Inken Hilgendorf

Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Hematologic Malignancies After Dose-Escalated Treosulfan/Fludarabine Conditioning

PURPOSEnTreosulfan was introduced recently as a conditioning agent for allogeneic blood stem-cell transplantation. The favorable nonhematologic toxicity profile at 3 x 10 g/m(2) was the basis for dose escalation in this prospective, multicenter trial.nnnPATIENTS AND METHODSnFifty-six patients with various hematologic malignancies who were not eligible for standard conditioning were treated with one of three doses: 10 g/m(2), 12 g/m(2), or 14 g/m(2) of intravenous treosulfan, which was administered on days -6 to -4 combined with fludarabine 30 mg/m(2) on days -6 to -2. Patients in complete remission (CR; 42%) or non-CR (58%) received grafts from matched related (47%) or matched unrelated (51%) donors; one patient had a mismatched related donor (2%).nnnRESULTSnNo engraftment failure occurred. Overall, extramedullary toxicity and the nonrelapse mortality rate at 2 years (20%) were low and did not increase with dose. Cumulative incidence of relapse/progression reached 31%. The overall survival and progression-free survival rates were 64% and 49%, respectively, in the total study population. An inverse dose dependency of relapse incidence was indicated in the subgroup receiving transplantations from matched related donors (P = .0568).nnnCONCLUSIONnTreosulfan-based conditioning was feasible at all three doses. The 3 x 14 g/m(2) dose was selected for additional studies, because it combines desired characteristics of low toxicity and a low relapse rate.

Current Practice in Diagnosis and Treatment of Acute Graft-versus-Host Disease: Results from a Survey among German-Austrian-Swiss Hematopoietic Stem Cell Transplant Centers

To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day nxa0=xa02, 0.5 to 1.0 mg/kg/day nxa0=xa010, above 1.0 to 2.5 mg/kg/day nxa0=xa019) without or with topical agents (steroids nxa0=xa010; calcineurin inhibitors nxa0=xa03). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (nxa0=xa014) and extracorporeal photopheresis (nxa0=xa010). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers own clinical experience.

Long-Term Follow-up After Allogeneic Stem Cell Transplantation

BACKGROUNDnOver 3000 persons undergo allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in Germany every year. Advances in allo-HSCT have prolonged the survival of treated patients but have concomitantly increased the risk of long-term complications that impair their quality of life.nnnMETHODSnThis literature review of the long-term sequelae of allo-HSCT is based on pertinent articles that were retrieved by a selective search of PubMed, and on current international guidelines. Case reports were excluded from consideration.nnnRESULTSnHardly any randomized clinical trials have been performed to investigate the long-term outcome of allo-HSCT, but international consensus-based guidelines have been published. 50% to 70% of patients treated with allo-HSCT develop chronic graft-versus-host disease (cGVHD) within ten years of treatment. Transplant recipients are at higher risk of infection, including the reactivation of dormant herpes viruses; therefore, vaccination is recommended, as described in the current guidelines. Gonadal dysfunction arises in up to 92% of men and up to 99% of women; its frequency depends on the timing of transplantation, on radiotherapy, and on other factors. The medications that transplant recipients need to take can impair liver function, and transfusionassociated hemosiderosis can do so as well. 40% to 50% of patients suffer from lipid metabolic disturbances that increase the risk of myocardial infarction, peripheral arterial occlusive disease, and stroke. Their life expectancy is shorter than that of the overall population.nnnCONCLUSIONnMeasures should be taken to prevent the potential long-term complications of allo-HSCT. All patients who have been treated with allo-HSCT should receive individualized, risk-adapted, and multidisciplinary follow-up care, so that any complications that arise can be correctly diagnosed and appropriately treated. Long-term follow-up care could be improved by prospective clinical trials investigating the long-term sequelae of allo-HSCT, as well as by consistent, uniform documentation of these sequelae in supraregional data registries.

Perforation of the Superior Vena Cava – a Rare Complication of Central Venous Catheters

Background: Central venous catheters (CVC) guarantee a reliable venous access and are an indispensable part of the therapy in patients with hematologic malignancies. On the other hand, they contribute significantly to the therapy-related morbidity in this group of patients. The most common complications are catheter-associated infections or thromboses. Here we report on the rare, but potentially life-threatening case of a vessel wall perforation by a CVC. Case Report: A 29-year-old female with newly diagnosed acute lymphoblastic leukemia had a CVC inserted via the left subclavian vein. After two weeks she complained about acute chest pain. Radiology revealed right-sided pleural effusion which was due to a vena cava superior vessel wall perforation by the CVC. Chemotherapy extravasation was excluded by pleural fluid analyses. Conclusion: A vessel wall perforation by a CVC is a rare and often late CVC complication with usually unspecific symptoms. Especially patients with leftsided, large-bore catheters are at risk. Awareness of this complication and immediate therapy are essential. We discuss the possible mechanisms and treatment options of this rare CVC complication.

