Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 19 recordsLinked to original sources

PubMed1999

Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission.

Acute myeloid leukemia arises from the clonal expansion of a malignant transformed progenitor cell. Despite intensive chemotherapy, final disease eradication is achieved by a small proportion of cases only and 50-70% of adults with AML will ultimately relapse and die from their disease. Hence residual disease below the level of morphological detectability must be assumed in clinical and morphological complete remission. CD34+/CD38- and CD34+/CD38+ subpopulations of seven patients in morphological complete remission were isolated by FACS (purity >98%) and were analyzed by conventional cytogenetics or FISH for chromosomal aberrations. In five of seven patients, clonal chromosomal abnormalities were detected in the CD34+/CD38+ subpopulation and in one patient with AML M2 (add (2)(q37)) in the most immature CD34+/CD38- stem cell compartment. One patient with AML M4Eo (inv(16),+8), showed a normal karyotype by conventional cytogenetic analysis, whereas four of 15 metaphases of the sorted CD34+/CD38+ subpopulation revealed the inversion 16. These observations underline that leukemic cells can survive intensive chemotherapy in the niche of the stem cell compartment. In some patients the sensitivity for the detection of persistent leukemic cells seems to be higher in FACS-sorted subpopulations than conventional cytogenetic analysis of the unseparated bone marrow. Immunophenotyping revealed minimal residual disease in four of the patients. Functional analysis has to be performed to investigate the leukemogenic potential of these residual cells.

ADP-ribosyl Cyclase↗

PubMed1999

Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenström's macroglobulinemia, and mantle-cell lymphoma.

PURPOSE: Fludarabine phosphate (F-AMP) has significant activity in follicular lymphoma and in B-cell chronic lymphatic leukemia, where it has demonstrated high complete response (CR) rates. Lymphoplasmacytoid (LPC) lymphoma, Waldenstrom's macroglobulinemia (WM), and mantle-cell lymphoma (MCL) also present with advanced-stage disease and are incurable with standard alkylator-based chemotherapy. A phase II trial was undertaken to determine the activity of F-AMP in patients newly diagnosed with these diseases. PATIENTS AND METHODS: Between 1992 and 1996, 78 patients (aged 18 to 75 years) received intravenous F-AMP (25 mg/m2/d for 5 days, every 4 weeks) until maximum response, plus two further cycles as consolidation. The primary end point was response rate; secondary end points included time to progression (TTP), duration of response, and overall survival (OS). RESULTS: Forty-four (62%) of 71 assessable patients had a response to F-AMP (LPC lymphoma, 63%; WM, 79%; MCL, 41%); the CR rate was 15%. At a median follow-up of 1.5 years, 19 of 44 responding patients have had progression of lymphoma; the median duration of response was 2.5 years. The median survival has not yet been reached. There was no significant difference in the duration of response or OS between patients with different histologies; TTP was shorter in patients with MCL (P = .015). Myelosuppression was relatively common, and the treatment-related mortality (TRM) was 5%, mostly associated with pancytopenia and infection. CONCLUSION: Single-agent fludarabine phosphate is active in previously untreated LPC lymphoma and WM, with only moderate activity in MCL. However, the CR rate is low, and the TRM is relatively high. Its role in combination chemotherapy remains to be demonstrated.

Adult↗

PubMed1998

Partial tandem duplications of the MLL gene are detectable in peripheral blood and bone marrow of nearly all healthy donors.

Partial tandem duplication within the MLL gene has recently been described as a novel genetic alteration in acute myeloid leukemia (AML). It has been associated with trisomy of chromosome 11, but was also identified in AML patients with normal karyotypes. The current study was performed to investigate whether MLL duplications are restricted to AML, and hence whether they may also occur in normal hematopoietic cells. MLL-duplication transcripts were analyzed by nested reverse-transcriptase polymerase chain reaction (RT-PCR) in peripheral blood in two groups of 45 and 20 patients, respectively, as well as in two bone marrow samples from healthy volunteers. Duplications were detected in two independent nested RT-PCR experiments in the peripheral blood samples of 38 of 45 (84%) and 20 of 20 (100%) of the two groups and in both bone marrow samples. On this basis, MLL duplications seem to occur frequently in a subset of cells in normal hematopoiesis. The type of partially duplicated MLL transcripts varied substantially. Three transcripts were identical to those known from AML. In addition, four new transcripts were characterized. Three of these four were in frame and potentially translatable. MLL duplications were also detected by seminested genomic PCR with intron 9- and intron 1-specific primers in 20 of 20 peripheral blood samples studied, indicating that the duplications are genomically fixed at the DNA level and are not an RT-PCR artifact. In summary, MLL duplications are regularly generated by homologous ALU recombination in a small number of hematopoietic cells of most or even all healthy donors. These data suggest that MLL duplications are not implicated in the malignant transformation in AML, or alternatively, that only a few cells will acquire additional oncogenic mutations necessary to establish the malignant phenotype of AML.

