Adult Matched Sibling Blood Cell Transplants (BCT) after Myeloablative Conditioning Incorporating Daily Intravenous (IV) Busulfan (BU) and Low-Dose Antithymocyte Globulin (ATG): Outcomes with Particular Respect to Transplant-Related Mortality (TRM) in 140 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2313-2313
Author(s):  
James A. Russell ◽  
Ahsan M. Chaudhy ◽  
Oluyeme Jeje ◽  
Diana Quinlan ◽  
Douglas Stewart ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Low Dose ◽  
Acute Gvhd ◽  
Myocardial Infarct ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Increase Risk ◽  
Cell Transplants ◽  
One Year ◽  
Related Mortality

Abstract Intravenous BU allows more predictable exposure and is more convenient to administer once daily than the conventional four times daily regimen. Low-dose pretransplant ATG may reduce morbidity and mortality from graft-versus-host disease (GVHD). We have investigated a myeloablative regimen incorporating these agents in 140 adults aged 18–65 (median 47) receiving a first MRD SCT between 05/99 and 01/04. Conditioning comprised fludarabine (FLU) 50mg/m2on days −6 to −2 and IV BU (Busulfex, ESP Pharma) 3.2 mg/kg daily days −5 to −2 inclusive (FLUBUP) in 116 patients (pts) with additional TBI 200cGy x 2 in 24 (14 ALL, 8AML, 2 biphenotypic). Forty-three pts had standard-risk (SR) acute leukemia in CR1 (35 AML, 8 ALL), and 23 had active acute leukemia (HA) (18 AML±MDS, 3 ALL, 2 biphenotypic). A third group of 74 other (OTH) pts comprised 2 AML CR2, 2 ALL CR2, 2 CML (1 AP, 1CP2), 13 MDS, 11 MM, 24 NHL, 6 HD (2 with CLL), 8 CLL, 5 other. All pts were given cyclosporine A, “short course” methotrexate with folinic acid and Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Followup of survivors is 6–61 months, median 26. Incidence of acute GVHD (aGVHD) grade II–IV was 19±4%, grade III–IV 6±2% and chronic GVHD (cGVHD) 66±5% (at 2 years). Projected TRM is 4±2% at 100 days, 10±3% at 1 year and 14±4% at 5 years. For acute leukemia pts projected TRM at one year is 5±5% vs 12±5% with (n = 24) and without (n = 47) TBI respectively (p = ns). Four non-relapse deaths occurred before day 100 one each from myocardial infarct (MI), acute GVHD, candidiasis and VOD. Ten deaths between days 102–569 were related to aGVHD in one and complications in pts with cGVHD in 9 (occurring in 1 pt after 2nd BCT for graft failure) including 1 VZV, 3 other infection, 1 PE, 1 MI. Of 11 follicular NHL pts 3 died of cGVHD and its complications after 1st BCT compared with 5 of 129 others (p = 0.02). Twelve of the transplant-related deaths were in 76 pts ≥ 46 years old compared with 2 in 64 younger pts (TRM = 23±6%, vs 4±3%, p = 0.01). Of 55 relapsed pts 17 are alive, 8 of these are in remission after more treatment and/or onset of GVHD. Projected 5-year disease-free survival and survival respectively is 46±5% and 57±5% for all pts, 62±8% and 76±7% for SR, 51±7% and 59±9% for OTH, and 9±6% and 16±8% for HA. This study indicates that: 1) regimen related mortality is low in MRD BCT recipients given this regimen 2) cGVHD is the main cause of TRM 3) pts with follicular NHL seem to be comparatively susceptible to death related to cGVHD 4) addition of 400cGy TBI does not increase risk of TRM and 5) older age remains a risk factor for TRM.

Double Unit Myeloablative Umbilical Cord Blood (UCB) Transplantation in Adults & Adolescents: High Incidence of Engraftment and Low Transplant-Related Mortality.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 826-826
Author(s):  
Juliet N. Barker ◽  
Daniel J. Weisdorf ◽  
Todd E. Defor ◽  
John E. Wagner
Keyword(s):  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Critical Determinant ◽  
Major Barrier ◽  
Neutrophil Recovery ◽  
Cell Dose ◽  
Low Incidence ◽  
Related Mortality

