Brentuximab Vedotin In Patients Research Articles

A multi-center and non-interventional registry of brentuximab vedotin in patients with relapsed or refractory CD30-positive lymphoma: the CISL1803/BRAVO study.

Brentuximab vedotin (BV), a potent antibody-drug conjugate, targets the CD30 antigen. In Korea, BV has been approved for the treatment of relapsed or refractory Hodgkin lymphoma (HL), anaplastic large-cell lymphoma (ALCL), and cutaneous T-cell lymphomas, including mycosis fungoides (MF). However, there are limited data reflecting real-world experiences with BV treatment for HL, ALCL, and MF. This was a multicenter, non-interventional registry study of the efficacy and safety of BV in patients with relapsed or refractory CD30-positive lymphoma (CISL1803/BRAVO). Outcomes were determined based on the occurrence of relapse or progression and overall survival after BV treatment. A total of 85 patients were enrolled in this study. The median number of BV cycles was 10 (range, 2‒16) in the patients with HL. The objective response rate (ORR) of patients with HL to BV was 85.4% (41/48), comprising 27 complete responses (CRs) and 14 partial responses (PRs). The ORR of ALCL was 88% (22/25), consisting of 17 CRs and five PRs, whereas the ORR of MF was 92% (11/12). At the median follow-up of 44.6 months after BV treatment, the median post-BV progression-free survival of HL, ALCL, and MF patients was 23.6 months, 29.0 months, and 16.7 months, respectively (P=0.641). The most common side effect of BV was peripheral neuropathy; 22 patients (25.9%, 22/85) experienced peripheral neuropathy (all grades). The treatment outcomes of patients with relapsed or refractory CD30-positive lymphoma improved with BV treatment, and the safety profile was manageable.

Impact of Brentuximab Vedotin in Patients with Breast Implant-Associated Anaplastic Large Cell Lymphoma with Capsule Infiltration Requiring Chemotherapy

Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon peripheral T-cell lymphoma most frequently arising around a textured surface breast implant. It has been shown that capsule infiltration (T2, T3 and T4 of the TNM staging system) was an adverse prognostic factor. In this context, chemotherapy (with or without brentuximab vedotin [BV]) may be proposed, considering other factors such as metastatic disease or incomplete resection. Furthermore, the need for adjuvant chemotherapy in patients with stage IIA (T4N0M0) and complete en-bloc excision without residual disease is debated. Aim: To assess the management of BIA-ALCL with capsule infiltration, in particular: 1) To assess the impact of BV in those patients; 2) To evaluate the need for adjuvant chemotherapy in patients with stage IIA and complete en-bloc excision without residual disease. Methods: Since 2016, a national multidisciplinary meeting has been implemented by the French National Cancer Institute (NCI) to optimize management of patients with BIA-ALCL, particularly those with advanced disease. Meanwhile, a national registry has been set up by the LYSA, in collaboration with health authorities. Central pathological review has been carried out within the French NCI-labeled Lymphopath network. Results: From 2009 to 2023, 125 patients with BIA-ALCL were recorded, of which 111 (94 from France and 17 from Belgium) had complete data and were included in the present analysis. Overall, median age at diagnosis of BIA-ALCL was 58 years (24-82 years). Reasons for initial implantation were breast cancer reconstruction (n=54; 49%), cosmetic (n=45; 41%) or other (n=12; 10%). The median interval from first implantation to diagnosis of BIA-ALCL was 12.3 years (4-40 years). The median number of implants in the breast involved by BIA-ALCL was 2 (1-8), including at least one silicone implant in 95 (86%) patients, and at least one textured implant in all informative cases (n=102; Most often Allergan Biocell implants). At diagnosis of BIA-ALCL, 78/110 (71%) patients presented with periprosthetic effusion only, 20 (18%) had effusion and a breast mass, 6 (5.5%) had a breast mass only, and 6 (5.5%) had neither. At pathological examination of the capsule, T-stage was T1 (confined to effusion or a layer on luminal side of capsule) in 73/111 (66%) cases, T2-T3 (capsule infiltration) in 5 (4.5%) cases, T4 (lymphoma infiltrates beyond the capsule) in 32 (29%) cases, and unclassifiable in 1 case. Moreover, 18/111 (16%) patients had at least one non-breast extranodal involvement. Among the 36 patients with capsule infiltration (5 T2-T3 and 31 T4), 13 (including 11 T4) were treated with BV-CH(E)P regimen, 12 (all T4) with a CHOP/CHOP-like regimen, and 11 (including 8 T4) did not receive any chemotherapy. The main reasons for receiving chemotherapy were metastatic disease, incomplete resection, or no surgery. Patients who did not receive chemotherapy had a localized disease (3 stage IB/IC and 8 stage IIA) with complete en-bloc excision and no residual disease. Patients treated with BV-CH(E)P regimen and CHOP/CHOP-like regimen had similar characteristics without significant differences regarding age, clinical presentation, stage and surgery. After a median follow-up of 47 months from BIA-ALCL diagnosis, for BV-CH(E)P and CHOP/CHOP-like groups, the respective 4-year PFS rates were 100% and 57% (p=0.01), and the respective 4-year OS rates were 100% and 73% (p=0.07). Regarding the 11 patients who did not receive chemotherapy, 4-year PFS and OS were both 75%, which corresponds to a single event being a death without progression occurring more than 3 years after the diagnosis of lymphoma (4-year lymphoma-specific survival was 100%). Conclusions: 1) In patients with capsule infiltration requiring chemotherapy, BV-CH(E)P regimen was associated with improved PFS and OS compared with CHOP/CHOP-like regimen; 2) Patients with stage IIA and complete en-bloc excision without residual disease had favorable outcome without the need for adjuvant chemotherapy. These results should be confirmed prospectively.

