Total Body Irradiation (TBI), Fludarabine (F), Melphalan (M) and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Advanced Pediatric Hematologic Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1827-1827 ◽  
Author(s):  
Demetrios Petropoulos ◽  
Laura L. Worth ◽  
Craig A. Mullen ◽  
Anita Mahajan ◽  
Mary S. Choroszy ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Failure ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Early Death ◽  
Disease Status ◽  
Hematologic Malignancies ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem

Abstract The FM reduced-intensity preparative regimen has been used successfully in adults for allogeneic HSCT. Its role in pediatric hematologic malignancies is unclear. We studied the engraftment efficacy and the antineoplastic effect of adding TBI to the FM combination. Between July 1998 and January 2004 a total of 29 pediatric (19 males) patients were treated. Twenty-two had acute lymphoblastic leukemia (ALL), 6 had acute myeloid leukemia (AML), and 1 anaplastic large cell lymphoma. Disease status at the time of SCT was: CR2 (19 patients), CR3 (5), CR1 (2, with Ph+ leukemia), and induction failure/relapse (3). Six patients received this regimen for a second HSCT. The donor was unrelated in 21 cases: 1–2 antigen mismatched cord blood (CB) in 20, and peripheral blood stem cells (PBSC) in one. Of the 8 related-donor HSCT, 2 were not genotypically identical. The conditioning regimen was TBI 9Gy (3 fractions on day -7, -6, and -5), F 30 mg/m2 IV daily (days -4 to -1) and M 140 mg/m2 IV on day -1. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. No anti-thymocyte globulin was used. The regimen was well-tolerated, with grade II-III oral mucositis and diarrhea the most common side effects seen. Twenty-seven patients achieved ANC engraftment after a median time of 16 days (range 11–35), and 23 also had platelet engraftment at a median of 42 days (range 14–200). There was one case of primary graft failure and one early death. Six of 27 evaluable patients developed grade III-IV acute GVHD and three chronic GVHD. There were seven deaths in the first 100 days (3 from interstitial pneumonitis, 1 GVHD, 1 renal failure, 1 VOD, 1 graft failure), all in patients with ALL. Nine patients (7 with ALL) relapsed at a median of 8 months post-transplant (range 2–54). With a median follow-up of 54 months (range 7–79), 7 of 22 ALL, 5 of 6 AML, 1 of 1 lymphoma patients are alive and in remission (12 are over two years post HSCT). In conclusion, the addition of TBI to FM leads to successful engraftment of allogeneic HSC (including 1–2 antigen mismatched unrelated cord blood units) in heavily pretreated pediatric patients with hematologic malignancies, without the inclusion of ATG. The regimen was well tolerated and its activity in AML deserves further evaluation.

Updated Analysis of Hematopoietic Stem Cell Transplantations after Reduced Intensity Conditioning Regimen (RIC HSCT) for Hematological Malignancies from the Société Française de Greffe de Moelle Osseuse et de Thérapie Cellulaire (SFGM-TC) Registry.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 45-45 ◽  
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Le ◽  
Thomas Prebet ◽  
Mohamad Mohty ◽  
Jean Michel Boiron ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
The Impact ◽  
Global Population