Abstract UCB cell dose is a critical determinant of hematopoietic recovery & survival after UCB transplantation (UCBT) & is the major barrier to adult UCBT. Therefore, we have investigated the combined transplantation of 2 partially HLA-matched UCB units to augment graft cell dose. Twenty-three patients with high-risk hematologic malignancy [median 24 yrs (range: 13–53)] received two UCB units [median infused dose 3.5 x 107 NC/kg (range 1.1–6.3); larger unit 1.9 (0.6–3.6) & smaller unit 1.5 (0.5–2.7)]. Of the 46 units used, only 3 were 6/6, 16 were 5/6 & 27 were 4/6 HLA-A,B,DRB1 antigen matched unit to the recipient. All patients received myeloablative conditioning using cyclophosphamide 120 mg/kg (60 mg/kg days −7 & −6), & TBI 1320 cGy in 8 fractions with cyclosporine-A (CSA) from day -3 for at least 6 months. In addition, the first 2 patients received ATG 15 mg/kg every 12 hours days −3 to −1 & methylprednisone (MP) 1 mg/kg every 12 hours days 5–19. Subsequent patients (n = 21) received fludarabine 75 mg/m2 (25 mg/m2 days −8 to −6) & mycophenolate mofetil 1 gm twice daily from days −3 to +30 instead of ATG/MP. All evaluable patients (n = 21) engrafted at a median of 23 days (range 15–41). At day 21, engraftment was derived from both donors in 24% and a single donor in 76%, with one unit predominating in all patients (median chimerism in day 21 BM 100%). Notably, the predominating unit had a relatively low infused cell dose [median 1.8 x 107 NC/kg (range 0.7–3.6); 1.5 x 105 CD34+/kg (range 0.6–10.4)]. While neither NC, CD34+ & CFU-GM dose, nor HLA-A,B,DRB1 match, predicted which unit would predominate, the predominating unit had a significantly higher CD3+ dose (p < 0.01). However, the NC, CD34+ & CFU-GM doses of the predominating unit were significantly associated with the speed of neutrophil recovery. For example, the median day of neutrophil recovery for patients (n=11) with a predominating unit of 1.6–10.4 x 105 CD34+/kg was day 19.5 (range 15–27) vs day 26 (range 15–41) in patients (n=10) with a predominating unit of 0.6–1.5 x 105 CD34+/kg (p=0.01). Incidences of grade II–IV & III–IV acute GVHD were 65% (95%CI: 42–88) and 13% (95%CI: 0–26) at day 100, respectively, with 23% (95%CI: 6–40) having chronic GVHD at 1 year. Six month transplant-related mortality was 22% (95%CI: 5–39). With a median follow-up of 10 months (range: 3.5 months–2.5 yrs), disease-free survival (DFS) is 57% (95%CI: 35–79) at 1 year, with 72% (95%CI: 49–95) of patients alive at 1 year if transplanted in remission. These data clearly demonstrate the safety of double unit UCBT. Despite the low infused CD34+ cell dose of the predominating unit, all evaluable patients achieved sustained engraftment, with a low incidence of severe acute GVHD despite HLA-disparity. This has resulted in a low TRM, & DFS is high if patients are transplanted in remission. While the NC & CD34+ cell doses of each unit do not predict unit predominance, these parameters in the predominating unit determine the speed of neutrophil recovery. As a suitable double unit graft can be identified for the majority of adults, this approach represents a major extension of access to HSC transplantation.

Treosulfan-Based Reduced Toxicity Regimen Prior to Allogeneic Hematopoietic Cell Transplantation in Non-Malignant Disorders.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5245-5245
Author(s):  
Jerzy Wojnar ◽  
Sebastian Giebel ◽  
Miroslaw Markiewicz ◽  
Malgorzata Krawczyk-Kulis ◽  
Iwona Wylezol ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Hematological Toxicity ◽  
Haemorrhagic Cystitis ◽  
Hematopoietic Disorders ◽  
One Year ◽  
Reduced Toxicity

Abstract Graft rejection is a major cause of failure after alloHCT in non-malignant hematopoietic disorders including severe aplastic anemia (SAA) and paroxysmal nocturnal hemaoglobinuria (PNH). For patients with high risk of this complication we introduced a novel conditioning regimens, based on treosulfan - an alkylating agent possesing both immuno- and myeloablative properties. Between 2003–2006, eleven patients (age: 23(14–35) years) with SAA (n=6) or PNH (n=5) were treated in a single institution with alloHSCT from either HLA-identical sibling (n=3) or an unrelated volunteer (n=8). For patients with SAA conditioning regimen consisted of treosulfan 10 g/m2/d on days -7, -6, cyclophosphamide 40 mg/kg/d on d. -5, -4, -3, -2, and anti-thymocyte globulin (ATG) 2 mg/kg/d on d. -3, -2, -1. PNH patients received treosulfan 14 g/m2/d on days -6, -5, -4, fludarabine 30 g/m2 on d. -6, -5, -4, -3, -2, and (ATG) 2 mg/kg/d on d. -3, -2, -1. Bone marrow was used as a source of stem cells in 5 patients and peripheral blood - in 6 cases. Graft-vs.-host disease (GVHD) prophylaxis consisted of Cyclosporin A and short-course Methotrexate. All patients engrafted with the median time to neutrophil >0.5×10e9/L and platelet >50×10e9/L recovery of 16 (14–22) days and 21.5 (12–29) days, respectively. Complete donor chimerism was achieved on day +30 in all cases. None of the patients developed grade III-IV acute GVHD, two patients experienced grade II acute GVHD. At one year the cumulative incidence of extensive chronic GVHD equaled 22%. No severe organ toxicity was observed. With the median follow-up of 19 months, the disease-free survival at 2.5 years was 91%. A single PNH patient died of haemorrhagic cystitis. We conclude that treosulfan-based preparative regimens are well-tolerated and allow stable engraftment in SAA and PNH patients. The use of treosulfan allows intensification of the conditioning without providing an additional non-hematological toxicity.

