Julian Topaly - Academia.edu (original) (raw)
Papers by Julian Topaly
Cytotherapy, 2009
Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow-derived cells.... more Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow-derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (ckit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow-derived angiogenesis, thus improving neuronal survival and functional outcome.
Hematological Oncology, Jun 1, 2019
Introduction: Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL) is ra... more Introduction: Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL) is rare but is associated with poor outcomes. The majority of CNS relapses in DLBCL occur in the brain parenchyma and are therefore unlikely to be prevented by intrathecal prophylaxis. There is increasing evidence to support use of high dose intravenous methotrexate (HDMTX) as a prophylactic regimen in selected highrisk patients. As most CNS relapses occur early in the disease course, ideally prophylaxis should be delivered as early as possible. There remains concern that HD MTX carries a risk of toxicity, especially renal, which could result in delays to systemic chemotherapy if delivered in an intercalated fashion. We performed a single centre, retrospective analysis of 45 patients who received HDMTX intercalated with R-CHOP chemotherapy with a focus on toxicity rates and subsequent delays in systemic therapy. Methods: 45 consecutive patients receiving HDMTX as CNS prophylaxis alongside R-CHOP chemotherapy for HIV negative DLBCL between 2012-2018 were identified and medical records analysed for toxicity rates, timing of chemotherapy cycles and evidence of CNS relapse. 60% were male (n=27) and median age was 60 years (range 37y-80y). The majority (78%) had stage IV disease and the median CNS IPI was 3, with 31% (n=14) falling in the high risk (4-6) CNS IPI group. Patients with known CNS disease at presentation were excluded. Local guidelines stipulated that 2 cycles of HDMTX at 3g/m2 should be delivered at day 14 following the R-CHOP courses 2 and 3. Results: 73% (n=33) received at least 2 cycles of MTX. Reasons for only delivering 1 cycle of MTX in 12 patients were patient fitness/frailty (n=7), renal toxicity (n=2) and mucositis (n=3). 5 (11%) patients experienced renal toxicity according to CTCAE definitions (3 = grade 2, 2 = grade 3). All patients had recovery of renal function without the need for invasive intervention. Mucositis occurred in 13 (29%) patients (grading not recorded). Hepatotoxicity was seen in 2/45 (4%) patients. 80 cycles of HD MTX were delivered in total. Neutrophil count on the scheduled day of subsequent RCHOP chemotherapy was >1.0 in 73/80 (91%) cycles. 5/45 (11%) patients experienced a delay of subsequent R-CHOP chemotherapy (7 or more days) directly attributable to methotrexate. 3/45 (7%) of patients suffered CNS relapse with median follow up of 32 monthsall relapses were parenchymal and 2/3 had only received 1 cycle HDMTX. Discussion: This retrospective analysis demonstrates that HDMTX can be delivered intercalated with R-CHOP chemotherapy with acceptable rates of toxicity and few delays in systemic chemotherapy. The rate of renal toxicity was low and was reversible in all patients. Although the numbers are small, the rate of CNS relapse (7%) was low in this selected, high-risk group. Careful assessment of patient fitness is required prior to consideration of HDMTX, but the median age of 60 years in our study suggests that age alone should not be a barrier to delivering this treatment.
Journal of Clinical Oncology, May 20, 2020
8060 Background: SDZ-RTX (Rixathon) is approved in more than 20 countries and regions, including ... more 8060 Background: SDZ-RTX (Rixathon) is approved in more than 20 countries and regions, including highly regulated markets e.g. Europe, Japan and Switzerland for all labeled indications of reference rituximab. REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with CD20+ DLBCL. This interim analysis adds up efficacy and additional safety results on the previously presented data (Welslau et al, ASCO and EHA 2019). Methods: Adult patients (pts) were treated with SDZ-RTX and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) according to the product label. The primary endpoint is to evaluate the effectiveness of Rixathon measured by complete response (CR) rate at the end of treatment. Secondary endpoints are overall response rate (ORR), progression-free survival at 24 months and adverse events (AEs). Data were collected at baseline and all scheduled treatment and follow-up visits, which is still ongoing. No imputation was made for missing values, and endpoints are summarized descriptively. Results: As of Sep 30, 2019, 170 pts were enrolled, and R-CHOP treatment was close to completion. The median age of pts was 70 years, and 52% were women. Overall, 38% of pts completed the first 12-month observation period, 41% were ongoing, while 21% of pts discontinued. Most of the pts (~80%) had an ECOG score of 0 (35%) or 1 (46%). Early staging (I–II2), low to intermediate disease risk (IPI 0-2), and known B symptoms were reported for 55%, 50%, and 30% of pts, respectively. CR rate at the end of treatment was 57% (defined as the revised response criteria for malignant lymphoma by Cheson et al, 2007 that excludes complete remission/unconfirmed [CRu]). Summary of efficacy is reported in the Table. Overall, 83% of pts experienced AEs, the most common being anemia (23%), fatigue (21%), and polyneuropathy (15%). Treatment-related AEs were reported for 28% of pts. Rates of any serious AEs (SAEs) and treatment-related SAEs were 37% and 6.5%, respectively. On-treatment deaths and all deaths were reported in 2.4% and 4.7% of pts, respectively. Conclusions: REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with DLBCL. This interim analysis results re-confirms the expected safety and efficacy profile for DLBCL patients treated with R-CHOP. [Table: see text]
Journal of Leukocyte Biology, Mar 1, 2002
Hematopoietic cells extend multiple podia of yet unknown function. Our morphological studies usin... more Hematopoietic cells extend multiple podia of yet unknown function. Our morphological studies using scanning electron microscopy and functional studies using time-lapse video microscopy suggest that podia formed by CD34؉ hematopoietic stem cells (HSC) on the bone marrow stroma component fibronectin are characteristic of lamellipodia at the leading edge and uropodia at the trailing edge, cytoskeletal structures that have previously been shown to be responsible for cell locomotion of lymphocytes. In the leukemic cells studied here, stroma-derived factor-1␣ (SDF-1␣) led to a significant eightfold increase in transmigration (BCR-ABL-positive BV173 leukemia cell line; P<0.05) and podia formation in all BCR-ABLpositive leukemic cell lines studied (BV173, K562, 32Dp210) and in two of three BCR-ABL-negative lines (HL60, 32D, not KG1a). We could show that SDF-1␣ exposure led to a down-regulation of the gene expression of the chemokine receptors CCR4, CXCR4, and CXCR5, which are associated with cell motility and podia formation, indicating a negative feedback control. In BCR-ABL-positive leukemic cells, the effects of SDF-1␣ on podia formation and cell migration were independent of BCR-ABL-tyrosine kinase activity. Our data are compatible with the hypothesis that formation of specific podia by hematopoietic cells is associated with egression of these cells from the bone marrow.
