neutrophil engraftment and TRM were virtually the same indicating that patients can receive single UCB unit grafts if the cell dose is high enough. There was a threefold higher incidence of grade II-IV aGVHD among recipients of double cords, but no difference in the incidence of grades III-IV aGVHD or cGVHD. An unexpected finding was a lower leukemia relapse rate among recipients of double UCB graft when transplanted in first and second complete remission. The results of the multivariate analysis indicated that transplantation with two units is associated with a 10-fold lower risk of relapse. This may be explained by the fact that recipients of a double UCB graft most often receive a 4/6 HLA-matched graft, which may lead to more GVL effect.

Double UCB transplantation after non-myeloablative transplantation: Non-myeloablative (NMA) preparative regimens have allowed patients who are older, and heavily pretreated, and with significant comorbidities to undergo allogeneic transplantation. Most groups have used fludarabine combined with an alkylating agent preparative regimen with our without low-dose TBI. In two studies, patients who received double UCB unit grafts, with a higher median infused NCD and CD34 cell dose, were more likely to have sustained donor engraftment, at a median of approximately 2 weeks. The incidence of acute and chronic GVHD varied widely but TRM was consistently lower than 30%. In the largest single-center experience, progression-free survival was 38% and overall survival was 44%. However, patients who receive an NMA preparative regimen because of poor organ function, recent fungal infection, or low performance status still have a significantly higher risk of TRM and poor survival. Patients who were not exposed to multiagent chemotherapy in the 3 months before NMA UCB were at high risk of graft failure, and patients who receive ATG have an increased risk of EBV viremia and post-transplant lymphoproliferative disorder. In summary, the data clearly support the utilization of UCB as an HSC source for NMA transplantation.

NOVEL STRATEGIES TO IMPROVE ENGRAFTMENT, REDUCE GVHD, REDUCE TRM AND ENHANCE GFL:

    1. Use of drugs or cell populations to reduce host resistance.
    2. Ex-vivo expansion to augment the HSC and progenitor cell numbers.
    3. Use of novel therapies that limit the use of myelotoxic drugs in the peritransplant period.
    4. Ways to minimize the non-specific loss of circulating HSCs and potentially homing to the marrow microenvironment.

 

  1. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplant outcomes in 110 adults with hematological disease. Brunstein CG, Barker JN, Weisdorf DJ, Defor TE, Miller JS, Blazar BR, McGlave PB, Wagner JE. Blood 2007;110:3064-70.

This report establishes the safety profile of a nonmyeloablative treatment regimen consisting of fludarabine (FLU), cyclophosphamide (CY) and single fraction total body irradiation (TBI) in recipients of UCB in 110 consecutive adult patients with hematological disease. Ninety-three of the 110 patients received a double cord transplant.

Inclusion Criteria. Patients with advanced or high-risk hematologic disease were eligible for UCB transplantation if they had no related donor matched at 5-6/6 HLA loci (A, B, and DRB1). Patients were eligible for nonmyeloablative therapy if they met any of the following criteria: age >45 years, pre-existing high risk clinical features for TRM (serious organ dysfunction; invasive mold infection within 4 months prior to transplantation; Karnofsky Performance score 50-60 or history of extensive prior therapy [defined as: >12 months alkylator-based chemotherapy; >6 months alkylator-based chemotherapy plus extensive radiation; or history of autologous transplantation]).

UCB unit selection algorithm. UCB units were required to be matched at >4 of 6 HLA antigens based on antigen-level HLA-A and B typing and allele-level HLA-DRB1 typing. UCB units were required to have a minimum cryopreserved total nucleated cell (TNC) dose of 2.0 x 107/kg. However, the target cell dose was ≥3.0 x 107 TNC/kg resulting in the selection of a second partially HLA matched UCB unit if available. In those for whom a second UCB unit could be identified, the second unit also had to be 4 of 6 antigen matched with the first unit.

Treatment. 110 patients received a single dose of CY 50 mg/kg on day -6, FLU 40 mg/m2 daily on days -6 to -2, and a single fraction of TBI 200 cGy without shielding on day -1. ATG was given at 15 mg/kg every 12 hours on days -3 to -1 in a subpopulation of patients who had received less than two cycles of multiagent chemotherapy within the 3 months prior to enrollment (and no history of autologous transplantation.). All patients received CsA twice daily from day -3 for at least 3 months with target trough levels of 200-400 ng/ml and MMF at 1 g intravenously or orally twice daily from day -3 to +30.

Results. Most patients received two UCB units (n=93) to achieve the required cryopreserved cell dose. Neutrophil recovery was achieved in 92% at median of 12 days. Incidences of grades III-IV acute and chronic GVHD were 22% and 23%, respectively. Transplant-related mortality was 26% at 3 years. Survival and event-frees survival at 3 years were 45% and 38%, respectively.

Favorable risk factors were absence of high risk clinical features and absence of severe GVHD (p=0.04) for survival, and absence of high risk clinical features (p<0.01) and use of two UCB units (p=0.07) for event-free survival.

Discussion. The study supports the use of UCB transplantation after a non-myeloablative therapy in adults with hematologic disease. It is clear that the use of the double UCB platform in the setting of a nonmyeloablative therapy extends the availability of transplantation to those who cannot find a suitably HLA matched adult volunteer marrow or peripheral blood donor and who are at increased risk of regimen-related toxicity and transplant related mortality, such as older or heavily treated patients.

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