Prognostic Significance of CD30 Expression and Response to Brentuximab Vedotin in Patients with Angioimmunoblastic T Cell Lymphoma

Background Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) characterized by a follicular helper T-cell phenotype. The standard frontline treatment for AITL typically involves CHOP or CHOP-like regimens, with consideration for autologous stem cell transplant. A promising treatment option for CD30-positive (CD30+) PTCLs, including AITL, is the anti-CD30 antibody drug conjugate, brentuximab vedotin (BV). The ECHELON-2 study demonstrated equivocal outcomes in CD30+ PTCL patients (pts) who received BV-CHP instead of CHOP. However, response of BV in CD30+ AITL pts is still uncertain. This study aims to evaluate the relationship between CD30 expression and the clinical response to BV in pts diagnosed with AITL. Methods This retrospective IRB approved study conducted at MD Anderson Cancer Center, where we analyzed pts with AITL diagnosed between 1997- 2023. Patient demographics, laboratory data at diagnosis, pathology review, treatment, and treatment response were collected and analyzed. Expression of CD30 expression in neoplastic cells was evaluated by immunohistochemistry and scored in 5% increments. Kaplan- Meier method was used to assess overall survival (OS) and log-rank used to compare different groups. Results This study included a cohort of 339 pts with AITL. Among them, 55 (23%, n=237) had no detectable CD30 expression (CD30=0%),182 (77%, n=237) patients had detectable CD30 expression (CD30>1%), and 102 pts had unknown CD30 expression. Table 1 shows patient characteristics by CD30 expression and response to first-, second-, and third- line BV treatment. There were 113 (48%, n=237) females and 124 (52%, n=237) males with a median age of 66 years. Most patients were Whites (88%, n=196) followed by Black (4%, n=196), and Asian (5%, n=196). Fifty-two (n=122) of pts who were CD30+ had stage III, 43% (n=122) had stage IV (p-value= <0.001), and 38% had BM involvement (p- value= 0.3). For pts with disease showing no CD30 expression (CD30neg) 16% (n=43) of pts had stage III, 70% (n=43) had stage IV, and 48% (n=42) had BM involvement. Auto-Stem cell transplant (ASCT) was performed in 48% of those with CD30+ and 43% of CD30neg. The most common first-line treatment was chemotherapy combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by other CHOP like regimens. In total, 35 pts received BV treatment as first-line, 32 patients received BV in combination with chemotherapy and 3 received BV only. For second-line treatment, 11 received BV treatment and for third- line only 6 received BV. First- line treatment with BV showed better clinical response rates, with 82% achieving complete response (CR, n= 34), followed by second line CR with 56% (n= 9) and third- line with 0% (n= 6). The median OS were similar between those with CD30+ who did or did not receive first line BV (20 months vs. 19 months, p>0.05). The median OS for CD30neg pts who did not receive BV was 25 months (p=0.42). Furthermore, there was no statistically significant difference in OS between pts who underwent a ASCT (CD30+ 24.5 months and CD30neg 32.5 months, respectively) and those who did not (CD30+ 18.5 months and CD30neg 24.5 months, respectively, p- value = 0.29). Conclusion While this study did not find CD30 expression to be a predictor of response to BV treatment or ASCT in AITL pts, it provides valuable insights into the prevalence of CD30 expression and BV response as first- line treatment. Notably, 77% of pts had CD30 expression and pts who received BV as first- line had a higher proportion of CRs compared to pts who received BV as second- and third- line treatments. Further investigations with larger patient cohorts are necessary to determine the prognostic and predictive role of CD30 in AITL. Additional studies analyzing CD30 expression levels in malignant cells, immunoblasts, and macrophages are planned for presentation at the upcoming annual meeting.