British Journal of Haematology, Jun 1, 1999
Peripheral blood progenitor cells (PBPC) can be mobilized using chemotherapy and granulocyte colo... more Peripheral blood progenitor cells (PBPC) can be mobilized using chemotherapy and granulocyte colony-stimulating factor (G-CSF). We and others previously reported a correlation of steady-state PBPC counts and the PBPC yield during mobilization in a small group of patients. Here we present data on 100 patients (patients: 25 non-Hodgkin's lymphoma (NHL), five Hodgkin's disease, 35 multiple myeloma (MM), 35 solid tumour) which enabled a detailed analysis of determinants of steady-state PBPC levels and of mobilization efficiency in patient subgroups. Previous irradiation (P = 0.0034) or previous chemotherapy in patients with haematological malignancies (P = 0.0062) led to a depletion of steady-state PB CD34+ cells. A correlation analysis showed steady-state PB CD34+ cells (all patients: r = 0.52, P < 0.0001; NHL patients, r = 0.69, P = 0.0003; MM patients: r = 0.66, P = 0.0001) and PB colony-forming cells can reliably assess the CD34+ cell yield in mobilized PB. In patients with solid tumour a similar trend was observed in mobilization after the first chemotherapy cycle (r = 0.51, P = 0.05) but not if mobilization occurred after the second or further cycle of a sequential dose-intensified G-CSF-supported chemotherapy regimen, when premobilization CD34+ counts were 18-fold elevated (P = 0.004). When the patients with MM (r = 0.63, P = 0.0008) or with NHL (r = 0.65, P = 0.006) were analysed separately, a highly significant correlation of the steady-state PB CD34+ cell count to the mean leukapheresis CD34+ cell yield was found, whereas no correlation was observed for patients with a solid tumour. For patients with haematological malignancies estimates could be calculated which, at a specific steady-state PB CD34+ cell count, could predict with a 95% probability a defined minimum progenitor cell yield. These results enable recognition of patients who mobilize PBPC poorly and may assist selection of patients for novel mobilization regimens.
PubMed, Jul 11, 2006
Background: Resistance to imatinib monotherapy frequently emerges in advanced stages of chronic m... more Background: Resistance to imatinib monotherapy frequently emerges in advanced stages of chronic myelogenous leukemia (CML), supporting the rationale for combination drug therapy. In the present study, the activities of the farnesyltransferase inhibitors (FTIs) L744,832 and LB42918, as single agents and in combination with imatinib, were investigated in different imatinib-sensitive and -resistant BCR-ABL-positive CML cells. Materials and methods: Growth inhibition of the cell lines and primary patient cells was assessed by MTT assays and colony-forming cell assays, respectively. Drug interactions were analyzed according to the median-effect method of Chou and Talalay. The determination of apoptotic cell death was performed by annexin V/propidium iodide staining. Results: Combinations of both FTIs with imatinib displayed synergism or sensitization (potentiation) in all the cell lines tested. In primary chronic phase CML cells, additive and synergistic effects were discernible for the combination of imatinib plus L744,832 and imatinib plus LB42918, respectively. Annexin V/propidium iodide staining showed enhancement of imatinib-induced apoptosis with either drug combination, both in imatinib-sensitive and -resistant cells. Conclusion: The results indicated the potential of L744,832 and LB42918 as combination agents for CML patients on imatinib treatment.
British Journal of Haematology, May 1, 2003
CROSS-RESISTANCE OF IMATINIB MESYLATE AND 17-AAG IN IMATINIB-RESISTANT CELLS THAT OVEREXPRESS BCR... more CROSS-RESISTANCE OF IMATINIB MESYLATE AND 17-AAG IN IMATINIB-RESISTANT CELLS THAT OVEREXPRESS BCR-ABL Imatinib mesylate (STI571, Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, is a breakthrough in the treatment of chronic myelogenous leukaemia (CML), as it is capable of producing very high rates of haematological and cytogenetic responses (Druker, 2002). However, in the advanced stages of CML, relapses are frequent after initial response, or primary resistance may be encountered (Sawyers et al, 2002). Point mutations of the BCR-ABL tyrosine kinase domain and an upregulation of the BCR-ABL protein with or without genomic amplification of the rearranged gene have been identified among the main mechanisms of imatinib mesylate resistance (Gorre et al, 2001; Hochhaus et al, 2002). Gorre et al (2001) reported recently that geldanamycin (GA) and its derivative 17-allylamino-geldanamycin (17-AAG), both blockers of the heat shock protein 90 (Hsp90), a chaperone of the BCR-ABL protein, are still active in cells rendered resistant to imatinib mesylate by introduction of point mutations into the BCR-ABL tyrosine kinase domain (Gorre et al, 2002). Strikingly, GA and 17-AAG were even more effective in cells carrying the mutated BCR-ABL protein compared with cells with its wild-type counterpart. However, the effect of 17-AAG on BCR-ABL-overexpressing cells was not reported. According to Hochhaus et al (2002), a > 10-fold increase of BCR-ABL transcripts was observed in seven out of 55 samples of imatinib-mesylate-resistant patients, representing a relevant proportion (about 13%) of resistant cases. We investigated the effect of 17-AAG in the CML cell lines K562 (imatinib-mesylate-sensitive parental cell line) and K562-r (imatinib-mesylate-resistant cell line overexpressing BCR-ABL, Fig 1A) and observed a clear cross-resistance between the two compounds, with significantly higher IC 50 values of both imatinib mesylate and 17-AAG in the K562-r cells after 48 h of incubation (Fig 1B). The phenomenon was probably due to the requirement of larger doses of 17-AAG for inhibition of Hsp90 in the presence of increased amounts of BCR-ABL protein. This means that therapy with 17-AAG alone may fail when imatinib mesylate resistance is caused by upregulation of BCR-ABL. Therefore, identification of the actual mechanism of resistance to imatinib mesylate in each patient should be mandatory prior to initiation of second-line therapy with 17-AAG.
