Maintenance Therapy with a Monthly Injection of Alemtuzumab Prolongs Response Duration in Patients with Refractory B-cell Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (B-CLL/SLL)

Abstract Monoclonal antibodies in combination with chemotherapy allowed us to obtain more responses and longer response duration in B-cell chronic lymphocytic leukemia (B-CLL), reducing disease burden to levels detectable only by flow cytometry. Moreover, it has been reported that low-dose rituximab decreases CD20 antigen loss via shaving and promotes enhanced targeting in CLL (Williams, 2006). We performed a phase II study that added rituximab to fludarabine (Flu) as therapy for symptomatic, untreated CLL. Remission status was assessed by a multiparametric flow cytometric method based on the detection of CD19+CD5+CD79b– residual B-CLL lymphocytes. VH mutational status, CD38, ZAP-70 and cytogenetics were obtained in all pts before treatment. We defined as “high risk” pts having at least two of the following markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate/unfavorable cytogenetics (trisomy 12 or del11q or del17p). Eighty-two CLL pts, median age 61 years, received six monthly courses of Flu (25 mg/m2 for 5 days) and four weekly doses of rituximab (375 mg/m2) starting after completion of Flu therapy. According to modified Rai stages, 8 pts had a low stage, 70 an intermediate stage and 4 a high stage. Based on NCI criteria, 66/82 (80%) pts achieved a complete remission (CR), 12/82 (15%) a partial remission (PR) and 4/82 (5%) no response or progression. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 42 pts) and thrombocytopenia (grade 3 and/or 4 in 4 pts). Thirty-five pts in clinical CR or PR, either with CD5+CD19+CD79b– bone marrow (BM) cells >1% (MRD+, n=20 pts) or MRD negative but presenting CD5+CD19+ peripheral blood lymphocytes (PBL) >1000/microl (n=15 pts) within 1 year after completion of the induction treatment, underwent consolidation/maintenance therapy with four monthly cycles of rituximab at 375 mg/m2 followed by twelve monthly doses of rituximab at 150 mg/m2. The median follow-up duration was 46 months. Noteworthy, all B-CLL pts experienced a long progression-free survival (PFS) from the end of induction treatment (68% at 5 years). Nevertheless, CLL pts that underwent consolidation and maintenance therapy (n=35) showed a significant longer response duration (85% at 5 years, Figure). On the other hand, BM and PBL persistently MRD negative (>1 year) pts (n=29) showed a response duration similar to that of the consolidated pts (87% at 5 years). A significant shorter PFS was observed within CD38+ pts (39% vs 78% at 5 years, P=0.002), unmutated pts (45% vs 94% at 2.5 years, P=0.001) and ZAP-70+ pts (36% vs 88% at 6 years; P=0.00002). Notably, within the “high risk” subset (n=30), considering only MRD+ pts in CR or PR (n=20), MRD+ consolidated pts (n=11) showed a significant longer response duration (64% vs 13% at 2 years, P=0.006) in comparison with MRD+ unconsolidated pts (n=9). In conclusion, consolidation/maintenance therapy with rituximab prolongs significantly the response duration in B-CLL, improving also the outcome of the “high risk” subset. Figure Figure

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Rituximab Maintenance Following Chemoimmunotherapy Improves Outcome in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.2364.2364 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2364-2364

Author(s):

Giovanni Del Poeta ◽

Maria Ilaria Del Principe ◽

Dario Ragusa ◽

Luca Maurillo ◽

Francesco Buccisano ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Maintenance Therapy ◽

