Single-agent Brentuximab Vedotin Research Articles

BV and beyond: how to incorporate novel agents into PTCL management.

Peripheral T-cell lymphomas (PTCLs) are a heterogenous yet aggressive group of lymphomas that arise from mature T- or NK-cell precursors. Nodal PTCLs include anaplastic large-cell lymphoma, PTCL not otherwise specified, and follicular helper T-cell lymphomas. Recent advances in understanding these heterogenous diseases have prompted investigation of novel agents to improve on treatment. Brentuximab vedotin, a CD30 antibody-drug conjugate, has been incorporated into frontline treatment regimens of CD30-expressing PTCLs based on the ECHELON-2 trial. Multiple ongoing trials are evaluating the addition of other targeted agents in the frontline and relapsed/refractory setting. These include single-agent brentuximab vedotin, histone deacetylase inhibitors, duvelisib, ruxolitinib, EZH2 inhibitors, and azacitidine, among others. Follicular helper T-cell lymphomas, given frequent mutations in epigenetic regulator genes, may preferentially respond to agents such as histone deacetylase inhibitors, EZH2 inhibitors, and hypomethylating agents. As these therapies evolve in their use for both relapsed/refractory disease and then into frontline treatment, subtype-specific therapy will likely help personalize care for patients with PTCL.

Immune-Related Gene Expression Signatures Identify a Patient's Subset Achieving Durable Complete Response to Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma

Background: In classical Hodgkin lymphoma (cHL), 20%-30% of patients experience relapse or progressive disease after standard chemotherapy, requiring salvage treatment strategies including targeted immunotherapy with brentuximab vedotin (BV). Molecular mechanisms underlying treatment resistance to BV in cHL are still poorly understood. The unique characteristics of cHL microenvironment, which represents >90% of the cellular infiltrate, make targeted gene expression profiling (T-GEP) a suitable technique to investigate immune-related determinants of BV sensitivity. Methods: 31 consecutive patients (pts) affected by relapsed-refractory (R/R) cHL treated at 2 italian Institutions from 2013 to 2018 with available formalin-fixed paraffin embedded (FFPE) tissue collected right before the start of BV therapy, were included in this retrospective study. FFPE tissue was profiled by T-GEP on the Nanostring platform, using the PanCancer Immune Profiling panel, encompassing 730 genes regulating the most relevant immunologic pathways. Disease response after BV treatment was evaluated by FDG-PET after 4, 8, 12 and 16 cycles. Results: Median age of the whole cohort was 38 years (y) (range 18-76). 18 pts (58%) were male. Median number of BV cycles was 8 (range 2-16). After a median follow-up of 3.5 y from the start of Brentuximab treatment, the overall survival (OS) and progression-free survival (PFS) rates were 87% and 32% respectively. Pts were classified as BV-responders in case of complete metabolic response (CMR) lasting more than 6 months (m); pts achieving less than CMR or short lasting (< 6 m) CMR were classified as non-responders (NR). By applying these criteria, 12 pts (39%) were classified as responders and 19 as non-responders. Differential expression (DE) analyses were performed and differentially expressed (DE) genes were selected by applying two statistical filters: (log2FC > 1 and p-value < 0.05). 61 genes were differentially expressed between responders and non-responders. The 61-gene signature included genes involved in JAK-STAT signaling, IL-17 signaling and cytokine-cytokine receptor interaction. Unsupervised clustering analyses identified two different pts clusters with clearly different BV-sensitivity profiles: cluster1 (22 pts) and cluster2 (9 pts). Among the 22 pts of cluster 1, only 4 pts were responders while 18 were non-responders. As opposite, 8 of 9 patients of Cluster2 were responders, while only 1 was non-responder (p=0.0005). In line with this, 4-y PFS rate of the 22 pts included in cluster1 was 19%, while the 4-y PFS rate of the 9 pts included in cluster2 was 66% (p=0.007). Median PFS of Cluster1 was only 5.7 months. The composition of the two clusters was not significantly different in terms of number of prior therapies and disease stage at the time of BV treatment. After achieving a CMR 6 of 9 pts were consolidated with autologous stem cell transplantation (ASCT) in cluster2. In cluster1, 1 patient was consolidated with ASCT after CMR, and 2 pts received allogeneic stem cell transplantation (allo-SCT) after BV-failure. Conclusions: With the limitation of the small sample size, these data suggest that the composition of cHL microenvironment could influence the activity of single agent BV. Pre-treatment microenvironment profiling with T-GEP could be a useful tool for selecting patients who may derive maximal benefit from BV in cHL.