Abstract This report updates a retrospective study from SFGM-TC registry concerning 738 patients who underwent RIC HSCT for hematological malignancies [280 F, 458 M, median age: 51 years (1–72)] between 1997 and 2004. The diagnosis were 173 AML, 40 ALL, 68 MDS, 152 NHL, 36 HD, 45 CLL, 70 CML, 154 MM; 332 patients have been previously transplanted. At time of conditioning, 261 patients were in CR, 224 in PR and 253 in progressive disease (PD). Peripheral blood stem cells (PBSC) were used in 574 patients and bone marrow in 164 patients from 655 HLA related donors and 83 unrelated donors. As conditioning, 152 patients received fludarabine and TBI (2 grays), 300 patients fludarabine, busulfan and anti-thymocyte globulins (FBS) (ATG 1d: 57, 2 d: 84, 3 d: 58, 4 d: 18, 5 d: 83) and 286 patients an other regimen. As GVHD prophylaxis, 722 patients received a cyclosporine A (CsA) based regimen. After transplant, 252 patients (35%) in the global population developed an acute GVHD ≥ grade II (grades III and IV: 116) and 208 patients (37%) in the PBSCT population (grades III and IV: 100). A chronic GVHD was present in 258 patients (38%) in the global population (115 limited and 143 extensive) and 221 patients (42%) in the PBSCT population (95 limited and 126 extensive). With a median follow-up of 27 months, the 3-year probability of overall survival (OS) and event-free survival (EFS) for the global population was 38% (33–44) and 28%(24–34) and for PBSC SCT patients 39%(33–46) and 32%(27–39) respectively. The 3-year probability of OS varied according to diagnosis (CLL: 62%, NHL:50%, CML:44%, MM:41%, MDS:37%, AML:26%, ALL:20%) and cGVHD (no:28%, yes:61%). The cumulative TRM incidence was 12% at 1 year and 13% at 3 years. A multivariate analysis was performed studying pre and post transplant factors for OS, EFS and GVHD:. Table 1 summarizes all variables showing a significant impact on OS and EFS. Furthermore, analyses showed the impact of one variable on AGVHD and cGVHD for PBSCT population: FBS with ATG 1day vs 2 days [HR:1.56(1.19–2.04) p=0.001, HR:1.50(1.14–1.97) p=0.003]. In conclusion, besides the influence of known factors on OS and EFS after RIC HSCT, this study pointed out, on a large series with a long-term follow-up, the major impact of disease status, acute and chronic GVHD and demonstrated the important role of ATG duration on GVHD incidence. Table 1: Multivariate analyses OS/EFS Variables OS (HR) p EFS (HR) p Conditionning :FBS ATG 1d vs 2 d Global 1.47 (1–2.2) 0,05 NS PBSC 1.6 (1.03–2.49) 0,04 NS FBS ATG 5d vs 2 d PBSC NS 1.13(1.04–1,24) < 0.01 PD vs CR Global 1.22 (1.1–1.32) < 0.01 1.15 (1.07–1.25) < 0.01 PBSC 1.2 (1.1–1,3) < 0.01 1.14 (1.05–1.24) < 0.01 Previous HSCT: yes vs no Global 1.27 (1.02–1,59) 0,04 1.25 (1.01–1.55) 0.04 AGVHD : Grade II vs 0-I PBSC 1.21 (1–1.47) 0,05 NS AGVHD : Grade III-IV vs 0-I Global 1,28 (1,14–1,43) < 0.01 1.12 (1–1.25) 0.04 PBSC 1.3 (1.14–1.47) < 0.01 1.13 (1–1.28) 0.05 cGVHD : yes vs no Global 0.2 (0.14–0.28) < 0.01 0.25 (0.19–0.35) < 0.01 PBSC 0.19 (0.13–0.28) < 0.01 0.25 (0.18–0.34) < 0.01

Unrelated Umbilical Cord Blood Transplantation for Hematological Malignancies Using Fludarabine/BUCY2 Conditioning Regimen

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4572-4572
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Liangquan Geng ◽  
Xingbing Wang ◽  
Kaiyang Ding ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Failure ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Myelogenous Leukemia ◽  
Blood Transplantation

