Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease

Background aimsThe value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis.MethodsBlood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD).ResultsIncomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003).ConclusionsHigh post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.     

A biomarker-guided,prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin

Background aimsIntensified immunosuppressive prophylaxis for graft-versus-host disease (GVHD) may be toxic and therefore warranted only in patients at high risk of developing GVHD. In patients who underwent allogeneic hematopoietic cell transplant at the authors’ center, high serum soluble IL-2 receptor alpha (sIL-2Rα) and low IL-15 levels on day 7 post-transplant were found to predict a high risk of developing clinically significant GVHD (sGVHD), defined as grade 2–4 acute GVHD or moderate to severe chronic GVHD.MethodsThis was a prospective, phase 2 trial in which high-risk patients (serum sIL-2Rα >4500 ng/L or IL-15 <31 ng/L) received rabbit anti-thymocyte globulin (ATG) 3 mg/kg on day 8 post-transplant. Controls consisted of patients who had their sIL-2Rα/IL-15 levels measured but did not participate in the trial. A total of 68 trial patients and 143 controls were accrued to this study. The primary endpoint was incidence of sGVHD.ResultsThere was a reduction in sGVHD in high-risk trial patients (received day 8 ATG) compared with high-risk controls (did not receive day 8 ATG) (sub-hazard ratio [SHR] = 0.48, P < 0.05). There was no significant difference between the groups in overall survival or relapse; however, there was a greater incidence of non-GVHD-associated non-relapse mortality in high-risk trial patients (SHR = 3.73, P < 0.05), mostly related to infections. This may be due in part to the biomarkers ineffectively stratifying GVHD risk.ConclusionsPre-emptive ATG therapy is both feasible and effective at reducing sGVHD without increasing relapse. Further mitigation strategies are needed to reduce the risk of infection associated with intensified GVHD prophylaxis. This study was registered at ClinicalTrials.gov (NCT01994824).     

Immunotherapy with CD25/CD71-allodepleted T cells to improve T-cell reconstitution after matched unrelated donor hematopoietic stem cell transplant: a randomized trial

Background aimsDelayed immune reconstitution is a major challenge after matched unrelated donor (MUD) stem cell transplant (SCT). In this randomized phase 2 multi-center trial, Adoptive Immunotherapy with CD25/71 allodepleted donor T cells to improve immunity after unrelated donor stem cell transplant (NCT01827579), the authors tested whether allodepleted donor T cells (ADTs) can safely be used to improve immune reconstitution after alemtuzumab-based MUD SCT for hematological malignancies.MethodsPatients received standard of care or up to three escalating doses of ADTs generated through CD25+/CD71+ immunomagnetic depletion. The primary endpoint of the study was circulating CD3+ T-cell count at 4 months post-SCT. Twenty-one patients were treated, 13 in the ADT arm and eight in the control arm.ResultsThe authors observed a trend toward improved CD3+ T-cell count at 4 months in the ADT arm versus the control arm (230/µL versus 145/µL, P = 0.18), and three ADT patients achieved normal CD3+ T-cell count at 4 months (>700/µL). The rates of significant graft-versus-host disease (GVHD) were comparable in both cohorts, with grade ≥2 acute GVHD in seven of 13 and four of eight patients and chronic GVHD in three of 13 and three of eight patients in the ADT and control arms, respectively.ConclusionsThese data suggest that adoptive transfer of ADTs is safe, but that in the MUD setting the benefit in terms of T-cell reconstitution is limited. This approach may be of more use in the context of more rigorous T-cell depletion.     

Pneumocystis Pneumonia: Epidemiology and Options for Prophylaxis in Non-HIV Immunocompromised Pediatric Patients

The pediatric population of non-HIV immunocompromised patients at risk for Pneumocystis pneumonia (PCP) continues to increase. While prophylactic therapy can be highly effective in preventing this opportunistic pathogen, identifying the at-risk populations appropriate for use of prophylaxis and navigating the risks and benefits of each therapeutic option can be challenging. In this article, the available epidemiology for baseline rates of PCP is presented for a variety of non-HIV immunocompromised pediatric populations. Additionally, the comparative effectiveness and side effect profiles for trimethoprim/sulfamethoxazole, dapsone, atovaquone, and pentamidine are discussed. Institutions are encouraged to review the data and to establish and implement a local practice guideline for PCP prophylaxis that can be monitored for effectiveness over time. An example of a standardized practice guideline is suggested.     

