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K Giannopoulos,
A Dmoszynska, M Kowal,
J Rolinski,
E Gostick,
D A Price,
J Greiner,
M Rojewski,
S Stilgenbauer,
H Döhner,
M Schmitt
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ABSTRACT: The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8(+) T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM(+) CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2(+) CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 microg per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 microg per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I degrees skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8(+) T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8(+) T cells that expressed high levels of CD107a and produced both interferon-gamma and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8(+) T-cell responses against the tumor antigen RHAMM.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2010; 24(4):798-805. · 8.30 Impact Factor
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ABSTRACT: Thalidomide represents a promising immunomodulatory drug that targets both leukemia cells and the tumor microenvironment. We treated patients with chronic lymphocytic leukemia (CLL) with a combined thalidomide/fludarabine regimen and monitored cellular and molecular changes induced by thalidomide in vivo before fludarabine treatment. Thalidomide was given daily (100 mg p.o. per day) and fludarabine was administered on days 7-11 (25 mg/m(2) i.v. per day) within each 4-week cycle (maximum of 6 cycles). Twenty patients received thalidomide/fludarabine as first-line therapy and 20 patients were previously treated. Unmutated IgVH mutation status was found in 36 cases and 13 had high-risk cytogenetic aberrations (del17p, del11q). The overall response rate was 80 and 25% for untreated and previously treated patients, respectively. Although thalidomide reduced the number of CLL cells, the number of CD3 lymphocytes showed no significant change, but the number of CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Tregs) was significantly decreased. Gene expression profiling revealed a thalidomide-induced signature containing both targets known to have a function in immunomodulatory drug action as well as novel candidate genes. Combined thalidomide/fludarabine therapy demonstrated efficacy in high-risk patients with CLL. Furthermore, our study provides novel biological insights into thalidomide effect, which might act by enhancing apoptosis of CLL cells and reducing Tregs, thereby enabling T-cell-dependent antitumor effect.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2009; 23(10):1771-8. · 8.30 Impact Factor
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ABSTRACT: The immunosuppression accompanies B-cell chronic lymphocytic leukemia (B-CLL) but might be also responsible for disease progression by enabling CLL cells to escape from the immunosurveillance. Some particles involved in the regulation of an immune system might represent prognostic value for B-CLL. Recently we found no correlation between HLA-G on messenger and protein level, suggesting that HLA-G is released in soluble form. To confront this hypothesis we characterized soluble HLA-G (sHLA-G) by the prognostic factors in the first cohort of 34 CLL patients. No correlation was observed between sHLA-G levels in ZAP-70(+) and ZAP-70(-) CLL as well as in CD38(+) CLL and CD38(-) CLL patients. Next, we wondered whether gene expression of HLA-G, which represent the whole HLA-G pool in the cell, posses prognostic value for CLL. In the second cohort of 41 CLL patients we assessed messenger levels of HLA-G by the strongest prognostic factors in CLL including cytogenetics, IgVH mutational status, ZAP-70 as well as CD38. No changes of HLA-G expression levels were found in different CLL groups characterized by IgVH gene mutational status, ZAP-70 as well as CD38. We observed no differences in expression of HLA-G in various cytogenetic groups of CLL including del17p, del13q, del11q, +8q, +3q, del14q and del6q when compared to those with normal karyotype or with 12+. Both, mRNA expression of HLA-G and levels of its soluble form in plasma bring no additional prognostic value for B-CLL patients.
Leukemia Research 06/2008; 32(12):1815-9. · 2.92 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2008; 22(1):222-4. · 8.30 Impact Factor
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M Kowal,
A Dmoszyńska,
K Lewandowski,
A Hellmann,
J Wegrzyn,
A B Skotnicki,
D Wołowiec,
K Kuliczkowski,
J Piszcz,
J Kłoczko,
K Roznowski,
M Komarnicki
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ABSTRACT: The aim of this study was to investigate the efficacy of a combination of fludarabine (F) and cyclophosphamide (C) in the treatment of patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL). Between November 1999 and December 2001, 63 patients with B-CLL (median age 60 years) received a regimen that consisted of F 25 mg/m2 and C 250 mg/m2, days 1-3, intravenously, every 4 weeks, for a maximum of 6 courses, Response and toxicity were assessed according to current criteria (NCI-WG and WHO). Complete and partial remissions were achieved in 17.5% and 55.6% of patients, respectively; 19% of patients had stable disease and 7.9% of patients showed disease progression. The median follow-up was 16.5 (range 1.5-32) months. The median duration of progression-free survival (PFS) has not been reached among patients treated with FC regimen as second-line therapy. The median PFS was 13 (range 8-26) months in the 19 responding patients treated with FC regimen as third-line therapy. The most frequent side-effects were neutropenia (45%), thrombocytopenia (42%) and infections (57%). We conclude that the combination of fludarabine and cyclophosphamide demonstrated significant efficacy in pretreated, advanced B-CLL patients, with tolerable toxicity.
