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• W2000745246 abstract "Reduced-intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative conditioning. We prospectively analyzed the outcomes of 123 patients (median age, 57 years; range, 23-70 years) with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total-body irradiation (200 cGy) with or without antithymocyte globulin followed by related donor allogeneic HCT at the University of Minnesota between 2002 and 2008. The cohort included 45 patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 27 with aggressive non-Hodgkin lymphoma (NHL), 8 with indolent NHL, 10 with Hodgkin lymphoma (HL), 10 with myeloma, and 23 with acute lymphocytic leukemia, chronic myelogenous leukemia, other leukemias, or myeloproliferative disorders. The probability of 4-year overall survival was 73% for patients with indolent NHL, 58% for those with aggressive NHL, 67% for those with HL, 30% for those with AML/MDS, and only 10% for those with myeloma. Corresponding outcomes for relapse in these patients were 0%, 32%, 50%, 33%, and 38%, and those for progression-free survival were 73%, 45%, 27%, 27%, and 10%. The incidence of treatment-related mortality was 14% at day +100 and 22% at 1 year. The incidence of grade II-IV acute graft-versus-host disease was 38% at day +100, and that of chronic graft-versus-host disease was 50% at 2 years. Multivariate analysis revealed superior overall survival and progression-free survival in patients with both indolent and aggressive NHL compared with those with AML/MDS, HL, or myeloma. Worse 1-year treatment-related mortality was observed in patients with a Hematopoietic Cell Transplantation Comorbidity Index score ≥3 and in cytomegalovirus-seropositive recipients. These results suggest that (1) RIC conditioning was well tolerated by an older, heavily pretreated population; (2) patients with indolent and aggressive NHL respond well to RIC conditioning, highlighting the importance of the graft-versus-lymphoma effect; and (3) additional peri-transplantation manipulations are needed to improve outcomes for patients with AML/MDS or myeloma receiving RIC conditioning before HCT. Reduced-intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative conditioning. We prospectively analyzed the outcomes of 123 patients (median age, 57 years; range, 23-70 years) with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total-body irradiation (200 cGy) with or without antithymocyte globulin followed by related donor allogeneic HCT at the University of Minnesota between 2002 and 2008. The cohort included 45 patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 27 with aggressive non-Hodgkin lymphoma (NHL), 8 with indolent NHL, 10 with Hodgkin lymphoma (HL), 10 with myeloma, and 23 with acute lymphocytic leukemia, chronic myelogenous leukemia, other leukemias, or myeloproliferative disorders. The probability of 4-year overall survival was 73% for patients with indolent NHL, 58% for those with aggressive NHL, 67% for those with HL, 30% for those with AML/MDS, and only 10% for those with myeloma. Corresponding outcomes for relapse in these patients were 0%, 32%, 50%, 33%, and 38%, and those for progression-free survival were 73%, 45%, 27%, 27%, and 10%. The incidence of treatment-related mortality was 14% at day +100 and 22% at 1 year. The incidence of grade II-IV acute graft-versus-host disease was 38% at day +100, and that of chronic graft-versus-host disease was 50% at 2 years. Multivariate analysis revealed superior overall survival and progression-free survival in patients with both indolent and aggressive NHL compared with those with AML/MDS, HL, or myeloma. Worse 1-year treatment-related mortality was observed in patients with a Hematopoietic Cell Transplantation Comorbidity Index score ≥3 and in cytomegalovirus-seropositive recipients. These results suggest that (1) RIC conditioning was well tolerated by an older, heavily pretreated population; (2) patients with indolent and aggressive NHL respond well to RIC conditioning, highlighting the importance of the graft-versus-lymphoma effect; and (3) additional peri-transplantation manipulations are needed to improve outcomes for patients with AML/MDS or myeloma receiving RIC conditioning before HCT. Allogeneic hematopoietic cell transplantation (HCT) is standard therapy for a wide range of hematologic malignancies. Advanced age, medical comorbidities, and previous treatment history can preclude the use of more toxic myeloablative conditioning and limit the applicability of this potentially curative therapy. Consequently, reduced-intensity conditioning (RIC) regimens have been developed to limit transplantation-related mortality (TRM) and broaden the use of HCT. RIC regimens have the added benefits of shorter duration of neutropenia and thrombocytopenia, decreased hospitalization time, and potential improvements in long-term survival due to decreased TRM. Previous studies have suggested that outcomes with RIC are affected by underlying disease type, disease stage at transplantation, comorbidity, and the degree of reduced conditioning intensity [1Martino R. Iacobelli S. Brand R. et al.Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes.Blood. 2006; 108: 836-846Crossref PubMed Scopus (296) Google Scholar, 2Martino R. Valcarcel D. Brunet S. et al.Comparable non-relapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission.Bone Marrow Transplant. 2008; 41: 33-38Crossref PubMed Scopus (58) Google Scholar, 3Shimoni A. Hardan I. Shem-Tov N. et al.Allogeneic hematopoietic stem cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: long-term follow-up.Leukemia. 2010; 24: 1050-1052Crossref PubMed Scopus (39) Google Scholar, 4Alyea E.P. Kim H.T. Ho V. et al.Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome.Biol Blood Marrow Transplant. 2006; 12: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 5Armand P. Kim H.T. Ho V.T. et al.Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome.Biol Blood Marrow Transplant. 2008; 14: 418-425Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 6Corradini P. Dodero A. Farina L. et al.Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome.Leukemia. 2007; 21: 2316-2323Crossref PubMed Scopus (124) Google Scholar, 7Sorror M.L. Storer B.E. Maloney D.G. et al.Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia.Blood. 2008; 111: 446-452Crossref PubMed Scopus (155) Google Scholar, 8Tomblyn M. Brunstein C. Burns L.J. et al.Similar and promising outcomes in lymphoma patients treated with myeloablative or nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2008; 14: 538-545Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. We report here on our experience with a consistent RIC platform of cyclophosphamide, fludarabine, and low-dose total-body irradiation (TBI), evaluating engraftment and toxicity, and present multiyear follow-up to assess risk of late relapse and long-term survival. All consecutive adult patients (age range, 18-70 years) undergoing RIC allogeneic HCT from adult related donors at the University of Minnesota between 2002 and 2008 were enrolled on this single-center trial and included in the analysis. Disease eligibility criteria included the following: (1) acute myelogenous leukemia (AML), high-risk complete remission (CR) 1 or CR2 or greater; (2) acute lymphoblastic leukemia (ALL), high-risk CR1 or CR2 or greater; (3) chronic myelogenous leukemia (CML), all phases except blast crisis; (4) non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), chronic lymphocytic leukemia or myeloma demonstrating chemosensitive disease; (5) myelodysplastic syndrome (MDS) of all subtypes, with severe pancytopenia or transfusion-dependency and blasts < 5%; and (6) chronic myeloproliferative disorders. To be eligible for this analysis, patients had to be aged ≤70 years with an HLA 5/6 or 6/6 related donor match. Younger patients were enrolled on myeloablative protocols when possible but were eligible if they had evidence of organ dysfunction, were heavily pretreated, or had a recent fungal infection, as described previously [9Brunstein C.G. Barker J.N. Weisdorf D.J. et al.Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease.Blood. 2007; 110: 3064-3070Crossref PubMed Scopus (432) Google Scholar]. Minimum required organ function was cardiac ejection fraction ≥35%, no decompensated heart failure or uncontrolled arrhythmia, CO diffusing capacity ≥30% predicted, no oxygen requirement, serum transaminases <5 upper limit of normal, serum bilirubin <3 upper limit of normal, serum creatinine ≤2 mg/dL or creatinine clearance >40 mL/min, Karnofsky performance status (KPS) >60, mold infections treated and responding after a minimum of 30 days of therapy, and serum albumin >2.5 g/dL. Patients with an active serious infection, previous TBI precluding the use of 200 cGy of TBI, CML in refractory blast crisis, or chemoresistant lymphoma or myeloma were not eligible for enrollment in this trial. Disease status at the time of transplantation was defined as early (CR1, refractory anemia, refractory anemia with ringed sideroblasts, CML chronic phase), intermediate (CR2, partial remission 1, refractory anemia with excess blasts), or advanced (CR3 or greater, partial remission 2 or greater, primary induction failure, minimally responsive or stable disease). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) scores were calculated and assigned retrospectively. Peripheral blood stem cells (PBSCs) were collected after priming with granulocyte-colony stimulating factor 10 μg/kg s.c. daily for 5 days. Donors were collected for 1-3 days with a target CD34+ cell dose of 5 × 106 CD34+ cells per kg of recipient weight. Donors who failed to collect the minimum required cell dose of 2 × 106 CD34+ cells/kg underwent bone marrow harvest, with a target nucleated cell dose of 3 × 108 per kg recipient weight. Grafts were not manipulated and were infused by gravity without line filtration after premedication with acetaminophen and diphenhydramine. Patients receiving ABO-incompatible grafts also received pretransplantation and posttransplantation hydration and red blood cell or plasma depletion as indicated. Conditioning for all patients consisted of fludarabine 40 mg/m2 i.v. on day -6 through day -2 for a total dose of 200 mg/m2 (reduced to 30 mg/m2/day for those with limited renal function, defined as raw creatinine clearance <70 mg/min/m2, and those with previous cranial radiation), cyclophosphamide 50 mg/kg i.v. on day -6, and a single 200-cGy dose of TBI on day -1. Equine antithymocyte globulin (ATG), 15 mg/kg i.v. every 12 hours for 6 doses on days -6, -5, and -4 with methylprednisolone 1 mg/kg, was administered to those not exposed to combination chemotherapy within the preceding 6 months. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine, targeting a trough level of 200-400 ng/mL, and mycophenolate mofetil (MMF) 2-3 g/day, from day -3 up to day +30. Cyclosporine was continued through day +100 and if no evidence of GVHD was seen, was then tapered at a rate of 10% per week. Granulocyte-colony stimulating factor 5 μg/kg was administered beginning on day +1 and continued until the absolute neutrophil count (ANC) was >2.5 × 109/L for 2 consecutive days. Infectious prophylaxis was directed to include antibacterial, antifungal, and antiviral therapies in accordance with institutional guidelines. This study’s primary clinical endpoint was engraftment. Successful sustained engraftment was defined as primary neutrophil recovery by day +42 and 90% donor cells at day +100. Additional endpoints for analysis were overall survival (OS), TRM, relapse, progression-free survival (PFS), donor engraftment, acute GVHD (aGVHD), and chronic GVHD (cGVHD). Safety endpoints were included, defined as the development of severe adverse events totaling ≥30% TRM at day +100. There was continuous monitoring for stopping rules for TRM by day +100. In brief, early termination of the study was defined to occur if the following number of TRM deaths occurred before day +100: 3 of 4, 4 of 6, 5 of 8, 6 of 11, 7 of 13, 8 of 16, and so on, with a type I error rate of 0.05, for a rate of 30% and power of 80% to detect a rate of 50%. Measures of engraftment included neutrophil recovery to an ANC of 0.5 × 109/L for 3 consecutive days and 7 days of untransfused platelet recovery >20 × 109/L. Diagnoses of aGVHD and cGVHD were based on standard clinical criteria, with histopathological confirmation where possible [10Przepiorka D. Weisdorf D. Martin P. et al.1994 consensus conference on acute GVHD grading.Bone Marrow Transplant. 1995; 15: 825-828PubMed Google Scholar, 11Akpek G. Zahurak M.L. Piantadosi S. et al.Development of a prognostic model for grading chronic graft-versus-host disease.Blood. 2001; 97: 1219-1226Crossref PubMed Scopus (168) Google Scholar]. Diagnosis of relapse was based on hematologic, morphologic, and cytogenetic or molecular evaluation. Probabilities of OS and PFS were estimated by the Kaplan-Meier method [12Kaplan E.L. Meier P. Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481Crossref Scopus (48509) Google Scholar]. Cumulative incidence rates and 95% confidence intervals (CIs) were estimated for neutrophil engraftment, relapse, TRM, and GVHD. Non-event deaths (or relapse for TRM) were defined as competing risks [13Lin D.Y. Non-parametric inference for cumulative incidence functions in competing risks studies.Stat Med. 1997; 16: 901-910Crossref PubMed Scopus (369) Google Scholar]. The variables of age, sex, CD34+ cell dose, KPS ≥90, HCT-CI (0-2 vs 3+), cytomegalovirus (CMV) serostatus, disease group, and ATG exposure were considered in multivariate analysis. Statistical comparison of time-to-event curves was completed using a log-rank test. Stem cell and donor source were not included as a variable in multivariate analysis, because nearly all were PBSCs from 6/6 HLA-matched related donors. Previous transplantation was not included in multivariate analysis because the majority were autologous transplantations for lymphoma and a surrogate marker of disease type, and disease stage was not included because of the heterogeneity of diseases and stages at transplantation in our cohort. Cox regression was used for engraftment, survival, and PFS, and the method of Fine and Gray was used in multivariate regression for the competing-risk endpoints relapse, TRM, and GVHD [14Fine J.P. Gray R.J. A proportional hazards model for the subdistribution of a competing risk.J Am Stat Assoc. 