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Biomedical subjects

Frank Griesinger

Publications and source records attributed to Frank Griesinger.

At least 19 recordsLinked to original sources
PubMed2026

Rationale and Study Design of the GUIDANCE trial: A Multicenter Phase II Trial of Maintenance Durvalumab and Olaparib After Standard Fist Line Treatment (Carboplatin/Cisplatin, Etoposide, and Durvalumab) in HRD Positive Extensive Disease (ED) Small-cell Lung Cancer (SCLC) (AIO-TRK-0124/ass).

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. METHODS: GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. DISCUSSION: This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.

DNA-damage repair↗
PubMed2006

The MLL partial tandem duplication in acute myeloid leukaemia.

Mixed lineage leukaemia gene-partial tandem duplications (MLL-PTD) characterise acute myeloid leukaemia (AML) with trisomy 11 and AML with a normal karyotype. MLL-PTD confer a worse prognosis with shortened overall and event free survival in childhood and adult AML. In spite of these clinical observations, the leukaemogenic mechanism has, so far, not been determined. This review summarises clinical studies on MLL-PTD positive AML and recent experimental findings on the putative leukaemogenic role of MLL-PTD.

Acute Disease↗
PubMed2006

Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group.

PURPOSE: Monitoring of residual disease (RD) by flow cytometry in childhood acute myeloid leukemia (AML) may predict outcome. However, the optimal time points for investigation, the best antibody combinations, and most importantly, the clinical impact of RD analysis remain unclear. PATIENTS AND METHODS: Five hundred forty-two specimens of 150 children enrolled in the AML-Berlin-Frankfurt-Muenster (BFM) 98 study were analyzed by four-color immunophenotyping at up to four predefined time points during treatment. For each of the 12 leukemia-associated immunophenotypes and time points, a threshold level based on a previous retrospective analysis of another cohort of children with AML and on control bone marrows was determined. RESULTS: Regarding all four time points, there is a statistically significant difference in the 3-year event-free survival (EFS) in those children presenting with immunologically detectable blasts at 3 or more time points. The levels at bone marrow puncture (BMP) 1 and BMP2 turned out to have the most significant predictive value for 3-year-EFS: 71% +/- 6% versus 48% +/- 9%, P(Log-Rank) = .029 and 70% +/- 6% versus 50% +/- 7%, P(Log-Rank) = .033), resulting in a more than two-fold risk of relapse. In a multivariate analysis, using a combined risk classification based on morphologically determined blasts at BMP1 and BMP2, French-American-British classification, and cytogenetics, the influence of immunologically determined RD was no longer statistically significant. CONCLUSION: RD monitoring before second induction has the same predictive value as examining levels at four different time points during intensive chemotherapy. Compared with commonly defined risk factors in the AML-BFM studies, flow cytometry does not provide additional information for outcome prediction, but may be helpful to evaluate the remission status at day 28.

Adolescent↗
PubMed2006

Lifelong persistence of AML associated MLL partial tandem duplications (MLL-PTD) in healthy adults.

AML-associated MLL-PTD contribute to leukemogenesis by a gain of function and confer an unfavorable prognosis. Like other leukemia associated aberrations they are also present in healthy adults. To delineate the leukemogenic mechanism we tracked down MLL-PTD in normal hematopoiesis and investigated cord blood samples. MLL-PTD were observed in 56/60 (93%) of all cord bloods. In contrast to AML, the transcript frequency in cord blood was four log scales lower as determined by real-time PCR. The CD34+ progenitor cell, CD33+ myeloid, CD19+ B-lymphoid and CD3+ T-lymphoid subfractions were positive. The ubiquitous presence of MLL-PTD in cord blood implicates a lifelong exposure, not an accumulation during lifetime. Since also present in the stem cell subfraction, these factors seem not to be major determinants in MLL-PTD leukemogenesis.

Adult↗
PubMed2005

Immunophenotypic differences between diagnosis and relapse in childhood AML: Implications for MRD monitoring.

