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Journal of Hematology & Oncology Nov 2016Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML)....
Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow...
BACKGROUND
Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach.
METHODS
We analyzed long-term outcomes in a cohort of 1423 AML patients, age ≥50 years, after SCT from HLA-matched siblings, during the years 1997-2005, median follow-up 8.3 years (0.1-17).
RESULTS
The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27-35) and 32 % (28-35) after MAC and RIC, respectively (P = 0.57). The 10-year GVHD/ relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18-25) and 21 % (18-24), respectively (P = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65-76) and 73 % (67-78) after MAC and RIC, respectively (P = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC.
CONCLUSIONS
Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.
Topics: Aged; Blood Donors; Cohort Studies; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myeloablative Agonists; Recurrence; Retrospective Studies; Siblings; Transplantation Conditioning
PubMed: 27821187
DOI: 10.1186/s13045-016-0347-1 -
Biology of Blood and Marrow... Nov 2015Myeloproliferative neoplasms (MPN) are chronic marrow disorders with variable prognoses. Most patients with polycythemia vera, essential thrombocythemia, or even primary... (Review)
Review
Myeloproliferative neoplasms (MPN) are chronic marrow disorders with variable prognoses. Most patients with polycythemia vera, essential thrombocythemia, or even primary myelofibrosis (PMF) are successfully treated with conservative strategies for years or even decades, and recent data suggest that even in patients with high-risk disease, in particular those with PMF, life expectancy can be extended by treatment with janus kinase (JAK2) inhibitors. However, none of those modalities are curative, and after marrow failure develops, the disease "accelerates," or transforms to acute leukemia, the only option able to effectively treat and, in fact, cure MPN is allogeneic hematopoietic cell transplantation (HCT). Outcome is superior if HCT is performed before leukemic transformation occurs. Several reports document survival in unmaintained remission beyond 10 years. The most recent analyses show reduced regimen-related mortality (less than 10% or even 5% at day 100) and progressively improved survival with both HLA-identical sibling and unrelated donors. The development of low/reduced-intensity conditioning regimens has contributed to the improved success rate and has allowed successful HCT in patients in their seventh and even eighth decade of life. We propose, therefore, that HCT should be offered to fit patients in these age groups and should be covered by their respective insurance carriers.
Topics: Acute Disease; Adult; Aged; Disease Progression; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Middle Aged; Myeloablative Agonists; Primary Myelofibrosis; Siblings; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Unrelated Donors
PubMed: 26371371
DOI: 10.1016/j.bbmt.2015.09.005 -
Clinical Advances in Hematology &... Oct 2019The significant advances made in the treatment of multiple myeloma (MM) have allowed for a paradigm shift away from the early use of high-dose melphalan with autologous... (Review)
Review
The significant advances made in the treatment of multiple myeloma (MM) have allowed for a paradigm shift away from the early use of high-dose melphalan with autologous stem cell transplant (HDM-ASCT). In 2015 alone, the US Food and Drug Administration (FDA) approved 4 novel drugs for MM. Novel drugs and regimens have shown unprecedented efficacy, which has increased the tempo of new drug development. Furthermore, the FDA recently approved a diagnostic test to detect minimal residual disease (MRD) that will allow community clinicians to conduct real-time testing of MRD. Most importantly, frontline regimens based on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have shown a large clinical benefit. The next era has begun, as several 4-drug combinations that include monoclonal antibodies are being evaluated in clinical trials in the attempt to replace HDM-ASCT in the treatment of MM. We and others have therefore questioned the need for early HDM-ASCT, especially in light of the possible complications. HDM-ASCT is associated not only with acute toxicities-cytopenia, infection, and even death-but also an increased risk of developing secondary cancers. This article discusses the historic context of HDM-ASCT, the modern role of HDM-ASCT given the availability of highly sensitive MRD testing, and the likely future of quadruplet treatment. In summary, patients who attain deep responses using IMiD- and PI-based regimens may not require early HDM-ASCT. A delayed approach to this treatment is acceptable, and might be preferred by patients.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Myeloablative Agonists; Prognosis; Time-to-Treatment; Transplantation Conditioning; Transplantation, Autologous
PubMed: 31730582
DOI: No ID Found -
Frontiers in Immunology 2021Allogenic hematopoietic stem cell transplant (allo-HSCT) can lead to sinusoidal obstruction syndrome (SOS) and graft-versus-host disease (GvHD) in some individuals. GvHD...
