Subcutaneous Alemtuzumab in Patients with Refractory/Relapsed B-Cell CLL after a Fludarabine-Based Regimen. An Interim Analysis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2843-2843
Author(s):  
R. Fernando Bezares ◽  
German Stemmelin ◽  
Daniel Argentieri ◽  
Emilio Lanari ◽  
Efrain Guy-Garay ◽  
...  
Keyword(s):  
B Cell ◽  
Interim Analysis ◽  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Prior Therapy ◽  
Barr Virus ◽  
Epstein Barr

Abstract Background: Alemtuzumab is the only single agent immunotherapy to demonstrate a survival benefit in patients with B-cell chronic lymphocytic leukemia (B-CLL), who have relapsed from or are refractory to Fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. Here, we report the second interim analysis of a new, less intensive schedule of alemtuzumab administered subcutaneously (SC) to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg twice week during the second and third weeks, and 30 mg once weekly during Weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg three-times daily. Results: Of the 38 patients who were recruited to participate in the trial, 12 (31.6%)were refractory and 26 (68.4%) had relapsed from prior therapy. Patients had a median age of 66.5 years (range, 43–86 years), 30 were male (79%), 45%/53% had Binet stage B/C disease. The median number of prior therapies was 1 (range: 1–4). The median duration of therapy was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 457 mg (range, 120–1,080 mg). Among the 35 patients who were evaluable for response, the overall response rate was 88.6%: 45.8%complete response (CR), 2.9% unconfirmed CR, 42.8% partial response (PR). Four patients ( 11.5%) did not respond to therapy. Of the 9 patients with refractory disease, 1 achieved a CR, 6 a PR and 2 did not respond. Median follow up was 13 months and median overall survival was not achieved. Minimal residual disease (MRD) was measured by flow cytometry in 6 patients who achieved a CR: 4 patients had <0.5% of CD5/CD19+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, over 38 evaluable patients, 4 (10,6%) experienced grade 3/4 infection; 2 patients had grade 2/3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia. Conclusion: Results of this second interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy.

Subcutaneous alemtuzumab in patients with refractory/relapsed B-CLL after a fludarabine-based regimen

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6600-6600
Author(s):  
R. Bezares ◽  
G. Stemmelin ◽  
D. Argentieri ◽  
E. Lanari ◽  
E. Guy-Garay ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Duration Of Treatment ◽  
Barr Virus ◽  
Epstein Barr ◽  
Grade 3 ◽  
Cmv Disease

6600 Background: Alemtuzumab is the only immunotherapy that is effective as a single agent in patients with B-CLL who are refractory to, or who have relapsed after, fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. We report the first interim analysis of a new, less intensive schedule of alemtuzumab SC to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg bid during the second and third weeks, and 30 mg once weekly during weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg tid. Results: Patients (N = 36) with refractory (19%) or relapsed (81%) B-CLL had a median age of 67 years (range, 43–86 years), 28 were male, 61%/39% had Binet stage B/C disease, and 2 had B-cell prolymphocytic transformation. The median number of prior therapies was 1 (range, 1–4). The median duration of treatment was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 412 mg (range, 150–1,080 mg). Thirty-two patients were evaluable for response. The overall response rate of 93%: complete response (CR), 34%; unconfirmed CR, 6%; partial response (PR), 53%. Two patients (7%) did not respond to therapy. Of the 7 refractory patients, 5 had a PR, 1 did not respond, and 1 was not yet evaluable. Median overall survival was 10 months, which correlated with response and pretreatment status. Minimal residual disease (MRD) was measured by flow cytometry in 5 patients who achieved a CR: 3 patients had <0.5% of CD5/CD19/CD23+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, 5 patients experienced grade 3/4 infection; 2 patients had grade 3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia. Conclusions: Results of this interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy. No significant financial relationships to disclose.