Abstract Abstract 4572 Cord blood transplantation (CBT) is largely used to treat patients affected by hematological malignant disorders. Myeloablative TBI-based conditioning appears to provide reliable engraftment after CBT for malignancies. However, the toxicity of TBI limits their widespread use. So far, a standard non-TBI based regimen has not been firmly established. In order to overcome graft failure, we investigated a strategy using Fludarabine (FLU)/BUCY2 regimen in CBT for patients with hematologic malignancies. Seventeen patients(children 16, adult 1) with hematologic malignancies who underwent single-unit CBT used a conditioning regimen comprising FLU 120 ‡r/‡u, intravenous busulfan (BU) 12.8‡r/kg and cyclophosphamide (CY)120 mg/kg (FLU/BUCY2). All patients were given a combination of cyclosporine A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Seventeen patients with acute leukemia (n=13), chronic myelogenous leukemia (n=4) were treated, thirteen of whom were high risk diseases and two were advanced-stage at CBT. Seventeen patients with a median age of 8 years (range,2.5–46 years) and a median weight of 32 kg (range, 12–55 kg)received the median number of nucleated cells and CD34+cells infused were 5.70× 107/kg (range: 3.15–9.60×107/kg) and 3.84× 105/kg (range:1.27–5.24 ×105/kg), respectively. The cumulative incidence of primary donor engraftment was 94% (16 patients); one patient had secondary graft failure. Median time to neutrophil≥0.5×109/L was 17 days (range 12–30) and platelet engraftment (≥20×109/L) was 35 days (range 14–56). Preengraftment syndrome (PES) developed in 71% of the patients at a median of 7days (range: 5–13).9 cases developed acute GVHD (56%), more than grade II in three cases. Two of fourteen patients who survived more than 100 days developed chronic GVHD. 12 cases are alive at a median follow-up of 7 months (range 3~ 11).The probability of overall survival at 100 days and 1 year are 88.2% and 67.9%, respectively. Two cases had extramedullary relapsed. Five cases died of severe GVHD (n=3), pulmonary toxicity (n=1) and secondary graft failure (n=1). Preliminary evidence of the small study suggests successful engraftment and decreasing relapse rate following FLU/BUCY2 regimen for CBT in patients with hematologic malignancies. But it had a tendency towards increasing the incidence of GVHD-related morbidity and mortality. Whether this regimen offers a survival benefit for patients with poor-risk leukemia has to be tested in larger prospective trials. Disclosures: No relevant conflicts of interest to declare.

Outcomes for Unrelated Donor Hematopoietic Cell Transplantation (URD-HCT) for Patients with Acute Lymphoblastic Leukemia (ALL) Using Fractionated Total Body Irradiation (FTBI) and Etoposide (VP16).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3286-3286
Author(s):  
Margaret O’Donnell ◽  
P Parker ◽  
A Dagis ◽  
ML Slovak ◽  
D Snyder ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Peripheral Blood Stem Cells ◽  
Free Survival

Abstract Although treatment outcomes for adult ALL remain stagnant at 35–40% 5 yr event free survival (EFS), allogeneic transplant particularly from unrelated donors has frequently been reserved for patient beyond first complete remission (CR1) with the exception of patients with a t(9;22) or Philadelphia (Ph+) cytogenetic abnormality. Between 4/1/2001 and 11/14/2007, 67 patients with ALL received URD-HCT; disease status at HCT was (CR1) in 27 pts (40%), CR2 in 20 pts (30%) and advanced disease (AD) which included induction failure, relapse or CR3 in 20 pts (30%). Age ranged from 2–58 yrs with median age of 29.5 yr. One third of the patients were Ph+. An additional 18 pts had high or very high risk cytogenetics abnormalities. The majority (≥75%) of Ph+ patients had received Gleevec prior to HCT. The conditioning regimen was FTBI 1320 Gy given as 11 fractions over four days followed by VP-16 60 mg/kg. Graft vs. host disease (GVHD) prophylaxis was tacrolimus (FK) and methotrexate (MTX) in 20 pts; sirolimus (Siro) was added to this regimen in 15 pts. Other GVHD regimens used were FK, MTX and Cellcept (12 pts) FK and siro (4 pts) and anti thymocyte globulin was added in 11 pts. Graft source was marrow in 12 pts and peripheral blood stem cells in 55 pts. Median time to ANC > 500 was 17 days (range 11–36d) and for platelets was 24 days (range 15–218d). Three patients died prior to day 18 of infectious complications and were considered unevaluable for engraftment. The incidence of acute GVHD Grade II-IV was 57% with Grade III-IV in 18%. Chronic GVHD occurred in 52% of 56 patients at risk. Treatment related mortality was 16% at 100 days and 28% at 1yr. At two years the event free survival (EFS) was 58% for CR1 pts vs 23% for CR2 and 17% for AD. Relapse rates were 18%, 24% and 40% respectively EFS was 62% at 2 yrs for Ph- pts and 50% for Ph+ in CR1 vs 19% for pt > CR1 who were Ph-and 40% for Ph+ (p=0.31). Remission status (CR1 vs > CR1) was a significant predictor of survival (p=0.01) and EFS (p=0.03) in multivariate analysis while age and Ph+ status had no impact on survival end points. Conclusion: The preparative regimen of FTBI and VP16 offers 2 yr EFS rates of 50–60% in patients receiving URD-HCT in CR1, including patients with Ph+ and other high risk cytogenetic risk groups. These results are comparable to those reported with sibling donor transplants and provide a curative option for patients in CR1 lacking a family donor. Figure Figure

