Dexamethasone palmitate successfully attenuates hemophagocytic syndrome after allogeneic stem cell transplantation: macrophage-targeted steroid therapy

Hemophagocytic syndrome (HPS) induced by uncontrolled macrophage activation and subsequent graft failure is a frequent and prominent complication after allogeneic stem cell transplantation (allo-SCT), a cause of severe morbidity and death, and a therapeutic challenge. Liposome-incorporated dexamethasone, dexamethasone palmitate (DP), shows greater efficacy against macrophages as compared to dexamethasone sodium phosphate (DSP). Based on our findings that DP achieves significantly larger decrease than DSP on the viability of primary human macrophages compared in vitro, we tested the effects of DP in patients with HPS. A decrease in number of macrophages in the bone marrow and prevention of engraftment failure were observed in all patients without any severe complications. In conclusion, these data provide a rationale for testing DP as a first-line treatment for patients with HPS after allo-SCT.     

Toxoplasma‐induced hemophagocytic lymphohistiocytosis after haploidentical allogeneic stem cell transplantation

Hemophagocytic lymphohistiocytosis (HLH) is a disorder of immune regulation, manifested by fever, pancytopenia, hyperferritiniemia, hypertriglyceridemia, and extensive hemophagocytosis involving the bone marrow and spleen. HLH can occur in adults with an underlying hematopoietic malignancy, or with systemic infections. HLH following hematopoietic stem cell transplantation (HSCT) is unusual, and the diagnosis may be challenging particularly because the diagnostic criteria in the HLH‐2004 guidelines overlap with common post‐transplant complications such as engraftment syndrome, graft‐vs‐host disease, and infections. HLH is commonly triggered by viral, bacterial and, less commonly, parasitic infections. Following HSCT, patients with latent Toxoplasma infection may develop systemic disease secondary to reactivation, and rarely this may lead to a HLH physiology, with a very high mortality rate. Herein we describe the successful management of disseminated toxoplasmosis associated with life‐threatening HLH using tocilizumab and antimicrobial therapy.     

Chronic graft-versus-host disease after allogeneic blood stem cell transplantation

The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P =.001), whereas the risk was increased with prior acute GVHD (HR, 1.67; P =.046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P <.001) and treatment failure (HR, 5.2; P <.001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.     

Relapse after allogeneic stem cell transplantation

Since allogeneic stem cell transplantation (SCT) represents an intensive curative treatment for high-risk malignancies, its failure to prevent relapse leaves few options for successful salvage treatment. While many patients have a high early mortality from relapse, some respond and have sustained remissions, and a minority has a second chance of cure with appropriate therapy. The prognosis for relapsed hematological malignancies after SCT depends on four factors: the time elapsed from SCT to relapse (with relapses occurring within 6 months having the worst prognosis), the disease type (with chronic leukemias and some lymphomas having a second possibility of cure with further treatment), the disease burden and site of relapse (with better treatment success if disease is treated early), and the conditions of the first transplant (with superior outcome for patients where there is an opportunity to increase either the alloimmune effect, the specificity of the antileukemia effect with targeted agents or the intensity of the conditioning in a second transplant). These features direct treatments toward either modified second transplants, chemotherapy, targeted antileukemia therapy, immunotherapy or palliative care.     

Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation

Allogeneic peripheral blood stem cell grafts contain about 10 times more T and B cells than marrow grafts. Because these cells may survive in transplant recipients for a long time, recipients of blood stem cells may be less immunocompromised than recipients of marrow. Immune reconstitution was studied in 115 patients randomly assigned to receive either allogeneic marrow or filgrastim-mobilized blood stem cell transplantation. Between day 30 and 365 after transplantation, counts of most lymphocyte subsets were higher in the blood stem cell recipients. The difference was most striking for CD4 T cells (about 4-fold higher counts for CD45RA(high) CD4 T cells and about 2-fold higher counts for CD45RA(low/-)CD4 T cells; P <.05). On assessment using phytohemagglutinin and herpesvirus antigen-stimulated proliferation, T cells in the 2 groups of patients appeared equally functional. Median serum IgG levels were similar in the 2 groups. The rate of definite infections after engraftment was 1.7-fold higher in marrow recipients (P =.001). The rate of severe (inpatient treatment required) definite infections after engraftment was 2.4-fold higher in marrow recipients (P =.002). The difference in the rates of definite infections was greatest for fungal infections, intermediate for bacterial infections, and lowest for viral infections. Death associated with a fungal or bacterial infection occurred between day 30 and day 365 after transplantation in 9 marrow recipients and no blood stem cell recipients (P =.008). In conclusion, blood stem cell recipients have higher lymphocyte-subset counts and this appears to result in fewer infections. (Blood. 2001;97:3380-3389)     

Second allogeneic peripheral blood stem cell transplantation with fludarabine-based low-intensity conditioning regimen for relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation

We describe the case of a 51-year-old patient with relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation (BMT), who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) after conditioning with a novel regimen consisting of fludarabine, busulfan, and antithymocyte globulin. The second PBSCT was performed early, at 3 months after the initial allogeneic BMT, but it was well tolerated and complete hematologic remission was documented. The patient did not experience any early transplantation-related organ toxicity but died from opportunistic infection 6 months after the second transplantation. Our experience suggests that this novel regimen may induce remission and could be offered to patients relapsing after the first transplantation; however, the fludarabine-containing regimen might be accompanied by profound immunosuppression.     

