ABSTRACT
BACKGROUND AIMS: Cytopenias after allogeneic stem cell transplantation (allo-SCT) are a common complication, the underlying pathogenic mechanisms of which remain incompletely understood. Multipotent mesenchymal stromal/stem cell (MSC) therapy has been successfully employed in the treatment of immune-related disorders and can aid in the restoration of the hematopoietic niche. METHODS: A phase II clinical trial to assess the efficacy and safety of administering four sequential doses of ex-vivo expanded bone marrow MSCs from a third-party donor to patients with persistent severe cytopenias after allo-SCT was performed. RESULTS: The overall response rate on day 90 was 75% among the 27 evaluable patients (comprising 12 complete responses, 8 partial responses, and 7 with no response). The median time to respond was 14.5 days. Responses were observed across different profiles, including single or multiple affected lineages, primary or secondary timing, and potential immune-mediated or post-infectious pathophysiology versus idiopathic origin. With a median follow-up for surviving patients of 85 months after MSC infusion, 53% of patients are alive. Notably, no adverse events related to MSC therapy were reported. CONCLUSIONS: In summary, the sequential infusion of third-party MSCs emerges as a viable and safe therapeutic option, exhibiting potential benefits for patients experiencing cytopenias following allo-SCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Transplantation, Homologous , Humans , Hematopoietic Stem Cell Transplantation/methods , Adult , Female , Mesenchymal Stem Cell Transplantation/methods , Male , Middle Aged , Mesenchymal Stem Cells/cytology , Transplantation, Homologous/methods , Aged , Treatment Outcome , CytopeniaABSTRACT
In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification.
Subject(s)
Bone Marrow Transplantation , Graft vs Host Disease , Leukemia, Myeloid, Acute , Peripheral Blood Stem Cell Transplantation , Remission Induction , Transplantation Conditioning , Humans , Middle Aged , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/mortality , Male , Female , Aged , Transplantation Conditioning/methods , Bone Marrow Transplantation/methods , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Transplantation, Haploidentical/methods , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Europe , Registries , Pathologic Complete ResponseABSTRACT
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma. METHODS: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18-75 years; with an Eastern Cooperative Oncology Group performance status of 0-2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 106 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 106 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 106 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11. FINDINGS: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53-65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1-13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1-2). No cases of neurotoxic events were observed. Persistent grade 3-4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19. INTERPRETATION: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach. FUNDING: Instituto de Salud Carlos III (co-funded by the EU), Fundación La Caixa, and Fundació Bosch i Aymerich.
Subject(s)
COVID-19 , Multiple Myeloma , Humans , Male , Female , Middle Aged , Multiple Myeloma/drug therapy , Immunotherapy, Adoptive/adverse effects , B-Cell Maturation Antigen , Pilot Projects , CytokinesABSTRACT
CD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0-1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.
Subject(s)
Lymphoma, Mantle-Cell , Neutropenia , Humans , Adult , Treatment Outcome , Immunotherapy, Adoptive , Progression-Free Survival , Lymphoma, Mantle-Cell/drug therapyABSTRACT
ABSTRACT: Primary cutaneous posttransplant lymphoproliferative disorders (PTLDs) after allogeneic hematopoietic stem cell transplant (allo-HSCT) are exceedingly rare, with only 6 published cases, all of them consisting in T-cell neoplasms. In this report, we present for the first time a donor-derived B-cell PTLD consisting in a primary, cutaneous, B-cell, marginal zone, lymphoproliferative disorder (PCMZLPD). The patient, a 37-year-old woman with a history of Hodgkin lymphoma received an allo-HSCT from her healthy, matched, related father, achieving complete host chimerism in the bone marrow and peripheral blood. However, 8 years after the allo-HSCT, she presented asymptomatic skin lesions consisting in oval, well-defined, slightly raised erythematous plaques, located on the arms, trunk, and legs. Skin biopsies of 2 lesions demonstrated a class-switched IgG+, EBV-, PCMZLPD, showing kappa light chain restriction and monoclonal rearrangement of the IgH gene. Microsatellite genotyping and 2-color fluorescence in situ hybridization (X and Y chromosomes) confirmed that the origin of the neoplastic cells was the donor graft. The lesions showed an indolent behavior, good response to topical corticosteroids, and no need for systemic treatment. Our case broadens the spectrum of PTLD, a diverse group of lymphoid and/or plasmacytic proliferations with variable clinical presentations and histopathological features.