Results from an Intergroup Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Classic Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Research Group (E4412)

Background: Relapsed/refractory (R/R) Classic Hodgkin lymphoma (cHL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is an intergroup Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (N), and ipilimumab (I) in patients with R/R cHL. Here we present the efficacy and safety data on the full adult cohort of patients treated in Phase 2 randomized between BV/N and BV/N/I. Methods: Patients with confirmed R/R cHL were randomized between the doublet of BV/N with BV 1.8mg/kg and N 3mg/kg and BV/N/I with I 1mg/kg. BV and N were administered every 3 weeks, and I every 12 weeks for up to 1 year for BV and up to 2 years for N and I. Results: One hundred twenty-six patients were enrolled and treated; 8 patients (4 from each arm) were excluded from efficacy analysis based on ineligibility. Patients were not heavily pretreated, 65% had one prior line of therapy and an additional 27% had two prior lines, and 8% had more than 2 prior lines. The median age was 34; 51% of patients were male. Sixteen patients had prior BV: 10 (BV/N arm) and 6 (BV/N/I). Response: One hundred eighteen patients are evaluable for response: 61 treated with BV/N and 57 with BV/N/I. With BV/N 37 of 61 (60.7%) of patients had a complete response (CR) compared to 38 of 57 (66.7%) with BV/N/I for a difference of 6.7% (p-value 0.31). Additionally, 17 (28%) with BV/N and 12 (21%) of patients treated with BN/N/I had a partial response (PR) for an overall response rate (ORR) of 88% in both arms. In a planned analysis of patients with prior treatment with BV the CR rate was 25% in BV/N arm (2 of 8) and 60% in BV/N/I arm (3 of 5). The median follow-up for progression free survival (PFS), duration of response (DOR), and overall survival (OS) is 24.8 months and 33.7 months. The median PFS, duration of response and OS have not been reached for either arm with 24 months of follow-up ( Figure 1). In B/N 30 of 61 patients came off study to receive alternative treatments (primarily autologous stem cell transplant (SCT)) and in BV/N/I 23 of 57 patients did. Safety: Table 1 shows treatment-related Grade 3+ toxicity occurring in > 1 patient and adverse events (AE) of special interest. All 126 patients (118 eligible and 8 ineligible) are evaluable for safety. The rate of Grade 3+ treatment related toxicity is 43% (28/65) and 52% (32/61) for BV/N and BV/N/I, respectively. However, when rash is excluded the rate of treatment related toxicities is similar between the two arms 38.5% vs 39.3%. There was no grade 4 rash, and the rash was treatable in all cases with topical or oral steroids. There were no Grade 5 toxicities in either arm. Conclusion: In this randomized Phase 2 study comparing BV/N vs. BV/ N/I the difference in CR rate of 6.7% between the doublet and the triplet was not statistically significant. Additionally, the triplet had more grade 3 rash than the doublet, there was otherwise no significant difference in grade 3 or greater toxicity between the two arms. With a median follow-up of 24 months the PFS and DOR have not been reached for either arm, suggesting excellent disease control from both regimens. Differences in response for BV pre-treated patients between the two arms is intriguing especially as more patients are treated with BV in the frontline, but the sample size is too small to draw firm conclusions. Correlative studies are underway to elucidate a response vs. resistance signature, and biological understanding of differential benefit.

Brentuximab vedotin plus nivolumab after autologous haematopoietic stem-cell transplantation for adult patients with high-risk classic Hodgkin lymphoma: a multicentre, phase 2 trial

After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma. We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795. Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed. Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted. Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.

Efficacy and Safety of Retreatment with Brentuximab Vedotin in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma or CD30-Expressing Peripheral T Cell Lymphoma

Introduction Brentuximab vedotin (BV) is approved for the treatment of adult patients (pts) with classical Hodgkin lymphoma (cHL), systemic anaplastic large cell lymphomas (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL). BV has been evaluated in combination with doxorubicin, vinblastine, and dacarbazine (A+AVD) in adult pts with advanced stage cHL in ECHELON-1 (Ansell S, 2022) and in combination with cyclophosphamide, doxorubicin, and prednisone (A+CHP) in pts with sALCL, PTCL-not otherwise specified (NOS), and angioimmunoblastic T-cell lymphoma (AITL) in ECHELON-2 (Horwitz S, 2022), demonstrating BV is well tolerated with a favorable efficacy profile in the first-line setting. Moreover, BV is approved as monotherapy for treatment of adults with cHL at high risk of relapse as consolidation therapy post autologous stem cell transplant, as well as in relapsed or refractory (r/r) sALCL. BV has also been studied in r/r cHL after auto-stem cell transplant (Younes A, 2012) and retreatment setting (Trümper L, 2020), with favorable efficacy. CD30 expression persists after BV treatment and SGN35-006 demonstrated that BV monotherapy is an effective retreatment option in pts with r/r cHL or sALCL who previously achieved an objective response with BV monotherapy (Bartlett N, 2014). Herein, we present efficacy and safety results from a phase 2 study, where BV was evaluated in pts with r/r cHL or CD30-expressing PTCL who previously received BV either alone or in combination. Methods SGN35-028 (NCT03947255) is a multicentered, single arm, phase 2 clinical trial that enrolled adult pts with r/r cHL and sALCL or other CD30-expressing PTCL who were previously treated with a BV-containing regimen at least 6 months prior that had evidence of an objective response, and subsequently experienced disease progression or relapse after discontinuing treatment. Pts were treated with BV 1.2 or 1.8 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoints were objective response rate (ORR) and the safety and tolerability of BV retreatment. Results Of the 12 pts enrolled, 11 received at least 1 dose of study treatment including 5 pts with cHL and 6 pts with PTCL (4 pts with sALCL, 1 pt with PTCL-NOS, 1 pt with AITL). Both pts with non-ALCL PTCL had CD30 expression on 1% of tumor cells. Of the 11 pts that received at least 1 dose of study treatment, most were Black or African American (55%), not of Hispanic, Latino, or Spanish origin (91%), and <65 years old (73%). Pts received a median of 8 doses of BV (range: 1, 16) over a median of 25 weeks (range: 3, 55), 3 pts (27%) had dose reductions. Three pts were still on treatment as of data cutoff date. For pts with cHL, median time from initial diagnosis to first dose was 76.2 months (range: 34, 162), 2 pts achieved complete response (CR) and 3 pts partial response (PR) on prior BV therapy, median time from completion of last BV therapy to first dose was 28.2 months, and median age was 31 years (range: 28, 55). The ORR per investigator assessment was 60% (95% CI: 14.7, 94.7) with 1 pt achieving CR. For pts with PTCL, median time from initial diagnosis to first dose was 31.2 months (range: 23, 138), 5 pts achieved CR and 1 pt PR on prior BV therapy, median time from completion of last BV therapy to first dose was 20.1 months, and median age was 63 years (range: 35, 77). The ORR per investigator assessment was 83% (95% CI: 35.9, 99.6) with 4 pts achieving CR. The 4 pts with sALCL had an ORR of 100% with a CR rate of 75%. Eight pts discontinued study treatment, 4 pts discontinued treatment due to disease progression, 2 pts due to investigator decision, and 2 pts due to treatment emergent adverse events (TEAEs), both with peripheral sensory neuropathy. Thirty-six percent of pts experienced ≥ Grade 3 treatment-related TEAEs, 2 (18%) each for neutropenia and peripheral sensory neuropathy and 1 (9%) each for amylase increased, fatigue, malaise, and nausea. One pt experienced a Grade 5 adverse event of decreased appetite related to progressive PTCL disease that was not treatment related. Conclusions Preliminary results from this study show BV is a viable retreatment option for adults with r/r cHL, sALCL, and PTCL. Moreover, safety results were consistent with the known safety profile and no new safety signals were observed. This study is ongoing, updated efficacy and safety results will be presented at the meeting.

