ibrutinib combined with rituximab for treatment of relapsed refractory myd88 and cd79a/b (or cd79b alone) dlbcl who have received at least two prior therapies

Conditions: DLBCL; MYD88 Gene Mutation; CD79A Gene Mutation; CD79B Gene Mutation; Relapse; Refractory Lymphoma

Summary: the purpose of this study is to evaluate the efficacy and safety of ibrutinib combined with rituximab in relapsed refractory myd88 and cd79a/b (or cd79b alone) dlbcl who have received at least two prior therapies.

recent studies have found that about 30% of dlbcl have mutations in myd88 and/or cd79a/b genes. myd88 and cd79a/b protein molecules belong to two signal transduction pathways, which regulate b cell proliferation. both myd88 and cd79a/b gene mutations can abnormally activate btk located downstream of myd88 and cd79a/b, leading to over activation and proliferation of b cells. ibrutinib is the first generation of oral btki, which may theoretically inhibit the tumorigenesis of dlbcl with abnormal btk activation caused by mutations in myd88 and cd79a/b genes. a phase ii clinical study of ibrutinib monotherapy in the treatment of relapsed and refractory dlbcl showed that the effective rate of ibutinib for single cd79b mutation was 55.5% (5/9 cases), and that for both cd79b and myd88 mutations was 80% (4/5 cases). about 40 \~ 50% of primary central nervous system large b cell lymphoma (pcnsl) have cd79b and myd88 mutations. a small sample study found that the overall response rate (orr) for the treatment of relapsed and refractory pcnsl with ibrutinib was 77% (10/13). an expanded sample study of 44 cases of pcnsl treated with ibrutinib found that the orr is 52% and progression-free survival (pfs) is 4.8 months. these results suggest that ibrutinib may be more effective in dlbcl with myd88 and cd79a/b or cd79b mutations. the relationship between mutations in myd88 and cd79b and therapeutic sensitivity of ibrutinib can not be simply categorized, because abnormalities in other genes of b cell signaling pathway, such as card11, tnfaip3, cxcr4, jak1 and pim1, may also affect the efficacy of ibrutinib. therefore, it is necessary to comprehensively analyze the gene abnormalities of other b cell related signaling pathways, such as downstream signal of bruton kinase, cxcr, jak-stat, and nfkb, to find out the most effective group of dlbcl patients treated with ibrutinib. this phase ii, single-arm, open-label, multi-center clinical trial will evaluate the efficacy and safety of ibrutinib combined with rituximab in treating relapsed refractory myd88 and cd79a/b (or cd79b alone) dlbcl who have received at least two prior therapies. the study will also explore the relationship between myd88 and/or cd79a/b and efficacy, and detect the gene abnormality by next generation sequencing (ngs) and evaluate the relationship between other gene abnormality and efficacy.

Eligibility criteria:
inclusion criteria: 1. participants must be able to understand and be willing to sign a written informed consent document; 2. men and woman who are at least 18 years of age on the day of consenting to the study; 3. according to the who 2016 classification criteria, pathologically confirmed cd20+diffuse large b-cell lymphoma; 4. patients with myd88 and cd79a/b mutations or cd79b alone; 5. relapse or progression after treatment with at least two prior therapies; 6. there is at least one measurable lesion, defined as a two-path measurable, intraductal lesion short neck \>1.5cm, extranodal lesion short diameter \>1.0cm; 7. eastern cooperative oncology group (ecog) performance status =\< 2 8. blood routine examination meets the following criteria: neutrophil count ≥ 1.0 x 109 / l; platelet ≥ 75 x 109 / l; hemoglobin ≥ 10.0 g / dl; 9. the main organ function meets the following criteria: aspartate aminotransferase and alanine aminotransferase ≤ 2.0 times the upper limit of normal value; bilirubin ≤ 2.0 mg / dl; creatinine clearance rate ≥ 60 ml / min; 10. must agree to effective contraception exclusion criteria: 1. transformed diffuse large b-cell lymphoma; 2. hbv dna positive or hcv rna positive; 3. patient is known to have an uncontrolled active systemic infection; 4. left ventricular ejection fraction \< 40%; 5. previous autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, dry syndrome, ankylosing spondylitis, etc; 6. immunosuppressive drugs are being or have been used in the past; 7. known hypersensitivity to the study drug or any of its excipients; 8. there are other active malignant tumors that may interfere with this study requiring treatment; 9. known history of human immunodeficiency virus (hiv) infection; 10. previous autologous stem cell transplantation or allogeneic hematopoietic stem cell transplantation; 11. the investigator judges that the patient has other inappropriate circumstances.

Keywords: r/r dlbcl myd88 gene mutation cd79a/b gene mutation ibrutinib rituximab