Lymphocyte Subset Recovery and Outcome after Autologous Hematopoietic Stem Cell Transplantation for Plasma Cell Myeloma

Rapid immune reconstitution—particularly of natural killer cells (NK cells)—after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with protection from relapse. Whether such an association also exists after autologous stem cell transplantation is less clear. We retrospectively assessed lymphocyte subsets after autologous HSCT in 114 patients and correlated lymphocyte recovery with outcome. CD8 T cell and NK cell counts recovered rapidly to pretransplantation levels, whereas B cell and CD4 T cell recovery were delayed. Compared with patients with low NK cells (<100/uL), high NK cell count at 1 month after HSCT was associated with significantly prolonged progression-free survival: for NK cells 100 to 200/uL hazard ratio [HR], .33 (95% confidence interval [CI]; .16 to .80; P = .004); for NK cells > 200/μL HR, .27 (95% CI, .13 to .58; P = .001). No significant protective effects were associated with rapid recovery of any other lymphocyte subset. None influenced overall survival (OS) or time to next treatment. Early NK cell recovery is associated with better progression-free survival after autologous HSCT. The failure to detect an effect on OS might be due to the salvage strategies available to these patients.     

Immune Reconstitution after Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical hematopoietic stem cell transplantation (HSCT) offers the benefits of rapid and nearly universal donor availability and has been accepted worldwide as an alternative treatment for patients with hematologic malignancies who do not have a completely HLA-matched sibling or who require urgent transplantation. Unfortunately, serious infections and leukemia relapse resulting from slow immune reconstitution remain the 2 most frequent causes of mortality in patients undergoing haploidentical HSCT, particularly in those receiving extensively T cell–depleted megadose CD34⁺ allografts. This review summarizes advances in immune recovery after haploidentical HSCT, focusing on the immune subsets likely to have the greatest impact on clinical outcomes. The progress made in accelerating immune reconstitution using different strategies after haploidentical HSCT is also discussed. It is our belief that a predictive immune subset–guided strategy to improve immune recovery might represent a future clinical direction.     

Association between an Impaired Bone Marrow Vascular Microenvironment and Prolonged Isolated Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation

Prolonged isolated thrombocytopenia (PT) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, it remains unclear whether abnormalities of the bone marrow (BM) microenvironment are involved in the pathogenesis of PT. This prospective, nested case-control study included 20 patients with PT, 40 matched patients with good graft function (GGF) after allo-HSCT, and 16 healthy donors (HDs). Cellular elements of the BM microenvironment, including BM endothelial cells (BMECs), perivascular cells, and endosteal cells, were analyzed via flow cytometry and via hematoxylin-eosin and immunohistochemical staining in situ. Moreover, stromal-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) were measured in the plasma of BM via an enzyme-linked immunosorbent assay. No significant differences in endosteal cells (15 per high-power field [hpf] versus 16 per hpf versus 20 per hpf, P > .05) were demonstrated among the patients with PT, GGF, and the HDs. The PT patients exhibited remarkable decreases in cellular elements of the vascular microenvironment, including BMECs (.01% versus .18% versus .20%, P < .0001) and perivascular cells (.01% versus .12% versus .13%, P < .0001), compared with the GGF allo-HSCT recipients and the HDs, respectively. Moreover, significantly lower levels of SDF-1 (3163 pg/mL versus 3928 pg/mL, P = .0002) and VEGF (56 pg/mL versus 123 pg/mL, P < .0001) were found in the BM plasma of the PT patients compared with the BM of the GGF patients. A multivariate analysis revealed that BMECs (odds ratio [OR] = 171.57, P = .002) and cytomegalovirus infection after HSCT (OR = 4.35, P = .009) were independent risk factors for PT. Our data suggested that an impaired BM vascular microenvironment and megakaryocyte-active factors may contribute to the occurrence of PT after HSCT.     

