Optimal conditioning regimens for cord blood transplantation: advances and challenges

Abstract Results of reduced intensity conditioning regimen (RIC) in unrelated cord blood transplantation (UCBT) have been reported, however more frequently RIC was performed using double cord blood transplants. In order to study risk factors in single RIC-UCBT we have analyzed 65 patients with hematological malignancies (ALL=10, AML=37, Hodking and NHL=10, MDS=4, CML=3, Myeloma =1) transplanted from 1999–2005 and reported to Eurocord and SFGM-TC. The median follow-up was 8 months (3–26) and the median age was 47 years (16–76). At transplant, 49% of the patients had advanced phase of disease and 39% had received a previous autologous transplants. The conditioning regimen varied according diasease and centers: Fludarabine(FLU)+Endoxan (EDX) +TBI (2Gy) was given to 33 patients, FLU+(EDX or Melphalan) in 11, FLU+BU (<8mg/kg) associated or not to other drugs in 13, FLU+TBI(2GY) in 3 and other regimens in 5 patients. ATG/ALG was added in 26% of the cases. GVHD prophylaxis most commonly (55%) consisted of CsA and MMF; 87% received hematopoietic growth factors (<day 8). The median nucleated cell dose infused was 2.4 x107/kg and the graft was HLA identical (6/6) ( HLA A and B low resolution and DRB1 allelic typing) in 3 cases, 5/6 in 15, 4/6 in 37 and 3/6 in 10. Results: Median time to neutrophil recovery (>500/mm3) was 20 days (0–56) and 35 dyas for platelets recovery (>20.000/mm3). At day 60 probability of neutrophil recovery was 87± 7% of the 33 patients who received the Flu+End+TBI conditioning regimen and was 65±10% for patients receiving other regimens (p<0.01). Chimerism analysis was available in 71% of the patients at 3 months and was full donor in 67%, mixed chimerism in 9% and autologous reconstitution in 24%. Grade II aGVHD was observed in 13%, grade III in 7% and grade IV in 7%; the TRM was 45±7% overall, 50±15% in acute leukemia, 30±15% in lymphomas and 27±16% for other diagnoses. The TRM at one year for those receiving <2.4 x 107 TNC/kg was 53±9% and for those receiving >2.4 x107TNC/kg was 39±10% (p=0.07). For patients receiving Flu+End+TBI the TRM at one year was 24±10% and for those receiving other conditioning regimens was 60±9% (p=0.001). DFS at one year for lymphomas was 50±9%, for leukemias was 27±7% and for other diagnoses was zero. When the HLA compatibility was 6/6 or 5/6, DFS at one year was 42±12%, for 4/6 disparities DFS was 27±9% and for 3/6 disparities DFS was zero. DFS was 43±11% for those receiving Flu+End+TBI, and was 16±7% for patients receiving other conditioning regimens (p=0.005). For patients receiving >2.4 x 107TNC/kg the DFS was 31±12% and for patients receiving <2.4 x 107TNC/kg the DFS was 14±8% (p=0.05). In collusion, results of single RIC-UCBT are encouraging; cell dose and HLA remain important factors in this setting. The type of conditioning (Flu+End+TBI) seems to be associated with decreased TRM and better DFS, but a multivariate analysis with a higher number of patients is needed.

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Umbilical Cord Blood Transplantation after Reduced-Intensity Conditioning for Adults: The Report from Japan Cord Blood Bank Network.

Blood ◽

10.1182/blood.v110.11.2030.2030 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2030-2030

Author(s):

Naofumi Matsuno ◽

Shuichi Taniguchi ◽

Satoshi Takahashi ◽

Shunro Kai ◽

Yasuji Kozai ◽

...

