Comparison of inpatient and outpatient palliative sedation practice - A prospective observational study.

INTRODUCTION: Palliative sedation (PS) is an intrusive measure to relieve patients at the end of their life from otherwise untreatable symptoms. Intensive discussion of the advantages and limitations of palliative care with the patients and their relatives should precede the initiation of PS since PS is terminated by the patient's death in most cases. Drugs for PS are usually administered intravenously. Midazolam is widely used, either alone or in combination with other substances. PS can be conducted in both inpatient and outpatient settings; however, a quality analysis comparing both modalities was missing so far. PATIENTS AND METHODS: This prospective observational study collected data from patients undergoing PS inpatient at the palliative care unit (PCU, n = 26) or outpatient at a hospice (n = 2) or at home (specialized outpatient palliative care [SAPV], n = 31) between July 2017 and June 2018. Demographical data, indications for PS, and drug protocols were analyzed. The depth of sedation according to the Richmond Agitation Sedation Scale (RASS) and the degree of satisfaction of staff members and patient's relatives were included as parameters for quality assessment. RESULTS: Patients undergoing PS at the PCU were slightly younger compared to outpatients (hospice and SAPV combined). Most patients suffered from malignant diseases, and midazolam was the backbone of sedation for inpatients and outpatients. The median depth of sedation was between +1 and -3 according to the RASS with a trend to deeper sedation prior to death. The median degree of satisfaction was "good," scored by staff members and by patient's relatives. Significant differences between inpatients and outpatients were not seen in protocols, depth of sedation, and degree of satisfaction. CONCLUSION: The data support the thesis that PS is possible for inpatients and outpatients with comparable results. For choosing the best place for PS, other aspects such as patient's and relative's wishes, stress, and medical reasons should be considered.

Allogeneic stem cell transplantation for mantle cell lymphoma-update of the prospective trials of the East German Study Group Hematology/Oncology (OSHO#60 and #74).

Mantle cell lymphoma (MCL) is a non-Hodgkin's lymphoma with an often aggressive course, incurable by chemotherapy. Consolidation with high-dose therapy and autologous stem cell transplantation (autoSCT) has a low transplant-related mortality but does not lead to a survival plateau. Allogeneic stem cell transplantation (alloSCT) is associated with a higher early mortality, but can cure MCL. To investigate alloSCT for therapy of MCL, we conducted two prospective trials for de novo MCL (OSHO#74) and for relapsed or refractory MCL (OSHO#60). Fifteen and 24 patients were recruited, respectively. Induction was mainly R-DHAP alternating with R-CHOP. Conditioning was either Busulfan/Cyclophosphamide or Treosulfan/Fludarabin. Either HLA-identical siblings or matched-unrelated donors with not more than one mismatch were allowed. ATG was mandatory in mismatched or unrelated transplantation. Progression-free survival (PFS) was 62% and overall survival (OS) was 68% after 16.5-year follow-up. Significant differences in PFS and OS between both trials were not observed. Patients below 56 years and patients after myeloablative conditioning had a better outcome compared to patients of the corresponding groups. Nine patients have died between day +8 and 5.9 years after SCT. Data from 7 long-term surviving patients showed an excellent Quality-of-life (QoL) after alloSCT. AlloSCT for MCL delivers excellent long-term survival data. The early mortality is higher than after autoSCT; however, the survival curves after alloSCT indicate the curative potential of this therapy. AlloSCT is a standard of care for all feasible patients with refractory or relapsed MCL and should offer to selected patients with de novo MCL and a poor risk profile. For defining the position of alloSCT in the therapeutic algorithm of MCL therapy, a randomized comparison of autoSCT and alloSCT is mandatory.

Allogeneic stem cell transplantation for mantle cell lymphoma--final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO).