The Effect of Natural Killer Cell Killer Ig-Like Receptor Alloreactivity on the Outcome of Bone Marrow Stem Cell Transplantation for Severe Combined Immunodeficiency (SCID)

Natural killer (NK) cell alloreactions against recipient cells in the setting of bone marrow transplantation have been associated with decreased rates of graft-versus-host disease (GVHD) and improved survival in transplant recipients with myeloid leukemia. These alloreactions are predicted by the absence of recipient HLA class I ligands for donor inhibitory killer Ig-like receptors (KIR). We hypothesized that donor NK cell alloreactions against recipient cells may affect the development of T and B-cell functions and incidence of GVHD in infants with severe combined immunodeficiency (SCID). Of the 156 patients with SCID who had received related bone marrow transplants without pretransplant chemotherapy or posttransplant GVHD prophylaxis, 137 patient-donor pairs were evaluated for the absence of recipient HLA class I ligands for donor inhibitory KIR. Analysis showed that the absence of a KIR ligand had no effect on the incidence or severity of GVHD (RR [corrected] = 0.95, p = 0.84), development of T-cell function (RR [corrected] = 1.05, p = 0.69), production of IgA (p = 0.46) or IgM (p = 0.33), or on 5-year survival (RR [corrected] = 1.21, p = 0.10). Further, in patients possessing native NK cells, the absence of KIR ligands in donors for recipient-inhibitory KIR did not alter transplantation outcomes. This study suggests that inhibitory KIR/HLA interactions do not play a significant role in bone marrow transplantation for SCID.     

Outcome and Prognostic Factors for Patients Who Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Disease relapse remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT), yet little is known about the relevant prognostic factors after relapse. We studied 1080 patients transplanted between 2004 and 2008, among whom 351 relapsed. The 3-year postrelapse overall survival (prOS) rate was 19%. Risk factors for mortality after relapse included shorter time to relapse, higher disease risk index at HSCT, myeloablative conditioning, high pretransplantation comorbidity index, and graft-versus-host disease (GVHD) occurring before relapse. Important prognostic factors did not vary by disease type. Based on this, we could stratify patients into 3 groups, with 3-year prOS rates of 36%, 14%, and 3% (P < .0001). This score was validated in an historical cohort of 276 patients. Postrelapse donor lymphocyte infusion or repeat HSCT was associated with improved prOS, as was the development of GVHD after relapse. These differences remained significant in models that accounted for other prognostic factors and in landmark analyses of patients who survived at least 2 months from relapse. The results of this study may aid with prognostication and management of patients who relapse after HSCT and motivate the design of clinical trials aimed at relapse prevention or treatment in higher-risk patients.     

Risk-Factor Analysis of Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

The objective of this study was to investigate the main risk factors for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), to allow the improvement of transplantation outcomes through preventive measures. Clinical data for 124 patients who received allo-HSCT were analyzed retrospectively. There were 83 males (66.9%) and 41 females (33.1%) with a median age of 28 years (4-60 years). The median follow-up time was 7 months (1-116 months). Factors analyzed included age, gender, disease diagnosis, source of hematopoietic stem cells, donor type, human leukocyte antigen (HLA) matching, conditioning regimen, numbers of infused mononuclear cells and CD34⁺ cells, donor-recipient sex and blood-type matching, prophylactic treatment of graft-versus-host disease (GVHD), grades of GVHD, Epstein-Barr virus or cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorders and hepatic veno-occlusive disease. Data were analyzed by univariate and multivariate conditional logistic regression analyses. Among the 124 patients who underwent allo-HSCT, 15 developed PGF (12.1%). Univariate logistic regression analysis identified age, donor-recipient blood type and CMV infection (in 30 days) as potential risk factors for PGF. Multivariate analysis of factors with P<0.1 in univariate analysis showed that age, donor-recipient blood type and CMV infection (in 30 days) were significant risk factors for PGF. Patients were divided into subgroups based on age <20, 20-30, 30-40, and >40 years. The risk of PGF increased 2.747-fold (odds ratio (OR)=2.625, 95% confidence interval: 1.411-5.347) for each increment in age level. Patients with mismatched blood type (OR=4.051) or CMV infection (OR=9.146) had an increased risk of PGF. We conclude that age, donor-recipient blood-type matching and CMV infection are major risk factors for PGF after allo-HSCT.     