BACKGROUND: Determination of antigen expression patterns is, in addition to morphologic analysis, essential to the diagnosis of acute myeloid leukemia (AML). The present study was performed to determine (a) the degree of changes in immunophenotype and their consequences on the monitoring of minimal residual disease (MRD) in childhood AML and (b) whether certain clusters of changes in antigen expression patterns exist between diagnosis and relapse. METHODS: Bone marrow specimens of 48 children enrolled in the German AML-BFM-93/98 (Acute Myeloid Leukemia-Berlin-Frankfurt-Munster) studies were analyzed immunologically, morphologically, and genetically at diagnosis and at first relapse. RESULTS: The immunophenotypes by flow cytometry differed by at least one antigen between samples at presentation and relapse in 42 of 48 children (88%). More children displayed an immature phenotype at relapse (43 of 47, 91.5%, vs. 37 of 48, 77%; P = 0.05) with expression of CD34 and/or CD117. This was reflected by a gain of markers that are associated with lineage immaturity in 18 of 25 (72%) of cases, whereas the loss of such antigens was observed in 6 of 25 (24%) patients. We did not observe significant changes for lineage specific markers, with comparable occurrences of loss or gain of myeloid and lymphoid antigens in the sample pairs. Only minimal changes were seen for morphologic and genetic features. CONCLUSION: An antigenic shift was observed in 88% of cases in this study. The antibody panels used for MRD monitoring in childhood AML should therefore not be restricted to the immunophenotype detected at presentation but should include in particular markers of lineage immaturity. The clinical observation of a shift toward a more immature phenotype of the myeloblasts is consistent with the model of a clonal evolution of a leukemic stem cell.

Acute Disease↗
PubMed2005

A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by the presence of a t(9;22)(q34;q11.2), which leads to the well-known BCR-ABL1 fusion protein. We describe a patient who was diagnosed clinically with a typical CML but on cytogenetic analysis was found to have a t(9;22)(p24;q11.2). Chromosomal fluorescence in situ hybridization showed that the BCR gene locus spanned the breakpoint at band 22q11.2 but that the ABL1 gene was not rearranged. By means of a candidate gene approach, the JAK2 gene, at 9p24, was identified as the fusion partner of BCR in this case. The BCR-JAK2 fusion protein contains the coiled-coil dimerization domain of BCR and the protein tyrosine kinase domain (JH1) of JAK2. The patient's disease did not respond to Imatinib, and this unresponsiveness was most likely a result of the BCR-JAK2 fusion protein.

Antineoplastic Agents↗
PubMed2005

AML1/ETO promotes the maintenance of early hematopoietic progenitors in NOD/SCID mice but does not abrogate their lineage specific differentiation.

AML1-ETO is generated by the t(8;21) translocation found in approximately 12% of acute myelogenous leukemia. Studies to delineate the mechanism by which AML1-ETO induces leukemia have primarily relied on transformed human cell lines or murine model systems. The goal of this study was to determine the effect of AML1-ETO expression on primary human hematopoietic cells in vitro and in a xenograft model. We used a FMEV retroviral vector for the transfer of AML1/ETO into human CD34 + cells. The repopulation, self-renewal, and differentiation potential of infected cells were assessed in serum-free liquid culture, colony assays, and in transplanted NOD-SCID mice. High transcription levels were confirmed by real-time PCR. AML1-ETO expressing cells were expandable for up to 12 weeks and retained an immature morphology. The capacity for prolonged survival, however, did not abrogate maturation, as AML1-ETO cells gave rise to normal colonies in a CFU-assay. AML1/ETO-expressing cells also contributed to myeloid (CD15, CD33), B-lymphoid (CD20), NK-cell (CD56) and erythroid (GPA) lineages in xenografted NOD/SCID mice. Although able to engraft all major lineages, AML1/ETO transplanted cells were primarily found in less differentiated fractions as measured by cell surface markers CD34 and CD38. In spite of a good engraftment and prolonged observation period none of the NOD/SCID-mice developed an acute myelogenous leukemia. Our findings demonstrate that AML1/ETO promotes the maintenance of early human hematopoietic progenitors, but does not abrogate their physiologic differentiation. Furthermore, the leukemogenic potential of AML1/ETO expressed in human progenitors is low, despite transcription levels equivalent to those found in AMLs.

Animals↗
PubMed2005

Immunophenotypic and genetic characterization of a CD8 positive mantle cell lymphoma in a patient with concomitant Mycosis fungoides.

Mantle cell lymphoma (MCL) is immunophenotypically characterized by cell surface co-expression of CD19, CD20, CD5, IgM and FMC7. However, the concomitant presence of other antigens distinctive of a particular leukocyte subset, e.g. T-lymphocytes, is an exceptional finding in MCL. Here, the first case of a blastic MCL in leukaemic phase with aberrant expression of the T-cell associated antigen CD8 occurring in a patient with concomitant Mycosis fungoides is described. Comprehensive immunophenotypic analysis showed that the MCL cells expressed the typical B-lymphocytic markers, were CD5 and CD8 positive, but did not express other T-cell proteins, such as CD2, CD3, CD4, CD7, TCRalphabeta and TCRgammadelta. The MCL cells expressed both CD8alpha and CD8beta chains indicating cell surface presence of CD8alphabeta heterodimers. Intriguingly, expression of the cytotoxic enzymes perforin and granzyme A was detected by RT-PCR. Cytogenetic and molecular genetic analysis of the lymphoma cells confirmed cyclin D1 overexpression secondary to the t(11;14)(q13;32) chromosomal translocation. Furthermore, trisomy 11, trisomy 14 and extra copies of t(11;14) translocated chromosomes were detected in sub clones of the analyzed MCL cells. Clinically, an aggressive course of disease including cerebral lymphoma involvement was noted in the reported patient. Hence, systematic studies addressing the incidence, biology and clinical behavior of this form of MCL seem to be justified in future.

