Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation

PURPOSE Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL. METHODS Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov identifier: NCT01920932 . RESULTS Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy. CONCLUSION The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.

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Frontline brentuximab vedotin as monotherapy or in combination for older Hodgkin lymphoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8032 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8032-8032 ◽

Cited By ~ 1

Author(s):

Christopher A. Yasenchak ◽

Rodolfo Eduardo Bordoni ◽

Dipti Patel-Donnelly ◽

Tim Larson ◽

Jerome H. Goldschmidt ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Older Patients ◽

Treatment Options ◽

Response Assessment ◽

Brentuximab Vedotin ◽

Disease Stage ◽

Antibody Drug Conjugate ◽

Open Label ◽

Data Set ◽

Part C

8032 Background: Older patients with classical Hodgkin lymphoma (cHL) have poor outcomes relative to younger patients, often due to comorbidities and toxicities related to standard first-line (1L) chemotherapy (5-yr PFS: 30%–45% vs 75%–80%) (Evens 2008; Proctor 2009). Brentuximab vedotin (BV, ADCETRIS®), a CD30-directed antibody-drug conjugate, has robust activity in patients refractory to several lines of chemotherapy. Methods: This phase 2, open-label study, SGN35-015 (NCT01716806), evaluated efficacy and tolerability of BV alone or combined with single-agents in treatment-naive cHL patients ≥60 yr. The full-analysis set (FAS) includes all patients who received BV (1.8 mg/kg IV). Patients in Part A received BV monotherapy on Day 1 of every 3-week cycle (n = 26); Part B: BV+dacarbazine (DTIC; 375 mg/m2; n = 19); Part C: BV+bendamustine (benda; 70 mg/m2; n = 20); and Part D: BV+nivolumab (nivo; 3 mg/kg; n = 20). The efficacy evaluable (EE) set includes all patients who had at least 1 post-baseline response assessment (n = 25, 19, 17, 19). Results: Demographic characteristics were generally similar: median age 78, 69, 75, and 72 yr in Parts A, B, C, and D, respectively, and 62% of patients (range 45%–70%) reported impaired physical functioning at baseline. Most patients had disease stage III/IV (62%, 68%, 75%, 80%), were ECOG 0/1 (77%, 74%, 80%, 95%), and male (54%, 68%, 50%, 75%). Median time from diagnosis was 1.2 to 1.5 mo (FAS; 10 Jan 2019 data cutoff). ORR were high (92%, 100%, 100%, 95%) at a median follow-up of 59.4, 58.6, 51.3, and 19.4 mo in the EE data set. Median OS in the FAS set was 77.5 mo with monotherapy; 64.0, 46.9, and not reached in the combination parts. Treatment-related AE ≥ Grade 3 occurred in 50%, 37%, 70%, and 60% of patients; peripheral neuropathy (PN) was most common (35%, 26%, 20%, 35%). Treatment-related SAEs occurred in 12%, 11%, 40%, and 5% of patients. Part C enrollment (BV+benda) closed early due to multiple acute toxicities. There were no treatment-related deaths in any part of the study. The median treatment cycles per patient were 8.0, 12.0, 5.0, and 14.5. Treatment discontinuation due to related AEs occurred in 42%, 42%, 40%, and 30% of patients, most commonly due to PN (38%, 37%, 30%, 20%). Conclusions: Older patients with cHL and multiple comorbidities have very high response rates with BV as monotherapy or combined with other single agents and improved tolerability versus combination chemotherapy. Median overall survival exceeded 6 yr with BV monotherapy. BV+nivo or BV+DTIC appeared to be the most reasonable combination treatment options in this study. Clinical trial information: NCT01716806 .