T100: Long term Follow-up of a Phase I Study Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A trial of the ECOG-ACRIN Research Group (E4412: Arms A-I)

T100: Long term Follow-up of a Phase I Study Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A trial of the ECOG-ACRIN Research Group (E4412: Arms A-I)

Comparative clinical and economic assessment of polatuzumab vedotin therapy in combination with bendamustine and rituximab for adult transplantation-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma

Aim. To evaluate the pharmacoeconomic feasibility of using polatuzumab vedotin in combination with bendamustine and rituximab for the treatment of adult transplantation-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma.Materials and methods. Study design - retrospective analysis of literature data. Pharmacoeconomic research methods - clinical and economic analysis (incremental cost-effectiveness analysis, case-based approach) using sensitivity assessment. The sources of the drug efficacy data were publications on conducted clinical trials; on the drugs cost -the State register of maximum selling prices, data from the manufacturer's company.Results. Polatuzumab vedotin is the unique drug from the class of monoclonal antibody-antimitotic agent conjugates registered in Russia for the treatment of adult transplantation-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma. for this reason a case-based approach was applied as part of the cost-effectiveness analysis. As a result of clinical and economic analysis, it was found that the cost of progression free life-year added when using polatuzumab vedotin in combination with bendamustine and rituximab in patients with relapsed/refractory diffuse large b-cell lymphoma by 50.7 %, or by 11.4 million rubles, lower than the cost of progression free life-year added when using brentuximab vedotin in patients with relapsed/refractory Hodgkin's lymphoma. The sensitivity assessment showed the stability of the obtained results to changes in the input parameters of treatment cost and efficacy in a wide range of values.Conclusion. Use of polatuzumab vedotin in combination with bendamustine and rituximab for the treatment of adult transplantation-ineligible patients with diffuse large B-cell non-Hodgkin's lymphoma is pharmacoeconomically justified and appropriate.

Efficacy of brentuximab vedotin in patients with CD30-positive lymphoproliferative skin diseases: results of the first prospective study in the Russian Federation

