Vinorelbine as substitute for vincristine in patients with diffuse large B cell lymphoma and vincristine-induced neuropathy.

BACKGROUND: A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology. METHODS: In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables. RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes. CONCLUSION: Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma-related bone disease in patients who had a partial response or better after frontline high-dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35-day cycles of bortezomib 1·6 mg/m2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent-to-treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End-of-treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression-free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival.

Impact of ATG-containing reduced-intensity conditioning after single- or double-unit allogeneic cord blood transplantation.

We analyzed 661 adult patients who underwent single-unit (n = 226) or double-unit (n = 435) unrelated cord blood transplantation (UCBT) following a reduced-intensity conditioning (RIC) consisting of low-dose total body irradiation (TBI), cyclophosphamide, and fludarabine (Cy/Flu/TBI200). Eighty-two patients received rabbit antithymocyte globulin (ATG) as part of the conditioning regimen (ATG group), whereas 579 did not (non-ATG group). Median age at UCBT was 54 years, and diagnoses were acute leukemias (51%), myelodysplastic syndrome/myeloproliferative neoplasm (19%), and lymphoproliferative diseases (30%). Forty-four percent of patients were transplanted with advanced disease. All patients received ≥4 antigens HLA-matched UCBT. Median number of collected total nucleated cells was 4.4 × 10(7)/kg. In the ATG group, on 64 evaluable patients, ATG was discontinued 1 (n = 27), 2 (n = 20), or > 2 days before the graft infusion (n = 17). In multivariate analyses, the use of ATG was associated with decreased incidence of acute graft-versus-host disease (hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.17-0.55; P < .0001), higher incidence of nonrelapse mortality (HR, 1.68; 95% CI, 1.16-2.43; P = .0009), and decreased overall survival (HR, 1.69; 95% CI, 1.19-2.415; P = .003). Collectively, our results suggest that the use of ATG could be detrimental, especially if given too close to graft infusion in adults undergoing UCBT following Cy/Flu/TBI200 regimen.

Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma.

Bendamustine with bortezomib and dexamethasone was evaluated in 79 patients with relapsed/refractory multiple myeloma. Median age was 64 years, and patients had a median of 2 prior treatment lines (range, 1 to 6 lines). Bendamustine 70 mg/m(2) days 1 and 4; bortezomib 1.3 mg/m(2) intravenously days 1, 4, 8, and 11; and dexamethasone 20 mg days 1, 4, 8, and 11 once every 28 days was given for up to 8 cycles. Primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, time to response, and toxicity. ORR was 60.8%, and when minor responses were included, 75.9%. Median time to response was 31 days. ORR rate was similar in patients previously exposed to bortezomib, lenalidomide, and bortezomib plus lenalidomide. PFS was 9.7 and OS was 25.6 months. Multivariate analysis showed high lactate dehydrogenase, ≥3 prior treatment lines, and low platelet counts correlating with short survival. Grade 3/4 thrombocytopenia was noted in 38%, and grade 3/4/5 infections were noted in 23%. Grade ≤2 polyneuropathy increased from 19% at baseline to 52% at cycle 8 and grade 4, from 0% to 7%. Bendamustine-bortezomib-dexamethasone is active and well tolerated in patients with relapsed/refractory myeloma. This trial was registered in the EudraCT database as No. 2008-006421-13.

Non-pegylated liposomal doxorubicin in lymphoma: patterns of toxicity and outcome in a large observational trial.

The anthracycline doxorubicin plays a major role in the treatment of lymphoproliferative disorders. However, its use is often limited due to cardiac toxicity, which seems to be much less in the liposomal non-pegylated formulation (Myocet®). The aim of this study was the evaluation of efficacy and toxicity of Myocet®-containing treatment regimens, with a focus on cardiotoxicity during treatment in lymphoma patients. A total of 326 consecutive patients, treated between March 2008 and December 2013 in 11 Austrian and 1 Italian cancer centers, were retrospectively assessed. Patients' baseline and treatment-related parameters were obtained by reviewing hospital records. Median age was 74 years (range 26-93). The most common histology was DLBCL (60 %), followed by FL (13 %) and MCL (8 %). At least one cardiovascular comorbidity was present in 72 % of patients. Most common grade 3/4 toxicities were hematologic, namely, leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia in 44, 40, 17, and 16 %. Overall, 43 patients suffered a cardiac event (any grade) with most patients developing congestive heart failure. Parameters significantly associated with severe cardiac events (grades 3-5) were the presence of cardiovascular comorbidities, chronic obstructive pulmonary disease, and elevated baseline NT-proBNP. Treatment response after first line Myocet®-containing therapy was ≥58 % among all entities (range 58-86 %) and therefore comparable to those of conventional therapeutic regimens. Herein, we provide a detailed toxicity profile of Myocet®-containing chemotherapy regimens. Despite the high rate of patients with preexisting comorbidities, the number of adverse events was encouraging. However, these results need to be confirmed in a prospective randomized trial.