Comparative Analysis of Single-Institute Transplantation From Unrelated Cord Blood and Related Adult Donors In Adults with Hematologic Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4570-4570
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Liangquan Geng ◽  
Xingbing Wang ◽  
Kaiyang Ding ◽  
...  
Keyword(s):  
Cord Blood ◽  
Research Funding ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Post Transplantation ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Unrelated Cord Blood

Abstract Abstract 4570 We compared the clinical outcomes of allogeneic hematopoietic stem-cell transplantation among 126 adults with hematologic malignancies: 40 received unrelated cord blood transplantation (CBT) and 86 received related bone marrow transplantation (BMT) and/or peripheral blood stem cells transplantation (PBSCT). All patients received myeloablative transplantations which performed from 2001 through 2010.Recipients of unrelated CBT were younger (median, 23.5 vs. 30 years of age; P<0.001) and had more advanced disease at the time of transplantation (68% vs. 34%, P<0.001) than recipients of related BMT/PBSCT. All related transplants were HLA matched, whereas 77 percent of CBT grafts were HLA mismatched (P<0.001). The median number of nucleated cells infused was 0.37×108 per kilogram of the recipient's body weight for CBT and 5.39×108 per kilogram for BMT/PBSCT recipients (P<0.001). Neutrophil recovery was significantly delayed after CBT (median, 19 vs. 12 days post transplantation, P<0.001), however, overall engraftment rates were almost the same for both grafts. Multivariate analysis demonstrated no apparent differences in transplantation-related mortality (TRM) (33% in CBT and 21% in BMT/PBSCT recipients), relapse rate (15% in CBT and 15.1% in BMT/PBSCT recipients), the incidence of grades III to ‡W acute graft-versus-host disease (aGVHD) (7.5% in CBT and 5.8% in BMT/PBSCT recipients), 2 years disease free survival (DFS) (52.5% in CBT vs. 62.8% in BMT/PBSCT recipients) and over survival (OS) (62.5% in CBT vs. 67.4% in BMT/PBSCT recipients) between both groups, but extensive chronic GVHD (cGVHD) was lower in CBT recipients (2.5% vs. 17.4%). These data suggest that unrelated CBT could be as safe and effective as matched related BMT or mobilized PBSCT for adult patients with hematologic malignancies. Disclosures: Sun: International Cooperation Research Fund of Anhui Provincial Scientific and Technologic Committee (08080703026): Research Funding; Fund of the Key Medical Project of Anhui Provincial healthy department (2010A005): Research Funding; Anhui Provincial “115” Industrial Innovation Program: Research Funding.

scholarly journals Treosulfan-based conditioning is feasible and effective for cord blood recipients: a phase 2 multicenter study

2020 ◽  
Vol 4 (14) ◽  
pp. 3302-3310
Author(s):  
Filippo Milano ◽  
Jonathan A. Gutman ◽  
H. Joachim Deeg ◽  
Eneida R. Nemecek ◽  
Joachim Baumgart ◽  
...  
Keyword(s):  
Cord Blood ◽  
Clinical Outcomes ◽  
Hematopoietic Cell Transplantation ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Hematologic Malignancies ◽  
Phase 2 ◽  
Acute Leukemias ◽  
Blood Transplantation

Abstract Although the use of treosulfan (TREO) in conventional donor hematopoietic cell transplantation (HCT) has been extensively evaluated, its use in cord blood transplantation (CBT) for hematologic malignancies has not been reported. Between March 2009 and October 2019, 130 CBT recipients were enrolled in this prospective multicenter phase 2 study. The conditioning regimen consisted of TREO, fludarabine, and a single fraction of 2 Gy total-body irradiation. Cyclosporine and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. The primary end point was incidence of graft failure (GF), and based on risk of GF, patients were classified as low risk (arm 1, n = 66) and high risk (arm 2, n = 64). The median age was 45 years (range, 0.6-65 years). Disease status included acute leukemias in first complete remission (CR; n = 56), in ≥2 CRs (n = 46), and myelodysplastic (n = 25) and myeloproliferative syndromes (n = 3). Thirty-five patients (27%) had received a prior HCT. One hundred twenty-three patients (95%) engrafted, with neutrophil recovery occurring at a median of 19 days for patients on arm 1 and 20 days for patients on arm 2. The 3-year overall survival, relapse-free survival (RFS), transplant-related mortality, and relapse for the combined groups were 66%, 57%, 18%, and 24%, respectively. Among patients who had a prior HCT, RFS at 3 years was 48%. No significant differences in clinical outcomes were seen between the 2 arms. Our results demonstrate that TREO-based conditioning for CBT recipients is safe and effective in promoting CB engraftment with favorable clinical outcomes. This trial was registered at www.clinicaltrials.gov as #NCT00796068.