1999; 94: 496-509Crossref Scopus (9493) Google Scholar]. Final multivariate models were selected by a backward-stepwise method using variables with P = .20 retained in the model. Because of the small numbers of patients with ALL, myeloproliferative disorders, CML, and “other leukemias,” these subsets were not included in multivariate analysis. Statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). All P values were two-sided. Groups with P values of ≤.05 were considered statistically different. This trial was a prospective clinical study that was reviewed and approved by the Masonic Cancer Center Protocol Review Committee and Human Subjects Institutional Review Board at the University of Minnesota. All patients provided Institutional Review Board–approved informed consent in accordance with the Declaration of Helsinki. The trial was registered at ClinicalTrials.gov (NCT00303719). The study cohort comprised 123 consecutive patients (65% males; median age, 57 years; range, 23-70 years) who underwent allogeneic related RIC HCT for hematologic malignancies (Table 1). AML/MDS (37%) and aggressive NHL (22%) were the most prevalent malignancies; others included indolent lymphomas, HL, myeloma, chronic leukemias, myeloproliferative disorders, and ALL. The median time from diagnosis to HCT was 24 months (range, 2.5-154), and the median duration of follow-up was 2.5 years (range, 0.3-6.6 years). An HCT-CI of 0-2 was seen in 47% of the patients; an HCT-CI 3+ was seen in a majority of the patients who otherwise would have qualified for myeloablative conditioning based on age. Fourteen percent had a previous HCT (3 allogeneic, 14 autologous); PBSCs were used in 96%, 92% had a matched related donor (6/6 HLA-matched), and 8% had a mismatched related donor (5/6 HLA-matched).Table 1Patient CharacteristicsTotal number of patients123Age at treatment, years, median (range)57 (23-70)Age group at treatment, years, n (%) <4010 (8) 40-4919 (15) 50-5955 (45) ≥6039 (32)Sex, n (%) Male80 (65) Female43 (35)Previous HCT, n (%) No106 (86) Yes17 (14)Allogeneic3 (18)Autologous14 (82)Disease group and disease status at HCT, n (%)∗Disease groups: • AML (n = 33) and MDS (n = 12) • Aggressive lymphoma: diffuse large cell (n = 10), other aggressive NHL (n = 12), mantle (n = 4), Burkitt (n = 1) • Other: “other leukemia” (n = 10), CML (n = 4), ALL (n = 3), myeloproliferative disease (n = 6) AML/MDS (early, n = 21; intermediate, n = 14; advanced, n = 10)45 (37) Aggressive NHL (early, n = 2; intermediate, n = 2; advanced, n = 23)27 (22) Indolent NHL (early, n = 1; advanced, n = 7)8 (7) HL, advanced10 (8) Myeloma (intermediate, n = 3; advanced, n = 7)10 (8) Other (early, n = 3; intermediate, n = 16; advanced, n = 4)23 (18)Time from diagnosis to HCT, months, median (range)23.6 (2.5-154)HCT-CI score, n (%) 020 (16) 1-238 (31) 3+65 (53)CD34+ cells × 106/kg, median (range)5.79 (0.64-21.84)ATG use in conditioning, n (%) No93 (76) Yes30 (24)Recipient CMV status, n (%) Negative55 (45) Positive68 (55)CMV status, n (%) D-R-38 (31) D+R-17 (14) D-R+32 (26) D+R+36 (29)Year of HCT, n (%) 2002-200334 (27.5) 2004-200535 (28.5) 2006-200854 (44)Cell source, n (%) Bone marrow†Four of the 5 patients with a bone marrow source had both bone marrow and PBSCs because they did not adequately collect peripherally and required bone marrow harvest to achieve the minimum cell dose.5 (4) PBSCs118 (96)HLA matching, n (%)‡HLA matching: • Matched related includes sibling with 6/6 or 8/8 match (n =112) and cousin with 6/6 match (n = 1). • Related mismatch includes sibling with 5/6 match (n = 9) and offspring mismatched (5/6) (n = 1). Matched related (6/6)113 (92) Mismatched related(5/6)10 (8)Follow-up of survivors, months, median (range)30.6 (3.3-81)HCT indicates hematopoietic cell transplantation; D, donor; R, recipient; M, marrow; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; P, peripheral blood.∗ Disease groups:• AML (n = 33) and MDS (n = 12)• Aggressive lymphoma: diffuse large cell (n = 10), other aggressive NHL (n = 12), mantle (n = 4), Burkitt (n = 1)• Other: “other leukemia” (n = 10), CML (n = 4), ALL (n = 3), myeloproliferative disease (n = 6)† Four of the 5 patients with a bone marrow source had both bone marrow and PBSCs because they did not adequately collect peripherally and required bone marrow harvest to achieve the minimum cell dose.