Subject(s)
Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Lymphoproliferative Disorders , Skin Diseases , Humans , Female , Adult , In Situ Hybridization, Fluorescence , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/pathology , Hematopoietic Stem Cell Transplantation/adverse effects , Plasma Cells/pathology , Epstein-Barr Virus Infections/pathologyABSTRACT
Prior studies of antibody response after full SARS-CoV-2 vaccination in hematological patients have confirmed lower antibody levels compared to the general population. Serological response in hematological patients varies widely according to the disease type and its status, and the treatment given and its timing with respect to vaccination. Through probabilistic machine learning graphical models, we estimated the conditional probabilities of having detectable anti-SARS-CoV-2 antibodies at 3-6 weeks after SARS-CoV-2 vaccination in a large cohort of patients with several hematological diseases (n= 1166). Most patients received mRNA-based vaccines (97%), mainly Moderna® mRNA-1273 (74%) followed by Pfizer-BioNTech® BNT162b2 (23%). The overall antibody detection rate at 3 to 6 weeks after full vaccination for the entire cohort was 79%. Variables such as type of disease, timing of anti-CD20 monoclonal antibody therapy, age, corticosteroids therapy, vaccine type, disease status, or prior infection with SARS-CoV-2 are among the most relevant conditions influencing SARS-CoV-2-IgG-reactive antibody detection. A lower probability of having detectable antibodies was observed in patients with B-cell non-Hodgkin's lymphoma treated with anti-CD20 monoclonal antibodies within 6 months before vaccination (29.32%), whereas the highest probability was observed in younger patients with chronic myeloproliferative neoplasms (99.53%). The Moderna® mRNA-1273 compound provided higher probabilities of antibody detection in all scenarios. This study depicts conditional probabilities of having detectable antibodies in the whole cohort and in specific scenarios such as B cell NHL, CLL, MM, and cMPN that may impact humoral responses. These results could be useful to focus on additional preventive and/or monitoring interventions in these highly immunosuppressed hematological patients.
Subject(s)
Antineoplastic Agents , COVID-19 , Antibodies, Monoclonal , Antibodies, Viral , BNT162 Vaccine , COVID-19/diagnosis , COVID-19/prevention & control , COVID-19 Vaccines , Early Detection of Cancer , Humans , SARS-CoV-2 , VaccinationABSTRACT
This is a multicenter prospective observational study that included a large cohort (n = 397) of allogeneic (allo-HSCT; (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) recipients who were monitored for antibody detection within 3-6 weeks after complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from February 1, 2021, to July 20, 2021. Most patients (n = 387, 97.4%) received mRNA-based vaccines. Most of the recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS-CoV-2-reactive antibodies were observed in 242 (78%) of allo-HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo-HSCT recipients identified lymphopenia < 1 × 109 /ml (odds ratio [OR] 0.33, 95% confidence interval [95% CI] 0.16-0.69, p = .003), active graft versus host disease (GvHD; OR 0.51, 95% CI 0.27-0.98, p = .04) and vaccination within the first year of transplant (OR 0.3, 95% CI 0.15-0.9, p = .04) associated with lower antibody detection whereas. In ASCT, non-Hodgkin's lymphoma (NHL; OR 0.09, 95% CI 0.02-0.44, p = .003) and active corticosteroid therapy (OR 0.2, 95% CI 0.02-0.87, p = .03) were associated with lower detection rate. We report an encouraging rate of SARS-CoV-2-reactive antibodies detection in these severe immunocompromised patients. Lymphopenia, GvHD, the timing of vaccine, and NHL and corticosteroids therapy should be considered in allo-HSCT and ASCT, respectively, to identify candidates for SARS-CoV-2 antibodies monitoring.
Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Hematopoietic Stem Cell Transplantation , SARS-CoV-2/immunology , Adolescent , Adult , Aged , COVID-19/epidemiology , COVID-19/immunology , Female , Humans , Immunocompromised Host , Male , Middle Aged , Prospective Studies , Spain/epidemiology , Young AdultABSTRACT
BACKGROUND: Defibrotide is approved in European Union for the treatment of severe sinusoidal obstruction syndrome (SOS) after HSCT. However, it has also been used for SOS prophylaxis, moderate SOS and in other complications such as transplant-associated thrombotic microangiopathy (TAM). The objective of this study was to evaluate current uses, effectiveness and safety of defibrotide in patients with HSCT. METHODS: This multicenter, retrospective study included patients treated with defibrotide for any indication at 28 HSCT centers of the Grupo Español de Trasplante Hematopoyetico (GETH) including the pediatric subgroup Grupo Español de Trasplante de Medula en Niños (GETMON). RESULTS: Three hundred and eighty eight patients treated with defibrotide between January 2011 and December 2018 were included. 253 patients were children, and 135 patients were adults. In total, 332 transplants were allogeneic, and the remainder were autologous. Main indications for defibrotide use were severe/very severe SOS in 173 patients, SOS prophylaxis in 135 patients, moderate SOS in 41 patients, TAM in six patients and suspected SOS in 33 patients. Overall survival (OS) at day +100 in the SOS prophylaxis group was 89% (95% CI, 87%-91%). In the group of patients with moderate and severe/very severe SOS, the OS at day +100 was 80% (95% CI, 74%-86%) and 62% (95% CI, 59%-65%), respectively (P = .0015). With a longer follow-up, median of 2 years (4 months-7 years), OS was 63% (95% CI, 59%-67%) in the SOS prophylaxis patients. OS for patients with moderate and severe/very severe SOS groups was 53% (95% CI, 47%-61%) and 26% (95% CI, 22%-30%), respectively (P = .006). 191 patients died, and SOS was the main cause of death in 23 patients (12%). CONCLUSIONS: Defibrotide has an acceptable safety profile with an improved response in severe/very severe SOS compared with historical controls, mainly in pediatric patients. Use of defibrotide for prophylaxis may improve prognosis of patients at high risk of complications due to endothelial damage such as those who receive a second transplant. SOS has an important impact on the HSCT long-term survival, as can be concluded from our study.
Subject(s)
Hematopoietic Stem Cell Transplantation , Polydeoxyribonucleotides/administration & dosage , Thrombotic Microangiopathies , Adolescent , Adult , Aged , Allografts , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Male , Middle Aged , Retrospective Studies , Spain/epidemiology , Survival Rate , Thrombotic Microangiopathies/etiology , Thrombotic Microangiopathies/mortality , Thrombotic Microangiopathies/prevention & controlABSTRACT
Treatment of steroid-refractory chronic graft-versus-host disease (cGVHD) is a challenge. Here, we describe a retrospective analysis of 66 patients with steroid-refractory cGVHD treated with imatinib (starting dose of 100 mg in 70% of patients; maximum dose of 100-200 mg in 74%). Most patients had multi-organ involvement (≥2 organs, 83%), with the most affected being skin (85%), oral mucosa (55%), eyes (42%), and lungs (33%). The overall response rate was 41% (21 partial and three complete responses). The organ with the best response rate was the skin (46%), followed by gastrointestinal tract (43%), liver (41%), the oral mucosa (36%), eyes (29%), and lungs (18%). Imatinib led to steroid tapering in 17/38 patients. Twenty-five (38%) patients experienced imatinib-related adverse events, comprising extra-hematologic toxicity (n = 24, 36%) and hematologic toxicity (n = 6, 9%). No cases of grade 4-5 toxicity were reported. The main causes of imatinib discontinuation were treatment failure (52%) and toxicity (9%). After a median follow-up of 41 months, the 3-year overall survival was 81%, with no difference between imatinib responders and non-responders. These real-life results show that imatinib is safe and has moderate efficacy in patients with heavily pre-treated cutaneous sclerotic cGVHD; however, activity against lung cGVHD is very limited.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Chronic Disease , Humans , Imatinib Mesylate , Retrospective Studies , SteroidsABSTRACT
We conducted a multicenter interventional study to assess the efficacy of Therakos ECP to treat steroid-resistant graft-vs-host disease (SRes-GVHD) after allogeneic HSCT and to identify biomarkers of GVHD response. A total of 62 patients were treated for acute SRes-GVHD (n = 37) or chronic SRes-GVHD (n = 25). Median time to best response was 35 days (range, 28-85) and 90 days (range, 27-240) in acute and chronic SRes-GVHD, respectively. Overall, 27 patients (72.9%) with SRes-aGVHD responded to treatment (40.5% CR and 32.4% PR). The response rate was significantly higher in grade I-II than in grade III-IV aGVHD (100% vs 50.0%, respectively, P-value = .001). In chronic SRes-GVHD, 22 patients (88%) achieved a clinical response (24.0% CR and 64% PR). Response was higher in moderate than in severe SRes-cGVHD (100% vs 75%, P = .096). In both acute and chronic SRes-GVHD patients, the percentage of peripheral blood CD3+ CD4+ was higher and CD3+ CD8+ lower in responding than nonresponding patients. Acute SRes-GVHD responding patients presented a higher number of Treg cells (CD4+ CD25+ CD127low/- ) at day 0 (P = .028) than nonresponding patients, differences that were maintained over the observation period. Phenotypic analysis of T-cell maturation showed a trend toward reduction in TCD8 naive cells, along with an increased percentage of TCD8 Mem Efect T cells after starting ECP in responding patients. None of the studied serum cytokines displayed statistically significant changes in either acute or chronic SRes-GVHD. ECP is an effective treatment for patients with SRes-GVHD. Biomarkers could help guide decision-making on ECP treatment initiation and duration.
