Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Receptors, Chimeric Antigen , Humans , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Immunotherapy, Adoptive , Costs and Cost Analysis , Delivery of Health Care , Receptors, Antigen, T-Cell , Antigens, CD19ABSTRACT
A 52-year-old patient developed pancytopenia of unknown origin 1.5 years after allogeneic stem cell transplantation. The bone marrow aspirate showed visceral leishmaniasis (VL). Although VL is distributed world-wide, the incidence in patients after allogeneic stem cell transplantation is rare.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Leishmania donovani/isolation & purification , Leishmaniasis, Visceral/diagnosis , Pancytopenia/etiology , Bone Marrow Examination , Graft vs Host Disease , Humans , Leishmaniasis, Visceral/blood , Leishmaniasis, Visceral/parasitology , Middle Aged , Opportunistic Infections/blood , Opportunistic Infections/diagnosis , Opportunistic Infections/parasitologyABSTRACT
We screened 136 patients with myelofibrosis and a median age of 58 years who underwent allogeneic stem cell transplantation (AHSCT) for molecular residual disease for JAKV617F (n=101), thrombopoietin receptor gene (MPL) (n=4) or calreticulin (CALR) (n=31) mutation in peripheral blood on day +100 and +180 after AHSCT. After a median follow-up of 78 months, the 5-year estimated overall survival was 60% (95% confidence interval (CI): 50-70%) and the cumulative incidence of relapse at 5 years was 26% (95% CI: 18-34%) for the entire study population. The percentage of molecular clearance on day 100 was higher in CALR-mutated patients (92%) in comparison with MPL- (75%) and JAKV617F-mutated patients (67%). Patients with detectable mutation at day +100 or at day +180 had a significant higher risk of clinical relapse at 5 years than molecular-negative patients (62% vs 10%, P<0.001) and 70% vs 10%, P<0.001, respectively) irrespectively of the underlying mutation. In a multivariate analysis, high-risk diseases status (hazard ratio (HR) 2.5; 95% CI: 1.18-5.25, P=0.016) and detectable MRD at day 180 (HR 8.36, 95% CI: 2.76-25.30, P<0.001) were significant factors for a higher risk of relapse.
Subject(s)
Calreticulin/genetics , Janus Kinase 2/genetics , Neoplasm, Residual/genetics , Pathology, Molecular/methods , Primary Myelofibrosis/diagnosis , Receptors, Thrombopoietin/genetics , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/mortality , Humans , Middle Aged , Mutation , Neoplasm, Residual/diagnosis , Neoplasm, Residual/mortality , Primary Myelofibrosis/genetics , Primary Myelofibrosis/mortality , Recurrence , Survival Rate , Transplantation, HomologousSubject(s)
Candida tropicalis/isolation & purification , Candidiasis/diagnosis , Fusariosis/diagnosis , Fusarium/isolation & purification , Infectious Encephalitis/diagnosis , RNA, Fungal/genetics , Sequence Analysis, RNA , Aged , Allografts , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Candidiasis/microbiology , Coinfection/diagnosis , Coinfection/microbiology , Combined Modality Therapy , Fatal Outcome , Fusariosis/microbiology , Hematopoietic Stem Cell Transplantation , Humans , Immunocompromised Host , Infectious Encephalitis/microbiology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/therapy , MaleSubject(s)
Calreticulin/genetics , Hematopoietic Stem Cell Transplantation/methods , Mutation , Primary Myelofibrosis/therapy , Adult , Aged , DNA Mutational Analysis , Humans , Middle Aged , Primary Myelofibrosis/genetics , Primary Myelofibrosis/mortality , Survival Analysis , Transplantation Conditioning/methods , Transplantation, Homologous , Treatment OutcomeABSTRACT
Allogeneic hematopoieteic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis (MF), but it is still associated with significant risks and complications. One of these complications is poor graft function, but incidence and risk factors have not been studied yet. We retrospectively studied a cohort of 100 patients with primary MF or post-ET/PV MF who received a reduced-intensity HSCT in our center. The cumulative incidence of primary leukocyte engraftment was 98%. The cumulative incidence of poor graft function was 17% and all of the cases occurred before day 100 after HSCT at a median of 49 days (range 24-99 days). In the univariate analysis, age as continuous parameter (P=0.05; hazard ratio 1042) and persistence of significant splenomegaly (defined as palpable splenomegaly of ⩾10 cm under costal margin) at d+30 after HSCT (33% vs 12%; P=0.05) showed an increased cumulative incidence of poor graft function. In conclusion, the incidence of poor graft function after HSCT for MF is rather high, but did not influence survival. Persistence of splenomegaly after transplantation is a significant factor for poor graft function in myelofibrosis patients. Whether therapeutic reduction of splenomegaly before HSCT would result in a lower incidence of poor graft function should be investigated in future studies.