Day 4 collection of granulocyte colony-stimulating factor-mobilized HLA-matched sibling donor peripheral blood allografts demonstrates no long-term increase in chronic graft-versus-host disease or relapse rates

Background aimsIn a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD).MethodsThis was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT.ResultsAt 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance.ConclusionsThe authors’ preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors.     

Immune reconstitution in patients with Fanconi anemia after allogeneic bone marrow transplantation

Background aimsFanconi anemia is an autosomal recessive or X-linked genetic disorder characterized by bone marrow (BM) failure/aplasia. Failure of hematopoiesis results in depletion of the BM stem cell reservoir, which leads to severe anemia, neutropenia and thrombocytopenia, frequently requiring therapeutic interventions, including hematopoietic stem cell transplantation (HSCT). Successful BM transplantation (BMT) requires reconstitution of normal immunity.MethodsIn the present study, we performed a detailed analysis of the distribution of peripheral blood subsets of T, B and natural killer (NK) lymphocytes in 23 patients with Fanconi anemia before and after BMT on days +30, +60, +100, +180, +270 and +360. In parallel, we evaluated the effect of related versus unrelated donor marrow as well as the presence of graft-versus-host disease (GVHD).ResultsAfter transplantation, we found different kinetics of recovery for the distinct major subsets of lymphocytes. NK cells were the first to recover, followed by cytotoxic CD8⁺ T cells and B cells, and finally CD4⁺ helper T cells. Early lymphocyte recovery was at the expense of memory cells, potentially derived from the graft, whereas recent thymic emigrant (CD31⁺ CD45RA⁺) and naive CD4⁺ or CD8⁺ T cells rose only at 6 months after HSCT, in the presence of immunosuppressive GVHD prophylactic agents. Only slight differences were observed in the early recovery of cytotoxic CD8⁺ T cells among those cases receiving a graft from a related donor versus an unrelated donor. Patients with GVHD displayed a markedly delayed recovery of NK cells and B cells as well as of regulatory T cells and both early thymic emigrant and total CD4⁺ T cells.ConclusionsOur results support the utility of post-transplant monitoring of a peripheral blood lymphocyte subset for improved follow-up of patients with Fanconi anemia undergoing BMT.     

Safety and Efficacy of Exenatide in Combination with Insulin in Patients with Type 2 Diabetes Mellitus

ObjectiveTo evaluate the 1-year efficacy and safety of treatment with exenatide in combination with insulin (a use not approved by the US Food and Drug Administration).MethodsElectronic medical records of 3 private-practice endocrinologists were reviewed to identify patients with type 2 diabetes mellitus (T2DM) receiving insulin who subsequently began exenatide therapy. Patients’ baseline hemoglobin A1c (A1C) levels, weights, lipid profiles, blood pressures, and medication utilization were compared with corresponding data obtained after a minimal duration of 12 months.ResultsWe identified 134 patients with T2DM initiating exenatide therapy in combination with insulin between April 2005 and April 2006. One-year follow-up information was available for 124 patients. Exenatide use resulted in a significant 0.87% reduction in A1C (P < .001), despite a 45% discontinuation of premeal insulin use (P < .001), a 9-U reduction in mean premeal insulin doses (P = .0066), a reduction in the median number of daily insulin injections from 2 to 1 (P = .0053), and a 59% discontinuation rate of sulfonylurea use (P = .0088). Exenatide use was associated with a mean weight loss of 5.2 kg (P < .001), with 72% of evaluable patients losing weight. Forty-eight patients (36%) discontinued exenatide therapy during the first year, primarily attributable to gastrointestinal intolerance. Fourteen patients (10%) experienced hypoglycemia, most of which was mild.ConclusionExenatide in combination with insulin in patients with T2DM was associated with significant reductions in A1C and weight after 1 year of therapy. This was offset, however, by an exenatide discontinuation rate of 36%, primarily due to adverse gastrointestinal effects. (Endocr Pract. 2008;14:285-292)     

