ABSTRACT
The use of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplantation (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multicenter prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients, treated with either myeloablative conditioning (MAC; n = 40) or reduced-intensity conditioning (RIC; n = 40), with the primary endpoint of 1-year overall survival (OS). The median follow-up for this study was 34 months (range, 12 to 46 months) in the RIC group and 36 months (range, 18 to 49 months) in the MAC group. Three-year OS and nonrelapse mortality were 70% and 15%, respectively, in the RIC group and 62% and 10% in the MAC group. No GVHD was reported after 1 year. The incidence of relapse was 29% in the RIC group and 51% in the MAC group. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4 to 6/8 strata). These encouraging outcomes, which were sustained for 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.
Subject(s)
Bone Marrow , Graft vs Host Disease , Humans , Follow-Up Studies , Prospective Studies , Cyclophosphamide/therapeutic use , Graft vs Host Disease/prevention & control , Unrelated Donors , RecurrenceABSTRACT
In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front-line setting. Recently, time-to-event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post-autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six-month [hazard ratio (HR) = 7·68], 12-month (HR = 6·68), and 18-month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non-relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high-risk group with inferior post-relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up-front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Mantle-Cell/therapy , Adult , Aged , Female , Humans , Lymphoma, Mantle-Cell/diagnosis , Male , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Retrospective Studies , Survival Analysis , Time Factors , Transplantation, AutologousABSTRACT
PURPOSE: Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT. PATIENTS AND METHODS: We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy. RESULTS: Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS. CONCLUSION: Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.
Subject(s)
Cyclophosphamide/administration & dosage , Hematopoietic Stem Cell Transplantation/methods , Leukemia/therapy , Lymphoma/therapy , Myelodysplastic Syndromes/therapy , Transplantation Conditioning/methods , Unrelated Donors , Adolescent , Adult , Aged , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Humans , Male , Medically Underserved Area , Middle Aged , Minority Groups , Prospective Studies , Registries , Young AdultABSTRACT
Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636.
Subject(s)
Living Donors , Peripheral Blood Stem Cell Transplantation , Peripheral Blood Stem Cells , Quality of Life , Unrelated Donors , Adolescent , Adult , Female , Humans , Male , Middle Aged , Prospective Studies , Young AdultABSTRACT
The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59â¯×â¯106/L; age 41 to 60, 81â¯×â¯106/L; age 18 to 40, 121â¯×â¯106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50â¯×â¯109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.
Subject(s)
Peripheral Blood Stem Cell Transplantation/methods , Peripheral Blood Stem Cells/metabolism , Adolescent , Adult , Aged , Blood Donors , Comorbidity , Female , Humans , Male , Middle Aged , Young AdultSubject(s)
Carcinoma, Renal Cell/secondary , Lung Neoplasms/secondary , Peripheral Blood Stem Cell Transplantation , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/complications , Carcinoma, Renal Cell/therapy , Cisplatin/administration & dosage , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Humans , Ifosfamide/administration & dosage , Kidney Neoplasms/complications , Kidney Neoplasms/drug therapy , Kidney Neoplasms/surgery , Lung Neoplasms/complications , Lung Neoplasms/therapy , Male , Nephrectomy , Paclitaxel/administration & dosage , Sickle Cell Trait/complications , Transplantation, AutologousABSTRACT
Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Neoplasm Recurrence, Local/prevention & control , Adult , Aged , Case-Control Studies , Female , Humans , Leukemia, Myeloid, Acute/mortality , Maintenance Chemotherapy/adverse effects , Maintenance Chemotherapy/methods , Male , Middle Aged , Myeloablative Agonists/administration & dosage , Myelodysplastic Syndromes/mortality , Neoplasm Recurrence, Local/epidemiology , Retrospective Studies , Time Factors , Transplantation Conditioning/methods , Transplantation, Homologous/adverse effects , Young AdultABSTRACT
Lymphoid recovery following myeloablative stem cell transplantation (SCT) displays a logistic pattern of exponential growth followed by a plateau. Within this logistic framework, lymphoid recovery is characterized by the parameters R (slope of ascent), a (time of maximal rate of ascent) and K (plateau), the 'steady-state' lymphocyte count. A retrospective analysis of allogeneic SCT performed from 2008 to 2013 was undertaken to compare lymphoid recovery and clinical outcomes in 131 patients with acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndromes. Using Prism software, a logistic curve was successfully fit to the absolute lymphocyte count recovery in all patients. Patients were classified according to the magnitude and rate of lymphoid recovery; pattern A achieved an absolute lymphocyte counts (ALC) of >1000/µL by day 45, pattern B an ALC 500 < x < 1000/µL, and pattern C an ALC <500/µL. Pattern A was characterized by a higher mean K (p < .0001) compared with patterns B and C. Patients with patterns B and C were more likely to have mixed T cell chimerism at 90 d following SCT (p = .01). There was a trend towards improved survival (and relapse-free survival) in those with pattern A and B at 1 year compared to pattern C (p = .073). There was no difference in cGVHD (p = .42) or relapse (p = .45) between pattern types. Cytomegalovirus (CMV), aGVHD, and all relapse were heralded by deviation from logistic behavior. Pattern C patients were more likely to require donor lymphocyte infusion (DLI) (p = .017). Weaning of tacrolimus post-transplant was associated with a second, separate logistic expansion in some patients. This study demonstrated that lymphoid reconstitution follows a prototypical logistic recovery and that pattern observed correlates with T cell chimerism and need for DLI, and may influence survival.