Brentuximab Vedotin in Frontline Therapy of Hodgkin Lymphoma in Patients with Significant Comorbidities Ineligible for Standard Chemotherapy (SGN35-015 Part E)

Brentuximab vedotin (BV) is approved for the treatment of adults with treatment-naïve stage III or IV classical Hodgkin lymphoma (cHL) combined with doxorubicin, vinblastine, and dacarbazine (AVD) and targets CD30, a receptor expressed on the Reed Sternberg cells. Treatment with BV plus AVD has demonstrated improved overall survival (OS) (6-year OS estimate of 93.9% vs 89.4%; HR, 0.59; 95% CI, 0.40-0.88; P=0.009) compared with the standard chemotherapy combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (Ansell 2022). For patients (pts) newly diagnosed with cHL, current treatment options have improved pt outcomes in recent years, but survival rates are still very low for those with significant comorbidities. Pts with comorbid conditions can have poor outcomes due to decreased ability to tolerate dose intensity, increased treatment-related toxicity, and cHL relapse. This study is evaluating the efficacy and safety of single-agent BV as frontline therapy in cHL pts who are ineligible for conventional combination chemotherapy because of comorbidities. SGN35-015 Part E (NCT01716806) was a phase 2, open-label study of BV as frontline cHL therapy. Eligible pts (≥18 years) were unfit for initial conventional combination chemotherapy for cHL as documented by a modified Cumulative Illness Rating Scale score ≥10 or because they required or depended on others for instrumental activities of daily living. Pts received BV (1.8 mg/kg) on Day 1 of each 3-week cycle for up to 16 cycles. Granulocyte colony-stimulating factor prophylaxis was not required. The primary endpoint, objective response rate (ORR), was assessed by Blinded Independent Central Review (BICR) according to the Modified Lugano Criteria (Cheson 2014). Key secondary endpoints included safety, duration of response (DOR), complete response (CR) rate using the Lugano Criteria (Cheson 2014), duration of CR, progression-free survival (PFS), and OS. Thirty pts with cHL received BV and the median age was 76 years (range, 54 to 93 years). Most pts were female (53%) and had a disease stage of II (37%) or III (37%), an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (50%; 10 pts [33%] and 5 pts [17%] had an ECOG performance status of 2 and 3, respectively). The median treatment duration was 18 weeks (range, 1 to 50 weeks). Per BICR, the ORR was 60% (18/30) (95% CI: 40.6%, 77.3%), including 33% (10/30) with a CR and 27% (8/30) with a partial response. Six pts (20%) did not respond to treatment: 1 (3%) with progressive disease and 5 (17%) with stable disease; one pt (3%) was not evaluable and the remaining 5 pts (17%) did not have postbaseline responses, either because of death before first scheduled response assessment or not yet reaching the first scheduled response assessment. Median DOR was 7.4 months (95% CI: 7.4 months, not estimable) and median PFS was 8.7 months (95% CI: 5.1 months, not estimable). Median duration of CR was not estimable (95% CI: 7.4 months, not estimable). With a median follow-up of 14.6 months (range, 0 to 44 months), the 2-year OS rate was 70% (95% CI: 48%, 84%). A total of 18 pts (60%) experienced grade ≥3 treatment-emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were fatigue (n=3; 10%), acute kidney injury, anemia, atrial fibrillation, back pain, gait disturbance, hypoxia, neutrophil count decreased, pneumonia, sepsis, syncope, and vomiting (n=2 each; 7%). Nine pts (30%) discontinued treatment because of a TEAE; 1 death due to a TEAE (failure to thrive) was considered treatment-related. Thirteen percent (n=4) of pts experienced grade ≥3 peripheral neuropathy. In pts with cHL who are unfit for initial conventional chemotherapy due to comorbidities, BV monotherapy as frontline treatment appears effective, has an acceptable safety profile, and despite the small sample size could be considered as an option for pts with cHL who are unfit for conventional chemotherapy.

SINGLE AGENT BRENTUXIMAB VEDOTIN AS BRIDGE TO ALLOGENEIC STEM CELL TRANSPLANT IN ADOLESCENTS WITH RELAPSED ANAPLASTIC LARGE CELL LYMPHOMA (ALCL): THE UCLH EXPERIENCE