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Near Complete Response in a Patient with Classical Hodgkin Lymphoma Treated with Brentuximab Vedotin Concurrent with Radiation Therapy

Case Reports in Oncology ◽

10.1159/000479224 ◽

2017 ◽

Vol 10 (3) ◽

pp. 795-801 ◽

Cited By ~ 2

Author(s):

Wilbur Montana ◽

Dennis Andrew Buck ◽

Tristan Smith

Keyword(s):

Radiation Therapy ◽

Complete Remission ◽

Hodgkin Lymphoma ◽

Complete Response ◽

Brentuximab Vedotin ◽

Second Line ◽

Antibody Drug Conjugate ◽

Multi Agent ◽

Third Line ◽

Line Setting

Brentuximab vedotin, an antibody drug conjugate that delivers monomethyl auristatin E into CD-30 expressing cells is FDA approved for the treatment of patients with Hodgkin lymphoma after the failure of autologous stem cell transplantation or at least 2 prior multi-agent chemotherapy regiments. This approval was based on a study that showed an overall response rate of 75% and complete remission in 34%. We present a case of a 24-year-old male with classical nodular sclerosing Hodgkin lymphoma who achieved near complete remission following 5 cycles of brentuximab concurrent with ISRT (involved site radiation therapy) following progression of first-line ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) and subsequent second-line ICE (ifosfamide, carboplatin, etoposide) chemotherapy. This case not only reiterates the efficacy of brentuximab vedotin in the third-line setting but introduces the role of and need for further clinical trials of combined radiotherapy with brentuximab in Hodgkin lymphoma patients following failure of second-line options.

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Excellent Outcome for Pediatric Patients with High Risk Hodgkin Lymphoma with Brentuximab Vedotin and Risk Adapted Residual Node Radiation

SSRN Electronic Journal ◽

10.2139/ssrn.3716895 ◽

2020 ◽

Author(s):

Monika Metzger ◽

Michael P. Link ◽

Amy L. Billett ◽

Jamie Flerlage ◽

John T. Lucas Jr. ◽

...

Keyword(s):

High Risk ◽

Hodgkin Lymphoma ◽

Pediatric Patients ◽

Brentuximab Vedotin ◽

Excellent Outcome

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Relabáló/refrakter Hodgkin-lymphoma brentuximab vedotin kezelése. Hazai tapasztalatok

Orvosi Hetilap ◽

10.1556/650.2017.30867 ◽

2017 ◽

Vol 158 (41) ◽

pp. 1630-1634

Author(s):

Zsuzsa Molnár ◽

László Imre Pinczés ◽

Klára Piukovics ◽

Ildikó Istenes ◽

Krisztina Wolf ◽

...

Keyword(s):

Survival Rate ◽

Complete Remission ◽

Hodgkin Lymphoma ◽

Remission Rate ◽

Single Agent ◽

Brentuximab Vedotin ◽

Common Symptom ◽

Antibody Drug Conjugate ◽

Hematopoietic Stem ◽

Refractory Hodgkin Lymphoma

Abstract: Introduction: The treatment of relapsed or refractory Hodgkin lymphoma is still a major therapeutic challenge. The use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, represents a promising approach for these patients, however clinical outcomes have not yet been evaluated in Hungary. Aim: Our aim was to assess the efficacy, safety and outcome of brentuximab vedotin treatment in Hungarian Hodgkin lymphoma patients. Method: In this retrospective case note review we enrolled patients at 6 clinical sites countrywide who were diagnosed with Hodgkin lymphoma and received brentuximab vedotin between 1 January 2013 and 31 December 2016. Results: A total of 86 patients were treated with brentuximab vedotin during the examined period. Before therapy initiation 66% of our patients had advanced-stage disease. Overall response rate to brentuximab vedotin, administered before autologous hematopoietic stem cell transplantation (n = 54) was 66.6%, complete remission rate was 42.6%. Thirty patients received brentuximab vedotin after AHSCT, 46.67% responded to treatment, 30% achieved complete remission. Thirty-six patients received the drug as a single-agent therapy, 50 patients were given brentuximab vedotin in combination, 39 of them with bendamustin. Toxicity was observed only in 13.95% of our patients, most common symptom was skin rash. Based on our analysis the estimated 5-year overall survival rate was 78.7%, the estimated progression free survival rate was 23.59 months (95% CI: 19.50–27.68). Conclusion: Brentuximab vedotin carries a substantial improvement in the treatment of relapsed or refractory Hodgkin lymphoma. Our results underline prior observations published in the literature. The use of brentuximab vedotin in combination can be beneficial, however further investigation is needed on the subject. Orv Hetil. 2017; 158(41): 1630–1634.