Adolescent↗

PubMed1998

Elevated serum level of soluble CD23 precedes development of B-non-Hodgkin's lymphoma in SIV-infected Rhesus monkeys.

Patients with HIV infection are at high risk for the development of high-grade B-non-Hodgkin's lymphoma (B-NHL). The aim of this study was identification of a predictive diagnostic marker for HIV-associated B-cell lymphomas, using simian-immunodeficiency-virus (SIV)-infected Rhesus monkeys as a well-established in vivo model of HIV-associated lymphomagenesis. We infected 26 monkeys (Macaca mulatta) with SIVmax and measured serum levels of sCD23 longitudinally until necropsy. Of the 26 monkeys, 9 developed high-grade B-NHL, which was preceded by lymphadenopathy (NHL+/LA+) (group 1). Among the 17 animals that remained without clinical evidence of lymphoma during the observation period, 8 developed LA (group 2) and 9 were NHL- and LA-negative (NHL-/LA-) (group 3). Elevation of sCD23 serum levels preceded B-cell lymphoma development, with a median of 44 U/ml in group 1 vs. 7 U/ml and 8 U/ml in groups 2 and 3 respectively, 32 weeks after infection. Differences in the serum level of sCD23 between group 1 vs. groups 2 and 3 became statistically significant 32 to 56 weeks after infection. At necropsy, serum levels of sCD23 were significantly higher in group 1 than in group 2 or group 3; 6/6 samples of SIV-associated B-NHL were positive for gene transcription of CD23 and its receptor CD21 as assessed by RT-PCR. The data point to a potential role of sCD23 as a predictive marker for the development of HIV-associated B-NHL. Moreover, the in vivo model of SIV-infected monkeys suggests the possibility of exactly analyzing the pathobiological role of sCD23 in the lymphomagenesis of SIV-associated B-NHL.

Animals↗

PubMed1998

Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia: results of a prospective randomized phase III study. German AML Cooperative Group.

BACKGROUND: Invasive fungal infections have increasingly become a matter of concern with regard to patients receiving intensive myelosuppressive therapy for hematologic malignancies. Such infections, especially prolonged neutropenia systemic fungal infections, may contribute substantially to infectious complications and early death. Measures for early detection and effective prophylactic strategies using active and nontoxic antifungal agents are therefore urgently needed. METHODS: The current randomized study was initiated to assess the efficacy of oral fluconazole as systemic antifungal prophylaxis for high risk patients with recurrent acute myeloid leukemia undergoing intensive salvage therapy. RESULTS: Of 68 fully evaluable patients, 36 were randomized to fluconazole in addition to standard prophylaxis with oral co-trimoxazol, colistin sulphate, and amphotericin B suspension, and 32 were randomized to standard prophylaxis only. No major differences between the two groups were observed in the number of episodes of fever of unknown origin (61% vs. 50%) or clinically defined infections (56% vs. 50%). Microbiologically defined infections were more frequent in the fluconazole group (50% vs. 31%), mainly due to a higher incidence of bacteremias (42% vs. 22%). There were two cases of proven invasive fungal infections in each group. Systemic amphotericin B was administered more frequently to patients receiving fluconazole prophylaxis (56% vs. 28%). Fluconazole prophylaxis had no impact on the rate of early death or overall survival. CONCLUSIONS: For patients with high risk recurrent acute myeloid leukemia undergoing intensive salvage therapy, antifungal prophylaxis with fluconazole was not superior to standard prophylaxis only.

Acute Disease↗

PubMed1998

MLL and CALM are fused to AF10 in morphologically distinct subsets of acute leukemia with translocation t(10;11): both rearrangements are associated with a poor prognosis.