Analysis of Minimal Residual Disease (MRD) from the Phase 2 Multicenter Study of Subcutaneous (SC) Alemtuzumab Combined with Fludarabine for Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3111-3111 ◽  
Author(s):  
Christopher Flowers ◽  
Hilary Rosenthal ◽  
Jennifer Brown ◽  
Wendy Stock ◽  
Harvey Katzen ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Residual Disease ◽  
Pearson Correlation ◽  
Single Agent ◽  
Complete Response ◽  
Salvage Chemotherapy ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Color Flow ◽  
Prior Therapy

Abstract Introduction: In patients (pts) with relapsed/refractory CLL, responses achieved with conventional salvage chemotherapy may have limited durability, likely due to the presence of residual disease remaining in the bone marrow (BM) or peripheral blood (PB). The anti-CD52 monoclonal antibody alemtuzumab (Campath®) demonstrates single-agent efficacy in relapsed/refractory CLL and has been shown to induce MRD-negative (-) responses in 20% of pts (Moreton et al J Clin Oncol2005;23:2971–2979). A recent phase 2 study reported that treatment with SC alemtuzumab with or without the addition of oral fludarabine in pts with relapsed/refractory CLL resulted in a 49% overall response (OR) rate and 16% complete response (CR) rate; MRD(-) CR was achieved in 10% of pts (Sayala et al Blood2006;108: abstract 34). We evaluated the safety and efficacy of SC alemtuzumab combined with intravenous (IV) fludarabine in pts with previously treated CLL and report the responses and results from MRD analysis. Methods: Eligible pts had active CLL requiring therapy and had relapsed after at least 1 prior therapy. SC alemtuzumab 30 mg days 1–5 and IV fludarabine 25 mg/m2 days 1–5 were administered on a 28-day cycle for 4 cycles. Pts with <CR after 4 cycles were eligible to receive 2 additional cycles up to a total of 6 cycles. Responses were assessed based on the 1996 NCI Working Group Criteria. MRD was measured in the BM and PB at baseline, interim analysis, end of treatment, and 2 and 9 months following treatment. Four-color flow cytometry assays (CD5+/CD19+/CD38+/CD20[dim], CD5+/CD19+/CD43+/CD79b[dim], CD5+/CD19+/CD81+/CD22[dim]) were used to evaluate 200,000 to 1,000,000 events per sample, with lower limits of detection (LLD) ranging from 0.005% to 0.01% of leukocytes. Results: The study completed enrollment with 56 pts (median age 62 years, range 37–86; 54% Rai stage III/IV; median 3 prior lines of therapy, range 1–14) receiving at least 1 dose of study treatment; 28 pts (50%) completed 4 or more cycles of therapy and were evaluable for response; of these, 17 (30%) pts completed 5 or more cycles and 11 (20%) completed 6 cycles of therapy. MRD evaluation of the BM was available in 17 pts. The ORR among 28 evaluable pts was 64%, with CR in 6 pts (21%). Four of 6 pts in CR achieved MRD(-) in both BM and PB, which was maintained at last evaluation in all 4 pts. In addition, 9 pts with PR showed no evidence of disease in PB and/or BM below LLD, with 4 of these pts having undetectable disease in BM. The correlation between MRD(-) in the PB and BM was 0.63 and between MRD(-) by 4-color flow and CD5+/CD19+ <1% in the BM was 0.67 (Pearson correlation). Conclusion: After treatment with SC alemtuzumab and IV fludarabine, 64% of pts responded, with 8 of 17 evaluable pts achieving molecular undetectable disease in the BM, suggesting that MRD(-) remissions can be attained in a portion of heavily pretreated pts with CLL. Four-color flow cytometry of the BM is necessary to monitor MRD after an alemtuzumab regimen.

Quantitative PCR Predicts Early Relapse in Patients with Chronic Lymphocytic Leukemia (CLL) Submitted to Autologous Stem Cell Transplantation. The Case for Early Clinical Intervention.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2255-2255
Author(s):  
Carol Moreno ◽  
Neus Villamor ◽  
Dolors Colomer ◽  
Jordi Esteve ◽  
Francesc Bosch ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Median Time ◽  
Residual Disease ◽  
Clinical Intervention ◽  
Complete Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Clinical Relapse ◽  
Risk Of Relapse

