Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Onkologie. Berlin, 1.–5. Oktober 2010, pp 207–294

2010 Onkologie (Basel)  
Abstracts 207 Results: Similar to the IGH-associated translocations in follicular and mantle cell lymphomas, the IGH-MALT1 junctions in MALT lymphoma showed all features of a recombination signal sequence-guided V(D)J-mediated translocation at the IGH locus. Furthermore, analogous to follicular and mantle cell lymphoma, templated nucleotides (T-nucleotides) were identified at the t(14;18)/IGH-MALT1 breakpoint junctions. On chromosome 18, we identified a novel major breakpoint region in MALT1
more » ... tream of its coding region. Moreover, the presence of duplications of MALT1 nucleotides in one case suggests an underlying staggered DNA-break process not consistent with V(D) J-mediated recombination. Conclusions: Our observations indicate that the pathomechanism underlying the t(14;18)/IGH-MALT1 in MALT lymphomas is probably based on an illegitimate V(D)J-mediated recombination at the IGH locus on chromosome 14 and a staggered double-stranded DNA break at the MALT1 locus on chromosome 18. Furthermore, we could identify a putative major breakpoint region (MBR) proximal to the 5' non-coding region of MALT1. The molecular characteristics of the t(14;18)/IGH-MALT1 resemble those found in the t(14;18)/ IGH-BCL2 in follicular lymphoma and t(11;14)/CCND1-IGH in mantle cell lymphoma, suggesting that these translocations could be generated by a common pathomechanism involving new synthesis of T-nucleotides and nonhomologous end joining (NHEJ) or alternative NHEJ repair pathways on the IGH-translocation partner. Disclosure: No conflict of interest disclosed. Introduction: Salvage treatment in primary CNS lymphoma (PCNSL) after initial high-dose methotrexate (HDMTX) containing chemotherapy is poorly defined. Temsirolimus is a selective inhibitor of cell proliferation promoting intracellular protein mTOR with proven activity in lymphatic malignancies. We designed a phase II study (NCT00942747) to evaluate activity and toxicity of a temisrolimus monotherapy in relapsed PCNSL and to study its penetration into cerebrospinal fluid (CSF). Methods: Included are immunocompetent patients with histologically confirmed PCNSL relapsing or progressive after HDMTX, age ≥18 years, ECOG PS ≤2, and adequate hepatic, renal and bone marrow function. Ten patients are planned to be treated with temsirolimus 25mg (cohort 1) and 75mg (cohort 2) once weekly. Primary endpoint is the overall response rate, secondary endpoints are toxicity, time to progression and CSF penetration of temsirolimus and its metabolite sirolimus. For CSF studies blood and CSF samples are simultaneously collected 30-60min after first, second and fourth infusion, and concentrations of temsirolimus and sirolimus are measured by HPLC with mass spectrometry detection. Results: Five patients (median age 57 years, median ECOG PS 2) have been included and treated with 25mg Temsirolimus thus far. Median number of previous therapy regimens was 3 including whole brain irradiation in 3 patients. Patients received a median of 6 temsirolimus infusions. After 4 infusions, one patient had a partial remission (PR), three patients had stable disease (SD) (with tumor volume reductions of 32%-45%), and one patient progressed. All patients with SD progressed after 2-4 further infusions. CTC ≥grade III toxicity was thrombocytopenia in 1 patient and pneumonia in two patients. Ten blood/CSF pairs were collected in 5 patients. Mean maximum blood concentration was 292ng/ml for temsirolimus and 37.2ng/ml for sirolimus. No drug was detected in CSF (lower detection level 1ng/ml). Conclusions: Temsirolimus 25 mg/week showed some activity in the first 5 patients treated. Neither temsirolimus nor sirolimus could be found in CSF at this dose level. The study will continue at the 75mg dose level. Introduction: The t(14;18)(q32;q21) involving the IGH and the MALT1 genes is a recurrent abnormality in mucosa-associated lymphoid tissue (MALT) lymphomas. However, the nucleotide sequence of only one t(14;18)/IGH-MALT1-positive MALT lymphoma has been reported so far. We herein report the molecular genetic characterization of the direct MALT1-JH and reciprocal DH-MALT1 junctions in 5 new MALT lymphomas harboring the t(14;18)/ IGH-MALT1. Methods: Five cases with the diagnosis of a MALT lymphoma, the presence of the t(14;18)/IGH-MALT1 as shown by interphase fluorescence in situ hybridization (FISH), and available frozen or paraffin-embedded tissue were collected. The direct IGH-MALT1 fusions (MALT1-JH) were confirmed in 5 cases and the reciprocal IGH-MALT1 fusion products (DH-MALT1) in 2 cases. The products were amplified and sequenced twice in both directions. 