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Bone Marrow Transplantation Jun 2023The optimal reduced intensity conditioning (RIC) regimen is a matter of debate. We retrospectively compared conditioning with fludarabine plus fractionated total body...
Fludarabine/TBI 8 Gy versus fludarabine/treosulfan conditioning in patients with AML in first complete remission: a study from the Acute Leukemia Working Party of the EBMT.
The optimal reduced intensity conditioning (RIC) regimen is a matter of debate. We retrospectively compared conditioning with fludarabine plus fractionated total body irradiation of 8 Gy (FluTBI) and fludarabine plus treosulfan 30, 36 or 42 g/m (FluTreo) in 754 patients with AML above the age of 40 years undergoing an allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR). After balancing patient characteristics by propensity score matching of 115 patients in each group, FluTBI was associated with a significantly lower probability of relapse compared to FluTreo (18.3% vs. 34.7%, p = 0.018) which was counteracted by a higher non-relapse mortality (NRM, 16.8% vs. 5.3%, p = 0.02). Thus, overall survival and graft-versus-host disease-free and relapse-free survival at 2 years were similar between groups (OS 66.9% vs. 67.8%, GRFS 50.3% vs. 45.6%). Univariate analysis by age group demonstrated a higher NRM exclusively in patients ≥55 years of age treated with FluTBI compared to FluTreo (27.6% vs. 5.8%, p = 0.02), while a similarly low NRM was observed in patients <55 years in both groups (6.0% vs. 4.7%, p = ns). We conclude that both conditioning regimens are effective and safe, but FluTBI may better be reserved for younger patients below the age of 55 years.
Topics: Humans; Adult; Middle Aged; Retrospective Studies; Whole-Body Irradiation; Busulfan; Leukemia, Myeloid, Acute; Acute Disease; Vidarabine; Recurrence; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease
PubMed: 37002412
DOI: 10.1038/s41409-023-01965-x -
Health Technology Assessment... Oct 2010This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment... (Review)
Review
The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche.
This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission's evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to modelling was reasonable and the sources and justification of estimates were generally sound. The base-case analysis produced an incremental cost-effectiveness ratio (ICER) of 13,189 pounds per quality-adjusted life-year (QALY) for R-FC versus FC, and 6422 pounds per QALY for the comparison of R-FC versus chlorambucil, suggesting that R-FC is cost-effective at normal willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from 10,249 pounds to 22,661 pounds per QALY for R-FC versus FC, and 5612 pounds and 6921 pounds per QALY for R-FC versus chlorambucil. Probabilistic sensitivity analysis results matched the deterministic results very closely. However, the sensitivity analysis did not fully investigate the uncertainty associated with differential values across arms or with the structural assumptions of the model, and utility values were not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.
Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Randomized Controlled Trials as Topic; Rituximab; United Kingdom; Vidarabine
PubMed: 21047488
DOI: 10.3310/hta14suppl2/04 -
Current Allergy and Asthma Reports Nov 2019Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments... (Review)
Review
PURPOSE OF REVIEW
Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID.
RECENT FINDINGS
Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far. Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.
Topics: Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Primary Immunodeficiency Diseases; Transplantation Conditioning; Vidarabine
PubMed: 31741098
DOI: 10.1007/s11882-019-0883-1 -
Bulletin Du Cancer Aug 2002The drugs concerned by this review are cytarabine (ara-C), gemcitabine and fludarabine. Seventy-eighty per cent of a dose of ara-C are excreted under the form of ara-U... (Review)
Review
The drugs concerned by this review are cytarabine (ara-C), gemcitabine and fludarabine. Seventy-eighty per cent of a dose of ara-C are excreted under the form of ara-U (main metabolite). Plasma concentrations of ara-C are not related to drug pharmacodynamics (response to treatment) in contrast to intracellular levels of ara-CTP (active metabolite) which are associated with cytotoxic activity. Gemcitabine is able to autoactivate its own mechanism of action. Gemcitabine is characterized by a short half-life of elimination (15-20 min) and plasma pharmacokinetics of the drug are not linked to pharmacodynamics. Prolonged administration of gemcitabine is pharmacokinetically and pharmacologically justified and should deserve more intense clinical investigations. Total body clearance of F-ara-A (main circulating metabolite of fludarabine) is linked to creatinine clearance and drug-related neutropenia are more frequent in patients with creatinine clearance below 50 mL/min. So far there are no relationships between intracellular levels of F-ara-CTP and response to treatment.