Subject(s)
Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Photopheresis/methods , Adult , Aged , Biomarkers , Cytokines/blood , Female , Graft vs Host Disease/immunology , Humans , Male , Middle Aged , Prospective Studies , Steroids/therapeutic use , T-Lymphocytes, Regulatory/immunology , Transplantation, Homologous , Treatment Outcome , Young AdultABSTRACT
Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P < .001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P < .001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Immunologic Factors/administration & dosage , Proteasome Inhibitors/administration & dosage , Adult , Aged , Allografts , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/drug therapy , Graft vs Host Disease/mortality , Humans , Incidence , Male , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Recurrence , Retrospective Studies , Spain/epidemiology , Survival RateABSTRACT
The aim of this study was to develop and validate a clinical and transplant-specific prognostic score using data from a large cohort of patients with myelodysplastic syndromes reported to the European Society for Blood and Marrow Transplantation registry. A Cox model was fitted to detect clinical and transplant-related variables prognostic of outcome. Then, cross-validation was performed to evaluate the validity and consistency of the model. Seven independent risk factors for survival were identified: age ≥50 years, matched unrelated donor, Karnofsky Performance Status <90%, very poor cytogenetics or monosomal karyotype, positive cytomegalovirus status of the recipient, blood blasts >1%, and platelet count ≤50 × 109/L prior to transplantation. Incorporating these factors into a four-level risk score yielded hazard ratios for death, with low-risk (score of 0-1) as reference, of 2.02 (95% CI: 1.41-2.90) for the intermediate-risk group (score of 2-3), 3.49 (95% CI: 2.45-4.97) for the high-risk group (score of 4-5), and 5.90 (95% CI: 4.01-8.67) for the very high-risk group (score of >5). The score was predictive of survival, relapse-free survival, relapse, and non-relapse mortality (P<0.001, respectively). Cross-validation yielded significant and reproducible improvement in prognostic ability with C-statistics being 0.609 (95% CI: 0.588-0.629) versus 0.555 for the Gruppo Italiano Trapianto di Midollo Osseo registry and 0.579 for the Center for Blood and Marrow Transplant Research registry. Prediction was even further augmented after applying a nomogram using age and platelets as continuous variables showing C-statistics of 0.628 (95% CI: 0.616-0.637). In conclusion, compared to existing prognostic systems, this proposed transplant-specific risk score offers improved performance with respect to post-transplant risk stratification in myelodysplastic syndromes.
Subject(s)
Hematopoietic Stem Cell Transplantation/mortality , Models, Statistical , Myelodysplastic Syndromes/mortality , Nomograms , Risk Assessment/standards , Adolescent , Adult , Aged , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/therapy , Prognosis , Risk Factors , Survival Rate , Transplantation, Homologous , Young AdultABSTRACT
Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34+ cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P < .001) and a higher comorbidity burden (Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI] ≥3: 51% versus 38%; P < .001) in the TCD cohort. Analysis of outcomes at 3 years showed a higher chronic graft-versus-host disease (GVHD)/relapse-free survival (CRFS) (51% versus 7%; P < .001), lower incidences of grade II-IV acute GVHD (18% versus 46% at day +180) and chronic GVHD (6% versus 55% at 3 years; P < .001), and a lower incidence of relapse (19% versus 33% at 3 years; P = .001) in the TCD group compared with the RIC group. Relapse-free survival (RFS), overall survival (OS), and NRM were similar in the 2 groups. Combining transplantation approach (RIC versus TCD) and comorbidity burden (HCT-CI 0-2 versus ≥3), patients with an HCT-CI score of 0-2 seemed to benefit from the TCD approach. In conclusion, in this retrospective study, the use of a CD34+ cell-selected graft and a myeloablative conditioning regimen was associated with higher CRFS and similar RFS and OS compared with unmodified allo-RIC in patients age >50 years with AML and MDS.