This study was conducted in order to evaluate allogeneic stem cell transplantation (alloSCT) as consolidation for patients with mantle cell lymphoma (MCL). Patients with MCL were included into two prospective trials OSHO #060 (refractory/relapsed) and #074 (de novo). Induction was rituximab and chemotherapy. Responding patients proceeded to alloSCT. Minimal residual disease was monitored by quantitative RT-PCR detecting either t(11;14) or clonospecific CDR-III regions. In case of circulating lymphoma cells, immunomodulation (cyclosporine A withdrawal, rituximab, donor lymphocyte infusion) was initiated. Thirty-three of 39 patients underwent alloSCT after myeloablative (n = 7) or toxicity-reduced (n = 26) conditioning. Leukocytes engrafted at day +16 (median, range 0-101) and platelets at day +14 (0-142). Acute graft-versus-host disease stages I-II occurred in 42 % and stages III-IV in 15 %. Five patients have relapsed after SCT. The overall mortality after SCT was 24 % (n = 8). Median follow-up after SCT was 2.8 years (range 0.0-10.9). Five-year progression-free survival was 67 %, and overall survival 73 % after SCT. The results were comparable for primary MCL and refractory/relapsed disease as well as for related vs. unrelated SCT. Younger patients had a significantly better outcome than the elderly. AlloSCT is a feasible and promising consolidation therapy for relapsed and refractory disease and an attractive option for young patients with de novo MCL of high risk.

Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation-a matched pair analysis.

Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA-identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10 mg; HLA mismatch, 20 mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant-related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p = 0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM-SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted.

Toxoplasmosis after allogeneic stem cell transplantation--a single centre experience.

Toxoplasmosis is a rare but possibly underestimated complication following allogeneic stem cell transplantation with a high mortality rate. One reason might be the limitation of the diagnostic instruments relying mainly on imaging and molecular-based techniques. In this report, we present three cases of toxoplasmosis identified among 155 allograft recipients treated at Greifswald University Hospital. Widely disseminated toxoplasmosis was detected post-mortem in two patients allografted for high-risk multiple myeloma. Clinical signs suspicious for toxoplasmosis occurred after days +32 and +75, respectively. In one case, serology and conventional Toxoplasma gondii PCR, targeting the B1 gene, revealed negative results, while in the other patient, toxoplasmosis was not investigated. Both patients received pentamidine for Pneumocystis jirovecii pneumonia (PcP) prophylaxis. The third patient, a 68-year-old woman allografted for AML, developed cerebral toxoplasmosis from day +395 after allogeneic SCT with typical signs in magnetic resonance tomography. Toxoplasma DNA was amplified from one of two samples of cerebrospinal fluid. The patient died of disseminated toxoplasmosis despite immediate initiation of therapy. Retrospective comparative testing of clinical specimens by the conventional T. gondii PCR and by a real-time PCR targeting a 529-bp genomic fragment suggests a higher sensitivity of the latter method in our patients. In conclusion, we suggest a rigorous real-time PCR monitoring for high-risk patients or patients with signs of infections suspicious for toxoplasmosis, even though low-copy results are presently difficult to interpret. Our reported cases might also encourage the use of trimethoprim-sufmethoxazole instead of pentamidine for PcP prophylaxis in those patients.

Mucositis after reduced intensity conditioning and allogeneic stem cell transplantation.

BACKGROUND: Therapyrelated mucositis is associated with considerable morbidity. This complication following allogeneic stem cell therapy (alloSCT) is less severe after reduced intense conditioning (RIC); however, even here it may be serious. METHODS: 52 patients (male: n = 35 (67%), female: n = 17 (33%)) at a median age of 62 years (35-73 years) underwent alloSCT after RIC. Conditioning was either total body irradiation (TBI)(2Gy)/±fludarabine (n = 33, 63.5%) or chemotherapy based. Graftversushost disease (GvHD) prophylaxis was carried out with cyclosporine A ± mycophenolate mofetil (MMF). 45 patients (87%) received shortcourse methotrexate (MTX). Mucositis was graded according to the Bearman and the World Health Organisation (WHO) scale. A variety of parameters were correlated with mucositis. RESULTS: The Bearman and WHO scales showed excellent correlation. Mucositis was significantly more severe after chemotherapybased conditioning compared to conditioning with TBI(2Gy)/±fludarabine (p < 0.002) as well as in cases with an increase in creatinine levels above the upper normal value (UNV) on day +1 after SCT (p < 0.05). Furthermore, the severity correlated with time to engraftment of leucocytes (correlation coefficient (cc) = 0.26, p < 0.02) and thrombocytes (cc = 0.38, p < 0.001). CONCLUSIONS: The conditioning regimen and increased creatinine levels at day +1 were identified as factors predicting the severity of mucositis after RICSCT. Creatinine levels on day +1 after SCT may help identify patients at risk for severe mucositis in the further course of transplantation.