Sirolimus in Combination with Tacrolimus in Allogeneic Stem Cell Transplantation—Timing and Conditioning Regimen May Be Crucial

In a recent issue of Biology of Blood and Bone Marrow Transplantation, Furlong and colleagues [1] reported on the results of 2 prospective trials evaluating the combination of Sirolimus (SIR) with either Cyclosporine (CsA) or Tacrolimus (TAC) and additional methotrexate (MTX) for prophylaxis of acute graftversus-host disease (aGVHD) after allogeneic stem cell transplantation from unrelated donors (URD). In contrast to previous publications by Antin and colleagues [2,3], both studies presented by Furlong et al. observed a high rate of toxicity and no reduction in aGVHD, which led to premature termination of both studies because of lack of efficacy. In this context 3 additional aspects need to be discussed. First, in the Furlong study, the immunosuppression combining CsA with SIR started on day 21, whereas in the phase II studies published by Antin et al. [2] immunosuppression started on day 23. Because SIR has a potential inhibitory effect on function of dendritic cells, the delayed start of immunosuppression may have contributed to the higher rate of aGVHD [4-6]. Moreover, in vitro data and comparative clinical studies in renal transplantation showed a higher efficacy and potentially improved toxicity profile of the combination of TAC and SIR compared to CsA and SIR [7-9]. Another potential reason for a higher failure rate may have been the combination of a conditioning regimen containing busulfan (Bu) with an immunosuppression regimen containing TAC and SIR. In prior studies, Bu as well as cyclophosphamide (Cy) have been associated with increased toxicity to endothelial cells via decreased glutathione levels in hepatocytes and subsequent VOD, which potentially overlaps with decreased glutathione synthesis caused by SIR as shown in a rat model [10-12]. This is supported by a report of Platzbecker et al. [13], who observed an increased rate of VOD after Busulfanbased conditioning regimen and posttransplantation immunosuppression with Everolimus and TAC. Fur-

Physical and psychosocial aspects of adolescent and young adults after allogeneic hematopoietic stem-cell transplantation: results from a prospective multicenter trial

PurposeAllogeneic hematopoietic stem-cell transplantation (alloHSCT) is physically and psychosocially demanding. Among transplant recipients, adolescent and young adults (AYA) represent a special group, as disease occurs early in life, resulting in the prospect of long survival time and high burden of alloHSCT sequelae. However, data focusing on AYA undergoing alloHSCT are rare.MethodsData resulting from a prospective multicenter trial initially focusing on graft-versus-host disease (GvHD) after alloHSCT were reused to analyse the differences between AYA and elderly patients. In total, data of 205 alloHSCT recipients were evaluated. Patients completed the FACT-BMT, HAP, SF-36, 24-AM, LOT-R, BSSS, HADS, and GvHD questionnaires.ResultsMedian age of AYA and non-AYA patients was 29 and 52xa0years. Using 24-AM-Test, evaluating personality traits, non-AYA reported to be more conscientious (pxa0=xa00.033). However, AYA described higher quality of life regarding physical role functioning (pxa0=xa00.001), physical functioning (pxa0=xa00.002), bodily pain (pxa0=xa00.023), and emotional role function (pxa0=xa00.027) in the SF-36. General health perception, vitality, social role functioning, and mental health were comparable among both groups. On HAP scale, AYA reported higher maximum (pxa0=xa00.003) and adjusted activity scores (pxa0=xa00.002), but showed similar restrictions regarding activity, self-supply, and self-determination.ConclusionAYA represent a particular group characterized by higher physical well-being and activity scores, and significantly vary from non-AYA patients in psychosocial aspects. Studies covering distinctive features of AYA undergoing alloHSCT are warranted to improve awareness of the special needs of this group.

Modulation of lymphocyte subpopulations by extracorporeal photopheresis in patients with acute graft-versus-host disease or graft rejection

Abstract Extracorporeal photopheresis (ECP) constitutes a promising treatment for patients with steroid-refractory acute graft-versus-host disease (aGvHD) after allogeneic stem cell transplantation and for patients with graft rejection after solid organ transplantation (SOT). There is an increasing body of evidence that modulation of lymphocyte subsets might play a crucial role in the mechanism of action in ECP. We therefore analyzed immunological effects concomitantly with clinical findings in patients under ECP therapy using multicolor flow cytometry. In a patient with steroid-refractory aGvHD and a patient with progressive bronchiolitis obliterans syndrome (BOS) after double-lung transplantation, clinical responses to ECP therapy were paralleled by an increase of CD4 + CD25hiFoxP3 + regulatory T cells and a decrease of T(EMRA) (CD3 + CD8+ CD45RA+ CD62L+ effector memory T) cells as well as of natural killer (NK)T cells. In summary, immunomonitoring of T cell subsets can elucidate the mechanism of action in ECP.

