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Purpose: Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML., Materials and Methods: Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile., Results: Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5-25.4) months vs 3 (95% CI 1.7-4.3) months (p < 0.001). 30- and 60-day mortality rates for all patients after the initial cycle of Mito-FLAG were 4.5% and 7.6%, respectively., Conclusion: The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown., (© 2021. The Author(s).)

Background: Acute myeloid leukemia (AML) with antecedent hematological disease (s-AML) and treatment-related AML (t-AML) predicts poor prognosis. Intensive treatment protocols of those high-risk patients should consider allogeneic stem cell transplantation (allo-HSCT) in first complete remission (CR). Despite allo-HSCT, relapse rate remains high. Induction chemotherapy with liposomal cytarabine and daunorubicin (CPX-351) has been approved for patients with AML with myeloid-related changes (AML-MRC) or t-AML based on improved survival and remission rates compared to standard 7 + 3 induction., Patients and Methods: 110 patients with newly diagnosed s-AML or t-AML at a university hospital were analyzed retrospectively. Median age was 62 years (24-77 years). A total of 65 patients with s-AML after MDS (59%) and 23 patients (20.9%) with t-AML were included. Induction chemotherapy consisted of intermediate-dosed cytarabine (ID-AraC) in combination with idarubicin (patients up to 60 years) or mitoxantrone (patients over 60 years). In patients subsequently undergoing allo-HSCT, reduced conditioning regimens (RIC) were applied prior to transplantation in 47 of 62 patients (76%)., Results: Induction chemotherapy with ID-AraC resulted in an overall response rate of 83% including complete remission (CR/CRi) in 69 patients (63%) with a low rate of early death (2.7%). Most relevant non-hematologic toxicity consisted of infectious complications including sepsis with need of intensive care treatment in five patients (4.5%) and proven or probable invasive fungal disease in eight patients (7.2%). Relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) of the whole cohort were 19 months (0-167), 10 months (0-234) and 15 months (0-234), respectively (p < 0.0001). A significant improvement of OS was observed in patients who underwent allo-HSCT compared to those without subsequent allo-HSCT: 9 vs. 46 months, p < 0.0001. Rate of transplantation-related mortality (TRM) in the early phase post allo-HSCT was low (0.9% at day 30 and 1.8% at day 90, respectively). RIC conditioning results in OS rate of 60% after 60 months post allo-HSCT (median OS not reached)., Conclusion: S-AML and t-AML patients receiving induction chemotherapy with intermediate-dosed cytarabine showed satisfactory response rate and consolidation therapy with allo-HSCT after full or reduced-intensity conditioning further improved survival in these patients with similar outcome as reported for CPX-351., (© 2021. The Author(s).)

Introduction: Multiple myeloma (MM) is a plasma cell disease that affects more men than women. Although there is an obvious imbalance in incidence, knowledge of differences in biology and outcome between the sexes is surprisingly rare., Methods: We performed a unicentric retrospective analysis of patients with MM treated at a tertiary cancer centre between 2003 and 2018., Results: We present a sex-disaggregated analysis of the characteristics and outcome of MM in a cohort of 655 patients (median age at diagnosis 62 years; 363 men with a median age at diagnosis 62 years and 292 women with a median age at diagnosis 63 years, p = 0.086). Most patients (n = 561, 86%) received myeloma-specific treatment. Median overall survival was 76 months (95% CI 63-89) (72 months in men [95% CI 54-90] and 83 months in women [95% CI 66-100], p = ns). Apart from a higher incidence of moderate and severe anaemia in women (p < 0.001), there were no statistically significant differences in the biology of the underlying MM. Similarly, in the group of patients who received high-dose therapy with autologous stem-cell transplantation (ASCT, n = 313), no statistically significant differences apart from more frequent anaemia in women were detected regarding the biology of the disease. However, there was a trend toward a higher plasma cell infiltration of the bone marrow and toward more frequent high-risk features in women. In contrast, relevant comorbidities were significantly more common in men (for example, coronary heart disease in 13% of men vs. 2% of women, p < 0.001). Toxicities after ASCT were not significantly different between the sexes with the exception of severe mucositis, which occurred in 22% of men versus 40% of women (p = 0.001)., Conclusion: In conclusion, this first sex-disaggregated analysis of MM patients in Germany supports previous findings that survival is comparable amongst sexes, but women experience more toxicity of high-dose therapy. The higher incidence of clinically relevant anaemia in women warrants further investigation to exclude underlying treatable causes., (© 2022 S. Karger AG, Basel.)

Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem., (© 2021. The Author(s).)

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.

Introduction: We report a chronic persistent Parvovirus B19 (PVB19) infection despite long-term immunoglobulin substitution intravenous immunoglobulin (IVIG) and tapering of immune-suppressive therapy in a 41-year-old patient after allogeneic haematopoietic stem cell transplantation (alloHSCT) and long-term immune-suppressive therapy due to a steroid-refractory graft versus host disease (GvHD)., Clinical Course: More than 18 month after alloHSCT the patient acquired a de novo transfusion-dependent pure red cell aplasia (PRCA) due to a PVB19 infection. Despite prompt tapering of GvHD-directed therapy and application of various IVIG regimens, transfusion-dependent anaemia (fourerythrocyte concentrates a month) persisted, and a high PVB19 replication is still evident for more than 3.5 years. Virological analysis at different time points showed a very high PVB19 load in the blood (range: 6.79E9-1.56E11), as well as highly elevated PVB19-IgG (range: 1.95-3.34) and -IgM (range: 1.97-9.74) levels in serology testing. Other virological parameters were not significantly elevated. After 30 months, a bone marrow (BM) examination still revealed a highly dysplastic erythropoiesis without any cellular maturation, and a high-grade expression of PVB19 within the dysplastic erythropoietic progenitor cells, consistent with a PRCA due to a PVB19 infection of the BM. We suggest that PRCA was most probably caused by a primary PVB19 infection of unknown source following alloHSCT with a PVB19-negative donor., Conclusion: PRCA due a PVB19 infection of the BM may persist over a long-time, despite prolonged administration of various IVIG regimen and tapering of GvHD-directed therapy. The case emphasizes the importance of PVB19 monitoring in heavily pre-treated haematological patients. Currently, PVB19-directed treatment options are extremely limited and optimized therapeutic strategies are urgently needed.