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Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.354 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 354-354 ◽

Cited By ~ 30

Author(s):

Scott T. Tagawa ◽

Bishoy Morris Faltas ◽

Elaine Tat Lam ◽

Philip James Saylor ◽

Aditya Bardia ◽

...

Keyword(s):

Phase I ◽

Treatment Options ◽

Objective Response ◽

Progression Free Survival ◽

Response Assessment ◽

Complete Response ◽

Clinical Activity ◽

Antibody Drug Conjugate ◽

Open Label ◽

Metastatic Urothelial Cancer

354 Background: Patients (pts) with mUC who progress after platinum (PLT)-based chemotherapy and immune checkpoint inhibitor (CPI) therapy have poor outcomes and limited treatment options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate. It consists of a monoclonal antibody targeting Trop-2, an epithelial cell surface antigen overexpressed in UC, conjugated to the active metabolite of irinotecan (SN38). Methods: We performed a phase I/II basket study in pts with advanced solid tumors receiving intravenous SG administered on day 1 and 8 of 21-day cycles, until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment. We evaluated pts with mUC who progressed after ≥1 prior systemic therapy and were treated with SG at the 10 mg/kg dose level. Endpoints included safety, objective response rate (ORR) by RECIST 1.1, clinical benefit rate (CBR; complete response [CR], partial response [PR], or else SD ≥6-mo), and Kaplan-Meier estimated duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 45 pts (41M/4F; median age 67, range 49-90; ECOG 0/1: 31%/69%) received a median of 2 (range: 1-6) prior treatment lines, including PLT-based chemotherapy (95%) and CPI (38%). 33 had visceral metastases involving liver (n=15), lung (n=27), and other organs (n=5). The ORR was 31% (14/45), with 2 CR and 12 PR. In pts with visceral involvement, the ORR was 27% (9/33). The ORR in CPI-treated pts was 23% (4/17). The median DOR was 12.6 mo (2 pts continuing >2 y), and the CBR was 47% (21/45). Median PFS and OS were 7.3 mo and 18.9 mo, respectively. The AE profile was consistent with prior reports. Grade ≥3 AEs in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Conclusions: SG demonstrated clinical activity in pts with relapsed/refractory mUC, including CPI-treated pts and pts with visceral disease. A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of SG in advanced UC.(TROPHY-U-01; NCT03547973). Clinical trial information: NCT03547973.

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Does Interim PET Scan After 2 Cycles of ABVD Predict Outcome in Hodgkin Lymphoma? Real-World Evidence

Journal of Global Oncology ◽

10.1200/jgo.19.00179 ◽

2019 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Arun Seshachalam ◽

Shashidhar V. Karpurmath ◽

Krishnakumar Rathnam ◽

S. Ganapathi Raman ◽

Murugesan Janarthinakani ◽

...

Keyword(s):