Mobilization of hemopoietic stem cells with high-dose methotrexate plus granulocyte-colony-stimulating factor in patients with primary central nervous system lymphoma.

BACKGROUND: High-dose therapy with autologous stem cell support after standard dose induction is a promising approach for therapy of primary central nervous system lymphoma (PCNSL). High-dose methotrexate (HD-MTX) is a standard drug for induction of PCNSL; however, data about the capacity of HD-MTX plus granulocyte-colony-stimulating factor (G-CSF) to mobilize hemopoietic progenitors are lacking. STUDY DESIGN AND METHODS: This investigation describes the data from stem cell mobilization and apheresis procedures after one or two cycles of HD-MTX for induction of PCNSL within the East German Study Group for Haematology and Oncology 053 trial. Eligible patients proceeded to high-dose busulfan/thiotepa after induction therapy and mobilization. RESULTS: Data were available from nine patients with a median age of 58 years. The maximal CD34+ cell count per microL of blood after the first course of HD-MTX was 13.89 (median). Determination was repeated in six patients after the second course with a significantly higher median CD34+ cell count of 33.69 per microL. Five patients required two apheresis procedures and in four patients a single procedure was sufficient. The total yield of CD34+ cells per kg of body weight harvested by one or two leukapheresis procedures was 6.60 x 10(6) (median; range, 2.68 x 10(6)-15.80 x 10(6)). The yield of CD34+ cells exceeded the commonly accepted lower threshold of 3 x 10(6) cells per kg of body weight in eight of nine cases. Even in the ninth, hemopoietic recovery after stem cell reinfusion was rapid and safe. CONCLUSION: HD-MTX plus G-CSF is a powerful combination for stem cell mobilization in patients with PCNSL and permits safe conduction of time-condensed and dose-intense protocols with high-dose therapy followed by stem cell reinfusion after HD-MTX induction.

Hygienic safety of reusable tap water filters (Germlyser) with an operating time of 4 or 8 weeks in a haematological oncology transplantation unit.

BACKGROUND: Microbial safe tap water is crucial for the safety of immunosuppressed patients. METHODS: To evaluate the suitability of new, reusable point-of-use filters (Germlyser, Aquafree GmbH, Hamburg, Germany), three variations of a reusable filter with the same filter principle but with different outlets (with and without silver) and inner surface coating of the filter encasements (with and without nano-crystalline silver) were tested. The filter efficacy was monitored over 1, 4 and 8 weeks operating time in a haematological oncology transplantation unit equipped with 18 water outlets (12 taps, 6 showers). RESULTS: The filtered water fulfilled the requirements of absence of pathogens over time. From 348 samples, 8 samples (2.3%) exceeded 100 cfu/ml (no sample > or = 500 cfu/ml). As no reprocessed filter exhibited 100% filter efficacy in the final quality control after each reprocessing, these contaminations could be explained by retrograde contamination during use. CONCLUSION: As a consequence of the study, the manufacturer recommends changing filters after 4 weeks in high risk areas and after 8 weeks in moderate infectious risk areas, together with routine weekly alcohol-based surface disinfection and additionally in case of visible contamination. The filter efficacy of the 3 filters types did not differ significantly regarding total bacterial counts. Manual reprocessing proved to be insufficient. Using a validated reprocessing in a washer/disinfector with alkaline, acid treatment and thermic disinfection, the filters were effectively reprocessable and now provide tap water meeting the German drinking water regulations as well as the WHO guidelines, including absence of pathogens.