Analysis of 120 Pediatric Patients with Non-Malignant Disorders Transplanted Using Unrelated Plasma Depleted Cord Blood and the Role of Post-Thaw Wash

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4406-4406
Author(s):  
Joseph Rosenthal ◽  
Tang-Her Jaing ◽  
Lee Lee Chan ◽  
Gretchen Eames ◽  
Michael L. Graham ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cord Blood ◽  
Cumulative Incidence ◽  
Pediatric Patients ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Free Survival ◽  
Disease Free ◽  
Related Mortality

Abstract Unrelated cord blood (UCB) is an important stem cell source for unrelated hematopoietic cell transplantation of patients with non-malignant disorders. Cell dosage is a critical factor for successful UCB hematopoietic stem cell transplantation (HSCT). The red cell reduced (RCR) and post-thaw wash techniques that are widely used incur significant nucleated cell loss. Three strategies were employed to maximize cell dose and improve outcome–use of cord blood processed with plasma depletion without red blood cell reduction (PD CB), avoidance of post-thaw wash, and the use of double cords (2X) when necessary. A CIBMTR-audited analysis was performed on all 120 pediatric patients with non-malignant disorders transplanted with PD CB at 29 U.S. and 17 international centers. Transplant characteristics: median age 3.5 years (range 0.1–14); median patient weight 15 kg (range 4–61); male 58%. The majority of patients (n=58; 55%) were Asian. Twenty-two (21%) patients were Hispanic, 15 (14%) were Caucasian, 6 (6%) were African-American, and three (3%) were of Middle Eastern background. HLA ABDR matches: 6/6–26; 5/6–48; 4/6–47; 3/6 or 2/6–6; median pre-freeze nucleated cell dose 10.5×107/kg; median pre-freeze CD34+ dose 3.7×105/kg; non-myeloablative regimen 24%; 58% infused without post-thaw wash (NW). Myeloid engraftment defined as ANC≥500 and 6-month platelet engraftment defined as ≥ 20K and ≥ 50K are 89±8%, 88±8%, and 84±6% respectively. The median time to myeloid and platelet engraftment are 21 days (range 11–64), 49 days (range 13–155), and 61.5 days (range 21–205) respectively. No major adverse event was observed in either the W or the NW group. The cumulative incidence of reported grade II–IV acute GVHD was 38±5%, and 19±4% had grade III–IV acute GVHD. 36±6% developed limited chronic GVHD, and 12±4% developed extensive chronic GVHD. With a median follow-up of 329 days (range 3–1928 days), the Kaplan-Meier estimates of 1-year TRM, OS and diseasefree survival were 20±6%, 88±6% and 72±6% respectively. Foregoing post-thaw wash for PD CB transplantation improved neutrophil (RR=1.75; p=0.01) and platelet engraftment (RR=1.72; p=0.02) and reduced TRM (RR=0.38; p=0.04). This series demonstrated that unrelated PD CB transplantation can be performed safely and effectively in children with life-threatening, non-malignant disorders. Additionally, the results demonstrate possible improvement in myeloid and platelet engraftment, overall and disease-free survival when post-thaw wash is not employed. Table 1. Summary of overall results Outcome All Patients N = 120 Washed CB N = 48 Unwashed CB N = 71 RR (Wash=Ref) P-value ANC500 Engraftment Cumulative Incidence Median # Days to Engraftment 87±6% d+21 86±9% d+25 89±8% d+19 1.75 0.01 Platelet 20K Engraftment Cumulative Incidence Median # Days to Engraftment 81±6% d+49 75±9% d+52 88±9% d+43 1.72 0.02 Autologous Recovery 3±2% 2±2% 4±3% 1.06 0.95 Acute GvHD II–IV Acute GvHD III–IV 38±5% 19±4% 31±7% 17±6% 45±7% 21±6% 1.74 1.38 0.11 0.50 Chronic GvHD Limited Chronic GvHD Extensive 36±6% 12±4% 14±6% 19±6% 60±10% 6±4% 5.69 0.24 &lt;0.001 0.08 Transplant-Related Mortality–100 Day Transplant-Related Mortality–3 Yr 10±3% 20±4% 11±5% 34±8% 9±4% 11±4% 0.38 0.04 Overall Survival–1 Yr Overall Survival–3 Yr 79±4% 79±4% 66±8% 66±8% 88±4% 88±4% 0.43 0.06 Disease-Free Survival–1 Yr Disease-Free Survival–3 Yr 72±5% 70±6% 58±9% 51±10% 84±5% 84±5% 0.48 0.07