The translocation t(10;11)(p13;q14) has been observed in acute lymphoblastic leukemia (ALL) as well as acute myeloid leukemia (AML). A recent study showed a MLL/AF10 fusion in all cases of AML with t(10;11) and various breakpoints on chromosome 11 ranging from q13 to q23. We recently cloned CALM (Clathrin Assembly Lymphoid Myeloid leukemia gene), the fusion partner of AF10 at 11q14 in the monocytic cell line U937. To further define the role of these genes in acute leukemias, 10 cases (9 AML and 1 ALL) with cytogenetically proven t(10;11)(p12-14;q13-21) and well-characterized morphology, immunophenotype, and clinical course were analyzed. Interphase fluorescence in situ hybridization (FISH) was performed with 2 YACs flanking the CALM region, a YAC contig of the MLL region, and a YAC spanning the AF10 breakpoint. Rearrangement of at least one of these genes was detected in all cases with balanced t(10;11). In 4 cases, including 3 AML with immature morphology (1 AML-M0 and 2 AML-M1) and 1 ALL, the signals of the CALM YACS were separated in interphase cells, indicating a translocation breakpoint within the CALM region. MLL was rearranged in 3 AML with myelomonocytic differentiation (2 AML-M2 and 1 AML-M5), including 1 secondary AML. In all 3 cases, a characteristic immunophenotype was identified (CD4+, CD13-, CD33+, CD65s+). AF-10 was involved in 5 of 6 evaluable cases, including 1 case without detectable CALM or MLL rearrangement. In 2 complex translocations, none of the three genes was rearranged. All cases had a remarkably poor prognosis, with a mean survival of 9.6 +/- 6.6 months. For the 7 AML cases that were uniformly treated according to the AMLCG86/92 protocols, disease-free and overall survival was significantly worse than for the overall study group (P = .03 and P = .01, respectively). We conclude that the t(10;11)(p13;q14) indicates CALM and MLL rearrangements in morphologically distinct subsets of acute leukemia and may be associated with a poor prognosis.

Acute Disease↗

PubMed1998

[Systemic therapy of low malignancy non-Hodgkin lymphomas].

Substantial progress has been achieved in eludicating the molecular mechanisms of malignant transformation, in establishing therapeutic standards and in evaluating innovative treatment strategies in patients with low grade Non-Hodgkin's Lymphoma. Correlation of genetic aberrations and immunologic marker profiles to histopathological entities and the clinical course has lead to a new transatlantic lymphoma classification. Today, application of 6-8 courses of moderately intensive induction polychemotherapy induces partial or complete remissions in 80% of patients in stage III or IV. Longterm maintenance therapy with interferon alpha significantly prolongs progression free survival. Current multicenter trials evaluate the curative potential of high-dose chemotherapy with autologous stem cell transplantation. Recently, several new approaches including new cytostatic drugs, immunotherapy with monoclonal antibodies and gene therapy with antisense oligonucleotides have been developed and have achieved remissions in pretreated patients. In the future, intensification of chemotherapy and the new treatment options may offer the potential for cure in patients with low malignant Non-Hodgkins Lymphoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

[Clinical studies in oncology. Relevance, design, ethical considerations].

BACKGROUND: Clinical research in oncology includes the evaluation of diagnostic, prognostic and therapeutic parameters in order to establish standards for the different tumor entities. Prerequisite is the retrospective and prospective analysis of large patient groups with established statistical methods. New potentially better strategies have to be compared in randomised studies with the respective "gold standard". The central role of clinical studies for evaluation and optimisation of therapy can be considered as moral obligation to included the maximal possible number of patients in clinical studies. However, only a small number of tumor patients in Germany is treated in controlled clinical studies. Reasons are lack of organisational structures, but also ethical considerations. STUDY DESIGNS: In this article several models for clinical studies are discussed with respect to their statistical significance, indication, and potential ethical objections. CONCLUSION: Aim of the discussion is to increase the acceptance of the necessity of clinical studies for evaluation and optimisation of therapeutic options in oncology.

Clinical Trials as Topic↗

PubMed1998

Meropenem monotherapy versus combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients.

