scholarly journals Influence of Donor Type (sibling vs matched-unrelated donor vs haplo-identical donor vs cord blood) on Outcomes after Clofarabine-Based Reduced-Intensity Conditioning Allograft for Myeloid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3451-3451
Author(s):  
Louise Bouard ◽  
Thierry Guillaume ◽  
Pierre Peterlin ◽  
Alice Garnier ◽  
Amandine Le Bourgeois ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cord Blood ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Post Transplant ◽  
Donor Type ◽  
Reduced Intensity

Abstract Background: Recently, we have reported the good results of a clofarabine-based reduced-intensity conditioning (RIC) regimen for peripheral blood stem cell (PBSC) allografts, using either matched (Le Bourgeois, ASH 2017) or haploidentical (haplo) donors (Chevallier, ASH 2017). However, the influence of donor type in this setting is unknown. Patients and Methods: We conducted a retrospective study including all adults (≥18 yo) allografted in our department with a clofarabine-based RIC regimen for a myeloid malignancy. All types of donors were accepted, and patients received allogeneic peripheral blood stem cells (PBSC) or cord blood (CB) transplants. The aim of this study was to assess whether or not the donor type (sibling, matched unrelated (MUD), haplo or CB) impacted outcomes. Results: Between October 2009 and February 2018, 122 patients met the inclusion criteria. Donors were sibling in 36 cases, "MUD" in 55 (including one 9/10 mismatched donor), haplo in 27 and CB in 4. The sibling+MUD patients received a CloB2A1/A2 RIC regimen consisting of clofarabine 30 mg/m²/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and 2.5mg/kg/day of rabbit anti-thymocyte globulin 1 or 2 days (A1 or A2). Haplo and CB recipients were conditioned by a Baltimore-like RIC regimen and a Minneapolis-like regimen, respectively, where fludarabine were replaced by clofarabine. All patients received cyclosporine (CsA) + mycophenolate mofetyl as GVHD prophylaxis, except sibling recipients who were given CsA alone. Haplo recipients received also 2 days of post-transplant cyclophosphamide. All non-CB patients received PBSC as source of graft. The median age of the whole cohort was 61,5 years old (range: 18-73) and the median follow-up 31 months (range: 4,5-106). All patients engrafted except 1 CB patient and 1 haplo recipient who died of infection before engraftment. All CB cases died at 1, 8, 9 and 11,5 months post-transplant, respectively (infection n=1, relapse n=2, chronic GVHD n=1). As a consequence, we thereafter compared outcomes only between the three other donor groups. There were no significant differences between sibling, MUD or haplo recipient groups in terms of gender, median age, type of disease, ELN 2010 classification for AML, status at transplant (complete remission vs active), disease risk index, donor/recipient CMV status or median graft quantity of CD34+ stem cells. The only differences were the partition of ABO compatibility, less frequent in the MUD group (42% vs sibling 69% vs haplo 67%, p=0,02) and a history of previous allograft (haplo n=7, sibling n=0, MUD n=6, p=0,005). Neutrophils (>0,5 Giga/L) and platelets (50 Giga/L) recoveries were significantly delayed in the haplo-group (19 days, vs sibling 15 vs MUD 15, p=0.0003; and 31 days vs 11 vs 12, p<0.0001). Acute grade 2-4 or 3-4 graft versus host disease (GVHD) incidences were similar between the three groups at 50% and 22% for sibling, 34,5% and 14,5% for MUD and 48% and 11% for haplo (p=0,18 for grade 2-4 and p=0,45 for grade 3-4) as well as moderate+severe chronic GVHD incidences (sibling 14%, MUD 16%, haplo 15% p=0,94). Follow-ups were similar at 34.2 (6-74), 33.7 (4.5-106) and 21.4 (7-53) months respectively for sibling, MUD or haplo donors. This was associated with similar 2-year overall survivals (OS) at 64,7% (50-83), 73,9% (62-87) and 60,2% (43-83) respectively (p=0.4) and 2-year disease-free survivals (DFS) at 57,7% (43-76), 70,9% (59-84) and 53,6% (37-77) respectively (p=0.1). Two-year GVHD-relapse free survival (GRFS) was also similar at respectively 37,9% (24-57), 54,3% (41-70) and 38,9% (23-63) (p=0.2) as well as 2-year non-relapse mortality (NRM) at 14%, 11% and 18,5% (p=0,63). When considering only AML patients, again similar 2-year survivals were observed between the three groups. OS was 71.4% (54-93) for sibling (n=21), 75.1% (62-90) for MUD (n=40) and 66.6% (46-95) for haplo (n=15, p=0.65) and DFS respectively 66,6% (49-90), 70,8% (57-87) and 66,6% (46-95 p=0.47). The same was observed for GRFS at 38% (22-65), 56% (41-75) and 40% (21-74, p=0.14) and NRM at 14%, 7,5% and 7%, p=0.34). In multivariate analysis, donor type remained independent of outcomes in this series. Conclusion: These data confirm that since no difference was observed in terms of outcomes, haplodonors represent a valid alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack a matched sibling donor. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals No Influence of Peripheral Blood CD34+ and CD3+ Graft Cell Counts on Outcomes after Reduced-Intensity Conditioning Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4577-4577
Author(s):  
Alice Garnier ◽  
Thierry Guillaume ◽  
Pierre Peterlin ◽  
Amandine Le Bourgeois ◽  
Alix Duquesne ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Cell Content ◽  
Post Transplant ◽  
Cell Counts ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Introduction Although associated with a higher incidence of acute GVHD, peripheral blood stem cells (PBSC) are increasingly used for haploidentical allogeneic transplantation with post-transplant cyclophosphamide (PTCY). Data reporting whether or not the composition of the PBSC graft impacts outcomes of patients receiving PTCY are still scarce. Materials and Methods This retrospective study included all adults allografted in our department who received a PBSC allotransplant after reduced-intensity conditioning (RIC) with PTCY. Grafts originated from a matched or haploidentical donor and recipients received a Baltimore-based or a Clo-Baltimore (where fludarabine is replaced by clofarabine)-based RIC regimen. All patients received cyclosporine + mycophenolate mofetyl and PTCY as GVHD prophylaxis. CD34+ and CD3+ graft cell contents were considered to study their potential impact on the following outcomes: OS, DFS, GRFS, acute grade 2-4 and 3-4 GHVD and chronic GVHD, early immune reconstitution (IR, lymphocytes and monocytes counts at days+30 and +100 post-transplant, CD4+, CD8+, NK and B cells at day+100 post-transplant). Results Between November 2013 and May 2017, 77 patients met the inclusion criteria. There were 48 males and 29 females with a median age of 58 years (range: 22-71) and a median follow-up for alive patients of 29.2 months (range: 8.4-53.2). Initial diagnoses were mainly acute myeloid (n=21) or lymphoid (n=6) leukemia, lymphoma (n=13), myelodysplastic syndrome (SMD, n=12), myelofibrosis (n=9). Thirty-eight patients were in complete remission at time of transplant (CR1 n=23; CR2 n=12, CR3 n=3) while 22 had active disease and 17 were in partial remission. Donors were sibling in 6 cases, matched unrelated (MUD) in 14, 9/10 mismatched unrelated in 1 and haploidentical in 56. Forty patients received a Baltimore RIC regimen and 37 a Clo-Baltimore RIC regimen. Analyses were performed in July 2018. Median infused CD34+ and CD3+ graft cell counts, based on recipients' weight, were 7.8 106/Kg (range: 