Unrelated cord blood transplantation for patients with primary or secondary myelofibrosis.

To determine whether umbilical cord blood transplantation (UCBT) is an alternative cure for myelofibrosis (MF), we evaluated 35 UCBTs reported to Eurocord. Seven patients had secondary acute myeloid leukemia (AML) at UCBT, and median age at UCBT was 54 years. Twenty-four patients received a reduced-intensity conditioning (RIC) regimen, and 17 of 35 patients received total body irradiation (2 to 12 Gy)-fludarabine-cyclophosphamide (TCF) conditioning. The median follow-up was 24 months. The cumulative incidence of neutrophil recovery at 60 days was 80%. Fifteen patients relapsed after UCBT. The 2-year overall survival and event-free-survival (EFS) rates were 44% and 30%, respectively. All patients given TCF achieved neutrophil and platelet recovery, and the use of TCF was associated with superior EFS in the RIC population (44% versus 0%, P = .001). Patients with transformation to AML had similar outcomes to patients with less advanced stages. In conclusion, despite graft failure remaining a major concern, the role of UCBT in the management of MF, especially using RIC TCF-based regimens, deserves further investigation to improve results.

Impact of minimal residual disease on outcomes after umbilical cord blood transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia: an analysis on behalf of Eurocord, Cord Blood Committee and the Acute Leukaemia working party of the European group for Blood and Marrow Transplantation.

The status of umbilical cord blood transplantation (UCBT) in adults with Philadelphia-positive acute lymphoblastic leukaemia (Ph+ALL) and the impact of minimal residual disease (MRD) before transplant are not well established. We analysed 98 patients receiving UCBT for Ph+ALL in first (CR1) or second (CR2) complete remission (CR1, n = 79; CR2, n = 19) with MRD available before UCBT (92% analysed by reverse transcription polymerase chain reaction). Median age was 38 years and median follow-up was 36 months; 63% of patients received myeloablative conditioning and 42% received double-unit UCBT. Eighty-three patients were treated with at least one tyrosine kinase inhibitor before UCBT. MRD was negative (-) in 39 and positive (+) in 59 patients. Three-year cumulative incidence of relapse was 34%; 45% in MRD+ and 16% in MRD- patients (P =0·013). Three-year cumulative incidence of non-relapse mortality was 31%; it was increased in patients older than 35 years (P = 0·02). Leukaemia-free survival (LFS) at 3 years was 36%; 27% in MRD+ and 49% in MRD- patients (P = 0·05), and 41% for CR1 and 14% for CR2 (P = 0·008). Multivariate analysis identified only CR1 as being associated with improved LFS. In conclusion, MRD+ before UCBT is associated with increased relapse. Strategies to decrease relapse in UCBT recipients with Ph+ALL and MRD+ are needed.

Lenalidomide in combination with vorinostat and dexamethasone for the treatment of relapsed/refractory peripheral T cell lymphoma (PTCL): report of a phase I/II trial.

Given the poor outcome of relapsed and refractory peripheral T cell lymphoma (PTCL), we explored a combination of lenalidomide, vorinostat, and dexamethasone to test the feasibility of this therapy in relapsed and refractory PTCL. Eight patients were accrued: two peripheral T cell lymphoma, unspecified; five angioimmunoblastic T cell lymphoma; and one ALK-negative anaplastic large-cell lymphoma. A dose escalation of lenalidomide (days 1-21, q28) was planned using a 3 + 3 design. As two patients treated with 10 mg/day experienced dose-limiting toxicity (thrombocytopenia grade 3, stroke grade 4), the primary end point of our trial was reached; the maximal tolerable dose of lenalidomide was 5 mg/day (level -I). Adverse events grade ≥3 were observed as thrombocytopenia (23 %), leukocytopenia (15 %), anemia (8 %), and neutropenia (8 %). One complete remission (10.3 months), one partial remission (11.3 months), one stable disease (11.9 months), and four progressive disease (overall response rate 25 %) were observed. The median progression-free survival was 2.2 months and the median OS was 6.7 months. In conclusion, the poor results obtained with lenalidomide in combination with vorinostat and dexamethasone provide no arguments that could justify further investigation of this drug combination for the treatment of relapsed PTCL.

Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group.

Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n = 302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20-30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53-10.7) months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.

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

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

Rituximab plus subcutaneous cladribine in patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a phase II study by the Arbeitsgemeinschaft Medikamentose Tumortherapie.

Currently, there is no standard systemic treatment for extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue. Both rituximab and cladribine have shown some activity in this disease, but the combination has not been tested so far. In view of this, we initiated a phase II study to assess the activity and safety of rituximab and cladribine in patients with histologically verified mucosa-associated lymphoid tissue lymphoma. Treatment consisted of rituximab 375 mg/m(2) i.v. day 1 and cladribine 0.1 mg/kg s.c. days 1 - 4 every 21 days. In case of complete remission after two courses, another two cycles of therapy were administered, while patients with a partial response or stable disease were scheduled to receive six cycles of treatment. Out of 40 evaluable patients (14 female, 26 male), 39 received treatment as scheduled while one patient died before initiation of therapy and was rated as having progressive disease in the intent-to-treat analysis. Twenty-one patients had gastric lymphoma, while 19 suffered from extragastric mucosa-associated lymphoid tissue lymphoma. Side effects consisted mainly of hematologic toxicity including leukopenia, lymphopenia, anemia and thrombocytopenia. Twenty-three patients had a complete remission (58%) and nine had a partial remission (23%) for an overall response rate of 81%, while five had stable disease (13%) and two progressed during therapy. After a median follow-up of 16.7 months (interquartile range: 15.9 - 18.7 months), 35 patients are alive (88%) while four patients have died and one patient withdrew consent and did not allow further follow up. Our data demonstrate that rituximab plus cladribine is active and safe in patients with mucosa-associated lymphoid tissue lymphoma.

Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial.

Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD.

European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) host factors and invasive fungal infections in patients with haematological malignancies.

OBJECTIVES: Fulfilment of host factors defined by the revised European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria is required for establishing the diagnosis of possible or probable invasive fungal infection (IFI). This case-control study evaluates EORTC/MSG host factors among patients with haematological malignancies. METHODS: Fifty-eight patients with haematological malignancies who developed probable (n = 38) or proven (n = 20) IFI over a 5 year period were retrospectively evaluated regarding EORTC/MSG host factors. Results were compared with those obtained from patients with haematological malignancies who did not develop IFI (116 patients who received systemic antifungal prophylaxis or empirical therapy and 116 patients who did not; all data collected in 2010). RESULTS: Fourteen patients had invasive yeast infection and 44 patients had invasive mould infection (IMI). Prolonged neutropenia (35/58, 60% versus 29/116, 25%), prolonged systemic corticosteroid (cut-off 21 days: 13/58, 22% versus 6/116, 5%; cut-off 14 days: 18/58, 31% versus 9/116, 8%) and T cell suppressive therapy (35/44, 80% versus 69/116, 59%) were significantly associated with development of IFI/IMI in our cohort. Previous allogeneic stem cell transplantation (SCT; >6 months prior to episode) was not significantly associated with development of IMI (8/44, 18% versus 22/116, 19%), while recent SCT (<6 months prior to episode) was (11/44, 25% versus 12/116, 10%). CONCLUSIONS: We conclude that host factors according to revised EORTC/MSG criteria were significantly associated with the development of IFI/IMI in our patients. Previous allogeneic SCT was not a predisposing host factor for the development of IMI. Concerning prolonged corticosteroid treatment, a cut-off of 14 days seems preferable to the proposed cut-off.

Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid leukemia.

The recent identification of DNMT3A mutations in de novo acute myeloid leukemia prompted us to determine their frequency, patterns and clinical impact in a cohort of 98 patients with either therapy-related or secondary acute myeloid leukemia developing from an antecedent hematologic disorder. We identified 24 somatic mutations in 23 patients with a significantly higher frequency in secondary acute myeloid leukemia (35.1%) as compared to therapy-related acute myeloid leukemia (16.4%, P=0.0486). DNMT3A mutations were associated with a normal karyotype and IDH1/2 mutations, but did not affect survival. In contrast to de novo acute myeloid leukemia, most mutations did not affect arginine on position 882, but were predominantly found in the methyltransferase domain. All DNMT3A mutations identified in secondary acute myeloid leukemia were already present in the antecedent disorders indicating an early event. Reduction to homozygosity by uniparental disomy was observed in 2 patients with secondary acute myeloid leukemia during disease progression.

Impact of galactomannan testing on the prevalence of invasive aspergillosis in patients with hematological malignancies.