Topics: Antimetabolites; Antimetabolites, Antineoplastic; Biotransformation; Cytarabine; Cytidine Deaminase; DCMP Deaminase; Deoxycytidine; Deoxycytidine Kinase; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Neoplasm Proteins; Phosphorylation; Prodrugs; Vidarabine; Gemcitabine
PubMed: 12449033
DOI: No ID Found -
American Journal of Hematology Feb 2015We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165... (Comparative Study)
Comparative Study
We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow-up of 61 months, median event-free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse.
Topics: Adult; Analysis of Variance; Antineoplastic Agents; Cyclophosphamide; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Vidarabine
PubMed: 25345651
DOI: 10.1002/ajh.23875 -
Biology of Blood and Marrow... Nov 2019Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal... (Clinical Trial)
Clinical Trial
Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12 Gy of total-body irradiation was demonstrated in 30 patients. We now present long-term outcome results, including an additional 52 patients, now with 47 months (16 to 96) median follow-up. Median patient age was 42 (19 to 61) years. The most common diagnoses were acute myelogenous leukemia (51%) and acute lymphoblastic leukemia (33%), and 39% had a high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3 to 4 acute graft-versus-host disease (GVHD) and moderate to severe chronic GVHD occurred in 17% and 23%, respectively. Nonrelapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-year overall survival (OS), disease-free survival, and cumulative incidence of relapse (CIR) were 67%, 60%, and 27%, respectively. CIR was significantly higher in patients with high/very high- versus low/intermediate-risk DRI (38% versus 20%, P= .032), which led to inferior 4-year OS (50% versus 77%, P = .001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-free, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57%, and 60%, respectively. This approach to MAC HIDT results in universal engraftment; low rates of NRM, infection, and clinically significant GVHD; and relatively rapid IST discontinuation, resulting in high rates of CGRFS and survival.
Topics: Acute Disease; Adult; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Hematologic Neoplasms; Humans; Male; Middle Aged; Recurrence; Retrospective Studies; Survival Rate; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation
PubMed: 31247313
DOI: 10.1016/j.bbmt.2019.06.017 -
Nefrologia : Publicacion Oficial de La... 2001
Topics: Adrenal Cortex Hormones; Animals; Antibodies, Monoclonal; Bone Marrow Transplantation; CD40 Ligand; Cladribine; Drug Administration Schedule; Drug Therapy, Combination; Forecasting; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Oligonucleotides; Plasmapheresis; Vidarabine
PubMed: 11881420
DOI: No ID Found -
Transplantation and Cellular Therapy Sep 2021Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients.... (Observational Study)
Observational Study
Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy.
Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients. The optimal exposure of these agents remains to be determined. We aimed to delineate the exposure-outcome associations of Flu and Cy separately and then both combined on HCT outcomes. This is a single-center, observational, pharmacokinetic (PK)-pharmacodynamic (PD) study of Flu and Cy in HCT recipients age ≥18 years who received Cy (50 mg/kg in a single dose), Flu (150 to 200 mg/m given as 5 daily doses), and total body irradiation (TBI; 200 cGy). We measured trough concentrations of 9-β-D-arabinosyl-2-fluoradenine (F-ara-A), an active metabolite of Flu, on days -5 and -4 (F-ara-A and F-ara-A, respectively), and measured phosphoramide mustard (PM), the final active metabolite of Cy, and estimated the area under the curve (AUC). The 89 enrolled patients had a nonrelapse mortality (NRM) of 9% (95% confidence interval [CI], 3% to 15%) at day +100 and 15% (95% CI, 7% to 22%) at day +180, and an overall survival (OS) of 73% (95% CI, 63% to 81%) at day +180. In multivariate analysis, higher PM area under the curve (AUC) for 0 to 8 hours (PM AUC) was an independent predictor of worse NRM (P < .01 at both day +100 and day +180) and worse day +180 OS (P < .01), but no associations were identified for F-ara-A trough levels. We observed lower day +100 NRM in those with both high F-ara-A trough levels (≥40 ng/mL; >25th percentile) and low PM AUC (<34,235 hr ng/mL; <75th percentile), compared with high exposures to both agents (hazard ratio, 0.06; 95% CI, 0.01 to 0.48). No patients with low F-ara-A (<40 ng/mL; <25th percentile) had NRM by day +100, regardless of PM AUC. The interpatient PK variability was large in F-ara-A trough and PM AUC (29-fold and 5.0-fold, respectively). Flu exposure alone was not strongly associated with NRM or OS in this reduced Flu dose regimen; however, high exposure to both Flu and Cy was associated with a >16-fold higher NRM. These results warrant further investigation to optimize reduced-intensity regimens based on better PK-PD understanding and possible adaptation to predictable factors influencing drug clearance.