Subject(s)
Allografts/physiopathology , Hematopoietic Stem Cell Transplantation/methods , Primary Myelofibrosis/therapy , Adult , Age Factors , Aged , Female , Humans , Incidence , Male , Middle Aged , Primary Myelofibrosis/complications , Retrospective Studies , Risk Factors , Splenomegaly , Transplantation Conditioning/methodsSubject(s)
Calreticulin/genetics , Hematopoietic Stem Cell Transplantation , Polymerase Chain Reaction , Primary Myelofibrosis/genetics , Alleles , Calreticulin/metabolism , Humans , Immunotherapy/methods , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Mutation , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/metabolism , Recurrence , Remission Induction , Time FactorsABSTRACT
TBI-based preparative regimens are considered as standard conditioning therapy for allogeneic stem cell transplantation (AHSC) in patients with ALL. We investigated toxicity and efficacy of a non-TBI-based regimen consisting of treosulfan, etoposide and cyclophosphamide for ALL within a prospective study. Major inclusion criteria were CR and non-eligibility for TBI. Fifty patients with a median age of 46.5 years (range, 18-64) were included. Donors were HLA-identical sibling (n=8), matched (n=42) or mismatched (n=10) unrelated. The toxicity was moderate, resulting in a cumulative incidence of non-relapse mortality (NRM) at 1 year of 8% (90% confidence interval: 2-15%). Acute GvHD grade II-IV and grade III/IV was noted in 53% and 14%, respectively. Chronic GvHD at one year was seen in 41%. After a median follow-up of 24 months the cumulative incidence of relapse was 36% (90% confidence interval: 24-48) and 51% (90% confidence interval: 37-65) at 1 and 2 years, respectively. The estimated 2-year disease-free and overall survivals were 36 and 48%, respectively. Treosulfan, etoposide and cyclophosphamide followed by AHSC has a favorable toxicity profile with low NRM and therefore represents a potential alternative regimen for ALL in 1. CR (NCT00682305).
Subject(s)
Myeloablative Agonists/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Stem Cell Transplantation , Transplantation Conditioning/methods , Adolescent , Adult , Allografts , Busulfan/administration & dosage , Busulfan/adverse effects , Busulfan/analogs & derivatives , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Humans , Male , Middle Aged , Myeloablative Agonists/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation Conditioning/adverse effectsABSTRACT
Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
Subject(s)
Adrenal Cortex Hormones/pharmacology , Drug Resistance, Neoplasm/drug effects , Graft vs Host Disease/drug therapy , Hematologic Neoplasms/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Pyrazoles/therapeutic use , Salvage Therapy , Adult , Aged , Animals , Disease Models, Animal , Female , Follow-Up Studies , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematologic Neoplasms/therapy , Humans , Janus Kinases/antagonists & inhibitors , Male , Mice , Middle Aged , Neoplasm Staging , Nitriles , Prognosis , Pyrimidines , Recurrence , Retrospective Studies , Survival Rate , Transplantation, Homologous , Young AdultABSTRACT
To investigate the impact of anti-lymphocyte globulin (ATG-Fresenius) as part of the HLA-sibling transplantation, we evaluated 238 patients (median age 48 years) with different diagnoses (AML, ALL, CML and lymphoproliferative disorders). A total of 79 patients received ATG and 159 patients did not. In the ATG group, there were more HLA-mismatched donors (6% vs 1%, p=0.02), bad risk patients (70% vs 55%, P=0.04), reduced intensity conditioning (RIC) regimens (65% vs 34%, P=<0.001) and older patients (median age 51 vs 48 years, P=0.002). The median time to leukocyte engraftment was significantly faster in the non-ATG group (13 vs 15 days, P < 0.001). EBV reactivation was more often seen in the ATG group (9% vs 2%, P=0.05). Cumulative incidence of acute and chronic GVHD was less observed in the ATG group (27% vs 40%, P=0.004, and 33% vs 54%, P=0.002). The cumulative incidence rates of non-relapse mortality and of relapse at 5 years were 20 and 34%, respectively, for ATG and 34 and 29%, respectively, for non-ATG (P=0.06 and P=0.3). ATG can prevent GVHD without an obvious risk of relapse but should be confirmed in a randomized study.
