Salivary Proteomic Analysis and Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), developing in 35%-70% of all allo-HSCT recipients despite immunosuppressive prophylaxis. The recent application of proteomic tools that allow screening for differentially expressed or excreted proteins in body fluids could possibly identify specific biomarkers for GVHD. Whole saliva is highly attractive for noninvasive specimen collection. In the present study, we collected saliva specimens from 40 consecutives patients who underwent allo-HSCT between December 2008 and March 2011 at our institution. The specimens were analyzed by HPLC coupled to electrospray-ionization mass spectrometry. Variable expression of S100 protein family members (S100A8, S100A9, and S100A7) was detected. Fourteen of 23 patients with GVHD demonstrated the presence of S100A8, compared with only 2 patients without GVHD and 0 patients in the control group (P = .001). S100A7 was detectable in 11 of the 23 patients with GVHD but was absent in the other 2 groups (P = .0001). S100A9-short was detected in 20 patients with GVHD, in 9 patients without GVHD, and in 8 healthy volunteers (P = .01) Further studies are needed to clarify the role of these proteins as a marker of GVHD or as an index of mucosal inflammation.     

HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n?=?31; UD: n?=?30; HRD: n?=?33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P?=?.006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P?=?.487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P?=?.411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P?=?.709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML.     

T Cell–Depleted Stem Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia: Long-Term Survival for Patients in First Complete Remission with a Decreased Risk of Graft-versus-Host Disease

Consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a survival benefit to patients with acute lymphoblastic leukemia (ALL). We have previously reported comparable survival and relapse rates after T cell–depleted (TCD) allo-HSCT compared with unmodified transplantations for acute myelogenous leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma with significantly decreased graft-versus-host disease (GVHD). We performed a 56-patient retrospective study to evaluate TCD allo-HSCT for the treatment of ALL after myeloablative total body irradiation–based therapy. The 2-year and 5-year overall survival rates for patients with ALL after TCD allo-HSCT were 0.39 (95% confidence interval [CI], 0.26-0.52) and 0.32 (95% CI, 0.19-0.44), respectively, and the 2-year and 5-year disease-free survival rates were 0.38 (95% CI, 0.25-0.50) and 0.32 (95% CI, 0.20-0.44). There was a trend toward improved survival of patients who underwent TCD allo-HSCT in first complete remission compared with those who did so in other remission states. The cumulative incidence of grade II-IV acute GVHD at 1 year was 0.20 (95% CI, 0.10-0.31), and no patients developed grade IV acute GVHD. The cumulative incidence of chronic GVHD in 41 evaluable patients at 2 and 5 years was 0.15 (95% CI, 0.04-0.26), and that of extensive chronic GVHD at 2 and 5 years was 0.05 (95% CI, 0-11.6). We demonstrate OS and DFS rates that compare favorably to unmodified allo-HSCT with lower rates of GVHD.     

Kinetics and Risk Factors of Relapse after Allogeneic Stem Cell Transplantation in Children with Leukemia: A Long-Term Follow-Up Single-Center Study

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment for high-risk hematological malignancies in the pediatric population, but relapse remains the leading cause of death. We analyzed risk factors associated with relapse.Data from 353 allo-HSCTs from 1989 to 2015 in our center were studied retrospectively. We performed a multivariate analysis of pre- and postransplantation variables and developed a predictive risk score for relapse using the significant factors in this training cohort. The results were confirmed in a validation cohort of 90 allo-HSCTs done in our institution from 2016 to the present.A total of 104 patients relapsed after allo-HSCT, with a relapse cumulative incidence of 31 ± 2%. In multivariate analysis, only 2 variables influenced relapse: disease phase (advanced versus early, HR, 2.84; 95% CI, 1.76 to 4.57; P?=?.001) and presence of chronic graft-versus-host disease (GVHD) (acute GVHD versus chronic GVHD [HR, 4.27; 95% CI, 1.99 to 9.15; P?=?.0001] and no GVHD versus chronic GVHD [HR, 6.86; 95% CI, 3.63 to 12.97] P?=?.0001]. Applying the personalized risk score (0 to 3), the relapse cumulative incidence was 70 ± 5% in patients with a score of 3 (without GVHD and in the advanced phase) compared with 6 ± 4% in patients with a score of 0 (with chronic GVHD and in an early phase). This score has been verified in the validation set. With a median follow-up of 54 months, the disease-free survival (DFS) and overall survival rate were 37 ± 3% and 45 ± 4%, respectively.The association of GVHD with the graft-versus-leukemia effect is clearly established in our study, and the form of GVHD associated with less relapse and the best DFS is the classical form of chronic GVHD according to the National Institutes of Health classification. The proposed relapse risk score was validated in an independent cohort and allows personalization of the prognosis.     