Introduction: Optimal treatment for relapsed ALCL in children and adolescents is still subject of debate. We present here the results of our salvage strategy in the TYA Unit at UCLH, using single agent brentuximab vedotin (BV) as bridge to allogeneic stem cell transplant (alloHSCT). Methods: Between 2011 and 2021 we treated 7 patients with relapsed ALCL; all patients had received first line treatment according to ALCL99 guidelines. All relapses were biopsy proven and centrally reviewed if not performed at UCLH. Brentuximab Vedotin was given at the standard dose of 1.8mg/kg intravenously every 3 weeks. Results: All 7 patients were male; median age at diagnosis was 16 (range 13–19). Baseline characteristics were as follows: 7/7 were CD30+, 3/7 were CD3+, 6/7 biopsies were ALK positive, and 3/7 presented with a small cell/lymphohistiocitic (SC/LH) pattern. Six/7 patients had stage IV disease, 4/7 had skin involvement, bone marrow involvement was seen in 3/7 cases (infiltrate between 2 and 10%); 1/7 patients had bulky disease. Of the 7 patients, 3 had primary progressive disease, while 4/7 patients initially achieved a complete metabolic response (CMR), but had a very early relapse, between 2 and 3 months after completion of treatment. 6/7 patients received BV as first line of salvage treatment, 1 as second salvage, after failing ICM (ifosfamide, carboplatin, mitoxantrone), which was still our standard of care in 2011. Median number of doses of BV received was 3 (range 2–5); 6/7 (86%) patients obtained a complete metabolic remission, after a median of 3 doses (range 3–5). One patient progressed on BV; after failing crizotinib he achieved CMR with vinblastine-dexamethasone, then proceeded to transplant and is in long term remission. All 6 patients who achieved a complete remission after BV proceeded to alloHSCT, 1/6 from fully matched sibling donor, 3/6 from haploidentical donors, 2/6 from matched unrelated donors. Conditioning regimen was myeloablative for 5/6 patients, using Cyclophosphamide/total body irradiation +/- Campath depending on donor source; one patient received intermediate intensity conditioning with BEAM (BCNU, etoposide, cytarabine, melphalan)-Campath. With a median follow up of 55 months (range 4–133), all 6 patients are alive and 5/6 (83%) remain in remission with no need for further treatment; 1/6 patients relapsed 8 months post-transplant. This patient was re-challenged with BV, with the addition of donor lymphocytes infusions (DLI) and achieved a complete remission. Conclusions: Salvage treatment with single agent BV followed by alloHSCT is effective in adolescents with relapsed ALCL and lead to durable responses in a cohort of patients with high prevalence of high-risk features (advanced stage, SC/LH pattern, CD3+, early relapse after first line treatment). Interestingly, in one patient who relapsed after alloHSCT, BV and DLI were successful in inducing another complete remission. Keywords: Molecular Targeted Therapies, Non-Hodgkin (Pediatric, Adolescent, and Young Adult), Stem Cell Transplant No conflicts of interests pertinent to the abstract.

Phase II single-arm study of brentuximab vedotin in Chinese patients with relapsed/refractory classical Hodgkin lymphoma or systemic anaplastic large cell lymphoma

Background Relapsed/refractory (R/R) classical HL (cHL) and systemic anaplastic large-cell lymphoma (sALCL) treatment options are limited in China and there is a need for new therapies. Research design and methods This single-arm, open-label, multicenter, Phase II study assessed efficacy, safety, and pharmacokinetics (PK) of single-agent brentuximab vedotin in Chinese patients with R/R cHL or sALCL. Patients received brentuximab vedotin as a 1.8 mg/kg intravenous infusion on Day 1 of a 3-week cycle (maximum 16 cycles). Results Patients (N=39) received a median of 10 cycles (range: 2–16) of brentuximab vedotin. The objective response rate was 69% (95% CI: 52–83%). Median duration of response, progression-free survival and overall survival were 12.1 months, 13.5 months (95% CI: 6.8 months–not estimable) and not reached after a median follow-up of 16.6 months. Twenty seven (69%) patients achieved an objective response (complete response: n=11 [28%]; partial response: n=16 [41%]). Brentuximab vedotin was well-tolerated with no on-study deaths. AEs were generally manageable and reversible. No new safety signals were identified. PK were consistent with those previously described in Western populations. Conclusion Brentuximab vedotin had a positive benefit-risk profile for Chinese patients with R/R cHL or sALCL confirming it as a potential treatment option. Clinical trial registration www.clinicaltrials.gov identifier is NCT02939014.

Monomorphic Cutaneous T-Cell Lymphoma in a Patient with Cadaveric Renal Transplant on Immunosuppressive Drugs and Renal Impairment Treated Successfully with Single Agent Brentuximab Vedotin