Early immune reconstitution as predictor for outcomes after allogeneic hematopoietic cell transplant; a tri-institutional analysis

Background aimsCD4 immune reconstitution (IR) after allogeneic hematopoietic cell transplant (allo-HCT) correlates with lower non-relapse mortality (NRM), but its impact on leukemia relapse remains less clear, especially in children. We studied the correlation between IR of lymphocyte subsets and HCT outcomes in a large cohort of children/young adults with hematological malignancies.MethodsWe retrospectively analyzed CD4, CD8, B-cell and natural killer (NK) cell reconstitution in patients after first allo-HCT for a hematological malignancy at three large academic institutions (n = 503; period 2008–2019). We used Cox proportional hazard and Fine–Gray competing risk models, martingale residual plots and maximally selected log-rank statistics to assess the impact of IR on outcomes.ResultsAchieving CD4 >50 and/or B cells >25 cells/μL before day 100 after allo-HCT was a predictor of lower NRM (CD4 IR: hazard ratio [HR] 0.26, 95% confidence interval [CI] 0.11–0.62, P = 0.002; CD4 and B cell IR: HR 0.06, 95% CI 0.03–0.16, P < 0.001), acute graft-versus-host disease (GVHD) (CD4 and B cell IR: HR 0.02, 95% CI 0.01–0.04, P < 0.001) and chronic GVHD (CD4 and B cell IR: HR 0.16, 95% CI 0.05–0.49, P = 0.001) in the full cohort, and of lower risk of relapse (CD4 and B cell IR: HR 0.24, 95% CI 0.06–0.92, P = 0.038) in the acute myeloid leukemia subgroup. No correlation between CD8 and NK-cell IR and relapse or NRM was found.ConclusionsCD4 and B-cell IR was associated with clinically significant lower NRM, GVHD and, in patients with acute myeloid leukemia, disease relapse. CD8 and NK-cell IR was neither associated with relapse nor NRM. If confirmed in other cohorts, these results can be easily implemented for risk stratification and clinical decision making.     

Less Graft-Versus-Host Disease after Rabbit Antithymocyte Globulin Conditioning in Unrelated Bone Marrow Transplantation for Leukemia and Myelodysplasia: Comparison with Matched Related Bone Marrow Transplantation

One of the major drawbacks for unrelated donor (UD) bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Despite results from randomized trials, antithymocyte globulin (ATG) is not routinely included for GVHD prophylaxis in UD BMT by many centers. One of ways to demonstrate the usefulness of rabbit ATG in UD BMT is to evaluate how its results approximate to those observed in matched related (MRD) BMT. Therefore, we compared the outcomes between UD BMT with rabbit ATG (Thymoglobulin) for GVHD prophylaxis (n = 25) and MRD BMT (n = 91) for leukemia and myelodysplasia. All but one patient received a myeloablative conditioning regimen. Grades II–IV acute GVHD were similar (39.5% vs. 36%, p = 0.83); however, MRD BMT recipients developed more moderate-severe chronic GVHD (36.5% vs. 8.6%, p = 0.01) and GVHD-related deaths (32.5% vs. 5.6%, p = 0.04). UD BMT independently protected against chronic GVHD (hazard ratio 0.23, p = 0.04). The 6-month transplant-related mortality, 1-year relapse incidence, and 5-year survival rates were similar between patients with non-advanced disease in the MRD and UD BMT groups, 13.8% vs. 16.6% (p = 0.50), 20.8% vs. 16.6% (p = 0.37), and 57% vs. 50% (p = 0.67), respectively. Stable full donor chimerism was equally achieved (71.3% vs. 71.4%, p = 1). Incorporation of rabbit ATG in UD BMT promotes less GVHD, without jeopardizing chimerism evolution, and may attain similar survival outcomes as MRD BMT for leukemia and myelodysplasia especially in patients without advanced disease.     