Haematologica, 2005
Autologous transplantation after myeloablation for myelofibrosis with myeloid metaplasia provides... more Autologous transplantation after myeloablation for myelofibrosis with myeloid metaplasia provides a palliative therapy with a long term relief of symptoms. We have transplanted three patients with more than 5 x 10(6) CD34+ cells/kg body weight after myeloablation with treosulfan (total dose 42 g/m(2)) with a 18 months follow-up. Two of the patients had symptomatic splenomegaly and severe anemia. One patient had symptomatic splenomegaly and thrombocytopenia (&amp;amp;amp;lt; 100x10(9)/L). Granulocyte colony-stimulating factor-supported peripheral blood progenitor cell mobilization and collection was not associated with increased toxicity. Following transplantation we observed a prolonged reconstitution period of 28-38 days without fever or severe mucositis. All patients became free of erythrocyte transfusions or recovered to normal thrombocyte counts. There was a significant reduction of max. spleen size in one patient. We conclude that myeloablation with treosulfan and autologous PBPCT in these three patients with myelofibrosis was safe and useful.
Stem Cells, Jul 1, 2004
Methods to analyze the clonality of an adverse event in preclinical or clinical retroviral stem c... more Methods to analyze the clonality of an adverse event in preclinical or clinical retroviral stem cell gene therapy protocols are needed. We analyzed the progeny of retrovirally transduced human peripheral blood progenitor cells (PBPCs) after transplantation and engraftment in immune-deficient mice. The integration site of the provirus serves as a unique tag of the individual transduced PBPC. A plasmid library of junctions between proviral and human genomic DNA was generated. We were able to detect individual transduced cell clones that amounted to 0.14%-0.0001% of chimeric bone marrow cells. This is the first report in which the contribution of individual marrow-repopulating cells to human hematopoiesis is directly quantified.
Cytotherapy, 2005
Stem cell transplantation, whether autologous or allogeneic, improves the outcome of patients wit... more Stem cell transplantation, whether autologous or allogeneic, improves the outcome of patients with a number of hematologic malignancies or solid tumors. A relevant proportion of these patients are excluded from this treatment because sufficient numbers of hematopoietic stem cells cannot be obtained by standard cytokine-assisted mobilization. In this article we review the physiology of peripheral blood progenitor cell (PBPC) mobilization and discuss the role of adhesion molecules, such as integrins and selectins, chemokines and their ligands, such as SDF-1a and CXCR4, and proteolytic enzymes. Based on this knowledge, several innovative pharmacologic approaches have been proposed to boost the PBPC harvest. Some of them (CTCE, C3a receptor agonist and GrobT) are still subject of pre-clinical development, others, such as chemokine receptor ligand AMD3100, have recently been introduced in clinical trials and already deliver promising results. It appears possible to harvest PBPC successfully in poor mobilizers and to cut down the number of collections required in the remaining PBPC donors.
British Journal of Haematology, Oct 1, 2002
Chronic myelogenous leukaemia (CML) is the first malignancy in which knowledge about the pathomec... more Chronic myelogenous leukaemia (CML) is the first malignancy in which knowledge about the pathomechanisms of the disease has led to the development of a specific and highly effective molecular therapy. The first clinical trials with the tyrosine kinase inhibitor imatinib mesylate showed high response rates with minimal toxicity and raised hope for a possible ÔcureÕ of CML by drug therapy alone. However, not all patients show a complete response and even in responders relapses continue to occur, particularly in advanced phases of the disease. Combination therapy with imatinib and established or investigational antileukaemic agents may lead to an increase in the response rates and remission duration. This review summarizes relevant in vitro studies in the hope that translation of promising preclinical data into clinical trials will lead to further increases in the life expectancy of CML patients.
Leukemia, Mar 1, 2001
The ABL-specific tyrosine kinase inhibitor STI571 (formerly CGP57148B) induced cytogenetic remiss... more The ABL-specific tyrosine kinase inhibitor STI571 (formerly CGP57148B) induced cytogenetic remissions in 33% of chronic myelogenous leukemia (CML) patients in a phase I trial (Druker et al 1999). Combination therapy may increase this proportion. We tested whether combinations of STI571 and cytarabine or other chemotherapeutic agents such as hydroxyurea, mafosfamide or etoposide would display synergistic activity in BCR-ABL-positive chronic myelogenous leukemia (CML) cell lines derived from patients in blast crisis. In addition, the toxicity of these combinations on BCR-ABL-negative cells was investigated. A tetrazolium-based MTT assay was used to quantify growth inhibition after 48 h of exposure to cytotoxic agents alone and in simultaneous combination with STI571. The drug interactions were analyzed using the median-effect method of Chou and Talalay. The combination index (CI) was calculated according to the classic isobologram equation. At growth inhibition levels of over 50%, STI571 + cytarabine as well as STI571 + etoposide were significantly synergistic (CI Ͻ 1, P Ͻ 0.05) in the BCR-ABL-positive cell lines evaluated. At 60% inhibition or higher, a similar synergistic pattern became apparent for STI571 + mafosfamide (P Ͻ 0.05), while STI571 + hydroxyurea showed ambiguous, cell line-dependent synergism (BV173), additivity (EM-3) or antagonism (K562) in CML cell lines. Furthermore, the BCR-ABL-negative HL-60, KG1a and normal CD34 + progenitor cells were not affected by 0.8 M STI571, a concentration which produced more than 50% growth inhibition in all BCR-ABL-positive cells tested, and no potentiation of growth inhibition was observed in these BCR-ABL-negative cells when STI571 was combined with chemotherapeutic agents. Our in vitro data with CML blast crisis cell lines strongly suggest that combinations of STI571 with cytarabine or etoposide be rapidly considered for clinical testing. Leukemia (2001) 15, 342-347.