BACKGROUND:Patients with renal transplants on immunosuppressive drugs are more likely to develop skin malignancies secondary to T-cell dysfunction and are at increased risk of viral reactivation. Cutaneous lymphomas are the second most common form of malignancy after skin cancer. B-cell lymphoma accounts for majority of the cases, with T-cell lymphoma accounting for 30% of the cases. T cell post-transplant lymphoproliferative disorder is usually an aggressive lymphoma. Skin lesions may be either erythematous, infiltrative plaque, nodular or ulcerative tumor. Cutaneous T-cell lymphoma expressing CD 30 generally have a good prognosis and can be treated with targeted antibody against CD30 avoiding systemic toxicity of chemotherapy. Brentuximab vedotin CD30 antibody is an antibody-drug conjugate (ADC) consisting of CD30-directed antibody, cAC10, conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). ADC binds to CD30-expressing cells, followed by internalization of the ADC-CD30 complex and the release of MMAE via proteolytic cleavage. MMAE then binds to tubulin to disrupt the microtubule network within the cell causing cell cycle arrest and apoptotic cell deathOBSERVATION:A 46 year old male received a Cadaveric Renal transplant in 1999 for presumed renal failure after Streptococcal Nephritis. Patient experienced couple of rejections and has Chronic Kidney Disease, stage III. He is maintained on immunosuppressive medication which included prednisone, Mycophenolate Mofetil and cyclosporine. Patient noticed progressive lumps in his neck, back and arms which gradually increased in size and number to occupy his front and back of neck, chest and abdomen as well as axilla. The patient did not have any constitutional symptoms. PET/CT prior to treatment revealed widespread hypermetabolic soft tissue nodules involving skin, subcutaneous fat and muscle throughout the neck, chest, abdomen and pelvis as well as anterior mediastinal lymph node consistent with malignancy. Excisional biopsy from right axillary mass showed High Grade Lymphoma in setting of post -transplant. The immunopheno type of tumor cells were positive for CD2, CD4, MUM1 and CD138 (focal, especially the larger cells). CD3 was positive mostly in apparent background lymphocytes. CD30 was strongly and diffusely positive. The malignant cells were negative for EBV, CD79A, ALK-1 and CD20. The complex immunophenotype was consistent with the diagnosis of monomorphic post-transplant lymphoproliferative disorder of T lymphocytes. The dose of immunosuppressive drug was reduced and the patient was treated with Brentuximab vedotin CD30 antibody - drug conjugate 1.2 mg/kg every 3 week (Dose adjusted for renal impairment). The patient tolerated the treatment very well with mild grade 1 peripheral sensory neuropathy localized to bilateral finger tips treated with Pregabalin. Repeat PET/CT after six cycles of treatment with Brentuximab vedotin showed interval resolution of previously described hypermetabolic soft tissue nodules and anterior mediastinal lymph node. No evidence of residual/recurrent hyper-metabolic foci. The patient continues to be on Brentuximab vedotin every three week now after 6 months of treatment.CONCLUSION:CD30+ Monomorphic cutaneous T-cell lymphoma occurring in post renal transplant patients with renal impairment and on immunosuppressive medication can be successively treated with targeted drug Brentuximab vedotin with dose adjustment with excellent response as in this case. Brentuximab Vedotin should be avoided in severe renal failure (Creatinine Clearance< 30 mlL/min) due to higher risk of Grade 3 adverse reactions. Brentuximab vedotincan be safely use with dose modification and close observation for toxicity in patients with moderate renal impairment and post renal transplant setting. [Display omitted] DisclosuresD'Cunha:Seattle Genetics Inc.: Honoraria.

Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Long-Term Follow-up Confirms Durability of Single-Agent Brentuximab Vedotin As Pre-Transplant Salvage for Classical Hodgkin Lymphoma

Long-Term Follow-up Confirms Durability of Single-Agent Brentuximab Vedotin As Pre-Transplant Salvage for Classical Hodgkin Lymphoma

An International Multicentre Study of Consecutively Diagnosed Patients with ALCL: Outcomes Following First-Line Therapy in Routine Clinical Practice

An International Multicentre Study of Consecutively Diagnosed Patients with ALCL: Outcomes Following First-Line Therapy in Routine Clinical Practice

Acute liver injury leading to death in the setting of brentuximab vedotin monotherapy

A 67-year-old man with an 11-year history of composite lymphoma was admitted with fevers in the context of neutropenia and acute liver injury, 4 months after the commencement of single-agent brentuximab vedotin. Fevers resolved with intravenous antibiotics, however, his liver function tests remained abnormal and he continued to be deeply jaundiced over the course of his 3-week illness. A liver screen failed to indicate a cause for his liver function test abnormalities and two separate liver biopsies were suggestive of drug-induced liver injury. There was no evidence on biopsy of lymphoma. After consultation with two hepatologists, trials of steroids and ursodeoxycholic acid were unsuccessful. Twenty-five days into admission, he became septic with a normal peripheral blood count and deteriorated rapidly. After discussion with the family, he was deemed not to be for further escalation of care, and he died within several hours. This report summarizes the evidence in relation to hepatotoxicity of brentuximab vedotin.

Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma

AbstractThis pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.

Brentuximab-induced peripheral neuropathy: Risk factors and patient experiences.

120 Background: Brentuximab vedotin (BV) is an immunoconjugate used in Hodgkin lymphoma (HL) and other CD30+ lymphomas. The dose-limiting adverse effect is peripheral neuropathy (BIPN). Predictors of BIPN, effect on outcomes, and the biopsychosocial impact are not well defined. Methods: We conducted a single institution, mixed-methods study of lymphoma patients (pts) who received BV between 1/2010 and 5/2016. A retrospective analysis was conducted in all pts; an open-ended survey was given to pts seen in the prior year. A univariate analysis examined the association between BIPN and potential predictors. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan Meier method. Survey data were analyzed qualitatively via a framework approach. Results: Eighty-nine pts were eligible: 56% were male, 54% had HL, 71% had prior neurotoxic drugs, 93% received single agent BV. The median number of BV doses was 5. Forty-three (48%) pts developed BIPN. It resolved completely in 14 (33%) pts at a median follow-up of 12 mo. The median time to resolution was 13 wks. BV therapy was altered in 21 (24%) pts due to BIPN. There was no difference in PFS (6 vs. 12 mo., p = 0.09) or OS (NR vs. 26 mo., p = 0.11) in pts who had therapy altered due to BIPN. Table 1 lists significant risk factors for BIPN. No additional factors investigated (age, sex, prior neurotoxic agent, underlying neuropathy, diabetes mellitus or BMI) increased risk for BIPN. Fourteen of the 18 (78%) surveyed pts reported BIPN. At a median follow-up of 24 mo., 10 (71%) pts reported ongoing symptoms. BIPN affected quality of life in 50% and work in 20% of pts. Despite significant symptoms from BIPN, all pts were satisfied with their decision to receive BV regardless of disease response. Conclusions: BIPN is a significant adverse event and may fail to resolve in a large subset of pts. Surveyed pts reported that the benefits of BV outweigh the risks. Changes in therapy due to BIPN occur, but this did not affect outcomes in our cohort. Clinicians should be aware of the risk for BIPN and educate pts accordingly. [Table: see text]