Background. Primary cutaneous lymphomas are the second most common group of extranodal lymphomas. Unlike nodal lymphomas, which are characterized by predominant B-cell proliferation, primary cutaneous T-cell lymphomas account for 6575% of all cutaneous lymphomas. About 50% of all cutaneous T-cell lymphomas are mycosis fungoides (MF). CD30-positive lymphoproliferative disorders (CD30+ LPD) occupy the second place in the incidence of cutaneous T-cell lymphomas, while 10% are rare disease forms such as primary cutaneous peripheral T-cell lymphoma not otherwise specified (PTLNOS), Szary syndrome (SS), etc.&#x0D; Treatment of MF/SS patients in the Russian Federation shows that about 30% of individuals are resistant to various therapeutic effects, especially in the later stages. The problem of CD30+ LPD treatment is extracutaneous dissemination in the case of primary cutaneous anaplastic large cell lymphoma (pcALCL) and steadily relapsing lymphomatoid papulosis (LyP) without symptom-free intervals. These aspects of the therapy of cutaneous lymphomas highlight the need to search for new treatment options.&#x0D; According to the results of the international randomized ALCANZA trial, brentuximab vedotin (BV) has shown high efficiency in the treatment of cutaneous T-cell lymphoproliferative disorders.&#x0D; Study objective. The study aim is to evaluate BV efficacy in the group of poor prognosis patients with cutaneous T-cell lymphomas who has received at least one line of systemic therapy.&#x0D; Materials and methods. The study included 21 patients: 16 men and 5 women. There were 8 patients with MF, 5 patients with SS; 6 individuals had cutaneous CD30+ LPD (including 5 patients with pcALCL and 1 individual with LyP) and 2 patients were diagnosed with PTLNOS. Cutaneous T-cell lymphoma was confirmed based on the medical history, nature of cutaneous lesions, as well as histological, immunohistochemical, and, in some cases, molecular genetic testing of the skin biopsy sample (analysis of T-cell receptor gene rearrangement).&#x0D; Results. Late stages of the disease were diagnosed in 12 out of 13 patients with MF/SS. Extracutaneous lesions were diagnosed in 57% of cases. The median of prior lines of therapy was 3 (18 variants of treatment). The overall response to the treatment was achieved in 91% of cases (19 out of 21 patients): complete remission was observed in 53% of patients, very good partial remission was achieved in 31% of individuals, and partial remission was noted in 16% of cases. Disease progression was found in 2 patients (after cycles 1 and 4). Some patients with partial remission after BV therapy underwent additional therapy (radiation therapy, interferon therapy, and cycles of systemic therapy), which made it possible to achieve a more pronounced antitumor response. Early relapse was diagnosed in 2 out of 19 patients who had responded to the treatment. The treatment tolerability was acceptable, and the toxicity did not exceed that described in the previous studies. Thus, the overall stable antitumor response persisted in 89% of patients (the median follow-up was 10 months).&#x0D; Conclusion. The use of targeted therapy with BV made it possible to achieve high treatment results in patients with advanced stages of the disease and the absence of response to several lines of therapy.

Multicentric EORTC retrospective study shows efficacy of brentuximab vedotin in patients who have mycosis fungoides and Sézary syndrome with variable CD30 positivity.

Brentuximab vedotin (BV) was approved as a therapy for mycosis fungoides (MF) based on the ALCANZA trial. Little real-world data, however, are available. To evaluate the efficacy and safety of BV in patients with MF/Sézary Syndrome (SS) with variable CD30 positivity in a real-world cohort and to explore potential predictors of response. Data from 72 patients with MF/SS across nine EORTC (European Organization for Research and Treatment of Cancer) centres were included. The primary endpoint was to evaluate the proportion of patients with: overall response (ORR), ORR lasting over 4 months (ORR4), time to response (TTR), response duration (RD), progression-free survival (PFS) and time to next treatment (TTNT). Secondary aims included a safety evaluation and the association of clinicopathological features with ORR, RD and TTNT. All 72 patients had received at least one systemic treatment. ORR was achieved in 45 of 67; ORR4 in 28 of 67 with a median TTR of 8 weeks [interquartile range (IQR) 5·5-14] and with a median RD of 9 months (IQR 3·4-14). Median PFS was 7 months (IQR 2-12) and median TTNT was 30 days (6-157·5). Patient response, RD, PFS and TTNT were not associated with any clinicopathological characteristics. In the MF group, patients with stage IIB/III vs. IV achieved longer PFS and had a higher percentage of ORR4. There was a statistically significant association between large-cell transformation and skin ORR (P = 0·03). ORR4 was more frequently achieved in patients without lymph node involvement (P = 0·04). BV is an effective option for patients with MF/SS, including those with variable CD30 positivity, large-cell transformation, SS, longer disease duration and who have been treated previously with several therapies.

Phase 2 Study of Brentuximab Vedotin in Patients with Advanced Systemic Mastocytosis

Phase 2 Study of Brentuximab Vedotin in Patients with Advanced Systemic Mastocytosis

A Pilot Study of Weekly Brentuximab Vedotin in Patients with CD30+ Malignancies Resistant to Every 3 Week Brentuximab Vedotin

