Evaluation of Prophylaxis with Norfloxacin and Ceftriaxone versus Ciprofloxacin during the Period of Neutropenia after Haematopoietic Stem Cell Transplantation:Retrospective Analysis of Two Sequencial Cohorts

Background: The aim of this study was to evaluate the occurrence of febrile neutropenia (FN) during aplasia after haematopoietic stem cell transplantation (HSCT) in patients who received anti-bacterial prophylaxis with norfloxacin/ceftriaxone or ciprofloxacin, between September 2006 and May 2009. Methods: We retrospectively examined all patients undergoing HSCT at S?o Paulo Hospital during the study period. Results: Of the 107 studied patients, 71 (66.3%) were included in the analysis. The exclusion criteria were as follows: occurrence of fever or infection before the transplantation (17), prophylactic use of norfloxacin (6), fever of probable non-infectious aetiology (2), and absence of prophylaxis during the aplasia period (11). Thirty-eight patients received norfloxacin and ceftriaxone as prophylaxis (Group I) and 33 received ciprofloxacin (Group II). The groups were comparable with respect to age, underlying diseases, comorbidities, and status of the underlying disease. Patients in Group II used antibiotics in a significantly higher frequency than those in Group I (66.7% vs 33.8%, p = 0.017), for 30 days before transplantation. The number of previous hospitalisations, length of hospitalisation until transplantation, type of transplant, progenitor cells used, number of CD34 cells infused, type of conditioning, and graft-versus-host disease prophylaxis were similar in both groups. After the transplantation, 28.9% and 39.4% of the patients in Groups I and II, respectively, presented Grade III and IV mucositis (p = 0.448). Neutropenia of <500 neutrophils/mm3 lasted an average of 9.5 and 9.3 days in Groups I and II, whereas neutropenia of <100 neutrophils/mm3 lasted between 6.6 and 5.7 days. FN occurred in 78.9% of patients in Group I and 81.8% in Group II, with no significant difference in the classification of these episodes. Six patients (15.8%) in Group I and five (15.2%) in Group II had bacteraemia. All patients who did not receive prophylaxis developed FN. Conclusions: The high incidence and classification of FN episodes were similar between groups;however, the frequency was lower than in those patients who did not receive prophylaxis.

Development of Non-ABO Red Blood Cell Alloantibodies in Patient Undergoing Allogeneic Haematopoietic Stem Cell Transplant

Alloantibodies that are non ABO Alloimmunization to protein antigens happens only after exposure, in contrast to ABO isohaemagglutinins, which are present naturally, even in the absence of prior exposure. It is recognized that while non-ABO RBC antibodies are less common than ABO antibodies, they generate essentially the same issues that lead to unfavorable clinical results. If non-ABO alloantibodies are identified early on, these issues related complications may be avoided This call for an in-depth understanding of the recipient and donor’s ABO-Rh grouping, antibody screening, and the phenotype of certain antigens. Equally important, the temporal association time between transplantation and hemolysis can help identify the underlying mechanism of hemolysis and direct appropriate management. Therefore, for that, it is crucial to identify the etiology of post-HSCT anemia for prevention and therapy, in addition to a thorough grasp of the mechanism of anemia in non-ABO-incompatible HSCT and the temporal link between HSCT and anemia. Finding the cause of post-HSCT anemia is essential for prevention and therapy, in addition to a thorough grasp of the mechanism of anemia in non-ABO-incompatible HSCT and the temporal link between HSCT and anemia. Therefore, for that, it is crucial to identify the etiology of post-HSCT anemia. In this case report review, we would like to highlight the vital role of transfusion medicine services and stem cell clinical teams in paying particular attention to the clinical significance of non-ABO alloantibodies involved to avoid causing overt hemolysis of incompatible donor RBCs or delayed erythropoiesis. Considering the fact that some of the Haematopoietic stem cell transplant centers do not give an attention to the other non-ABO RBC antigens.

Real-time fluorescent quantitative PCR assay for measuring cytomegalovirus DNA load in patients after haematopoietic stem cell transplantation

Cytomegalovirus （CMV） infection is a major and often deadly complication of haematopoietic stem cell （HSC） transplantation. Successful preemptive CMV therapy in transplant patients depends on the availability of sensitive, specific, and timely diagnostic tests for CMV infections. The pp65 antigenemia assay has been used for this purpose with considerable success but has disadvantages of being time-consuming and labor-intensive .