Keyword(s):

Cord Blood ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Alkylating Agent ◽

Cord Blood Transplantation ◽

Cell Number ◽

Blood Transplantation ◽

Conditioning Regimens ◽

Standard Risk ◽

Neutrophil Engraftment

Abstract Umbilical cord blood transplantation (UCBT) is an alternative to bone marrow transplantation in adults when no sibling donor is available. Recently, UCBT after reduced-intensity conditioning (RI-UCBT) has been increasing in high risk adults not eligible for conventional conditioning. To evaluate the feasibility and effectiveness of RI-UCBT, we retrospectively analyzed the outcomes of 777 patients with hematologic diseases, who received RI-UCBT as the first allograft between 1997 and 2006 in Japan. Of 777 patients, 303 were women and 474 were men. Their median age was 56 years (range, 16–79 years). The patients’ diagnoses included 190 with acute myeloid leukemia, 66 with acute lymphoblastic leukemia, 22 with chronic myeloid leukemia, 172 with myelodysplastic syndrome, 193 with malignant lymphoma, 68 with adult T-cell leukemia/lymphoma, 44 with multiple myeloma, and 22 with aplastic anemia. Of 770 evaluable patients, 272 were defined as standard risk, whereas 498 were defined as high risk. Cord blood units were obtained from Japan Cord Blood Bank Network. The median total nucleated cell (TNC) number and median CD34+ cell number were 2.54 (range, 1.10–6.42) × 107/kg and 0.77 (range, 0.01–12.32) × 105/kg, respectively. Forty-two, 216, 512 and 4 patients received 6 of 6, 5 of 6, 4 of 6 and 3 of 6 serological HLA matched cord blood, respectively. The most frequently used conditioning regimens were fludarabine (Flu), alkylating agent (melphalan, busulfan or cyclophosphamide) with total body irradiation (TBI). The most frequently used prophylaxis regimens for graft-versus-host disease (GVHD) were calcineurin inhibitor (CI) alone in 431 patients and CI plus methotrexate in 206 patients. Cumulative incidence of neutophil engraftment was 67% at a median of 20 days after transplantation. Platelet recovery more than 20 × 109/L was observed in 47% at a median of 39 days. Among 542 evaluable patients, 206 developed acute GVHD of grade II or higher (cumulative incidence: 38%). The Kaplan-Meier estimates of overall survival (OS) and disease free survival at 2 years were 25% and 20%, respectively. Cumulative incidence of treatment-related mortality at day 100 was 36%. In univariate analyses, TNC number (>2.5 × 107/kg) and CD34+ cell number (>0.7 × 105/kg) were significantly associated with the neutrophil engraftment (P=0.0009 and P<0.0001, respectively). Conditioning regimens consist of Flu, alkylating agent plus TBI were associated with favorable neutrophil engraftment and survival (P<0.0001 and P=0.0013, respectively). Patients with younger age (<56 years) or standard risk showed significantly longer OS (P=0.0013 and P<0.0001, respectively). Multivariate analyses revealed that CD34+ cell number and conditioning regimens consist of Flu, alkylating agent plus TBI were significant independent factors for neutrophil engraftment (P<0.0001 and P<0.0001, respectively). Regarding survival, multivariate analyses revealed that age, disease risk and conditioning regimens were significant independent factors for OS (P=0.0013, P<0.0001 and P=0.0002, respectively). In our retrospective analyses, a significant number of patients did not achieve engraftment or died from treatment-related complications. Further optimization of the treatment protocol is warranted to establish the safety of RI-UCBT.

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Adult cord blood transplant results in comparable overall survival and improved GRFS vs matched related transplant

Blood Advances ◽

10.1182/bloodadvances.2020001554 ◽

2020 ◽

Vol 4 (10) ◽

pp. 2227-2235

Author(s):

Prashant Sharma ◽

Enkhtsetseg Purev ◽

Bradley Haverkos ◽

Daniel A. Pollyea ◽

Evan Cherry ◽

...

Keyword(s):

Overall Survival ◽

Cord Blood ◽

Cumulative Incidence ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Blood Transplantation ◽