Infections remain the major cause of morbidity and mortality among neutropenic cancer patients. The current study addresses the question whether monotherapy with the new broad-spectrum carbapenem meropenem exhibits efficacy comparable to that of the standard combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients. Seventy-one patients with hematological malignancies (55%) or solid tumors (45%), neutropenia < 500/microliter, and fever > 38.5 degrees C were randomly assigned to either meropenem (1 g every 8 h) or ceftazidime (2 g every 8 h) and amikacin (15 mg/kg/day) intravenously. Meropenem (n = 34) and ceftazidime/amikacin (n = 37) were equivalent with respect to the clinical response at 72 h (62% versus 68%) (p > 0.05) and at the end of unmodified therapy (59% versus 62%). Gram-positive bacteremia responded poorly in the meropenem and ceftazidime/amikacin group (29% versus 25%), whereas all gram-negative bacteremias responded except for one in the meropenem group caused by Pseudomonas aeruginosa. All patients survived to 72 h. One patient in each group died of gram-positive sepsis resistant to study medication. No significant side effects occurred in any regimen. This study suggests that meropenem monotherapy might be as effective as combination therapy with ceftazidime and amikacin for the empirical treatment of febrile neutropenic patients.

Adolescent↗

PubMed1998

Plasmacytosis in acute myeloid leukemia: two cases of plasmacytosis and increased IL-6 production in the AML blast cells.

An increased plasma cell count in the bone marrow occurs in a subgroup of patients with acute myeloid leukemia (AML). The pathogenic mechanism for this plasmacytosis is unclear. In this report we describe two patients with AML and plasmacytosis who shared some features of their diseases. The morphological subtypes were AML M4 and M4eo; the leukemias were secondary to cytotoxic pretreatment, and complex cytogenetic changes were found in the leukemic cells of both patients. There was a marked increase in the number of bone marrow plasma cells in both cases and no monoclonal immunoglobulin was detectable. The IgH-CDR3 gene scan depicted a monoclonal IgH rearrangement in the bone marrow cells of one patient. Analysis of the cytokine production of the leukemic cells showed a high production of IL-6 of the leukemic blast cells in the in vitro cell culture and a high cytoplasmic IL-6 in the leukemic cells as revealed by immunocytology. We describe the clinical picture of a type of secondary AML with FAB M4 morphology associated with bone marrow plasmacytosis. We suggest that paracrine growth stimulation of plasma cells by paraneoplastic IL-6 production of the leukemic blast cells contributes to the plasmacytosis observed in patients with AML.

Acute Disease↗

PubMed1998

Granulocyte colony-stimulating factor shortens duration of critical neutropenia and prolongs disease-free survival after sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy for refractory and relapsed acute myeloid leukemia. German AML Cooperative Group.

Patients with primary refractory or relapsed acute myeloid leukemia (AML) who undergo intensive salvage chemotherapy carry a high risk of treatment failure due to infectious complications and early relapses. The study presented here assessed the effect of granulocyte colony-stimulating factor (G-CSF) on the duration of post-treatment neutropenia, the incidence of infection-related deaths, and the disease-free and overall survival. Sixty-eight evaluable patients with relapsed and refractory AML received G-CSF 5 microg/kg per day subcutaneously starting 2 days after the completion of salvage treatment with the S-HAM regimen, consisting of high-dose cytosine arabinoside twice daily on days 1, 2, 8, and 9 and mitoxantrone on days 3, 4, 10, and 11. Ninety-one patients who were treated with the identical S-HAM regimen but without G-CSF support during a preceding study served as controls. The application of G-CSF resulted in a significant shortening of critical neutropenia of less than 500 microl (36 vs. 40 days; p = 0.008), which translated into a trend towards a lower early death rate (21% vs. 30%) and an increase of complete remissions (56% vs. 47%, p=0.11). In patients younger than 60 years a significant prolongation of time to treatment failure (159 vs. 93 days, p=0.038) and of duration of disease-free survival (203 vs. 97 days, p=0.003) was observed. These results indicate a beneficial effect of G-CSF on early mortality as well as on long-term outcome when administered after S-HAM salvage therapy for advanced AML.

Acute Disease↗

PubMed1998

Intensive therapy for high-risk myelodysplastic syndromes and the biological significance of karyotype abnormalities.

Therapy for myelodysplastic syndromes (MDS) has been less than effective when based on low-dose treatment or supportive measures only, including hematopoietic growth factors. Recently, based on the percentage of bone marrow blasts, the number of cytopenic cell lines and cytogenetics, clinical risk groups have been defined more precisely. Recent studies applying intensive acute myeloid leukemia (AML)-type therapy to high-risk MDS have produced remissions ranging from 45 to 79%. Advances in the understanding of the biology of MDS clearly point to cytogenetics rather than morphologic subtype as being of prognostic relevance. Hence, new treatments need to be developed for patients with unfavorable karyotypes and complex abnormalities in particular. These MDS subtypes are characterized by low spontaneous proliferative activity and low autocrine production of hematopoietic growth factors. The subtypes are, however, highly sensitive to external stimulation by granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). New therapies could emerge from these findings, for example, priming high-risk MDS patients with hematopoietic growth factors in combination with intensive AML-type treatment. Recent studies suggest that incorporating high-dose AraC into an intensive drug combination could further improve the outcome of high-risk MDS.