Subject(s)
Antilymphocyte Serum/therapeutic use , Graft vs Host Disease/prevention & control , Hematologic Diseases/therapy , Lymphocyte Depletion , Peripheral Blood Stem Cell Transplantation , T-Lymphocytes/cytology , Adolescent , Adult , Aged , Child , Clinical Trials as Topic , Disease-Free Survival , Female , HLA Antigens/immunology , Humans , Incidence , Leukocytes/cytology , Male , Middle Aged , Recurrence , Retrospective Studies , Risk , Siblings , Transplantation Conditioning , Transplantation, Homologous , Young AdultSubject(s)
Antigens, CD19/immunology , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/surgery , Myelodysplastic Syndromes/immunology , Myelodysplastic Syndromes/surgery , Neprilysin/immunology , Precursor Cells, B-Lymphoid/immunology , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
In a retrospective study of 168 patients with AML in CR who underwent allo-SCT, we compare the impact of young unrelated donors (UD) vs older matched related donors (MRD) on 5-year OS (5-yr OS). Median follow-up was 59 months and median donor age was 39 years, which was used as cutoff for young vs older donors. Kaplan-Meier-estimated 5-yr OS was better with UD ≤39 years vs MRD >39 years (66% vs 34%, P=0.001). In multivariate analysis, only donor age and cytogenetic risk impacted 5-yr OS. Compared with UD ≤39 years, both MRD >39 years (relative risk (RR): 4.31, P=0.001) and UD >39 years (RR: 2.14, P=0.03) were associated with poorer 5-yr OS. Standard-risk cytogenetics was associated with better 5-yr OS compared with bad-risk cytogenetics, (RR: 0.53, P=0.02). Subgroup analyses of patients ≥50 years (n=76) revealed similar results, with 5-yr OS of 62% for UD ≤39 yrs and 26% for MRD >39 yrs (P=0.022). In patients undergoing allo-HSCT for AML, young UD may improve outcome as compared with older MRD.
Subject(s)
Donor Selection/methods , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/surgery , Living Donors , Adult , Age Factors , Donor Selection/standards , Female , Hematopoietic Stem Cell Transplantation/standards , Humans , Male , Remission Induction , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
Relapse after dose-reduced allograft in advanced myeloma patients remains high. To reduce the risk of relapse, we investigated a myeloablative toxicity-reduced allograft (aSCT) consisting of i.v. BU and CY followed by lenalidomide maintenance therapy in 33 patients with multiple myeloma (MM) who relapsed following an autograft after a median of 12 months. The cumulative incidence of non-relapse mortality at 1 year was 6% (95% confidence interval (CI): 0-14). After a median interval of 168 days following aSCT, 24 patients started with a median dose of 5 mg (r, 5-15) lenalidomide without dexamethasone. During follow-up, 13 patients discontinued lenalidomide owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). Major toxicities of lenalidomide were GvHD II-III (28%), viral reactivation (16%), thrombocytopenia (III-IV°,16%), neutropenia (III/IV°, 8%), peripheral neuropathy (I/II°, 16%), or other infectious complication (8%). Cumulative incidence of relapse at 3 years was 42% (95% CI: 18-66). The 3-year estimated probability of PFS and OS was 52% (95% CI: 28-76) and 79% (95% CI: 63-95), respectively. Toxicity-reduced myeloablative allograft followed by lenalidomide maintenance is feasible and effective in relapsed patients with MM, but the induction of GvHD should be considered.
Subject(s)
Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/therapeutic use , Multiple Myeloma/therapy , Stem Cell Transplantation/methods , Thalidomide/analogs & derivatives , Transplantation Conditioning/methods , Adolescent , Adult , Aged , Disease-Free Survival , Female , Humans , Lenalidomide , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/surgery , Recurrence , Salvage Therapy , Stem Cell Transplantation/adverse effects , Thalidomide/adverse effects , Thalidomide/therapeutic use , Transplantation Conditioning/adverse effects , Transplantation, Homologous , Young AdultSubject(s)
Bone Marrow/pathology , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes/pathology , Adult , Aged , Female , Humans , Leukemia, Myelomonocytic, Chronic/pathology , Leukemia, Myelomonocytic, Chronic/surgery , Male , Middle Aged , Myelodysplastic Syndromes/surgery , Transplantation ConditioningABSTRACT
Estimation of relapse risk in AML after allo-SCT is critical. The negative impact of increased blast count post transplant is widely accepted. Here, we studied cellularity and dysplasia in BM cytomorphology on days 30 and 100 in 112 AML patients who achieved haematological CR after SCT. Overall cellularity on day 30 was normal in 45.3%, reduced in 37.3% and increased in 17.3% of samples (day 100: normal: 54.8%; reduced: 38.7%; and increased: 6.5%). Dysplasia in ≥10% of cells was frequent on day 30 (granulopoiesis: 25.0% of samples; erythropoiesis: 34.6%; and megakaryopoiesis: 47.7%) and also on day 100. Relapses were less frequent in patients with normal BM cellularity on day 30 (7/34; 20.6%) when compared with reduced (9/28; 32.1%) or increased cellularity (10/13; 76.9%; P = 0.001). Estimated 2-year OS was 59.0% for patients with normal overall cellularity, followed by patients with increased (44.0%) and reduced cellularity (31.4%, P = 0.009). In contrast, cellularity at day 100 and dysplasia at days 30 and 100 did not correlate with outcome measures. Thus, in the cohort studied, BM cellularity represents a prognostic parameter for the post-transplant period in AML patients. Dysplasia seems to be an unspecific phenomenon in the cohort analysed.