Infusion of haploidentical hematopoietic stem cells combined with mesenchymal stem cells for treatment of severe aplastic anemia in adult patients yields curative effects

Background aimsDespite the great advances in immunosuppressive therapy for severe aplastic anemia (SAA), most patients are not completely cured. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been recommended as an alternative treatment in adult SAA patients. However, haplo-HSCT presents a higher incidence of graft failure and graft-versus-host disease (GVHD). The authors designed a combination of haplo-HSCT and umbilical cord-derived mesenchymal stem cells (UC-MSCs) for treatment of SAA in adult patients and evaluated its effects.MethodsAdult patients (≥18 years) with SAA (N = 25) were given HLA-haploidentical hematopoietic stem cells (HSCs) combined with UC-MSCs after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin and intensive GVHD prophylaxis, including cyclosporine, basiliximab, mycophenolate mofetil and short-term methotrexate. Additionally, the effects of the protocol in adult SSA patients were compared with those observed in juvenile SAA patients (N = 75).ResultsAll patients achieved myeloid engraftment after haplo-HSCT at a median of 16.12 days (range, 11–26). The median time of platelet engraftment was 28.30 days (range, 13–143). The cumulative incidence of grade II acute GVHD (aGVHD) at day +100 was 32.00 ± 0.91%. No one had grade III–IV aGVHD at day +100. The cumulative incidence of total chronic GVHD was 28.00 ± 0.85%. The overall survival was 71.78 ± 9.05% at a median follow-up of 42.08 months (range, 2.67–104). Promisingly, the protocol yielded a similar curative effect in both young and adult SAA patients.ConclusionsThe authors’ data suggest that co-transplantation of HLA-haploidentical HSCs and UC-MSCs may provide an effective and safe treatment for adult SAA.     

Bone marrow haploidentical transplant with post-transplantation cyclophosphamide: does graft cell content have an impact on main clinical outcomes?

We analyzed data relative to cell content in 88 consecutive patients receiving HLA haploidentical bone marrow (BM) transplants with post-transplantation cyclophosphamide (PT-CY). Median age was 54.5 (range, 17–72); diagnoses were acute leukemia (n = 46), lymphoproliferative disorders (n = 24), myelofibrosis (n = 11) and myelodysplastic syndromes (n = 5). Total nucleated cell (TNC) and CD34+, CD3+, CD4+ and CD8+ cell doses were stratified as higher than first, second and third quartile and the dose effect on various clinical outcomes was assessed. Median time to engraftment was 17 days for neutrophils and 24 days for platelets. To receive a dose of TNC ≥3.2 x 10⁶/kg or CD34+ cells ≥2.7 x 10⁶/kg significantly shortened the time to neutrophil and platelet engraftment and reduced the blood product requirements in the 30-day period after transplantation. Overall, TNC and CD34+ cell doses had no effect on acute graft-versus-host disease (GVHD) incidence, whereas patients receiving higher CD3+ and CD8+ cell doses seemed to have less chronic GVHD. No effect on non-relapse mortality, progression-free survival and overall survival was observed at different cell dose thresholds. These data suggest that in HLA haploidentical BM transplant with PT-CY, appropriate cell doses are relevant to the engraftment. The association between low CD3+/CD8+ cells and chronic GVHD deserves further investigation.     

Predictors of Prolonged Euthyroidism After Radioactive Iodine Treatment for Graves’ Disease: A Pilot Study

ObjectivePatients with Graves’ disease who remain hyperthyroid under the treatment of antithyroid drugs (ATD) or cannot tolerate ATD usually receive radioactive iodine (RAI) to control disease activity. This pilot study aimed to identify predictors of prolonged euthyroidism > 12 months after receiving RAI.MethodsDemographic, clinical, and laboratory data from 117 patients receiving RAI were retrospectively collected, including age, gender, body surface area, smoking status, free thyroxine, thyrotropin, thyrotropin binding inhibiting immunoglobulin, microsomal antibody, thyroglobulin antibody, medication history, and thyroid volume. Only 85 patients without missing values were included in statistical analysis. The calculated RAI dose was the estimated thyroid volume × 0.4. The difference and ratio between the actual and calculated RAI doses were examined. A stepwise logistic regression analysis was conducted to identify important predictors of prolonged euthyroidism > 12 months. The cut-off values for discretizing continuous covariates were estimated by fitting generalized additive models.ResultsAmong the 85 patients on RAI, 18 (21.2%) achieved prolonged euthyroidism > 12 months, 38 (44.7%) remained hyperthyroid with decreased ATD doses, but 29 (34.1%) suffered permanent hypothyroidism and needed long-term levothyroxine. Logistic regression analysis revealed that patients with age > 66 years, 33 < age ≤ 66 years, quitting smoking vs nonsmoking or current smoking, 600 < micorsomal antibody ≤ 1729 IU/mL, 47% < thyrotropin binding inhibiting immunoglobulin ≤ 81%, 7 < thyroglobulin antibody ≤ 162 IU/mL, 0.63 < ratio between actual and calculated RAI doses ≤ 1.96, or taking hydroxychloroquine would have a higher chance of reaching prolonged euthyroidism > 12 months after receiving RAI. Its area under the Receiver Operating Characteristic (ROC) curve was 0.932.ConclusionPatients with Graves’ disease who received an actual RAI dose close to the calculated RAI dose achieved prolonged euthyroidism > 12 months if they also took hydroxychloroquine during RAI treatment.     

