Gero Massenkeil

Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system

Clinical trials have indicated that immunoablation followed by autologous hematopoietic stem cell transplantation (ASCT) has the potential to induce clinical remission in patients with refractory systemic lupus erythematosus (SLE), but the mechanisms have remained unclear. We now report the results of a single-center prospective study of long-term immune reconstitution after ASCT in 7 patients with SLE. The clinical remissions observed in these patients are accompanied by the depletion of autoreactive immunologic memory, reflected by the disappearance of pathogenic anti-double-stranded DNA (dsDNA) antibodies and protective antibodies in serum and a fundamental resetting of the adaptive immune system. The latter comprises recurrence of CD31(+)CD45RA(+)CD4(+) T cells (recent thymic emigrants) with a doubling in absolute numbers compared with age-matched healthy controls at the 3-year follow-up (P = .016), the regeneration of thymic-derived FoxP3(+) regulatory T cells, and normalization of peripheral T-cell receptor (TCR) repertoire usage. Likewise, responders exhibited normalization of the previously disturbed B-cell homeostasis with numeric recovery of the naive B-cell compartment within 1 year after ASCT. These data are the first to demonstrate that both depletion of the autoreactive immunologic memory and a profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE.

Bisphosphonate-induced osteonecrosis of the jaws: Prospective study of 80 patients with multiple myeloma and other malignancies

A prospective study was performed in 80 patients receiving bisphosphonates in order to determine frequency of occurrence, risk factors, clinical presentation, radiology, pathology and proper treatment of osteonecrosis of the jaw (ONJ). Of 80 patients, 22 (28%) developed ONJ. There were 11 male and 11 female patients. Median age was 65 years. Ten patients (46%) had multiple myeloma (MM), 5 (23%) had breast cancer and 7 (32%) had other malignancies. Of 22 patients with ONJ, 14 patients (64%) received zoledronate, 3 (14%) received pamidronate, 4 (18%) received pamidronate later followed by zoledronate and 1 patient received ibandronate later followed by zoledronate. The median time of exposure in ONJ group was 32 months compared with 27 months in patients without ONJ. The mean induction time until bone exposure was 26 months for patients who received zoledronate, 54 months for pamidronate and 48 months for pamidronate followed by zoledronate. Thirteen patients (59%) had ONJ with bone exposure of mandible, 6 (27%) of maxilla and 3 (14%) of both jaws. ONJ occurred spontaneously in 5 patients (23%) and in 17 patients (77%) occurred after tooth extractions and surgical tooth removals (P<0.001). Nine patients (41%) had previous extractions of molars, 6 (27%) of premolars and 2 (9%) of front teeth. The cumulative hazard is significantly higher in zoledronate group (P=0.015). It was 3.48 times higher than the other group (pamidronate alone; pamidronate followed by zoledronate; ibandronate alone; etidronate alone; ibandronate followed by pamidronate; ibandronate followed by zoledronate; ibandronate followed by pamidronate and zoledronate). There was no association of ONJ with age, sex, use of high-dose or conventional chemotherapy or the use of corticosteroids, thalidomide or bortezomib (P>0.05). Patients diagnosed with multiple myeloma and breast cancer were found significantly associated with ONJ (P=0.001 and P=0.014, respectively). Long-term use of bisphosphonates (>2.5 years) increases the risk for development of ONJ. Intravenous application of zoledronate and previous dental extractions or surgical tooth removals are important risk factors of ONJ. Neither treatment with high-dose chemotherapy with autologous stem cell transplantation nor treatment with corticosteroids, thalidomide or bortezomib is a risk factor in this study.

Management of sepsis in neutropenia: guidelines of the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

These guidelines from the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO) give recommendations for the management of adults with neutropenia and the diagnosis of sepsis. The guidelines are written for clinicians and focus on pathophysiology, diagnosis, and treatment of sepsis. The manuscript contains evidence-based recommendations for the assessment of the quality and strength of the data.

Management of sepsis in neutropenic patients: guidelines from the infectious diseases working party of the German Society of Hematology and Oncology

Sepsis is a leading cause of mortality in neutropenic cancer patients. Early initiation of effective causative therapy as well as intensive adjunctive therapy is mandatory to improve outcome. We give recommendations for the management of adults with neutropenia and sepsis. The guidelines are written for clinicians involved in care of cancer patients and focus on pathophysiology, diagnosis and treatment of sepsis during neutropenia.

Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation

BACKGROUND Total body irradiation followed by bone marrow transplantation is well established as a part of the conditioning regimen in high dose therapy. The immediate tolerance of fractionated total body irradiation (FTBI) was investigated prospectively. METHODS From January 1995 to December 1998 162 patients received a FTBI, 6x2 Gy on 3 consecutive days, lung dose 10 Gy, for allogeneic (n=112) or autologous (n=50) bone marrow transplantation. High dose chemotherapy (mostly Cyclophosphamide) was administered after the FTBI. A standardized supportive therapy was administered. The immediate toxicity of FTBI was evaluated prospectively prior to each radiation fraction using a defined questionnaire. RESULTS Main symptoms distressing the patient during irradiation period were gastrointestinal symptoms like nausea and emesis. The prevalence of nausea per fraction increased to 26.1% after the 4th fraction, with a significant higher prevalence in children younger than 10 years at 1st and 2nd fractions. 42.6 and 22. 8%, respectively, of all patients complained of nausea and episodes of emesis, during FTBI. Mild xerostomia and parotiditis were observed in 29.9 and 7.1% of all patients. Further gastrointestinal side effects during FTBI were loss of appetite in 16.0%, indisposition in 25.3%, mild oesophagitis in 3.7% and diarrhoea in 3. 7% of the patients. During FTBI 41.4% of the patients developed a temporary skin irritation (mild erythema). Pruritus was registered in 3.7% of the patients. Headache was observed in 14.8% and Fatigue syndrome in 49.2% of women and 28.3% of men (P<0.005). CONCLUSION FTBI is a well tolerated therapeutic regimen in high dose therapy. The 162 patients investigated revealed no severe immediate side effects.

A modified EBMT risk score and the hematopoietic cell transplantation-specific comorbidity index for pre-transplant risk assessment in adult acute lymphoblastic leukemia

Background Disease stage is the most important prognostic parameter in allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia, but other factors such as donor/host histocompatibility and gender combination, recipient age, performance status and comorbidities need to be considered. Several scoring systems are available to predict outcome in HCT recipients; however, their prognostic relevance in acute lymphoblastic leukemia is not well defined. Design and Methods In the present study we evaluated a modified EBMT risk score (mEBMT) and the HCT-specific comorbidity index (HCT-CI) in 151 adult acute lymphoblastic leukemia patients who received allogeneic HCT from 1995 until 2007 at our center. Results Disease status was first complete remission (CR1) (47%), CR>1 (21%) or no CR (32%). Overall survival (OS) at one, two and five years was 62%, 51% and 40% and non-relapse mortality (NRM) was 21%, 24% and 32%. Median mEBMT was 3 (0–6). Higher mEBMT was associated with inferior OS (hazard ratio per score unit (HR): 1.50, P<0.001), higher NRM (HR: 1.36, P=0.042) and higher relapse mortality (HR: 1.68, P<0.001). Disease stage was the predominant prognostic factor in this score. Comorbidities were present in 71% of patients with mild hepatic disease (29%), moderate pulmonary disease (28%) and infections (23%) being the most common. Median HCT-CI was 1 (0–9). In univariate analysis a trend for inferior OS (HR: 1.08, P=0.20) and higher NRM (HR: 1.14, P=0.11) with increasing HCT-CI was observed but the level of significance was not reached. In additional analyses we found that reduced Karnofsky Performance Status (KPS) was associated with inferior OS (HR: 1.34, P=0.023) and higher relapse mortality (HR: 1.71, P=0.001) when analyzed univariately. However, KPS was associated with disease stage and significance was lost in multivariate analysis. Conclusions The mEBMT was prognostic in our patient cohort with predominant influence of disease stage, whereas a trend but no significant prognostic value was observed for the HCT-CI.

Loss of bone mass and vitamin D deficiency after hematopoietic stem cell transplantation: standard prophylactic measures fail to prevent osteoporosis.