‡ HLA matching:• Matched related includes sibling with 6/6 or 8/8 match (n =112) and cousin with 6/6 match (n = 1).• Related mismatch includes sibling with 5/6 match (n = 9) and offspring mismatched (5/6) (n = 1). Open table in a new tab HCT indicates hematopoietic cell transplantation; D, donor; R, recipient; M, marrow; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; P, peripheral blood. All patients achieved neutrophil recovery by day +42, with a median time to ANC recovery of 8 days (range, 0-15 days). Seventy-five percent (95% CI, 67%-82%) had platelet recovery by day 42, at a median of 16.5 days (range, 0-37 days). At day +100, 110 patients (89.4%) had >90% donor chimerism in the marrow. One patient lost donor engraftment at day 309 with no evidence of recurrent small lymphocytic lymphoma but with marrow morphology and chimerism studies demonstrating recipient-derived MDS. At a median follow-up of 2.5 years (range, 0.3-6.75 years), 64 patients survived, for a 4-year OS of 45% (95% CI, 35%-55%). The underlying diagnosis had a significant affect on OS, with the best survival seen in those with indolent NHL (73%; 95% CI, 28%-93%), HL (67%; 95% CI, 27%-88%), or aggressive NHL (58%; 95% CI, 34%-77%) compared with those with AML/MDS (30%; 95% CI, 14%-47%), or myeloma (10%; 95% CI, 1%-36%) (P ≤ .01) (Figure 1 and Table 2).Table 2One-Year and 4-Year Univariate Outcomes by Disease GroupDisease GroupOS, % (95% CI)PFS, % (95% CI)Relapse, % (95% CI)TRM, % (95% CI),1-Year4-Year1-Year4-Year1-Year4-Year1-YearIndolent NHL (n = 8)88 (39-98)73 (28-93)88 (39-98)73 (28-93)0013 (0-34)Aggressive NHL (n = 27)81 (60-92)58 (34-77)70 (49-84)45 (21-66)15 (2-29)32 (9-54)7 (0-17)HL (n = 10)80 (41-95)67 (27-88)40 (12-67)27 (5-56)50 (19-81)50 (19-81)10 (0-27)AML + MDS (n = 45)51 (35-65)30 (14-47)40 (26-55)27 (13-44)29 (15-43)33 (17-49)28 (14-42)Myeloma (n = 10)40 (12-67)10 (1-36)20 (3-47)10 (1-36)38 (0-48)38 (7-69)34 (4-63)NHL indicates non-Hodgkin lymphoma; HL, Hodgkin lymphoma; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; PFS, progression-free survival; OS, overall survival; CI, confidence interval. Open table in a new tab NHL indicates non-Hodgkin lymphoma; HL, Hodgkin lymphoma; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; PFS, progression-free survival; OS, overall survival; CI, confidence interval. In multivariate analysis, only disease group significantly affected OS. Compared with patients with AML/MDS, survival was better in patients with aggressive NHL (relative risk [RR], 0.41; 95% CI, 0.19-0.89), indolent NHL (RR 0.25; 95% CI, 0.06-1.09), and HL (RR, 0.32; 95% CI, 0.09-1.06) and considerably worse in those with myeloma (RR, 1.69; 95% CI, 0.78-3.65) (P < .01). Interestingly, age and HCT-CI had no impact on OS (Table 3).Table 3Multivariate AnalysisOutcomeFactorRR (95% CI)P ValueOS at 4 yearsDisease groupAML/MDS1.0<.01Aggressive NHL0.41 (0.19-0.89)Indolent NHL0.25 (0.06-1.09)HL0.32 (0.09-1.06)Myeloma1.69 (0.78-3.65)PFS at 4 yearsDisease groupAML/MDS1.00.02Aggressive NHL0.49 (0.25-0.97)Indolent NHL0.26 (0.06-1.10)HL1.14 (0.49-2.63)Myeloma1.87(0.87-4.02)TRM at 1 yearHCT-CI0-21.0.043+2.41 (1.02-5.70)Recipient CMV statusNegative1.0.03Positive2.71 (1.08-6.79)RR indicates relative risk; CI, confidence interval; PFS, progression-free survival; TRM, treatment-related mortality.Only significant outcomes and factors are shown: Relapse at 4 years showed no significant variables and thus is not shown. Variables of age, sex, CD34+ cell dose, KPS, HCT-CI, CMV status, disease group, and ATG exposure were evaluated. Open table in a new tab RR indicates relative risk; CI, confidence interval; PFS, progression-free survival; TRM, treatment-related mortality. Only significant outcomes and factors are shown: Relapse at 4 years showed no significant variables and thus is not shown. Variables of age, sex, CD34+ cell dose, KPS, HCT-CI, CMV status, disease group, and ATG exposure were evaluated. The 4-year PFS for the entire cohort was 29% (95% CI, 20%-38%). Underlying diagnosis was the only feature that significantly affected PFS. Patients with indolent and aggressive NHL had the best 4-year PFS, at 73% (95% CI, 28%-93%) and 45% (95% CI, 21%-66%), respectively (P = .02). In contrast, 4-year PFS was only 27% (95% CI, 5%-56%) for patients those with HL, 27% (95% CI, 13%-44%) for those with AML/MDS, and 10% (95% CI, 1%-36%) for those with myeloma (Table 2). The impact of disease type on 4-year PFS was substantiated in multivariate analysis. Compared with AML/MDS, outcomes were better in indolent