Association of an Impaired Bone Marrow Microenvironment with Secondary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether abnormalities of the bone marrow (BM) microenvironment are involved in the pathogenesis of PGF is unclear. In the present prospective nested case-control study, 19 patients with secondary PGF, 38 matched patients with good graft function (GGF) after allo-HSCT, and 15 healthy donors (HDs) were enrolled. The cellular elements of the BM microenvironment, including endosteal cells, perivascular cells, and vascular cells, were analyzed by flow cytometry as well as hematoxylin and eosin and immunohistochemical staining in situ. The median time to occurrence of secondary PGF was 90 days post-transplantation (range, 58 to 264 days). The patients with PGF showed markedly hypocellular marrow (10% versus 45% versus 45%; P < .0001) with scattered hematopoietic cells and significantly lower CD34⁺ cells (0.07% versus 0.26% versus 0.26%; P < .0001), endosteal cells (4 per high-power field [hpf] versus 16 per hpf versus 20 per hpf; P < .001), perivascular cells (0.008% versus 0.10% versus 0.12%; P < .0001), and endothelial progenitor cells (0.008% versus 0.16% versus 0.18%; P < .0001) compared with GGF allo-HSCT recipients and HDs, respectively. Multivariate analyses revealed that endothelial progenitor cells (odds ratio, 150.72; P = .001) and the underlying disease (odds ratio, 18.52; P = .007) were independent risk factors for secondary PGF. Our results suggest that the impaired BM microenvironment may contribute to the occurrence of secondary PGF post-HSCT.     

Viral Respiratory Infections Diagnosed by Multiplex PCR after Allogeneic Hematopoietic Stem Cell Transplantation: Long-Term Incidence and Outcome

Viral respiratory infections (VRIs) are frequent after hematopoietic stem cell transplantation and constitute a potential cause of mortality. We analyzed the incidence, risk factors, and prognosis of VRIs in a cohort of transplanted patients. More frequent viruses were human coronavirus and human rhinovirus followed by flu-like viruses and adenovirus. Risk factors for death were lymphocytopenia and high steroid dosage.     

Innate Immune Recovery Predicts CD4+ T Cell Reconstitution after Hematopoietic Cell Transplantation

Innate immune cells are the first to recover after allogeneic hematopoietic cell transplantation (HCT). Nevertheless, reports of innate immune cell recovery and their relation to adaptive recovery after HCT are largely lacking. Especially predicting CD4⁺ T cell reconstitution is of clinical interest, because this parameter directly associates with survival chances after HCT. We evaluated whether innate recovery relates to CD4⁺ T cell reconstitution probability and investigated differences between innate recovery after cord blood transplantation (CBT) and bone marrow transplantation (BMT). We developed a multivariate, combined nonlinear mixed-effects model for monocytes, neutrophils, and natural killer (NK) cell recovery after transplantation. A total of 205 patients undergoing a first HCT (76 BMT, 129 CBT) between 2007 and 2016 were included. The median age was 7.3years (range, .16 to 23). Innate recovery was highly associated with CD4⁺ T cell reconstitution probability (P < .001) in multivariate analysis correcting for covariates. Monocyte (P < .001), neutrophil (P < .001), and NK cell (P < .001) recovery reached higher levels during the first 200days after CBT compared with BMT. The higher innate recovery after CBT may be explained by increased proliferation capacity (measured by Ki-67 expression) of innate cells in CB grafts compared with BM grafts (P?=?.041) and of innate cells in vivo after CBT compared with BMT (P?=?.048). At an individual level, patients with increased innate recovery after either CBT or BMT had received grafts with higher proliferating innate cells (CB; P?=?.004, BM; P?=?.01, respectively). Our findings implicate the use of early innate immune monitoring to predict the chance of CD4⁺ T cell reconstitution after HCT, with respect to higher innate recovery after CBT compared with BMT.     