Chromosome Aberrations↗

PubMed1998

Overexpression of ribosomal proteins L4 and L5 and the putative alternative elongation factor PTI-1 in the doxorubicin resistant human colon cancer cell line LoVoDxR.

A better understanding of the regulatory network underlying cellular drug resistance and stress response may be helpful to overcome the phenomenon of therapy-induced cross-resistances against a variety of antineoplastic agents. Two new powerful molecular techniques, mRNA differential display reverse transcriptase polymerase chain reaction (DDRT-PCR) and subtractive suppressive hybridisation were applied for the comparative analysis of the gene expression profile of a doxorubicin resistant and its corresponding sensitive parental colon carcinoma cell line (LoVo H67P). DDRT-PCR generated partial cDNAs from the doxorubicin resistant, sensitive and stress (dexamethasone, doxorubicin, cadmium chloride or heat) exposed sensitive cells, were size-separated on polyacrylamide gels. The expression patterns of more than 9000 bands of the resistant, sensitive and stressed sensitive cell populations were identical by more than 95%. Of the differentially expressed mRNAs, 20 cDNA fragments were reamplified after isolation from the gel, used as probes for Northern blot analysis to verify their differential expression and sequenced after cloning. Among the differentially expressed cDNAs, homologies of 96% and 87%, respectively, were found to the human proto-oncogene PTI-1 and the human ribosomal protein L4. Subtractive suppressive hybridisation revealed overexpression of the ribosomal protein L5 in the doxorubicin resistant line. These data point to the control of gene expression at the translational level as an important mechanism involved in cellular stress response.

Antibiotics, Antineoplastic↗

PubMed1998

Detection of hyperdiploid karyotypes (>50 chromosomes) in childhood acute lymphoblastic leukemia (ALL) using fluorescence in situ hybridization (FISH).

ALL patients with a hyperdiploid karyotype of more than 50 chromosomes (high hyperdiploidy) carry a better prognosis in contrast to patients presenting with other cytogenetic features, and an appropriate less intensive therapy protocol should be developed for these patients. For this reason it is desirable to have a quick screening method identifying those with this type of hyperdiploidy. We therefore studied the bone marrow and/or blood cells of 278 children with ALL using double target fluorescence in situ hybridization (FISH) on interphase. A combination of DNA probes (repetitive, centromere specific) was applied detecting chromosomes which are most frequently overrepresented in patients with hyperdiploidy (>50), at chromosomes 6, 10, 17 and 18. All patients showing hybridization signals differing from the normal signal distribution of two spots for each tested chromosome were analyzed cytogenetically as well. 102 children (102/278; 36.7%) were found to have a clone with aberrant FISH results. In 80 patients (80/278, 28.8%) the cytogenetic analysis detected a hyperdiploid karyotype >50 chromosomes, whereas the remaining patients (n=12) could be related to other ploidy subgroups, ie hyperdiploidy with 47-50 chromosomes, haploidy, triploidy/tetraploidy. Comparison of the FISH results with the measurements of the DNA content showed good agreement for 88.8% (208/234) of the investigated patients. The detected rate of 28.8% patients with a high hyperdiploid karyotype in our investigated cohort is comparable to the frequency of other studies. Only one patient was not identified as having a hyperdiploid karyotype with our combination of DNA probes. Our results indicate that FISH is a feasible and quick screening method for the detection of hyperdiploid karyotypes (>50 chromosomes) and other ploidy subgroups.

Aneuploidy↗

PubMed1998

Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison.