Bone mineral density (BMD) and biochemical markers of bone metabolism were analyzed in 67 adults with ALL (n = 27), AML (n = 14), MDS (n = 6) and CML (n = 20) before and after allogeneic stem cell transplantation (SCT). Median age was 36 years (17–56). Twenty-six out of 53 patients (49%) had osteopenia and osteoporosis before SCT, 21/26 had acute leukemias and 5/26 had chronic myeloid leukemia (CML). T-score before SCT was −1.23 in patients with acute leukemias and 0.62 in CML patients (P = 0.001). After SCT, a significant loss of BMD was observed in all patients. After 6 months, 24 of 36 evaluable patients (67%) had pathologic BMD, 11 of them (30%) had developed osteoporosis. After 12 months, 20 of 32 evaluable patients (62%) had BMD values below normal and nine of them (28%) had osteoporosis. Increased pyridinium excretion was observed in 12/20 patients (60%) with acute leukemias, but only in 3/13 (23%) with CML (P = 0.014). A prolonged vitamin D deficiency for more than 6 months developed early after SCT in all patients. Patients with acute leukemias frequently have osteopenia and osteoporosis before SCT. After SCT, a further loss of BMD occurs independent from the underlying disease. Standard prophylactic measures are not sufficient to prevent loss of bone mass. Studies on prophylactic interventions are needed to prevent severe osteoporosis in long-term survivors of SCT.

Direct assessment of thymic reactivation after autologous stem cell transplantation.

Methods to quantify Th cell reconstitution after immunosuppressive therapies such as hematopoietic stem cell transplantation are becoming a key issue since persistent Th cell deficiencies may result in severe complications and adverse events. We employed here cytometric monitoring of CD31+ thymus-naive Th cells for the direct assessment of human thymic function in 10 patients undergoing autologous stem cell transplantation for severe autoimmune diseases. High frequencies of posttransplant recurring naive Th cells coexpressed CD31 and stable long-term reconstitution with elevated absolute counts of CD31+ thymus-naive Th cells that were enriched with T cell receptor excision circles was demonstrated. Cytometric monitoring of CD31+ thymus-naive Th cells enables to directly evaluate human thymic function ex vivo.

Antiviral prophylaxis in patients with solid tumours and haematological malignancies—update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO)

Reactivation of viral infections is common in patients with solid tumour or haematological malignancy. Incidence and severity depend on the extent of cellular immunosuppression. Antiviral prophylaxis may be effective to prevent viral reactivation. In 2006, the Infectious Diseases Working Party of German Society for Hematology and Medical Oncology (DGHO) published guidelines for antiviral prophylaxis in these patient populations. Here, we present an update of these guidelines for patients with solid and haematological malignancies undergoing antineoplastic treatment but not allogeneic stem cell transplantation. Relevant literature for reactivation of different viruses (herpes simplex virus (HSV), varicella zoster virus (VZV), hepatitis B virus (HBV) and respiratory viruses) is discussed to provide evidence-based recommendations for clinicians taking care of this patient population. We recommend a risk-adapted approach with (val)acyclovir against HSV and VZV in patients treated with alemtuzumab, bortezomib or purine analogues. Seasonal vaccination against influenza is recommended for all patients with solid or haematological malignancies regardless of antineoplastic therapy. Hepatitis B screening is recommended in lymphoproliferative disorders, acute leukaemia, and breast cancer, and during treatment with monoclonal anti-B-cell antibodies, anthracyclines, steroids and in autologous stem cell transplantation. In those with a history of hepatitis B prophylactic lamivudine, entecavir or nucleotide analogues as adefovir are recommended to prevent reactivation.

A modified EBMT risk score predicts the outcome of patients with acute myeloid leukemia receiving allogeneic stem cell transplants

The systematic and standardized pretransplant risk assessment represents an important tool to predict the outcome of patients undergoing allogeneic stem cell transplantation (alloSCT). To investigate the capacity of a modified European group for blood and marrow transplantation (mEBMT) risk score to predict the outcome of patients with acute myeloid leukemia (AML) receiving allogeneic stem cell transplants, we retrospectively analyzed 214 patients transplanted at our center between 1995 and 2008. Overall survival (OS) of the whole cohort at 1, 3, and 5 yr was 62%, 48%, and 45%, whereas the cumulative incidence of relapse or non‐relapse mortality (NRM) was 26%, 33%, and 33% or 19%, 21%, and 22%. In univariate analysis, a higher mEBMT risk score was associated with an inferior OS ranging from 69% for patients with a score of 0/1 to 26% for patients with a score of 5/6 at 5 yr (P < 0.0001) and steadily increasing hazard ratios for each additional score point. Likewise, a higher mEBMT risk score was associated with an increased incidence of relapse (P = 0.049). Importantly, the prognostic value of the mEBMT risk score in terms of OS and relapse was maintained in multivariate analysis. Taken together, this indicates that a mEBMT risk score may be used to predict the outcome of patients with AML following alloSCT.