Risk Factors and Outcome of Children with Relapsed/Refractory Acute Leukemia after T-Cell-Rich Haploidentical Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4604-4604
Author(s):  
Atsushi Kikuta ◽  
Hideki Sano ◽  
Kazuhiro Mochizuki ◽  
Shogo Kobayashi ◽  
Mitsuko Akaihata ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
T Cell Therapy ◽  
Gvhd Prophylaxis ◽  
Significant Difference

Abstract Background: T-cell rich (TCR) HLA-haploidentical SCT (haplo-SCT) is a form of T-cell therapy that has a high degree of efficacy in hematologic malignancies. Previously we reported the safety profile assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate (MTX) and prednisolone (PSL) in unmanipulated haplo-SCT (Clin Transplant 2010, Transfus Med 2014). We evaluated efficacy and toxicity of TCR haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL). Methods: VHR-R/R AL were defined as: relapse after SCT, very early or early relapse, induction failure(2 or more) and relapse of risk factor with MLL rearrangement, Ph+, Mo7 and 5q-. From Aug 2000 to April 2014, consecutive 38 patients (pts) with VHR-R/R AL who underwent TCR-haplo-SCT were included. The median age of pts was 8.2(0.3-19.1) years old. The diagnosis included ALL (n=27), AML (n=8), M/NKL (n=3). The disease status at TCR-haplo-SCT were 18 in CR (positive MRD: 8 pts), 20 in non-CR. HLA disparities were 2/8 in 1pt, 3/8 in 9 pts, 4/8 in 28 pts. Donors included fathers (n=21), mothers (n=14), and siblings (n=3). Thirty one pts received myeloablative conditioning (TBI based: 20 pts, Bu based: 11 pts) and 34 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus, MTX and PSL. Thirty four pts received peripheral blood stem cells and 4 pts received BM. Results: Neutrophil engraftment (defined as >0.5x109/L) was 95% with a median day of 13 (range, 10-15). With a median 1640 days follow-up (range, 320-5510 days) in pts without events, the actuarial 3-year overall survival (OS) and disease-free survival (DFS) were 57% and 39%, respectively. On competing-risk analysis, 1-year cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 71% and 63%, respectively; 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 40% and 20%. On univariate analysis, 3-year OS in pts with acute GVHD vs. without acute GVHD were 70% vs. 22% (p=.0006), in pts CR vs. non-CR at TCR-SCT were 83% vs. 32% (p=.007), in pts infused CD3 cell doses >=5 x 108/kg vs. <5 x 108/kg were 83% vs. 25% (p=.005), according to age at TCR-SCT <9 vs. >=9 were 79% vs. 34% (.008), respectively. In contrast, the occurrence of acute GVHD had no significant difference in infused CD3 cell doses. Conclusions: These data suggest that TCR haplo-SCT following low-dose ATG containing conditioning combined with our GVHD prophylaxis is well tolerated, facilitates engraftment, and has significant anti-leukemic activity, particularly in pediatric patients with refractory/ relapsed population. Disclosures No relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplantation (SCT) for Hematologic Malignancy from Matched Related Donors (MRD) with a Myeloablative Once Daily IV Busulfan (Bu)/Fludarabine (Flu) Based Regimen (FLUBUP) with Thymoglobulin: Outcomes in 200 Patients with over One Year Follow-Up.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3009-3009
Author(s):  
James A. Russell ◽  
Nizar J. Bahlis ◽  
Mary Lynn Savoie ◽  
M. Ahsan Chaudhry ◽  
A. Robert Turner ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Chronic Gvhd ◽  
Disease Stage ◽  
Once Daily ◽  
One Year