Blood, Nov 16, 2005
Autologous peripheral blood stem cell (PBSC) transplantation leads to significant prolongation of... more Autologous peripheral blood stem cell (PBSC) transplantation leads to significant prolongation of survival in patients with different malignancies. For PBSC mobilization a combination of myelosuppressive chemotherapy and granulocyte colony stimulating factor (G-CSF) are administered. The optimal application of G-CSF is twice daily. New G-CSF formulations with prolonged half-life carry the promise of reduced patient strain, increased compliance and via continuously high G-CSF serum levels possibly improved PBSC mobilization. We initiated a study with pegfilgrastim-supported mobilization chemotherapy in stage II and III myeloma patients. Patients received up-front treatment with three cycles of vincristin, doxorubicin, dexamethason (VAD) or thalidomide, doxorubicin, dexamethason (TAD). The mobilization regime consisted of four days chemotherapy with cyclophosphamide 1g/m2 day1, doxorubicin 15mg/m2 day 1–4, dexamethason 40 mg d 1–4 p.o. (CAD) and a single administration of 12 mg pegfilgrastim subcutaneously on day five. 25 patients (median age 57, 12 female, 13 male) received pegfilgrastim and leukapheresis was started 6–17 days (mean 10 days) after treatment with a range of maximum CD34 cell count between 7,2 and 842 (mean: 119) CD34+ cells/μl peripheral blood. After leukapheresis 6.2 * 10e6 to 40.5 * 10e6 (mean 13.8 *10e6) CD34+ cells per kilogram body weight were collected. 11 patients achieved the target number of 7.5 * 10e6 CD34+ cells per kilogram body weight during a single apheresis, while 5 patients needed two, 7 patients needed three and 2 patients needed four apheresies on consecutive days. 3 patients required additional administration of filgrastim. 2 patients received 6 mg pegfilgrastim off study. Both achieved sufficient numbers of CD34+ cells (12.7 and 20.8 * 10e6 CD34+ per kg BW). There were only minimal adverse effects. Four patients reported of bone pain or nausea. Mobilization failures did not occur in this patient population. To date, 16 patients have been transplanted with a mean of 6,03* 10e6 CD34+ per kg BW (range 2,4 to 13,5). Reconstitution (reaching a leukocyte count of &amp;amp;amp;gt;1,0/nl) was reached within a mean of 13 days (range 11–21). On the basis of these first results we conclude that a single dose application of 12 mg pegfilgrastim after CAD treatment allows collection of more than 3 autografts in two or less apheresis session in the majority of myeloma patients. Reduction of apheresis sessions is a significant clinical cost-effectiveness end point in PBPC mobilization.
Annals of Hematology, May 25, 2001
In the conventionally treated group of patients with chronic myelogenous leukemia (CML) the progn... more In the conventionally treated group of patients with chronic myelogenous leukemia (CML) the prognosis has been significantly improved by interferon-α (IFN-α). Several side effects in association with IFN-α treatment have been reported. Here we present the first case of a CML patient with reversible pulmonary artery hypertension (PAH) during IFN-α therapy. The patient received IFN-α-2b (up to 10 million U/day) for 6 months until he started to complain of dyspnea on exertion and an afebrile non-productive cough. An echocardiography and right heart catheterization showed signs of right heart failure with PAH (80 mmHg). A reduced carbon monoxide diffusion capacity and partial respiratory insufficiency were noted. Inflammatory markers were not elevated and pulmonary infiltrates could not be detected. Respiratory infections, thromboembolic causes or autoimmune diseases were carefully ruled out. IFN-α was suspected as causative agent, because experimental investigations in sheep showed that IFN-α can stimulate the thromboxane cascade which resulted in transient PAH. A reduced pulmonary diffusion capacity had been observed secondary to PAH. After discontinuation of IFN-α, our patient's clinical status improved rapidly. After 6 months the pulmonary artery pressure had returned to near normal values (35 mmHg) and the pulmonary diffusion capacity was normal. It took one year until the electrocardiogram reverted to the pre-IFN-α pattern. PAH should be included in the differential diagnosis of patients treated with IFN-α who complain of exertional dyspnea in the absence of inflammatory signs.
Leukemia & Lymphoma, 2002
Rituximab (IDEC C2B8) is a chimeric human-mouse monoclonal anti-CD20 antibody that has been prove... more Rituximab (IDEC C2B8) is a chimeric human-mouse monoclonal anti-CD20 antibody that has been proven to be effective for the treatment of patients with CD20 positive leukemia and lymphoma. The level of CD20-expression in patients with B-cell chronic lymphocytic leukemia (B-CLL) is low in comparison to other B-cell lymphomas and normal B-cells. Previous experience with rituximab treatment in small series of patients with B-CLL suggest that it is less effective in B-CLL than in follicular lymphomas. We analyzed the correlation between CD20-expression level and efficacy of rituximab treatment in eight patients with refractory or relapsed B-CLL and two patients with B-cell prolymphocytic leukemia (B-PLL). We could not identify any correlation between CD20-expression and efficacy of rituximab treatment.
Blood, Nov 16, 2005
In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to r... more In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to result in better reduction of leukemia cell load and may delay or offset clonal selection of resistant leukemia cells, thus improving the survival. We carried out a prospective phase I/II combination trial for patients (pts) with myeloid blast crisis of chronic myelogenous leukemia (CML). Pts were treated with imatinib+mitoxantrone/etoposide in four cohorts starting from mitoxantrone 10mg/m2/d and etoposide 100 mg/m2/d for 2 or 3 consecutive days and start of imatinib 600mg/d from day 15 (coh. 1 and 2) or from day 1 (coh. 3 and 4, respectively). After hematologic reconstitution following the cytopenic phase, cytarabine was administered at a dose of 10mg/m2/d s.c. in addition to imatinib as maintenance treatment. A total of 16 pts (8 m, 8 f) are available for analysis, median age 59 years (range 37–74). All pts who received more intensive induction treatment (coh. 3 and 4, n=7) achieved a hematologic response (HR). In contrast, HR was achieved in 6 of 9 pts treated in coh. 1 and 2. The induction treatment was well tolerated with a treatment-related mortality rate of 12.5% (1 intracranial hemorrhage in coh. 1, and 1 pneumonia in coh. 4). A median of 8 (2–18) red blood cell concentrates and a median of 5 (1–8) platelet concentrates were required. Antibiotic treatment for febrile episodes was administered for a median of 10d (0–38). Of note, CTC grade 3 or grade 4 mucositis did not occur. Pts who received imatinib on day 1 (coh. 3–4) had a longer duration of severe leukopenia (WBC &amp;lt;1/nl) with a median of 19 days (0–23) vs. 2 (0–14) but without increase of infection incidence. Six pts who achieved HR received an allogeneic stem cell transplantation with myeloablative conditioning. Three of 6 transplanted patients are alive and in complete cytogenetic remission at 735, 723, and 279 days after initiation of study treatment. Two patients died of transplant-related complications (GvHD and sepsis), 1 patient died from hematologic relapse. Of 10 pts who received only conventional treatment, 1 (coh. 1) is still alive and in a complete cytogenetic remission at day 1280 after initiation of study treatment. Median survival of transplanted pts was 486 days, and 142 days in the group with conventional treatment only (p=0.078). We conclude that the combination of mitoxantrone/etoposide and imatinib is a well tolerated induction protocol with mild non-hematological toxicity even in older patients. Eligible pts have an advantage from an allogeneic stem cell transplantation following response to the induction treatment.