Abstract Autologous stem cell transplants (auto-SCT) are increasingly performed in patients with CLL. Although this procedure results in a high complete response (CR) rate, most patients eventually relapse. The median time to relapse is around 5 years. Increasing levels of minimal residual disease (MRD), detected by PCR or flow cytometry (FC) are associated with clinical relapse. The early detection of patients likely to relapse shortly after SCT may be useful in the management of these patients. With this background, we analyzed the levels of MRD and its correlation with the risk of relapse and clinical outcome in 19 patients with CLL submitted to auto-SCT. MRD was assessed by FC and quantitative real time PCR of the IgH region using allele-specific oligonucleotides (ASO-PCR) in peripheral blood and/or bone marrow DNA samples obtained before SCT and at different time points thereafter. After SCT, 17 patients achieved CR and 2 partial response. A continuous pattern of relapses was observed and, after a median follow-up of 48 months (range, 11–101), 11/19 patients have progressed. The median number of CLL cells detected prior to SCT was 2.4x10−2 decreasing to 5.31x10−4 at 3–6 months after auto-SCT. No further decrease was observed beyond that point. At 3–6 months after auto-SCT, only 3/17 patients in CR had undetectable levels of disease. Patients with a MRD level >10−3 at this time point (3–6 months after transplant) had a significantly higher risk of progression than those who had less than 10−3 CLL cells. All but one patients with MRD>10−3 have relapsed (7/8) whereas only 4/9 with MRD<10−3 did so. As shown in the figure, median time to progression was significantly shorter in those patients with a higher MRD level (16 vs. 55 months; p=0.003) Figure Figure In conclusion, quantification of MRD within the first 6 months after auto-SCT allows the identification of CLL patients with a high risk of early clinical relapse. These data provide background to investigate whether early treatment, before clinically overt relapse occurs, might be useful in patients with high risk of relapse after SCT.

Influence of Chromosomal Aberrations on Response to First Line Therapy in B-Cell Chronic Lymphocytic Leukemia: Interim Analysis of PALG-CLL3 Randomized Study Comparing Cladribine Plus Cyclophosphamide vs Fludarabine Plus Cyclophosphamide.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2046-2046
Author(s):  
Tadeusz Robak ◽  
Jerzy Z. Blonski ◽  
Ewa Wawrzyniak ◽  
Aleksandra Palacz ◽  
Joanna Gora-Tybor ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Aberrations ◽  
Interim Analysis ◽  
Chromosomal Abnormalities ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Lower Probability ◽  
Trisomy 12 ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Impact of cytogenetic abnormalities on treatment with different purine nucleoside analogs in patients (pts) with B-cell chronic lymphocytic leukemia (B-CLL) is largely unknown. One of objectives of PALG-CLL3 trial, comparing cladribine plus cyclophosphamide (CC) with fludarabine plus cyclophosphamide (FC) in previously untreated progressive B-CLL, was to verify the response to treatment in subsets of pts characterized by common cytogenetic abberrations. Chromosomal abnormalities were assessed using fluorescence in situ hybridization (FISH) on interphase nuclei of lymphocytes on whole blood smears prior to the start of the study treatment. Pts were screened for trisomy 12, deletions (del) 11q, del 13q and del 17p using DNA probes: CEP12, LSI: ATM, D13S319 and p53 (Vysis), respectively. For the purpose of the present interim analysis complete cytogenetic results were available in 133 pts out of 423 pts included to the study. In this group the chromosomal aberrations were detected in 102 pts (77%) including single abnormalities observed in 69 pts (52%) and two or more aberrations in 33 pts (25%). Thirty-one pts (23%) exhibited a normal interphase FISH pattern. The most frequent single abnormality was del 13q found in 38 pts (29%), while del 17p, trisomy 12 and del 11q were identified in 14 pts (11%), 11 pts (8%), and 6 pts, (5%), respectively. The most frequently observed associations of chromosomal aberrations were: del 13q with del 11q (11 pts, 8%) and del 13q with del 17p (10 pts, 8%). Four pts (3%) revealed three chromosomal abnormalities including association of trisomy 12/del 11q/del 13q in two pts, trisomy 12/del 11q/del 17p in one pt and del 11q/del 13q/del 17p in one pt. Overall, treatment was completed and response assessed in 113 out of 133 pts with known FISH pattern. In this group of pts del 17p was the only chromosomal abnormality that correlated significantly with treatment outcome. Pts with del 17p (21, 19%) had lower probability to achieve a complete response (CR) (0.044). Interestingly, in independent analyses of both treatment arms, the negative impact of 17p was seen in pts treated with FC (p=0.002), but not in pts treated with CC (p=0.6). Moreover, comparing response rates between treatment arms we found that CC was superior to FC in terms of complete response in pts with del 17p (57% CR in CC v 14% CR in FC arm, p=0.04). In conclusion, chromosomal abnormalities can be detected in majority B-CLL pts requiring treatment. Our preliminary results suggest that CC combination may have some advantage in terms of CR achievement in B-CLL pts harboring del 17p.

