Hartmut Bertz

Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial

BACKGROUND Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). METHODS Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III-IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. FINDINGS The number of patients in the ATG-F group who had severe aGVHD grade III-IV or who died within 100 days of transplantation was 12 and 10 (21.4%, 95% CI 13.4-29.3), respectively, compared with 24 and nine (33.7%, 24.3-43.0) patients, respectively, in the control group (adjusted odds ratio 0.59, 95% CI 0.30-1.17; p=0.13). The cumulative incidence of aGVHD grade III-IV was 11.7% (95% CI 6.8-19.8) in the ATG-F group versus 24.5% (17.3-34.7) in the control group (adjusted hazard ratio [HR] 0.50, 95% CI 0.25-1.01; p=0.054), and cumulative incidence of aGVHD grade II-IV was 33.0% (n=34; 95% CI 25.1-43.5) in the ATG-F group versus 51.0% (n=50; 95% CI 42.0-61.9) in the control group (adjusted HR 0.56, 0.36-0.87; p=0.011). The 2-year cumulative incidence of extensive chronic GVHD was 12.2% (n=11; 95% CI 7.0-21.3) versus 42.6% (n=34; 95% CI 33.0-55.0; adjusted HR 0.22, 0.11-0.43; p<0.0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. INTERPRETATION The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. FUNDING Fresenius Biotech GmbH.

ESPEN guidelines on nutrition in cancer patients

Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each institution involved in treating cancer patients. All cancer patients should be screened regularly for the risk or the presence of malnutrition. In all patients - with the exception of end of life care - energy and substrate requirements should be met by offering in a step-wise manner nutritional interventions from counseling to parenteral nutrition. However, benefits and risks of nutritional interventions have to be balanced with special consideration in patients with advanced disease. Nutritional care should always be accompanied by exercise training. To counter malnutrition in patients with advanced cancer there are few pharmacological agents and pharmaconutrients with only limited effects. Cancer survivors should engage in regular physical activity and adopt a prudent diet.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

Allogeneic Stem-Cell Transplantation From Related and Unrelated Donors in Older Patients With Myeloid Leukemia

PURPOSE To improve outcome for older patients with poor-prognosis myeloid malignancies by using allogeneic hematopoietic stem-cell transplantation (alloHSCT) from unrelated and sibling donors after reduced-intensity conditioning (RIC). PATIENTS AND METHODS Nineteen older patients (median age, 64 years; range, 60 to 70 years) with active myeloid malignancies were treated with an RIC regimen that was based on fludarabine, melphalan, and carmustine followed by alloHSCT from matched unrelated (n = 12) or sibling donors (n = 7). Before transplantation, patients had a median of 50% bone marrow blasts (range, 0% to 70%). Graft-versus-host-disease (GvHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil or methotrexate. Eleven of 12 patients with an unrelated donor also received anti-T-lymphocyte globulin (ATG). RESULTS Engraftment was successful for all 19 patients. Seventeen assessable patients achieved complete response (CR). Four patients experienced relapse; three achieved CR again after donor lymphocyte infusion (n = 1) or a second alloHSCT (n = 2). Six patients died as a result of relapse (n = 2), GvHD-associated complications (n = 2), or fungal infections (n = 2), resulting in a 1-year nonrelapse mortality rate of 22%. With a median follow-up of 825 days (range, 595 to 1,028 days), 13 of 19 patients are alive, resulting in a 1-year survival rate of 68% (95% confidence interval, 48% to 89%). CONCLUSION In older patients with untreated poor-prognosis leukemia, this RIC regimen combined with alloHSCT sufficiently reduces the leukemic burden, resulting in a high CR rate. When ATG is added, matched unrelated donor transplantation can be performed safely in older patients. For these patients, early transplantation after diagnosis offers a fair chance of cure.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: A multicenter survey

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3–90.7%, 95% confidence interval (CI)) and 97.4% (92.3–100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Adoptive immunotherapy for relapsed multiple myeloma after allogeneic bone marrow transplantation (BMT): Evidence for a graft-versus-myeloma effect