Abstract Earlier reports indicated that a myelablative protocol based on once daily IV Bu with Flu plus rabbit antithymocyte globulin appeared effective and relatively well tolerated. Since 1999 this has been our standard regimen for all pts with hematologic malignancy, including those who might otherwise be candidates for non-myeloablative regimens. Two hundred MRD SCT patients (pts) were treated between 05/99 and 07/05. Chemotherapy comprised fludarabine 50mg/m2 on days -6 to -2 and IV busulfan (Busulfex, PDL Pharma) 3.2 mg/kg daily days -5 to -2 inclusive. Forty-six acute leukemia pts had additional TBI 200cGy x 2 on day (D) -1 or 0. Prophylaxis for GVHD was cyclosporine A, methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Cell source was mobilized blood cells (BCT) in 172 and marrow (BMT) in 28. Median age was 46 (range 18–65) and follow-up of survivors was 13–87 months (median 42). As engraftment and GVHD did not differ significantly data for BMT and BCT were combined. Two pts had graft failure (1 with autologous recovery) and two died before D28. The remaining 196 evaluable pts engrafted granulocytes at median of 16 days (range 2–42). Platelets engrafted in 194 pts at a median of 18 days (0–101), 2 died before engraftment on days 29 & 72. Incidence of acute GVHD grade II-IV, acute GVHD grade III-IV and chronic GVHD was 14±2%, 3±1% and 54±4% respectively. Five pts died before D100 of GVHD (1), candidiasis (1), influenza B (1), veno-occlusive disease (1) and myocardial infarction (1), after D100 15 deaths were related to GVHD (11), pneumonia/ARDS (2), graft failure (1) and pulmonary embolus (1). One case of PTLD resolved with rituxan, there was no serious neurological toxicity. For low-risk (acute leukemia CR1/CR2, CML CP1) pts 3 year TRM was 4±3% for those ≤45 years old (n = 54) and 6±4% for those >45 (n = 31). Corresponding figures for all others (high risk) were 6±4% (n = 40) and 27±7% (18±5% at one year, n = 75) (p = 0.04). [table 1] We conclude that FLUBUP appears to be well-tolerated with little mortality attributable to the regimen itself. In partular, concerns about excessive immune suppression (partularly causing PTLD) and neurotoxicity have not been substantiated. Chronic GVHD is the major cause of non-relapse death. Control of early morbidity and mortality from GVHD may allow intensification of the regimen, for example by adding TBI. There is also evidence that the safety can be improved by monitoring Bu levels. The effect of age on TRM is only apparent in high-risk pts, the challenge is to reduce mortality from chronic GVHD in these individuals without sacrificing graft-vs.-malignancy. 3 year outcomes (%) for groups with >10 pts Disease/stage n survival TRM * p = 0.07 AML CR1/2 (no TBI) 32 66±8 9±5 AML CR1/2 (TBI)* 16 94±6 0 AML advanced (no TBI) 18 22±10 17±9 MDS 15 79±11 24±12 ALL CR1/2 15 73±11 8±7 CML CP1 22 100% 0 CLL/Richter’s (as primary indication) 14 68±13 16±10 Multiple Myeloma 13 54±14 8±7 NHL (low grade/mantle) 21 75±10 17±9 All pts 200 66±3 12±3

Hematopoietic Stem Cell Transplantation after Reduced Intensity Conditioning in Acute Myeloid Leukemia Patients Older Than 40 Years.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5074-5074
Author(s):  
Cynthia Huisman ◽  
Ellen Meijer ◽  
Eefke J. Petersen ◽  
Henk M. Lokhorst ◽  
Leo F. Verdonck
Keyword(s):  
Stem Cell ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Free

Abstract Reduced intensity conditioning (RIC) protocols are increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients. We retrospectively analyzed the outcome of RIC HSCT in a homogeneous group of acute myeloid leukemia (AML) patients over the age of 40. Forty-three AML or high-risk myelodysplastic syndrome patients were treated with a fludarabine and low dose total body irradiation (TBI) based regimen, followed by a full peripheral stem cell graft. Antithymocyte globulin was given to matched unrelated recipients (34%) before infusion of fludarabine. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin and mycophenolate mofetil. All but 2 AML patients were in complete remission at the time of transplantation. Seventy-six percent of patients had a poor risk profile. Hematologic recovery was fast and primary graft failure occurred in one patient. Two patients with active disease at the time of HSCT experienced ongoing relapse. Infections were diagnosed in 9 patients (21%) and 6 patients (14%) were treated for CMV reactivation. Sixty percent of patients developed acute GVHD, which was grade 2 in 40% and grade 3 in 12%. Chronic GVHD occurred in 33% of patients. The incidence and severity of both acute and chronic GVHD was similar in patients with related and unrelated donors (P = 0.84 and 0.74, respectively). Treatment-related mortality (TRM) was low (9%), total nonrelapse mortality was 19%. After a median follow-up of 571 days, 16 patients (37%) experienced relapse. One-year progression-free and overall survival were 61% and 67%, respectively. Median disease-free survival has not been reached yet (> 58 months) and median overall survival was 31 months (Fig 1 and 2, respectively). Poor risk AML was significantly associated with disease-free survival in multivariate analysis (P = 0.02). Age > 60 years, gender, donor type, timing of RIC HSCT (upfront or after relapse) and acute GVHD were not identified as prognostic factors. In conclusion, fludarabine plus low-dose TBI-based RIC HSCT is effective in AML patients over the age of 40 without active disease at the time of transplant and is associated with low TRM. Figure Figure Figure Figure

Low Incidence of Acute Graft-VS.-Host Disease (GVHD) Using Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) after Matched Sibling Donor (MSD) Non-Myeloablative Stem-Cell Transplants (NST) Conditioned with Fludarabine (FLU) and Low-Dose Total Body Irradiation (TBI).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5065-5065
Author(s):  
Yago Nieto ◽  
Nigel Patton ◽  
Timothy Hawkins ◽  
Ruth Spearing ◽  
Scott I. Bearman ◽  
...  
Keyword(s):  
Low Dose ◽  
Acute Gvhd ◽  
Multiorgan Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Large Cell ◽  
Survival Times ◽  
Gvhd Prophylaxis ◽  
Cell Transplants ◽  
Low Incidence