The uncoupled couple? Prolactin and CD4 lymphocytes in HIV infection

The possible role of prolactin (PRL) in human immunodeficiency virus (HIV) infection is unknown, despite the modulatory role of this hormone in humoral and cell-mediated immune responses. Recent studies have evidenced: (a) intralymphocyte synthesis of dopamine (DA) which down-regulates their own proliferation and differentiation; (b) decreased DA but increased PRL concentrations in cerebrospinal fluid of HIV-infected men; and (c) diminished hypothalamic DA tone in HIV-infected men. The present hypothesis proposes that, in HIV-infected men, a diminished generalized DA tone exists to stimulate human lymphocyte proliferation and differentiation at a maximum possible rate by: (1) decreasing the inhibitory influence of intralymphocyte DA; and (2) maintaining pituitary and extrapituitary (i.e. lymphocyte) PRL synthesis and release as high as possible. If this hypothesis is correct, it may have a potentially important therapeutic implication: the possibility to rebuild the battered immune system in HIV-infected patients from inside the body in a physiologic manner by the parenteral administration of recombinant human PRL.     

Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation

Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution. In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P = .0427 compared with patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P = .012), and flow cytometric analyses revealed lower numbers of CD19⁺ B cells and a significantly increased CD4 to CD8 ratio (P = .0002) in these patients. Our data, for the first time to our knowledge, summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients.     

Acute dopaminergic blockade augments the naloxone-induced LH rise in estrogen-treated postmenopausal women

Objectives: To assess the effect of estrogen replacement on the simultaneous blockade of the dopaminergic (DA) and opioidergic neural control of hypothalamic-gonadotropic function in postmenopausal women. Methods: Twenty healthy postmenopausal women, 48–55 years old were randomly assigned to receive either a 4-h naloxone infusion at 2 mg/h (group 1, n = 7) or a 10 mg i.v. bolus of metoclopramide (group 2, n = 7) or both drugs, simultaneously (group 3, n = 6) before and after 3 weeks of transdermal estradiol (100 μg/day). Blood samples were obtained at 30-min intervals during 4 h and duplicate determinations of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E₂) and prolactin (PRL) were performed in all samples. Results: In group 1 only a mild but significant LH rise after but not before estrogen replacement was seen. In group 2 PRL had a greater rise after than before estrogen therapy, without other hormonal changes. In group 3 a greater rise in PRL occurred after than before estrogen administration and serum LH had a sustained rise throughout the test only after estrogen replacement (greater than in group 1). No FSH changes were observed. The after-estradiol PRL response was nearly similar in groups 2 and 3. Conclusions: Our results indicate that in the untreated postmenopausal women, the dopaminergic system has little and the opioidergic system has no significant input in the control of gonadotropin or prolactin release. However, following estrogen replacement, opioids are involved in the inhibition of LH release and stimulating PRL release, while the dopaminergic system acts to inhibit PRL release and modulates LH release or inhibition, depending on the levels of circulating estrogens.     