Cord Blood Transplant ◽

Conditioning Regimens ◽

Related Donor

Abstract We compared outcomes among adult matched related donor (MRD) patients undergoing peripheral blood stem cell transplantation and adult patients undergoing double unit cord blood transplantation (CBT) at our center between 2010 and 2017. A total of 190 CBT patients were compared with 123 MRD patients. Median follow-up was 896 days (range, 169-3350) among surviving CBT patients and 1262 days (range, 249-3327) among surviving MRD patients. Comparing all CBT with all MRD patients, overall survival (OS) was comparable (P = .61) and graft-versus-host disease (GVHD) relapse-free survival (GRFS) was significantly improved among CBT patients (P = .0056), primarily because of decreased moderate to severe chronic GVHD following CBT (P < .0001; hazard ratio [HR], 3.99; 95% confidence interval [CI], 2.26-7.04). Among patients undergoing our most commonly used MRD and umbilical cord blood (CB) myeloablative regimens, OS was comparable (P = .136) and GRFS was significantly improved among CBT patients (P = .006). Cumulative incidence of relapse trended toward decreased in the CBT group (P = .075; HR, 1.85; CI 0.94-3.67), whereas transplant-related mortality (TRM) was comparable (P = .55; HR, 0.75; CI, 0.29-1.95). Among patients undergoing our most commonly used nonmyeloablative regimens, OS and GRFS were comparable (P = .158 and P = .697). Cumulative incidence of both relapse and TRM were comparable (P = .32; HR, 1.35; CI, 0.75-2.5 for relapse and P = .14; HR, 0.482; CI, 0.18-1.23 for TRM). Our outcomes support the efficacy of CBT and suggest that among patients able to tolerate more intensive conditioning regimens at high risk for relapse, CB may be the preferred donor source.

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Total body irradiation-containing conditioning regimens without antithymocyte globulin in adults with aplastic anemia undergoing umbilical cord blood transplantation

Annals of Hematology ◽

10.1007/s00277-021-04664-z ◽

2021 ◽

Author(s):

Nobuhiro Hiramoto ◽

Hirohito Yamazaki ◽

Yukinori Nakamura ◽

Naoyuki Uchida ◽

Makoto Murata ◽

...

Keyword(s):

Cord Blood ◽

Aplastic Anemia ◽

Umbilical Cord Blood ◽

Total Body Irradiation ◽

Antithymocyte Globulin ◽

Cord Blood Transplantation ◽

Umbilical Cord Blood Transplantation ◽

Blood Transplantation ◽

Conditioning Regimens ◽

Total Body

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Reduced-Intensity Cord Blood Transplantation in Adult Patients for the Recurrence after Allogeneic Transplantation.

Blood ◽

10.1182/blood.v108.11.5346.5346 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5346-5346

Author(s):

Sachiko Seo ◽

Naoyuki Uchida ◽

Hisashi Yamamoto ◽

Naofumi Matsuno ◽

Yoshiko Matsuhashi ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cord Blood ◽

Cell Transplantation ◽

Cord Blood Transplantation ◽

Blood Transplantation ◽

Stem Cell Source ◽

Cell Source ◽

Conditioning Regimens ◽

Reduced Intensity

Abstract Backgrounds: For more than 10 years, umbilical cord blood has become an alternative stem cell source for the patients with hematological malignancies requiring allogeneic stem cell transplantation. Cord blood transplantation (CBT) can be performed more quickly than other stem cell transplantation, since cord blood units are preserved in the deep freeze and 1–3 HLA mismatched donors are acceptable. Considering these advantage, we examined the feasibility of cord blood transplantation using reduced-intensity regimens (RI-CBT) for adult relapsed patients after allogeneic tranplantation. Patients/methods: We reviewed medical records of 26 patients who received RI-CBT at Toranomon Hospital between November 2003 and June 2006. Median age of the patients was 36 years (range, 20–66). Underlying diseases were acute leukemia (n=17), myelodysplastic syndrome (n=4) and lymphoma (n=5). The stem cell source of the first transplantation were bone marrow from sibling donor (n=2), bone marrow from unrelated (n=5) donor, peripheral blood stem cell from sibling donor (n=5) and unrelated cord blood (n=14). Conditioning regimens comprised fludarabine 125–180 mg/m2 in several combination with melphalan 80–140 mg/m2, Busulfan 8–16mg/kg and total body irradiation (TBI) (4–8 Gy). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n=5) or tacrolimus (n=21). Median number of total nucleated cells and CD34+ cells was 2.56×106 cells/kg (1.91–5.94), and 0.86×105 cells/kg (0.57–1.77) respectively. HLA disparities were 5/6 (n=2), 4/6 (n=22), and 3/6 (n=2). Results: Median observation period was 58 days (range, 32–380). Overall survival for 1 year was 15% and 16 patients were died of disease progression (n=5) and infection (n=11). The infection in 4 patients was considered to be caused by regimen related toxicity (RRT). No grade IV toxicities (NCI-CTC Ver.3.0) were observed. The duration between two transplantations was longer in surviving patients compared to dead patients (98 days (range, 39–2108) and 262 days (range, 95–901), respectively), although significant difference was not detected. The stage of the disease in the second transplantation, conditioning regimens and HLA disparities did not influence to the outcome. Discussion: We demonstrated that RI-CBT could be an available and feasible treatment for the relapsed patients after stem cell transplantation. Moreover, the RRT is acceptable even in the patients with an advanced disease.