Abstract Randomized studies after conventional allografting showed that in combination with methotrexate TAC was superior to cyclosporine for prevention of acute GVHD. Using the Seattle conditioning regimen of FLU/low-dose TBI we evaluated TAC/MMF as a substitute for cyclosporine/MMF as post-grafting immunosuppression after MSD PBPC NST. Thirty-two patients (median age 57, range 32–68 years), who were poor candidates for a conventional myeloablative transplant, were enrolled. Patient diagnoses included lymphoma (N=12) (7 follicular, 2 transformed, 1 mantle-cell, 1 diffuse large cell, 1 NK), myeloma (N=12), high-grade MDS (N=5), AML (N=2), Hodgkin’s (N=1). Patients were conditioned with FLU (30 mg/m2/d x 3), TBI (200 cGy), were infused donor PBPCs on day 0, and received GVHD prophylaxis with TAC (0.06 mg/kg PO b.i.d. from day −3), targeting initially 10–20 ng/mL, and MMF (15 mg/kg PO b.i.d., from day 0 to +27, discontinued without taper). TAC was tapered from day +100 to +180 and from day +35 to +56, in those patients with indolent (N=25) and aggressive malignancies (N=7), respectively. Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a non-fatal graft rejection. The % patients with mixed/donor T-cell chimerism were as follows: 1 month: 77%/23%, 3 mo: 86%/14%, and 1 yr: 20%/80%. Five patients (15.6%) experienced stage II–IV acute GVHD, presenting at median day +61. Eleven patients (34%) experienced chronic GVHD (1 limited, 10 extensive) at median onset day +190. In 6 of those patients (22%), chronic CVHD was not elicited by immunosuppression withdrawal or DLI upon tumor progression. Day+100 transplant-related mortality (TRM) was 0%. Overall TRM was 9%, with 3 deaths from GVHD-related multiorgan failure on days +105, +343, and +354, respectively. At median follow-up of 19 (2–41) months, 20 patients (62.5%) were alive, 17 patients (53%) remained progression-free, 13 of them (41%) in complete remission. Median progression-free and overall survival times were 21 and 33 months, respectively. Conclusion: TAC/MMF after a MSD NST provides effective acute GVHD prophylaxis, and is associated with an excellent early safety profile. As compared to reported outcomes with cyclosporine/MMF, acute GVHD incidence appeared lower and onset was delayed.

Low Dose Thymoglobulin Results In Improved Outcomes After Allogeneic Unrelated Hematopoietic Stem Cell Transplantation (HCT) For Patients With Acute Myeloid Leukemia/ Myelodysplastic Syndrome Conditioned With Intravenous Busulfan and Fludarabine

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5453-5453
Author(s):  
Yasser Khaled ◽  
Megan Smith ◽  
Tori Smith ◽  
Jason Balls ◽  
Abraham Matar ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Improved Outcomes ◽  
Daily Dose ◽  
One Year ◽  
Related Mortality

Abstract Low Dose Thymoglobulin Result in Improved Outcomes after Allogeneic Unrelated Hematopoietic Stem Cell Transplantation (HCT) for Patients with Acute Myeloid Leukemia/ Myelodysplastic Syndrome Conditioned with Intravenous Busulfan and Fludarabine. Intravenous Busulfan/Fludarabine (Bu/Flu) based conditioning regimens have resulted in lower treatment related mortality (TRM) after allogeneic HCT in both reduced and full intensity dosing in AML/MDS. The addition of thymoglobulin to such regimens to minimize the risk of graft versus host disease after unrelated donor (MUD) HCT has been linked to the increased concerns of relapse risk. Method In order to study the impact of addition of low dose thymoglobulin to Bu/Flu regimens in MUD recipients, the medical records of 38 consecutive AML/MDS patients who underwent MUD HCT with BU/Flu and low dose thymoglobulin were retrospectively reviewed. All the patients received single daily dose of iv Bu 3.2 mg/kg for 2 days (RIC, Bu2-Flu) or 4 days (FIC, Bu4-Flu) based on age,  older or younger than 65 respectively. Fludarabine was given as a single daily dose of 40 mg/Kg for 4 days. Graft versus host disease prophylaxis was Tacrolimus/Methotrexate in FIC recipients and Tacrolimus/Mycophenolate in RIC recipients. Additionally, all the patients received thymoglobulin 1.5 mg/Kg on day -3, -2 and -1. All patients received peripheral stem cells except one patient with mismatch MD who received bone marrow product. Results Patient Characteristics are shown in Table 1. All the patient engrafted except one who received marrow product.  All the patients but 3 (8%) achieved 90% or more donor chimerism by day 100. With Mean follow up of 500 days (range, 100-1242) the overall survival (OS) was 77% ± 7 (CI 63-91%) at 1 year and 67% ± 9 (CI 49-85%) at 2 years. Similarly, disease free survival was 66% ±8 (CI 50-82%) at 1 and 2 years. Cumulative incidence of acute GVHD grade II-IV was 55% with grade III-IV 12%. Cumulative incidence of chronic GVHD at 1 year was 43% with extensive chronic GVHD in 17%. The regimen was associated with low treatment related mortality (TRM) with cumulative incidence of only 5% at one year, CI 14-21%. The cumulative incidence of relapse at one year was 29%, CI 17-49%. On univariate analysis only high risk CIBMTR status was predictive of poor OS (p=0.05). Conclusion The addition of low dose thymoglobulin to RIC and FIC regimens with iv Busulfan/Fludarabine prior to MUD HCT results in low TRM and improved OS for patients with AML/MDS. Relapse rate does not seem to be increased in this cohort by the addition of low dose thymoglobulin in comparison to historical control. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Azacitidine Administration Following Hematopoietic Stem Cell Transplantation Is Safe and Feasible in Children with Acute Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4805-4805 ◽  
Author(s):  
Justin T. Wahlstrom ◽  
Biljana N. Horn ◽  
Carol Fraser-Browne ◽  
Rebecca Hoeweler ◽  
Ying Lu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Low Dose ◽  
Pediatric Patients ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem

Abstract Introduction High dose chemotherapy with or without radiation followed by hematopoietic stem cell transplantation (HSCT) is standard therapy for pediatric patients with very high risk acute leukemia. Despite maximal therapy, a significant number of these patients will relapse after HSCT (Bitan Blood 2014; Tracey BBMT 2013). The hypomethylating agent azacitidine has immunomodulatory activity at a low dose and may augment anti-leukemic graft alloreactivity when used after HSCT (Goodyear Blood 2012; Craddock BBMT 2016). We report on the feasibility and safety of azacitidine administration following HSCT for pediatric acute leukemia. Methods Enrollment of pediatric patients with acute leukemia in this phase I/ II prospective study (NCT02458235) started in May of 2015 and is ongoing. Intravenous azacitidine (160 mg/m2 divided over 4 days) was administered as early as Day +30 post-HSCT for up to 7 consecutive cycles. Patients underwent myeloablative conditioning regimens according to standard protocols using a backbone of either total body irradiation or busulfan, combined with one or more of the following: thiotepa, melphalan, fludarabine, and clofarabine. Any stem cell source was allowed. Azacitidine was combined with immunomodulatory interventions such as fast withdrawal of immunosuppression and donor lymphocyte infusion if indicated, based on mixed chimerism or persistent minimal residual disease. Study subjects were monitored for azacitidine toxicity via weekly blood tests (complete blood count and biochemistry panel). Lymphocyte subsets and function were tested prior to each azacitidine cycle. Azacitidine was not administered in cases of hepatic injury as measured by elevated transaminases >5 times upper limit of normal; cytopenias requiring regular blood product transfusions or growth factor support; vital sign instability; or at the discretion of the treating physician. If tolerated, azacitidine was continued in 6-weekly cycles for a maximum of 7 cycles. Results Of 11 patients registered on the study with intent to receive azacitidine, 6 received the first dose of azacitidine prior to Day +60 (ranging from day +38 to day +60). An additional 4 patients received the first dose of azacitidine when clinically stable (ranging from Day +67 to Day +95), while 1 patient did not receive the drug due to early death from infection following HCT. Following azacitidine administration, thrombocytopenia requiring transfusion (10 x 109/L) was observed in 1 patient; anemia requiring transfusion (Hb 6.4 g/dL) in 1 patient; and transient elevated LFT's > 5 times the upper normal limit in 4 patients which resolved spontaneously. An additional 2 patients developed sustained elevation in LFT's related to GVHD and no further azacitidine was administered. No patients required delays in subsequent cycles by > 4 weeks due to side effects of azacitidine. One patient developed VOD at Day +50 post-HSCT following azacitidine administration and did not receive further cycles of azacitidine. One patient developed Grade 4 acute GVHD and went on to develop severe chronic GVHD. An additional 3 patients developed Grade 2-3 acute GVHD which resolved in two of these. At a median follow up of 8 months, 2 patients had experienced leukemia relapse. All of the 6 patients followed for >6 months achieved T cell reconstitution with CD4 and CD8 counts >200 (Figure 1). Five of these 6 patients achieved CD3 phytohemagglutinin response > 50% of control; one patient did not due to treatment for chronic GVHD. Conclusion Low-dose azacitidine administration is feasible in the post-HSCT setting for pediatric patients with acute leukemia. No severe toxicity directly attributable to azacitidine was observed; the role of azacitidine in the development of late VOD in one patient is unclear. Although transient liver abnormalities and cytopenias were common, low-dose azacitidine appears to be safe in the immediate post-transplant period. Further studies of immunomodulatory effects of azacitidine are required in order to optimize post-HSCT graft alloreactivity and minimize the risk of post-HSCT relapse. Disclosures No relevant conflicts of interest to declare.