Prolactin and growth hormone secretion after thyrotrophin-releasing hormone infusion and dopaminergic (DA2) blockade in infertile patients with minimal/mild endometriosis

BACKGROUND: The origin of infertility in patients with endometriosis without tubal occlusion has not yet been clearly defined. Several reports show an abnormal pituitary-ovarian axis in this group of patients. Moreover, prolactin (PRL) and growth hormone (GH) secretion is closely related to reproductive status. This study aimed to evaluate PRL and GH secretion after metoclopramide and thyrotrophin-releasing hormone (TRH) infusion in infertile patients with minimal/mild endometriosis. METHODS: A total of 64 women participated in the study: 33 fertile patients without endometriosis; 10 fertile patients with minimal/mild endometriosis; and 21 infertile patients with minimal/mild endometriosis. TRH or metoclopramide was administered randomly in two sequential menstrual cycles (cycle days 3-5). Serum PRL and GH secretion before and after dopaminergic type 2 (DA2) receptor blockade and TRH were compared. RESULTS: Higher serum PRL levels were observed in patients with endometriosis at baseline and after 15 and 30 min of TRH administration. Also, infertile patients with endometriosis had lower serum estradiol levels than fertile patients. Moreover, the dopaminergic blockade did not result in abnormal PRL or GH secretion. CONCLUSIONS: Decreased serum estradiol levels and altered PRL secretion after TRH administration in infertile patients with minimal/mild endometriosis are related to ovulatory dysfunction and infertility in this group of patients without tubal occlusion.     

Evaluation of hypothalamic-pituitary-adrenal axis in amenorrhoeic women with insulin-dependent diabetes

Diabetes is associated with a higher incidence of secondary hypogonadotrophic amenorrhoea. In amenorrhoeic women with insulin-dependent diabetes a derangement in hypothalamic-pituitary-ovary axis has been proposed. No data exist on hypothalamic-pituitary-adrenal function in these women. Gonadotrophin releasing hormone (GnRH), corticotrophin releasing hormone (CRH), metoclopramide and thyroid releasing hormone (TRH) tests were performed in 15 diabetic women, eight amenorrhoeic (AD) and seven eumenorrhoeic (ED). Frequent blood samples were taken during 24 h to evaluate cortisol plasma concentrations. There were no differences between the groups in body mass index, duration of diabetes, insulin dose and metabolic control. The AD women had lower plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, oestradiol, androstenedione and 17-hydroxyprogesterone (17-OHP) than the ED women. The responses of pituitary gonadotrophins to GnRH, and of thyroid stimulating hormone (TSH) to TRH, were similar in both groups. The AD women had a lower prolactin response to TRH and metoclopramide, and lower ACTH and cortisol responses to CRH, than the ED women. Mean cortisol concentrations > 24 h were higher in the amenorrhoeic group. Significant differences in cortisol concentrations from 2400 to 1000 h were found between the two groups. Insulin-dependent diabetes may involve mild chronic hypercortisolism which may affect metabolic control. Stress-induced activation of the hypothalamic-pituitary-adrenal axis would increase hypothalamic secretion of CRH. This would lead directly and perhaps also indirectly by increasing dopaminergic tonus to inhibition of GnRH secretion and hence hypogonadotrophic amenorrhoea. Amenorrhoea associated with metabolically controlled insulin-dependent diabetes is a form of functional hypothalamic amenorrhoea that requires pharmacological and psychological management.     

Comparison of Characteristics of Bacterial Bloodstream Infection between Adult Patients with Allogeneic and Autologous Hematopoietic Stem Cell Transplantation

Although autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are fundamentally different procedures, a tailored approach to bacterial bloodstream infection (BSI) according to the type of HSCT has not yet been suggested. We evaluated the characteristics of BSI after HSCT, with a focus on comparison of BSIs between recipients of autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT). Among 134 patients (59 received allo-HSCT and 75 received auto-HSCT) who underwent HSCT, BSIs were reported earlier in patients who underwent auto-HSCT, compared with those who underwent allo-HSCT (mean 12.1 ± 3.4 days versus 32.8 ± 27.1 days, P = .006). Among patients receiving allo-HSCT, postneutrophil-engraftment bacterial BSI showed an association with grade ≥2 acute graft-versus-host disease (GVHD). In patients who underwent auto-HSCT, results of multivariate analysis showed that not receiving prophylactic antibiotics (P = .004) and having elevated serum C-reactive protein (P = .034) were risk factors of BSI. Elevated CRP (P = .01) and acute GVHD ≥ grade 2 (P = .002) were independent risk factors in patients who underwent allo-HSCT. Those differences originated mainly from the impact of acute GVHD-related postengraftment BSIs of patients who underwent allo-HSCT. To establish the best defense strategy against BSI, the distinctive natures of bacterial BSI after HSCT between auto-HSCT and allo-HSCT should be considered.     