Unexpected and Serious Toxicity Observed with Combined Idelalisib, Lenalidomide and Rituximab in Relapsed/Refractory B Cell Lymphomas: Alliance A051201 and A051202

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3091-3091 ◽  
Author(s):  
Sonali M. Smith ◽  
Brandelyn Pitcher ◽  
Sin-Ho Jung ◽  
Nancy L. Bartlett ◽  
Nina Wagner-Johnston ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Clin Oncol ◽  
Research Funding ◽  
Treatment Initiation ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Cell Transplant

Abstract Background: A number of targeted and orally available agents show promising activity in lymphoid malignancies, and a rational strategy is to evaluate combinations for safety and efficacy. Idelalisib (idela) is a highly specific and potent inhibitor of the delta isoform of PI3K, downstream of B-cell receptor signaling and upstream of other survival pathways in lymphoma. Idela has single agent activity in both follicular lymphoma (FL) and mantle cell lymphoma (MCL), with response rates over 50% (N Engl J Med. 2014;370:1008). Idela and rituximab (ritux) have been safely combined in chronic lymphocytic leukemia (N Engl J Med. 2014;370:997) and other indolent lymphomas. Two previous Cancer and Leukemia Group B and Alliance studies demonstrated high levels of clinical activity of lenalidomide (len) and ritux in combination without significant toxicity. In relapsed/refractory FL, len plus ritux had higher overall (ORR) and complete response (CR) rates (75% ORR, 32% CR) versus len alone (49% ORR, 13% CR)(J Clin Oncol. 2012;30(suppl; abstr 8000). In frontline FL, len plus ritux achieved 93% ORR and 72% CR rates (J Clin Oncol 32:5s, 2014 (suppl; abstr 8521). A051201 and A051202 were designed to evaluate the safety and activity of len and ritux, in combination with idela, in pts with relapsed MCL or FL, respectively. Methods: Both A051201 and A051202 are phase I trials with 3+3 designs and pre-specified dose-limiting toxicities (DLT). Treatment in the two trials was similar but not identical. A051201 started with len 15mg po day (d) 1-21 q28d idela 150mg bid with continuous 28-d cycles, and ritux weekly during cycle 1. A051202 started with len 10mg po d1-21 q28d and idela 150mg po bid with continuous 28-d cycles, and ritux on C1d8, C1d15, C1d22 and C2d1. Both studies included a maintenance component (data not presented). Biweekly conference calls for safety were established. After 3 patients (pts) from A051202 and 1 pt from A051201 developed severe and unexpected DLT, both trials were suspended and modified. Results: At the time of study suspension, 7 FL pts and 1 MCL pt had been enrolled. Pt characteristics include median age 58.5 years (y) (range, 47-77), 5 male/3 female, and median 1 (range, 1-7) prior treatment; all pts had prior ritux. The MCL pt had an autologous stem cell transplant 3 y prior to enrollment. This pt had a DLT consisting of grade (gr) 4 AST/ALT elevation in the setting of fevers, chills, hypotension at 22 d after treatment initiation. 3 FL pts had DLT consisting of gr 3 lung infection, gr 3 hypotension and rash, and gr 4 sepsis syndrome (culture-negative), respectively. Each of the 3 FL pts with DLT developed fevers and hypotension with or without a rash 11-17 d after treatment initiation and within 24-120 hours of last ritux exposure; 2 pts had pulmonary infiltrates. 3 DLT pts required ICU level support. Other notable toxicities in all 8 pts include gr 1/2 AST/ALT elevation (n=5), gr 3 lymphopenia (n=5), gr 1/2 thrombocytopenia (n=4), grade1/2/3 neutropenia (n=4). Conclusion: Whereas doublet therapy with len/ritux and idela/ritux has been safely combined in other trials and disease settings, we observed 4 DLTs among the first 8 pts, all concerning for high-level immune activation. Although the mechanism of these toxicities is unknown, the combination of rash, fevers, and hypotension is suggestive of cytokine release syndrome (CRS), which is a known but uncommon IL-6-mediated event seen with ritux, rarely reported after single agent len, and, to date, not observed with idela. Our observation of 4 potential CRS-like reactions among 8 pts suggests an additive and previously undescribed risk of this combination. Based on the severe toxicities noted, both trials have been amended to remove ritux and pursue a phase I safety assessment of idela and len without ritux in pts with relapsed FL or MCL. Disclosures Smith: Celgene: Consultancy, Research Funding; Gilead: Consultancy; Genentech: Consultancy, DSMB for another compound, DSMB for another compound Other. Off Label Use: Phase I results of combined idela/len and rituximab. Bartlett:Gilead: Consultancy, Research Funding; Celgene: Research Funding. Wagner-Johnston:Gilead: Consultancy; Celgene: Research Funding. Richards:Genentech: Consultancy; Celgene: Honoraria. Cashen:Celgene: Speakers Bureau. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Leonard:Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy.

Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3742-3747 ◽  
Author(s):  
Rainer Hubmann ◽  
Josef D. Schwarzmeier ◽  
Medhat Shehata ◽  
Martin Hilgarth ◽  
Markus Duechler ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Core Promoter ◽  
Lymphocytic Leukemia ◽  
Mobility Shift ◽  
Aberrant Expression ◽  
Barr Virus ◽  
Epstein Barr ◽  
Cell Chronic Lymphocytic Leukemia

Members of the Notch family encode transmembrane receptors that modulate differentiation, proliferation, and apoptotic programs of many precursor cells, including hematopoietic progenitors. Stimulation of Notch causes cleavage followed by translocation of the intracellular domain (NotchIC) to the nucleus, where it activates transcription of CBF1 responsive genes. The aim of this study was to elucidate the mechanisms leading to the overexpression of CD23, a striking feature of B-cell chronic lymphocytic leukemia (B-CLL) cells. By electrophoretic mobility shift assays, we identified a transcription factor complex (C1) that binds sequence specific to one known and 4 newly identified putative CBF1 recognition sites in the CD23a core promoter region. With the use of Epstein-Barr virus (EBV)–infected B cells as a model for CBF1 mediated CD23a expression, C1 was found to be EBV inducible. Supershift assays revealed that the nuclear form of Notch2 is a component of C1 in B-CLL cells, supporting a model in which NotchIC activates transcription by binding to CBF1 tethered to DNA. Transient transfection of REH pre–B cells with an activated form of Notch2 induced endogenous CD23a, confirming thatCD23a is a target gene of Notch2 signaling. Finally, reverse transcription-polymerase chain reaction and kinetic analysis demonstrated that the Notch2 oncogene is not only overexpressed in B-CLL cells but might also be related to the failure of apoptosis characteristic for this disease. In conclusion, these data suggest that deregulation of Notch2 signaling is involved in the aberrant expression of CD23 in B-CLL.

scholarly journals CD5 and immunoglobulin V gene expression in B-cell lymphomas and chronic lymphocytic leukemia

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1518-1524
Author(s):  
R Mayer ◽  
T Logtenberg ◽  
J Strauchen ◽  
A Dimitriu-Bona ◽  
L Mayer ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
B Cell Lymphomas ◽  
Barr Virus ◽  
Gene Usage ◽  
Variable Gene ◽  
Epstein Barr ◽  
T Cell Malignancies

We studied the expression of CD5 and immunoglobulin variable gene families in a panel of monoclonal Epstein-Barr virus (EBV) transformed lines, chronic lymphocytic leukemias (CLLs) and CD5+ and CD5- B-cell lymphomas. The CD5 gene expression was in all cases identical to that of T-cell malignancies. The utilization of the various VH and VK gene families was roughly proportional to the estimated gene family size in EBV lines obtained from adult healthy subjects. In contrast we found a statistically significant biased usage of VH6 in CLL and VH5 in CD5+ lymphomas as compared with EBV lines, and of VKIII in both CLL and CD5+ lymphomas as compared with EBV lines. Some differences in the variable gene usage were also noted when comparing CD5+ and CD5- lymphomas. These findings are analyzed in the context of possible mechanisms involved in the malignant transformation of CD5+ B cells.

scholarly journals Extensive and selective mutation of a rearranged VH5 gene in human B cell chronic lymphocytic leukemia.