Background:Brentuximab vedotin (BV) is effective in treating of relapsed/refractory CD30 positive malignancies, such as classical Hodgkin lymphoma (CHL) and systemic anaplastic large cell lymphoma (ALCL). BV combines an anti-CD30 monoclonal antibody with a potent anti-microtubule agent, Monomethyl auristatin E (MMAE), disrupting the cell cycle of CD30 positive cells. Patients (pts) with relapsed/refractory CHL and systemic ALCL have shown promising overall response rates (ORR) with BV, but most patients will eventually suffer progressive disease (PD). The mechanism of resistance to BV remains unclear, however, most lymphomas with PD following BV still demonstrate CD30 expression suggesting that it may remain a viable target. Prior clinical data indicate that weekly BV dosing given on Days 1, 8 and 15 of a 28 day cycle was tolerable, had an ORR of 59% and a higher complete remission rate than was seen in a similar phase I trial of 21-day dosing of BV. We, thus, hypothesized that patients with CD30-positive lymphomas who progressed on standard BV dosing may still respond to weekly BV dosing and tested this in a prospective phase II trial. We also quantified CD30 expression to evaluate the impact of BV on CD30 expression and the impact of CD30 on response to BV, and assessed T and NK cell infiltrates for correlation with response.Methods:Eligible pts were age >18 or older with relapsed or refractory CD30 positive lymphoma who had progressed during or achieved less than a partial response following a minimum of 2 cycles of BV. Key inclusion criteria included documented expression of CD30 on tumor cells following the last dose of prior BV, as well as adequate marrow, hepatic and renal function and no major infections. Key exclusion criteria were ECOG > 2, prior transplant within 100 days, radioimmunotherapy within 12 weeks, active CNS involvement, and pre-existing neuropathy > NCI-CTCAE Grade 2 (or > Grade 1 if secondary to prior BV). Each cycle consisted of BV at 1.2 mg/kg (capped at 120mg) given over 30 minutes on Days 1, 8 and 15 every 28 days. Patients with stable disease or better could remain on therapy for up to 4 cycles. CD30 expression was quantified using multiparameter flow cytometry to identify the Hodgkin-Reed-Sternberg (HRS) cells.Results:Eight (8) pts enrolled in the study. The median age was 42 (27-68). The pts were heavily pretreated (median 6 prior lines of treatment) and 63% had undergone autologous transplant (Table 1). Histologies included CHL (7) and ALK-negative systemic ALCL (1). Pts received between 2 to 16 (median 5) prior cycles of Q3 week BV prior to enrolling in the study. All patients suffered eventual progressive disease (PD) on Q3 week BV, though 3 had a transient prior partial response (PR). Weekly BV was well tolerated with only one grade 3 event (hypokalemia). Neuropathy was seen in 5 (63%) pts: 3 Grade 1, 2 Grade 2 resulting in one treatment discontinuation. Two pts completed all 4 BV cycles on study; both had progressive disease after the 4th cycle. Of the 6 pts who terminated the study early, the majority (67%) did so due to progressive disease. One pt had a partial response to BV after 3 cycles (with a 50% decrease in size of target nodes compared to baseline). Reduction in target lesions were seen in 5/7 (71%) response-evaluable patients (Figure 1). The overall response rate (ORR) of 13% triggered the protocol-defined early stopping rule. None of the screened patients were found to have lost CD30 expression following prior BV, however expression only ranged from dim to intermediate by IHC. CD30 surface density was quantified in paired pre and post BV samples from 3 patients and did not show a significant change or correlation with response. NK and T cell infiltrates were not correlated with response.Conclusions:Pts with BV-refractory CD30 positive malignancies can safely receive weekly BV at 1.2 mg/kg dosing given on Days 1, 8 and 15 of a 28-day cycle. Even though a majority demonstrated reduction in target lesions, the response rate was low. Alterations in CD30 density on HRS cells was not observed following BV when quantified by flow cytometry. Elucidation of tumor- and immune-related mechanisms of BV resistance is needed, as BV is poised for increased use earlier in the course of therapy for HL and ALCL. [Display omitted] DisclosuresSmith:Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Sharp: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Merck: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding.

Long-term survival outcomes of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma: a systematic review and meta-analysis.

The short-term benefits of brentuximab vedotin (BV) for classical Hodgkin lymphoma (cHL) are well established, but its long-term benefits for refractory/relapsing (r/r) cHL are unknown. A meta-analysis was undertaken to examine the overall survival (OS), and progression-free survival (PFS) from relevant studies with patients with r/r cHL post-autologous stem cell transplantation (ASCT) exposed to BV. PubMed, Embase, and the Cochrane library were searched for available papers published up to January 2020. The main outcomes included 3-year OS/PFS and/or 5-year OS/PFS. Data were pooled using random-effects models. Four studies were included: one randomized controlled trial, one single-arm trial, and two retrospective studies. The four studies included a total of 383 patients (mean of 95.75/study). The proportion of females was 21%-89%. The median age was 26-33 years. The 3-year OS was available for one study and was 41% in patients with r/r cHL with BV after ASCT (OR=0.41, 95% CI: 0.16-0.67). The 5-year OS was available for two studies and was 34% in patients with r/r cHL with BV after ASCT (OR=0.34, 95% CI: 0.19-0.48; mixed-effects model). The 5-year PFS was available for three studies and was 31% in patients with r/r cHL with BV after ASCT (OR=0.31, 95% CI: 0.02-0.61; mixed-effects model). The 5-year OS in patients with r/r cHL treated with BV after ASCT is 34% (95 CI: 19%-48%). The 5-year PFS in patients with r/r cHL treated with BV after ASCT is 31% (95 CI: 2%-61%).

Response to brentuximab vedotin versus physician’s choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis

IntroductionMycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study. MethodsBaseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min < 10% (≥1 biopsy with <10% CD30 expression), or CD30min ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS). ResultsClinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician’s choice in patients: with CD30min < 10% (40.9% versus 9.5%), with CD30min ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician’s choice in patients: with CD30min < 10% (16.7 versus 2.3 months), with CD30min ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups. ConclusionThese exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician’s choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status. Clinical trial registrationClinicaltrials.gov, NCT01578499.

