Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

Because information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.     

Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

Strategies that increase homing to the bone marrow and engraftment efficacy of ex?vivo expended CD34(+) cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34(+) cells cultured with cytokines. In the presence of NAM, the fraction of CD34(+)CD38(-) cells increased and the fraction of differentiated cells (CD14(+), CD11b(+), and CD11c(+)) decreased. CD34(+) cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD(+)-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34(+) cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not?inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest?a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the?clinical utility of NAM for ex?vivo expansion of functional CD34(+) cells.     

Bisphosphonates for preventing bone disease in kidney transplant recipients: a meta‐analysis of randomized controlled trials

An estimated 60% of kidney transplant recipients have mineral bone disease and about 0.5% break their hip within the first year after transplantation. We conducted a systematic review of benefits and harms of bisphosphonates in kidney transplant recipients. We searched CENTRAL (Issue 5, 2015) for randomized controlled trials in all languages and screened the reference list of an earlier Cochrane review. One reviewer identified the trials, extracted all data, and assessed risk of bias. Meta‐analysis used a random effects model, with results expressed as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). Bisphosphonates have uncertain effects on death (RR 0.45, CI 0.04–4.69) and vertebral fractures (RR 0.58, CI 0.24–1.43, I² 0%). Bisphosphonates moderately to importantly reduce the loss of vertebral bone mineral density (MD 5.98%, CI 3.77–8.18% change from baseline in g calcium/cm² at 12 months, I² 91%) and femoral bone mineral density (MD 5.57%, 3.12–8.01% change from baseline in g calcium/cm² at 12 months, I² 69%). At this stage, insufficient evidence exists to support routine use of bisphosphonates to reduce fracture risk after kidney transplantation. Data on important health outcomes are lacking, surrogate outcomes poorly reflect bone quality in kidney transplant recipients, and serious adverse events are not studied and reported systematically.     

Immune Basis for Cimetidine-Induced Pancytopenia

We report a case of a female patient with chronic myelogenous leukemia who presented, 8 yr after initial diagnosis, with pancytopenia, encephalopathy, and myalgia. The tentative diagnosis was accelerated phase of chronic myelogenous leukemia. However, because the patient had been treated with cimetidine for 7 months we first omitted this drug. When cimetidine was stopped, bone marrow recovered, and myalgia and encephalopathy subsided. Immunological studies showed stimulation of the patient's lymphocyte blastogenesis by cimetidine and a marked increase in the proportion of cytotoxic/suppressor T lymphocytes after incubation of peripheral blood lymphocytes with cimetidine for 6 days. These findings indicate a role for cell-mediated immunity in the pathogenesis of cimetidine-induced pancytopenia in this patient.     

Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemias with a del(5q)

Interleukin-4 (IL-4) is a potent mediator of growth and differentiation of cells of several hematopoietic lineages. Interleukin-5 (IL-5) is a lineage-specific hematopoietic growth factor that stimulates the production of eosinophils and eosinophil colonies from normal human bone marrow cells. By using somatic cell hybrids and in situ chromosomal hybridization, we localized the IL-4 and IL-5 genes to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the IL-4 and IL-5 genes were found to be deleted in the 5q- chromosome of four patients with refractory anemia (RA) or therapy-related acute nonlymphocytic leukemia (t-ANLL), who had a del(5q). Thus a small segment of chromosome 5 contains IL-4, IL-5, IL- 3, and GM-CSF as well as other genes such as CD14 and EGR1. Our findings that each of these genes was deleted in the 5q- chromosome suggest that loss of function of one or more of these genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).     

Asynchronous globin chain synthesis in rabbit reticulocyte lystates induced by hemin-controlled repressor

To define further the role of hemin-controlled repressor (HCR) in globin synthesis, we studied its effect on the synthesis of individual globin chains in a rabbit reticulocyte lysate cell-free system. In the presence of HCR there was a marked globin chain imbalance, resulting in a lowered alpha/beta ratio. These findings in vitro may have relevance to certain clinical heme deficiency states in which a similar globin chain imbalance has been observed.     

Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases

Translocations and deletions of the short arm of chromosome 12 [t(12p) and del(12p)] are common recurring abnormalities in a broad spectrum of hematologic malignant diseases. We studied 20 patients and one cell line whose cells contained 12p13 translocations and/or 12p deletions using fluorescence in situ hybridization (FISH) with phage, plasmid, and cosmid probes that we previously mapped and ordered on 12p12-13. FISH analysis showed that the 12p13 translocation breakpoints were clustered between two cosmids, D12S133 and D12S142, in 11 of 12 patients and in one cell line. FISH analysis of 11 patients with deletions demonstrated that the deletions were interstitial rather than terminal and that the distal part of 12p12, including the GDI-D4 gene and D12S54 marker, was deleted in all 11 patients. Moreover, FISH analysis showed that cells from 3 of these patients contained both a del(12p) and a 12p13 translocation and that the affected regions of these rearrangements appeared to overlap. We identified three yeast artificial chromosome (YAC) clones that span all the 12p13 translocation breakpoints mapped between D12S133 and D12S142. They have inserts of human DNA between 1.39 and 1.67 Mb. Because the region between D12S133 and D12S142 also represents the telomeric border of the smallest commonly deleted region of 12p, we also studied patients with a del(12p) using these YACs. The smallest YAC, 964c10, was deleted in 8 of 9 patients studied. In the other patient, the YAC labeled the del(12p) chromosome more weakly than the normal chromosome 12, suggesting that a part of the YAC was deleted. Thus, most 12p13 translocation breakpoints were clustered within the sequences contained in the 1.39 Mb YAC and this YAC appears to include the telomeric border of the smallest commonly deleted region. Whether the same gene is involved in both the translocations and deletions is presently unknown.     

Salivary glands and the aging process: mechanistic aspects, health-status and medicinal-efficacy monitoring

Xerostomia is a major complaint of many elderly individuals, and although they seek medical help, it usually provides no adequate relief. This complaint is considered a major clinical problem, since not less than 25% to 50%-60% of the population over the age of 65 complain of xerostomia. By definition, Xerostomia is a subjective feeling and in up to one-third of the cases does not reflect a real reduction in salivary flow rate but rather the subjective feeling of a dry mouth. Moreover, only a minute portion of the patients suffer from xerostomia with a known aetiology such as radiotherapy or Sjögren's syndrome, while in the majority of the cases, the aetiology is assumed to be related to age, disease, various medications and drugs or is simply idiopathic. The current review focuses on age-related histological, sialometrical and sialochemical changes and on the possible mechanisms which underlie these changes. Finally, directions for further exploring the subject are suggested.     

Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor.

Myelodysplastic syndromes (MDS) are characterized by chronic refractory cytopenias resulting in increased risk of infection, bleeding, and conversion to acute leukemia. In an effort to improve these cytopenias we have treated 18 patients over a 6- to 8-week period with increasing daily subcutaneous doses of recombinant human granulocyte colony-stimulating factor (G-CSF). Sixteen patients responded with improvement in neutrophil counts. On cessation of treatment these counts returned to baseline values over a 2- to 4-week period. To maintain these improved blood counts 11 patients were treated with G-CSF for more prolonged periods. Ten patients again responded with an increase in total leukocyte counts (1.6- to 6.4-fold) and absolute neutrophil counts (ANC) (3.6- to 16.3-fold), with responses persisting for 3 to 16 months. A significantly decreased risk of developing bacterial infections was noted during periods with ANC greater than 1,500/mm3 as compared with periods of time with ANC less than 1,500/mm3. Two anemic patients had a greater than 20% rise in hematocrit over the study period, and 2 additional patients had a decrease in red blood cell transfusion requirements during G-CSF treatment. Bone marrow myeloid maturation improved in 7 of 9 maintenance phase patients. Three patients progressed to acute myeloid leukemia during treatment. The drug was generally well-tolerated and no severe toxicities were noted. These data demonstrated that G-CSF administered to MDS patients by daily subcutaneous administration was well-tolerated and effective in causing persistent improvement of the neutrophil levels and marrow myeloid maturation. These effects were associated with a decreased risk of infection and, in some patients, with decreased red blood cell transfusion requirements.