Clofarabine and Treosulfan as Conditioning for Matched Related and Unrelated Hematopoietic Stem Cell Transplantation: Results from the Clo3o Phase II Trial

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m² (days -6 to -2) and treosulfan 14 g/m² (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (n = 22) or a well-matched unrelated donor (n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.     

Ex Vivo T Cell-Depleted Hematopoietic Stem Cell Transplantation for Adult Patients with Acute Myelogenous Leukemia in First and Second Remission: Long-Term Disease-Free Survival with a Significantly Reduced Risk of Graft-versus-Host Disease

Large series of patients with acute myelogenous leukemia (AML) after ex vivo T cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) have not been reported previously. We retrospectively analyzed the outcomes of 266 patients (median age, 54 years) with AML who received CD34-selected TCD allo-HSCTs while in first (75%) or second (25%) complete remission (CR1/CR2) at a single institution. The conditioning regimens were all myeloablative, and no additional graft-versus-host disease (GVHD) prophylaxis was given. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 180 days were 14% (95% confidence interval [CI], 10% to 18%) and 3% (95% CI, 1% to 5%), respectively. The cumulative incidence of chronic GVHD at 3 years was 3% (95% CI, 1% to 6%). The 3-year cumulative incidence of nonrelapse mortality was 21% (95% CI, 16% to 26%) and that of relapse was 21% (95% CI, 17% to 27%). Overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years were 75%, 61%, and 56% and 68%, 57%, and 53%, respectively. There were no significant differences in OS, DFS, and relapse rates for patients who underwent transplantation in CR1 and those who did so in CR2. However, patients with high-risk cytogenetics at diagnosis had significantly poorer outcomes. The OS and DFS rates compare favorably with those for unmodified allo-HSCT, but with considerably lower rates of GVHD.     

Excellent Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Single-Center Study

We analyzed the outcomes of 44 patients with paroxysmal nocturnal hemoglobinuria (PNH) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) (haploidentical [haplo]-donors, 25; matched sibling donors [MSDs], 15; and matched unrelated donors, 4) between July 2007 and May 2018. All patients achieved successful donor engraftment. The median time was 12 days (range, 7 to 26) for myeloid engraftment and 13 days (range, 11 to 75) for platelets. The cumulative incidences were 15.91% and 2.27% for grades II to IV and grades III to IV acute graft-versus-host disease (GVHD), respectively, with a median follow-up time of 36 months (range, 4 to 132). The cumulative incidences were 26.73% for chronic GVHD and 9.70% for moderate to severe chronic GVHD. No patients relapsed. The probabilities of 3-year overall survival (OS) and GVHD-free, failure-free survival (GFFS) were 90.4% ± 4.6% and 85.6% ± 5.4%, respectively. The 3-year OS rates of the haplo-donor and MSD groups were 86.5% ± 7.3% versus 93.3% ± 6.4% (P = .520). The 3-year GFFS rates of the haplo-donor and MSD groups were 78.3% ± 8.6% versus 92.9% ± 6.9% (P = .250). The preliminary results indicated that allo-HSCT is a feasible option for patients with PNH; however, this should not be considered as a first-choice therapy, because the results seemed to only suggest rather than confirm that haplo-HSCT and MSD-HSCT exerted similar therapeutic efficacies.     