Cytotherapy, 2009
Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow-derived cells.... more Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow-derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (ckit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow-derived angiogenesis, thus improving neuronal survival and functional outcome.
Hematological Oncology, Jun 1, 2019
Introduction: Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL) is ra... more Introduction: Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL) is rare but is associated with poor outcomes. The majority of CNS relapses in DLBCL occur in the brain parenchyma and are therefore unlikely to be prevented by intrathecal prophylaxis. There is increasing evidence to support use of high dose intravenous methotrexate (HDMTX) as a prophylactic regimen in selected highrisk patients. As most CNS relapses occur early in the disease course, ideally prophylaxis should be delivered as early as possible. There remains concern that HD MTX carries a risk of toxicity, especially renal, which could result in delays to systemic chemotherapy if delivered in an intercalated fashion. We performed a single centre, retrospective analysis of 45 patients who received HDMTX intercalated with R-CHOP chemotherapy with a focus on toxicity rates and subsequent delays in systemic therapy. Methods: 45 consecutive patients receiving HDMTX as CNS prophylaxis alongside R-CHOP chemotherapy for HIV negative DLBCL between 2012-2018 were identified and medical records analysed for toxicity rates, timing of chemotherapy cycles and evidence of CNS relapse. 60% were male (n=27) and median age was 60 years (range 37y-80y). The majority (78%) had stage IV disease and the median CNS IPI was 3, with 31% (n=14) falling in the high risk (4-6) CNS IPI group. Patients with known CNS disease at presentation were excluded. Local guidelines stipulated that 2 cycles of HDMTX at 3g/m2 should be delivered at day 14 following the R-CHOP courses 2 and 3. Results: 73% (n=33) received at least 2 cycles of MTX. Reasons for only delivering 1 cycle of MTX in 12 patients were patient fitness/frailty (n=7), renal toxicity (n=2) and mucositis (n=3). 5 (11%) patients experienced renal toxicity according to CTCAE definitions (3 = grade 2, 2 = grade 3). All patients had recovery of renal function without the need for invasive intervention. Mucositis occurred in 13 (29%) patients (grading not recorded). Hepatotoxicity was seen in 2/45 (4%) patients. 80 cycles of HD MTX were delivered in total. Neutrophil count on the scheduled day of subsequent RCHOP chemotherapy was >1.0 in 73/80 (91%) cycles. 5/45 (11%) patients experienced a delay of subsequent R-CHOP chemotherapy (7 or more days) directly attributable to methotrexate. 3/45 (7%) of patients suffered CNS relapse with median follow up of 32 monthsall relapses were parenchymal and 2/3 had only received 1 cycle HDMTX. Discussion: This retrospective analysis demonstrates that HDMTX can be delivered intercalated with R-CHOP chemotherapy with acceptable rates of toxicity and few delays in systemic chemotherapy. The rate of renal toxicity was low and was reversible in all patients. Although the numbers are small, the rate of CNS relapse (7%) was low in this selected, high-risk group. Careful assessment of patient fitness is required prior to consideration of HDMTX, but the median age of 60 years in our study suggests that age alone should not be a barrier to delivering this treatment.
Journal of Clinical Oncology, May 20, 2020
8060 Background: SDZ-RTX (Rixathon) is approved in more than 20 countries and regions, including ... more 8060 Background: SDZ-RTX (Rixathon) is approved in more than 20 countries and regions, including highly regulated markets e.g. Europe, Japan and Switzerland for all labeled indications of reference rituximab. REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with CD20+ DLBCL. This interim analysis adds up efficacy and additional safety results on the previously presented data (Welslau et al, ASCO and EHA 2019). Methods: Adult patients (pts) were treated with SDZ-RTX and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) according to the product label. The primary endpoint is to evaluate the effectiveness of Rixathon measured by complete response (CR) rate at the end of treatment. Secondary endpoints are overall response rate (ORR), progression-free survival at 24 months and adverse events (AEs). Data were collected at baseline and all scheduled treatment and follow-up visits, which is still ongoing. No imputation was made for missing values, and endpoints are summarized descriptively. Results: As of Sep 30, 2019, 170 pts were enrolled, and R-CHOP treatment was close to completion. The median age of pts was 70 years, and 52% were women. Overall, 38% of pts completed the first 12-month observation period, 41% were ongoing, while 21% of pts discontinued. Most of the pts (~80%) had an ECOG score of 0 (35%) or 1 (46%). Early staging (I–II2), low to intermediate disease risk (IPI 0-2), and known B symptoms were reported for 55%, 50%, and 30% of pts, respectively. CR rate at the end of treatment was 57% (defined as the revised response criteria for malignant lymphoma by Cheson et al, 2007 that excludes complete remission/unconfirmed [CRu]). Summary of efficacy is reported in the Table. Overall, 83% of pts experienced AEs, the most common being anemia (23%), fatigue (21%), and polyneuropathy (15%). Treatment-related AEs were reported for 28% of pts. Rates of any serious AEs (SAEs) and treatment-related SAEs were 37% and 6.5%, respectively. On-treatment deaths and all deaths were reported in 2.4% and 4.7% of pts, respectively. Conclusions: REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with DLBCL. This interim analysis results re-confirms the expected safety and efficacy profile for DLBCL patients treated with R-CHOP. [Table: see text]
Journal of Leukocyte Biology, Mar 1, 2002
Hematopoietic cells extend multiple podia of yet unknown function. Our morphological studies usin... more Hematopoietic cells extend multiple podia of yet unknown function. Our morphological studies using scanning electron microscopy and functional studies using time-lapse video microscopy suggest that podia formed by CD34؉ hematopoietic stem cells (HSC) on the bone marrow stroma component fibronectin are characteristic of lamellipodia at the leading edge and uropodia at the trailing edge, cytoskeletal structures that have previously been shown to be responsible for cell locomotion of lymphocytes. In the leukemic cells studied here, stroma-derived factor-1␣ (SDF-1␣) led to a significant eightfold increase in transmigration (BCR-ABL-positive BV173 leukemia cell line; P<0.05) and podia formation in all BCR-ABLpositive leukemic cell lines studied (BV173, K562, 32Dp210) and in two of three BCR-ABL-negative lines (HL60, 32D, not KG1a). We could show that SDF-1␣ exposure led to a down-regulation of the gene expression of the chemokine receptors CCR4, CXCR4, and CXCR5, which are associated with cell motility and podia formation, indicating a negative feedback control. In BCR-ABL-positive leukemic cells, the effects of SDF-1␣ on podia formation and cell migration were independent of BCR-ABL-tyrosine kinase activity. Our data are compatible with the hypothesis that formation of specific podia by hematopoietic cells is associated with egression of these cells from the bone marrow.