Galactomannan (GM) is a polysaccharide component of the cell wall of Aspergillus spp. and is released into the host's circulation by growing hyphae. GM testing of patients with hematological malignancies has been rarely considered in recent epidemiologic studies of invasive mould infections (IMIs). The aim of the investigation was to analyze the impact of GM testing on the reported prevalence of IMI by comparing detection rates of IMI before and after the introduction of this diagnostic procedure. Prevalence of IMI was assessed by conducting a prospective single-centre study over seven months in 2010. Results obtained were then compared to those obtained with a representative collection of patients assessed by the same investigators at the same institution over seven months in 2007, i.e., prior to the introduction of GM testing. We found that, in general, detection rates of invasive aspergillosis (IA) and invasive mould infections increased significantly after the introduction of GM analysis. This study may therefore indicate that GM testing has a significant impact on the reported prevalence of IMI. Broad usage of such testing in patients with hematological malignancies may be able to produce a realistic picture of IMI rates when current diagnostic criteria are applied.

Histiocytic sarcoma - targeted therapy: novel therapeutic options? A series of 4 cases.

BACKGROUND: Histiocytic sarcoma (HS) is a rare but highly aggressive disease. The cancer-specific survival of patients with HS is short and only limited response to conventional chemotherapy or radiation therapy is seen. Some data from single case reports have suggested efficacy for high-dose chemotherapy and autologous/allogeneic stem cell transplantation. CASE REPORT: We report on 4 cases of HS, and demonstrate that different druggable receptors are expressed on HS. Using immunohistochemistry, we detected the expression of platelet-derived growth factor receptor, vascular endothelial growth factor receptor and epidermal growth factor receptor, which are all well-known targets for novel targeted agents. Based on the marker profile, different novel targeted therapies including imatinib, sorafenib and bevacizumab were applied to the patients. We observed a varying clinical course for each patient. CONCLUSION: In our case series, we demonstrated that different receptors, which represent potential targets for novel drugs, are expressed on HS tumor cells. For a definitive assessment of the efficacy of these agents a prospective case study of a larger number of patients should be performed.

Humanized large-scale expanded endothelial colony-forming cells function in vitro and in vivo.

Endothelial progenitor cells are critically involved in essential biologic processes, such as vascular homeostasis, regeneration, and tumor angiogenesis. Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells with robust proliferative potential. Their profound vessel-forming capacity makes them a promising tool for innovative experimental, diagnostic, and therapeutic strategies. Efficient and safe methods for their isolation and expansion are presently lacking. Based on the previously established efficacy of animal serum-free large-scale clinical-grade propagation of mesenchymal stromal cells, we hypothesized that endothelial lineage cells may also be propagated efficiently following a comparable strategy. Here we demonstrate that human ECFCs can be recovered directly from unmanipulated whole blood. A novel large-scale animal protein-free humanized expansion strategy preserves the progenitor hierarchy with sustained proliferation potential of more than 30 population doublings. By applying large-scale propagated ECFCs in various test systems, we observed vascular networks in vitro and perfused vessels in vivo. After large-scale expansion and cryopreservation phenotype, function, proliferation, and genomic stability were maintained. For the first time, proliferative, functional, and storable ECFCs propagated under humanized conditions can be explored in terms of their therapeutic applicability and risk profile.

Plerixafor and granulocyte-colony-stimulating factor (G-CSF) in patients with lymphoma and multiple myeloma previously failing mobilization with G-CSF with or without chemotherapy for autologous hematopoietic stem cell mobilization: the Austrian experience on a named patient program.

BACKGROUND: Plerixafor in combination with granulocyte-colony-stimulating factor (G-CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease who demonstrated with previous mobilization failure. In this named patient program we report the Austrian experience in insufficiently mobilizing patients. STUDY DESIGN AND METHODS: Twenty-seven patients from eight Austrian centers with a median (range) age of 58 (19-70) years (18 female, nine male) were included in the study. Plerixafor was limited to patients with previous stem cell mobilization failure and was given in the evening of Day 4 of G-CSF application. RESULTS: A median increase of circulating CD34+ cells within 10 to 11 hours from administration of plerixafor by a factor of 4.7 over baseline was noted. Overall, 20 (74%) patients reached more than 10 × 10(6) CD34+ cells/L in the peripheral blood, resulting in 17 (63%) patients collecting at least 2 × 10(6) CD34+ cells/kg body weight (b.w.; median, 2.6 × 10(6) CD34+ cells/kg b.w.; range, 0.08 × 10(6) -8.07 × 10(6) ). Adverse events of plerixafor were mild to moderate and consisted of gastrointestinal side effects and local reactions at the injection site. Thirteen (48%) patients underwent autologous transplantation receiving a median of 2.93 × 10(6) CD34+ cells/kg (range, 1.46 × 10(6) -5.6 × 10(6) ) and showed a trilinear engraftment with a median neutrophil recovery on Day 12 and a platelet recovery on Day 14. CONCLUSION: Our study confirms previous investigations showing that plerixafor in combination with G-CSF is an effective and well-tolerated mobilization regimen with the potential of successful stem cell collection in patients with previous mobilization failure.