Outcomes after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia. An Eurocord-Netcord Survey.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 304-304 ◽  
Author(s):  
Vanderson Rocha ◽  
Gerard Michel ◽  
Nabil Kabbara ◽  
William Arcese ◽  
Juan Ortega ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Advanced Phase ◽  
Unrelated Cord Blood

Abstract Unrelated cord blood transplantation (UCBT) is an alternative option to treat children with haematological diseases without an HLA-identical donor. We have analyzed a total of 323 children with ALL receiving an UCBT, from 1994 to 2004 in 99 transplant centres in 24 countries, mostly in Europe. Cumulative incidence with competing risk and KM estimates were used to calculate outcomes. Seventy six children were transplanted in CR1, 136 in CR2 and 111 in more advanced phase of the disease. Among those children poor cytogenetics were observed in 89% of children in 1CR, 33% in 2CR and 42% in advanced phase. Twenty percent of children transplanted in advanced phase had been previously autografted. The median age was 6.5 years at UCBT, median cell dose infused was 4.1x107/kg and the median follow time was 22 months (3–96). The cord blood was HLA identical (6/6) in 12% of the cases, 5/6 in 46%, 4/6 in 39% and 3/6 in 3%. All children received myeloablative conditioning regimen (TBI in 66%) and the majority (67%) received CsA+corticoids as GVHD prophylaxis. Cumulative incidence of neutrophil recovery at day 60, platelets recovery (&gt;20.000) at day 180, acute (grade II–IV) and chronic GVHD were 76±5%, 54±5%, 42±3%, 14±2%, respectively. Overall 2 year-LFS was 36±3%. In a multivariate analysis, only CR1 or CR2 were associated with better LFS (HR=1.8; p&lt;0.0001). Outcomes CR1 (n=76) CR2 (n=136) Advanced (n=111) TRM at day 100 22+/−5% 25+/−4% 34+/−5% Relapse at 2 years 34+/−8% 37+/−5% 48+/−7% LFS at 2 years 42+/−6% 41+/−4% 24+/−4% For those patients transplanted with poor cytogenetics, LFS at 2 years was 32±6% and it was 37% for CR1, 43% for CR2 and 0% for advanced phase of the disease. In conclusion, in these large series of high risk ALL patients, these results show that UCBT should be proposed as alternative source of allogeneic transplantation for children lacking an HLA identical donor, in earlier status of the disease.

Development of Late over Early Full Donor Chimerism (FDC) Results in Improved Progression-Free and Overall Survival in Patients with Advanced Malignant Lymphomas Receiving Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3665-3665
Author(s):  
David T. Ting ◽  
Bimalangshu Dey ◽  
Ahmed Chaudhary ◽  
Christine Colby ◽  
Karen Power ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Mixed Chimerism ◽  
Early Group ◽  
Malignant Lymphomas ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Equal Distribution ◽  
Late Group

