i. Cord Blood Transplants

1. Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Majhail NS, Brunstein CG, Tomblyn M, Thomas AJ, Miller JS, Arora M, Kaufman DS, Burns LJ, Slungaard A, McGlave PB, Wagner JE, Weisdorf DJ. Biol Blood Marrow Transplant. 2008;14:282-9.

The authors hypothesized that reduced-intensity conditioning (RIC) hematopoietic cell transplants (HCT) using UCB would be safe and efficacious in older patients. They compared the treatment-related mortality (TRM) and overall survival (OS) of RIC HCT in patients older than 55 years using either an adult matched related donor (MRD) (n = 47) or, in patients with no 5 of 6 or 6 of 6 HLA compatible related donors, UCB (n = 43).

The RIC regimen consisted of total-body irradiation (TBI; 200 cGy) and either cyclophosphamide and fludarabine (n = 69), or busulfan and fludarabine (n = 16) or busulfan and cladribine (n = 5). The median age of MRD and UCB cohorts was 58 (range, 55-70) and 59 (range, 55-69) years, respectively. Acute myelogenous leukemia/myelodysplastic syndrome (AML/MDS) (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 88% received 2 UCB units to optimize cell dose and 93% received 1-2 HLA mismatched grafts. The median follow-up for survivors was 27 (range: 12-61) months.

The 3-year probabilities of progression-free survival (PFS; 30% versus 34%, P = .98) and OS (43% versus 34%, P = .57) were similar for recipients of MRD and UCB. The cumulative incidence of grade II-IV acute graft-versus-host (aGVHD) disease (42% versus 49%, P = .20) and TRM at 180-days (23% versus 28%, P = .36) were comparable. However, UCB recipients had a lower incidence of chronic graft-versus-host disease (cGVHD) at 1 year (40% versus 17%, P = .02). On multivariate analysis, graft type had no impact on TRM or survival, and the HCT comorbidity index score was the only factor independently predictive for these endpoints.

The investigators conclude that their study supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have an MRD. The use of RIC and UCB extends the availability of transplant therapy to older patients previously excluded on the basis of age and lack of a suitable MRD. A careful review of existing comorbidities is necessary when considering older patients for HCT.

2. Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases. Bradley MB, Satwani P, Baldinger L, Morris E, van de Ven C, Del Toro G, Garvin J, George D, Bhatia M, Roman E, Baxter-Lowe LA, Schwartz J, Qualter E, Hawks R, Wolownik K, Foley S, Militano O, Leclere J, Cheung YK, Cairo MS. Bone Marrow Transplant. 2007;40:621-631.

The authors investigated reduced intensity umbilical cord blood transplantation (RI-UCBT) in 21 children and adolescents with malignant (n=14), and non-malignant diseases (n=7). RI conditioning consisted of fludarabine (150-180 mg/m2) with either busulfan (< or = 8 mg/kg)+rabbit antithymocyte globulin (R-ATG; n=16) or cyclophosphamide+R-ATG+/-etoposide (n=5). HLA matches were as follows: 4/6 (n=13), 5/6 (n=5) and 6/6 (n=3). The median total nucleated cell and CD34+ cell dose per kilogram were 3.58 x 10(7) and 2.54 x 10(5), respectively.

The median time for neutrophil and platelet engraftment was 17.5 and 52 days, respectively. There were six primary graft failures (chronic myelogenous leukemia (CML), beta-thalassemia, hemophagocytic lymphohistiocytosis (HLH) and myelodysplastic syndrome (MDS)). Five of the six patients had diseases that were not treated with chemotherapy or immunosuppressive therapy before RI conditioning. Four of these patients achieved full-donor chimerism after undergoing a second, but this time myeloablative UCBT.

The probability of developing grade II to grade IV acute graft-versus-host disease (GVHD) and chronic GVHD was 28.6 and 16.7%, respectively. The incidence of transplant-related mortality (TRM) was 14%. The 5 years overall survival (OS) in all patients was 59.8%. The 5 years OS for patients with average versus poor-risk malignancy was 77.8 versus 22.2% (P=0.03).