Background: Activating mutations of the receptor tyrosine kinase FLT3 (fms-related tyrosine kinase 3) reflect the most frequent molecular aberration in acute myeloid leukemia (AML). In particular, FLT3 internal tandem duplications (FLT3-ITD) are characterized by an unfavorable prognosis and allogeneic stem cell transplantation (allogeneic SCT) in first complete remission is recommended. In case of imminent or frank relapse following allogeneic SCT, treatment with FLT3 tyrosine kinase inhibitors (TKI) constitutes a promising clinical approach to induce hematologic remission without conventional chemotherapy., Patients and Methods: We retrospectively analyzed the response to induction chemotherapy and the outcome of 76 patients with FLT3-ITD-positive AML including 50 patients who underwent allogeneic SCT. Furthermore, efficacy of TKI treatment was evaluated in 18 patients (median age 54 years, range 21-74) with relapsed or refractory FLT3-ITD-positive AML., Results: Response to induction chemotherapy in 76 FLT3-ITD-positive AML patients was characterized by a complete remission (CR) rate of 68%. In total, 50 of 76 patients (66%) underwent allogeneic SCT including 40 patients (80%) in CR. Relapse of AML was observed in 21 of 47 patients (45%) after allogeneic SCT with a median relapse-free survival (RFS) of 13 months (range 3-224) for patients with CR prior to or at day +30 after SCT. Myeloablative conditioning resulted in an improved median RFS of 29 months (4-217) as compared to a reduced intensity conditioning protocol prior to allogeneic SCT with a RFS of 8 months (1-197, P = 0.048), respectively. Median OS of FLT3-ITD-positive AML was 17 months (5-225) for patients who received an allogeneic SCT as compared to 9 months (1-184) for patients who did not undergo SCT. Response of FLT3-ITD-positive AML to sorafenib was characterized by only 3 of 18 patients achieving a bone marrow response (17%), while there was no response to second-line treatment with ponatinib., Conclusion: This "real-life" data reflect the continuing challenge of FLT3-ITD-positive AML and confirm the poor outcome even after allogeneic SCT. Furthermore, efficacy of TKI treatment of relapsed or refractory FLT3-ITD AML is still limited and requires substantial improvement, e.g., by the introduction of second-generation inhibitors targeting constitutively active FLT3.

Introduction: Even in the era of proteasome inhibitors and immunomodulatory drugs, the autologous stem cell transplantation after high-dose melphalan continues to represent a standard approach for myeloma patients in first-line therapy. Different mobilization chemotherapies before stem cell apheresis have been published while cyclophosphamide at a dose level of up to 4 g/m 2 has been evaluated and is commonly applied. In contrast, lower dose levels of cyclophosphamide (e.g., 1.5 g/m 2 ) did not result in a sufficient collection of stem cells., Methods: We retrospectively analyzed the impact of "intermediate-dose" (ID-CY, 2.5 g/m 2 ) versus "high-dose" (HD-CY, 4 g/m 2 ) cyclophosphamide in 101 (48 vs. 53) consecutively evaluable myeloma patients (median age 59 years, range 32-72 years) who underwent stem cell mobilization after induction chemotherapy. Successful stem cell harvest was defined as a stem cell yield of at least 5 million CD34 cells per kg bodyweight. Evaluation of toxicity especially considered infectious complications and hematological toxicity in both subgroups., Results: Successful stem cell mobilization was achieved in 40 of 48 (83 %) and 44 of 53 (83 %) patients, respectively. The median time to apheresis (11 vs. 12 days) and the median CD34 content of stem cell harvest (8.3 vs. 7.6 million CD34 cells per kg bodyweight) did not differ significantly between both groups. There was a significant difference of WBC nadir in favor of the cyclophosphamide regimen with 2.5 g/m 2 (0.8 vs. 0.3 Gpt/L, p = 0.021), and neutropenic fever was more often observed in patients who received 4 g/m 2 cyclophosphamide (34 vs. 15 %, p = 0.078). Importantly, after induction chemotherapy using the VCD regimen (bortezomib, cyclophosphamide, dexamethasone), successful stem cell mobilization was achieved in 26 of 29 (90 %) patients treated with 2.5 g/m 2 and 21 of 25 (84 %) patients receiving 4 g/m 2 cyclophosphamide, respectively., Conclusions: ID-CY is safe and highly effective for stem cell mobilization in patients with newly diagnosed myeloma and associated with a reduced toxicity compared to HD-CY.

Purpose: Infections and subsequent septicemia are major complications in neutropenic patients with hematological malignancies. Here, we identify biomarker candidates for the early detection of an infectious origin, and monitoring of febrile neutropenia (FN)., Methods: Proteome, metabolome, and conventional biomarkers from 20 patients with febrile neutropenia without proven infection (FNPI) were compared to 28 patients with proven infection, including 17 patients with bacteremia., Results: Three peptides (mass to charge ratio 1017.4-1057.3; p-values 0.011-0.024), six proteins (mass to charge ratio 6881-17,215; p-values 0.002-0.004), and six phosphatidylcholines (p-values 0.007-0.037) were identified that differed in FNPI patients compared to patients with infection or bacteremia. Seven of these marker candidates discriminated FNPI from infection at fever onset with higher sensitivity and specificity (ROC-AUC 0.688-0.824) than conventional biomarkers i.e., procalcitonin, C-reactive protein, or interleukin-6 (ROC-AUC 0.535-0.672). In a post hoc analysis, monitoring the time course of four lysophosphatidylcholines, threonine, and tryptophan allowed for discrimination of patients with or without resolution of FN (ROC-AUC 0.648-0.919) with higher accuracy compared to conventional markers (ROC-AUC 0.514-0.871)., Conclusions: Twenty-one promising biomarker candidates for the early detection of an infectious origin or for monitoring the course of FN were found which might overcome known shortcomings of conventional markers.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