The impact of cytomegalovirus infection on clinical severity and outcomes in kidney transplant recipients with Pneumocystis jirovecii pneumonia

Cytomegalovirus (CMV) infection is associated with Pneumocystis jirovecii pneumonia (PJP) in kidney transplant recipients (KTRs), but its impact on clinical severity and outcomes in KTRs with PJP is unknown. We reviewed 1994 medical records of KTRs from January 1997 to March 2019. PJP or CMV infection was diagnosed by polymerase chain reaction or culturing using blood or respiratory specimens. We divided patients into PJP and PJP+CMV groups, and evaluated the clinical severity and outcomes. Fifty two patients had PJP (2.6%) in the whole study cohort. Among patients with PJP, 38 (73.1%) had PJP alone and 14 (26.9%) had combined PJP and CMV co-infection. The PJP+CMV group showed worse laboratory findings (serum albumin and C-reactive protein, P = 0.010 for both) and higher requirement of continuous renal replacement therapy than the PJP group (P = 0.050). The pneumonia severity was worse in the PJP+CMV group than in the PJP group (P < 0.05), and CMV infection was a high risk factor of pneumonia severity (odds ratio 16.0; P = 0.002). The graft function was worse in the PJP+CMV group (P < 0.001), and the incidence of graft failure was higher in the PJP+CMV group than in the PJP group (85.7% vs 36.8%; P < 0.001). Mortality was double in the PJP+CMV group than in the PJP group, but not statistically significant (21.4% vs 10.5%; P = 0.370). Our results show that approximately one in four patients with PJP after kidney transplantation develops CMV with increased clinical severity and risk of graft failure. The possibility of increased clinical severity and worse clinical outcomes by CMV co-infection should be considered in KTRs with PJP.     

Hematopoietic stem cell transplantation with umbilical cord multipotent stromal cell infusion for the treatment of aplastic anemia—a single-center experience

Background aimsThe purpose of this study was to observe the outcome of co-transfusion of umbilical cord multipotent stromal cells (UC-MSC) and allogeneic hematopoietic stem cells in the treatment of heavily-transfused patients with severe aplastic anemia.MethodsOf the 22 patients, eight cases received haploidentical hematopoietic stem cells from granulocyte colony-stimulating factor–primed bone marrow and peripheral blood grafts; the other patients received granulocyte colony-stimulating factor–mobilized peripheral blood grafts from human leukocyte antigen–matched related (six cases) and unrelated donors (eight cases). MSCs were intravenously infused at a mean dose of 1.2 × 10⁶/ kg (range, 0.27–2.5 × 10⁶/kg). Fludarabine-based conditioning was conducted, and graft-versus-host disease prophylaxis containing cyclosporine A, methotrexate and mycophenolate mofetil with or without addition of anti-CD25 monoclonal antibody was performed. Hematopoietic engraftment, the occurrence of graft-versus-host disease (GVHD) and infections and overall survival were documented.ResultsAll patients had rapid engraftment; mean time for neutrophil and platelet recovery was 13.95 d and 20.27 d, respectively. No acute toxicity associated with UC-MSC transfusion was observed. Acute GVHD developed in seven cases (grade I–II), and none had development of chronic GVHD. Cytomegalovirus reactivation was observed in 11 cases. One patient died of pulmonary complication 6 months after transplantation. Twenty-one patients are currently alive, at a median follow-up of 15 months; they are transfusion-independent and reached full donor chimerism at the time of reporting.ConclusionsUC-MSC infusion might be an alternative option to promote hematopoietic engraftment and reduce the occurrence of GHVD in hematopoietic stem cell transplantation in the treatment of heavily transfused patients with severe aplastic anemia.     