The authors concluded that RI-UCBT may result in graft failure in specific high-risk chemo-naïve patients (CML, beta-thalassemia, HLH and MDS), but in more heavily pretreated pediatric and adolescent recipients results in rapid engraftment and may be associated with decreased severe GVHD and TRM. The results need to be interpreted with caution because they were obtained with a heterogeneous group of patients and different RI conditioning regimens. A larger cohort of patients should be studied with much longer follow-up.

3. 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; 110:3064-3070.

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.

4. Are 2 cords better than 1? Shpall E, De Lima M, Jones R, Champlin R. Blood. 2007;110:2789-2790.
   (This article is a commentary on an article by Brunstein et al., (Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplant outcomes in 110 adults with hematological disease. Blood. 2007;110:3064-3070) In this study, most patients received two UCB units (n=93) to achieve the required cryopreserved cell dose. The Brunstein article is posted on the Cord Blood Forum in the Annotated Bibliography. See Topic IV, Reduced Intensity and Non-Myeloablative Transplants, i. Cord Blood Transplants, Citation #3.)

A major limitation of UCBT has been the small cell dose and resulting delayed time to engraftment in adults. The data in the report by Brunstein et al convincingly demonstrate that rapid neutrophil recovery with ultimate predominance of a single cord can be achieved using double cord blood transplants. Although the follow-up is short, the favorable relapse-free survival following a non-myeloablative regimen suggests a potent UCB-mediated graft-versus-tumor effect.

A single very large UCB unit meeting the protocol transplant standard was found and used in only 17 of the 110 patients, underscoring the limitations of comparing transplantation of 1 versus 2 cords in this study. Nevertheless, as suggested by the authors, it appears unlikely that a randomized comparison of unmanipulated single versus double UCBT will be performed for adults. Double UCBT seems likely to emerge as a standard to which newer adult UCBT techniques will be compared in the future.

The authors of this commentary go on to address a number of important questions that continue to surround double UCBT. An important one of these is that 2 cords may produce a somewhat higher incidence of acute GVHD which brings up the question of whether GVHD should be modulated using high-dose anti-thymocyte globulin (ATG) or similar techniques.

The authors conclude that the report of Brunstein et al., as well as other studies which they cite, provide increasing evidence that UCBT represents a practical and important advance in hematopoietic cell transplantation

5. Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Ballen KK, Spitzer TR, Yeap BY, McAfee S, Dey BR, Attar E, Haspel R, Kao G, Liney D, Alyea E, Lee S, Cutler C, Ho V, Soiffer R, Antin JH. Biol Blood Marrow Transplant. 2007;13:82-89.

In an effort to increase the cell dose and decrease transplantation-related toxicity, the authors treated 21 adult patients (24-63 years) with a reduced-intensity conditioning regimen followed by sequential infusion of 2 partially matched umbilical cord blood (UCB) units. Two patients had aplastic anemia, one had myelodysplastic syndrome and the others had hematologic malignancies, the most common diagnosis being acute myeloid leukemia.

The reduced-intensity conditioning regimen consisted of fludarabine, melphalan, and antithymocyte globulin. The UCB units were a 4/6 HLA match or better with each other and with the patient and achieved a minimum precryopreservation cell dose of 3.7 x 10⁷ nucleated cells/kg.

The median time to an absolute neutrophil count > 0.5 x 10⁹/L was 20 days, and the median time to an unsupported platelet count > 20 x 10⁹/L was 41 days. Two patients experienced primary graft failure and underwent a second UCB transplantation. One patient had a late graft failure. Acute graft-versus-host disease (GVHD) grade II-IV occurred in 40% of patients. The 100-day TRM was 14%, and the 1-year disease-free survival was 67%. Mixed chimerism was associated with a higher risk of chronic GVHD.

The authors concluded that their findings indicate that adult patients can tolerate double UCB transplantation well and achieve sustained antitumor responses using this reduced-intensity conditioning regimen.