Leukemia and Lymphoma 07/2004; 45(6):1159-65. · 2.58 Impact Factor
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A Wrzesień-Kuś,
T Robak,
E Lech-Marańda,
A Wierzbowska,
A Dmoszyńska, M Kowal,
J Hołowiecki,
S Kyrcz-Krzemień,
S Grosicki,
S Maj,
A Hellmann,
A Skotnicki,
W Jedrzejczak,
K Kuliczkowski
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ABSTRACT: To evaluate the efficacy and toxicity of cladribine (2-chlorodeoxyadenosine, 2-CdA), cytarabine (Ara-C), and granulocyte-colony stimulating factor (G-CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study.
The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C2 g/m2, and G-CSF. In the case of partial remission (PR), a second CLAG was administered. Patients in complete remission (CR) received two consolidation courses based on HD Ara-C, mitoxantrone or idarubicine, with or without 2-CdA.
Fifty-eight patients from 11 centers were registered; 50 primary resistant and eight early relapsed (CR1 < 6 months). CR was achieved in 29 (50%) patients, 19 (33%) were refractory, and 10 (17%) died early. Forty of 50 primary resistant patients received daunorubicin (DNR) and Ara-C as the first-line induction therapy (DA-7), 10 received additional 2-CdA (DAC-7). The CR rates after CLAG were 58% and 10%, respectively in each group (P = 0.015). Five of six patients with myelodysplastic syndrome (MDS)/AML achieved CR. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS, 1 yr) for the 58 patients as a whole, and the 29 patients in CR were 42% and 65%, respectively. Disease-free survival (DFS, 1 yr) was 29%. Only first-line induction treatment with DA-7 significantly influenced the probability of CR after CLAG. None of the analyzed factors significantly influenced DFS and OS.
CLAG regimen has significant anti-leukemic activity and an acceptable toxicity in refractory AML. The addition of 2-CdA to the first-line induction treatment may worsen the results of salvage with CLAG. The high CR rate in patients with MDS preceding AML deserves further observation.
European Journal Of Haematology 09/2003; 71(3):155-62. · 2.61 Impact Factor
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ABSTRACT: The aim of the study was efficacy and toxicity evaluation of combination of 2-Chlorodeoxyadenosine (2-CdA) with cytarabine (Ara-C) and G-CSF (CLAG regimen) as reinduction therapy in patients with refractory or relapsed acute myeloid leukemia (AML). The protocol stipulated an infusion of 5 mg/m2 of 2-CdA over 2 hours daily for 5 consecutive days. A 4-hour infusion of Ara-C (2 g/m2) was started 2 hours after each infusion of 2-CdA. G-CSF at a dose 300 microg s.c was given 24 hours before the first dose of 2-CdA for 6 days. In case of WBC>20x10(9)/l G-CSF was started simultaneously with 2-CdA. In the case of complete response (CR) consolidation treatment with 2-CdA containing regimens was started. In case of partial response a second identical course of CLAG was given. Response criteria were established according to those developed by the NCI Sponsored Workshop. Among 20 patients accrued all but 2 received at least one course of CLAG induction therapy in the planned doses. 10/20 (50%) (95% CI 27-73%) patients achieved a CR with a median duration of 22.5 weeks (range 3.5-53 weeks). Two (10%) patients had a PR and 8 were non-responders. One patient underwent peripheral blood stem cell transplantation. Overall 4 patients are in continuous CR with a median duration of 16.2 weeks (range 3.5-36.5). Among non-responders two patients did not receive the full dose of treatment because of complications during the cycle, both of them died; 3 died early after complete induction therapy before recovery of the bone marrow and 3 were resistant to CLAG. All 20 patients but one experienced granulocytopenia <0.2x10(9)/l and thrombocytopenia <20x10(9)/l. Median time to reach PMN>0.5x10(9) G/l was 18.7 days and platelets>50x10(9)/l was 27.2 days. In conclusion, the CLAG regimen had significant antileukemic activity and acceptable toxicity as reinduction treatment in refractory or relapsed AML patients.