Background: Posterior reversible encephalopathy syndrome (PRES) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Among others, calcineurin inhibitors (CNI) for prophylaxis of graft-versus-host disease (GvHD) may promote the development of PRES, but the pathomechanism is still controversial. Discontinuation of CNI facilitates remission of symptoms but might contribute to the unfavorable prognosis of PRES due to an elevated incidence of GvHD., Methods: This is a case series of 7 patients with PRES from a retrospective analysis of 146 consecutive patients who received alloHSCT for hematologic malignancies., Results: At the onset of PRES, all patients presented a systemic infection, while no influence was seen for underlying disease, conditioning regimen, donor type, or GvHD. Discontinuation of CNI and control of the blood pressure reversed neurological symptoms in 6 patients, while 1 patient died from septic multiorgan failure. After bridging with prednisolone and/or mycophenolic acid, replacement of CNI by the mammalian target of rapamycin (mTOR) inhibitor everolimus effectively prevented severe GvHD without recurrence of PRES., Conclusions: A systemic infection/inflammation may be an important cause of PRES. Prophylaxis of GvHD by the mTOR inhibitor everolimus in case of PRES after alloHSCT demonstrated promising results but needs to be validated in larger cohorts., (© 2015 S. Karger AG, Basel.)

Introduction: Hematopoietic stem cell transplantation (HCT) is considered a standard treatment for high-risk acute myeloid leukemia (AML) in first or second complete remission (CR). Unfortunately, not all patients achieve complete remission prior to HCT. We sought to establish predictive factors for survival after HCT for refractory AML after FLAMSA-RIC., Patients and Methods: We analyzed the outcome of 44 consecutive patients aged between 21 and 65 years transplanted at the University Hospitals of Jena and Leipzig for refractory AML between 2006 and January 2013. Conditioning for HCT was performed with chemotherapy consisting of fludarabine, cytarabine, and amsacrine followed by total body irradiation or busulfan combined with cyclophosphamide. Antithymocyte globulin was given when transplanting from unrelated donors (FLAMSA-RIC)., Results: Estimated overall survival (OS) and event-free survival (EFS) at 3 years after a median follow-up of 34 (range 6-71) months were 15 and 12 %, respectively. Causes of death were relapse in 66 %, infection in 11 %, and graft-versus-host disease (GvHD) in 7 % of all patients. Twenty-five from 42 evaluable patients (60 %) achieved CR 4 weeks after HCT, while eight patients had partial remission (PR), and nine patients had stable disease (SD). Another six patients with PR and SD achieved CR (overall CR rate 74 %) from 4 weeks to day 90 after HCT following reduction in immunosuppression. The strongest favorable factors in univariate analysis for OS, EFS, and RI were ≥98 % total donor chimerism 2-4 weeks after HCT and <3 lines of pretreatment prior to HCT. In addition, better OS was detected in patients with <20 % bone marrow blasts alone (32 vs. 5 % at 3 years) and in combination with <3 lines of pretreatment (38 vs. 4 % at 3 years). Only a trend for better EFS and lower RI was observed in patients with limited chronic GvHD. In addition, a lower RI was seen in patients with <5 % blasts 4 weeks after HCT. Multivariate analysis revealed that ≥98 % donor chimerism 2-4 weeks after HCT for OS, EFS, and RI and <3 lines of pretreatment for OS and EFS are the strongest predictors for better outcome., Conclusion: FLAMSA-RIC shows long-term survival in refractory AML patients. Factors for favorable outcome are <20 % bone marrow blasts prior to HCT, <3 lines of pretreatment and complete donor chimerism after HCT.

Introduction: Treatment of patients (pts) with acute myelogenous leukaemia (AML) above 60 years remains a challenge. We report long-term follow-up of the AML97 study, where pts were registered at diagnosis and received treatment dependent on their comorbidities: dose-intense cytarabine (AraC) and anthracycline in the curative arm, and low-dose chemotherapy in the palliative arm or best supportive care., Materials and Methods: A total of 618 pts were enrolled in this protocol (curative 471, palliative 115 and supportive 32). In the curative arm, complete remission (CR) was obtained in 66.8 % of pts and the estimated probability of being alive at 2 years was 0.30 (±0.02 SE). In multivariate analysis, gender (p = 0.005), performance status (p = 0.04) and cytogenetics (p = 0.002) were significant factors for CR. With a median follow-up of 10 (range 0.1-11.8) years, the estimated probability of being event-free after 2 and 5 years according to cytogenetics was 0.48 ± 0.11 and 0.48 ± 0.11 for favourable, 0.20 ± 0.03 and 0.09 ± 0.03 for normal, 0.18 ± 0.06 and 0.10 ± 0.05 for other standard risk and 0.10 ± 0.03 and 0.05 ± 0.02 for unfavourable karyotypes, respectively. The median survival time for pts treated with palliative chemotherapy was 54 and 11 days with best supportive care only., Conclusion: In conclusion, treatment of older AML pts with dose-intense AraC is feasible in the majority of pts and induces high rates of CR. Nevertheless, except for favourable karyotype, OS and event-free survival remain low. These results need to be viewed in relation to the new modalities including stem cell transplantation following non-myeloablative conditioning, epigenetic and molecular therapies.

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.