Pharmacokinetics and Clinical Activity of Very Low Dose (10mg) Alemtuzumab In Transplantation for Acute Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1275-1275
Author(s):  
Alexandros Spyridonidis ◽  
Maria Liga ◽  
Evangelia Triantafyllou ◽  
Maria Themeli ◽  
Marina Karakantza ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Peak Level ◽  
Clinical Activity ◽  
Pharmacokinetic Studies ◽  
Acute Leukemias ◽  
Median Serum

Abstract Abstract 1275 The impressive safety and efficacy demonstrated with the in vivo use of the rat Campath-1G led to the introduction of the commercially available humanized Campath-1H (alemtuzumab) with the same schedule, i.e. total dose (TD) 100mg and later the TD was reduced to 50mg. However, studies with such high doses of alemtuzumab revealed increased incidence of relapse and severe viral infections. The most probable explanation for the untoward effects seen turned out to be the prolonged half-life of alemtuzumab (15-21 days) as compared to rat Campath-1G (13 hours). Pharmacokinetic studies showed that the peak serum alemtuzumab levels with the 100mg and 50mg schedule were 13700 ng/ml and 2500 ng/ml, respectively. Concentrations remained at high levels >1000 ng/ml at least 4 weeks (TD 100mg) and >500 ng/ml at least 2 weeks (TD 50mg), and thus far above the lymphotoxic levels of 100ng/ml. We report here for the first time pharmacokinetic studies and clinical activity of very low dose alemtuzumab (TD 10mg) in transplantation for acute leukemia. 18 consecutive pts (median age 38y, 20–65) with acute leukemias (AML 12, ALL 6 pts) underwent sibling (39%) or unrelated (61%) allogeneic transplantation and received a TD of only 10 Campath-1H (5mg/d at d-2 and d-1) as part of the conditioning and post-transplant cyclosporine (Cya) without methotrexate. 39% of patients had advanced disease (>CR1) at tranpslant. Conditioning was BuCy=7, TBI/VP16/Cy=4, Flu/BCNU/Thiotepa +/− HD-ARA-C=10. All pts except one received peripheral blood stem cells. All pts engrafted promptly (WBC>1.000/μl on d+14, 11–21 and PLT> 20.000/μl on d+12, 7–27). 17% pts developed grade I skin acute GVHD, 11% VUD-recipients developed steroid-sensible grade II acute GvHD and further 2 (11%) VUD-recipients, who had refractory AML at transplant, developed GvHD III after early Cya discontinuation (d+43, d+95). TRM on d+100 was 0. Cya was stopped at median on d+109 (30-202). Chronic GvHD observed in only 2 patients (1 limited, 1 fulminant and fatal liver GvHD on d+143 in a HbsAg +/+ pair). 72% seropositive patients revealed CMV reactivation but no CMV disease occurred. A median absolute CD4 count higher than 200/μL was reached at 9 months. After a median follow up of 200 days (71-486), 14/18 pts are alive and in CR (Karnofsky 100%) and 4 died (relapse n=1, TRM n=3). Causes of death were liver GvHD, H1N1 infection and post-DLI GvHD. We measured serum alemtuzumab levels in 8 patients (5 AML, 3 ALL) with a sensitive (limit of detection 31.25 ng/ml) ELISA technique (performed at BioAnaLab Ltd, Oxford, UK). A total of 54 samples (median 7 samples/patient) were tested from d-2 (15 minutes after the end of the first infusion of 5mg Campath-1H) up to d+30 after transplantation. The median serum peak level was 176 ng/ml (range 135–281) and was found at day of transplantation (day 0). Alemtuzumab levels declined slowly thereafter reaching a median serum level at d+7 of 78 ng/ml (41-114) and at d+20 just above the detection limit (median 42 ng/ml). Alemtuzumab was still detected only in 1 out of 4 patients at day+30. Campath levels were not influenced by disease (AML vs ALL), body weight or body surface area (r2 test). Taken together, with our administration dose and timing (5mg/d at d-2 and d-1) we achieve the maximum peak level at day of stem cell infusion which is lymphotoxic but still 1–2 log lower as compared with the 100mg and the 50mg schedules. Levels decline fast thereafter and at the time of engraftment nearly no Campath antibody remains in the patient's serum. Such fast clearance of the low dose alemtuzumab may prove beneficial regarding safety and GvL efficacy. Though the follow-up period is still relatively short, the clinical results reported here are very encouraging. Disclosures: No relevant conflicts of interest to declare.

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