Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

Besien, Koen van; Artz, Andrew S.; Smith, Sonali M.; Cao, David; Rich, Shayna E.; Godley, Lucy A.; Jones, D. Breese; Cerro, Paula del; Bennett, Diane; Casey, B.; Odenike, Olatoyosi; Thirman, Michael J.; Daugherty, C. K.; Wickrema, Amittha; Zimmerman, Todd; Larson, Richard A.; Stock, Wendy

doi:10.1200/jco.2005.15.602

Cited by 135 publications

(96 citation statements)

References 60 publications

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“…However, formal analysis of these comorbidities on transplant outcome is rarely performed. 19,21,33 The HCT-CI was specifically developed for use in recipients of HSCT whereby it showed an improved predictive value in identifying patients receiving myeloablative and nonmyeloablative HSCT who had a subsequent inferior NRM and survival. 19 There is, however, a lack of data on the use of comorbidity scores in the T-cell-depleted allo-HSCT setting.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, in patients with high-risk disease MDS or AML undergoing RIC HSCT, patients with an HCT-CI of X3 had a 2-year OS of only 29%. 20 Various groups have used in vivo T-cell depletion with either alemtuzumab (Campath-1H) or anti-thymocyte globulin to lower the incidence of both acute GVHD (aGVHD) and chronic GVHD (cGVHD) 6,[21][22][23][24][25] with the aim of reducing NRM.…”

Section: Introductionmentioning

confidence: 99%

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Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML

Lim

Ingram

Brand

et al. 2009

Bone Marrow Transplant

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We report a retrospective analysis of 128 consecutive patients with high-risk myelodysplastic syndrome (MDS) and AML who received an alemtuzumab-based reducedintensity conditioning hematopoietic SCT (RIC HSCT). The median recipient age was 53 years (range 21-72 years). A total of 49 (38%) recipients had a sibling donor and 79 (62%) had a volunteer-unrelated donor. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was assigned to all patients with a score of 0 in 40 (31%), of 1-2 in 45 (35%) and X3 in 43 (34%) patients. The 3-year non-relapse mortality (NRM) was 31%, disease-free survival (DFS) was 41% and overall survival (OS) was 46%. The 3-year NRM for patients with a HCT-CI score of 0, 1-2 or X3 was 16, 24 and 42%, respectively. The 3-year DFS and OS by HCT-CI was 58 and 69% (score 0), 39 and 39% (score 1-2) and 24 and 32% (score X3), respectively. On multivariate analysis, HCT-CI was an independent variable affecting 3-year NRM, DFS and OS (P-value ¼ 0.04, 0.01 and o0.01, respectively). Although the disease stage at the time of transplant was an additional independent predictive variable on transplant outcomes, recipient age (4/o50 years) did not have a significant predictive impact. In MDS or AML patients with advanced disease receiving alemtuzumab-based RIC HSCT, the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML

Lim

Ingram

Brand

et al. 2009

Bone Marrow Transplant

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“…5,6 Allo-SCT following reduced-intensity conditioning (RIC) is being increasingly used as treatment for patients with AML who are too old or too frail to tolerate high-dose conditioning regimens. [7][8][9][10][11][12][13][14][15][16][17][18][19] The goal of RIC allo-SCT is to harness the GVL effect, 7 while minimizing toxicities and the risk of GVHD. However, this is a delicate balance as a number of prior studies have shown a lower risk of relapse in AML patients who experienced chronic GVHD after RIC allo-SCT compared with those patients who did not, [10][11][12]20,21 while some other studies failed to find such an association.…”

Section: Introductionmentioning

confidence: 99%

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation

et al. 2012

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This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR) ¼ 0.7, P ¼ 0.02) translating into a trend for better overall survival (OS; HR ¼ 1.3; P ¼ 0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR ¼ 0.4, Po0.0.001) owing to high risk of nonrelapse mortality (NRM; HR ¼ 5.2, Po0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR ¼ 0.72; P ¼ 0.07) translating into a better OS (HR ¼ 1.8; Po0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR ¼ 0.65; P ¼ 0.02) but also with higher NRM (HR ¼ 3.5; Po0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (Po0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR ¼ 0.65; P ¼ 0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD.

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“…Alternatively, post transplant manipulation has been attempted, such as immune modulation with donor lymphocyte infusions or anti-leukemic therapy with hypomethylating agents. 7 Lower disease burden before HCT strongly correlates with improved outcome; 5,6,8,9 however, it is unknown if further cytotoxic salvage therapy before HCT improves outcomes or simply selects for chemosensitive patients. Prolonged pre-HCT treatment may lead to considerable toxicity and delay or eventually preclude HCT.…”

Section: Introductionmentioning

confidence: 99%

“…4 Reduced intensity conditioning has fewer treatment-related complications, but is associated with even higher rates of recurrence in those with residual disease burden at the time of conditioning. 5,6 Multiple strategies have been considered to improve outcomes for patients with relapsed/refractory disease. The HCT regimen may be re-intensified by adding agents with limited extramedullary and non-overlapping toxicities.…”

Section: Introductionmentioning

confidence: 99%

Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML

Locke

Artz

Rich

et al. 2010

Bone Marrow Transplant

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To control disease before allogeneic hematopoietic cell transplantation (HCT) for relapsed/refractory AML, we used clofarabine cytoreduction. Seventeen patients received clofarabine 30-40 mg/m 2 i.v. daily for 5 days with plans to initiate conditioning during the nadir, 14 days later. Bone marrow biopsy 12 days after clofarabine showed effective cytoreduction (that is,o20% cellularity with o10% blasts) in 10 of 17 patients (59%). Ineffective cytoreduction correlated with lower PFS (3.8 vs 6.4 months; HR ¼ 2.7, 95% CI ¼ 1.10-14.29, P ¼ 0.035) and OS (5.1 vs 16.6 months; HR ¼ 2.5, 95% CI ¼ 0.98-12.17, P ¼ 0.053). Significant toxicities before HCT, attributable to clofarabine, were grade 1-2 hyperbilirubinemia (18%); grade 1-2 (59%) or grade 3-4 (18%) transaminitis; and grade 1-2 (18%) creatinine elevation. Sixteen patients proceeded to HCT infusion 22 days (median) after initiation of clofarabine. Day 100 and 2-year transplant-related mortality were 6 and 36%. Nine patients relapsed. One year PFS and OS were 25 and 38%, respectively. Two patients are alive in remission at 18 and 52 months. Clofarabine cytoreduction followed by immediate HCT is feasible with acceptable toxicity and TRM. Outcomes for this cohort of patients with refractory AML remain poor and we are studying this approach in a prospective manner.

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Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

Cited by 135 publications

References 60 publications

Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML

Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation

Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML

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