Christian Junghanss

Early related or unrelated haematopoietic cell transplantation results in higher overall survival and leukaemia-free survival compared with conventional chemotherapy in high-risk acute myeloid leukaemia patients in first complete remission

Between 1996 and 2004, a total of 708 patients were enrolled in the acute myeloid leukaemia (AML) ‘96 and ‘02 studies of the East German Study Group (OSHO). Of these, 138 patients (19.5%) had unfavourable cytogenetics defined as complex karyotype, del (5q)/-5, del (7q)/-7, abn (3q26) and abn (11q23). In all, 77 (56%) achieved complete remission 1 (CR1) after induction chemotherapy and were eligible for haematopoietic cell transplantation (HCT). HCT was performed after a median of two cycles of consolidation chemotherapy (CT) in the AML ‘96 and one cycle in the AML ‘02 study (P=0.03). After a median follow-up of 19 months, overall survival (OS) at two years was significantly better in the donor group (52±9%) versus the no-donor group (24±8%; P=0.005). Differences in outcomes were mainly because of a lower relapse incidence in patients after HCT (39±11%) compared with a higher relapse incidence in patients undergoing CT (77±10%; P=0.0005). Treatment-related mortality was low and not statistically significantly different between the two treatment groups (15±7 and 5±5% for HCT and chemotherapy, respectively; P=0.49).We conclude that early HCT from related or unrelated donors led to significantly better OS and leukaemia-free survival compared with chemotherapy in patients with unfavourable karyotype.

Infectious risks and outcomes after stem cell transplantation: Are nonmyeloablative transplants changing the picture?

Purpose of review Opportunistic infections contribute to morbidity and mortality after myeloablative allogeneic stem cell transplantation. The development of nonmyeloablative or toxicity-reduced conditioning regimens for allogeneic hematopoietic stem cell transplantation might change this picture significantly. These regimens are in general highly immunosuppressive, but effects on myelopoiesis and mucosal toxicities are usually reduced compared with myeloablative hematopoietic stem cell transplantation conditioning regimens. This review summarizes the infectious risks associated with each type of hematopoietic stem cell transplantation conditioning regimen, and presents the results of early clinical studies. Recent findings Although the data are preliminary, the results of recent studies suggest that nonmyeloablative conditioning regimens may decrease the risks of bacterial infections associated with mucosal damage and persistent neutropenia; however, risks for late viral and fungal infections persist during severe graft versus host disease. Results of several case reports and series emphasize that therapeutic outcomes of infections may be improved in patients who receive nonmyeloablative conditioning regimens. Summary Infectious risks and outcomes after hematopoietic stem cell transplantation appear to be in evolution given the introduction of alternative, nonmyeloablative conditioning regimens. Although infections remain a prominent cause of transplant-related mortality, the timing and types of infections may differ. Further studies are necessary to define appropriate preventative strategies, and to determine whether patients with ongoing infections might benefit from nonmyeloablative hematopoietic stem cell transplantation.

Impact of unrelated donor status on the incidence and outcome of cytomegalovirus infections after non‐myeloablative allogeneic stem cell transplantation

Summary.u2002 Little is known about the impact of cytomegalovirus (CMV) infections that occur after human leucocyte antigen (HLA)‐matched unrelated donor (MUD) non‐myleoablative haematopoietic stem cell transplantation (HCT). We analysed the incidence, onset and outcomes of CMV infections in 59 recipients of MUD and in 109 recipients of HLA‐matched related donor (MRD) allogeneic HCT following non‐myeloablative conditioning containing 2u2003Gy total body irradiation and fludarabine. In CMV seropositive recipients, antigenaemia occurred in 68% (MUD) and in 49% (MRD, Pu2003=u20030·08); there were no differences in the maximum levels of CMV antigenaemia and the time to cessation with antiviral therapy. CMV viraemia by culture was more common in MUD compared with MRD HCT recipients in univariate analysis (26% vs. 6%, Pu2003=u20030·01), however, this difference was not detectable after controlling for other factors. The rates of CMV disease in the first 100u2003d were similar in MUD (9%) and MRD (5%) HCT recipients. CMV disease tended to occur earlier in the MUD compared with the MRD recipients (median day 41 vs. day 80). Beyond day 100, rates of CMV disease remained similar in both cohorts (cumulative incidence: MUD 21% and MRD 14%). The 30‐d and 1‐year survivals after CMV disease diagnosis were not significantly different in both groups. Thus, there appeared to be a trend toward increased CMV reactivation in MUD compared with MRD non‐myeloablative allogeneic HCT recipients; however, these differences did not reach statistical significance in this cohort and preemptive therapy was similarly effective in preventing CMV diseases.

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-

Methotrexate-albumin and aminopterin-albumin effectively prevent experimental acute graft-versus-host disease.