Clinical course and end-of-life care in patients who have died after allogeneic stem cell transplantation.

PURPOSE: Allogeneic stem cell transplantation may cure approximately 50% of patients, however, a significant part of the other half might benefit from a high-quality palliative care medicine at the end of life. Somatic, psychic and spiritual needs of these patients may differ from those of patients suffering from incurable solid tumours and are not comprehensively evaluated so far. METHODS: To address this question, data from charts of 123 patients who have died after allogeneic stem cell transplantation were extracted. In detail, the time line of the clinical course, the symptoms, the administered drugs and other applied procedures were analysed. RESULTS: Approximately one half of the patients, who have died after stem cell transplantation, did not live more than 5 months. Two-thirds of patients died within 14 months after SCT. 28.5% of the patients could not be discharged after transplantation. However, a significant proportion had a low ECOG-score (0-1) prior to death, indicating a high degree of mobility. Major symptoms were weakness, fatigue and need for aid at daily activities. Severe pain, dyspnoea and obstipation, as known from patients suffering from advanced solid tumours, were rare. In consequence, use of opioids seemed to be less frequent than in patients with solid tumours. Measures of intensive care and i.v.-drug administration were applied to a significant proportion of patients. CONCLUSION: The present investigation indicates that the somatic, psychic and spiritual end-of-life-care after allogeneic stem cell transplantation could be optimised. A significant problem for the transplantation team seems to be the realisation of necessity to switch the curative concept into a palliative ambition. Requirements are a subsequent prospectively conducted investigation and an intensification of cooperation between transplant and palliative care teams.

Hyaluronate and its receptors in bone marrow.

Cell-cell and cell-matrix interactions, which are mediated by cell adhesion molecules, play a fundamental role during many cellular processes including growth, differentiation, cell migration and cancer metastasis. One molecule playing a major role in these processes is the CD44 surface receptor, which is expressed in a wide range of cells including many cells of the hemopoietic system, where it mediates the interaction with its major ligand, hyaluronate. However, little is known about CD44 and hyaluronate in bone marrow and this was investigated immunohistochemically in trephine biopsies and in cultivated human bone marrow stromal cells. In biopsy specimens, patches of hyaluronate deposition were detected in the extracellular matrix (ECM). However, most of the areas of the ECM were devoid of hyaluronate. Single mast cells and lymphocytes scattered throughout the marrow were CD44 immunopositive. Marrow-derived stromal cells (MDSC) expanded in cell culture were immunopositive for CD44, hyaluronate synthase, and hyaluronate. Hence, a marked difference between CD44 immunolocalisation and hyaluronate deposition can be observed between in situ and under cell culture conditions. Since in normal marrow in situ the number of CD44 immunopositive cells was low, interactions of CD44 and hyaluronate would appear to not to play a major role in cell adhesion in the normal bone marrow.

Reduced platelet transfusions and earlier platelet engraftment using alemtuzumab-based conditioning regimen in allogeneic stem cell transplantation.

PURPOSE: In patients undergoing allogeneic stem cell transplantation, conditioning regimens containing alemtuzumab instead of anti-thymocyte globulin (ATG) may result in an earlier platelet engraftment and a reduced number of platelet transfusions. METHODS: We performed a retrospective, single-center, case-control study analyzing time to engraftment and transfusion needs using alemtuzumab in comparison with ATG as part of conditioning protocol. RESULTS: Median values for time to platelet engraftment, number of transfused platelet concentrates and number of transfused red cell concentrates were 12 versus 19.5 days (p < 0.001), 2 versus 14 (p < 0.001) and 6 versus 14.5 (p = 0.003) in the alemtuzumab and ATG group. Time to leukocyte engraftment did not differ with median 15 days in both groups. Patients in the ATG group showed a significant higher decrease in platelet count during conditioning (68 vs. 29 %, p = 0.001), leading to significant lower median platelet counts at the day of stem cell infusion (38 vs. 95.5 Gpt/l, p = 0.008), and higher values for median C-reactive protein after first antibody infusion (69.0 vs. 43.6 mg/l, p = 0.001) compared with alemtuzumab group. Test for significance was done by using Wilcoxon rank-sum test. Subgroup analysis considering the type of ATG used (Thymoglobulin vs. ATG Fresenius) revealed that differences between alemtuzumab and ATG group were more due to effects of ATG Fresenius than Thymoglobulin. CONCLUSIONS: The use of alemtuzumab in comparison with ATG as part of the conditioning regimen may be an approach to reduce the number of transfused platelet and red cell concentrates after allogeneic stem cell transplantation.