British Journal of Haematology, Jun 1, 1999
Peripheral blood progenitor cells (PBPC) can be mobilized using chemotherapy and granulocyte colo... more Peripheral blood progenitor cells (PBPC) can be mobilized using chemotherapy and granulocyte colony-stimulating factor (G-CSF). We and others previously reported a correlation of steady-state PBPC counts and the PBPC yield during mobilization in a small group of patients. Here we present data on 100 patients (patients: 25 non-Hodgkin's lymphoma (NHL), five Hodgkin's disease, 35 multiple myeloma (MM), 35 solid tumour) which enabled a detailed analysis of determinants of steady-state PBPC levels and of mobilization efficiency in patient subgroups. Previous irradiation (P = 0.0034) or previous chemotherapy in patients with haematological malignancies (P = 0.0062) led to a depletion of steady-state PB CD34+ cells. A correlation analysis showed steady-state PB CD34+ cells (all patients: r = 0.52, P < 0.0001; NHL patients, r = 0.69, P = 0.0003; MM patients: r = 0.66, P = 0.0001) and PB colony-forming cells can reliably assess the CD34+ cell yield in mobilized PB. In patients with solid tumour a similar trend was observed in mobilization after the first chemotherapy cycle (r = 0.51, P = 0.05) but not if mobilization occurred after the second or further cycle of a sequential dose-intensified G-CSF-supported chemotherapy regimen, when premobilization CD34+ counts were 18-fold elevated (P = 0.004). When the patients with MM (r = 0.63, P = 0.0008) or with NHL (r = 0.65, P = 0.006) were analysed separately, a highly significant correlation of the steady-state PB CD34+ cell count to the mean leukapheresis CD34+ cell yield was found, whereas no correlation was observed for patients with a solid tumour. For patients with haematological malignancies estimates could be calculated which, at a specific steady-state PB CD34+ cell count, could predict with a 95% probability a defined minimum progenitor cell yield. These results enable recognition of patients who mobilize PBPC poorly and may assist selection of patients for novel mobilization regimens.
PubMed, Jul 11, 2006
Background: Resistance to imatinib monotherapy frequently emerges in advanced stages of chronic m... more Background: Resistance to imatinib monotherapy frequently emerges in advanced stages of chronic myelogenous leukemia (CML), supporting the rationale for combination drug therapy. In the present study, the activities of the farnesyltransferase inhibitors (FTIs) L744,832 and LB42918, as single agents and in combination with imatinib, were investigated in different imatinib-sensitive and -resistant BCR-ABL-positive CML cells. Materials and methods: Growth inhibition of the cell lines and primary patient cells was assessed by MTT assays and colony-forming cell assays, respectively. Drug interactions were analyzed according to the median-effect method of Chou and Talalay. The determination of apoptotic cell death was performed by annexin V/propidium iodide staining. Results: Combinations of both FTIs with imatinib displayed synergism or sensitization (potentiation) in all the cell lines tested. In primary chronic phase CML cells, additive and synergistic effects were discernible for the combination of imatinib plus L744,832 and imatinib plus LB42918, respectively. Annexin V/propidium iodide staining showed enhancement of imatinib-induced apoptosis with either drug combination, both in imatinib-sensitive and -resistant cells. Conclusion: The results indicated the potential of L744,832 and LB42918 as combination agents for CML patients on imatinib treatment.
British Journal of Haematology, May 1, 2003
CROSS-RESISTANCE OF IMATINIB MESYLATE AND 17-AAG IN IMATINIB-RESISTANT CELLS THAT OVEREXPRESS BCR... more CROSS-RESISTANCE OF IMATINIB MESYLATE AND 17-AAG IN IMATINIB-RESISTANT CELLS THAT OVEREXPRESS BCR-ABL Imatinib mesylate (STI571, Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, is a breakthrough in the treatment of chronic myelogenous leukaemia (CML), as it is capable of producing very high rates of haematological and cytogenetic responses (Druker, 2002). However, in the advanced stages of CML, relapses are frequent after initial response, or primary resistance may be encountered (Sawyers et al, 2002). Point mutations of the BCR-ABL tyrosine kinase domain and an upregulation of the BCR-ABL protein with or without genomic amplification of the rearranged gene have been identified among the main mechanisms of imatinib mesylate resistance (Gorre et al, 2001; Hochhaus et al, 2002). Gorre et al (2001) reported recently that geldanamycin (GA) and its derivative 17-allylamino-geldanamycin (17-AAG), both blockers of the heat shock protein 90 (Hsp90), a chaperone of the BCR-ABL protein, are still active in cells rendered resistant to imatinib mesylate by introduction of point mutations into the BCR-ABL tyrosine kinase domain (Gorre et al, 2002). Strikingly, GA and 17-AAG were even more effective in cells carrying the mutated BCR-ABL protein compared with cells with its wild-type counterpart. However, the effect of 17-AAG on BCR-ABL-overexpressing cells was not reported. According to Hochhaus et al (2002), a > 10-fold increase of BCR-ABL transcripts was observed in seven out of 55 samples of imatinib-mesylate-resistant patients, representing a relevant proportion (about 13%) of resistant cases. We investigated the effect of 17-AAG in the CML cell lines K562 (imatinib-mesylate-sensitive parental cell line) and K562-r (imatinib-mesylate-resistant cell line overexpressing BCR-ABL, Fig 1A) and observed a clear cross-resistance between the two compounds, with significantly higher IC 50 values of both imatinib mesylate and 17-AAG in the K562-r cells after 48 h of incubation (Fig 1B). The phenomenon was probably due to the requirement of larger doses of 17-AAG for inhibition of Hsp90 in the presence of increased amounts of BCR-ABL protein. This means that therapy with 17-AAG alone may fail when imatinib mesylate resistance is caused by upregulation of BCR-ABL. Therefore, identification of the actual mechanism of resistance to imatinib mesylate in each patient should be mandatory prior to initiation of second-line therapy with 17-AAG.