and aggressive NHL (RR, 0.26 [95% CI, 0.06-1.10] and 0.49 [95% CI, 0.25-0.97], respectively) and worse in myeloma (RR, 1.87; 95% CI, 0.87-4.02) (P = .02). No other factors in the multivariate analysis had a significant impact on PFS. The 4-year cumulative incidence of relapse for the entire cohort was 36% (95% CI, 25-47%). In univariate analysis, the relapse rate varied depending on the underlying disease. Notably, no patients with indolent NHL relapsed. Patients with AML/MDS, aggressive NHL, and myeloma had similar rates of relapse: 33% (95% CI, 17%-49%), 32% (95% CI, 9%-54%), and 38% (95% CI, 7%-69%), respectively (P = .12). The majority of relapses in patients with AML/MDS and myeloma occurred within the first year, whereas relapses occurred out to 3-4 years in patients with aggressive NHL. Patients with HL had the highest incidence of relapse (50%; 95% CI, 19%-81%), with all relapses occurring within the first year (Figure 2). Multivariate analysis for relapse at 4 years showed no significantly different outcomes based on disease group or any other variable tested, likely related to the timing of relapse within each disease group. Day +100 TRM for the entire cohort was 14% (95% CI, 8%-20%). In univariate analysis, day +100 TRM was 7% (95% CI, 0-13%) for patients with an HCT-CI of 0-2 and 20% (95% CI, 10%-30%) for those with an HCT-CI of 3+ (P = .04). One-year TRM was 22% (95% CI, 14%-29%) for the entire cohort, 13% (95% CI, 2%-25%) for patients with an HCT-CI of 0-2, and 29% (95% CI, 17%-40%) for those with an HCT-CI of 3+ (P = .04) (Figure 3). One-year TRM was only 13% (95% CI, 4%-22%) for CMV-seronegative recipients, compared with 29% (95% CI, 17%-41%) in CMV-seropositive recipients (P = .04). In multivariate analysis, TRM at 1 year was significantly affected by recipient CMV serologic status (RR, 2.71; 95% CI, 1.08-6.79; P = .03 in CMV-seropositive recipients) and by HCT-CI (RR, 2.41; 95% CI, 1.02-5.70; P = .04) in patients with an HCT-CI of 3+). Age, sex, CD34+ cell dose, KPS, ATG exposure, and disease type were included as factors in the multivariate analysis and found to have no significant impact on outcomes (Table 3). At 100 days, the cumulative incidence of aGVHD was 38% (95% CI, 29%-47%) for grade II-IV and 20% (95% CI, 13%-27%) for grade III-IV. Rates of day +100 aGVHD grade II-IV were decreased in more recent years, with an incidence of only 24% (95% CI, 13%-36%) in 2006-2008 versus that of 52% (95% CI, 33%-70%) in 2002-2003 (P = .05). ATG use increased in the latter years; only 6% (n = 2) of patients received ATG in 2002-2003, compared with 31% (n = 11) in 2004-2005 and 31% (n = 17) in 2006-2008. The 6-month cumulative incidence of aGVHD was 47% (95% CI, 37%-56%) for grade II-IV and 26% (95% CI, 18%-34%) for grade III-IV. Interestingly, the previously seen trend of decreased aGVHD in more recent years documented by the day +100 aGVHD rates was no longer present at 6 months post-HCT. The rate of aGVHD was not affected by disease status at transplantation, underlying disease, cell source, or degree of HLA matching (given that the majority of patients were a 6/6 or 8/8 match). The 2-year cumulative incidence of cGVHD was 50% (95% CI, 39%-61%) for the entire cohort. The incidence was 42% (95% CI, 27%-57%) in patients who underwent HCT in 2006-2008, compared with 68% (95% CI, 47%-88%) in those who underwent HCT in 2002-2003 (P = .01). No other factors significantly affected the incidence rate of cGVHD. RIC extends the potentially curative therapy of HCT to older patients or those who would otherwise be ineligible for full myeloablative therapy. We studied a cohort of patients with high-risk advanced hematologic malignancies who received a uniform conditioning regimen and found that (1) RIC was well tolerated by our heavily pretreated cohort of older patients with advanced disease, and low HCT-CI correlated with low TRM; (2) our uniform RIC platform produced successful engraftment and donor chimerism; (3) PFS was significantly affected by primary disease, with superior outcomes seen in patients with indolent and aggressive NHL; and (4) poorer outcomes were seen in patients with myeloid malignancies, HL, and myeloma, highlighting the need for additional peritransplantation manipulations. We found low TRM even in older patients. Similar to younger patients, high HCT-CI score and CMV-seropositive status identified patients at higher risk. In our cohort, the reasonable rates of severe grade III-IV aGVHD and prompt neutrophil engraftment with high donor chimerism at day +100 possibly contributed to the low TRM. Interestingly, neither underlying hematologic malignancy nor disease stage at transplantation (advanced vs early) had a significant affect on TRM. These data support previous findings suggesting that chronological age should not be the primary determining factor for HCT eligibility [15Koreth J. Aldridge J. Kim H.T. et al.Reduced-intensity conditioning hematopoietic stem cell transplantation in patients over 60 years: hematologic malignancy outcomes are not impaired in advanced age.Biol Blood Marrow Transplant. 