1.45-14.24) and 22.23 107/kg (range: 1.95-66.75), respectively. All patients but three engrafted, the latter being 1 patient transplanted with a haplodonor, 1 with a MUD and 1 who died of infection during induction. Two-year OS, DFS and GRFS were 62.6% (52-74), 51.5% (40-63) and 36.6% (27-49), respectively. The incidences of grade 2-4 and 3-4 acute GVHD were 46.7% and 14.2%, respectively, while the incidence of moderate + severe chronic GVHD was 14%. Relapse occurred in 26 patients and non-relapse mortality (NRM) was 15.5%. Baltimore vs Clo-Baltimore patients shared similar median infused CD34+ and CD3+ graft cell counts and outcomes. The same was observed for patients allografted with a haplodonor or not, except for the incidence of grade 2-4 acute GVHD which was significantly higher for the haplo group at 57.1% vs 19% (p=0.006). This difference was first attributed to the higher CD3+ cell content infused in this group (median: 24.05 vs 18.85 107/kg, p=0.04). However, using the median of CD3+ cell graft content as threshold, the incidence of acute grade 2-4 GVHD was not different between low vs high groups when considering haplo patients. This suggests that it was rather the type of donor that did influence acute GVHD occurrence and that PTCY is of particular interest for GVHD prophylaxis when using matched donors. Partitioning the patients according to the median level of CD34+ cells, there was no difference in terms of 2-year OS (57.1% vs 60.7%, p=0.53), DFS (44.5% vs 55.6%, p=0.47) , GRFS (31.7% vs 44.3%, p=0.32), acute grade 2-4 (59% vs 39%, p=0.13) and 3-4 GVHD (17% vs 6.4%, p=0.29), and moderate + severe chronic GVHD (19.5% vs 20%, p=0.57). Similarly, partitioning patients according to median graft CD3+ cell content, outcomes were similar for 2-year OS (64.8% vs 55.8%,p=0.45), DFS (46.3% vs 55.8%, p=0.62), GRFS (36.3% vs 40.4%, p=0.63), acute grade 2-4 (44.7% vs 56.4%, p=0.42) and 3-4 GVHD (10.5% vs 15.3%, p=0.76), and moderate + severe chronic GVHD (14% vs 17.6%, p=0.91). Finally, early IR was not influenced by CD34+ and CD3+ graft cell contents. Conclusion: PBSC CD34+ and CD3+ graft cell contents have no impact on survivals, GVHD incidence nor early IR after a RIC allotransplant using PTCY as GVHD prophylaxis. As a consequence, there is no need to manipulate the graft nor cap the stem cells dose to be infused. These data have to be confirmed prospectively on a larger cohort of patients. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Myeloablative Versus Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia in Patients with Prior Myelodysplastic Syndrome/ Myeloproliferative Disorders: An ALWP of EBMT Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 907-907
Author(s):  
Bipin N. Savani ◽  
Ariane Boumendil ◽  
Myriam Labopin ◽  
Jürgen Finke ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Myeloproliferative Disorders ◽  
Registry Study ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Secondary Acute Myeloid Leukemia ◽  
Reduced Intensity

Abstract Secondary acute myeloid leukemia (sAML) includes a heterogeneous group of diseases evolved from myelodysplasia, myeloproliferative disorders (MDS/ MPN), bone marrow failure syndrome or after exposure to leukemogenic agents such as chemotherapy and/or radiation therapy for malignant hematological (other malignant hematological diseases) or solid tumors. