Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 3080-3088 ◽  
Author(s):  
Ronjon Chakraverty ◽  
Guillermo Orti ◽  
Michael Roughton ◽  
Jun Shen ◽  
Adele Fielding ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Immune Reconstitution ◽  
Human Leukocyte ◽  
Compartment Model ◽  
Allogeneic Transplantation ◽  
Pharmacokinetic Studies ◽  
Reduced Intensity Conditioning ◽  
Total N ◽  
Reduced Intensity

Abstract In vivo alemtuzumab reduces the risk of graft-versus-host disease (GVHD) and nonrelapse mortality after reduced intensity allogeneic transplantation. However, it also delays immune reconstitution, leading to frequent infections and potential loss of graft-versus-tumor responses. Here, we tested the feasibility of alemtuzumab dose deescalation in the context of fludarabine-melphalan conditioning and human leukocyte antigen (HLA)–identical sibling transplantation. Alemtuzumab was given 1-2 days before graft infusion, and dose reduced from 60 mg to 20 mg in 4 sequential cohorts (total n = 106). Pharmacokinetic studies were fitted to a linear, 2-compartment model in which dose reduction led to incomplete saturation of CD52 binding sites and greater antibody clearance. Increased elimination was particularly evident in the 20-mg group in patients who had CD52-expressing tumors at time of transplantation. The 20-mg dose was also associated with greater risk of severe GVHD (acute grade III-IV or chronic extensive) compared with > 20 mg (hazard ratio, 6.7; 95% CI, 2.5-18.3). In contrast, dose reduction to 30 mg on day −1 was associated with equivalent clinical outcomes to higher doses but better lymphocyte recovery at 12 months. In conclusion, alemtuzumab dose reduction to 30 mg is safe in the context of reduced intensity conditioning and HLA-identical sibling transplantation. This trial was registered at http://www.ncrn.org.uk as UKCRN study 1415.

HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5147-5153 ◽  
Author(s):  
Adam J. Mead ◽  
Kirsty J. Thomson ◽  
Emma C. Morris ◽  
Sajir Mohamedbhai ◽  
Shari Denovan ◽  
...  
Keyword(s):  
Human Leukocyte ◽  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Unrelated Donors ◽  
Uniform Conditioning ◽  
The Impact ◽  
Reduced Intensity ◽  
Related Mortality

Abstract The impact of human leukocyte antigen (HLA) mismatch after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIT) using unrelated donors (UD) is unclear, and may be modulated by T-cell depletion. We therefore examined outcomes of 157 consecutive patients undergoing RIT after uniform conditioning with fludarabine, melphalan, and alemtuzumab (FMC). Donors were 10/10 HLA-matched (MUDs, n = 107) and 6 to 9/10 HLA-matched (MMUDs, n = 50), with no significant differences in baseline characteristics other than increased cytomegalovirus seropositivity in MMUDs. Rates of durable engraftment were high. Graft failure rates (persistent cytopenias with donor chimerism) were similar (8% vs 3%, P = .21), though rejection (recipient chimerism) was more frequent in MMUDs (8% vs 0%, P < .01). There were no significant differences between donors in the incidences of acute graft-versus-host disease (GVHD; 20% vs 22% grade 2-4, respectively, P = .83), chronic extensive GVHD (3-year cumulative incidence [CI] 23% vs 24%, P = .56), or treatment-related mortality (1-year CI 27% vs 27%, P = .96). Furthermore, there was no difference in 3-year overall survival (OS; 53% vs 49%, P = .44). Mismatch occurred at the antigenic level in 40 cases. The outcome in these cases did not differ significantly from the rest of the cohort. We conclude that RIT using HLA-mismatched grafts is a viable option using FMC conditioning.