Abstract Mixed chimerism (MC) can be induced in mice after non-myeloablative conditioning and allogeneic HSCT. Full donor hematopoiesis conversion from MC can occur when nontolerant donor lymphocyte infusions (DLI) are given weeks following the transplant as a result of lymphohematopoietic GVH reactions that eradicate leukemia/lymphoma without GVHD. Based on this murine model, we initiated a trial in patients with advanced hematologic malignancies of non-myeloablative therapy with HLA-matched related donor HSCT with intentional induction of MC followed by prophylactic DLI (pDLI) at day +35 post-HSCT in those without clinical GVHD. This analysis examines the influence of the kinetics of sustained donor lymphoid (CD3+ cells) chimerism on transplant outcomes. Fifty-four patients with advanced hematologic malignancies received nonmyeloablative preparative therapy (cyclophosphamide, equine antithymocyte globulin, thymic irradiation and a brief course of cyclosporine) and HLA-matched HSCT (bone marrow, BM, n=42; GCSF-mobilized peripheral blood stem cells, PBSC, n=12). Chimerism analyses were performed weekly until day +100 post-HSCT and then once monthly for a year. Twenty-nine patients with aggressive malignant lymphomas (NHL, n=21; HD, n=8) were selected out of 50 evaluable patients in an effort to analyze a relatively uniform group in terms of their disease and sustained chimerism; patients who lost the allograft were removed from this analysis. Twenty five patients attained stable FDC, defined as &gt; or = 90% donor T cells, and 4 maintained stable MC. Using 42 days post-HSCT as the defining point for chimerism conversion 13 patients achieved early FDC and 16 patients achieved late FDC. Median time to achieve FDC in the early and late groups was 14 days (range, 7–42) and 70 days (range, 49–91) respectively. Separation produced fairly equal distribution by disease characteristics as follows (early to late): NHL, 10 to 11 and HD, 3 to 5. The early group included 10 PBSC recipients who did not receive pDLI because of the spontaneous conversion to FDC; in contrast, the majority of the late group received BMT and 13 of them received DLI (pDLI, n=10, therapeutic DLI, n=3). The incidence of acute GVHD (grades II–IV) was similar between the early and late groups with rates of 77% (n=10 of 13) and 69% (n=11 of 16) respectively; for chronic GVHD, there was a tendency toward an increased rate in the early group of 75% (3/4) compared to the late group rate of 63% (5/8). Overall disease response rates in the early and late groups were 62% and 69%, but there was a trend toward improved complete remission rates in the late group relative to the early group (50% vs 31%). Progression-free survival (PFS) and overall survival (OS) at 1 year were improved in the late compared to the early group [31% (5/16) vs 15% (2/13) and 50% (8/16) vs 38% (5/13), respectively]. At 5 years, there was a statistically significant improved PFS and OS rate in the late group over the early group [31% (5/16) vs 0% (0/13), p =0.037, for both PFS and OS]. In conclusion, these data support the observation from our mouse models that the most potent graft-vs-tumor effect occurs in mixed chimeras with late chimerism conversion, often after delayed pDLI.

Primary Graft Failure (GF) after Unrelated Donor Cord Blood Transplants (UCBT): Risk Factors and Management.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 44-44 ◽  
Author(s):  
Ka Wah Chan ◽  
Michael S. Grimley ◽  
Candace Taylor ◽  
Donna A. Wall
Keyword(s):  
Risk Factors ◽  
Cord Blood ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Viral Reactivation ◽  
Unrelated Donor ◽  
Cell Dose