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy but relapse is a frequent cause of failure after HCT occurring in more than 50% of patients. No systematic large analysis of HCT for sAML has evaluated risk factors and outcome based on a prior diagnosis of MDS or MPN. Therefore, the EBMT Acute Leukemia Working Party (ALWP) performed a multicenter retrospective registry study on patients undergoing HCT for sAML following MDS/MPN comparing myeloablative (MAC) to reduced intensity conditioning (RIC). ALWP-EBMT supplemental data forms were used to establish the occurrence of any prior hematological disorder or non-hematological malignancy as well as details of cytogenetic data and therapy. We studied 811 patients with a previous diagnosis of MDS/ MPD and available cytogenetic data who had received HCT for sAML from an HLA-identical sibling (MRD, n=344 [42.4%]) or unrelated donor transplant (URD- 9/10 or 10/10) during 2000-16. Median time from diagnosis (sAML) to transplant was 137 days (IQR 94-204). Median age at HCT was 59.57 years (IQR 52-65). sAML with adverse cytogenetics accounted for 269 (33.2%) patients. At the time of HCT, 401 (49.5%) patients were in CR1 and 367 (45.3%) had active disease. Median follow-up of surviving patients was 32 months (IQR, 11-62). Regimen intensity was assessed by EBMT criteria. MAC regimens were used in 326 (40.2%) patients while 485 (59.8%) received RIC. Older patients were more likely to receive RIC than MAC regimens (p&lt;0.001). Most patients received peripheral blood stem cell grafts (n=731 [90.3%]; MAC 85.6% vs RIC 93.4%, p&lt;0.001). A total of 534 (67.9%) patients were cytomegalovirus (CMV) seropositive pre-HCT. There were no significant differences in disease characteristics (e.g. disease status at transplant, cytogenetic risk category), donor source, year of transplant or CMV serology status between MAC and RIC cohorts. All patients received a calcineurin inhibitor-based combination as prophylaxis against graft versus host disease (GVHD) and 516 (63%) received in vivo T-cell depletion (rATG 474 (58%). A total of 667 (95.2%) patients engrafted (MAC 94.5% vs. RIC 95.6%; p=0.596). Acute GVHD (grade II-IV) within 100 days of HCT occurred in 24% (95% CI, 21-27; MAC vs. RIC, p=0.126) and 2-year cumulative incidence of chronic GVHD was 33% (95% CI 30-37; MAC vs. RIC, p=0.150). Three-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 41% (95% CI, 38-45; MAC 37% [31-42] vs. RIC 45% [40-49], p=0.029) and 25% (95% CI, 22-28%, MAC 25% [20-30] vs. RIC 25% [21-29], p=0.959), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia free survival (LFS) at 3 years were 40% (95% CI, 37-44; MAC 44% [38-50] vs. RIC 38% [33-43], p=0.041) and 34% (95% CI, 31-38; MAC 38% [33-45] vs. RIC 31% [27-36], p=0.032), respectively (Figure 1). In multivariate analysis by Cox Regression, a higher RI was seen after RIC regimens (HR 1.72 [1.16-2.55]; p=0.0063). Patients receiving RIC regimens had a higher risk of chronic GVHD (HR 1.37 [1.02-1.84], p=0.0389). Non-relapse mortality (NRM) was equivalent in MAC and RIC groups.MAC regimens were associated with superior OS (HR 1.46, 95% CI 1.1-1.94; p=0.0085) and LFS (HR 1.37, 95% CI 1.02-1.85; p=0.0387). High risk cytogenetics and older age contributed significantly to inferior outcomes. In summary, this EBMT registry study of HCT for sAML after MDS/MPN is the largest cohort reported. Myeloablative conditioning regimens were associated with a lower relapse risk and superior survival. Given that NRM after HCT has declined in the current era, these data indicate that the outcome of HCT for sAML may be improved by careful patient selection for MAC regimens. Survival may be further enhanced by effective pre-HCT disease control (also associated with decreased NRM) and post-HCT pre-emptive therapy to decrease RI. Figure 1 Figure 1. Disclosures Savani: Jazz Pharmaceuticals: Speakers Bureau. Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Schmid: Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; MoilMed: Membership on an entity's Board of Directors or advisory committees. Mohty: Sanofi: Honoraria, Speakers Bureau.