Subject(s)
Graft vs Host Disease/epidemiology , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Neoplasm Recurrence, Local/epidemiology , T-Lymphocytes/immunology , Adult , Disease-Free Survival , Female , Graft vs Host Disease/blood , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/blood , Hematologic Neoplasms/immunology , Hematologic Neoplasms/mortality , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Kinetics , Lymphocyte Count , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Male , Middle Aged , Models, Biological , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/prevention & control , Retrospective Studies , Survival Analysis , Transplantation Conditioning/methods , Transplantation, Homologous , Treatment Outcome , Young AdultABSTRACT
The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization. This was a study of patients with non-Hodgkin lymphoma (NHL; n = 167) and multiple myeloma (MM; n = 163) who were enrolled in the long-term follow-up of 2 pivotal phase III studies (NCT00741325 and NCT00741780) of 240 µg/kg plerixafor plus 10 µg/kg G-CSF, or placebo plus 10 µg/kg G-CSF to mobilize and collect CD34+ cells for autologous hematopoietic stem cell transplantation. Overall survival (OS) and progression-free survival (PFS) were evaluated over a 5-year period following the first dose of plerixafor or placebo. The probability of OS was not significantly different in patients with NHL or MM treated with plerixafor or placebo (NHL: 64%; 95% confidence interval [CI], 56% to 71% versus 56%; 95% CI, 44% to 67%, respectively; MM: 64%; 95% CI, 54% to 72% versus 64%; 95% CI, 53% to 73%, respectively). In addition, there was no statistically significant difference in the probability of PFS over 5 years between treatment groups in patients with NHL (50%; 95% CI, 44% to 67% for plerixafor versus 43%; 95% CI, 31% to 54% for placebo) or those with MM (17%; 95% CI, 10% to 24% for plerixafor versus 30%; 95% CI, 21% to 40% for placebo). In this long-term follow-up study, the addition of plerixafor to G-CSF for stem cell mobilization did not affect 5-year survival in patients with NHL or patients with MM.
Subject(s)
Granulocyte Colony-Stimulating Factor/therapeutic use , Heterocyclic Compounds/therapeutic use , Lymphoma, Non-Hodgkin/therapy , Multiple Myeloma/therapy , Adolescent , Adult , Aged , Benzylamines , Child , Cyclams , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cell Mobilization/mortality , Hematopoietic Stem Cell Transplantation/methods , Humans , Longitudinal Studies , Middle Aged , Multiple Myeloma/mortality , Survival Analysis , Transplantation, Autologous/methods , Transplantation, Autologous/mortality , Young AdultSubject(s)
Hematopoietic Stem Cell Transplantation , Preoperative Care , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/therapy , Radiation Dosage , Splenomegaly/pathology , Splenomegaly/radiotherapy , Aged , Biomarkers , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Transplantation Conditioning , Treatment OutcomeABSTRACT
PURPOSE: To determine if there is a difference in toxicity and effectiveness between obese and non-obese patients who receive high-dose cyclophosphamide (Cy) prior to allogeneic hematopoietic stem cell transplant (allo-HCT). METHODS: Patients were included in this study if they were at least 18 years of age and received high-dose Cy in combination with total body irradiation (CyTBI) or busulfan (BuCy) prior to allo-HCT between 1 January 2008 and 29 February 2012. The primary endpoint was the difference in overall toxicity between obese and non-obese patients. Secondary objectives examined differences in effectiveness between groups assessed by relapse at day +100, relapse at 1 year, death at 1 year, chimerisms at days +30, +60, and +90, and incidence of acute graft versus host disease (aGVHD). RESULTS: Sixty-one patients met the inclusion criteria, 28 obese and 33 non-obese. Overall toxicity was greater in obese patients compared to non-obese patients (82% vs. 52%, OR 4.3 [95% CI 1.3-14.1]; p = 0.01), which was driven by a greater incidence of renal dysfunction (79% vs. 48%, OR 3.9 [95% CI 1.3-12.1]; p = 0.02). There were no differences in rates of grade 3 or 4 toxicity, hepatic dysfunction, or any measure of effectiveness between groups. CONCLUSION: Obese patients receiving high-dose Cy and allo-HCT are at increased risk for toxicity, although there appears to be no difference in the rate of relapse or survival between obese and non-obese patients.
