Tanja Gromke

Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients

The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag-identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients.

Hematopoietic Stem-Cell Transplantation for Advanced Systemic Mastocytosis

PURPOSE Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown. PATIENTS AND METHODS In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non-mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC). RESULTS Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response. CONCLUSION AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis.

Background Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis. Design and Methods We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55±7.5 months. Results Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001). Conclusions The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation.

Bronchiolitis obliterans after allogeneic hematopoietic SCT: further insight—new perspectives?

Bronchiolitis obliterans (BO) is a late non-infectious pulmonary complication after allogeneic hematopoietic SCT. Among 982 patients after myeloablative hematopoietic SCT between January 2000 and October 2010, 68 were diagnosed with BO according to NIH criteria. The median onset of BO was 18 months post transplant, 5-year cumulative incidence was 5.8% and 5-year mortality 41%. BO prevalence rate was 10% among all long-term surviving hematopoietic SCT recipients and 12% among chronic GVHD-patients. Chronic GVHD, peripheral SCT and ABO blood group incompatibility were identified as risk factors associated with BO. IgG levels were significantly decreased at the onset of BO (6.7 g/L±0.7, P=0.001), the mean exhaled NO concentrations were lower in BO-patients than in stem cell recipients without BO (14 p.p.b.±0.9 vs 20 p.p.b.±2.1) or healthy controls (25 p.p.b.±2.4, P<0.001). Hypoxia-inducible factor 1 alpha (HIF-1α) was significantly elevated in BO as compared with healthy controls or GVHD-patients without lung involvement (340±61 vs 127±22 vs 140±32, P=0.02). Calculated 5-year survival was superior in female than in male BO-patients (86 vs 45%, P=0.04). These results emphasize the relevance of BO as serious late complication with substantial mortality and point to essential pathophysiological changes due to regulatory responses to hypoxia.

Human chorionic gonadotropin and indolamine 2,3-dioxygenase in patients with GVHD

GVHD is a major complication following allogeneic hematopoietic SCT, and is associated with substantial morbidity and mortality. Based on the results of our previous clinical study with females treated with human chorionic gonadotropin (hCG) as preconditioning therapy for in vitro fertilization, we hypothesized that low-dose hCG stimulates indoleamine-2,3-dioxygenase (IDO), IL 10 and regulatory T cells (Treg), thereby suppressing clinical manifestations of chronic GVHD. Active chronic GVHD localized at skin, subcutaneous tissue, joints orgastrointestinal tract that was refractory or intolerant to glucocorticoid therapy improved substantially in 12 of 20 patients treated with hCG for 8 weeks (off-label), enabling a glucocorticoid dose reduction of 28% (average). Twelve of 19 patients with chronic GVHD of the skin responded to hCG therapy with a reduction of 25% (average) in their total skin score. HCG treatment increased IDO expression at median by sevenfold in peripheral mononuclear cells and IL10 levels in serum up to twofold at median from the pretreatment baseline. Further, an expansion of the Treg cell population was measured in one patient, which is also associated with the induction of tolerance. This novel application of low-dose hCG was well tolerated and is of clinical interest for GVHD treatment.

Delayed graft-versus-mast-cell effect on systemic mastocytosis with associated clonal haematological non-mast cell lineage disease after allogeneic transplantation

Delayed graft-versus-mast-cell effect on systemic mastocytosis with associated clonal haematological non-mast cell lineage disease after allogeneic transplantation

CD34+ highly enriched allogeneic stem cell transplantation in a patient with mixed phenotype acute leukemia and Fusarium solani sepsis.

Dear Editor, Fusarium species are ubiquitous molds and may cause disseminated infections in immunocompromised patients [1]. Fusarium solani is the most frequent and most virulent in human infections. The frequency of invasive fusariosis is particularly high in patients receiving autologous or allogeneic hematopoietic stem cell transplantation (HSCT). We here present a case of disseminated fusariosis in a patient with mixed phenotype acute leukemia (MPAL) undergoing allogeneic HSCT with a CD34+ highly enriched graft. MPAL in general have a poor outcome which is inferior to AML or ALL. It is recommended to treat MPAL patients with an ALL-like regimen and in case of BCR-ABL positivity with a TKI, followed by an allogeneic HSCT [2]. The patient at the time of admission to our center was in critical septic condition and being treated with posaconazole 800 mg/day and liposomal amphotericin B 5 mg/kg body weight (BW). We could confirm the infection with F. solani in blood cultures and skin swabs. Antifungal susceptibility testing showed resistance to itraconazole, caspofungin, and posaconazole and only intermediate susceptibility to amphotericin B and voriconazole. Due to the proven resistance to posaconazole and to the fact that a severe hepatotoxicity developed, we discontinued posaconazole and reduced liposomal amphotericin B to 3 mg/kg BW. This led to a normalization of hepatic function. We have already described the transplantation modality of highly purified CD34+ HSCT elsewhere [3]. We deliberately chose CD34+ enrichment for this graft in order to minimize the duration of neutropenia and to avoid immunosuppressive therapy. The patient received myeloablative conditioning with fludarabine, thiotepa, and TBI (8 Gy). In vivo T cell depletion was performed using ATG (cumulatively 60 mg/kg BW). The patient received 12.3×10/kg BW CD34+ stem cells from his HLA-identical brother. CD3+ cells were 0.24×10/kg BW. The patient did not develop any GvHD. The patient was treated consistently with liposomal amphotericin B 3 mg/kg BW until discharge. CT examination showed a remarkable regression of fusariosis pneumonia (Fig. 1). Antifungal prophylaxis was switched to voriconazole in the outpatient setting and terminated 1 year after HSCT. Six years after allogeneic HSCT, the patient is well and in CR. There have been no further infectious complications. Only several scars are left from the cutaneous manifestations of F. solani. Severely immunocompromised patients are particularly vulnerable to infection with Fusarium species, and disseminated disease has a poor prognosis. A single-center study with 26 cases of invasive fusariosis showed mortality rates with disseminated, skin, and pulmonary fusariosis of 50, 40, and 37.5 %, respectively [4]. Due to high resistance to antifungal agents, therapy remains difficult. A recent European guideline recommends voriconazole and surgical debridement where possible and posaconazole as salvage treatment [5]. In most published cases, a fusariosis developed as an infectious complication after allogeneic HSCT and all of these cases were fatal [6–11]. To our knowledge, our case is the first describing a patient undergoing allogeneic HSCT with a clinically relevant disseminated fusariosis at the time of HSCT. The fact that this patient survived the severe infection might at least in part be attributed to the CD34+ highly enriched graft which minimized the duration of neutropenia and allowed us to avoid immunosuppressive therapy after HSCT. * Lambros Kordelas lambros.kordelas@uk-essen.de