scholarly journals Haploidentical Stem Cell Transplantation in Advanced Stage Mycosis Fungoides and Sézary Syndrome: A Report of Four Consecutive Cases from a Single Center

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5744-5744
Author(s):  
Francesco Onida ◽  
Giorgia Saporiti ◽  
Viviana Beatrice Valli ◽  
Silvia Alberti Violetti ◽  
Federica Irene Grifoni ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
The Other ◽  
Advanced Stage ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Introduction: In patients with advanced stage mycosis fungoides (MF) and Sézary syndrome (SS), allogeneic hematopoietic stem cell transplantation (allo-HSCT) continues to represent the only potentially curative treatment strategy. We have previously reported long-term outcome of our reduced intensity conditioning-based allo-HSCT program in MF and SS, including 38 patients who consecutively underwent transplantation from matched sibling or unrelated donor in the 2001-2018 time interval, with a 5-yr overall and disease-free survivals of 52% and 43%, respectively, and a 1-yr non relapse mortality of 17% (ASH annual meeting, 2018). In the most recent years, haploidentical donors are considered an increasing valid alternative for patients with haematological malignancies lacking a suitable matched donor. Here we report the results of our first series of haploidentical SCT (haplo-HSCT) in patients witn MF and SS. Patients & Methods: From May 2016 to June 2019, 4 patients (2 males and 2 females) underwent haplo-HSCT from family donors (3 siblings and 1 son) in our center. Median age was 53 years (range 19-62). Two patients had stage IV refractory MF - involving nodes and lungs in one case and blood in the other one, while two patients had SS. Median number of previous treatment lines was 4 in SS and 4.5 in MF (range 2-6) while median time from diagnosis to transplantation was 21 months (range 17-101). Two patients (1 SS and 1 MF) received 24Gy total skin electron beam (TSEB) therapy as a bridge to transplant, associated to brentuximab vedotin (5 cycles) in one case showing also lung CD30+ involvement. At the time of transplant two patients were in CR and 2 were in very good partial remission, with limited nodal involvement in one SS and limited skin disease in one MF patient, respectively. The source of stem cells was bone marrow in SS and peripheral blood in MF patients. A reduced-intensity conditioning regimen including Thiotepa 10 mg/kg, Cy 30 mg/kg, Fludarabine 120 mg/m2 (over 4 days) and low dose TBI (200 cGy) was used in all patients. GvHD prophylaxis included CsA/MMF and post-transplant CTX (50 mg/kg on days +3 e +4), with the addition of ATG 2.5 mg/kg in the most recently transplanted patient for whom donor peripheral blood was the selected source of stem cells. Results: Hematologic engraftment occurred in all patients, with a median time to ANC >0.5 x 109/L of 16.5 days (range 14-18) and to PLT >20 x 109/L of 15 days (range 13-45). At +100 days after transplantation, donor chimerism was 100% in 3 patients, and 90% in one. Acute GvHD occurred in 3 patients, always of grade II (involving skin in all, gastrointestinal in 2 and liver in 1 patient), with overlap characteristics in one case. Major early infectious complications included two cases of fungal pneumonia and 1 case of bacteremia from P. aeruginosa. Chronic GvHD was observed in 2 out of the 3 evaluable patients - i.e. with a follow-up longer than 100 days - being mild in one case (with joints involvement) and severe in the other case (skin). With all patients and their donors being CMV positive at baseline, CMV reactivations occurred in 3 cases, successfully treated with preemptive valganciclovir. Following transplantation, a complete remission (CR) was achieved in all the four patients. One patient with SS who experienced a skin biopsy-proven relapse 9 months after transplant, achieved a new and durable CR following the occurrence of a severe skin chronic GvHD triggered by an inadvertent sunburn, which required steroids + ECP treatment. At the last visit, all patients were alive in CR with a follow-up of 38, 36, 6 and 3 months, respectively. Conclusions: Even though with a limited follow-up time, our preliminary experience of haplo-HSCT appears particularly safe and highly encouraging in inducing and maintaining remission in patients with advanced MF/SS eligible to allo-HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

scholarly journals Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6438-6445 ◽  
Author(s):  
Hongtao Liu ◽  
Elizabeth S. Rich ◽  
Lucy Godley ◽  
Olatoyosi Odenike ◽  
Loren Joseph ◽  
...  