Although cytosine arabinoside (AraC) represents the most effective single agent in the treatment of adults with acute myeloid leukemia (AML) when given at doses exceeding 200 to 500 mg per application, its optimal dosage is still a matter of controversial discussion. While pharmacokinetic investigations suggest that the AraC-activating enzyme deoxycytidine kinase is saturated at drug concentrations achieved by short-term infusion of 0.5 to 1.0 g/m2 AraC and that higher doses are therefore not more effective, recent evidence indicates that additional mechanisms of AraC cytotoxicity may exist which could be enhanced by further dose escalation. In order to test this thesis in the clinical setting, a prospective randomized comparison of high-dose (HD-AraC) vs intermediate-dose (ID-AraC) AraC was carried out in patients with refractory or relapsed AML on the basis of the sequential high-dose AraC and mitoxantrone regimen (S-HAM). AraC was given as a 3-h infusion q 12 h on days 1, 2, 8 and 9. Patients younger than 60 years were randomized to AraC doses of 3.0 g/m2 vs 1.0 g/m2 while older patients received either 1.0 g/m2 or 0.5 g/m2 per single dose. Mitoxantrone was given to all patients on days 3, 4, 10 and 11 at a daily dose of 10 mg/m2. Randomization was stratified for primary refractoriness against induction therapy and length of first remission in relapsed patients. From 186 evaluable patients, 88 (47%) and 10 cases (5%) achieved a complete (CR) or partial (PR) remission, 39 patients (21%) had persisting leukemia (non-response (NR)), and 49 cases (26%) died within 6 weeks after the start of therapy (early death (ED)). In patients younger than 60 years the higher dose level resulted in a significant reduction of NR (12% vs 31%; ordinal chi2 test: P = 0.01) but also a higher rate of ED (32% vs 17%) thus leading to a marginally higher CR rate only (52% vs 45%). Within the subgroup of patients with refractory AML the tendency towards a higher CR rate after HD-AraC was more pronounced (46% vs 26%; P = 0.045). In patients older than 60 years, corresponding though less evident differences were observed with a higher rate of NR in the lower dose group (26% vs 16%) and ED occurring more frequently after higher doses (36% vs 26%). These data indicate that HD-AraC reveals a significantly higher antileukemic efficacy than ID-AraC as expressed by a significant reduction of failure from NR. This advantage, however, does not fully translate into an increase in remission rate due to a higher incidence of ED after HD-AraC predominantly from uncontrolled infections. In order to take full advantage of the higher antileukemic activity of HD-AraC an improvement of supportive care and infection control is warranted.

Acute Disease↗

PubMed1998

Oral cytarabine ocfosfate in acute myeloid leukemia and non-Hodgkin's lymphoma--phase I/II studies and pharmacokinetics.

Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamination with half-lives ranging from 1 h (i.v.) to 4 h (s.c.) -- and cannot be applied orally due to its hydrophilic properties. These limitations might be overcome by YNK01 -- a lipophilic prodrug of AraC -- that is resistant to deoxycytidine deaminase and can be applied orally. In the present study the therapeutic activity, side-effects and pharmacokinetics of YNK01 were evaluated in a phase I/II study including patients with relapsed or refractory acute myeloid leukemia (AML) (n=23) or low-grade non-Hodgkin's lymphoma (NHL) (n=20). YNK01 was given by 14 day cycles with escalating doses starting with a daily dose of 50 mg/m2 (equivalent to 20 mg/m2 AraC on a molar basis). The maximum tolerated dose was reached at the 600 mg/m2 dose level with WHO grade 3-4 diarrhoea as the main toxicity. In the 23 patients with AML two complete remissions, four partial remissions and three patients with stable disease were observed. In the 23 patients with AML two complete remissions, four partial remissions and three patients with NHL two cases reached partial remission and six other patients mainained stable disease. Pharmacokinetic evaluations were performed during 34 treatment cycles in 28 patients. The data suggest that YNK01 was absorbed in the distal part of the small intestine and taken up into hepatocytes. After hepatic psi and subsequent beta-oxydation of YNK01 the released AraC (and its deamination product AraU) appeared in the systemic circulation. Time of maximum concentration (h), half-life (h) and area under the curve (ng x h/ml, at the 1200 mg dose level) were as follows (VC variation coefficient) YNK01: 1.0 (0.58), 10.1 (0.43), 12622 (0.65); AraC: 23.2 (0.57), 22.6 (0.36), 3496 (0.76); AraU: 19.2 (0.58) 22.3 (0.33) 15441 (0.66). Of the total dose of YNK01 15.8% was absorbed and metabolized to AraC and AraU, defining the metabolic bioavailability of this prodrug. A linear relationship was observed between YNK01 dose and YNK01 AUC and AraC AUC over the whole dose range tested. AraC was released from hepatocytes over a prolonged period of time resulting in long lasting plasma levels similar to a continuous i.v. infusion. After administration of YNK01 at a dosage of 100-150 mg/m2 plasma levels of AraC were comparable to those achieved after low-dose AraC treatment (20 mg/m2) while at doses of YNK01 of 450-600 mg/m2 concentrations of standard-dose AraC (100 mg/m2) were obtained. We conclude that YNK01 shows considerable activity against relapsed and refractory AML and NHL and that its pharmacokinetic properties offers advantages in comparison to (standard) i.v. or s.c. AraC in clinical practice.