Chronic Graft versus Host Disease but not the Intensity of Conditioning has Impact on Survival after Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Hematological Diseases

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is often performed in cases of advanced hematological diseases, but because of the associated mortality and a high risk of relapse it is life prolonging only in some patients. Patients and Methods: A retrospective multi-center analysis of 401 patients was conducted to analyze the variables associated with outcome after alloHSCT in advanced hematological diseases. The Cox proportional hazards model was used to assess the independence of overall survival (OS) and disease-free survival (DFS) from prognostic factors in a multivariate model. Results: The 5-year OS and DFS were 27.3 and 21.1% respectively. Multivariate analysis showed that the underlying malignancy had a significant influence on OS and DFS (p < 0.001 and p < 0.011, respectively), whereas development of severe acute graft versus host disease (GvHD) had a negative impact on OS (p < 0.001). Development of chronic GvHD showed a trend to a better OS (p = 0.085) and DFS (p = 0.199). No impact was seen for the intensity of conditioning. Conclusion: Development of chronic GvHD but not the conditioning regimen improved the outcome after alloHSCT for advanced malignancies, underlining the importance of immunological rather than cytotoxic effects.

Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia

FLT3 mutations represent the most frequent molecular aberrations in acute myeloid leukemia (AML), and are associated with a higher probability of relapse and worse outcome. Activating mutations of FLT3 predominantly comprise internal tandem duplications (FLT3-ITDs), and can be detected in up to 30%

Headache after hematopoietic stem cell transplantation: Being aware of chronic bilateral subdural hematoma

Chronic bilateral subdural hematoma (SDH) is a rare but serious complication after hematopoietic stem cell transplantation (HSCT) [1 – 3]. Risk factors such as thrombocytopenia, intra-thecal chemotherapy and intra-cranial metastasis have been suggested. The diagnosis may be difficult because symptoms and signs may not be pathognomonic. Here we report about a 36-year-old man with Ann Arbor stage IIIBE peripheral T-cell lymphoma, unspecified without CNS involvement. Two weeks after completion of eight chemotherapy cycles with CHOEP-14 and G-CSF he developed left-sided facial paresis. CNS involvement was diagnosed by cytologic examination of the cerebrospinal fluid (CSF). He received 12 cycles of intra-thecal therapy with methotrexate (MTX) and additional 2 mg dexamethasone orally. Two months later systemic relapse was diagnosed, which was treated with combined intra-thecal and systemic chemotherapy including intravenous (i.v.) MTX by applying the GMALL-B-ALL/NHL 2002 protocol for patients younger than 55 years. After a temporary response the lymphoma progressed and the neuronal axis and the mediastinum were irradiated with 10 Gy each (single doses 2 Gy) and an autologous HSCT was undertaken after conditioning with total body irradiation (12 Gy) and cyclophosphamide 60 mg kg i.v. One month later he received an allogeneic HSC graft from an unrelated donor containing 8.17610E þ 6 kg CD 34þ cells after conditioning with treosulfan 12 g m i.v. day-6 until day-4, fludarabine 30 mg m i.v. day-6 until day-2, ATG-thymoglobulin 2 mg kg i.v. day-3 until day-1. Up to the day of allogeneic HSCT the patient had received a total of 22 lumbar punctures. A MRT scan of the brain as well as cytological examination of the CSF before HSCT was without pathological findings. He developed headache at day þ1 after HSCT that was thought to be due to side effects of the conditioning regime. However, at day þ11 the patient became somnolent. The MRT scan showed a chronic bilateral SDH with signs of a beginning CSF circulation disturbance and foramen Monroe blockade. An emergency surgical drainage was performed. Cytological examination of the evacuated material showed no evidence of lymphoma. After this procedure his level of consciousness improved, but he was treated twice again with burr-hole decompression because of recurrent symptomatic SDH and died from severe sepsis on day þ45 after HSCT. Autopsy revealed meningeal involvement by lymphoma. The causes for chronic SDH besides trauma and coagulopathy include diagnostic measures, cytostatic treatment and CNS involvement by malignant disease. For non-Hodgkin lymphomas, CNS involvement by leptomeningeal infiltrates or parenchymal masses is known to occur in 5 – 9% of the patients [4,5]. Furthermore, SDH also may develop in the aplastic phase after HSCT, when the thrombocytopenia itself is a high-risk factor of hemorrhage