Introduction: Myelodysplastic syndrome (MDS) comprises a heterogeneous group of clonal disorders of haematopoietic stem cells, characterised by dysplastic haematopoiesis and dysregulated apoptosis resulting in various degrees of cytopenia, whereas canonical cytologic, cytogenetic and histopathologic findings guiding the diagnosis MDS are widely accepted, the MDS-phenotype can be masked by coexisting/paraneoplastic immunologic disease. Autoimmune disorders have an estimated incidence of 10% among patients suffering from MDS and are causally related to increased morbidity and mortality, younger age at diagnosis and more complex genetics. Conversely, systemic inflammatory disorders may be an early manifestation of MDS, show good response to immunosuppressive therapy and frequently disappear during the course of specific haematologic therapy., Objective: Monocentric report on clinical phenotypes found in MDS or bone marrow failure with paraneoplastic inflammatory disease., Methods: Clinical case reports and systematic review about MDS pathophysiology and treatment., Results: We report eight patients diagnosed with MDS or bone marrow failure, who presented with paraneoplastic autoimmune diseases. Six of eight patients were treated with the hypomethylating agent 5-azacytidine, three of which achieved meaningful response with regard to inflammation control and haematologic recovery., Conclusions: As paraneoplastic syndromes are often mistakenly diagnosed as idiopathic autoimmune disorders, we propose that coexistence of an underlying myelodysplastic syndrome should be considered early in the diagnostic work up. 5-Azacytidine is effective in controlling paraneoplastic inflammation., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The treatment of refractory or relapsed non-Hodgkin lymphoma (NHL) remains challenging. In this retrospective study, 88 patients with refractory or relapsed NHL received treosulfan and fludarabine as a reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Of the 88 intensely pre-treated patients, 73 experienced a relapse, with 18 of the 88 patients experiencing an early relapse (ER; <6 months from the last chemotherapy). At the time of allo-HSCT, 26 patients were in complete remission (CR) and 43 in partial remission (PR), 12 patients had progressive disease (PD) and 7 had stable disease (SD). A total of 47 patients received an autologous graft followed by allo-HSCT. Following allo-HSCT, 69 of the 88 patients were in CR and 7 were in PR, resulting in an overall response rate of 86.4% (76/88). A total of 33 patients achieved a CR from PR, as did 6 patients from PD and 5 from SD. Of the 88 patients, 43 (49%) were alive at the end of the follow-up period. The patients who directly underwent allo-HSCT without prior auto-HSCT exhibited a better disease-free survival (DFS; P=0.038) with a tendency (P=0.077) for a better overall survival (OS). The patients with ER exhibited a probability of OS of 0.35±0.12 after 3 and 7 years. Chronic graft-versus-host disease (cGvHD) exerted a positive effect on OS and DFS (for limited cGvHD vs. no cGvHD, P=0.002 and 0.004, respectively). In conclusion, allogeneic stem cell transplantation following conditioning with treosufan and fludarabine constitutes a viable therapeutic option for patients with refractory or relapsed NHL and should be considered early during the course of salvage treatment.

Purpose: In the two consecutive German studies III and IIIA on chronic myeloid leukemia, between 1995 and 2004, 781 patients were randomized to receive either allogeneic hematopoietic stem cell transplantation with a related donor or continued drug treatment. Despite comparable transplantation protocols and most centers participating in both studies, the post-transplant survival probabilities for patients transplanted in first chronic phase were significantly higher in study IIIA (144 patients) than in study III (113 patients). Prior to the decision on a combined analysis of both studies, reasons for this discrepancy had to be investigated., Methods: The Cox proportional hazard cure model was used to identify prognostic factors for post-transplant survival., Results: Donor-recipient matching for human leukocyte antigen, patient age, time between diagnosis and transplantation, and calendar time showed a significant influence on survival and/or the incidence of cure. Added as a further factor, affiliation to study IIIA had no significant impact any longer., Conclusions: Discrepancies in influential prognostic factors explained the different post-transplant survival probabilities between the studies. The significance of calendar time suggests a lack of consistency of transplantation practice over time. Accordingly, the prerequisite for a common assessment of overall survival in the two randomized transplantation arms was not met. Moreover, our analyses provide an independent validation of established prognostic factors and their cutoffs. The statistical approach in investigating and modeling potential prognostic factors for survival sets an example for the examination of studies with unexpected outcome differences in concurrent treatment arms.

Since the outcome of relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL) is highly variable, a risk-adapted treatment approach was evaluated. After two cycles of DHAP, patients received high-dose treosulfan/etoposide/carboplatinum (TEC) and autologous stem cell rescue. After TEC, low-risk patients with late relapse (>1 year after first CR who achieved CR after DHAP received no further treatment. Patients with late relapse who achieved CR or PR only after TEC underwent a second cycle of TEC. High-risk patients with early relapse/refractory disease received treosulfan/fludarabine followed by allogeneic transplantation. Rituximab was added in patients with B-cell lymphoma (86%). At entry, 36% of all 57 patients had refractory disease, 32% early and 32% late relapse. During DHAP treatment, progression occurred in 32% of patients. Of 33 patients who received TEC, 5 received second TEC and 15 allogeneic transplantation. Main toxicity after TEC was oral mucositis (CTC grades 3 and 4 in 50% and 13%, respectively). In total, 42% patients achieved CR. Median OS was 21.4 months for all patients and 32.6 for those who underwent allogeneic transplantation. International prognostic index (IPI) at study entry was highly discriminative at predicting OS (P<0.0001). Risk-adapted, treosulfan-based therapy with auto- and allo-SCT is feasible. Long-term survival is possible with allogeneic transplantation.

Purpose: The existence of platelet-derived growth factor (PDGF) receptor autoantibodies in systemic sclerosis is conflicting, and such antibodies were also detected in patients with chronic graft-versus-host disease (GvHD) after allogeneic peripheral blood stem cell transplantation (PBSCT). We therefore aimed to screen for PDGF receptor autoantibodies in patients with chronic GvHD., Patients and Methods: We evaluated the existence of PDGF receptor autoantibodies in 39 patients, while 17 patients presented with a limited and 8 patients with an extensive chronic GvHD, respectively. Furthermore, 14 out of 39 patients had no chronic GvHD., Results: We detected at least low levels of PDGF receptor autoantibodies in nearly all (35 of 39) patients after allogeneic PBSCT. Interestingly, only one of six patients with high levels of PDGF receptor autoantibodies presented with an extensive chronic GvHD, while the remaining six patients had no clinical signs of chronic GvHD. Thus, there was no correlation between the quantitative detection of antibodies directed against the PDGF receptor and the presence or severity of chronic GvHD., Conclusion: Platelet-derived growth factor receptor autoantibodies could easily be detected in patient sera. Nevertheless, we did not observe any correlation between the presence of PDGF receptor autoantibodies and the severity of chronic GvHD in patients who underwent allogeneic PBSCT.