2010; 16: 792-800Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] and supporting the use of HCT-CI as a powerful prognostic tool. The patterns of outcomes in OS, PFS, and relapse based on underlying hematologic malignancy in our cohort highlight important findings of this study. In disease-specific subsets, we observed trends consistent with the natural history of these diseases and their potential responsiveness to RIC HCT. Patients with indolent and aggressive NHL had promising PFS and encouraging long-term OS despite having been heavily pretreated and some having undergone previous autologous HCT. Our findings in patients with indolent and aggressive NHL compare favorably with other recent analyses [5Armand P. Kim H.T. Ho V.T. et al.Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome.Biol Blood Marrow Transplant. 2008; 14: 418-425Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 6Corradini P. Dodero A. Farina L. et al.Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome.Leukemia. 2007; 21: 2316-2323Crossref PubMed Scopus (124) Google Scholar] and are supported by other studies suggesting that conditioning intensity is less important for disease control in lymphomas and may contribute more to TRM in those patients who undergo HCT with underlying comorbidities [7Sorror M.L. Storer B.E. Maloney D.G. et al.Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia.Blood. 2008; 111: 446-452Crossref PubMed Scopus (155) Google Scholar, 8Tomblyn M. Brunstein C. Burns L.J. et al.Similar and promising outcomes in lymphoma patients treated with myeloablative or nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2008; 14: 538-545Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Our patients with indolent NHL experienced no relapses, perhaps demonstrating the sensitivity of this disease to graft-versus-leukemia (GVL) reactions. Relapses in patients with aggressive NHL were modest and mainly occurred early; however, some later relapses occurred at 3-4 years post-HCT, indicating no relapse plateau in the observation period. Given that the majority of the patients with NHL had advanced disease at the time of HCT, these data underscore the point that patients with these diseases might not require myeloablative conditioning, and support the concept that immunologic eradication of lymphoma might be the precedent for long-term survival. The outcomes in our patients with AML/MDS highlight a very different natural history and responsiveness to GVL. Notably, all of the patients with MDS had low a volume of blasts (<5%), and most of the patients with AML were in CR1 or CR2 at that time of HCT. Despite good disease control at transplantation, relapse rates were substantial, and corresponding PFS and OS were reduced. However, when posttransplantation remission was obtained and maintained for 1-2 years, late relapse was not observed, and extended survival was maintained. These findings suggest that even with optimal disease status at transplantation, GVL might not be adequate to control disease, and conditioning intensity may be a critical factor in patients with certain myeloid malignancies. Numerous nonrandomized studies have addressed the importance of conditioning intensity in patients with myeloid malignancies, with conflicting data reported. Some studies have suggested only a minimal increased benefit from myeloablative conditioning in patients undergoing HCT in CR [1Martino R. Iacobelli S. Brand R. et al.Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes.Blood. 2006; 108: 836-846Crossref PubMed Scopus (296) Google Scholar, 2Martino R. Valcarcel D. Brunet S. et al.Comparable non-relapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission.Bone Marrow Transplant. 2008; 41: 33-38Crossref PubMed Scopus (58) Google Scholar, 3Shimoni A. Hardan I. Shem-Tov N. et al.Allogeneic hematopoietic stem cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: long-term follow-up.Leukemia. 2010; 24: 1050-1052Crossref PubMed Scopus (39) Google Scholar], some have suggested that myeloablative conditioning is important for disease control when undergoing HCT with active disease [4Alyea E.P. Kim H.T. Ho V. et al.Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome.Biol Blood Marrow Transplant. 