208 Onkologie 2010;33(suppl 6):1-294 Abstracts Conclusion: Our results demonstrate that ITK-SYK causes T-cell lymphomas in mice which mimic the human disease. Therefore, pharmacological inhibition of Syk in patients with PTCLs carrying the ITK-SYK fusion protein or other Syk fusions might be a new and effective treatment strategy. Onkologie 2010;33(suppl 6):1-294 Abstracts plants (46%) were unrelated, and 60 (19%) were mismatched at 1-2 loci. Haploidentical SCT were not included. Median follow-up of survivors was 39 months (range, 3.1 -253). In 94 transplants, in-vivo T cell depletion was applied, mainly by using anti thymocyte globulin. Results: 120 recipients (38%) were C1/C1 and 50 (16%) were C2/C2 homozygous, while 147 (46%) were C1/C2 heterozygous. Following PBSCT, the 3-year Kaplan-Meier estimate for progression-free survival (PFS) was 0.23 for C2/C2 homozygous recipients, compared to 0.36 and 0.41 for C1/C1 and C1/C2 recipients (p=0.07). Following sibling donor PBSCT (n=130), the respective probabilities were 0.14 (C2/C2), 0.36 (C1/C1), and 0.52 (C1/C2; p=0.002). Multivariate analysis of PBSCT confirmed the adverse effect of C2/ C2 homozygosity on PFS (RR 1.62; p=0.03 in PBSCT, and RR 2.31; p=0.007 in sibling donor PBSCT). In contrast, following BMT, 3-y PFS of C2/C2 recipients (0.65) was at least comparable to that of C1/C1 (0.35) and C1/C2 recipients (0.26; p=0.26). Vice versa, the graft source had no significant impact on PFS in C1/C1 and C1/C2 recipients. However, C2/C2 recipients had superior 3y-PFS and overall survival in case of BMT (0.59 and 0.65) compared to PBSCT (0.23 and 0.20; p=0.01 and p=0.023, respectively). The HLA-C group had no significantly different impact on PFS in the TCD vs the non-TCD cohort. Conclusion: According to the present data, the graft source is the major factor influencing effects of HLA-C KIR ligands. Particularly, C2/C2 recipients may fare better with a BM than with a PBSC graft. Our data do not support the decision for or against TCD on the basis of HLA-C constellations. Introduction: Epstein Barr Virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a serious and underestimated complication of allogeneic stem cell transplantation (alloSCT). Valuable diagnostic tools are needed to help establish the diagnosis early. Patients and methods: We retrospectively analyzed 24 cases of EBVassociated PTLD diagnosed in our centre among 887 consecutive patients (pts) following related (n = 300) or unrelated (n= 587) allogeneic transplantation between 1997 and 2009. Special attention was paid to cytological and immunophaenotypical changes of peripheral blood (PB) cells at the time of diagnosis. Results: 10 female and 14 male pts with probable or definite EBV-PTLD were selected on the basis of their records following alloSCT. Median (md) age was 55 (22-62) years at transplant. 9 pts had received their graft from a well matched, 6 from a partially matched, 6 from a mismatched unrelated donor, and three from a related donor. Most pts had positive EBV-serology whereas 3 pts were serologically negative before alloSCT and acquired primary infection. All but one pt had been treated with ATG. Md time of diagnosis was day (d)+58 (28-378), with one exceptional case before d0. In 17 pts the diagnosis was proven by histology (7 monomorphic, 9 polymorphic and one unclassified lesions), whereas in the remaining cases positive EBV-PCR from PB and typical clinical symptoms established the diagnosis leading to an overall incidence of 2,7% PLTD. From 14 pts PB cytology and immunophaenotyping (IP) were available at the time of diagnosis: In 5 pts IP was diagnostic and in another 5 pts suspicious for the diagnosis. Typical cytological findings ranged from a mononucleosis-like picture with few immunoblasts and plasma cells to various numbers of circulating lymphoma cells. IP revealed a spectrum from CD8-cell expansion with low numbers of polyclonal, activated B-cells to predominantly oligoclonal or monoclonal B-cell proliferations with a typical CD19+, CD20+, CD38++ antigen pattern. 16 pts received Rituximab®, combined with either DLI, radiation or chemotherapy in 5 pts. One CD20-negative pt was treated with chemotherapy and radiation alone. 5 pts are alive, at a md V702
doi:10.1159/000321411 fatcat:5if4sndkdzechng5l4pzf4pw7m