Antigens, CD↗
PubMed2004

Secondary leukaemia after cure for locally advanced NSCLC: alkylating type secondary leukaemia after induction therapy with docetaxel and carboplatin for NSCLC IIIB.

Specific cytogenetic alterations in t-MDS and t-AML are associated with different chemotherapeutic agents, such as loss of chromosomal material from #5 and #7 with alkylators. No data have been published on secondary leukemias following the taxane docetaxel. We report a patient, who being in long-term remission after docetaxel-based induction chemotherapy with docetaxel and carboplatin, surgery and adjuvant radiotherapy for non-small cell lung cancer stage IIIB, developed a t-MDS and subsequently a t-AML 40 months after start of therapy. The t-MDS was characterised by a complex aberrant karyotype including monosomy #13 and partial monosomies of #5 and #7. This is the first report in the literature of t-MDS after docetaxel chemo-radiotherapy, implicating a possible association of docetaxel with alkylator type t-MDS and t-AML. The case will be discussed in the context of a review of the current literature.

Acute Disease↗
PubMed2004

B-cell chronic lymphocytic leukemia with aberrant CD8 expression: genetic and immunophenotypic analysis of prognostic factors.

B-cell chronic lymphocytic leukemia (B-CLL) is phenotypically characterized by cell surface co-expression of CD19, CD20, CD5, and CD23. However, the concomitant presence of other antigens distinctive of a particular leukocyte subset, e.g. T cells, is an unusual finding in B-CLL. In the present report, a case of B-CLL with aberrant expression of the T-cell-associated antigen CD8 is described. Flow cytometric analysis of the patient's cells demonstrated lack of CD38 expression, and cytogenetic analysis by FISH did not show any abnormalities of chromosomes 17p, 11q, and 12. Furthermore, the B-CLL cells expressed only low levels of the tyrosine kinase ZAP-70, which was in agreement with the mutated status of the immunoglobulin heavy-chain variable-region gene (IgVH). In summary, the determined profile of prognostic markers together with the highly stable and indolent disease in the described patient suggest a good prognosis of B-CLL with aberrant CD8 expression.

Aged↗
PubMed2004

ABC transporter ABCA3 is expressed in acute myeloid leukemia blast cells and participates in vesicular transport.

Drug resistance is a major issue in the treatment of acute myeloid leukemia (AML), and drug efflux by ATP-binding-cassette (ABC) transporters is one of the main mechanism involved in this resistance. We determined the prevalence of the intracellular transporter ABCA3 in specimens from patients with AML, and addressed its biology with attention to intracellular compartmentalization.

ATP-Binding Cassette Transporters↗
PubMed2003

FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance.

FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3/ITDs) are reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3/ITDs in 11.5% of 234 children with de novo AML. FLT3/ITD-positive patients were significantly older and had higher percentages of normal cytogenetic findings or French-American-British (FAB) classification M1/M2 and lower percentages of 11q23 abnormalities or FAB M5. FLT3/ITD-positive patients had lower remission induction rates (70% vs 88%; P =.01) and lower 5-year probability rates of event-free survival (pEF) (29% vs 46%; P =.0046) and overall survival (32% vs 58%; P =.037). Patients with high ratios (higher than the median) between mutant and wild-type FLT3 had significantly worse 2-year EFS rates than FLT3/ITD-negative patients (pEFS 20% vs 61%; P =.037), whereas patients with ratios lower than the median did not (pEFS 44% vs 61%; P =.26). FLT3/ITD was the strongest independent predictor for pEFS, with an increase in relative risk for an event of 1.92 (P =.01). Using an MTT (methyl-thiazol-tetrazolium)-based assay, we studied cellular drug resistance on 15 FLT3/ITD-positive and 125 FLT3/ITD-negative AML samples, but we found no differences in cellular drug resistance that could explain the poor outcomes in FLT3/ITD-positive patients. We conclude that FLT3/ITD is less common in pediatric than in adult AML. FLT3/ITD is a strong and independent adverse prognostic factor, and high ratios between mutant and WT-FLT3 further compromise prognosis. However, poor outcomes in FLT3/ITD-positive patients could not be attributed to increased in vitro cellular drug resistance.