Haematologica, 2005
Autologous transplantation after myeloablation for myelofibrosis with myeloid metaplasia provides... more Autologous transplantation after myeloablation for myelofibrosis with myeloid metaplasia provides a palliative therapy with a long term relief of symptoms. We have transplanted three patients with more than 5 x 10(6) CD34+ cells/kg body weight after myeloablation with treosulfan (total dose 42 g/m(2)) with a 18 months follow-up. Two of the patients had symptomatic splenomegaly and severe anemia. One patient had symptomatic splenomegaly and thrombocytopenia (&amp;amp;amp;lt; 100x10(9)/L). Granulocyte colony-stimulating factor-supported peripheral blood progenitor cell mobilization and collection was not associated with increased toxicity. Following transplantation we observed a prolonged reconstitution period of 28-38 days without fever or severe mucositis. All patients became free of erythrocyte transfusions or recovered to normal thrombocyte counts. There was a significant reduction of max. spleen size in one patient. We conclude that myeloablation with treosulfan and autologous PBPCT in these three patients with myelofibrosis was safe and useful.
Stem Cells, Jul 1, 2004
Methods to analyze the clonality of an adverse event in preclinical or clinical retroviral stem c... more Methods to analyze the clonality of an adverse event in preclinical or clinical retroviral stem cell gene therapy protocols are needed. We analyzed the progeny of retrovirally transduced human peripheral blood progenitor cells (PBPCs) after transplantation and engraftment in immune-deficient mice. The integration site of the provirus serves as a unique tag of the individual transduced PBPC. A plasmid library of junctions between proviral and human genomic DNA was generated. We were able to detect individual transduced cell clones that amounted to 0.14%-0.0001% of chimeric bone marrow cells. This is the first report in which the contribution of individual marrow-repopulating cells to human hematopoiesis is directly quantified.
Cytotherapy, 2005
Stem cell transplantation, whether autologous or allogeneic, improves the outcome of patients wit... more Stem cell transplantation, whether autologous or allogeneic, improves the outcome of patients with a number of hematologic malignancies or solid tumors. A relevant proportion of these patients are excluded from this treatment because sufficient numbers of hematopoietic stem cells cannot be obtained by standard cytokine-assisted mobilization. In this article we review the physiology of peripheral blood progenitor cell (PBPC) mobilization and discuss the role of adhesion molecules, such as integrins and selectins, chemokines and their ligands, such as SDF-1a and CXCR4, and proteolytic enzymes. Based on this knowledge, several innovative pharmacologic approaches have been proposed to boost the PBPC harvest. Some of them (CTCE, C3a receptor agonist and GrobT) are still subject of pre-clinical development, others, such as chemokine receptor ligand AMD3100, have recently been introduced in clinical trials and already deliver promising results. It appears possible to harvest PBPC successfully in poor mobilizers and to cut down the number of collections required in the remaining PBPC donors.
British Journal of Haematology, Oct 1, 2002
Chronic myelogenous leukaemia (CML) is the first malignancy in which knowledge about the pathomec... more Chronic myelogenous leukaemia (CML) is the first malignancy in which knowledge about the pathomechanisms of the disease has led to the development of a specific and highly effective molecular therapy. The first clinical trials with the tyrosine kinase inhibitor imatinib mesylate showed high response rates with minimal toxicity and raised hope for a possible ÔcureÕ of CML by drug therapy alone. However, not all patients show a complete response and even in responders relapses continue to occur, particularly in advanced phases of the disease. Combination therapy with imatinib and established or investigational antileukaemic agents may lead to an increase in the response rates and remission duration. This review summarizes relevant in vitro studies in the hope that translation of promising preclinical data into clinical trials will lead to further increases in the life expectancy of CML patients.
Leukemia, Mar 1, 2001
The ABL-specific tyrosine kinase inhibitor STI571 (formerly CGP57148B) induced cytogenetic remiss... more The ABL-specific tyrosine kinase inhibitor STI571 (formerly CGP57148B) induced cytogenetic remissions in 33% of chronic myelogenous leukemia (CML) patients in a phase I trial (Druker et al 1999). Combination therapy may increase this proportion. We tested whether combinations of STI571 and cytarabine or other chemotherapeutic agents such as hydroxyurea, mafosfamide or etoposide would display synergistic activity in BCR-ABL-positive chronic myelogenous leukemia (CML) cell lines derived from patients in blast crisis. In addition, the toxicity of these combinations on BCR-ABL-negative cells was investigated. A tetrazolium-based MTT assay was used to quantify growth inhibition after 48 h of exposure to cytotoxic agents alone and in simultaneous combination with STI571. The drug interactions were analyzed using the median-effect method of Chou and Talalay. The combination index (CI) was calculated according to the classic isobologram equation. At growth inhibition levels of over 50%, STI571 + cytarabine as well as STI571 + etoposide were significantly synergistic (CI Ͻ 1, P Ͻ 0.05) in the BCR-ABL-positive cell lines evaluated. At 60% inhibition or higher, a similar synergistic pattern became apparent for STI571 + mafosfamide (P Ͻ 0.05), while STI571 + hydroxyurea showed ambiguous, cell line-dependent synergism (BV173), additivity (EM-3) or antagonism (K562) in CML cell lines. Furthermore, the BCR-ABL-negative HL-60, KG1a and normal CD34 + progenitor cells were not affected by 0.8 M STI571, a concentration which produced more than 50% growth inhibition in all BCR-ABL-positive cells tested, and no potentiation of growth inhibition was observed in these BCR-ABL-negative cells when STI571 was combined with chemotherapeutic agents. Our in vitro data with CML blast crisis cell lines strongly suggest that combinations of STI571 with cytarabine or etoposide be rapidly considered for clinical testing. Leukemia (2001) 15, 342-347.