TARGETED DRUG BRENTUXIMAB VEDOTIN FOR TREATMENT OF RELAPSED OR REFRACTORY CD30-POSITIVE HODGKIN’S LYMPHOMA

Objective. To perform literature review of clinical trials reporting on the use of single-agent brentuximab vedotin (BV) 1.8 mg/kg therapy in adult patients with relapsed/refractory (R/R) CD30-positive Hodgkin lymphoma (HL). Methods. A literature search was performed in Pubmed and eLIBRARY. RU databases to identify all studies published from 1 July 2007 until 1 July 2017. We used the key words “brentuximab vedotin” and “Hodgkin lymphoma” simultaneously. The inclusion criteria required that study population included ≥ 20 adult patients with R/R HL. We included clinical trials, systematic reviews, meta-analysis, pharmacoeconomic studies: total 25 publications met inclusion criteria. Publications were grouped by 3 BV indications in instruction for use: adult patient with relapsed/refractory CD30-positive Hodgkin lymphoma post-autologous stem cell transplantation (postASCT), adult patient with refractory CD30-positive HL after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not candidates for ASCT, adult patient with classical HL at high risk of relapse or progression post-ASCT. Results. Overall response rate (ORR) and complete rate (CR) were 75% and 34% respectively in adult patients with R/R CD30-positive HL post-ASCT in SGN35–0003 study. In patients with refractory HL after failure of at least 2 prior multiagent chemotherapy regimens who are not candidates for auto-SCT ORR and CR were 40% and 30% respectively. In mixed population ORR were 56-80%, CR – 10-46.5%. In patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT ORR was not evaluated, median progression-free survival was improved in patients in BV group compared with those in placebo group (42.9 and 24.1 months respectively). Overall survival in both group was similar. In patients with R/R CD30-positive HL the incremental cost-effectiveness ratio per quality-adjusted life year (ICER/QALY) was 6.7 million rub. и 3 million rub. from a Russian and a Scottish healthcare payer respectively. ICER/QALY when BV compared with best supportive care was 9.79 million rubles. In patients who were at risk for HL repapse after ASCT if BV consolidation compared with active surveillance ICER/QALY was 8.86 million rub. Conclusion. As a result of the literature review, it was found that the response rate, the complete response to BV therapy, and the overall survival and progression-free survival with use of BV in different patient populations differ; in most cases, the result of effectiveness favors BV. The found safety data indicated a good tolerability of the drug. The results of the found pharmacoeconomic studies differ depending on the comparison therapy and the accepted pharmacoeconomic indicator.

Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Four-Year Survival and Durability Results of Brentuximab Vedotin in Combination with CHP in the Frontline Treatment of Patients with CD30-Expressing Peripheral T-Cell Lymphomas