Background. During the last several years, major progress has been made in developing targeted chemotherapy using cytotoxic drugs covalently bound to human serum albumin (HSA). We explored the activity of two antifolates methotrexate (MTX) and aminopterin (AMPT) bound to HSA in prophylaxis and treatment of experimental acute graft-versus-host disease (aGVHD). Methods. In all, 113 female F1 hybrid BN/Lew-rats were irradiated with 8.2 Gy (n=103) or 9.9 Gy (n=10). One day after irradiation each rat received 4×107 bone marrow cells and 1.5×107 spleen T-cells from female Lew-rats. GVHD prophylaxis consisted of MTX-HSA 2 mg/kg (n=25), MTX-HSA 0.5 mg/kg (n=8), AMPT-HSA 0.65 mg/kg (n=8), MTX 0.5 mg/kg (n=17), or native HSA (n=39) given intraperitoneally (IP) on days 0, 4, 8, and 12. Treatment of aGVHD consisted of MTX-HSA 2 mg/kg (n=8) or AMPT-HSA 0.5 mg/kg (n=8) given intraperitoneally at the time of onset of aGVHD and subsequently every fourth day (a total of four doses). Results. All animals receiving native HSA developed lethal aGVHD. Prophylactic treatment with MTX-HSA 2 mg/kg prevented aGVHD in 18 of 25 animals and in 6 of 8 receiving AMPT-HSA. In contrast, five out of nine rats receiving free MTX died due to aGVHD. The survival rates in the prophylactic MTX-HSA 2 mg/kg and AMPT-HSA groups were significantly higher compared to the MTX and control groups (P<0.05), while non hematologic toxicity of MTX-HSA was not detectable. AMPT-HSA at a dose of 0.65 mg/kg as well as MTX at a dose of 0.5 mg/kg were associated with temporary weight loss and lethargy. Conclusions. The albumin conjugates MTX-HSA and AMPT-HSA effectively prevent experimental aGVHD.

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.

Questions arising on phlebotomy in polycythemia vera: prophylactic measures to reduce thromboembolic events require patient-focused decisions

More than 1500 years ago, Scribonius Largus published the maxime ‘primum non nocere, secundum cavere, tertium sanare’ to focus his Roman colleagues on the central aspect of therapeutic measures: the patient’s health and well-being. It implicates that therapeutic measures (and their side effects) need to be balanced in regard to expected benefits and outcome. Treatment of myeloproliferative neoplasia has been focused on cytoreduction for a long time, as pathophysiological aspects (e.g., identification of the underlying driver mutation) had not been clarified and targeted therapies had not been developed or approved. Following discovery of molecular targets within the last decade and the emergence of Janus-kinase (JAK) inhibitors, which can ameliorate and even abrogate constitutional and inflammatory symptoms [1], quality of life has come into focus as a therapeutic goal [2]. Physical activity, productivity and well-being of patients suffering from polycythemia vera (PV) are severely hampered by the disease and improvement of quality of life as well as reduction of symptom burden have become a major therapeutic goal for both PV patients and their physicians [3–5]. Therefore, therapeutic goals for patients diagnosed with PV clearly need to be redefined. Among a variety of measures, physicians as well as patients have clarified clinical needs that should be taken into consideration:

A prospective, randomized evaluation of the feasibility of exergaming on patients undergoing hematopoietic stem cell transplantation

The positive effects of physical and sports therapy for strain dependent physical practice and improved quality of life (QoL) are well known. Nevertheless, the available capacities and problem-oriented therapies in the setting of hematopoietic stem cell transplantation (HSCT) are limited. We conducted a prospective, randomized study among 42 HSCT recipients in order to investigate the influence of exergaming on Nintendo Wii® or classical physiotherapy (PT) on physical fitness and psychological well-being. The trial included evaluation of muscle strength, endurance, physical activity, distress, QoL, anxiety, and depression. Within the first 2 weeks after HSCT endurance, muscle strength and physical well-being decreased, while the value of distress increased significantly in both groups. However, exergaming on Nintendo Wii® resulted in a decrease of anxiety and depression and improved emotional well-being, while the PT group showed a contrariwise pattern of these features. Analysis of the FACT-BMT revealed a decline of QoL domains 2 and 4 weeks after HSCT and an improvement afterwards. The decrease of functional status after HSCT was accompanied by a drop of QoL and an increase of distress in both groups. However, our prospective study demonstrates that exergaming using the Nintendo Wii® is feasible and well tolerated in HSCT recipients.

Genetic Mutations in a Patient with Chronic Myeloid Leukemia Showing Blast Crisis 10 Years After Presentation

Since the introduction of tyrosine kinase inhibitors (TKI), the prospects for patients with chronic myeloid leukemia (CML) have improved significantly. Herein we present the case of a patient with CML who experienced blast crisis and development of acute myeloid leukemia (AML) 10 years after presentation. The CML was characterized by the gene fusion of breakpoint cluster region BCR and tyrosine-protein kinase ABL1. During treatment different therapeutic protocols including imatinib, nilotinib, dasatinib and ponatinib were applied due to development of resistance or non-response. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used to describe cytogenetic and molecular aberrations elucidating the development into AML: A loss of chromosome 7, as well as an arising frequency of variants in the gene met proto-oncogene MET (p.T110I) and tyrosine-protein phosphatase non-receptor type 11 PTPN11 (p.Q510L) was observed. This report describes the comprehensive characterization of a clinical case showing multiple therapeutic resistances correlated with genetic aberrations.