Abstract Primary GF is recognized as a major risk in UCBT. Both graft (cell dose and quality of the cord blood unit) and recipient (diagnosis of aplastic anemia, prior chemotherapy exposure) characteristics have been reported as being associated with non-engraftment. Here we present a large series of UCBT patients from a single institution and analyze the risk factors and management of this complication. Between 3/2001 and 7/2006, 106 consecutive patients (pts), of median age 5.3 (range 0.1–18.4) years and weight median 22 (range 4–85) kg, received UCBT at Texas Transplant Institute. 13 did not achieve donor engraftment as documented by recovery of ANC&lt; 500/μl by day + 42, and lack of donor cells on ≥2 RFLP analysis of the bone marrow. Failure to attain engraftment occurred in 5/27 with a non-malignant disorders, and 8/79 with hematologic malignancies (p&lt; 033). Non-engraftment was less common in better HLA matched transplants (≥5/6 HLA match: 1/45 vs ≤ 4/6 HLA : 12/61; p&lt; 0.02). Preliminary analysis showed no difference in cord blood TNC/kg, CD34/kg and pre thaw CFU/kg in pts who had primary GF compared to the rest of the cohort. A post thaw CFU/pre-freeze ratio of &lt;20% was more common in primary GF. Among the 79 pts with hematologic malignancies (HM), 8 did not engraft. 4 died early; 1 from persistent leukemia, and 3 from transplant-related complications (TRM). Of the remaining 4 pts with HM, 2 were ALL children in CR1. The other primary GF occurred in 2/5 children with HLH (both with active disease at UCBT), 2/8 the children transplanted for aplastic anemia, and one pt with CD40L deficiency who had primary GF. The 9 pts who had not relapsed or died of TRM went on to second (2nd) UCBT 33 to 95 (median 55) days after first transplant (1st UCBT). Conditioning regimen for 2nd UCBT was fludarabine 175mg/m2, cyclophosphamide 50mg/kg, TBI 2 Gy, ± ATG in 7/9 patients. Median cell dose for 2nd UCBT were 3.6 × 107/kg. HLA matching was similar to 1st UCBT. There was one TRM (respiratory failure) but the rest (8/8) engrafted; with ANC &gt;500/μl at a median of 15 (range 5–64) days, and platelets &gt; 20000/μl at a median of 92 (range 24 to 137) days. All became transfusion-independent, and as of 8/1/2006, 7 of 9 pts are alive. All have complete donor chimerism 164–1616 (median 672) days after 2nd UDCBT. EBV-lymphoproliferatve disorders developed in 2 patients and it was fatal in one. Other viral infections encountered were BKV(1), HHV-6(1), CMV(3) in the blood; adenovirus(1) and enterovirus(1) in the stool; and BKV (1) in the urine. Acute graft-versus-host disease (GVHD) was diagnosed in 2/8 pts. 7/8 pts surviving &gt;100 days had chronic GVHD, and it was extensive in 5 pts. It is important that primary GF be recognized as a risk of UDCBT and a back-up donor source be identified prior to transplant. Children with intact/active immune systems prior to transplant are at greater risk. Early 2nd UCBT, before patient’s condition deteriorates, is a feasible treatment alternative. This immunosuppressive preparative regimen is well tolerated early post first UCBT and can result in reliable engraftment, albeit a greater risk of chronic GVHD and viral reactivation post transplant.

Analysis of Mismatched Umbilical Cord Blood Transplants for Adults Patients 45 Years or Older.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5067-5067
Author(s):  
Seah H. Lim ◽  
Willaim V. Esler ◽  
Yana Zhang ◽  
Jian Zhang ◽  
Colleen Burris ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Older Patients ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Leukemia Relapse ◽  
Older Populations

Abstract Although hematopoietic stem cell (HSC) transplants are curative for some patients with hematologic malignancies, they have been applied primarily to younger patients. Yet, hematologic malignancies are commoner in the older populations. Therefore, despite advances in HSC transplants, many patients, especially older patients, still die of their disease. Umbilical cord blood (UCB) transplants have been shown to produce comparable results to those obtained from unrelated bone marrow transplants for adults with hematologic malignancies. UCB transplants may be particularly suitable for older patients needing unrelated HSC transplants since the incidence of GVHD is lower despite the less stringent HLA-matching requirement. Furthermore, UCB procurement is fast and can be accomplished in two weeks. However, data on the applicability of UCB transplants in older adult patient is lacking. The outcome of 14 consecutive adult patients (9 males and 5 females), 45 years or older, needing HSC transplants but without matched sibling donors in a single institution was analyzed. The median age was 55.5 years (range 45–78). The median weight was 72 kg (range 60–105). The median CD34 cells infused were 2.3 x 105/kg. Four patients received one-antigen mismatched, five patients two-antigen mismatched and five patients three-antigen mismatched transplants. Conditioning regimens consisted of Bu/Cy with (n=5) or without (n=1) ATG, Flu/Mel (n=7) and BEAM (n=1). GVHD prophylaxis consisted of cyclosporin A and methylprednisone. Five patients received double UCB transplants. The diagnosis: AML (n =8; 2 untreated secondary AML, 2 primary refractory AML, 2 secondary AML in CR1, 1 secondary AML in CR2 and 1 AML in CR3 and has failed a previous autologous transplant), CML (n=3; 2 in BC and 1 in CP1), CLL (n =2; both with advanced refractory disease) and SAA due to Hep C (n=1). Despite the age of these patients, Grade I–II acute GVHD occured in 10 patients and Grade III–IV in only 2 patients. Three patients died, all from septicemia, before engraftment could be documented. Other deaths include severe GVHD (n=2), VOD (n=1), stroke (n=1), septicemia (n=1) and leukemia relapse (n=1). Five patients are alive and disease-free. As of August 1, 2007, the 5-year actuarial DFS and OS are both 31% for the group and 50% for those <65 years (Figure 1). All five patients >65 years died within 100 days of transplants. In conclusion, some older patients needing HSC transplants may benefit from mismatched UCB transplants if they are not candidates for autologous transplants and do not have HLA-matched siblings. Obviously longer follow-up is needed in these patients to better determine the long-term effect of this approach in older patients. However, further optimization of the conditioning regimen is needed for patients older than 65 years to reduce early TRM due to toxicities. Figure Figure