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Unrelated Umbilical Cord Blood Transplantation: Characteristics and Outcomes In Older Patients With Hematological Malignancies In Europe and United States: A Eurocord/European Group For Blood and Marrow Transplantation (EBMT) and Center For International Blood and Marrow Transplant Research (CIBMTR) Study

Blood ◽

10.1182/blood.v122.21.3339.3339 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3339-3339

Author(s):

Annalisa Ruggeri ◽

Mary Eapen ◽

Fernanda Volt ◽

Chantal Kenzey ◽

Federica Giannotti ◽

...

Keyword(s):

North America ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Older Patients ◽

Cord Blood Transplantation ◽

Lymphocytic Leukemia ◽

Blood Transplantation ◽

The Us ◽

Conditioning Regimens

Abstract Introduction Transplantation with umbilical cord blood rather than adult donor cells is a valid alternative for adults with malignant and non-malignant hematological diseases. The use of unrelated umbilical cord blood transplantation (UCBT) in adults has increased recently for 2 reasons: use of 2 cord blood units to obtain an adequate number of cells; and, use of reduced-intensity conditioning regimens (RIC) for older persons who are unable to tolerate myeloablative conditioning regimens. Recent data from Eurocord and CIBMTR indicate that 35% of adults UCBT recipients are older than 50 years. This study describes the increasing use of UCBT and the patient characteristics and transplant strategies used in older (>50 years) patients receiving UCBT in Europe and United States, as well as UCBT outcomes in this population. Methods Retrospective registry based cross-sectional study on patients transplanted in Europe and North America; Patients: 1529 patients 50 years or older who received UCBT for hematologic malignancies or non-malignant hematologic disorders from 2005 through 2011, and whose transplants were reported to EUROCORD/EBMT or CIBMTR. 848 patients were transplanted in North America; 681 were transplanted in Europe. Acute myeloid leukemia (AML) (50%) was the most frequent indication in both registries, followed by myelodysplastic syndrome (MDS) and non-Hodgkin Lymphoma (NHL). Myeloma (MM) was the indication for UCBT for 15% of patients in Europe, but accounted for only a single case in the US (Refer to table 1 for complete UCBT distribution according to diagnosis). Most AML patients (80%) in both registries were transplanted in CR1 or CR2. RIC regimens were used more frequently for patients in Europe: 76% of patients reported to Eurocord versus 49% reported to CIBMTR for patients in the age range 50-59y and 93% in Eurocord and 69% in CIBMTR for patients 60y or older. Graft-versus-host disease prophylaxis in Europe was predominantly with cyclosporine and prednisone; tacrolimus and mycophenolate was more often used in the US. Double UCBT accounted for 61% of cases reported to Eurocord and for 71% of cases reported to CIBMTR. Results Probability of 2-y overall survival (OS) was similar in both cohorts. In Eurocord, 2-y OS rates were 33% for AML in CR1, 48% in CR2, 10% with advanced disease for patients aged 50-59y; corresponding rates in older patients were 58%, 29% and 15%, respectively. In CIBMTR, 2-y OS rates were 41% for AML in CR1, 30% in CR2 and 15% with advanced disease for patients aged 50-59y; corresponding rates for older patients were 22%, 29%, and 16%, respectively. For other malignancies, in Eurocord, for patients aged 50-59y, 2-y OS rates were 57% in MM, 52% in ALL (acute lymphocytic leukemia), 49% in NHL, 47% in CLL (chronic lymphocytic leukemia) and 25% in MDS. In CIBMTR, corresponding OS rates were 54% in ALL, 48% in MDS, 41% in NHL and 40% in CLL Conclusion The number of UCBT for the elderly has been increasing over the years, and survival rates are comparable for this population in Europe and North America, with similar trends in both registries. The encouraging results of this survey show that UCBT is a good alternative source of stem cells for elderly patients with hematologic diseases. Comparative studies between umbilical cord blood and other stem cell sources are needed to define the best graft indication for patients aged 50 years and older lacking an HLA identical adult donor. Disclosures: No relevant conflicts of interest to declare.

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