2006; 12: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar], and still others have suggested that myeloablative conditioning is optimal even in patients in CR or with <5% blasts [16Warlick E.D. Cioc A. Defor T. et al.Allogeneic stem cell transplantation for adults with myelodysplastic syndromes: importance of pretransplantation disease burden.Biol Blood Marrow Transplant. 2009; 15: 30-38Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. Despite the controversy, most studies in the literature stress that when myeloablative conditioning is not an option, RIC is a reasonable alternative that might be associated with slightly higher rates of relapse that are frequently offset by reduced TRM. Comparing these trials is challenging due to heterogeneous patient populations, varying disease burden at transplantation, diversity in the degree of conditioning intensity, and varying follow-up. Randomized trials addressing this question are crucial and are currently in development. Although significant, our 4-year relapse rate of 33% is comparable to rates cited in other studies (21%-61% [1Martino R. Iacobelli S. Brand R. et al.Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes.Blood. 2006; 108: 836-846Crossref PubMed Scopus (296) Google Scholar, 4Alyea E.P. Kim H.T. Ho V. et al.Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome.Biol Blood Marrow Transplant. 2006; 12: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 17Oran B. Giralt S. Saliba R. et al.Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan.Biol Blood Marrow Transplant. 2007; 13: 454-462Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 18Gyurkocza B. Storb R. Storer B.E. et al.Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia.J Clin Oncol. 2010; 28: 2859-2867Crossref PubMed Scopus (179) Google Scholar]) and underscores the need for therapeutic adjustments before and/or after HCT in patients with myeloid malignancies. The rates of severe aGVHD and cGVHD were acceptable and comparable to those reported in previous series [4Alyea E.P. Kim H.T. Ho V. et al.Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome.Biol Blood Marrow Transplant. 2006; 12: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 5Armand P. Kim H.T. Ho V.T. et al.Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome.Biol Blood Marrow Transplant. 2008; 14: 418-425Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 19Aoudjhane M. Labopin M. Gorin N.C. et al.Comparative outcome of reduced-intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT).Leukemia. 2005; 19: 2304-2312Crossref PubMed Scopus (381) Google Scholar]. Interestingly, we observed a decrease in day +100 aGVHD and cGHVD rates in more recent years (2006-2008 compared with 2002-2003). Although supportive care measures did not change significantly between these two periods, and all patients were treated with a uniform conditioning regimen platform, MMF dosing increased from 2 g/day in 2002-2003 to 3 g/day in 2005. ATG use also increased slightly in the 2004-2005 and 2006-2006 periods, possibly due to more defined criteria for use and a slight increase in the number of patients with MDS who underwent HCT during that period. Both MMF dosing and ATG use possibly could explain the decreases in day +100 aGVHD and cGVHD in more recent years. We also observed a slightly higher rate of cGVHD in patients with indolent lymphomas, similar to a previous report [5Armand P. Kim H.T. Ho V.T. et al.Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome.Biol Blood Marrow Transplant. 2008; 14: 418-425Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar], which seemed to correlate with the improved disease control in that cohort. In summary, our platform of RIC was well tolerated in elderly patients, produced successful engraftment, and yielded promising clinical outcomes in patients with indolent and aggressive NHL, but underscores the need for further antitumor approaches in patients with AML/MDS and myeloma. Maintenance therapy posttransplantation with such agents as azacitidine or decitabine for myeloid malignancies [20Jabbour E. Giralt S. Kantarjian H. et al.Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia.Cancer. 2009; 115: 1899-1905Crossref PubMed Scopus (174) Google Scholar, 21de Lima M. Giralt S. Thall P.F. et al.Maintenance therapy with low-dose azacitidine after allogeneic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose- and schedule-finding study.Cancer. 2010; (July 29. Epub)Google Scholar] or rituximab for CD20+ malignancies might further improve these outcomes. Financial disclosure: The authors have nothing to disclose." @default.
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