Dynamic of Bone Marrow Fibrosis Regression Predicts Survival after Allogeneic Stem Cell Transplantation for Myelofibrosis

We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post–essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation.     

Risk Factors for Invasive Fungal Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Single Center Experience

Invasive fungal disease (IFD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HCT). We performed a retrospective review of 271 adults with a hematologic malignancy undergoing allogeneic HCT to determine the incidence of and risk factors for IFD and to examine the impact of IFD on nonrelapse mortality and overall survival. We defined IFD using standard criteria and selected proven and probable cases for analysis. Diagnoses in the study group included acute leukemia (42%), non-Hodgkin lymphoma (24%), myelodysplastic syndrome (15%), chronic lymphocytic leukemia (5%), and other hematologic disorders (14%). Conditioning included reduced-intensity (64%) and myeloablative (36%) regimens. Donor sources were HLA-matched sibling (60%), matched unrelated (20%), haploidentical (12%), and cord blood (8%). A total of 51 episodes of IFD were observed in 42 subjects (15%). Aspergillus spp (47%) was the most frequent causative organism, followed by Candida spp (43%). The majority of IFD cases (67%) were reported after day +100 post-HCT. In multivariate analysis, haploidentical donor transplantation (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.49-9.77; P = .005) and grade II-IV acute graft-versus-host disease (HR, 2.55; 95% CI, 1.07-6.10; P = .03) were risk factors for the development of IFD. Conversely, higher infused CD34⁺ cell dose was associated with a lower risk of IFD (HR, 0.80; 95% CI, 0.68-0.94; P = .006, per 1 × 10⁶ cells/kg increase in CD34⁺ cell infusion). IFD-related mortality was 33.3%. Nonrelapse mortality was significantly higher in patients who developed IFD compared with those without IFD (P < .001, log-rank test). Patients with IFD had lower overall survival (5.8 months versus 76.1 months; P < .001, log-rank test). Further studies exploring strategies to increase the infused cell dose and determine adequate prophylaxis, especially against aspergillus, beyond day +100 are needed.     

Risk Factor and Clinical Outcome of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation

PurposeThe development of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) deteriorates patients'' quality of life. This study aimed to analyze the prevalence, clinical features, risk factors and prognostic factors of BOS.ResultsOf 860 patients who survived for ≥100 days, 36 (4.2%) met the diagnostic criteria. The duration of BOS development after transplantation was 466.00 (284.00–642.75) [median (interquartile range)] days. The risk factor for the development of BOS was peripheral blood as the stem cell source with a hazard ratio (HR) of 2.550 [95% confidence interval (CI): 1.274–5.104, p=0.008]. In multivariate analysis, pretransplant FEV₁/FVC (HR: 0.956, 95% CI: 0.921–0.993, p=0.020) and time from HSCT to diagnosis of BOS (HR: 0.997, 95% CI: 0.994–0.999, p=0.009) were independent prognostic factors associated with mortality.ConclusionPeripheral blood as a stem cell source is a risk factor for the development of BOS. A decreased pretransplant FEV₁/FVC and shorter duration of time from transplantation to diagnosis of BOS are poor prognostic factors for BOS.     

Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation

Epstein-Barr virus (EBV)-related post-transplantation lymphoproliferative disorders (EBV-PTLDs) are rare but potentially fatal complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT), characterized by uncontrolled proliferation of EBV-infected lymphocytes. The most common risk factors include T cell depletion of graft, HLA mismatch, severe graft-versus-host disease (GVHD), and EBV seromismatch (recipient-negative/donor-positive), among others. EBV-PTLDs commonly manifest as fever and lymphadenopathy and may rapidly progress to multiorgan failure and even death. Histopathological evidence is indispensable for the diagnosis, and positive findings of EBV-DNA (EBV-DNAemia) and imaging are also very helpful. Active prophylaxis, such as optimization of the donor choice, conditioning regimen, and GVHD prevention, or passive prophylaxis, such as low dose of rituximab, unselected donor lymphocyte infusion (DLI), and EBV-specific cytotoxic T lymphocyte (EBV-CTLs) infusion, can decrease the incidence of EBV-DNAemia. Rituximab- based preemptive treatment can prevent EBV-DNAemia from developing into EBV-PTLDs, particularly benefiting recipients with higher loads of EBV-DNA, although the long-term outcome has not been significantly improved. To date, there is no consensus as to whether and when to initiate prophylactic or preemptive treatment. The current treatment strategies for probable and proven EBV-PTLDs include reduction of immunosuppression (RI), rituximab, adoptive cell therapy (DLI or EBV-CTLs), chemotherapy, radiotherapy, and surgery, among which rituximab?plus?RI is the mainstay. However, the mortality of EBV-PTLDs remains considerably high, and novel strategies merit exploration.     

Iron Overload in Allogeneic Hematopoietic Cell Transplantation Outcome: A Meta-Analysis

An elevated ferritin level before allogeneic hematopoietic cell transplantation (HCT) is an adverse prognostic factor for overall survival (OS) and nonrelapse mortality. Because ferritin is an imperfect surrogate of iron stores, the prognostic role of iron overload remains unclear. We conducted a patient-level meta-analysis of 4 studies that used magnetic resonance imaging to estimate pre-HCT liver iron content (LIC). An elevated LIC was not associated with a significant increase in mortality: the hazard ratio (HR) for mortality associated with LIC > 7 mg/g dry weight (primary endpoint) was 1.4 (P = .18). In contrast, ferritin >1000 ng/mL was a significant prognostic factor (HR for mortality, 1.7; P = .036). There was, however, no significant association between ferritin > 2500 and mortality. This meta-analysis suggests that iron overload, as assessed by LIC, is not a strong prognostic factor for OS in a general adult HCT population. Our data also suggest that ferritin is an inadequate surrogate for iron overload in HCT.     

Intermittent Zoledronic Acid Prevents Bone Loss in Adults after Allogeneic Hematopoietic Cell Transplantation

Bone mineral density (BMD) loss is common in survivors of allogeneic hematopoietic cell transplantation (alloHCT). We performed a multicenter, phase II, randomized open-label trial of intravenous zoledronic acid (ZA) to prevent BMD loss in adult recipients of alloHCT with osteopenia before HCT. The treatment group received ZA 4 mg intravenously within 28 days pre-HCT and at 3 and 6 months after HCT. Both treatment and control groups received calcium carbonate and vitamin D supplements. Of 61 patients, 32 were randomized to the ZA cohort and 29 to the control cohorts. More patients in the ZA group had an HCT comorbidity index high-risk score of ≥3 (50% versus 21%, P < .01). Baseline BMD, T-scores, serum osteocalcin, bone alkaline phosphatase, and urine N-telopeptide (UNTX) levels were similar in both cohorts. Thirty patients were evaluable for outcomes (11 from the treatment and 19 from the control group). At 12 months, subjects in the treatment group had an improvement in BMD at the femoral neck (mean change, .018 for ZA group versus −.054 for controls; P = .04) and a significant decline in levels of UNTX (−56 for ZA group versus −9 for control; P = .04) compared with baseline. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw or renal impairment. Lower survival observed in the ZA cohort was likely related to baseline imbalance in HCT-CI scores. Intermittent ZA is effective in preserving long-term bone health in adult alloHCT recipients at risk for osteoporosis.     

Hematopoietic Stem Cell Transplantation: Current Status of Old Issues

Since 1968 hematopoietic stem cell transplantation (HSCT) has progressed from an experimental to standard therapeutic procedure. There are many obstacles to the successful outcome of HSCT procedures. Some of these obstacles are lack of healthy histocompatible donors, graft versus host disease, graft rejection and infections. Many advances have been made to overcome these obstacles with significant success. However, these issues and associated problems continue to persist at different levels as the field evolves with expanding indications for HSCT, use of alternative sources for hematopoietic stem cells and alternative transplant procedures. Newer interventions have allowed us to overcome some of these obstacles.     

Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs.     

Long-Term Immune Reconstitution and Infection Burden after Mismatched Hematopoietic Stem Cell Transplantation

Mismatched unrelated donor (MMUD) or umbilical cord blood (UCB) can be chosen as alternative donors for allogeneic stem cell transplantation but might be associated with long-lasting immune deficiency. Sixty-six patients who underwent a first transplantation from either UCB (n = 30) or 9/10 MMUD (n = 36) and who survived beyond 3 months were evaluated. Immune reconstitution was prospectively assessed at sequential time points after transplantation. NK, B, CD4⁺, and CD8⁺ T cells and their naïve and memory subsets, as well as regulatory T cells (Treg), were studied. Detailed analyses on infections occurring after 3 months were also assessed. The 18-month cumulative incidences of infection-related death were 8% and 3%, and of infections were 72% and 57% after MMUD and UCB transplantation, respectively. Rates of infection per 12 patient-month were roughly 2 overall (1 for bacterial, .9 for viral, and .3 for fungal infections). Memory, naïve CD4⁺ and CD8⁺T cells, naïve B cells, and Treg cells reconstitution between the 2 sources were roughly similar. Absolute CD4⁺T cells hardly reached 500 per μL by 1 year after transplantation and most B cells were of naïve phenotype. Correlations between immune reconstitution and infection were then performed by multivariate analyses. Low CD4⁺ and high CD8⁺T cells absolute counts at 3 months were linked to increased risks of overall and viral (but not bacterial) infections. When assessing for the naïve/memory phenotypes at 3 months among the CD4⁺ T cell compartment, higher percentages of memory subsets were protective against late infections. Central memory CD4⁺T cells protected against overall and bacterial infections; late effector memory CD4⁺T cells protected against overall, bacterial, and viral infections. To the contrary, high percentage of effector- and late effector-memory subsets at 3 months among the CD8⁺ T cell compartment predicted higher risks for viral infections. Patients who underwent transplantation from alternative donors represent a population with very high risk of infection. Detailed phenotypic analysis of immune reconstitution may help to evaluate infection risk and to adjust infection prophylaxis.     

Impact of Cytomegalovirus Replication and Cytomegalovirus Serostatus on the Outcome of Patients with B Cell Lymphoma after Allogeneic Stem Cell Transplantation

Cytomegalovirus (CMV) replication after allogeneic hematopoietic stem cell transplantation (HSCT) was historically associated with increased nonrelapse mortality (NRM). More recently, different groups have reported an association between CMV replication and reduced risk of acute myeloid leukemia (AML) relapse. Given the conflicting results, we evaluated the impact of CMV replication and other covariates on the outcome of a retrospective cohort of 265 adults with B cell lymphoma receiving allogeneic HSCT from HLA-identical siblings or alternative donors. In time-dependent multivariate analysis, CMV replication, evaluated by pp65 antigenemia, had no independent effect on the risk of relapse (hazard ratio [HR], 1.0; 95% confidence interval [CI], .6 to 1.6; P = .9), although it was associated with a reduced overall survival (HR, 2.0; 95% CI, 1.3 to 3.2; P = .001) and an increased NRM (HR, 2.5; 95% CI, 1.1 to 5.3; P = .01). Consistently, donor and/or recipient CMV seropositivity were not associated with a different outcome relative to CMV double-negative serostatus. In multivariate models, a diagnosis of follicular lymphoma (P < .0001) and pretransplantation complete remission status (P < .0001) were the main independent predictors for improved relapse-free survival. In summary, contrary to what is observed in patients with AML, this report identifies no independent role for CMV replication or serostatus on the relapse of patients with B cell lymphomas undergoing allogeneic HSCT.