Lowering the alemtuzumab dose in reduced intensity conditioning allogeneic hematopoietic cell transplantation is associated with a favorable early intense natural killer cell recovery

Background aimsThe anti-CD52 monoclonal antibody alemtuzumab is employed in allogeneic hematopoietic cell transplantation (alloHCT) for the prevention of graft-versus-host disease (GVHD). However, its optimal dosing in this setting has not been determined yet. We compared three different alemtuzumab dose levels in reduced intensity conditioning (RIC) alloHCT with respect to lymphocyte recovery and outcome.MethodsIn 127 consecutive patients with predominantly advanced stage hematologic malignancies, a first alloHCT after RIC was performed, applying a fludarabine-based protocol (in 93% FBM: fludarabine, bis-chloroethyl-nitrosourea [BCNU], and melphalan). For GVHD prophylaxis, cyclosporine and alemtuzumab at three different dose levels (40 mg, 20 mg, 10 mg) were administered. Recovery of the peripheral blood (PB) lymphocyte sub-populations and clinical outcome were determined with regard to the alemtuzumab dose.ResultsNatural killer (NK) cell concentrations in PB around day +30 correlated inversely with the alemtuzumab dose, whereas other PB lymphocyte subtypes remained essentially unaffected by dosing of alemtuzumab. Lower alemtuzumab doses were associated with a tendency toward improved overall survival mainly during the early post-transplantation months. With regard to the PB NK cell concentration around day +30, “early intense NK cell reconstituters” tended to show an overall survival benefit.ConclusionsAn alemtuzumab dose reduction to only 10–20 mg provides sufficient GVHD prophylaxis and supports improved NK cell regeneration early after alloHCT in PB (“NK cell saving effect”), which may have a positive effect on overall survival.     

Impact of chronicity of injury on the proportion of mesenchymal stromal cells derived from anterior cruciate ligaments

Background aimsThe graft-healing potential of mesenchymal stromal cells (MSCs) derived from the remnants of ruptured anterior cruciate ligaments (ACLs) after ACL reconstruction may depend on the chronicity of the injury. The aim of this study was to assess the quantitative and phenotypic differences between MSCs isolated from ACL remnants in patients with (sub)acute and chronic tearing.MethodsTorn ACL remnants were harvested during ACL reconstruction from 41 patients, 24 with (sub)acute ACL (<6 months from injury to surgery) and 17 with chronic ACL (time interval >6 months) tears. MSCs isolated from these samples were assessed for quantitative and phenotypic differences, and the correlation between the proportion of MSCs and the chronicity of ACL tear was evaluated.ResultsAt passage 0, the mean proportion of MSCs (CD34⁻, CD44⁺, CD90⁺ and CD105⁺) was higher in (sub)acute than in chronic ACL tear samples (20.69% ± 7.82% versus 9.85% ± 8.01%, P < 0.001). At passages 1 and 2, however, MSC proportions did not differ significantly in the two groups. Time interval showed a negative correlation with MSC proportion only at passage 0 (r = −0.505, P < 0.001). The optimal cutoff value for time from injury to surgery yielding <10% freshly isolated ACL-MSCs, a percentage expected to have low tissue healing potential, was 23.5 months.ConclusionsThe proportion of freshly isolated MSCs was higher in samples from patients with (sub)acute tearing than in chronic ACL tearing and negatively correlated with the time interval between trauma and surgery.     