Leukemia and Lymphoma 09/2000; 39(1-2):121-9. · 2.58 Impact Factor
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Polskie archiwum medycyny wewnȩtrznej 11/1995; 94(4):349-57. · 1.37 Impact Factor
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ABSTRACT: A 26-year old man had pancytopenia and marrow hypoplasia in association with a CD 3+, CD 8+ clonal large granular lymphocyte. At first treatment with cyclophosphamide and prednisone resulted in normalization of the patient's cell counts. During the second episode of illness it was observed infiltration of lymphnodes, stomach and bones. Application of steroids combination chemotherapy was inefective. The patient died.
Polskie archiwum medycyny wewnȩtrznej 04/1993; 89(3):235-9. · 1.37 Impact Factor
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ABSTRACT: In a group of 16 patients with chronic lymphocytic leukaemia and leukaemic forms of the lymphoma lymphoplasmocytoides immunophenotypes of peripheral blood and lymph node lymphocytes were studied. Conclusions: 1) immunophenotype heterogeneity observed in a minority of patients in lymph-nodes or peripheral blood seems to be connected with the co-existence of leukaemic and normal reactive B-cells, 2) SIgG+ cells seem to represent activated B lymphocytes producing and secreting autoantibodies, 3) circulating peripheral T lymphocytes do not reflect the distribution of T cell subpopulations in lymph-nodes.
Acta haematologica Polonica 02/1992; 23(1):29-41.
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ABSTRACT: This article contains the review and the critical discussion of studies of T and B lymphocytes in chronic B-cell lymphocytic leukaemia. It is not explicitly known now, which stage of differentiation of lympho-haemopoietic cells undergoes malignant transformation in CLL-B. Basing on VDJ recombination activity it is supposed that some cases derive from the stem cell, others--from B lineage cells.
Acta haematologica Polonica 02/1992; 23(1):21-7.
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Polskie archiwum medycyny wewnȩtrznej 01/1983; 68(6):391-400. · 1.37 Impact Factor
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Postȩpy higieny i medycyny doświadczalnej 38(1):39-60.
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ABSTRACT: In a group of 9 patients with chronic lymphocytic or lymphoplasmocytic leukaemia in clinical stage from 2 to 4 (classification of Rai et al.) 8 various CHOP programmes (cyclophosphamide, hydroxyldaunomycin, oncovin, prednisone) were used. In 6 cases (67%) partial remission was obtained, with normalization of peripheral blood and bone marrow patterns, with statistically significant decrease of the proportion of cells forming rosettes with murine erythrocytes, and with reduction or full normalization of the size of previously enlarged lymph nodes. In one case the control examination of a lymph node failed to demonstrate the previously present clone of cells with chromosomal aberration, although in histological examination the diagnosis of lymphoplasmocytic lymphoma was maintained. In the remaining 3 cases no partial remission was noted, and in one case progression was recognized. We think similarly as the French haematologists studying chronic lymphatic leukaemia, that the CHOP programme is effective in the treatment of chronic lymphatic or lymphoplasmocytic leukaemia.
Acta haematologica Polonica 21(2):185-91.
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ABSTRACT: The purpose of the study was evaluation of the effect of treatment on the immunological phenotype of peripheral blood lymphocytes in patients with chronic lymphocytic leukaemia or in leukaemic forms of non-Hodgkin lymphomas, with low or medium grade malignancy. The study was carried out in 13 patient. In those responding to treatment a tendency was observed for normalization of the immunological phenotype of peripheral blood lymphocytes (increased proportion of cells forming rosettes with sheep erythrocytes, reduced proportion of cells forming rosettes with murine erythrocytes), and a tendency for polyclonal pattern of B-cells with immunoglobulins on their surface (although this feature was not a rule). In non-responders these tendencies were much less pronounced or absent. Similarly, in non-responders the tendency for polyclonal B-cell pattern may be only apparent, and may be connected with proliferation of a new lymphocyte population with another type of light chain.
Acta haematologica Polonica 21(2):192-206.
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ABSTRACT: In a group of 23 patients with chronic lymphocytic leukaemia in 1-4 clinical stages of the disease according to Rai et al (34) classification, mostly untreated (only 5 treated) considerable heterogeneity was found as evidenced by: variability of the morphological patterns of bone marrow, differences of immunological phenotypes of peripheral blood lymphocytes between individual cases, --coexistence of the features of maturity and immaturity in the populations of peripheral blood lymphocytes in the same case.
Acta haematologica Polonica 21(1):32-45.