Clinical outcomes after autologous haematopoietic stem cell transplantation in patients with progressive multiple sclerosis

Background Multiple sclerosis （MS） is a continuously disabling disease and it is unresponsive to high dose steroid and immunomodulation with disease progression. The autologous haematopoietic stem cell transplantation （ASCT） has been introduced in the treatment of refractory forms of multiple sclerosis. In this study, the clinical outcomes followed by ASCT were evaluated for patients with progressive MS. Methods Twenty-two patients with secondary progressive MS were treated with ASCT. Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony stimulating factor. Etoposide, melphalan, carmustin and cytosine arabinoside were administered as conditioning regimen. Outcomes were evaluated by the expanded disability status scale and progression free survival. No maintenance treatment was administered during a median follow-up of 39 months （range, 6 to 59 months）. Results No death occurred following the treatment. The overall confirmed progression free survival rate was 77% up to 59 months after transplantation which was significantly higher compared with pre-transplantation （P=0.000）. Thirteen patients （59%） had remarkable improvement in neurological manifestations, four （18%） stabilized their disability status and five （23%） showed clinical recurrence of active symptoms. Conclusions ASCT as a therapy is safe and available. It can improve or stabilize neurological manifestations in most patients with progressive MS following failure of conventional therapy.

Fludarabine and cytarabine combined chemotherapy followed by transfusion of donor blood stem cells for treating relapse of acute leukaemia after allogeneic haematopoietic stem cell transplantation

Background Relapse remains an obstacle to successful allogeneic haematopoietic stem cell transplantation （allo-HSCT） for patients with acute leukaemia and no standard treatment is available. We assessed fludarabine and cytarabine with transfusion of donor haematopoietic stem cell in treating the relapse of acute leukaemia after allo-HSCT. Methods Seven patients, median age 34 years, with relapse of acute leukaemia after allo-HSCT received combination chemotherapy of fludarabine with cytarabine for 5 days. Five patients suffered from acute myeloid leukaemia （2 refractory） and 2 refractory acute lymphoblastic leukaemia. After the transplantation, the median relapse time was 110 days （range, 38-185 days）. Two days after chemotherapy, 5 patients received infusion of donor＇s peripheral blood stem cells, mobilized by granulocyte colony stimulating factor. No prophylactic agents of graft versus host diseases were administered, Results Six patients achieved haematopoietic reconstitution. DNA sequence analysis at day 30 after treatment identified all as full donor chimera type. The median observation time was 189 days. After the treatment, the median time for neutrophilic granulocyte value 〉0.5×10^9/L and for platelet value 〉20×10^9/L were 13 days （range, 10-18 days） and 15 days （range, 11-24 days）, respectively. Graft versus host disease occurred in 2 patients （acute） and 3 （chronic）. Five patients suffered from pulmonary fungal infection （2 died）, 3 haemorrhagic cystitis and 2 cytomegalovirus viraemia. The other patients died of leukaemia related deaths. Three patients with chronic graft versus host disease who had received donor peripheral blood stem cells reinfusion have survived for 375 days, 232 days and 195 days, respectively. Conclusions Fludarabine with cytarabine plus the donor haematopoietic stem cell should be considered as an effective therapeutic regimen for relapse of acute leukaemia after alIo-HSCT. The disease free state of patients may increase, though with high risk of secondary fungal infection.

Therapy with stem cells in inflammatory bowel disease

Inflammatory bowel disease (IBD) affects a part of the young population and has a strong impact upon quality of life. The underlying etiology is not known, and the existing treatments are not curative. Furthermore, a significant percentage of patients are refractory to therapy. In recent years there have been great advances in our knowledge of stem cells and their therapeutic applications. In this context, autologous hematopoietic stem cell transplantation (HSCT) has been used in application to severe refractory Crohn&#x02019;s disease (CD), with encouraging results. Allogenic HSCT would correct the genetic defects of the immune system, but is currently not accepted for the treatment of IBD because of its considerable risks. Mesenchymal stem cells (MSCs) have immune regulatory and regenerative properties, and low immunogenicity (both autologous and allogenic MSCs). Based on these properties, MSCs have been used via the systemic route in IBD with promising results, though it is still too soon to draw firm conclusions. Their local administration in perianal CD is the field where most progress has been made in recent years, with encouraging results. The next few years will be decisive for defining the role of such therapy in the management of IBD.

Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules;stronger cytotoxicity against HCMV-infected fibroblasts;and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32–0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18–0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.

Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease

Although glucorticosteroids(GCs)are the standard first-line therapy for acute graft-versus-host disease(a Gv HD),nearly 50%of a Gv HD patients have no response to GCs.The role of T cell metabolism in murine a Gv HD was recently reported.However,whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate a Gv HD remains to be elucidated.Increased glycolysis,characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(PFKFB3),and higher rates of glucose consumption and lactate production were found in Tcells from a Gv HD patients.Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells.In a humanized mouse model,PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented a Gv HD,respectively.Importantly,our integrated data from patient samples in vitro,in a humanized xenogeneic murine model of a Gv HD and graft-versus-leukaemia(GVL)demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate a Gv HD without loss of GVL effects.Together,the current study indicated that glycolysis is critical for T cell activation and induction of human a Gv HD.Therefore,the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for a Gv HD patients.GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for a Gv HD patients.