Combined immunoradiotherapy induces long-term remission of CNS relapse of peripheral, diffuse, large-cell lymphoma after allogeneic stem cell transplantation: case study.

Relapse of peripheral non-Hodgkin's lymphoma (NHL) in the central nervous system commonly has a poor prognosis. Graft-versus-leukemia effects (GvL) contribute substantially to eradication of hematological malignancies after allogeneic stem cell transplantation. Few data are available describing GvL activity within the brain. We report the case of a man allografted for peripheral NHL. On day +83 after transplantation a CNS relapse of the lymphoma occurred. The brain was irradiated with 44 Gy, anti-CD20 antibodies were given, and the immunosuppression was withdrawn. Subsequently, limited-stage, chronic graft-versus-host disease occurred. The lymphoma regressed completely, and the patient has been in continuous complete remission for 30 months. The favorable course suggests substantial contribution of immunomodulation to excellent outcome.

Treatment of High-Risk T-NHL with Stem Cell Transplantation: A Single Center Experience.

Prognosis of peripheral and other advanced T cell lymphomas is poor. 20 patients with a median age of 46.4 (range 20.5-64.1) years were treated with autoSCT (n = 6) or alloSCT (n = 14) from 1996 to 2013. All patients were at high risk either due to the IPI-score or to the fact that SCT was part of a salvage therapy. Conditioning prior to alloSCT was myeloablative in seven cases (50 %). The patients were pretreated with 8.5 (median, range 2-38) cycles of chemotherapy. Ten patients are alive in CR after a median follow-up of 1.3 years (range 0.1-13.3). OS was 53 % after one and 40 % after 10 years. Best survival was reached after related alloSCT (80 % at 10 years) compared to other modalities. GvHD did not influence survival. AlloSCT from related donors can cure patients from T-cell lymphomas. Unrelated alloSCT or high-dose therapy and autoSCT are an option for patients without a familiar donor.

Allogeneic stem cell transplantation in patients above 55: suggestion for a further stratification of the HCT-CI.

INTRODUCTION: Allogeneic stem cell transplantation (alloSCT) has become available for elderly patients or for patients with comorbidities by introduction of reduced-intense conditioning. Comorbidity-related prognosis after alloSCT can be estimated by the hematopoietic cell transplantation comorbidity index (HCT-CI). MATERIAL AND METHODS: The charts from 85 patients who have undergone 90 alloSCTs between 1999 and 2011 were analysed. Most patients received a dose-reduced conditioning and a graft from an unrelated donor. Patients were stratified for age, HCT-CI, cGvHD versus no cGvHD, and a modified HCT-CI with a further split high-risk score. RESULTS: Age over 60 years did not affect the outcome. Manifestation of cGvHD improved the prognosis significantly. An additional stratification of the high-risk group of the HCT-CI revealed that even a fraction of these patients can have considerable benefit from an alloSCT. Furthermore, this high-risk collective could be clearly discriminated into two groups with different outcomes. CONCLUSIONS: The investigation confirms that age is no absolute risk factor for alloSCT and demonstrates the heterogeneity of the high-risk group of the HCT-CI. A comprehensive investigation of an additional stratification is suggested. Furthermore, the authors encourage early withdrawal of immunosuppression, even in elderly patients and patients with comorbidities to permit graft-versus-leukaemia/lymphoma, since cGvHD is associated with a significantly better prognosis.

Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation.

Therapy of indolent lymphomas with involvement of the central nervous system (CNS) has not been standardized so far. A 42-year old male patient presented with neurological signs because of leukemic splenic marginal zone lymphoma (SMZL) manifested in bone marrow, lymph nodes and CNS. Due to the aggressiveness of the disease and the young age of the patient, an intensive immunochemotherapy followed by high-dose therapy with busulfan, thiotepa and fludarabine and subsequent unrelated allogeneic stem cell transplantation (alloSCT) was performed. The haemopoietic stem cells engrafted in time and the patient is doing well (ECOG 0) without evidence for active lymphoma three years after transplantation. Highly sensitive tests by specific quantitative real-time polymerase chain reaction for presence of lymphoma cells in blood and bone marrow indicated also a molecular remission. The reported case shows the feasibility of high-dose therapy and allogeneic stem cell transplantation in high-risk patients with CNS-involvement of indolent non-Hodgkin's lymphoma. In addition, the case supports the hypothesis that the graft-versus lymphoma effect after alloSCT is also active within the CNS.

Aminoglycoside-free interventional antibiotic management in patients undergoing haemopoietic stem cell transplantation.

The position of aminoglycosides within interventional antibiosis in the early phase after stem cell transplantation has not been fully clarified so far although their use can induce serious renal impairment. To investigate this question early-infection data from 152 patients undergoing 195 allogeneic and autologous stem cell transplantations were investigated. Prophylaxis and treatment of infections followed international standards; however, aminoglycosides were omitted to avoid additional risks such as ototoxicity and nephrotoxicity and increased selection of resistant pathogens. Costs were another aspect.The overall-incidence of infections was 78% (152/195) and 67 patients showed more than one episode of infection. Fever of unknown origin and bacteriaemia/septicaemia dominated the spectrum of infections. The overall-response to interventional regimen consisting of ß-lactam or carbapenem plus glycopeptides was 48%. Aminoglycosides were given in three patients in the late course of disease. Overall mortality was 15/195 (7.7%) and clearly related to infection in nine cases mostly due to mould infection. A comparison with previous published literature showed no hint for inferiority of 'aminoglycoside-free' antibiotic management in stem cell transplant patients. In conclusion, the present analysis supports the policy to omit aminoglycosides in the therapy of early infections in patients undergoing stem cell transplantation to avoid additional toxicity.

Complete remission and early relapse of refractory plasma cell leukemia after bortezomib induction and consolidation by HLA-mismatched unrelated allogeneic stem cell transplantation.

BACKGROUND: Chromosomal deletion of q13 (del q13) and plasma cell leukemia predict both a worse prognosis in myeloma. Experiences with bortezomib in plasma cell leukemia prior to allogeneic stem cell transplantation (SCT) have not yet been reported. CASE REPORT: A 66- year-old male patient was admitted for IgA myeloma(IIIA) with del q13. The myeloma progressed to plasma cell leukemia. Bortezomib was given, free light chain (FLC) excretion decreased, and myeloma cells disappeared from blood and decreased in marrow. An unrelated, mismatched allogeneic SCT was performed. The patient was discharged after engraftment with full chimerism without signs of GvHD. FLC excretion increased, and immunosuppression was discontinued. From day +84 on, bortezomib was infused again and FLC excretion decreased rapidly. Relapse was confirmed in marrow, and bortezomib was continued. Donor lymphocyte infusions (DLI) had no effect, and a further cycle of bortezomib and thalidomide had only minor effects. On day +209, the patient died from myeloma. CONCLUSION: This case gives evidence for an excellent initial response of plasma cell leukemia to bortezomib, however, early relapse after SCT clearly indicates limitations of both bortezomib therapy and allogeneic SCT in high-risk myeloma. Future developments are mandatory and could include combination of bortezomib with other cytostatics and early DLI in the absence of GvHD. In addition, there is need to clarify if graft-versus-myeloma effect is diminished by bortezomib therapy after allogeneic SCT.