Allogenic hematopoietic stem cell transplant (allo-HSCT) can lead to sinusoidal obstruction syndrome (SOS) and graft-versus-host disease (GvHD) in some individuals. GvHD is characterised by an immune triggered response that arises due to donor T cells recognizing the recipient tissue as "foreign". SOS results in impaired liver function due to microvascular thrombosis and consequent obstruction of liver sinusoids. Endothelial damage occurs following chemotherapy and allo-HSCT and is strongly associated with GvHD onset as well as hepatic SOS. Animal models of GvHD are rarely clinically relevant, and endothelial dysfunction remains uncharacterised. Here we established and characterised a clinically relevant model of GvHD wherein Balb/C mice were subjected to myeloablative chemotherapy followed by transplantation of bone marrow (BM) cells± splenic T-cells from C57Bl6 mice, resulting in a mismatch of major histocompatibility complexes (MHC). Onset of disease indicated by weight loss and apoptosis in the liver and intestine was discovered at day 6 post-transplant in mice receiving BM+T-cells, with established GvHD detectable by histology of the liver within 3 weeks. Together with significant increases in pro-inflammatory cytokine gene expression in the liver and intestine, histopathological signs of GvHD and a significant increase in CD4+ and CD8+ effector and memory T-cells were seen. Endothelial activation including upregulation of vascular cell adhesion molecule (VCAM)- 1 and downregulation of endothelial nitric oxide synthase (eNOS) as well as thrombosis in the liver indicated concomitant hepatic SOS. Our findings confirm that endothelial activation is an early sign of acute GvHD and SOS in a clinically relevant mouse model of GvHD based on myeloablative chemotherapy. Preventing endothelial activation may be a viable therapeutic strategy to prevent GvHD.
Topics: Animals; Disease Models, Animal; Endothelial Cells; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloablative Agonists; T-Lymphocytes; Transplantation Conditioning
PubMed: 34421913
DOI: 10.3389/fimmu.2021.708554 -
The Journal of Nutrition Jul 2015Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality....
BACKGROUND
Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive strategies against gut toxicity and the role of diet is unknown.
OBJECTIVE
We hypothesized that the severity of chemotherapy-induced gut toxicity in early life is diet-dependent, and that intake of bovine colostrum (BC) provides better gut protection than an artificial milk replacer (MR).
METHODS
A total of 37 3-d-old pigs received for 6 d either intravenous saline control or myeloablative treatment with busulfan and cyclophosphamide, and were fed either BC or MR, resulting in the following 4 treatments (n = 8-10/group): bovine colostrum plus saline control (Ctr-BC), milk replacer plus saline control (Ctr-MR), bovine colostrum plus busulfan and cyclophosphamide chemotherapy (BUCY-BC), and milk replacer plus busulfan and cyclophosphamide chemotherapy (BUCY-MR). The gut was collected for analysis 11 d after the start of chemotherapy.
RESULTS
Relative to the control groups, both busulfan and cyclophosphamide chemotherapy (BUCY) groups showed signs of gut toxicity, with oral ulcers, reduced intestinal dimensions, and hematologic toxicity. Diet type did not affect mucosal structure on day 11, but BUCY-BC pigs had less vomiting than BUCY-MR pigs (1 of 10 vs. 10 of 10, P < 0.05). Markers of intestinal function were higher (up to 20-fold greater galactose absorption and 2-3-fold greater brush border enzyme activity, all P < 0.05), and tissue inflammatory cytokine concentrations and serum liver enzyme values were lower in BUCY-BC than in BUCY-MR pigs (30-50% reductions in interleukin 6 and 8, aminotransferase, and bilirubin concentrations, P < 0.05). Gut colonization was not significantly affected except that BUCY pigs had lower microbial diversity with a higher abundance of Lactobacilli.
CONCLUSION
BC may reduce gut toxicity during myeloablative chemotherapy in piglets by preserving intestinal function and reducing inflammation. Whether similar effects occur in children remains to be tested.
Topics: Animals; Animals, Newborn; Bilirubin; Busulfan; Cattle; Citrulline; Colostrum; Cyclophosphamide; Diet; Endpoint Determination; Interleukin-6; Interleukin-8; Intestinal Mucosa; Intestines; Microbiota; Myeloablative Agonists; Swine; Transaminases
PubMed: 26019247
DOI: 10.3945/jn.114.203430 -
Biology of Blood and Marrow... Dec 2015Autologous stem cell transplantation (ASCT) after high-dose melphalan conditioning is considered a standard of care procedure for patients with multiple myeloma (MM)....
A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation.