Adoptive immunotherapy with donor-derived buffy coat cells for relapsed hematological malignancies after allogeneic BMT is an established and highly effective treatment. We report a patient who relapsed on day +330 after allogeneic sibling BMT for multiple myeloma with multiple solid subcutaneous tumors consisting of plasma cells. Histology and immunocytology of the bone marrow did not show plasma cell infiltration. After cessation of the immunosuppression consisting of cyclosporine and methylprednisolone, a total of 6.2 × 107/kg recipient body weight CD3+ T cells derived from the donor by leukapheresis were transfused on 4 consecutive days. To enhance the T cell effect six doses of 5 million units alpha interferon were given subcutaneously. Five days later the tumors started to shrink and have completely vanished since day ×400 after BMT. The patient developed acute GVHD grade III of the liver and gut which was treated by reinduction of various immunosuppressive drugs. Up to now there is no evidence for relapse of the multiple myeloma, but the patient suffers from extensive chronic GVHD (gut and liver). This is the first report to demonstrate a graft-versus-myeloma effect for relapse with solid tumor manifestation after sibling BMT with donor-derived buffy coat cells as adoptive immunotherapy.

High- Versus Standard-Dose Filgrastim (rhG-CSF) for Mobilization of Peripheral-Blood Progenitor Cells From Allogeneic Donors and CD34+ Immunoselection

PURPOSE The efficacy of a high- versus a standard-dose filgrastim (recombinant human granulocyte colony-stimulating factor, or rhG-CSF) regimen to mobilize peripheral-blood progenitor cells (PBPCs) for allogeneic transplantation was investigated in 75 healthy donors. PATIENTS AND METHODS From December 1994 to December 1997, 75 consecutive donors (median age, 38 years; range, 17 to 67 years) were assigned to two different schedules of rhG-CSF for PBPC mobilization. Fifty donors received 24 microg rhG-CSF/kg body weight (BW) divided into two daily subcutaneous injections (two doses of 12 microg, group A), whereas 25 were treated with 10 microg rhG-CSF once daily (group B). Apheresis was started on day 4 in group A and on day 5 in group B. Target CD34(+) cell numbers in apheresis products were >/= 4 x 10(6)/kg recipient BW. RESULTS Cytokine priming and collection of PBPCs were equally well tolerated in both groups. Significantly higher CD34(+) cell numbers in group A with 3. 7 x 10(6)/kg recipient BW/apheresis (0.47 x 10(6)/L apheresis) compared with 2 x 10(6)/kg recipient BW/apheresis (0.25 x 10(6)/L apharesis) in group B were obtained (P <.05). Using standard aphereses (median, 9 L), two doses of 12 microg rhG-CSF/kg allowed collection of >/= 4 x 10(6)/kg CD34(+) cells with two aphereses (range, one to three) in group A versus three aphereses (range, one to six) in group B (P <.015). Donor age, sex, and BW influenced the collection of CD34(+) cell numbers: in particular, significantly higher apheresis results were obtained in donors younger than 40 years compared with donors older than 40 years of age (P <.05). In 65 CD34(+) selection procedures using avidin-biotin immunoabsorption columns (Ceprate SC System, CellPro, Bothell, WA), a median CD34(+) purity of 53%, CD34(+) recovery of 40%, and the collection of 2 x 10(6)/kg CD34(+) cells/selection were achieved. In group A with higher CD34(+) cells/kg/apheresis, CD34(+) purity, recovery, and cell yields were 60%, 45%, and 2.3 x 10(6)/kg/selection, respectively, as compared with 48%, 31%, and 0.7 x 10(6)/kg in group B (P <.05). CONCLUSION Our results demonstrate that twice daily rhG-CSF (two doses of 12 microg/kg BM) compared with once daily rhG-CSF (10 microg/kg BW), in addition to being well tolerated, significantly improves PBPC mobilization, allows the collection of higher numbers of CD34(+) cells with one or two standard aphereses, and facilitates subsequent selection procedures in healthy allogeneic donors.

Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD

This consensus statement established under the auspices of the German working group on BM and blood stem cell transplantation (DAG-KBT), the German Society of Hematology and Oncology (DGHO), the Austrian Stem Cell Transplant Working Group, the Swiss Blood Stem Cell Transplantation Group (SBST) and the German-Austrian Pediatric Working Group on SCT (Päd-Ag-KBT) summarizes current evidence for diagnosis, immunosuppressive and supportive therapy to provide practical guidelines for the care and treatment of patients with pulmonary manifestations of chronic GVHD (cGVHD). Pulmonary cGVHD can present with obstructive and/or restrictive changes. Disease severity ranges from subclinical pulmonary function test (PFT) impairment to respiratory insufficiency with bronchiolitis obliterans being the only pulmonary complication currently considered diagnostic of cGVHD. Early diagnosis may improve clinical outcome, and regular post-transplant follow-up PFTs are recommended. Diagnostic work-up includes high-resolution computed tomography, bronchoalveolar lavage and histology. Topical treatment is based on inhalative steroids plus beta-agonists. Early addition of azithromycin is suggested. Systemic first-line treatment consists of corticosteroids plus, if any, continuation of other immunosuppressive therapy. Second-line therapy and beyond includes extracorporeal photopheresis, mammalian target of rapamycin inhibitors, mycophenolate, etanercept, imatinib and TLI, but efficacy is limited. Clinical trials are urgently needed to improve understanding and treatment of this deleterious complication.

Infectious complications after allogeneic stem cell transplantation: epidemiology and interventional therapy strategies Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

The risk of infection after allogeneic stem cell transplantation is determined by the underlying disease, the intensity of previous treatments and complications that may have occurred during that time, but above all, the risk of infection is determined by the selected transplantation modality (e.g. HLA-match between the stem cell donor and recipient, T cell depletion of the graft, and others). In comparison with patients treated with high-dose chemotherapy and autologous stem cell transplantation, patients undergoing allogeneic stem cell transplantation are at a much higher risk of infection even after hematopoietic reconstitution, due to the delayed recovery of T and B cell functions. The rate at which immune function recovers after hematopoietic reconstitution greatly influences the incidence and type of post-transplant infectious complications. Infection-associated mortality, for example, is significantly higher following engraftment than during the short neutropenic period that immediately follows transplantation.

Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease

A major obstacle of allogeneic haematopoietic stem cell transplantation is graft-versus-host disease, an immune-mediated disorder that affects multiple tissues and organs with varying severity. Neurological complications of acute and chronic graft-versus-host disease are rare but can produce severe clinical problems with significant morbidity and mortality. In this article, we review neurological manifestations of chronic graft-versus-host disease that comprise immune-mediated neuropathies, myasthenia gravis and myositis in the peripheral nervous system and various cerebrovascular complications, demyelination and immune-mediated encephalitis in the central nervous system. The National Institutes of Health consensus on criteria for clinical trials in chronic graft-versus-host disease recommended that the diagnosis of chronic graft-versus-host disease of the nervous system can be made only when other organs are affected by graft-versus-host disease and frequent neurological differential diagnoses such as drug-induced toxicities or opportunistic infections are excluded. The Consensus Conference on Clinical Practice in chronic graft-versus-host disease, held in autumn 2009 in Regensburg, aimed to summarize the literature and to provide guidelines for the diagnostic approach in children and adults with neurological manifestations of chronic graft-versus-host disease. Moreover, we present therapeutic recommendations and their level of evidence for the management of these complications. Overlapping symptoms and comorbidities after allogeneic haematopoietic stem cell transplantation and the limited knowledge about the underlying biological mechanisms of chronic graft-versus-host disease affecting the nervous system emphasize the need for further experimental and clinical investigations.