High Risk ◽

Hodgkin Lymphoma ◽

Tertiary Care ◽

Stage Iv ◽

Secondary Data ◽

Response Assessment ◽

Complete Response ◽

Female Ratio ◽

Entire Cohort ◽

Interim Pet

PURPOSE Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) improves overall survival (OS) in patients with Hodgkin lymphoma (HL) relative to ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. However, the associated higher cost and toxicity discourage clinicians from prescribing it. Identifying high-risk patients and administering escalated BEACOPP remains an effective strategy. We assessed the significance of interim positron emission tomography (iPET) scan after 2 cycles (iPET2) in identifying this high-risk subset. PATIENTS AND METHODS This cohort study used secondary data from 12 tertiary care centers in South India gathered over 10 years (2008-2018). OS, event-free survival (EFS), determinants of EFS, and complete response (CR) in iPET2 were assessed. RESULTS The study included 409 patients with HL (mean age, 34.5 years; male/female ratio, 1.4:1). The median duration of follow-up was 2.8 years. Of 409 patients, 63% underwent PET-based staging and 37% underwent computerized tomography (CT) staging. Stage IV (28.9%) and bone involvement (9.2%) were seen more often with PET than with CT staging (9.2% and 2%, respectively). Among 171 patients with iPET2 results, 24% did not achieve CR, and no factors were significantly associated. The 5-year EFS and OS rates of the entire cohort were 78% and 97%, respectively. The 5-year EFS and OS rates of patients with CR on iPET2 were 90% and 99%, respectively, whereas these were 65% and 100%, respectively, for patients not achieving CR. On univariable analysis, sex, stage, and iPET2 response significantly predicted inferior EFS. On multivariate analysis, only iPET2 response significantly predicted EFS ( P < .000). CONCLUSION Our study supports the use of PET for staging and iPET2 for response assessment. Nonachievement of CR on iPET2 indicates unfavorable outcome, and such patients may benefit from more intensive treatment.

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One Year of Maintenance Metronomic Cyclophosphamide, Methotreaxate & Celecoxib in High Risk Diffuse Large B Cell Non Hodgkin Lymphoma After Complete Response.

Research in Oncology ◽

10.21608/resoncol.2014.882 ◽

2014 ◽

Vol 10 (Issue 1-2) ◽

pp. 40-45

Author(s):

S. AlHassanin ◽

T. Hashem ◽

K. ElDin ◽

H. Kohail ◽

H. ElSheridy ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Hodgkin Lymphoma ◽

Complete Response ◽

Non Hodgkin Lymphoma ◽

One Year ◽

Metronomic Cyclophosphamide ◽

Large B Cell

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Obinutuzumab short-duration infusion (SDI) in previously untreated advanced follicular lymphoma: Results from the end of induction analysis of the phase IV GAZELLE study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7545 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7545-7545

Author(s):

Miguel Angel A. Canales Albendea ◽

Thomas A. Buchholz ◽

Koji Izutsu ◽

Takayuki Ishikawa ◽

Laura Maria Fogliatto ◽

...

Keyword(s):