A Phase II Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Epstein-Barr Virus-Positive- and CD30-Positive Lymphomas

Background: CD30 is frequently expressed in Epstein-Barr virus (EBV)-infected lymphoid cells and overexpressed in EBV-positive lymphomas. This open-labeled, multi-center, and investigator-initiated phase-II study evaluated the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory EBV-positive and CD30-positive lymphomas (NCT02388490). Methods: Twenty-five patients with relapsed or refractory EBV-positive lymphomas having CD30-positivity (≥ 1% of tumor cells) were administered with 1.8 mg/kg brentuximab vedotin intravenously every 3 weeks up to 16 cycles until disease progression. The primary endpoint was objective response rate and toxicities, duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were the secondary endpoints. Findings: Twenty-two patients (88%), median age of 65 years, were EBV-positive mature T/NK cell neoplasms (angioimmunoblastic T-cell lymphoma, n = 10; EBV-positive peripheral T-cell lymphoma, unspecified, n = 5; extranodal NK/T-cell lymphoma, nasal type, n = 4; and others, n = 3). Most patients (90%) had initial stage III/IV and 15 (60%) received ≥2 prior regimens. The objective response rate was 48% (90% CI, 31·0% to 64·3%; 12 of 25 patients), including five complete responses (20%) and seven partial responses (28%). Median DoR, PFS and OS were 10·1, 6·1, and 15·6 months, respectively. Common adverse events were peripheral neuropathy (48%), neutropenia (40%), thrombocytopenia (20%), and rashes (16%). Grade 3 and 4 adverse events were neutropenia (20%), thrombocytopenia (12%), and anemia (8%). Interpretation: Brentuximab vedotin is active and well tolerated in patients with relapsed or refractory EBV-positive and CD30-positive lymphomas. Trial Registration: (NCT02388490) Funding Statement: Takeda Pharmaceuticals Co. Ltd and Korea Health Industry Development Institute. Declaration of Interests: TMK received a research grant from AstraZeneca-KHIDI outside this work. DWK received travel and accommodation support for advisory board meeting attendance from Amgen and Daiichi-Sankyo outside this work. All other authors declare no competing interests. Seoul National University Hospital received grants from Alpha Biopharma, Amgen, Astrazeneca/Medimmune, Boehringer-Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan. Ethics Approval Statement: The study was approved by the institutional review board at each participating site and written informed consent was obtained.

Patient Characteristics of Long-Term Responders to Mogamulizumab: Results from the MAVORIC Study

Patient Characteristics of Long-Term Responders to Mogamulizumab: Results from the MAVORIC Study

Pembrolizumab Improves Progression-Free Survival in Relapsed/Refractory Hodgkin Lymphoma.

In the phase III KEYNOTE-204 trial, pembrolizumab significantly improved progression-free survival compared with brentuximab vedotin in patients with relapsed or refractory classic Hodgkin lymphoma (cHL), confirming pembrolizumab as the new standard of care in this setting.

A Phase 2 Study of Retreatment with Brentuximab Vedotin in Patients with cHL, sALCL or Other CD30-Expressing PTCL

Background Brentuximab vedotin is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Targeted delivery of MMAE to CD30-expressing cells is the primary mechanism of action of brentuximab vedotin (Sutherland 2006). Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cell. In addition, the direct cytotoxicity associated with brentuximab vedotin may be augmented by secondary effects, including the bystander effect (Li 2016) and several important immuno-oncology related effects, such as immunogenic cell death (Gardai 2015; Muller 2014) and antibody-dependent cellular phagocytosis (Oflazoglu 2007). Brentuximab vedotin has been approved for several indications, including the recent US Food and Drug Administration approval for the treatment of adults with previously untreated systemic anaplastic large cell lymphoma (sALCL) and other CD30-expressing peripheral T-cell lymphomas (PTCL). Given that CD30 expression has been shown to persist during treatment with brentuximab vedotin, and after treatment when patients have relapsed (Porpaczy 2013), there is rationale to support evaluation of brentuximab vedotin in a retreatment setting. Encouraging safety and antitumor activity were observed in a phase 1 study (Clinicaltrials.gov: NCT00947856) of brentuximab vedotin retreatment in patients with relapsed/refractory classic Hodgkin lymphoma (cHL) or sALCL. The objective response rate (ORR) for retreatment of cHL was 60% (12 of 20 evaluable patients) with a complete response (CR) rate of 30% (6 of 20 evaluable patients). For retreated sALCL, the ORR was 88% (7 of 8 patients) with a CR rate of 63% (5 of 8 patients). The estimated median duration of response (DOR) for patients with an objective response was 9.5 months, and for patients with a CR, the estimated median DOR was 12.3 months (Bartlett 2014). However, interpretation from this study is limited because it did not include patients who received brentuximab vedotin as part of frontline treatment or in patients with non-sALCL PTCL. The potential of retreatment with brentuximab vedotin to offer a meaningful treatment option throughout the continuum of these diseases is under investigation. Study Design and Methods This is a phase 2, multicenter, single-arm study to determine the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory cHL, sALCL, or other CD30-expressing PTCL who experienced CR or partial response with a brentuximab vedotin-containing regimen and subsequently experienced disease progression or relapse. Patients who previously discontinued brentuximab vedotin due to any Grade 3 or higher toxicity or have existing Grade 2 or higher peripheral neuropathy will not be eligible. It is anticipated that approximately 50 patients will enroll in this study. All patients will be administered 1.8 mg/kg brentuximab vedotin intravenously, up to a maximum of 180 mg, over 30 minutes once per 21-day cycle. Patients who previously required a dose reduction due to adverse events (AE) will be administered brentuximab vedotin at 1.2 mg/kg. The primary efficacy endpoint of this study is ORR (per blinded independent central review), a direct measure of anti-tumor activity. To further assess the significance of ORR in this study, durability, CR rate, overall survival, and progression-free survival will be evaluated as secondary endpoints. Safety will be monitored throughout the trial via laboratory values and AE collection. The study's sample size was chosen to allow adequate precision of estimates of response rates and characterization of safety data. Enrollment in this study is expected in September 2019 (Clinicaltrials.gov: NCT03947255). Disclosures Lisano: Seattle Genetics, Inc.: Employment, Equity Ownership. Newhook:Seattle Genetics, Inc.: Employment. OffLabel Disclosure: Brentuximab vedotin is being investigated as a retreatment option.