6A. Successful engraftment in reduced-intensity cord blood transplantation (CBT) as a salvage therapy for graft failure after primary CBT in adults. Kawamori Y, Yakushijin K, Okamura A, Nishikawa S, Minagawa K, Shimoyama M, Yamamoto K, Katayama Y, Matsui T. Transplantation. 2007;83:1281-1282.

The authors stated that they performed a second CBT in four cases with primary graft failure after CBT and all cases successfully achieved engraftment.

Three points were emphasized. First, they tried to confirm graft failure and to make a decision to perform the salvage CBT as quickly as possible. The confirmation of graft failure was made by no donor chimerism in bone marrow cells on day 28 or by no sign of hematopoietic recovery until day 35 after primary CBT. Second, reduced-intensity CBT was chosen for the second transplant to avoid regimen-related toxicity and mortality. They used a fludarabine-based preparative regimen. Third, to intensify the immunosuppression in combination with a key drug tacrolimus, they utilized mycophenolate mofetil (MMF) instead of methotrexate. The authors add that it would be important to make sure of the availability of a cord blood unit for salvage transplant as early as possible.

[Note: The general principles put forward by this and the subsequent 4 papers are (1) Graft failure must be diagnosed expeditiously, (2) A search for a cord blood unit (or units) should be undertaken as soon as the possible need is identified, and (3) A reduced-intensity transplant is preferable in order to minimize transplant-related morbidity.]

6B. Second transplant with two unrelated cord blood units for early graft failure after haematopoietic stem cell transplantation. Fernandes J, Rocha V, Robin M, de Latour RP, Traineau R, Devergie A, Ribaud P, Réa D, Larghero J, Gluckman E, Socié G. Br J Haematol. 2007;137:248-251.

This is a report of four patients who developed early graft failure after unrelated HSCT and who subsequently received a double unrelated cord blood transplant after reduced-intensity conditioning, at a median 15 days after the decision to perform a second transplant. Neutrophil recovery was observed in all four patients between day +15 and +31 with full donor chimerism of one unit. Acute GVHD grades II-IV was observed in three patients. Three are alive, between 12 and 25 months after the double UCBT. The authors concluded that double UCBT is a promising procedure to treat early GF.

6C. Successful second cord blood transplantation using fludarabine and cyclophosphamide as a preparative regimen for graft rejection following reduced-intensity cord blood transplantation. Mizutani E, Narimatsu H, Murata M, Tomita A, Kiyoi H, Naoe T. Bone Marrow Transplant. 2007;40:85-87.

The authors describe 5 patients who had received a second CBT for graft rejection using a preparative regimen consisting of fludarabine and melphalan with or without TBI. Although 4 of the patients achieved engraftment, three ultimately died of transplant-related mortality. All 5 patients developed grades 3-5 regimen-related toxicities.

As a result of the above experience, the authors performed a reduced-intensity CBT using fludarabine and cyclophosphamide without TBI in a patient with initial graft rejection. The patient received the second transplant as treatment for the initial graft rejection 35 days after the initial CBT. The preparative regimen consisted of 125 mg/m² fludarabine (day -6 to -2, 25 mg/m²/day) and 60 mg/kg cyclophosphamide on day -6. Prophylaxis for GVHD consisted of 0.02 mg/kg tacrolimus and short-term methotrexate (day 1, 10 mg/m²/day; days 3 and 6, 7 mg/m²/day).

The patient had HHV-6 encephalitis that resolved spontaneous and an invasive fungal infection that responded to antifungal therapy. She did not develop acute GVHD. Engraftment of neutrophils (>500/µL) occurred on day 19 and complete donor chimerism was achieved. Although the patient’s neutropenic period lasted 44 days, she did not develop fatal infectious complications. The bone marrow examination done on day 97 revealed normal hematopoiesis and complete donor chimerism.

The authors emphasize that rapid diagnosis of graft rejection and re-transplantation is important. In this patient graft failure was diagnosed on day 28 based on chimerism analysis of the bone marrow cells. However, monitoring of chimerism in the peripheral blood on a weekly basis might have helped to establish the diagnosis more rapidly.

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