Background: This case report highlights the relevance of quantifying the BCR-ABL gene in cerebrospinal fluid of patients with suspected relapse of chronic myeloid leukemia in the central nervous system., Case Presentation: We report on a female patient with isolated central nervous system relapse of chronic myeloid leukemia (CML) during peripheral remission after allogeneic hematopoietic stem cell transplantation. The patient showed a progressive cognitive decline as the main symptom. MRI revealed a hydrocephalus and an increase in cell count in the cerebrospinal fluid (CSF) with around 50% immature blasts in the differential count. A highly elevated BCR-ABL/ ABL ratio was detected in the CSF, whilst the ratio for peripheral blood and bone marrow was not altered. On treatment of the malresorptive hydrocephalus with shunt surgery, the patient showed an initial cognitive improvement, followed by a secondary deterioration. At this time, the cranial MRI showed leukemic infiltration of lateral ventricles walls. Hence, intrathecal administration of cytarabine, methotrexate, and dexamethasone was initiated, which caused a significant decrease of cells in the CSF. Soon after, the patient demonstrated significant cognitive improvement with a good participation in daily activities. At a later time point, after the patient had lost the major molecular response of CML, therapy with dasatinib was initiated. In a further follow-up, the patient was neurologically and hematologically stable., Conclusions: In patients with treated CML, the rare case of an isolated CNS blast crisis has to be taken into account if neurological symptoms evolve. The analysis of BCR-ABL in the CSF is a further option for the reliable detection of primary isolated relapse of CML in these patients.

Purpose: Single-dose pegylated filgrastim (pegfilgrastim) after autologous hematopoietic stem cell transplantation (AHSCT) showed similar efficacy compared to daily lenograstim. To address the question of the optimal application time, we randomly assigned patients (pts) to pegfilgrastim on day + 1 (Peg1) or day + 4 (Peg4) after AHSCT., Method: Fifty-three pts with different hematological malignancies were included in this prospective randomized multicenter study. Primary endpoint of this study was time to neutrophil recovery (>500 Gpt/l), and secondary endpoint was time to neutrophil recovery (>1,000 Gpt/l), platelet recovery (>20,000 Gpt/l), number and duration of febrile episodes, i.v. antibiotics, and number of transfusions. Time to engraftment endpoints were estimated according to Kaplan-Meier., Results: Median time to neutrophil recovery (>500 Gpt/l) was 10 days (95% CI: 10-11) in Peg1 versus 10 days (95% CI: 10-11) in Peg4 (P = 0.68, logrank test; hazard ratio: 0.93). The corresponding mean values were 10.2 and 10.4 days. Median time to platelet recovery (>20,000 Gpt/l) was 10 (95% CI: 10-11) in Peg1 versus 10 (95% CI: 9-11) in Peg4, again not significantly different (P = 0.54). There was no difference regarding the incidence (67% vs. 60%, P = 0.77, Fisher's exact test) or duration of febrile neutropenia episodes in both groups (median: 1 vs. 1; mean: 2.8 vs. 2.4 days; P = 0.73, Wilcoxon test)., Conclusion: In terms of neutrophil or platelet recovery after AHSCT, number and duration of febrile episodes, the use of i.v. antibiotics, early and late administration of pegfilgrastim are equally effective.

Purpose: The aim of the study was to investigate the recovery of the innate immune system within the first 100 days after allogeneic peripheral blood stem cell transplantation (PBSCT) and to elucidate a potential correlation with such important events as severe infectious complications or graft-versus-host disease (GvHD)., Methods: In 30 consecutive patients who underwent allogeneic PBSCT, absolute numbers of neutrophils and monocytes were determined and different functional analyses performed at different time points (day +30, +60 and +90, respectively). The capacity to phagocyte Escherichia coli (E. coli) as well as the induction of oxidative burst after incubation with different stimuli (Phorbol-12-myristate-13-acetate; PMA, the chemotactic peptide N-formyl-Met-Leu-Phe; f-MLP or opsonized E. coli) were analysed after engraftment., Results: There was a rapid reconstitution concerning the capability of both neutrophils and monocytes to phagocyte E. coli without a significant increase between day +30 and +90. In contrast, a twofold increase of monocyte oxidative burst after incubation with PMA at day +90 was observed (P = 0.017). Furthermore, the ability of neutrophils to induce oxidative burst after ingestion with E. coli was impaired on day +30 with a significant functional reconstitution on day +60 (P = 0.01). The oxidative burst activity following incubation with f-MLP did not show significant changes after stem cell engraftment. Analysis of numeric reconstitution of CD14+CD16+ monocytes demonstrated a potential correlation with a decreased incidence of chronic GvHD., Conclusion: The functional recovery of neutrophils and monocytes in the early period after allogeneic PBSCT differs not only concerning phagocytosis and oxidative burst but also with respect to the stimulus and the cell population that was analysed for oxidative burst activity. The subset of CD16+CD14+ monocytes might be a predictor for a reduced risk of chronic GvHD.

The impact of chromosome architecture in the formation of chromosome aberrations is a recent finding of interphase directed molecular cytogenetic studies. Also positive correlation of translocation frequencies and spatial proximity of chromosomes was described. Thus, disease specific chromosomal translocations could be due to tissue specific genomic organization. However, no three-dimensional interphase fluorescence in situ hybridization (FISH) studies for the nuclear architecture of bone marrow (BM) cells have previously been done. In this study, BM of three secondary acute myelogenous leukemia (AML) cases with trisomy 8 and otherwise normal karyotype were evaluated. Bone marrow cells of one AML and one ALL (acute lymphoblastic leukemia) case, peripheral blood lymphocytes and human sperm, all of them with normal karyotype, served as controls. Multicolor banding (MCB) probes for chromosomes 8 and 21 were applied in suspension-FISH (S-FISH). Interestingly, in myeloid bone marrow cells chromosomes 8 (di- and trisomic) and 21 tended to co-localize with their homologue chromosome(s), rather than to be separated. Thus, the co-localization of chromosomes 8 and 21 might promote a translocation providing a selective advantage of t(8;21) cells in AML-M2. In summary, the concept that tissue specific spatial proximity of chromosomes leads to enhanced translocation frequencies was further supported.

Legionnaires' disease is an acute bacterial infection, generally caused by Legionella pneumophila, which primarily involves the lower respiratory tract, although it is often associated with multisystemic extrapulmonary features. Cutaneous features are very uncommon and may include erythematous or petechial, macular or maculopapular lesions. We report a male patient who expressed all features of a severe lobular pneumonia. Over the course of the disease the patient developed a livid erythematous, maculopapular exanthem rapidly extending over the entire body. Given the rapid development and target-like appearance of the skin lesions with extensive skin involvement and blister formation, the initial diagnosis was that of a severe cutaneous drug reaction. However, histological examination of biopsy did not confirm this diagnosis, but instead was suspicious for a viral exanthem or a more aggressive inflammatory response due to sensitization to bacterial antigens. L. pneumophila infection was verified during the course of the disease.