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

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

Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation.

BACKGROUND: Anagrelide hydrochloride is an anti-thrombotic agent indicated for the treatment of essential thrombocythemia (ET). In various previously published clinical trials of 2 branded formulations of anagrelide in patients with ET at high risk for thrombohemorrhagic events, the rates of adverse events and discontinuation were strikingly divergent between brands. Because the formulations and manufacturers differed, the differences in tolerability, as well as platelet counts, might have been related to differences in pharmacokinetic properties between the 2 formulations. OBJECTIVES: The present series of investigations (1) determined the pharmacokinetic profile of anagrelide and its metabolites; (2) compared the pharmacokinetic profiles of the test and reference formulations of anagrelide; (3) investigated the in vitro release of anagrelide as a marker of intragastric anagrelide release of the test and reference formulations; and (4) compared the platelet-reducing effects of the test and reference formulations in patients with thrombocythemia in 2 longitudinal studies over 4 weeks. METHODS: A series of 4 in vivo studies and 1 in vitro study were conducted. In a pilot, prospective, singledose study in healthy volunteers, the pharmacokinetic properties (C(max), T(max), and AUC(0-infinity)) of a test formulation of anagrelide were assessed using high-performance liquid chromatography analysis of plasma samples. Based on the results from that study, a single-dose, randomized, double-blind, 2-period crossover study in healthy volunteers was conducted to determine bioequivalence of 2 formulations of anagrelide 2 mg/d (taken as 4 capsules). In vitro dissolution properties of the test or reference formulation containing 0.5 mg anagrelide as the active ingredient were studied in an assay mimicking gastrointestinal release. To test for effects on platelet counts of switching from the reference formulation (previous treatment on stable dose for 3 months) to the test formulation, two 4-week longitudinal trials were conducted: one in patients with ET (in Germany), and one in patients with thrombocythemia associated with chronic myeloproliferative disorders (CMPDs) (in Austria). RESULTS: The pilot pharmacokinetic study of the test formulation in 16 volunteers (10 women, 6 men; mean [SD] age, 20.5 [1.5] years; weight, 69.0 [10.0 kg) suggested that anagrelide was metabolized to 3-hydroxyanagrelide (AUC(0-infinity) 50% compared with anagrelide) and the inactive metabolite 2-amino-5,6-dichloro-,4-dihydroquinazolone. The subsequent bioequivalence study in 24 volunteers (14 women, 10 men; mean [SD] age, 23 [4] years; white, 100%; weight, 67.5 [10.2] kg) found that the test formulation was associated with a significantly lower C(max) (point estimation [PE], 66%; 90% CI, 58%-76%; P < 0.001) and AUC(0-infinity) (PE, 77%; 90% CI, 68%-86%; P = 0.001). T(max) values for anagrelide and 3-hydroxyanagrelide were 1 hour longer with the test formulation compared with the reference formulation. The total number of adverse events with the reference formulation was 46; the test formulation, 29 (P = 0.05). In vitro, anagrelide from the reference formulation was immediately released (89.1% at 5 minutes), whereas there was a delayed release (93.6% at 30 minutes) from the test formulation (P < 0.05). In the last 2 studies, 2 cohorts of white patients (cohort 1, 15 patients with ET; 10 women, 5 men; mean [SD] age, 49.0 [10.7] years [range, 31-66 years]; weight, 73.2 [12.6] kg; cohort 2, 19 patients with thrombocythemia associated with CMPD; 12 women, 7 men; age, 62.6 [12.4] years [range, 38-80 years]; weight, 66.1 [13.3] kg) who had received treatment for > or =3 months with the reference formulation were switched to the same dose of the test formulation and maintained on this dose for 4 weeks. Platelet counts did not change significantly from baseline over 4 weeks and stayed within a predefined margin of 150 x 10(3) cells/microL. CONCLUSIONS: The pharmacokinetic properties, adverse event rates, and in vitro dissolution profile differed between the test and reference anagrelide formulations in these healthy volunteers. In patients with ET or thrombocythemia associated with CMPD, platelet counts did not differ significantly from baseline at 4 weeks when subjects were switched from the reference to the test anagrelide formulation.