1992 ◽  
Vol 176 (4) ◽  
pp. 1073-1081 ◽  
Author(s):  
J Cai ◽  
C Humphries ◽  
A Richardson ◽  
P W Tucker
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Lymphocytic Leukemia ◽  
Barr Virus ◽  
Charge Analysis ◽  
Epstein Barr ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Human B Cell

B cell chronic lymphocytic leukemia (CLL) is the malignant, monoclonal equivalent of a human CD5+ B cell. Previous studies have shown that the VH and VL genes rearranged and/or expressed in CLL have few and apparently random mutations. However, in this study, we have found that the rearranged VH251 gene, one of the three-membered VH5 family, has extensive and selective mutations in B-CLL cells. Somatic mutation at the nucleotide level is 6.03% in B-CLLs whereas the somatic mutation levels are much lower in CD5+ and CD5- cord B cells, adult peripheral blood B cells, and Epstein-Barr virus-transformed CD5+ B cell lines (0.45, 0.93, and 1.92%, respectively). Complementary determining region 1 (CDR1) mutation in CLLs is particularly prevalent, and interchanges in CDRs often lead to acquisition of charge. Analysis of somatic mutations and mutations to charged residues demonstrated that the mutations in CLLs are highly selected.

scholarly journals Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial)

Blood ◽  
2020 ◽  
Vol 136 (11) ◽  
pp. 1284-1297 ◽  
Author(s):  
Juan C. Ramos ◽  
Joseph A. Sparano ◽  
Amy Chadburn ◽  
Erin G. Reid ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
B Cell ◽  
Negative Impact ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hiv Reservoirs ◽  
Herpesvirus Type ◽  
Barr Virus ◽  
Epstein Barr

Abstract EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count &lt;200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.

scholarly journals A phase II study of ibrutinib in combination with rituximab-cyclophosphamide-doxorubicin hydrochloride-vincristine sulfate-prednisone therapy in Epstein-Barr virus-positive, diffuse large B cell lymphoma (54179060LYM2003: IVORY study): results of the final analysis

2020 ◽  
Vol 99 (6) ◽  
pp. 1283-1291
Author(s):  
Sang Eun Yoon ◽  
Seok Jin Kim ◽  
Dok Hyun Yoon ◽  
Youngil Koh ◽  
Yeung-Chul Mun ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Barr Virus ◽  
Large B Cell Lymphoma ◽  
Matched Case ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV) positivity in diffuse large B cell lymphoma (DLBCL) provokes a critical oncogenic mechanism to activate intracellular signaling by LMP1. LMP1 specifically mimics the role of BTK-dependent B cell receptor. Therefore, a trial considering RCHOP therapy along with ibrutinib (I-RCHOP) in combination was conducted among patients with EBV-positive DLBCL. This study was an open-label, single-arm, prospective multicenter phase II clinical trial. Patients received 560 mg of ibrutinib with RCHOP every 3 weeks until 6 cycles were completed or progression or unacceptable toxicity was observed. The primary endpoint was objective response, while secondary endpoints included toxicity, progression-free survival, and overall survival. A matched case-control analysis was completed to compare the efficacy and toxicity of I-RCHOP and RCHOP, respectively, in EBV-positive DLBCL patients. From September 2016 to August 2019, 24 patients proven to have EBV-positive DLBCL in the tissue were enrolled and received I-RCHOP. Their median age was 58 years (range, 28–84 years). The objective overall response was 66.7%, including 16 patients who achieved complete response after 6 cycles. Patients aged younger than 65 years presented a superior OR (87.5%) as compared with those older than 65 years (25.0%; p = 0.01). In a matched case-control study, I-RCHOP therapy provoked a more favorable complete response rate (87.3%) than did RCHOP (68.8%) in those younger than 65 years. Treatment-related mortality was linked most frequently with I-RCHOP therapy (four patients presented with unusual infection without Gr3/4 neutropenia) in the older age group (age ≥ 65 years). In conclusion, in this phase II trial for EBV-positive DLBCL, I-RCHOP was effective but did not show a significant improvement in response and survival in comparison with RCHOP. Also, I-RCHOP promoted serious toxicity and treatment-related death in older patients.

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