Autologous stem cell transplantation (ASCT) after high-dose melphalan conditioning is considered a standard of care procedure for patients with multiple myeloma (MM). Current formulations of melphalan (eg, Alkeran for Injection [melphalan hydrochloride]; GlaxoSmithKline, Research Triangle Park, NC, USA) have marginal solubility and limited chemical stability upon reconstitution. Alkeran requires the use of propylene glycol as a co-solvent, which itself has been reported to cause such complications as metabolic/renal dysfunction and arrhythmias. EVOMELA (propylene glycol-free melphalan HCl; Spectrum Pharmaceuticals, Inc., Irvine, CA, USA) is a new i.v. melphalan formulation that incorporates Captisol (Ligand Pharmaceuticals, Inc., La Jolla, CA, USA), a specially modified cyclodextrin that improves the solubility and stability of melphalan and eliminates the need for propylene glycol. This new formulation has been shown to be bioequivalent to Alkeran. EVOMELA (200 mg/m(2)) was administered as 2 doses of 100 mg/m(2) each in a phase IIb, open-label, multicenter study to confirm its safety and efficacy as a high-dose conditioning regimen for patients with MM undergoing ASCT. At 5 centers, 61 patients (26 women) with a median age of 62 years (range, 32-73) were enrolled. All patients achieved myeloablation with a median time of 5 days post-ASCT, and all successfully achieved neutrophil and platelet engraftment with median times of 12 days post-ASCT and 13 days post-ASCT, respectively; treatment-related mortality on day 100 was 0%. Overall response rate (according to independent, blinded review) was high (100%), with an overall complete response rate of 21% (13% stringent complete response; 8% complete response) and overall partial response rate of 79% (61% very good partial response; 18% partial response). The incidence of grade 3 mucositis and stomatitis was low (10% and 5%, respectively) with no grade 4 mucositis or stomatitis reported (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events). Based on investigators' assessment of mucositis using the World Health Organization (WHO) oral toxicity scale, 75% of patients had a shift in mucositis score from WHO grade 0 at baseline to a higher grade on study, of which 13% of patients reported WHO grade 3 as the worst post-treatment mucositis over the course of the study; there were no reports of WHO grade 4 mucositis during the study. This study confirms the efficacy and acceptable safety profile of EVOMELA, a new propylene glycol-free melphalan formulation, as a high-dose conditioning regimen for ASCT in patients with MM.
Topics: Adult; Aged; Cyclodextrins; Drug Administration Schedule; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Myeloablative Agonists; Propylene Glycol; Severity of Illness Index; Solubility; Stomatitis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome
PubMed: 26327631
DOI: 10.1016/j.bbmt.2015.08.026 -
Annals of Hematology Jun 2019In the pathway inhibitor era, the number of allogeneic stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL) continues to decrease and this approach...
In the pathway inhibitor era, the number of allogeneic stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL) continues to decrease and this approach should be offered only after careful risk-benefit assessment. Nevertheless, ASCT still remains only curative therapeutic modality for CLL, especially in countries with limited access to novel agents. Thirty patients with CLL at median age of 42 years at diagnosis (range 29-64) underwent ASCT between years 2002 and 2018. Thirteen patients were transplanted in complete remission (CR), ten patients achieved partial response (PR), and seven had stable disease. The median time from diagnosis to transplant was 4 years (range 0.5-12). Twenty-three patients received HLA-matched related donor stem cell grafts, and seven patients received either matched unrelated donor or HLA-mismatched grafts. Reduced intensity conditioning (RIC) and myeloablative regimen (MAC) were used in 24 and 6 patients, respectively. Mortality to day + 100 after transplant was 16% (8% for RIC only). Acute and chronic graft versus host disease (GVHD) developed in 40% and 63% of patients, respectively. Fifteen patients relapsed or progressed after transplant. Thirteen patients (43%) are alive at last follow-up and 10 (77%) remain in clinical CR. Median follow-up for survivors was 6.8 years (range 0.4-15.2). Three-year progression-free and overall survivals were 56% and 60%, respectively. These outcomes were better for patients who received RIC conditioning: 64% and 72%, respectively. CR at transplant was found to have favorable impact on post-allograft survival. RIC should be preferred over MAC. ASCT may remain a valuable option for some CLL patients.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease-Free Survival; Female; Follow-Up Studies; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Myeloablative Agonists; Proportional Hazards Models; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome
PubMed: 30919074
DOI: 10.1007/s00277-019-03679-x -
Transplantation and Cellular Therapy Nov 2021Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in...
Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80 mg/m busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40 mg/m and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% μmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Topics: Aged; Busulfan; Humans; Middle Aged; Myeloablative Agonists; Prospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 34329753
DOI: 10.1016/j.jtct.2021.07.021 -
Journal of Clinical Immunology Jan 2021A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where...