Background: A new chimerism analysis based on automated interphase fluorescence in situ hybridization (FISH) evaluation was established to detect residual cells after allogene sex-mismatched bone marrow or blood stem-cell transplantation.Cells of 58 patients were characterized as disease-associated due to presence of a bcr/abl-gene-fusion or a trisomy 8 and/or a simultaneous hybridization of gonosome-specific centromeric probes. The automatic slide scanning platform Metafer with its module MetaCyte was used to analyse 3,000 cells per sample., Results: Overall 454 assays of 58 patients were analyzed. 13 of 58 patients showed residual recipient cells at one stage of more than 4% and 12 of 58 showed residual recipient cells less than 4%, respectively. As to be expected, patients of the latter group were associated with a higher survival rate (48 vs. 34 month). In only two of seven patients with disease-marker positive residual cells between 0.1-1.3% a relapse was observed. Besides, disease-marker negative residual cells were found in two patients without relapse at a rate of 2.8% and 3.3%, respectively., Conclusion: The definite origin and meaning of disease-marker negative residual cells is still unclear. Overall, with the presented automatic chimerism analysis of interphase FISH slides, a sensitive method for detection of disease-marker positive residual cells is on hand.

The role of different cytogenetic changes has been extensively evaluated in patients with acute myeloid leukemia (AML), and cytogenetic analysis of AML blasts is essential to form prognostic subgroups in order to stratify for the extent of therapy. Nevertheless, 40-45% of AML patients lack such cytogenetic markers, i.e., cytogenetically normal AML (CN-AML). In the past decade, different molecular aberrations were identified in AML and especially CN-AML can now be discriminated into certain prognostic subgroups. This review considers the latest advances to define the prognostic impact of molecular aberrations in AML and gives insights how such molecular markers can be applied for analysis of minimal residual disease. Furthermore, therapeutic implications as well as the potential role of new methodological techniques in analyzing expression patterns of AML blasts are discussed.

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.

Although mycoses are among the most common diseases worldwide, infections with Fusarium spp. occur only rarely. Mostly patients suffering from underlying immune deficiency are infected with this mould, resulting in a considerably decreasing prognosis. In immunocompromised patients, cutaneous manifestations are more often associated with Fusarium sp. than with Candida sp. or Aspergillus sp. We describe one patient with acute lymphoblastic leukaemia, who was first treated with chemotherapy after GMALL protocol 07/03. After relapse, the patient was successfully transplanted in second remission with a human leukocyte antigen (HLA)-matched unrelated peripheral blood stem cell graft. Ten months later, the patient died from respiratory insufficiency and recurrence of leukaemia. Previously, Aspergillus antigen was detected in blood. In the latter course, disseminated papules appeared. One of these was examined histologically and mycologically. Conventional cultural diagnostics led to the diagnosis of a fusariosis, further supported by internal transcribed spacer (ITS) sequencing and matrix assisted laser desorption/ionisation-time-of-flight mass spectrometry (MALDI-TOF) mass spectrometry, both determining the isolated strain as Fusarium proliferatum, which is a very infrequent pathogen within this genus. Our investigations underline the potential of MALDI-TOF MS based identification of Fusarium species as an innovative, time and cost efficient alternative to ITS sequencing.

Background: Antithymocyte globulin or human Jurkat T-cell-line-derived antilymphocyte globulin is used in allogeneic stem cell transplantation to induce in vivo T-cell depletion to facilitate engraftment and lower graft-versus-host disease. In vitro studies suggest that antithymocyte globulin, besides causing T-cell depletion, has strong anti-myeloma activity., Design and Methods: We evaluated the anti-myeloma activity of antilymphocyte globulin in a melphalan/fludarabine-based reduced intensity conditioning regimen as well as the incidence of graft-versus-host disease in 138 multiple myeloma patients who underwent allogeneic stem cell transplantation with (n=79) or without (n=59) antilymphocyte globulin., Results: Leukocyte and platelet engraftment were faster in the group not receiving antilymphocyte globulin (13 vs. 16 days, p<0.001 and 11 vs. 19 days, p< 0.001, respectively). Inclusion of antithymocyte globulin led to a better day 100 overall response rate (93% vs. 78%, p=0.03) and complete response rate (59% vs. 39%, p=0.04), to a lower incidence of both acute grade III/IV graft-versus-host-disease (11% vs. 22%, p=0.10) and chronic graft-versus-host disease (23% vs. 65%, p<0.001) and to a trend to improved event-free survival at 3 years (39% vs. 27%, p=0.5). There was no difference in the estimated cumulative incidence of treatment-related mortality at 1 year between the groups receiving or not antilymphocyte globulin (25% vs. 26%). In a multivariate analysis treatment with antilymphocyte globulin was the only significant factor for achievement of a complete remission (RR:2.57, p=0.02)., Conclusions: Inclusion of antithymocyte globulin in allogeneic stem cell transplantation protocols for patients with multiple myeloma may increase remission rates and at the same time prevent graft-versus-host disease with no increase of relapses.

Purpose: The study investigated in detail neutrophil functions shortly after allogeneic peripheral blood stem cell transplantation (PBSCT)., Methods: Different functions of neutrophils in 14 patients who received allogeneic PBSCT were investigated. The migratory capacity as well as the ability to induce oxidative burst following stimulation with either Phorbol-12-myristate-13-acetate (PMA), the chemotactic peptide N-formyl-Met-Leu-Phe (f-MLP) or opsonized Escherichia coli was analysed after engraftment (between day +30 and +40) and compared with the results obtained from healthy volunteers., Results: There are no differences in terms of the migratory capacity (P = 0.17), as well as regarding the oxidative burst after incubation with PMA (P = 0.08) or f-MLP (P = 0.06), compared with healthy men. In contrast, the capacity of neutrophils to induce oxidative burst following stimulation with E. coli is highly impaired (P = 0.0001) in patients shortly after engraftment., Conclusion: The recovery of neutrophils after allogeneic PBSCT is not only influenced by the varying time of engraftment, but also represents a process that differs in distinct biological functions compared to normal granulopoieses.