Keyword(s):  
Cord Blood ◽  
Opportunistic Infections ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Length Of Hospital Stay ◽  
Progression Free Survival ◽  
Reduced Intensity Conditioning ◽  
Actuarial Survival ◽  
Transfusion Requirements ◽  
Reduced Intensity

Abstract We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34+ stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800.

Comparative Single-Institute Analysis of Cord Blood Transplantation from Unrelated Donors with Unrelated Bone Marrow or Related Peripheral Blood Stem-Cell Transplants in Elderly Patients with Hematologic Diseases after Reduced Intensity-Conditioning Regimen.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2011-2011
Author(s):  
Naoyuki Uchida ◽  
Atsushi Wake ◽  
Kazuhiro Masuoka ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Elderly Patients ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Cord Blood Transplantation ◽  
Long Term Outcome ◽  
Post Transplant ◽  
Unrelated Donors ◽  
Reduced Intensity

Abstract Although cord blood (CB) transplantation with reduced-intensity (RI) conditioning (RICBT) has been widely applied to those who lack available related or unrelated donors and are not eligible for conventional conditioning, indication of RICBT to elderly patients relative to other stem-cell sources is still controversial due to higher early mortality post-transplant and undefined long-term outcome. Since there has been not much data available regarding this issue, we retrospectively reviewed patients aged 55 and older who underwent RI allogeneic stem-cell transplantation at our institute from Nov. 2000 to Dec. 2006 consecutively. The study includes 121 recipients of CB (n=42), unrelated bone marrow (UBM, n=41), and related mobilized peripheral blood (RPB, n=38) for AML / MDS (n=66), ALL (n=11), CML (n=4), ML (n=31), MF (n=3), and AA (n=6). The median age for CB, UBM, and RPB recipients were 61 (range 56–69), 60 (55–70), and 60 (55–66), respectively. CB recipients had more serologically HLA-mismatched grafts (98% vs. 24% vs. 5%, P &lt; .05), were conditioned more frequently with melphalan (90% vs. 34% vs. 32%, P &lt; .05) and with total body irradiation (88% vs. 71% vs. 16%, P &lt; .05), used more tacrolimus (100% vs. 71% vs. 18%, P &lt; .05) and less methotrexate (0% vs. 76% vs. 74%, P &lt; .05) for GVHD prophylaxis, had shorter duration of donor search (median 41 days (14–151) vs. 166 (93–345) vs. 130 (41–311), P &lt; .05), and were transplanted more recently (2005–2006: 71% vs. 56% vs. 37%, P &lt; .05). CB recipients tended to have high-risk disease status (76%) relative to UBM (59%) and RPB (66%) recipients, although not statistically significant. Other characteristics such as sex, diagnosis, and body weight were balanced among three groups. Median follow-up time of survivors was 554 days (25–1132), 667 days (315–1794), and 703 days (57–2214) for CB, UBM, and RPB recipients, respectively. CB recipients tended to show slower neutrophil recovery (median 19 days (12–36) vs. 16 (10–27) vs. 13 days (10–21)), and lower rate of myeloid engraftment (86% vs. 90% vs. 100%), although not statistically significant. The incidence of grades II–IV acute GVHD among evaluable CB recipients (61%) was lower than that of UBM (83%, P &lt; .05) and comparable to that of RPB recipients (50%). The incidences of chronic GVHD for evaluable CB, UBM, and RPB recipients were 45%, 71%, and 71%, respectively (N.S.). The disease-free survival and overall survival (OS) at 2 years post-transplant were 23+/–7% and 33+/–8% for CB, 42+/–8% and 47+/–8% for UBM, and 35+/–9% and 40+/–9% for RPB recipients, respectively (N.S.). Within those who had standard risk diseases, 2-year OS were 67+/–15.7%, 48+/–13%, and 59+/–14% for CB (n=10), UBM (n=17), and RPB (n=13) recipients, respectively (N.S.). These data suggest that CB could be a viable stem-cell source for elderly patients as UBM or RPB, not just expanding opportunity of transplant. A larger-sized, randomized study is needed to further define the position of CB for this population of patients.