Blood, Nov 16, 2005
Autologous peripheral blood stem cell (PBSC) transplantation leads to significant prolongation of... more Autologous peripheral blood stem cell (PBSC) transplantation leads to significant prolongation of survival in patients with different malignancies. For PBSC mobilization a combination of myelosuppressive chemotherapy and granulocyte colony stimulating factor (G-CSF) are administered. The optimal application of G-CSF is twice daily. New G-CSF formulations with prolonged half-life carry the promise of reduced patient strain, increased compliance and via continuously high G-CSF serum levels possibly improved PBSC mobilization. We initiated a study with pegfilgrastim-supported mobilization chemotherapy in stage II and III myeloma patients. Patients received up-front treatment with three cycles of vincristin, doxorubicin, dexamethason (VAD) or thalidomide, doxorubicin, dexamethason (TAD). The mobilization regime consisted of four days chemotherapy with cyclophosphamide 1g/m2 day1, doxorubicin 15mg/m2 day 1–4, dexamethason 40 mg d 1–4 p.o. (CAD) and a single administration of 12 mg pegfilgrastim subcutaneously on day five. 25 patients (median age 57, 12 female, 13 male) received pegfilgrastim and leukapheresis was started 6–17 days (mean 10 days) after treatment with a range of maximum CD34 cell count between 7,2 and 842 (mean: 119) CD34+ cells/μl peripheral blood. After leukapheresis 6.2 * 10e6 to 40.5 * 10e6 (mean 13.8 *10e6) CD34+ cells per kilogram body weight were collected. 11 patients achieved the target number of 7.5 * 10e6 CD34+ cells per kilogram body weight during a single apheresis, while 5 patients needed two, 7 patients needed three and 2 patients needed four apheresies on consecutive days. 3 patients required additional administration of filgrastim. 2 patients received 6 mg pegfilgrastim off study. Both achieved sufficient numbers of CD34+ cells (12.7 and 20.8 * 10e6 CD34+ per kg BW). There were only minimal adverse effects. Four patients reported of bone pain or nausea. Mobilization failures did not occur in this patient population. To date, 16 patients have been transplanted with a mean of 6,03* 10e6 CD34+ per kg BW (range 2,4 to 13,5). Reconstitution (reaching a leukocyte count of &amp;amp;amp;gt;1,0/nl) was reached within a mean of 13 days (range 11–21). On the basis of these first results we conclude that a single dose application of 12 mg pegfilgrastim after CAD treatment allows collection of more than 3 autografts in two or less apheresis session in the majority of myeloma patients. Reduction of apheresis sessions is a significant clinical cost-effectiveness end point in PBPC mobilization.
Annals of Hematology, May 25, 2001
In the conventionally treated group of patients with chronic myelogenous leukemia (CML) the progn... more In the conventionally treated group of patients with chronic myelogenous leukemia (CML) the prognosis has been significantly improved by interferon-α (IFN-α). Several side effects in association with IFN-α treatment have been reported. Here we present the first case of a CML patient with reversible pulmonary artery hypertension (PAH) during IFN-α therapy. The patient received IFN-α-2b (up to 10 million U/day) for 6 months until he started to complain of dyspnea on exertion and an afebrile non-productive cough. An echocardiography and right heart catheterization showed signs of right heart failure with PAH (80 mmHg). A reduced carbon monoxide diffusion capacity and partial respiratory insufficiency were noted. Inflammatory markers were not elevated and pulmonary infiltrates could not be detected. Respiratory infections, thromboembolic causes or autoimmune diseases were carefully ruled out. IFN-α was suspected as causative agent, because experimental investigations in sheep showed that IFN-α can stimulate the thromboxane cascade which resulted in transient PAH. A reduced pulmonary diffusion capacity had been observed secondary to PAH. After discontinuation of IFN-α, our patient's clinical status improved rapidly. After 6 months the pulmonary artery pressure had returned to near normal values (35 mmHg) and the pulmonary diffusion capacity was normal. It took one year until the electrocardiogram reverted to the pre-IFN-α pattern. PAH should be included in the differential diagnosis of patients treated with IFN-α who complain of exertional dyspnea in the absence of inflammatory signs.
Leukemia & Lymphoma, 2002
Rituximab (IDEC C2B8) is a chimeric human-mouse monoclonal anti-CD20 antibody that has been prove... more Rituximab (IDEC C2B8) is a chimeric human-mouse monoclonal anti-CD20 antibody that has been proven to be effective for the treatment of patients with CD20 positive leukemia and lymphoma. The level of CD20-expression in patients with B-cell chronic lymphocytic leukemia (B-CLL) is low in comparison to other B-cell lymphomas and normal B-cells. Previous experience with rituximab treatment in small series of patients with B-CLL suggest that it is less effective in B-CLL than in follicular lymphomas. We analyzed the correlation between CD20-expression level and efficacy of rituximab treatment in eight patients with refractory or relapsed B-CLL and two patients with B-cell prolymphocytic leukemia (B-PLL). We could not identify any correlation between CD20-expression and efficacy of rituximab treatment.
Blood, Nov 16, 2005
In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to r... more In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to result in better reduction of leukemia cell load and may delay or offset clonal selection of resistant leukemia cells, thus improving the survival. We carried out a prospective phase I/II combination trial for patients (pts) with myeloid blast crisis of chronic myelogenous leukemia (CML). Pts were treated with imatinib+mitoxantrone/etoposide in four cohorts starting from mitoxantrone 10mg/m2/d and etoposide 100 mg/m2/d for 2 or 3 consecutive days and start of imatinib 600mg/d from day 15 (coh. 1 and 2) or from day 1 (coh. 3 and 4, respectively). After hematologic reconstitution following the cytopenic phase, cytarabine was administered at a dose of 10mg/m2/d s.c. in addition to imatinib as maintenance treatment. A total of 16 pts (8 m, 8 f) are available for analysis, median age 59 years (range 37–74). All pts who received more intensive induction treatment (coh. 3 and 4, n=7) achieved a hematologic response (HR). In contrast, HR was achieved in 6 of 9 pts treated in coh. 1 and 2. The induction treatment was well tolerated with a treatment-related mortality rate of 12.5% (1 intracranial hemorrhage in coh. 1, and 1 pneumonia in coh. 4). A median of 8 (2–18) red blood cell concentrates and a median of 5 (1–8) platelet concentrates were required. Antibiotic treatment for febrile episodes was administered for a median of 10d (0–38). Of note, CTC grade 3 or grade 4 mucositis did not occur. Pts who received imatinib on day 1 (coh. 3–4) had a longer duration of severe leukopenia (WBC &amp;lt;1/nl) with a median of 19 days (0–23) vs. 2 (0–14) but without increase of infection incidence. Six pts who achieved HR received an allogeneic stem cell transplantation with myeloablative conditioning. Three of 6 transplanted patients are alive and in complete cytogenetic remission at 735, 723, and 279 days after initiation of study treatment. Two patients died of transplant-related complications (GvHD and sepsis), 1 patient died from hematologic relapse. Of 10 pts who received only conventional treatment, 1 (coh. 1) is still alive and in a complete cytogenetic remission at day 1280 after initiation of study treatment. Median survival of transplanted pts was 486 days, and 142 days in the group with conventional treatment only (p=0.078). We conclude that the combination of mitoxantrone/etoposide and imatinib is a well tolerated induction protocol with mild non-hematological toxicity even in older patients. Eligible pts have an advantage from an allogeneic stem cell transplantation following response to the induction treatment.