Background: Stem cell therapy has been suggested to be beneficial in patients after acute myocardial infarction (AMI). Strategies of treatment are either a local application of mononuclear bone marrow cells (BMCs) into the infarct-related artery or a systemic therapy with the granulocyte-stimulating factor (G-CSF) to mobilize BMCs. Nevertheless, the mechanisms responsible for improvement of cardiac function and perfusion are speculative at present. This study has been performed to investigate the effect of G-CSF on systemic levels of vascular growth factors and chemokines responsible for neovascularization, that might help to understand the positive effects of a G-CSF therapy after AMI., Methods and Results: Five patients in the treatment group and 5 patients in the control group were enrolled in this study. The patients in the treatment group received 10 microg/kg bodyweight/day of G-CSF subcutaneously for a mean treatment duration of 6.6 +/- 1.1 days. In both groups, levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and monocyte chemotactic protein-1 (MCP-1) were measured on day 2 to 3 and day 5 after AMI. The regional wall perfusion and the ejection fraction (EF) were evaluated before discharge and after 3 months with ECG-gated MIBI-SPECT and radionuclide ventriculography, respectively. Significant higher levels of VEGF (p < 0.01), bFGF (p < 0.05) and MCP-1 (p < 0.05) were found in the treatment group compared to the control group. Levels of VEGF and bFGF remained on a plateau during the G-CSF treatment and decreased significantly in the control group. The wall perfusion improved significantly within the treatment group and between the groups (p < 0.05), respectively. The EF improved significantly within the treatment group (p < 0.05), but the change of the EF between the groups was not significant., Conclusion: In patients with AMI, the treatment with G-CSF modulates the formation of vascular growth factors that might improve neovascularization and result in an improved myocardial perfusion and function.

Acute myeloid leukaemia (AML) is mainly affecting elderly patients. Elderly patients are increasingly affected by impairment of functional status (FS). FS is of prognostic relevance for survival in different tumours. Data for patients with AML are rare. Within a prospective trial we recruited patients with newly diagnosed AML and measured FS by two different methods: Karnofsky performance status (KPS) and instrumental activities of daily living (IADL). Sixty-three patients aged 19-85 years (median 61.1) were included. Twenty-three had prior myelodisplastic syndrome (MDS), 7 favourable, 17 unfavourable karyotype. Fifty received induction chemotherapy, 13 palliative chemotherapy. Median survival was 15.2 months (95% CI, 10.8-22.3) in all patients. Age, cytogenetic risk group, and impaired KPS and IADL significantly influenced median survival in univariate analysis. Impairment of IADL was the single most predictive variable. In multivariate analysis, impairment of IADL Score (HR:4.3, 95% CI 1.7-10.5, P = 0.001) and of KPS (HR:4.8, 95% CI 1.9-12.3, P = 0.001), and unfavourable cytogenetic risk group (HR:6.0, 95% CI 2.5-14.3, P < 0.001) significantly predicted median survival. In patients with AML, FS and not age is a major predictor of survival. The influence of FS is independent from cytogenetic risk group. IADL measurement adds information to KPS. The results have to be confirmed in a large sample of patients.

Background and Objectives: Imatinib is an effective treatment for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, relapse is common in patients with advanced or high risk disease. Such patients may be eligible for allogeneic stem cell transplantation (SCT), raising the question whether imatinib therapy may compromise the outcome of subsequent SCT., Design and Methods: We retrospectively analyzed 70 patients with CML and 21 with Ph+ ALL who had received imatinib prior to SCT. Data were retrieved by directly contacting centers. Multivariate analysis was used to define factors associated with major outcomes (engraftment, graft-versus-host disease, relapse, non-relapse mortality) in addition to descriptive statistics. For the CML patients major outcomes were compared with those of historical controls drawn from the EBMT registry., Results: At SCT, 44% of CML patients were in accelerated phase or blast crisis and 40% of ALL patients had active disease compared to 84% and 95% prior to imatinib. At 24 months, estimated transplant-related mortality was 44% and estimated relapse mortality 24%. Factors associated with shorter overall and progression-free survival were advanced disease at SCT and a female donor/male recipient pairing. No unusual organ toxicities were observed. Compared to historical controls, prior imatinib treatment did not influence overall survival, progression-free survival or non-relapse mortality, while there was a trend towards higher relapse mortality and significantly less chronic graft-versus-host disease., Interpretation and Conclusions: Within the limits of a heterogeneous and relatively small cohort of patients, we found no evidence that imatinib negatively affects major outcomes after SCT, suggesting that imatinib prior to SCT is safe.

We report on a 54-year-old male patient with an aggressive T cell non-Hodgkin's lymphoma with abdominal manifestation undergoing autologous peripheral blood stem cell transplantation after high-dose chemotherapy in April 2003. About 4 months after transplantation, he developed severe upper abdominal pain. Ultrasound examination, X-ray, computed tomography of the abdomen and cardiac diagnostics could not explain the symptoms. While empiric therapy with high-dose acyclovir was started, we could document herpetic lesions in the gastric antrum by endoscopy. The epigastric pain rapidly decreased within several days after the start of acyclovir therapy. No herpetic skin lesions were observed at any time during the disease. This report demonstrates the importance of viral-induced gastritis in the differential diagnosis of severe abdominal pain in patients receiving autologous peripheral blood stem cell transplantation.

Objective: To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome-positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM)., Methods: We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling (n = 18) or unrelated (n = 43) donors after having been treated with IM. Forty-one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan (n = 25) or total-body irradiation (n = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose-reduced conditioning with fludarabine-based regimens., Results: The incidence of grades II-IV and III-IV graft-versus-host disease was 66% and 38% respectively. The probability of overall survival (OS), disease-free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non-relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine-based conditioning therapy, age > or = 40 yr and >12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM., Conclusion: These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant-related mortality.