Acute Disease↗

PubMed1998

Combination of aclarubicin and etoposide for the treatment of advanced acute myeloid leukemia: results of a prospective multicenter phase II trial. German AML Cooperative Group.

In order to develop new strategies for the treatment of relapsed or refractory acute myeloid leukemia, the German AML Cooperative Group performed a prospective multicenter phase II study to evaluate the antileukemic efficacy of aclarubicin 60 mg/m2/day and etoposide 100 mg/m2/day each given for 5 days. Of 37 heavily pretreated evaluable patients (median age 42 years, range 18-81) 15 (40%) achieved a remission after one or two courses of treatment consisting of nine complete (24%) and six partial remissions (16%). Fourteen (38%) cases were non-responders and eight (22%) patients suffered from early deaths. Disease-free survival for patients in remission and overall survival were 3.2 months each. The median duration of critical neutropenia <500/microl was 27 days. The most frequent non-hematologic side-effects were stomatitis (WHO III/IV, 48%), infections (40%), nausea/vomiting (26%) and diarrhea (24%). Cardiac toxicity was mild. This study suggests a substantial antileukemic efficacy and an acceptable toxicity of aclarubicin in combination with etoposide in heavily pretreated patients with advanced acute myeloid leukemia, and warrants further evaluations in a more favorable stage of the disease.

Aclarubicin↗

PubMed1998

Structure of Bcl-1 and IgH-CDR3 rearrangements as clonal markers in mantle cell lymphomas.

Mantle cell lymphoma represent a clinicopathologically distinct entity of malignant non-Hodgkin's lymphoma (NHL) and are characterized by a specific chromosomal translocation t(11;14)(q13;q32) involving the cyclin D1 gene also designated as bcl-1/PRAD1 gene on chromosome 11 and the heavy chain immunoglobulin joining region on chromosome 14. We have established a PCR method to amplify t(11;14) junctional sequences in DNA from fresh frozen and paraffin-embedded tissue by bcl-1-specific primers in combination with a consensus immunoglobulin JH primer. A total of 65 cases histologically classified as mantle cell lymphoma (MCL) were analyzed for the presence of a t(11;14) translocation and monoclonal IgH-CDR3 rearrangements. From 26 patients with classical MCL and three cases with the anaplastic variant of MCL fresh frozen biopsy material was available for DNA extraction. We detected a bcl-1/JH rearrangement in 12 out of 29 samples (41%). In 36 cases paraffin-embedded lymph node tissue was the only source of DNA. In this material we found a bcl-1/JH rearrangement in six out of 31 samples with intact DNA (20%). To confirm the specificity of the PCR and to determine the bcl-1/JH junctional region sequences as clone-specific marker in individual patients we characterized the junctional DNA sequences by direct PCR sequencing in 16 cases. Interestingly we found that six bcl-1/JH junctions harbored DH segments in their N regions indicating that bcl-1/JH rearrangements can occur in a later stage of B cell ontogeny during which the complete VH to DH-JH joining or VH-replacement takes place. To investigate the suitability of IgH-CDR3 as sensitive molecular marker for those MCL patients in which a t(11;14) translocation can not easily be amplified, we additionally analysed 60 cases for the presence of monoclonally rearranged IgH genes by IgH-CDR3-PCR. A monoclonal IgH-CDR3 PCR product could be identified in 24 out of 29 fresh frozen samples (79%) whereas only 11 out of 31 samples (36%) with paraffin-derived DNA were positive. We demonstrate that automated fluorescence detection of monoclonal IgH-CDR3 PCR products allows the rapid and sensitive monitoring of minimal residual disease also in cases that lack a PCR amplifiable t(11;14) translocation. In combination with allele-specific primers the procedure may improve current experimental approaches for detection of occult MCL cells at initial staging and residual disease during and after therapy.

Base Sequence↗