Subject(s)
Antigens, CD34/blood , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Transplantation Conditioning/methods , Aged , Female , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/standards , Humans , Leukemia, Myeloid, Acute/mortality , Lymphocyte Depletion/methods , Male , Middle Aged , Myeloablative Agonists/therapeutic use , Myelodysplastic Syndromes/mortality , Recurrence , Retrospective Studies , Transplantation, Homologous/methodsABSTRACT
There is significant interest in immunotherapy for the treatment of high-risk smoldering multiple myeloma (SMM), but no available data on the immune status of this particular disease stage. Such information is important to understand the interplay between immunosurveillance and disease transformation, but also to define whether patients with high-risk SMM might benefit from immunotherapy. Here, we have characterized T lymphocytes (including CD4, CD8, T-cell receptor γδ, and regulatory T cells), natural killer (NK) cells, and dendritic cells from 31 high-risk SMM patients included in the treatment arm of the QUIREDEX trial, and with longitudinal peripheral blood samples at baseline and after 3 and 9 cycles of lenalidomide plus low-dose dexamethasone (LenDex). High-risk SMM patients showed at baseline decreased expression of activation-(CD25/CD28/CD54), type 1 T helper-(CD195/interferon-γ/tumor necrosis factor-α/interleukin-2), and proliferation-related markers (CD119/CD120b) as compared with age-matched healthy individuals. However, LenDex was able to restore the normal expression levels for those markers and induced a marked shift in T-lymphocyte and NK-cell phenotype. Accordingly, high-risk SMM patients treated with LenDex showed higher numbers of functionally active T lymphocytes. Together, our results indicate that high-risk SMM patients have an impaired immune system that could be reactivated by the immunomodulatory effects of lenalidomide, even when combined with low-dose dexamethasone, and support the value of therapeutic immunomodulation to delay the progression to multiple myeloma. The QUIREDEX trial was registered to www.clinicaltrials.gov as #NCT00480363.
Subject(s)
Dexamethasone/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Cell Proliferation/drug effects , Demography , Dexamethasone/pharmacology , Female , Humans , Immunophenotyping , Induction Chemotherapy , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lenalidomide , Longitudinal Studies , Maintenance Chemotherapy , Male , Middle Aged , Risk Factors , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Thalidomide/pharmacology , Thalidomide/therapeutic useABSTRACT
BACKGROUND: High-risk acute leukemia (AL) and myelodysplastic syndrome (MDS) remain a therapeutic challenge. Unmanipulated haploidentical-related donor transplantation based on a myeloablative conditioning regimen (HAPLO-MAC) and post-transplant cyclophosphamide (PT-Cy) as prophylaxis against graft vs host disease (GvHD) is now a promising rescue strategy that could become universally available. OBJECTIVE: To evaluate the results of HAPLO-MAC with PT-Cy in patients with AL and MDS reported to the Haploidentical Transplantation Subcommittee of the Spanish Group for Hematopoietic Transplantation (GETH). PATIENTS AND METHODS: We report our multicenter experience using an IV busulfan-based HAPLO-MAC regimen and PT-Cy for treatment of 65 adults with high-risk AL and MDS. RESULTS: Engraftment was recorded in 64 patients (98.5%), with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 28.6% and 27.5%, respectively. After a median follow-up of 31 months for survivors, the cumulative incidence of non-relapse mortality and relapse at 2 years was 18.8% and 25%, respectively. Estimated 30-month event-free survival and overall survival were 56% and 54.5%, respectively. CONCLUSION: HAPLO-MAC comprising an IV busulfan-based conditioning regimen enabled long-term disease control with acceptable toxicity in high-risk AL and MDS.