B Cell ◽

Response Duration ◽

Lymphocytic Leukemia ◽

Induction Treatment ◽

Hematologic Toxicity ◽

Grade 3 ◽

Cell Chronic Lymphocytic Leukemia

Abstract Abstract 2364 Poster Board II-341 The treatment goal of B-cell chronic lymphocytic leukemia (B-CLL) has already shifted from symptom palliation to the attainment of maximal disease control combining purine analogs with monoclonal antibodies. This immunochemotherapeutic approach resulted both in more complete responses (CR) and longer response duration, often remaining only a minimal residual disease (MRD) detectable by flow cytometry. We treated in first line 120 B-CLL symptomatic patients (pts), median age 62 years, with six monthly courses of intravenous or oral fludarabine at conventional doses and then, after a median time of 31 days, with four weekly doses (375 mg/sqm) of rituximab (rtx). Fourteen pts had a low Rai stage, 103 an intermediate stage and 3 a high stage. We defined as high risk pts having at least two of these markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate unfavorable cytogenetics (trisomy 12 or del11q or del17p). Based on NCI criteria, 92/120 (77%) pts achieved a CR, 24/120 (20%) a partial remission (PR) and 4/120 (3%) no response or progression. Ten pts underwent grade 3 (WHO) infective lung toxicity, 1 patient acute fatal B hepatitis and 2 pts progressed towards Richter's syndrome. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 56 pts) and thrombocytopenia (grade 3 and/or 4 in 8 pts). Fifty-four pts either in CR with B-CLL bone marrow cells >1% (MRD+, n=16 pts) or in CR MRD negative, but with B-CLL peripheral cells going up >1000/microl within 1 year after induction (n=22 pts) or in PR (n=16 pts), underwent consolidation and maintenance therapy with four monthly cycles of rtx at 375 mg/sqm followed by twelve monthly low doses of rtx (150 mg/sqm). The median follow-up duration was 50 months. All treated pts experienced a long progression-free survival from the end of induction treatment (40% at 9 years). On the other hand, global overall survival (OS) was 54% at 10 years. Nevertheless, CLL pts undergoing consolidation and maintenance therapy (n=54) showed a longer response duration vs MRD+ not consolidated pts (n=16; 75% vs 9% at 4 years; P<0.00001, Figure). Noteworthy, persistently MRD negative (>1 year) pts (n=43) showed a very long response duration (79% at 6 years, Figure). Moreover, OS was shorter in MRD+ not consolidated pts (0% vs 79% at 15 years; P=0.0007). Noteworthy, within the high risk subset (n=48), consolidated pts (n=17) showed a longer response duration (56% vs 0% at 2.5 years, P=0.003) vs MRD+ not consolidated pts (n=11). Therefore, rituximab consolidation and maintenance immunotherapy improve response duration in B-CLL, thus potentially increasing OS, also within the high risk subset. Disclosures: No relevant conflicts of interest to declare.

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COMPARISON OF CHROMOSOMAL REARRANGEMENTS IN BONE MARROW CELLS AND BLAST TRANSFORMED B-CELLS IN RELAPSE OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA/ SMALL LYMPHOCYTIC LYMPHOMA

Experimental Oncology ◽

10.31768/2312-8852.2017.39(2):141-144 ◽

2017 ◽

Vol 39 (2) ◽

pp. 141-144

Author(s):

S V Andreieva ◽

K V Korets ◽

O E Ruzhinska ◽

I M Skorokhod ◽

O G Alkhimova

Keyword(s):

Bone Marrow ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Chromosomal Rearrangements ◽

Lymphocytic Leukemia ◽

Banding Technique ◽

Small Lymphocytic Lymphoma ◽

Detection Frequency ◽

Cell Chronic Lymphocytic Leukemia

Aim: The genetic mechanisms of resistance to chemotherapy in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) are not clear. We aimed to determine the peculiarities of abnormal karyotype formation in bone marrow (BM) cells and peripheral blood (PB) blast transformed B-cells in relapse of B-CLL/SLL. Materials and Methods: Cytogenetic GTG banding technique and molecular cytogenetic in interphase cells (i-FISH) studies of BM cells and PB blast transformed B-lymphocytes were performed in 14 patients (10 males and 4 females) with B-CLL/SLL. Results: The results of karyotyping BM and PB cells revealed the heterogeneity of cytogenetic abnormalities in combined single nosological group of B-CLL/SLL. In PB B-cells, chromosome abnormalities related to a poor prognosis group were registered 2.5 times more often than in BM cells. Additional near tetraploid clones that occurred in 57.1% cases were the peculiar feature of BM cell karyotypes. Chromosomal rearrangements characteristic of the group of adverse cytogenetic prognosis were revealed in all cases from which in 2 cases by karyotyping BM cells, in 6 cases in PB B-cells and in 8 cases by the i-FISH method in BM cells, i.e. their detection frequency was 3 times higher in PB B-cells and 4 times higher when analyzing by i-FISH in BM cells. Conclusions: Mismatch in abnormal karyotypes in BM and PB B-cells by the presence of quantitative and structural chromosomal rearrangements may be indicative of simultaneous and independent processes of abnormal clone formation in the lymph nodes and BM hematopoietic cells. Accumulation the information about previously unidentified chromosomal rearrangements in relapse of the disease may help to understand the ways of resistance formation to chemotherapy.

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