Therapeutic use of Brentuximab Vedotin In Cd30+ hematologic malignancies

5nononeThe CD30 antigen is strongly expressed on neoplastic cells in classical Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL) and other hematologic malignancies (such as DLBCL and cutaneous TCL), while is almost undetectable on healthy tissues, representing an ideal immunotherapeutic target. Since unconjugated anti-CD30 antibody (SGN-30) demonstrated limited clinical activity, researchers' effort aimed to create an antibody-drug conjugate (ADC), leading to discovery of SGN-35 (brentuximab vedotin), in which an anti-CD30 antibody is linked to the antimitotic agent monomethyl auristatin E (MMAE). In the first phase I study in CD30+ hematologic malignancies (the majority of patients with HL) the maximum tolerated dose was fixed at 1.8mg/Kg every 3 weeks, overall response rate (ORR) and complete response (CR) rate were 38% and 24%. In 2 subsequent phase II studies amazing results were reported, that permitted accelerated FDA approval for relapsed/refractory patients and led to the development of many clinical trials including BV as first-line HL and ALCL treatment. Moreover, as CD30 antigen may be expressed by other malignancies, the potential therapeutic application is increasing, including at least diffuse large B-cell lymphoma, T-cell lymphomas other than ALCL and cutaneous lymphoproliferative disorders. BV is administrated as outpatient regimen and is usually well tolerated; sensorial peripheral neuropathy represents the most common toxic effect, although it is dose-dependent and at least partially reversible in most cases, after dose reduction and/or treatment ending. © 2017, Bentham Science Publishers.noneFabbri, Alberto; Cencini, Emanuele; Gozzetti, Alessandro; Schiattone, Luana; Bocchia, MonicaFabbri, Alberto; Cencini, Emanuele; Gozzetti, Alessandro; Schiattone, Luana; Bocchia, Monic

Durable response after VNCOP-B and rituximab in an elderly patient with high-grade B-cell lymphoma

Objectives and Methods: High-grade B-cell lymphoma, NOS (HGBL) have an aggressive clinical behavior and poor outcome using regimens currently employed for diffuse large B-cell lymphoma (DLBCL) such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Promising results have been reported with more intensive regimens but this strategy is not suitable for elderly or unfit patients. Rituximab in association with cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (R-VNCOP-B) demonstrated high efficacy and manageable toxicity as first-line treatment for elderly aggressive non-Hodgkin lymphoma patients. Results and Conclusion: In this case study, we report the rapid improvement, long-lasting complete remission, and mild toxicity of R-VNCOP-B regimen in an elderly, triple-expressor HGBL patient, with aggressive disease and poor-risk profile

Minimal residual disease-driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL

Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton's tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10-4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035