Conditioning Regimen of 5-Day Decitabine Administration for Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome and Myeloproliferative Neoplasms

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). However, post-HSCT relapse remains a major cause of treatment failure. Here we assessed the efficacy of a new conditioning regimen comprising decitabine (Dec), busulfan (Bu), cyclophosphamide (Cy), fludarabine (Flu), and cytarabine (Ara-c) for allo-HSCT in patients with MDS and MDS/MPN. A total of 48 patients were enrolled, including 44 with MDS and 4 with chronic myelomonocytic leukemia (CMML). Patients received Dec 20 mg/m²/day on days -9 to -5, combined with a Bu/Cy/Flu/Ara-c-modified preparative regimen. At a median follow-up of 522 days (range, 15 to 1313 days), the overall survival (OS) was 86%, relapse incidence was 12%, and nonrelapse mortality was 12%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 23% and that of chronic GVHD was 15%. At 2 years, OS was 74% and 86%, respectively for high-risk and very-high-risk patients with MDS. Survival was promising in patients with poor-risk gene mutations, such as TP53 and ASXL1 (88%), and in those with ≥3 gene mutations (79%). Results of immunomonitoring studies revealed that proper natural killer cells made essential contributions to these favorable clinical outcomes. Overall, this new regimen was associated with a low relapse rate, low incidence and severity of GVHD, and satisfactory survival in allo-HSCT recipients with MDS and MDS/MPN.     

Preconditioning Absolute Lymphocyte Count and Transplantation Outcomes in Matched Related Donor Allogeneic Hematopoietic Stem Cell Transplantation Recipients with Reduced-Intensity Conditioning and Antithymocyte Globulin Treatment

The integration of antithymocyte globulin (ATG) into therapy has significantly reduced the incidence of graft-versus-host disease (GVHD) and is being actively used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The ATG dosage is determined by the recipient's body weight, but some insist that this approach does not reflect the actual target of ATG. In this respect, weight-based dosing may lead to ATG overdose, particularly in recipients with a relatively low absolute lymphocyte count (ALC). We retrospectively analyzed 84 patients with acute leukemia or myelodysplastic syndrome who underwent matched related donor (MRD) allo-HSCT with reduced-intensity conditioning (RIC) at a single institution. Patients were dichotomized according to the ALC measured on the first day of conditioning (day -7) to investigate the associations of the ALC with GVHD and survival outcomes. The median duration of follow-up was 29 months. The preconditioning ALC was closely correlated with the ALC at the first ATG administration (day -3). The cumulative incidences of both acute GVHD and chronic GVHD were significantly lower in the preconditioning ALC <500/μL group compared with the ALC ≥500/μL group. There was no significant difference in disease relapse incidence between the 2 groups; however, mortality was significantly higher in the ALC <500/μL group. Multivariate analysis including disease status, modified European Blood and Marrow Transplantation score, and preconditioning ALC (≥500/μL versus <500/μL) identified disease status and ALC as being independently associated with overall survival (OS). In particular, infection was the most common cause of death in the ALC <500/μL group. Our data suggest that uniform weight-based ATG dosing in MRD allo-HSCT with RIC is associated with an increase in nonrelapse mortality and a relatively inferior OS in patients with a significantly low preconditioning ALC. Therefore, alternative strategies for the integration of ATG should be considered in allo-HSCT, at least for patients with a substantially low preconditioning ALC.     

Antithymocyte Globulin in Reduced-Intensity Conditioning Regimen Allows a High Disease-Free Survival Exempt of Long-Term Chronic Graft-versus-Host Disease

Nonmyeloablative (NMA) regimens allow the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients considered unfit for standard myeloablative conditioning (MAC) regimens using high-dose alkylating agents with or without total body irradiation (TBI). Reduced-intensity conditioning (RIC) regimens, based on fludarabine (Flu), busulfan (Bu), and rabbit antithymocyte globulin (r-ATG), represent an intermediate alternative between NMA and MAC regimens. This platform was subsequently optimized by the introduction of i.v. Bu and the use of 5 mg/kg r-ATG, based on the hypothesis that these modifications would improve the safety of RIC allo-HSCT. Here we report a study conducted at our institution on 206 patients, median age 59 years, who underwent allo-HSCT after conditioning with Flu, 2 days of i.v. Bu, and 5 mg/kg r-ATG (FBx-ATG) between 2005 and 2012. The prevalence of grade III-IV acute graft-versus-host disease (GVHD) was 9%, and that of extensive chronic GVHD was 22%. Four-year nonrelapse mortality (NRM), relapse, and overall survival (OS) rates were 22%, 36%, and 54%, respectively. NRM tended to be influenced by comorbidities (hematopoietic cell transplantation–specific comorbidity index [HCT-CI] <3 versus HCT-CI ≥3: 18% versus 27%; P = .075), but not by age (<60 years, 20% versus ≥60 years, 25%; P = .142). Disease risk significantly influenced relapse (2 years: low, 8%, intermediate, 28%, high, 34%; very high, 63%; P = .017). Both disease risk (hazard ratio [95% confidence interval]: intermediate, 2.1 [0.8 to 5.2], P = .127; high, 3.4 [1.3 to 9.1], P = .013; very high, 4.0 [1.1 to 14], P = .029) and HCT-CI (hazard ratio [95% confidence interval]: HCT-CI ≥3, 1.7 (1.1 to 2.8), P = .018) influenced OS, but age and donor type did not. The FBx-ATG RIC regimen reported here is associated with low mortality and high long-term disease-free survival without persistent GVHD in both young and old patients. It represents a valuable platform for developing further post-transplantation strategies aimed at reducing the incidence of relapse, particularly in the setting of high-risk disease.     

Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria: Multicenter Analysis by the Polish Adult Leukemia Group

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole potential cure for paroxysmal nocturnal hemoglobinuria (PNH); however, the data on its utility in PNH are limited. This retrospective analysis of patients with PNH who underwent allo-HSCT in 11 Polish centers between 2002 and 2016 comprised 78 patients with PHN, including 27 with classic PNH (cPNH) and 51 with bone marrow failure-associated PNH (BMF/PNH). The cohort was 59% male, with a median age of 29 years (range, 12 to 65 years). There was a history of thrombosis in 12% and a history of hemolysis in 81%, and 92% required erythrocyte transfusions before undergoing allo-HSCT. No patient received eculizumab, and 26% received immunosuppressive treatment. The median time from diagnosis to allo-HSCT was 12 months (range, 1 to 127 months). Almost all patients (94%) received reduced-toxicity conditioning, 66% with treosulfan. The stem cell source was peripheral blood in 72% and an identical sibling donor in 24%. Engraftment occurred in 96% of the patients. With a median follow-up of 5.1 years in patients with cPNH and 3.2 years in patients with BMF/PNH, 3-year overall survival (OS) was 88.9% in the former and 85.1% in the latter (P = not significant [NS]). The 3-year OS for patients with/without thrombosis was 50%/92% (P = NS) in the cPNH group and 83.3%/85.3% (P = NS) in the BMF/PNH group. The 3-year OS for in the BMF/PNH patients with/without hemolysis was 93.9%/62.9% (hazard ratio, .13; P = .016). No other factors impacted OS. After allo-HSCT, the frequency of the PNH clone was reduced to 0%, <1%, and <2.4% in 48%, 48%, and 4% of cPNH patients and in 84%, 11%, and 5% of BMF/PNH patients, respectively. The frequency of acute graft-versus-host disease (GVHD) grade II-IV was 23%, and the cumulative 1-year incidence of extensive chronic GVHD was 10.8% in the BMF/PNH group and 3.7% in the cPNH group. Allo-HSCT is a valid option for PNH patients, effectively eliminating the PNH clone with satisfactory overall survival and acceptable toxicity. Reduced-toxicity conditioning with treosulfan is effective and safe in patients with cPNH and BMF/PNH.     

Serum prolactin and thyrotropin responses to thyrotropin-releasing hormone in men with alcoholic cirrhosis

The serum concentrations of prolactin (PRL) and thyrotropin (TSH) in 12 males with alcoholic cirrhosis during basal condition and after stimulation with thyrotropin-releasing hormone (TRH) were compared with the concentrations in ten thiazide-treated hypertensive and nine normal men. The basal as well as the TRH-stimulated increase in serum PRL was significantly elevated in the cirrhotic males, while the increase in serum TSH was unchanged, compared with hypertensive and normal men. No correlation between clinical or laboratory parameters and serum PRL was found. Serum estradiol was equal in cirrhotic and control subjects and no correlation was found between serum PRL and serum estradiol. These findings favour the concept that raised serum PRL in cirrhotic patients might be caused by a diminished dopaminergic neurotransmission.