Subject(s)
Busulfan/administration & dosage , Hematopoietic Stem Cell Transplantation , Leukemia/therapy , Myelodysplastic Syndromes/therapy , Transplantation Conditioning , Transplantation, Haploidentical , Adolescent , Adult , Aged , Combined Modality Therapy , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Leukemia/diagnosis , Leukemia/mortality , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/mortality , Recurrence , Retreatment , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention. METHODS: In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety. RESULTS: After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. CONCLUSIONS: Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00480363.).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/therapeutic use , Multiple Myeloma/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/adverse effects , Disease Progression , Female , Follow-Up Studies , Humans , Induction Chemotherapy , Lenalidomide , Male , Middle Aged , Multiple Myeloma/mortality , Risk , Survival Rate , Thalidomide/adverse effects , Thalidomide/therapeutic useABSTRACT
Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33 months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life-threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3 years among patients without bleeding was 67·1% for only 17·1% for patients with life-threatening bleeding (P < 0·001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hemorrhage/epidemiology , Hemorrhage/etiology , Adult , Aged , Female , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Hemorrhage/mortality , Humans , Incidence , Male , Middle Aged , Patient Outcome Assessment , Risk Factors , Transplantation Conditioning/adverse effects , Transplantation, HomologousABSTRACT
The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil (group 3). Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors.
Subject(s)
Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Premedication , Transplantation Conditioning , Aged , Antilymphocyte Serum/administration & dosage , Female , Follow-Up Studies , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunosuppressive Agents/therapeutic use , Incidence , Leukemia, Myeloid, Acute/diagnosis , Male , Middle Aged , Retrospective Studies , Risk Factors , Survival Analysis , Transplantation, Homologous , Treatment OutcomeABSTRACT
We evaluated the feasibility, safety, and efficacy of the administration of 4 sequential doses (intravenously administered on days 1, 4, 11, and 18) of cryopreserved bone marrow-derived mesenchymal stromal cells (MSC) expanded with platelet lysate and obtained from third-party donors as a second-line treatment for steroid-refractory acute graft-versus-host (aGVHD) disease in a series of 25 patients. All patients received at least 2 doses of MSC, whereas 21 received 3 doses and 18 received the initially planned 4 doses. Because of the achievement of partial response, 4 patients received additional doses of MSC. Median single cell dose administered was 1.1 × 10(6) MSC/kg of recipient body weight. There were no adverse events related to the MSC infusion in the 99 procedures performed, with the exception of a cardiac ischemic event that occurred twice in a patient with prior history of cardiac ischemia. Response to MSC at 60 days after the first dose was evaluable in 24 patients. Seventeen patients (71%) responded (11 complete and 6 partial responses), with a median time to response of 28 days after the first MSC dose, whereas 7 patients did not respond. In summary, we can conclude that sequential cryopreserved third-party MSC therapy administered on days 1, 4, 11, and 18 is a safe procedure for patients with steroid-refractory aGVHD. This strategy may provide a high rate of overall responses of aGVHD with a low toxicity profile.
Subject(s)
Cryopreservation , Graft vs Host Disease/therapy , Hematologic Neoplasms/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Transplantation Conditioning/methods , Acute Disease , Adult , Antineoplastic Agents/therapeutic use , Blood Platelets/chemistry , Cell Count , Drug Resistance, Neoplasm , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Graft vs Host Disease/pathology , Hematologic Neoplasms/immunology , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Humans , Immunosuppressive Agents/therapeutic use , Male , Mesenchymal Stem Cells/immunology , Middle Aged , Prospective Studies , Steroids/therapeutic use , Survival Analysis , Transplantation, Homologous , Treatment Outcome , Unrelated DonorsABSTRACT
A multistep model has been proposed of disease progression starting in monoclonal gammopathy of undetermined significance continuing through multiple myeloma, sometimes with an intermediate entity called smoldering myeloma, and ending in extramedullary disease. To gain further insights into the role of the transcriptome deregulation in the transition from a normal plasma cell to a clonal plasma cell, and from an indolent clonal plasma cell to a malignant plasma cell, we performed gene expression profiling in 20 patients with monoclonal gammopathy of undetermined significance, 33 with high-risk smoldering myeloma and 41 with multiple myeloma. The analysis showed that 126 genes were differentially expressed in monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma as compared to normal plasma cell. Interestingly, 17 and 9 out of the 126 significant differentially expressed genes were small nucleolar RNA molecules and zinc finger proteins. Several proapoptotic genes (AKT1 and AKT2) were down-regulated and antiapoptotic genes (APAF1 and BCL2L1) were up-regulated in multiple myeloma, both symptomatic and asymptomatic, compared to monoclonal gammopathy of undetermined significance. When we looked for those genes progressively modulated through the evolving stages of monoclonal gammopathies, eight snoRNA showed a progressive increase while APAF1, VCAN and MEGF9 exhibited a progressive downregulation. In conclusion, our data show that although monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma are not clearly distinguishable groups according to their gene expression profiling, several signaling pathways and genes were significantly deregulated at different steps of the transformation process.