High Rates of Early Donor Chimerism and Low Risk of Chronic GVHD Can Be Achieved in Poor Risk Patients Undergoing Unrelated Donor Stem Cell Transplantation Using a Reduced Intensity Conditioning Regimen Incorporating Fludarabine, Busulfan, and Rabbit ATG.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5080-5080
Author(s):  
Mehdi Hamadani ◽  
Patrick Elder ◽  
Farrukh Awan ◽  
David Krugh ◽  
William Blum ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Post Transplant ◽  
Ebv Reactivation ◽  
Risk Patients ◽  
Reduced Intensity

Abstract Reduced intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT) in patient groups with relative contraindications for transplantation since they promote effective engraftment of donor cells with minimal regimen related toxicity. However, following unrelated donor (URD) transplantation, high rates of acute and extensive chronic GVHD have mitigated the overall benefits of this approach. We pursued a strategy designed to enhance early full donor hematopoietic chimerism while potentially reducing the risk of severe acute and extensive chronic GVHD using an RIC regimen containing fludarabine (F), busulfan (B), rabbit antithymocyte globulin (A) (FBA) followed by URD SCT in 30 consecutive high risk patients (pts). Criteria for selection included advanced age (>55yrs), prior autograft, and/or high co-morbidity index (median 2, range 0–4). There were 24 male and 6 female pts with a median age of 53 years (range 22–66yrs). Diagnoses included AML (N=10), NHL (N=7), Hodgkin’s lymphoma (N=6), advanced CML (N=4), and advanced CLL (N=4). Nine pts had previously undergone autologous SCT. 43% had a Karnofsky performance status of 70 or 80% at the time of transplant. 80% were matched with their donor at HLA-A, B, C, and DRB1 by high-resolution DNA typing, while 3 were mismatched at 1 antigen and 3 mismatched at 1 or 2 alleles. All pts were conditioned with F (30 mg/m2/day, days −7 to −3), B (0.8 mg/kg/dose IV x 8 doses) and A (2.5 mg/kg/day, days −4 to −2) followed by micro-dose methotrexate and tacrolimus. Stem cell source included peripheral blood (n=26) or bone marrow (n=4). All pts engrafted neutrophils and platelets promptly (median 15 and 16 days, respectively). There were no primary graft failures. Rates of grade II-IV and III-IV acute GVHD were 43% (n=13) and 23% (n=7) respectively. Nine pts (30%) developed chronic GVHD but extensive chronic GVHD was seen in only 10% (n=3). Day 100 TRM was 10% (n=3). Causes of death included disease progression=2, post-transplant lymphoproliferative disorder (PTLD) =1 and sepsis=1. CMV and EBV reactivation occurred in 30% (n=9) and 20% (n=6) respectively. 2 pts developed PTLD requiring rituximab. Three pts had BK-virus associated hemorrhagic cystitis. Lineage-specific chimerism analysis showed 100% donor CD33+ at all time points (days 30, 60, 100) and median donor CD3+ chimerism of 94% at day +30 and 100% at day +100. One patient had secondary graft failure. 23 pts (76%) were in CR after SCT. The median follow-up of surviving patients is 6 months (range 1–32 months). Kaplan-Meier estimates of overall survival (OS) and progression free survival (PFS) at 1year are 62% and 43% respectively. Using the Log-Rank test, OS (P=0.95) and PFS (P=0.65) was not statistically significant between recipients of matched and mismatched grafts. In conclusion, this approach using FBA and a tacrolimus based GVHD prophylaxis achieved rapid donor chimerism and a favorably low incidence of TRM, acute, and chronic GVHD despite being tested in a poor risk group of pts. Although rates of infectious complications were within expected ranges, the rate of both EBV reactivation and disease relapse warrant further exploration of this approach using lower doses of ATG (e.g. 5–6mg/kg total dose) combined with post transplant immunomodulation.

Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults Using Reduced Intensity Conditioning and CD3/CD19-Depleted Grafts: Interim Analysis of a Phase I/II Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1962-1962
Author(s):  
Birgit Federmann ◽  
Martin Bornhauser ◽  
Dietrich W. Beelen ◽  
Gernot Stuhler ◽  
Lambros Kordelas ◽  
...  
Keyword(s):  
Stem Cells ◽  
High Risk ◽  
Complete Remission ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Cd34 Cells ◽  
Risk Patients ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with a megadose of CD34-selected stem cells has been complicated by regimen related toxicities, slow engraftment and delayed immune reconstitution leading to high treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and immunomagnetic CD3/CD19 graft depletion may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also graft-facilitating cells, CD34- progenitors, dendritic and natural killer cells which may allow stable engraftment even without a megadose of CD34+ cells. A multicenter phase I/II study of HHCT using RIC with fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2), OKT-3 (5 mg/day, day -5 to +14) and CD3/CD19 graft depletion has been initiated. No post grafting immunosuppression was applied if the graft contained &lt;5x104 CD3+ cells/kg. To date, 51 patients with a median age of 45 years (range, 19–65) have been enrolled in this study. Diagnosis were AML (n=34), ALL (n=7), NHL (n=6), MM (n=2), and CML (n=2). Patients were “high risk” because of relapsed or refractory disease (n=30), or relapse after preceding HCT (auto=7, allo=14). Stage at HCT was complete remission (n=25) and partial remission (n=26). The CD3/CD19 depleted haploidentical grafts contained a median of 7.1 x 106 (range, 3.4–18x106) CD34+cells/kg, 3.9 x104 (range, 0.6–44x104) CD3+T cells/kg and 2.8x107 (range, 0.02–37.3x107) CD56+cells/kg. The regimen was well tolerated with maximum acute toxicity being CTC-grade 1–2 mucositis. Five cases of reversible peripheral neuropathy and three cases of progressive multifocal leukencephalopathy (PML) occurred posttransplant in heavily pretreated patients. Engraftment was rapid with median time to &gt;500 granulocytes/μL of 12 days (range, 9–50) and to &gt;20000 platelets/μL of 11 days (range, 7–38). Full donor chimerism was reached after 2–4 weeks in all but four patients (median of 14 days (range, 7–215)). Four patients experienced rejection/non-engraftment, two were rescued by a second CD3/CD19 depleted graft from another haploidentical donor. Incidence of grade II-IV acute GVHD was 51% with grade II=16, III=6 and IV=4. So far there are six cases of limited chronic GVHD and one case of extensive chronic GVHD. TRM in the first 100 days was 11/51 (22%) and overall 20/51 (39%). Overall survival is 17/51 patients (33%) with deaths due to relapse (n=14), infection (n=15), PML (n=2), GVHD (n=2) and cardiac failure (n=1), with a median follow-up of alive patients of 397 days (range, 62–1180). This results in a Kaplan-Meier estimate 1-year survival of 37%. So far, we did not observe a statistical significant survival advantage for patient transplanted from a KIR-mismatched donor (28/51 patients). This regimen with low toxicity as well as fast and sustained engraftment is promising in high risk patients lacking a suitable donor. To investigate the treatment protocol earlier in course of disease a new study for high-risk patients with acute leukemia in first complete remission is in preparation.

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