Subject(s)
Bone Marrow Cells/pathology , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/surgery , Stem Cell Transplantation/methods , Adolescent , Adult , Aged , Bone Marrow Cells/metabolism , Cytodiagnosis/methods , Cytogenetics , Female , Humans , Male , Middle Aged , Prognosis , Recurrence , Risk Factors , Transplantation Chimera , Treatment Outcome , Young AdultSubject(s)
Antigens, CD34/blood , Primary Myelofibrosis/blood , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/therapy , Stem Cell Transplantation , Adult , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Primary Myelofibrosis/genetics , Prognosis , Retrospective Studies , Transplantation, HomologousABSTRACT
Mannan-binding lectin (MBL) deficiency is determined by MBL gene polymorphisms and is associated with an increased infection risk. To clarify the role of MBL in Allo-SCT, 131 recipients-donors were analysed. MBL genotypes were determined by PCR and heteroduplex analyses, MBL serum levels by ELISA, and MBL oligomers by western blotting. MBL levels <400 ng/ml were associated with increased susceptibility to fungal pneumonia (7/12 vs 35/111; P=0.04, adjusted P=0.002), HSV/VZV (7/12 vs 26/111; P=0.03), CMV reactivation and acute GVHD. Donor genotypes had no influence. Pre-SCT MBL levels corresponded to recipients' genotypes (P<0.001), changed significantly post-SCT, but were not influenced by donors' genotypes. MBL oligomer profiles were similar pre-/post-SCT. Cultured CD34+ cells were found not to synthesise MBL. In conclusion, low MBL levels pre-transplant predisposed patients to sepsis, fungal and viral infection. Donors' MBL genotypes did not influence infection rates. Prospective studies should clarify the importance of MBL as a prelude for MBL replacement after SCT.
Subject(s)
Mannose-Binding Lectin/genetics , Stem Cell Transplantation/adverse effects , Adolescent , Adult , Aged , Disease Susceptibility , Female , Genotype , Graft vs Host Disease/etiology , Graft vs Host Disease/genetics , Humans , Male , Mannose-Binding Lectin/blood , Middle Aged , Mycoses/etiology , Phenotype , Prospective Studies , Retrospective Studies , Sepsis/etiology , Stem Cell Transplantation/mortality , Tissue Donors , Transplantation, HomologousABSTRACT
We investigated efficacy and toxicity of lenalidomide in 24 heavily pretreated myeloma patients with a median age of 59 years (range: 37-70) and relapse after allo-SCT. Lenalidomide was given at a dose of 15 mg (n=4), or 25 mg (n=20), orally once daily on day 1 to day 1 every 28 days, with (n=20) or without (n=4) DHAP. The median number of lenalidomide cycles was five (range: 2-17). Major side effects were leukopenia (grade 4: 4%, grade 3: 21% and grade 2: 17%) and thrombocytopenia (grade 3: 17% and grade 2: 29%); infectious complications were observed in 50%. Non-hematological toxicity consisted of muscle cramps (n=9), fatigue (n=5) and constipation (n=2). Mild grade I-II GVHD was seen in three patients. Response was achieved in 66%: CR in 8%, VGPR in 8%, PR in 50% and SD in 13%. The median time to progression was 9.7 months (95% confidence interval (CI): 7.5-11.9), and median OS was 19.9 months (95% CI: 17.3-22.5). Immunomonitoring after lenalidomide showed significant increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells, as well as regulatory T cells (CD4(+), CD25(+), CD127(lo)), supporting an immunomodulating anti-myeloma effect of lenalidomide.