Acute Disease↗
PubMed2003

Molecular whole-body cancer staging using positron emission tomography: consequences for therapeutic management and metabolic radiation treatment planning.

A prospective analysis was performed in 124 non-small cell lung cancer patients to determine the role of F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) for molecular (metabolic) staging (n=63), therapy monitoring after induction-chemotherapy (n=34), and conformal radiation treatment planning (n=27). Staging by FDG-PET was significantly more accurate than CT (p<0.001) and changed therapeutic management in 52% of all patients. After induction-chemotherapy, patients with complete metabolic remission histologically did not show vital tumor cells in contrast to patients with metabolic partial remission or progressive disease. Metabolic radiation treatment planning by PET led to smaller planning target volumes (PTVs) for radiation therapy (between 3% and 21% in 25/27 patients), resulting in a reduction of dose exposure to healthy tissue. In two patients, PET-PTV was larger than CT-based PTV, since PET detected lymph node metastases smaller than 1 cm. FDG-PET provides clinically important information; changes therapeutic management, can predict noninvasively effectiveness of chemotherapy, and may lead to better tumor control with less radiation-induced toxicity.

Disease Progression↗
PubMed2002

High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin lymphoma with the iodine-131-labeled chimeric anti-CD20 antibody C2B8 and autologous stem cell support. Results of a pilot study.

BACKGROUND: CD20 has been used successfully as a target molecule for conventional low-dose, as well as high-dose, myeloablative radioimmunotherapy (RIT) of B-cell non-Hodgkin lymphoma (NHL). Mantle cell lymphoma (MCL) is an especially aggressive, prognostically unfavorable subtype of B-cell NHL, associated with an overall 5-year survival rate of less than 20%. Recent evidence has failed to show convincing therapeutic efficacy of conventional, nonmyeloablative RIT in patients with MCL. The aim of this pilot study was to investigate whether high-dose, myeloablative RIT with the iodine-131 ((131)I)-labeled chimeric anti-CD20 antibody C2B8 (rituximab, obtained as Mabthera from Roche Pharma, Reinach, Switzerland) is therapeutically effective in MCL patients. METHODS: A total of seven patients with chemorefractory or relapsed MCL were studied in this pilot trial. All had relapsed after high-dose chemotherapy with autologous stem cell transplantation (four of them combined with 12 grays (Gy) total-body irradiation). A diagnostic-dosimetric study was performed with approximately 10 mCi of (131)I-labeled C2B8 at a protein dose of 2.5 mg per kg body weight, in order to assess its biodistribution and dosimetry. If splenic pooling was observed, as is typically the case in patients with splenomegaly, the protein dose was doubled in additional studies until a "favorable" biodistribution was obtained. Therapy was performed with myeloablative doses of 261-495 mCi of (131)I-labeled C2B8 at the previously optimized protein dose, aiming at lung doses less-than-or-equal 27 Gy. Homologous stem cell support was provided. Clinical follow-up was obtained at 3-month intervals for up to 38 months (median observation time, 25 months). Overall, in six patients the 2.5 mg/kg protein dose was used, whereas in one patient with splenomegaly, 10 mg/kg was necessary to overcome the splenic antigenic sink. RESULTS: Blood cell nadirs were reached at 2-3 weeks after therapy infusion, but all patients reengrafted at 7-10 days after stem cell reinfusion. Nonhematologic toxicity was restricted to mild-to-moderate nausea, fever, transient bilirubin, or liver enzyme elevations. One patient with preexisting alcoholic cirrhosis experienced a deterioration of liver function. Despite thyroid blocking, 5 of 7 patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. Six patients experienced a complete and one a good partial remission. Five patients were still in CR at the time this article was written, and six are still alive for more than 3 years; one patient relapsed locally at 3 months and one systemically at 26 months after RIT. CONCLUSIONS: High-dose myeloablative radioimmunotherapy with (131)I-labeled anti-CD20 antibodies seems to be associated with a high response rate and moderate toxicity in patients with MCL. Further follow-up to monitor the long-term outcome as well as systematic prospective clinical studies are indicated.

Adult↗
PubMed2002

Radioimmunotherapy of small-volume disease of metastatic colorectal cancer.

BACKGROUND: Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small-volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine-131 ((131)I)-labeled humanized anti-carcinoembryonic antigen (anti-CEA) antibody (MAb) hMN-14 in small-volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this (131)I-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting. METHODS: Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions less-than-or-equal 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4-6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of (131)I-hMN-14 immunoglobulin G at a 60 mCi/m(2) dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months. RESULTS: At a mean blood-based red marrow dose of 1.8 +/- 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m(2) dose level at 8-16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection. CONCLUSIONS: These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated.

Antibodies, Monoclonal↗