A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3591-3593 ◽  
Author(s):  
Laura Rosiñol ◽  
José Antonio Pérez-Simón ◽  
Anna Sureda ◽  
Javier de la Rubia ◽  
Felipe de Arriba ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Complete Remission ◽  
Autologous Transplantation ◽  
Human Leukocyte ◽  
Progression Free Survival ◽  
Allogeneic Transplantation ◽  
High Morbidity ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Reduced Intensity

One hundred ten patients with multiple myeloma (MM) failing to achieve at least near-complete remission (nCR) after a first autologous stem cell transplantation (ASCT) were scheduled to receive a second ASCT (85 patients) or a reduced-intensity-conditioning allograft (allo-RIC; 25 patients), depending on the human leukocyte antigen (HLA)–identical sibling donor availability. There was a higher increase in complete remission (CR) rate (40% vs 11%, P = .001) and a trend toward a longer progression-free survival (PFS; median, 31 months vs not reached, P = .08) in favor of allo-RIC. In contrast, it was associated with a trend toward a higher transplantation-related mortality (16% vs 5%, P = .07), a 66% chance of chronic graft-versus-host disease and no statistical difference in event-free survival and overall survival. Although the PFS plateau observed with allo-RIC is very encouraging, this procedure is associated with high morbidity and mortality, and therefore it should still be considered investigational and restricted to well-designed prospective clinical trials. This trial is registered at ClinicalTrials.gov ID number NCT00560053

Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 404-406 ◽  
Author(s):  
Emma C. Morris ◽  
Peppy Rebello ◽  
Kirsty J. Thomson ◽  
Karl S. Peggs ◽  
Charalampia Kyriakou ◽  
...  
Keyword(s):  
T Cell ◽  
Adoptive Immunotherapy ◽  
Immune Reconstitution ◽  
Infectious Complications ◽  
Reduced Intensity Conditioning ◽  
Cd4 Counts ◽  
Graft Versus Leukemia ◽  
Reduced Intensity

Abstract Persistence of alemtuzumab at lympholytic concentrations after reduced-intensity conditioning allogeneic stem cell transplantations (RITs) could impair immune reconstitution and reduce donor T-cell–mediated graft-versus-leukemia/lymphoma (GVL) effects, derived from the graft or subsequent adoptive immunotherapy. We have studied the pharmacokinetics of alemtuzumab in 2 different groups: RIT (100 mg alemtuzumab in vivo over 5 days) and myeloablative allografts (20 mg alemtuzumab added in vitro to the stem cells prior to return). Alemtuzumab concentrations in RIT patients were in excess of that required to kill infused donor CD52+ cells at the time of transplantation and remained at potentially lympholytic levels (&gt; 0.1 μg/mL) for approximately 56 days after transplantation, 26 days longer than for the myeloablative group. Total lymphocyte counts were significantly lower in the RIT group persisting beyond 6 months after transplantation (P = .005), and median absolute CD4 counts higher than 200 × 106/L were delayed until 9 months after transplantation. (Blood. 2003;102:404-406)

Allogeneic Stem-Cell Transplantation Using a Reduced-Intensity Conditioning Regimen Has the Capacity to Produce Durable Remissions and Long-Term Disease-Free Survival in Patients With High-Risk Acute Myeloid Leukemia and Myelodysplasia

2005 ◽  
Vol 23 (36) ◽  
pp. 9387-9393 ◽  
Author(s):  
Sudhir Tauro ◽  
Charles Craddock ◽  
Karl Peggs ◽  
Gulnaz Begum ◽  
Premini Mahendra ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Purpose The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural. Patients and Methods Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years). Results The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation. Conclusion The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.

scholarly journals Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens

2006 ◽  
Vol 135 (3) ◽  
pp. 367-373 ◽  
Author(s):  
Mats Merup ◽  
Vladimir Lazarevic ◽  
Hareth Nahi ◽  
Björn Andreasson ◽  
Claes Malm ◽  
...  
Keyword(s):  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Conditioning Regimens ◽  
Reduced Intensity
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