Advantages of peripheral blood stem cells from unrelated donors versus bone marrow transplants in outcomes of adult acute myeloid leukemia patients

Background aimsIn allogeneic stem cell transplantation, unrelated donors are chosen in cases where appropriate related donors are not available. Peripheral blood stem cells (PBSCs) are more often selected as a graft source than bone marrow (BM). However, the prognostic benefits of PBSCs versus BM transplants from unrelated donors have not been carefully examined in patients with acute myeloid leukemia (AML). This study compared outcomes of adult AML patients who underwent unrelated PBSC and BM transplantation, evaluating post-transplant complications, including engraftment, graft-versus-host disease (GVHD) and infections, and determined subgroups of patients who are most likely to benefit from unrelated PBSCs compared with BM transplants.MethodsThe authors analyzed 2962 adult AML patients who underwent unrelated PBSC or BM transplants between 2011 and 2018 (221 PBSC and 2741 BM) using the Japanese nationwide registry database, in which graft source selection is not skewed toward PBSCs.ResultsIn 49.7% of patients, disease status at transplantation was first complete remission (CR1). In 57.1% of cases, HLA-matched donors were selected. Myeloablative conditioning was performed in 75.1% of cases, and anti-thymocyte globulin (ATG) was added to conditioning in 10.5%. Multivariate analyses showed a trend toward favorable non-relapse mortality (NRM) in PBSC recipients compared with BM recipients (hazard ratio [HR], 0.731, P = 0.096), whereas overall survival (OS) (HR, 0.959, P = 0.230) and disease-free survival (DFS) (HR, 0.868, P = 0.221) were comparable between PBSC and BM recipients. Although the rate of chronic GVHD (cGVHD) was significantly higher in PBSC patients (HR, 1.367, P = 0.016), NRM was not increased, mainly as a result of significantly reduced risk of bacterial infections (HR, 0.618, P = 0.010), reflecting more prompt engraftments in PBSC recipients. Subgroup analyses revealed that PBSC transplantation was advantageous in patients transplanted at CR1 and in those without ATG use. PBSC recipients experienced significantly better OS and/or DFS compared with BM recipients in this patient group.ConclusionsThe authors' results confirmed the overall safety of unrelated PBSC transplantation for adult AML patients and suggested an advantage of PBSCs, especially for those in CR1. Further optimization of the prophylactic strategy for cGVHD is required to improve the overall outcome in transplantation from unrelated PBSC donors.     

Iatrogenic Cushing Syndrome in Patients Receiving Inhaled Budesonide and Itraconazole or Ritonavir: Two Cases and Literature Review

ObjectiveTo present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole.MethodsWe present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options.ResultsA 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 µg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 µg/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 µg/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation.ConclusionClinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir. (Endocr. Pract. 2013;19:e138-e141)     

Finding safe dose-volume constraints for re-irradiation with SBRT of patients with prostate cancer relapse: The IEO experience

AimThe primary aim of this study is to provide preliminary indications for safe constraints of rectum and bladder in patients re-irradiated with stereotactic body RT (SBRT).MethodsData from patients treated for prostate cancer (PCa) and intraprostatic relapse, from 1998 to 2016, were retrospectively collected. First RT course was delivered with 3D conformal RT techniques, SBRT or volumetric modulated arc therapy (VMAT). All patients underwent re-irradiation with SBRT with heavy hypofractionated schedules. Cumulative dose-volume values to organs at risk (OARs) were computed and possible correlation with developed toxicities was investigated.ResultsTwenty-six patients were included. Median age at re-irradiation was 75 years, mean interval between the two RT courses was 5.6 years and the median follow-up was 47.7 months (13.4–114.3 months). After re-irradiation, acute and late G ≥ 2 GU toxicity events were reported in 3 (12%) and 10 (38%) patients, respectively, while late G ≥ 2 GI events were reported in 4 (15%) patients. No acute G ≥ 2 GI side effects were registered. Patients receiving an equivalent uniform dose of the two RT treatments < 131 Gy appeared to be at higher risk of progression (4-yr b-PFS: 19% vs 33%, p = 0.145). Cumulative re-irradiation constraints that appear to be safe are D_30% < 57.9 Gy for bladder and D_30% < 66.0 Gy, D_60% < 38.0 Gy and V_{122.1 Gy} < 5% for rectum.ConclusionPreliminary re-irradiation constraints for bladder and rectum have been reported. Our preliminary investigation may serve to clear some grey areas of PCa re-irradiation.