Late Pulmonary Dysfunction in Long-Term Survivors after allogeneic Hematopoietic Stem Cell Transplantation with Intensified Conditioning Regimen Including Thiotepa, Cyclophosphamide, and Total Body Irradiation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2137-2137
Author(s):  
Satomi Ito ◽  
Maki Hagihara ◽  
Kenji Motohashi ◽  
Atsuo Maruta ◽  
Yoshiaki Ishigatsubo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Pulmonary Dysfunction ◽  
Hematopoietic Stem ◽  
Related Donor ◽  
Total Body ◽  
Long Term Survivors

Abstract Background: Late pulmonary dysfunction is a clinical problem influencing on quality-of-life (QOL) in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). In this study we retrospectively assessed pulmonary function test (PFT) in patients surviving 5 years or more after HSCT with intensified conditioning regimen and identified pre-and post-transplant risk factors. Methods: Sixty-five long-term survivors transplanted between May 1994 and March 2003 (minimum 5 years follow-up after HSCT) were included in this analysis. There were 36 males and 29 females. Median age was 39 years, with a range of 16 to 53 years. All patients were transplanted because of hematologic malignancies (20 patients with AML, 16 with ALL, 9 with MDS, and 20 with CML). The pre-transplant conditioning regimen consisted of thiotepa (200 mg/m2 for 2 days), cyclophosphamide (2,000–2,250 mg/m2 for 2 days), and total body irradiation (12.5 Gy in five fractions). The prophylaxis of graft-versus-host disease (GVHD) consisted of short-term methotrexate and cyclosporine or tacrolimus. Bone marrow (BM) from related donor or unrelated donor, and peripheral blood stem cell (PBSC) from related donor were transplanted in 33 patients, 22, and 10, respectively. PFT was performed pre-conditioning and then post-transplant at 3 months, 1 year, and thereafter annually. Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV1/FVC ratio were used to measure ventilatory capacity. Vital capacity (VC) and total lung capacity (TLC) were used to measure lung volumes. Diffusion capacity for carbon monoxide (DLCO) was determined by using a carbon monoxide single-breath technique with correction for hemoglobin concentration. Results: Seven (11%) patients showed abnormalities in PFT after HSCT. Temporary abnormality (restrictive pattern) within 1 year was detected in 2 patients. Five patients developed late-onset and continuous abnormality (restrictive pattern in 2 patients, obstructive in 2, and mixed in 2) with a cumulative incidence of 8%. These were clinically diagnosed as having bronchiolitis obliterans in 3 patient and interstitial pneumonia in 1. DLCO was significantly lower after transplantation of PBSC than after BM (P=0.02 at 3 year and P=0.00 3 at 5 year). More than 40 years old, female, high risk of disease status, and abnormal PFT pre-transplant were related with a decline of PFT within 1 year after HSCT, but there were no association with PFT abnormality at 3 or 5 years. The cumulative incidence of late PFT abnormality in patients with CML was significantly higher than that in those with other than CML (P=0.01).Other factors including age, sex, smoking, disease status, and donor sources were not significant for developing late pulmonary dysfunction. Extensive chronic GVHD was associated with late PFT abnormality with statistical significance (P=0.002 for VC and P=0.01 for FEV1). Three of 7 patients receiving immunosuppressant at 5 years after HSCT had pulmonary complication. Conclusions: The results showed relatively a low incidence of PFT abnormality in long-term survivors who received HSCT with intensified conditioning regimen. However, late pulmonary dysfunction lowers QOL in survivors despite long-term remission of leukemia Longer follow-up should be needed to determine whether more patients with chronic GVHD will develop PFT abnormality.

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