BackgroundPeripheral T-cell lymphomas (PTCLs) encompass ~10-15% of aggressive non-Hodgkin lymphomas. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or variations thereof, are the most commonly used treatment regimens with complete remission (CR) rates ranging from 39-55% (Reimer 2009, d'Amore 2012). With the exception of low international prognostic index (IPI)-anaplastic lymphoma kinase (ALK)-positive ALCL, with 4-year progression-free survival (PFS) and overall survival (OS) ranging from 25-35% and 30-40%, respectively (Ellin 2014). We previously reported the results of this phase 1 trial that evaluated brentuximab vedotin (BV) administered in sequence with CHOP, or in combination with CHP (CHOP without vincristine) in treatment-naive patients (pts) with CD30-expressing PTCL (NCT01309789). The combination therapy (BV+CHP) showed safety and activity at standard doses, with an objective response rate (ORR) of 100% and complete response (CR) rate of 88% (Fanale 2014). The most common adverse events (AEs) experienced by pts were nausea and peripheral sensory neuropathy (69% each). Four-year durability data and updated results on peripheral neuropathy (PN) resolution from the BV+CHP combination treatment arm are presented herein.MethodsAdults with CD30-expressing PTCL, including systemic ALCL (anaplastic large cell lymphoma, ALK-negative, or ALK-positive with IPI score ≥2) were eligible for this study. CD30 expression for non-ALCL pts was defined as ≥1% CD30 expression in malignant cells. Pts on the combination treatment arm received 1.8 mg/kg BV and standard-dose CHP q3wk for up to 6 cycles. Pts who achieved at least a partial response (PR) following treatment could receive continued BV 1.8 mg/kg q3wk as single-agent for up to 10 additional cycles. Antitumor response was assessed by the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).ResultsTwenty-six previously untreated pts received BV+CHP. Disease diagnoses included systemic ALCL (n=19; including ALK-negative, n=16 and ALK-positive, n=3), PTCL-NOS (n=2), angioimmunoblastic T-cell lymphoma (AITL, n=2), adult T-cell leukemia/lymphoma (ATLL, n=2), and enteropathy-associated T-cell lymphoma (EATL, n=1). Twenty-one of the 26 pts who achieved remission with combination treatment continued on to receive single-agent BV. Overall, the 26 pts received a median of 13 cycles (range, 3 to 16) of BV.After a median observation period of 52 months (range 4.6 to 58.3) from first dose, 18 pts remain on study. The estimated 4-year PFS and OS rates are 52% (95% CI: 31, 69) and 80% (95% CI: 59, 91), respectively. The median PFS has not been reached (95% CI: 12.3, -). To date, 15 of 19 ALCL (3/3 ALK-positive, 12/16 ALK-negative), and 6 of 7 non-ALCL pts were alive at last follow-up. Five pts (19%) received subsequent treatment with single-agent BV in long-term follow-up and 3 pts received stem cell transplants (1 autologous, 2 allogeneic) for relapsed disease. There were no pts who underwent a consolidative stem cell transplant.Of the 26 pts treated with combination therapy, 19 (73%) experienced PN. Of these pts, 95% (18 of 19) experienced complete resolution (8 pts), or some resolution or improvement (defined as a decrease by at least 1 grade from worst grade, 10 pts). Of the pts who experienced improvement, 1 pt each improved from Grade 3 to a lowest Grade 2 and from Grade 3 to a lowest Grade 1, and 5 pts improved from Grade 2 to a lowest Grade 1. The median time to resolution of PN symptoms was 5.7 months. Eleven pts had ongoing neuropathy at last follow-up, of which, 9 pts had Grade 1 severity and 2 pts had Grade 2.ConclusionsThese 4-year durability results demonstrate that among pts with PTCL, initial therapy with BV in combination with CHP can induce long-term remissions with a tolerable safety profile. A phase 3 randomized trial comparing BV+CHP with CHOP for the frontline treatment of CD30-expressing PTCL is ongoing (NCT01777152).Progression-free Survival [Display omitted] DisclosuresHorwitz:Celgene: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Research Funding; Infinity: Research Funding; Huya: Consultancy; FortySeven: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Bartlett:Gilead: Consultancy. Pro:Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Davies:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; GSK: Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; Bayer: Research Funding; Karyopharma: Honoraria, Research Funding; Pfizer: Research Funding. Illidge:Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Uttarwar:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Ren:Seattle Genetics: Employment, Equity Ownership.

Outcome of Hodgkin Lymphoma after Progression Following Autologous Stem Cell Transplantation

Background Clinical trials have demonstrated a high level of effectiveness for brentuximab vedotin (BV) for patients with relapsed or refractory classical Hodgkin lymphoma (HL); however, how patients fare in routine clinical practice if their HL recurs after autologous stem cell transplant (ASCT) is less clear. Our primary objective was to characterize overall survival (OS) and progression-free survival (PFS) among a cohort of real-world patients treated with BV after ASCT. The secondary objective was to characterize the outcome of treatment after failure of ASCT or ASCT and BV.Methods We screened the population-based British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database to identify patients with classical HL (excluding lymphocyte predominant HL) who were aged >16 years at initial diagnosis, staged and treated in BC, had primary treatment with ABVD or equivalent chemotherapy, underwent ASCT as part of first treatment for refractory or relapsed disease and relapsed again after ASCT. We excluded patients who have been treated at any time with a checkpoint inhibitor. We determined Kaplan-Meier estimates of overall (OS) and progression free survival (PFS) from the date of the progression that occurred after ASCT and, for those treated with the agent, after subsequent BV. Therapies given in sequence without a pause between therapies were considered part of the same line of therapy.Results Between 1986 and 2015 93 patients experienced recurrence of HL after ASCT. Their median age at initial diagnosis was 30 years and 51% were male. After failure of ASCT 23 (25%) received radiation monotherapy and 61 received chemotherapy (66%), either as a single agent or in various combinations and of these 9 (10%) also received radiation; 6 (6%) received a second transplant (5 allogeneic and 1 repeat ASCT); and 5 refused or were too frail for treatment other than with corticosteroids. The median PFS and OS from the time of relapse after ASCT for these 93 patients were 7.1 (range 0.2-352) and 16.2 months (range 0.2-352), respectively. Of those 93, 17 patients received BV alone or BV+bendamustine at some point following ASCT. The median age of BV-treated patients was 33 years at the time of their original diagnosis and 29% were male. Among those 17 patients, 9 received single agent BV and 8, BV+bendamustine as part of a clinical trial. The median time from ASCT to the start of BV was 27.5 months. Counting ASCT as 2nd line treatment, 10 individuals received BV as 3rd line, 6 as 4th line and 1 as 5th line therapy. For all 17 patients the subsequent median PFS and OS from the time of BV initiation were 5.1 (range 1.5-34.6) and 18.8 months (range 2.4-40.5), respectively. 12 of these patients relapsed again and their subsequent median PFS and OS were 0.6 (range 0.5-29) and 3 (range 0.5-30) months, respectively. All 9 patients who received single agent BV relapsed again at a median of 2 months (range 1.2-9.7); 5 of the 8 patients treated with BV+bendamustine remain in remission 6 to 36 months later.Conclusions These data highlight the poor prognosis for patients with relapsed or refractory cHL, particularly for those whose lymphoma recurs after brentuximab vedotin as well as the highly individualized management of patients whose lymphoma has recurred after ASCT. Future therapies that prevent or significantly delay relapse will help in alleviate the substantial clinical burden due to relapsed and refractory Hodgkin lymphoma. DisclosuresConnors:Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding.