Subject(s)
Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Graft vs Host Disease/drug therapy , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Obesity/physiopathology , Adult , Busulfan/therapeutic use , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Retrospective Studies , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Whole-Body Irradiation/methodsABSTRACT
Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. A total of 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (clinicaltrials.gov identifier: 00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease, diagnosis and activity. Measures gathered by the transplant clinician included Schirmer's tear test and National Institutes of Health 0-3 Eye Score. Patient-reported outcome measures were the ocular subscale of the Lee Chronic Graft-versus-Host Disease Symptom Scale and Chief Eye Symptom Intensity Score. Altogether, 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; 133 of 157 patients (85%) had active disease. In a multivariable model, the National Institutes of Health Eye Score (P<0.0001) and Schirmer's tear test (P<0.0001) were independent predictors of ocular chronic graft-versus-host disease (sensitivity 93.0%, specificity 92.2%). The Lee ocular subscale was the strongest predictor of active ocular chronic graft-versus-host disease (P<0.0001) (sensitivity 68.5%, specificity 82.6%). Ophthalmology specialist measures that were most strongly predictive of diagnosis in a multivariate model were Oxford grand total staining (P<0.0001) and meibomian score (P=0.027). These results support the use of selected transplant clinician- and patient-reported outcome measures for ocular chronic graft-versus-host disease screening when providing care to allogeneic hematopoietic stem cell transplantation survivors with moderate to severe chronic graft-versus-host disease. Prospective studies are needed to determine if the Lee ocular subscale demonstrates adequate responsiveness as a disease activity outcome measure.
Subject(s)
Eye Diseases/diagnosis , Eye Diseases/pathology , Graft vs Host Disease/diagnosis , Graft vs Host Disease/pathology , Hematopoietic Stem Cell Transplantation , Models, Biological , Adolescent , Adult , Aged , Allografts , Child , Chronic Disease , Eye Diseases/etiology , Female , Graft vs Host Disease/etiology , Humans , Male , Middle Aged , Predictive Value of TestsABSTRACT
Systems that evolve over time and follow mathematical laws as they evolve are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using antithymocyte globulin (ATG) and 4.5-Gy total body irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft-versus-host disease (GVHD) were not significantly different in 2 cohorts of patients receiving different doses of ATG. However, donor-derived CD3(+) cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated 1 of 3 sigmoid growth patterns: Pattern A (n = 15) had rapid growth with high lymphocyte counts, pattern B (n = 14) had slower growth with intermediate recovery, and pattern C (n = 10) had poor lymphocyte reconstitution. There was a significant association between lymphocyte recovery patterns and both the rate of change of donor-derived CD3(+) at day 30 after stem cell transplantation (SCT) and clinical outcomes. GVHD was observed more frequently with pattern A, relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution after SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk.
Subject(s)
Antilymphocyte Serum/therapeutic use , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Models, Immunological , Transplantation Conditioning , Adult , Aged , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Hematologic Neoplasms/immunology , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Humans , Immunosuppressive Agents/therapeutic use , Lymphocyte Transfusion/statistics & numerical data , Male , Middle Aged , Nonlinear Dynamics , Prognosis , Prospective Studies , Recurrence , Risk , Siblings , Survival Analysis , Transplantation, Homologous , Unrelated Donors , Whole-Body IrradiationABSTRACT
Outcomes in stem cell transplantation (SCT) are modeled using probability theory. However, the clinical course following SCT appears to demonstrate many characteristics of dynamical systems, especially when outcomes are considered in the context of immune reconstitution. Dynamical systems tend to evolve over time according to mathematically determined rules. Characteristically, the future states of the system are predicated on the states preceding them, and there is sensitivity to initial conditions. In SCT, the interaction between donor T cells and the recipient may be considered as such a system in which, graft source, conditioning, and early immunosuppression profoundly influence immune reconstitution over time. This eventually determines clinical outcomes, either the emergence of tolerance or the development of graft versus host disease. In this paper, parallels between SCT and dynamical systems are explored and a conceptual framework for developing mathematical models to understand disparate transplant outcomes is proposed.