Background: Changes within the ABO system are regularly observed phenomena in allogeneic bone marrow transplantation (BMT) and peripheral blood progenitor cell transplantation (PBPCT). Major ABO mismatch can lead to different clinical problems including acute hemolysis after infusion of the allograft, delay of red blood cell (RBC) engraftment, or even manifestation of pure red cell aplasia (PRCA)., Study Design and Methods: This retrospective study demonstrates the safety and the impact of donor-type RBC transfusion before allogeneic PBPCT in major ABO settings as routinely performed at our transplantation unit. This study reports on transfusion of mismatched RBCs at the end of the conditioning period in 35 patients who underwent allogeneic PBPCT, which led to a decrease in isoagglutinin titers in most cases., Results: A decrease of isoagglutinin titer after donor-type RBC transfusion can significantly reduce the demand of RBC transfusion between transplantation and Day +30 (p = 0.003). Interestingly, patients who developed PRCA were not observed, a complication being regularly documented by other groups., Conclusion: A decrease of isoagglutinin titers by in vivo immunoadsorption before allogeneic PBPCT does not only lack severe complication but also leads to a reduction in demand of RBC transfusion after engraftment and may reduce the incidence of PRCA in these patients.

Background: This study was undertaken to evaluate the hypothesis that treatment with granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow cells (BMCs) is feasible and safe and promotes neovascularization and myocardial function in patients with acute myocardial infarction., Methods: Fourteen patients in the treatment group and 9 patients in the control group were enrolled in this prospective, nonrandomized, open-label study. Forty-eight hours after successful recanalization and stent implantation, the patients of the treatment group received 10 microg/kg body weight per day G-CSF subcutaneously for mean treatment duration of 7.0 +/- 1.0 days. Nine patients fulfilled the entry criteria but refused participation and served therefore as control group. In both groups, regional wall motion and perfusion was evaluated with electrocardiogram-gated sestamibi single-photon emission computed tomography imaging and ejection fraction with radionuclidventriculography before discharge and after 3 months., Results: No severe side effects of G-CSF treatment were observed. There was a significant improvement of the regional wall motion and perfusion within the treatment group (P < .0001) and between the treatment and control group (P < .05 and P < .01, respectively). Ejection fraction in the treatment group increased from 0.40 +/- 0.11 to 0.48 +/- 0.13 (P < .01), whereas in the control group, ejection fraction increased from 0.40 +/- 0.13 to 0.43 +/- 0.13 (P = .049). A control angiography of the treatment group after 12.4 +/- 6.6 months showed an in-stent restenosis in 1 patient., Conclusion: In patients with acute myocardial infarction, treatment with G-CSF to mobilize BMCs is feasible and safe and seems to be effective under clinical conditions. The therapeutic effect might be attributed to BMC-associated promotion of myocardial regeneration and neovascularization.

Among activating class III receptor tyrosine kinase (Flt3) mutations, internal tandem duplications of Flt3 (Flt3-ITD) are detected in about 25% of patients with acute myeloid leukemia (AML). In contrast, mutations within the tyrosine kinase domain of Flt3 (Flt3-TKD mutations) are less frequent (approximately 7%), and there are only limited data on the frequency of recently demonstrated activating Flt3 point mutation at codon 592 (Flt3-V592A mutation). We evaluated a new approach for rapid screening of Flt3-TKD and Flt3-V592A mutations using the fluorescence resonance energy transfer (FRET) principle in a group of 122 patients. Based on individual Flt3-TKD mutations, we designed patient-specific primers to perform a highly sensitive polymerase chain reaction (PCR) assay for rapid detection of minimal residual disease (MRD). We also used a model system with MonoMac-6 cells carrying the Flt3-V592A mutation to establish a mutation-specific real-time PCR approach also for this molecular aberration. We identified 9 cases (8%) of Flt3-TKD mutations (5 cases of mutation D835Y, 3 cases of mutation D835H, and 1 case of mutation Del836), and no cases of Flt3-V592A mutation. Screening for Flt3-TKD mutations with fluorescent probes is equivalent to conventional screening using standard PCR followed by EcoRV restriction. We present a real-time PCR protocol that can be used for MRD analyses based on individual Flt3-TKD mutations. Examples of MRD analyses are presented for all 3 subtypes of Flt3-TKD mutation identified in this study. In summary, we demonstrate new methodological approaches for rapid screening of Flt3 point mutations and for detection of MRD based on patient-specific Flt3-TKD mutations.

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma.

Purpose: Activating Flt3 mutations are observed in about 30% of patients with acute myeloid leukaemia (AML) and individual Flt3 mutations are applicable for minimal residual disease (MRD) analyses., Methods: We investigated the MRD status in four AML patients carrying different Flt3 mutations (three patients with Flt3 length mutations of the juxtamembrane domain, one patient carrying a mutation of the Flt3 tyrosine kinase domain, i.e. Flt3-TKD mutation) who underwent allogeneic peripheral blood stem cell transplantation (PBSCT). Residual leukaemia cells were retrospectively determined by real-time PCR at different time points., Results: We can demonstrate a good correlation between the course of MRD status and clinical events in all four investigated patients., Conclusion: These examples demonstrate the potential impact of Flt3 based MRD status not only after but also prior to allogeneic PBSCT.

Background: Recent data suggest that transplantation of autologous bone marrow cells (BMC) may contribute to myocardial repair after acute myocardial infarction. We hypothesized that patients with chronic ischemic cardiomyopathy could also benefit from autologous BMC transplantation in addition to established heart failure therapy., Methods and Results: Five patients with chronic ischemic cardiomyopathy caused by anterior myocardial infarction, 1.3+/-0.5 years ago and open infarct artery, received autologous mononuclear BMC transplantation via balloon catheter in the target vessel at the site of previous occlusion. Patients were followed up at 3 months (left heart catheterisation, 2D-echocardiography, dobutamine stress echocardiography, cardiopulmonary exercise testing) and at 12 months (2D-echocardiography, cardiopulmonary exercise testing). Follow-up examination showed no significant improvement neither in global, regional, and microvascular function, nor in physical performance., Conclusions: In this pilot trial intracoronary transplantation of autologous, mononuclear BMC did not lead to any significant improvement in myocardial function and physical performance of patients with chronic ischemic heart disease.