Follicular Lymphoma ◽

Stage Iv ◽

Progression Free Survival ◽

Response Assessment ◽

Complete Response ◽

Primary Analysis ◽

Open Label ◽

Secondary Endpoints ◽

To Receive ◽

Phase Iv

7545 Background: Obinutuzumab (G)-chemotherapy (chemo) has demonstrated improved progression-free survival compared with rituximab (R)-chemo in previously untreated advanced follicular lymphoma (FL). G is currently administered by IV infusion over ̃3–4 hours. A shorter duration of infusion in Cycle (C) 2 and subsequent cycles, as is standard practice with R, could improve convenience for patients (pts) and efficiency for infusion facilities. We report the primary analysis of the prospective, open-label, multicenter, single-arm, Phase IV, GAZELLE study (NCT03817853), which evaluated the safety of G administered as a 90-minute (min) SDI from C2 onwards in pts with FL. Methods: Pts with previously untreated FL received G (1000mg) intravenously on Day (D) 1, 8, and 15 of C1, and on D1 thereafter, plus chemo (bendamustine, CHOP, or CVP) for 6–8 cycles. In C1, pts received G at the standard infusion rate. Pts without a Grade (Gr) ≥3 infusion-related reaction (IRR) in C1 were eligible to receive G as a 90-min SDI from C2. Pts with a Gr 3 IRR in C1 received the standard G infusion in C2, and were eligible for G SDI in subsequent cycles if no Gr ≥3 IRRs occurred. Pts with a second Gr 3/4 IRR discontinued G. At the end of induction (EOI), responding pts received maintenance G (1000mg) as SDI for 2 years or until disease progression (PD). The primary endpoint was incidence of Gr ≥3 IRRs during C2. IRRs were defined as any event occurring ≤24 hours from infusion judged to be related to treatment. Secondary endpoints included adverse events (AEs) and investigator-assessed overall response rate at EOI. Results: As of December 3, 2020, 113 pts had received study treatment. Median age was 62.0 years, 50.4% were male, 61.9% had stage IV FL, and 45.1% were classified as high-risk FLIPI. Of the 110 pts who were eligible for G SDI from C2, no pt experienced a Gr ≥3 IRR with SDI in C2 (Table). One pt experienced a Gr 3 IRR with SDI in C5, presenting hypertension. All other IRRs with SDI were Gr 1/2. No Gr 4/5 IRRs were reported. Other AEs were similar to those observed in previous studies. At the clinical cut-off date, 104 pts had a CT imaging-based response assessment at EOI and 9 pts had no response assessment; 76/113 (67.3%) had a complete response, 22 (19.5%) had a partial response, and six (5.8%) had PD. Conclusions: In GAZELLE, G SDI in C2 and beyond appeared to be safe. No Gr 3 IRRs were observed in C2 and only one Gr 3 IRR was reported in subsequent cycles. The safety profile of G SDI was comparable with the established profile of G in advanced FL. Clinical trial information: NCT03817853. [Table: see text]

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Inhibitors of A Disintegrin And Metalloproteinases-10 reduce Hodgkin lymphoma cell growth in 3D microenvironments and enhance brentuximab-vedotin effect

Haematologica ◽

10.3324/haematol.2021.278469 ◽

2021 ◽

Author(s):

Roberta Pece ◽

Sara Tavella ◽

Delfina Costa ◽

Serena Varesano ◽

Caterina Camodeca ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Drug Testing ◽

Cell Damage ◽

Three Dimensional ◽

3D Culture ◽

Glucose Consumption ◽

3D Models ◽

Brentuximab Vedotin ◽

Collagen Scaffolds ◽

Antibody Drug Conjugate

Shedding of A Disintegrin And Metalloproteinases (ADAM10) substrates, like TNFα or CD30, can affect both anti-tumor immune response and antibody-drug-conjugate (ADC)-based immunotherapy. We have published two new ADAM10 inhibitors, LT4 and MN8 able to prevent such shedding in Hodgkin lymphoma (HL). Since tumor tissue architecture deeply influence the outcome of anti-cancer treatments, we set up new three-dimensional (3D) culture systemsto verify whether ADAM10 inhibitors can contribute to, or enhance, the anti-lymphoma effects of the ADC brentuximab-vedotin (BtxVed).To recapitulate some aspects of lymphoma structure and architecture, we assembled two 3D culture models: mixed spheroids made of HL lymph node (LN) mesenchymal stromal cells (MSC) and Reed Sternberg/Hodgkin lymphoma cells (HL cells) or collagen scaffolds repopulated with LN-MSC and HL cells. In these 3D systems we found that: 1) the ADAM10 inhibitors LT4 and MN8 reduce ATP content or glucose consumption, related to cell proliferation, increasing lactate dehydrogenase (LDH) release as a cell damage hallmark; 2) these events are paralleled by mixed spheroids size reduction and inhibition of CD30 and TNFα shedding; 3) the effects observed can be reproduced in repopulated HL LN-derived matrix or collagen scaffolds; 4) ADAM10 inhibitors enhance the antilymphoma effect of the anti-CD30 ADC BtxVed both in conventional cultures and in repopulated scaffolds. Thus, we provide evidence for direct and combined anti-lymphoma effect of ADAM10 inhibitors with BtxVed, leading to improvement of ADC effects; this is documented in 3D models recapitulating features of LN microenvironment, that can be proposed as reliable tool for antilymphoma drug testing.

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