High incidence of engraftment syndrome after haploidentical allogeneic stem cell transplantation

We determined the incidence, clinical manifestations, and outcomes of engraftment syndrome (ES) in haploidentical stem cell transplantation (SCT) recipients. We compared the incidence of ES between the patient group that received haploidentical SCT (n = 516) and the patient group that received HLA‐identical sibling SCT (n = 393). The transplantations were performed in the Peking University People's Hospital in the period between October 2001 and October 2012. The ES incidence data were collected retrospectively. Patients that presented non‐infectious fever or skin rash within the 24‐h window before or after the beginning of neutrophil recovery were diagnosed with ES in accordance with the Maiolino criteria. ES incidence in haploidentical SCT recipients (21.9%) was significantly higher than that in HLA‐identical sibling SCT recipients (2.0%; P < 0.001). Major symptoms included fever (119/121, 98.3%), skin rash (98/121, 81.0%), and diarrhea (51/121, 42.1%), with the median time of +10 d (range: 6–20 d). The median C‐reactive protein level of the ES group (99.0 mg/L; n = 13) was significantly higher than that of the non‐ES group (13.9 mg/L; n = 38; P < 0.001). Similarly, the results showed that the median C3 plasma concentration of the ES group (1.30 g/L) was higher than that of the non‐ES group (1.16 g/L, P = 0.003). ES was not associated with non‐relapse mortality or overall survival. High incidence of ES was observed in haploidentical SCT recipients; however, ES did not predict poor clinical outcomes.     

Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation

Neurotoxicity is a significant complication of the use of tacrolimus. From April 1998 to December 2001, we identified 10 patients (six women, four men) who developed 11 episodes of tacrolimus-associated posterior reversible encephalopathy syndrome (PRES) after allogeneic haematopoietic stem cell transplantation for haematological malignancies. The diagnosis was made by characteristic clinical findings (mental status changes, seizures, neurological deficits) with the exclusion of other causes and characteristic imaging findings. The median age was 35.5 years (range 19-57 years). Seven patients received a matched-unrelated donor transplant and three received a cord blood transplant. The overall incidence of PRES was 1.6%, while the incidence in matched-unrelated, mismatched-related and cord blood transplants was 3.5%, 4.9% and 7.1% respectively. Mental status changes, cognitive deficits, seizures and lethargy were the most common clinical findings. Eight of 10 patients had characteristic findings of hyperintensity of the white matter on T2-weighted images and FLAIR (fluid-attenuated inversion recovery) sequence on magnetic resonance imaging of the brain. Serum tacrolimus levels were within the therapeutic range in most patients. Tacrolimus treatment was continued (n = 4) or temporarily withheld (n = 7) for 1-14 d. One patient was changed to cyclosporine. In most patients, subsequent treatment with tacrolimus was well tolerated without recurrence of neurotoxicity.     

Distinct reconstitution of neutrophil functions after allogeneic peripheral blood stem cell transplantation

Purpose The study investigated in detail neutrophil functions shortly after allogeneic peripheral blood stem cell transplantation (PBSCT). Methods Different functions of neutrophils in 14 patients who received allogeneic PBSCT were investigated. The migratory capacity as well as the ability to induce oxidative burst following stimulation with either Phorbol-12-myristate-13-acetate (PMA), the chemotactic peptide N-formyl-Met-Leu-Phe (f-MLP) or opsonized Escherichia coli was analysed after engraftment (between day +30 and +40) and compared with the results obtained from healthy volunteers. Results There are no differences in terms of the migratory capacity (P = 0.17), as well as regarding the oxidative burst after incubation with PMA (P = 0.08) or f-MLP (P = 0.06), compared with healthy men. In contrast, the capacity of neutrophils to induce oxidative burst following stimulation with E. coli is highly impaired (P = 0.0001) in patients shortly after engraftment. Conclusion The recovery of neutrophils after allogeneic PBSCT is not only influenced by the varying time of engraftment, but also represents a process that differs in distinct biological functions compared to normal granulopoieses.     

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation: etiology and pathogenesis

In this study we investigated the etiology and pathogenesis of nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 257 patients with hematopoietic malignancies who survived more than 2 months post allo-HSCT. Associations of NS with the conditioning regimen, graft versus host disease (GVHD), and other variables were analyzed. Pathologic features of the kidney, regulatory T cells (Tregs), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were studied. NS was identified in 9 patients. The number of Tregs at day+30, 60, 90, and 180 was lower in NS patients than non-NS patients (P=0.001, 0.001, 0.007, 0.003). Serum levels of IFN-γ and TNF-α were higher in NS patients (P=0.032, 0.001, respectively). NS post allo-HSCT was associated with the occurrence of chronic GVHD (P=0.02). NS post-HSCT is an immune disorder that may involve immune complex deposition, Th1 cytokines, and Tregs.     

Early onset Pneumocystis carinii pneumonia after allogeneic peripheral blood stem cell transplantation

Pneumocystis carinii (P. carinii) is one of the major opportunistic pathogens responsible for hematopoietic stem cell transplantation (HSCT)-related pneumonias. Although trimethoprim-sulfamethoxazol (TMP/SMX) prophylaxis has been shown to prevent almost all P. carinii infections, 1%-2% of patients may still experience this complication. P. carinii pneumonia (PCP) is usually a late complication in patients receiving TMP/SMX prophylaxis, with most cases occurring later than 2 months post-transplant. We report a patient who developed early onset PCP after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling donor. On day 12, the patient complained of dyspnea and cough. A chest X ray showed infiltrates in right upper lobe with bilateral pleural effusion. By the findings of Grocott stain on bronchoalveolar lavage fluid obtained on day 14, he was diagnosed as having PCP. Intravenous TMP/SMX failed to improve the lesion. This is the earliest onset PCP in the literature after HSCT despite the prophylactic administration of TMP/SMX before transplant.