ABSTRACT
PURPOSE: To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor-mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201. PATIENTS AND METHODS: Fresh aliquots of 161 BM and 147 PB stem-cell allografts from North American donors randomly assigned to donate BM or PB stem cells and numbers of transplanted cells were correlated with overall survival (OS), relapse, and graft-versus-host disease (GvHD). RESULTS: Patients with evaluable grafts were similar to all BMTCTN 0201 patients. The numbers of plasmacytoid dendritic cells (pDCs) and naïve T cells (Tns) in BM allografts were independently associated with OS in multivariable analyses including recipient and donor characteristics, such as human leukocyte antigen mismatch, age, and use of antithymocyte globulin. BM recipients of > median number of pDCs, naïve CD8(+) T cells (CD8Tns), or naïve CD4(+) T cells (CD4Tns) had better 3-year OS (pDCs, 56% v 35%; P = .025; CD8Tns, 56% v 37%; P = .012; CD4Tns, 55% v 37%; P = .009). Transplantation of more BM Tns was associated with less grade 3 to 4 acute GvHD but similar rates of relapse. Transplantation of more BM pDCs was associated with fewer deaths resulting from GvHD or from graft rejection. Analysis of PB grafts did not identify a donor cell subset significantly associated with OS, relapse, or GvHD. CONCLUSION: Donor immune cells in BM but not PB stem-cell grafts were associated with survival after unrelated-donor allogeneic hematopoietic stem-cell transplantation. The biologic activity of donor immune cells in allogeneic transplantation varied between graft sources. Donor grafts with more BM-derived Tns and pDCs favorably regulated post-transplantation immunity in allogeneic hematopoietic stem-cell transplantation.
Subject(s)
Bone Marrow Transplantation/methods , Dendritic Cells/immunology , Myeloproliferative Disorders/therapy , T-Lymphocytes/immunology , Adolescent , Adult , Child , Child, Preschool , Dendritic Cells/cytology , Female , Humans , Infant , Infant, Newborn , Leukemia/therapy , Male , Middle Aged , Myelodysplastic Syndromes/therapy , Primary Myelofibrosis/therapy , Survival Analysis , Survival Rate , T-Lymphocytes/cytology , Unrelated Donors , Young AdultABSTRACT
Allogeneic stem cell transplantation is the standard approach to Philadelphia chromosome positive acute lymphoblastic leukemia. We hypothesized that imatinib plus sequential chemotherapy will result in significant leukemia cell cytoreduction in patients with Philadelphia chromosome positive acute lymphoblastic leukemia, allowing collection of normal hematopoietic stem cells uncontaminated by residual BCR/ABL1(+) lymphoblasts and thus reduce the likelihood of relapse after autologous stem cell transplantation for patients under 60 years of age without sibling donors. We enrolled 58 patients; 19 underwent autologous and 15 underwent allogeneic stem cell transplantation on study. Imatinib plus sequential chemotherapy resulted in reverse-transcriptase polymerase chain reaction-negative stem cells in 9 patients and remained minimally positive in 4 (6 were not evaluable). Overall survival (median 6.0 years vs. not reached) and disease-free survival (median 3.5 vs. 4.1 years) were similar between those who underwent autologous and those who underwent allogeneic stem cell transplantation. We conclude that autologous stem cell transplantation represents a safe and effective alternative for allogeneic stem cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients without sibling donors (clinicaltrials.gov identifier:00039377).
Subject(s)
Hematopoietic Stem Cell Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adult , Female , Humans , Karyotype , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Transplantation, Autologous , Transplantation, Homologous , Treatment OutcomeABSTRACT
BACKGROUND: Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS: We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS: The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS: We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).
Subject(s)
Bone Marrow Diseases/therapy , Bone Marrow Transplantation/mortality , Leukemia/therapy , Peripheral Blood Stem Cell Transplantation/mortality , Unrelated Donors , Adult , Bone Marrow Diseases/mortality , Bone Marrow Transplantation/adverse effects , Cause of Death , Female , Graft Rejection/epidemiology , Graft vs Host Disease/epidemiology , Histocompatibility Testing , Humans , Intention to Treat Analysis , Kaplan-Meier Estimate , Leukemia/mortality , Male , Peripheral Blood Stem Cell Transplantation/adverse effects , Proportional Hazards Models , Recurrence , Survival RateABSTRACT
Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT.
Subject(s)
Antigens, Neoplasm/immunology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/pharmacology , DNA Methylation/drug effects , Epigenesis, Genetic/drug effects , Immunity, Cellular/drug effects , Lymphocyte Transfusion , Multiple Myeloma/immunology , Peripheral Blood Stem Cell Transplantation , T-Cell Antigen Receptor Specificity/drug effects , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Azacitidine/administration & dosage , Boronic Acids/administration & dosage , Bortezomib , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Drug Administration Schedule , Female , Humans , Lenalidomide , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/surgery , Plasma Cells/immunology , Prospective Studies , Pyrazines/administration & dosage , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives , Transplantation, AutologousABSTRACT
Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m(2)), and antithymocyte globulin was associated with excessive organ toxicity.