Efficacy of Brentuximab-Vedotin (BV) in Peripheral T-Cell Lymphomas (PTCLs) Other Than Anaplastic Large Cell Lymphoma (ALCL)

Background. BV, an anti-CD30 antibody-drug conjugate, has been approved for the treatment of Hodgkin lymphoma (HL) and ALCL. Of interest, BV has shown activity in PTCLs other than ALCL that express low or even undetectable levels of CD30. In particular BV has been reported effective in angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL-nos). Here, we report 4 cases with relapsed/resistant PTCLs (1 AITL, 1 NK-T nasal type, 1 PTCL with T-helper follicular phenotype-PTCL-TFH and 1 PTCL-nos) who responded to BV therapy.Results. On August 2014, a 53-y-old caucasian male was diagnosed with 5% CD30-positive AITL. The final stage was IIIA, because of a single left axillar node was documented at the PET-TC scan in addition to the excised inguinal lymphadenopathy. A complete metabolic PET remission (PET-CR) was documented after the 3th and confirmed after the 6th cycle of cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone (CHOEP). However, relapsing disease was documented 6 mths later. At that time, diffuse over and under-diaphragm nodal involvement was observed. A PET-CR was achieved after 2 cycles of dexamethasone, cytarabine, and cisplatin (DHAP), but disease progressed shortly after the 4th cycle before the planned autotransplantation (ASCT). A 3th line chemotherapy, consisting of mitoxantrone and high dose ARA-C (modified HAM), was performed and failed to control the disease. Furthermore HAM chemotherapy was associated with severe infectious complications (sepsis from MDR S. Epidermidis and pulmonary aspergillosis). On December 2015, BV was begun. A PET-CR was documented after the 4th and confirmed after the 8th cycle of therapy. The patients is still in CR, in continuous therapy (12th cycle), waiting for HLA matched unrelated donor.On July 2012 a 62-y-old caucasian man was diagnosed with extranodal NK/T-cell nasal type lymphoma. Both Epstein Barr virus (EBV) and CD30 molecule were not expressed by neoplastic cells. Weekly cisplatin and radiotherapy were concomitantly given followed by 3 cycles of etoposide, ifosfamide, cisplatin and dexamethasone. This treatment resulted in PET-CR. At the time of first relapse (Nov 2013), 3 cycles of methotrexate, L-asparaginase and dexamethasone, followed by ASCT (fotemustine, etoposide, cytarabine, melphalan), induced a 2nd PET-CR. However, two subsequent PET evaluations suggested the presence of active disease shortly after (December 2015) a biopsy proven relapse was documented. A PET-CR was observed after 2 and confirmed after 7 cycles of single agent BV. The patient is still undergoing treatment.On September 2015, a 49-y-old african man was diagnosed with PTCL-THF, showing AITL signs, with both EBV and CD30 positive (50-75%) Hodgkin/Reed-Sternberg cells. A progressive disease was documented after the 4th cycle of CHOEP. At that time, patient was not candidate to receive further chemotherapy, because of worsening of perfomance status (PS). BV, given as salvage therapy, resulted in a rapid control of all signs and symptoms after the 6th administration. Because of improved PS and a partial metabolic remission, the DHAP combination was begun on June 2016 and ASCT is now planned as consolidation.On November 2009, a 46-y-old caucasian man was diagnosed with classical HL. The final stage was IEA. The disease was refractory to doxorubicin, bleomycin, vinblastine, dacarbazine and radiotherapy. A PET-CR was achieved in response to ifosfamide, gemcitabine, vinorelbine and prednisone chemotherapy. After 3 yrs, a lymph node biopsy confirmed a relapsed HL. Four cycles of DHAP followed by ASCT resulted in a 2nd PET-CR. After 3 mths, a PTCL-NOS associated with blastic lymphoid B EBV positive cells was diagnosed on an excisional lymph node biopsy. On May 2014 BV as single-agent was started. A PET-CR lasted for 8 mths. Relapsing disease was documented on January 2015. The patient refused further chemotherapy and died because of disease progression on July 2015.Conclusion. In this experience BV, regardless of CD30 expression, has shown significant clinical activity in recurrent or refractory T-cell lymphomas and no significant toxicity, even in heavily pretreated patients. In consideration of the BV activity in PTCLs, combination studies with other molecules, such as romidepsine, are desirable. DisclosuresNo relevant conflicts of interest to declare.

Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma

AbstractPresented here are the 5-year end-of-study results from the pivotal phase 2 trial of brentuximab vedotin in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. At 5 years, the overall patient population (N = 102) had an estimated overall survival (OS) rate of 41% (95% confidence interval [CI]: 31-51) and progression-free survival (PFS) rate of 22% (95% CI: 13-31). Patients who achieved a complete response (CR) to brentuximab vedotin (N = 34) had estimated OS and PFS rates of 64% (95% CI: 48-80%) and 52% (95% CI: 34-69%), respectively. The median OS and PFS were not reached in CR patients, with 13 patients (38% of all CR patients) remaining in follow-up and in remission at study closure. Of the 13 patients, 4 received consolidative hematopoietic allogeneic stem cell transplant, and 9 (9% of all enrolled patients) remain in sustained CR without receiving any further anticancer therapy after treatment with brentuximab vedotin. Of the patients who experienced treatment-emergent peripheral neuropathy, 88% experienced either resolution (73%) or improvement (14%) in symptoms. These 5-year follow-up data demonstrate that a subset of patients with R/R HL who obtained CR with single-agent brentuximab vedotin achieved long-term disease control and may potentially be cured. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

Brentuximab vedotin in pretreated Hodgkin lymphoma patients: a systematic review and meta-analysis

ABSTRACTObjectives: This meta-analysis evaluated the effect of single agent brentuximab vedotin (BV) in patients with relapsed/refractory Hodgkin lymphoma (HL).Patients and methods: A systematic literature search was performed and included studies published from 1st January 2012 to 1st July 2015 investigating BV in patients with relapsed/refractory HL. Data was extracted and reviewed by two investigators then analyzed using the comprehensive meta-analysis version 3 software.Results: 22 out of 4048 screened records met the eligibility criteria. These records included 903 patients. The median age of the cohort was 31 years (range: 26-45). 86% received ≥ 3 previous lines of systemic therapy. 529 (58.7%) and 232 (25.7%) underwent high dose chemotherapy and autologous and/or allogeneic stem transplantation prior of BV respectively. The overall response rate to BV was 62.7% (range: 30-100%). The complete response, partial response, stable disease and progressive disease rates were 31.8%, 35.1%, 19.5% and 11.7% respectively. The one year progression free survival and estimated one year overall survival were 47.6% and 79.5% respectively.Conclusion: In this largest published pooled cohort, BV produces high responses with encouraging progression free and overall survival in relapsed/refractory HL patients. Our results enhance the role of BV in heavily pretreated HL patients.

Complete response in a critically ill patient with ALK-negative anaplastic large cell lymphoma treated with single agent brentuximab-vedotin

ABSTRACTAnaplastic large cell lymphoma (ALCL) is a rare hematological malignancy and a distinct subtype of mature T-cell lymphomas. ALCL is comprised of two clinically distinct but morphologically similar sub-class under 2008 WHO classification: cutaneous and systemic. Primary systemic ALCL is further sub-categorized into tumors that carry the anaplastic lymphoma kinase (ALK) gene rearrangement or not; ALK-positive versus ALK-negative disease respectively. Traditionally, both forms of primary systemic ALCL have been treated upfront with an anthracycline based combination chemotherapy such as CHOP. More recently an antibody drug conjugate, brentuximab-vedotin (BV), directed against CD30 antigen has shown promise in CD30 expressing hematologic malignancies such as Hodgkin's lymphoma and ALCL. At the present time, this novel antibody-drug conjugate has been approved in the treatment of patients with ALCL after failure of at least one prior multi-agent chemotherapy regimen in the United States. We present a case describing a previously healthy 48 year-old female diagnosed with ALK-negative ALCL who achieved complete response with upfront single agent brentuximab-vedotin. It is the first case described in the literature utilizing BV in the first line setting particularly in a patient with multi-organ failure and critically ill at time of diagnosis. This case highlights the full potential that targeted therapies can exert over hematological malignancies while also minimizing treatment related toxicities.Abbreviations: AE: adverse event; ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ASCT: autologous stem cell transplant; BEAM: BCNU/carmustine, etoposide, ara-C, and melphalan; BV: brentuximab vedotin; CHEOP: cyclophosphamide, daunorubicin, vincristine, prednisone, etoposide; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; CR:complete response; G3+: grade 3 or higher; MTD: maximum tolerated dose; ORR: overall response rate; OS: overall survival; PFS: progression-free survival.