PURPOSE
A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where myeloablation or high donor myeloid chimerism is required to achieve cure. We adapted a busulfan and fludarabine regimen by Gungor et al. for children and young adults undergoing allogeneic HCT for non-CGD primary immune deficiencies requiring myeloablation or high donor myeloid chimerism, and herein report our experience.
METHODS
We retrospectively reviewed records of 41 consecutive patients who underwent allogeneic HCT for Wiskott-Aldrich syndrome (n = 12), primary HLH/XLP (n = 10), CD40L deficiency (n = 7), or other (n = 12) primary immune deficiencies with a conditioning regimen containing pharmacokinetic-guided busulfan dosing which achieved a cumulative AUC between 57 and 74 mg/L × h (65-80% of conventional myeloablative exposure), along with fludarabine and alemtuzumab or anti-thymocyte globulin at 3 transplant centers between 2014 and 2019.
RESULTS
Forty-one patients underwent a first (n = 33) or second (n = 8) allogeneic HCT. Median age was 2.3 years (range, 0.3 years-19.8 years). All but one patient (97.5%) achieved neutrophil recovery at a median of 14 days (range, 11-34 days). One patient developed sinusoidal obstruction syndrome and two patients developed diffuse alveolar hemorrhage. Four patients developed grades II-IV acute GVHD. Three patients developed chronic GVHD. One-year overall survival was 90% (95% confidence interval [CI] 81-99%) and event-free survival was 83% (95% CI 71-94%).
CONCLUSIONS
Our experience suggests that a reduced toxicity busulfan-fludarabine regimen offers low toxicity, low incidence of grades 2-4 GVHD, durable myeloid engraftment, and excellent survival, and may be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.
Topics: Adolescent; Biomarkers; Child; Child, Preschool; Disease Management; Disease Susceptibility; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Myeloablative Agonists; Primary Immunodeficiency Diseases; Prognosis; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome
PubMed: 33067658
DOI: 10.1007/s10875-020-00888-2 -
Biology of Blood and Marrow... Feb 2007Myeloablative high-dose therapy and single autologous stem cell transplantation (HDT) is frequently performed early in the course of multiple myeloma, supported by some... (Meta-Analysis)
Meta-Analysis Review
High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials.
Myeloablative high-dose therapy and single autologous stem cell transplantation (HDT) is frequently performed early in the course of multiple myeloma, supported by some randomized controlled trials (RCTs) indicating overall survival (OS) and progression-free survival (PFS) benefit compared with nonmyeloablative standard-dose therapy (SDT). Other RCTs, however, suggest variable benefit. We therefore undertook a systematic review and meta-analysis of all RCTs evaluating upfront HDT versus SDT in myeloma. The primary objective was to quantify OS benefit with HDT, with PFS benefit a secondary objective. Anticipating heterogeneity, sensitivity and subgroup analyses were undertaken to assess robustness of results. Assessment of harms (treatment-related mortality) was also undertaken. We searched the PubMed, Embase, and Cochrane Collection of Controlled Trials databases using the terms myeloma combined with autologous or transplant or myeloablative or stem cell. In total, 3407 articles were accessed, and 10 RCTs prospectively comparing upfront HDT with SDT, with > or =2-year follow-up, and reporting OS benefit on an intent-to-treat basis were identified. Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (with 95% confidence interval) were determined. Nine studies comprising 2411 patients were fully analyzed. Significant heterogeneity was present. The combined hazard of death with HDT was 0.92 (95% confidence interval, 0.74-1.13). The combined hazard of progression with HDT was 0.75 (95% confidence interval, 0.59-0.96). The totality of the randomized data indicates PFS benefit but not OS benefit for HDT with single autologous transplantation performed early in multiple myeloma. Sensitivity and subgroup analyses supported the findings and indicated that, contrary to current reimbursement criteria, PFS benefit with upfront HDT is not restricted to chemoresponsive myeloma. However, the overall risk of developing treatment-related mortality with HDT was increased significantly (odds ratio, 3.01; 95% confidence interval, 1.64-5.50). Hence, evaluating alternative therapeutic options upfront may also be reasonable.
Topics: Dose-Response Relationship, Radiation; Hematopoietic Stem Cell Transplantation; Humans; Multiple Myeloma; Myeloablative Agonists; Odds Ratio; Randomized Controlled Trials as Topic; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous
PubMed: 17241924
DOI: 10.1016/j.bbmt.2006.09.010