1073P - Prognostic factors influencing outcome after therapy with brentuximab vedotin in patients with relapsed or refractory Hodgkin’s lymphoma

BackgroundBrentuximab Vedotin (BV) treatment has improved the prognosis and survival of patients with Hodgkin’s lymphoma, relapsed after stem cell transplantation or having refractory disease. Aim: To analyze the prognostic factors, influencing the outcome after therapy with BV in relapsed or refractory patients with Hodgkin’s lymphoma. MethodsWe studied sixty-four (64) Hodgkin’s lymphoma patients treated with BV in six Hematology clinics in Bulgaria. The male / female ratio was 1 / 1, the mean age at the time of BV therapy was 40.66+/-13.1 years. The most common histological variant was nodular sclerosis 46 (71.9%). In the II clinical stage there were 26 patients (40.6%), in IIIrd - 17 (26.6%), in IVth - 21 (32.8%). All patients before treatment with BV received median of 4 (2-12) treatment lines, 30 ( 46.9%) received =/>3 lines. Autologous stem cell transplantation (autoSCT) was performed in 45 (70.3%) patients, two of which were second autologous SCTs, and in one auto/ allo SCT. ResultsORR was 60.9% (N=39). Complete response was achieved in 39.1% (25) and partial response in 21.9% (14) patients. Stable disease was registered in 10.9% (7) and progression in 28.1% (18). PFS for the entire group was 14 months. The median survival (MS) was not reached by the end of the analysis. At least partial therapeutic response was significantly higher in patients with chemosensitive disease before autoSCT ( P=0.006, R=+0.340), these who have undergone autoSCT ( P=0.021, R= -0.335) and when BV was started as consolidation therapy by month 3 after autoSCT ( P=0.02, R=+0.287). The only significant prognostic factor that determines a remarkably longer EFS is the type of therapeutic response itself: in the CR + PR group, the median PFS is not reached by the time of the analysis, while in patients with stable disease and progression EFS is 7 months (P<0.001). ConclusionsBV is most effective in patients with chemosensitive disease, and when used as consolidation therapy early, by 3-rd month after autoSCT. Our results confirm the international experience. BV improves the therapeutic response and prolongs progression-free survival in the patients with Hodgkin’s lymphoma who previously had really bad prognosis. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis

AbstractThere is an unmet need for effective therapies for advanced systemic mastocytosis (advSM). CD30 is expressed on the surface of neoplastic mast cells (MC) in more than 50% of patients with advSM. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate with preclinical evidence supporting both an antineoplastic effect and an attenuation of immunoglobulin E-associated mediator release. These observations are the basis for this phase 2 trial of BV monotherapy (1.8 mg/kg IV every 3 weeks up to 8 cycles) in patients with CD30-positive advSM. The primary objective was to determine the efficacy of BV according to International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria. Secondary objectives included evaluation of safety, changes in bone marrow (BM) MC burden, serum tryptase level, flow cytometric quantification of MC surface expression of CD30, and self-reported symptom burden. The trial enrolled 10 patients with a diagnosis of CD30+ advSM (aggressive SM, SM with an associated hematologic neoplasm [SM-AHN], or mast cell leukemia [MCL]) with 1 or more signs of SM-related organ damage. According to IWG-MRT-ECNM criteria, none of the patients demonstrated better than stable disease with BV. In addition, there were no significant reductions in BM MC burden, serum tryptase levels, or MC surface expression of CD30. Self-reported symptom scores showed no durable improvement with BV treatment. We conclude that BV is not active as a single agent in CD30+ advSM. This trial was registered at www.clinicaltrials.gov as #NCT01807598.