Topics: Adolescent; Adult; Cyclophosphamide; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Vidarabine
PubMed: 34044184
DOI: 10.1016/j.jtct.2021.05.013 -
Bulletin Du Cancer Mar 2005Chronic lymphocytic leukemia follows an extremely variable clinical course with survival range from months to decades. Some patients present minimal symptoms and others... (Review)
Review
Chronic lymphocytic leukemia follows an extremely variable clinical course with survival range from months to decades. Some patients present minimal symptoms and others organomegaly requiring rapidly therapy. Therapeutic options take into account efficacy, toxicity and prognostic factors. One of the well known prognosis factor is the clinical staging developed either by Rai et al. or by Binet et al. However, there is an important heterogeneity concerning the course of the disease among patients within a single stage group. Recently, several important observations related to the biologic significance of VH gene mutational status, expression of CD38, over-expression of ZAP-70 and chromosomal aberrations have led to the ability to identify high risk patients with rapid disease progression and lower survival. It has been demonstrated that the VH mutation status is clinically highly relevant. CLL patients with unmutated VH gene show an unfavourable course with a very rapid progression. Specific genomic aberrations have been associated with disease characteristics such as lymphadenopathy related to 11q deletion and resistance to treatment related to 17p deletion. VH gene mutation status and genomic aberrations appear separate parameters when considering their prognostic relevance but nevertheless they are correlated: unfavourable aberrations (11q- and 17p-) occur more frequently in VH unmutated CLL patients. According to these prognostic factors, several treatments including purine analogues and/or monoclonal antibodies have been tested with different schedules and doses of monoclonal antibodies (rituximab and alemtuzumab) considering safety to determine the better efficacy. Infections and haemolytic anemia remain the most frequent complications during conventional chemotherapy. In autologous transplant setting, the transplant related mortality is less than 10%, but survival curve do not show a plateau with about 50% of patients relapsing at 4 years. Conventional allogeneic transplantation could achieve durable remission and probably cure the disease but at the price of a too high transplant related mortality related to depressive immune status and old age of CLL population. In order to minimize the toxicity and to improve graft-versus-leukemia effect, development of reduced intensity conditioning (RIC) regimens appear particularly important for CLL patients. Recent studies, although a still short follow-up show very promising results and use of monoclonal antibodies in the conditioning or just after transplant could improve the results of allogeneic stem cell transplantation and cure a larger number of CLL patients. Recent advances to categorize CLL patients according to risk stratification regarding new prognostic factors (FISH, CD38, ZAP70, Ig mutational status) should allow to define better the best therapeutic strategy. In parallel, age, co morbidities and the notion of the risk-adapted strategy have also an important impact adding.
Topics: Age Factors; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease Progression; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis; Vidarabine
PubMed: 15820919
DOI: No ID Found -
Blood Advances Jul 2022The reduced-intensity conditioning regimen, fludarabine and melphalan, is frequently used in allogeneic hematopoietic stem cell transplantation (HSCT). Melphalan and the...
The reduced-intensity conditioning regimen, fludarabine and melphalan, is frequently used in allogeneic hematopoietic stem cell transplantation (HSCT). Melphalan and the active metabolite of fludarabine, F-ara-A, are excreted via the kidneys. Existing methods to assess clearance in this setting are based on serum creatinine, which has known limitations for glomerular filtration rate (GFR) estimation in patients with malignancy. Measured GFR (mGFR) may better predict drug dosing to mitigate toxicity and increase the chances of successful engraftment. The primary objective of this study was to assess the association between mGFR and risk for nonrelapse mortality (NRM) in patients who have undergone allogeneic HSCT receiving conditioning with fludarabine and melphalan. In the 109 included patients, mGFR <65 mL/min/1.73 m2 predicted a significantly higher rate of overall NRM (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.35; P = 04) and 1-year incidence of infection (HR, 2.63; 95% CI, 1.54-4.55; P < .001) in addition to a significantly lower 2-year survival (P = .019). Kidney function estimated via estimated GFR (eGFR) and estimated creatinine clearance did not correlate with posttransplant outcomes. These results suggest that mGFR is a promising approach for assessing clearance in patients who have undergone allogeneic HSCT and may be preferred to standard creatinine-based eGFR strategies.
Topics: Creatinine; Graft vs Host Disease; Humans; Iothalamic Acid; Melphalan; Retrospective Studies; Vidarabine
PubMed: 35522968
DOI: 10.1182/bloodadvances.2021006395