Brentuximab Vedotin As Consolidation Therapy Following Autologous Stem Cell Transplantation in Children and Adolescents with Relapsed/Refractory Hodgkin Lymphoma: A Multi-Center Retrospective Analysis

Abstract Background: Although the prognosis for children with Hodgkin lymphoma (HL) is excellent, up to 25% of patients experience relapse and require salvage therapy. Event-free survival (EFS) for patients with relapsed or refractory disease (R/R) who require high-dose therapy with autologous stem cell transplantation (ASCT) is between 31-67% (Daw, 2011), and efforts to improve these outcomes are an area of urgent clinical need. Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate combined with monomethyl auristatin E. The phase III AETHERA study (NCT01100502) was a randomized, placebo-controlled trial that demonstrated consolidation with BV following ASCT for adults with R/R HL improved progression-free survival (PFS) in comparison to placebo (5-year PFS 59% vs. 41%) in patients identified as having a high-risk of post-ASCT progression (Moskowitz, 2015, 2018). However, there is limited data on post-ASCT BV consolidation in pediatric patients. Here, we report a retrospective multi-center study of BV as consolidation post-ASCT in pediatric patients with R/R HL. Patients and Methods: We performed a retrospective analysis of pediatric patients aged ≤ 21 years who received BV as consolidative therapy following ASCT for the treatment of relapsed/refractory HL. Data was collected on disease risk factors (refractory disease or relapse ≤ 12 months after frontline therapy, best response of partial remission or stable disease to salvage therapy, presence of extranodal involvement, presence of B symptoms, and number of systemic treatments pre-ASCT ≥ 2), treatment history, BV-related toxicity, and response to therapy. The primary endpoint was 3-year EFS. Events were defined as relapse, progression of disease, or death from any cause. Results: Seventy patients were identified from 14 academic centers. Eighteen received BV >90 days after ASCT and were excluded due to significant delay in initiation of BV. Of the remaining 52 patients, the median age at diagnosis was 15 years (range 4-21), and the median age at diagnosis of R/R disease was 16 years (range 8-22). Twenty-eight patients (54%) were male, 13 (25%) had B symptoms, 19 (37%) had extranodal disease. Six patients (12%) had primary refractory disease and 24 patients (47%) relapsed <12 months after frontline therapy. The median number of salvage regimens received pre-ASCT was 2 (range 1-7). Forty-two patients (81%) received BV as part of a pre-ASCT salvage regimen, 4 (8%) of whom did not receive BV in the regimen immediately prior to ASCT. Radiation therapy was used pre or post-ASCT in 16 patients (31%). Prior to ASCT, 40 patients (77%) were PET-negative (Deauville 1-3), 11 (21%) were PET-positive (Deauville 4-5), and response in 1 (2%) was unknown. The median time from ASCT to the start of BV consolidation was 52 days (range 30-90 days). The most frequent adverse events were peripheral neuropathy of any grade (sensory 19/52 [37%]; motor (14/52 [27%]), and cytopenias (grade 3 or 4: (25/52 [48%]), including neutropenia (13/52 [25%]), thrombocytopenia (7/52 [14%]), and anemia (5/52 [10%]). Three patients (6%) experienced infusion-related reactions. The median number of BV cycles completed post-ASCT was 12 (range 1-17), and 16 patients (31%) completed the full 16 cycles of BV. The most common reason for premature termination was adverse effects (22/36 [61%]). Additional reasons included: physician plan for shorter duration (4/36 [11%]), patient/family decision (3/36 [8%]), and progression (1/36 [3%]). Treatment was still ongoing in 3 patients and reason for premature termination was not reported for 17/36 patients (47%). With a median follow of 2.8 years (range 0.1 to 6.25 years) the three-year EFS was 92% [95%CI: 83-100]. Patients with 0-1 risk factors (15/52 [29%]) and ≥ 2 risk factors (37/52 [71%]), had a 3-year EFS of 100% and 90% [95%CI: 79-100], respectively. Fifty patients (96%) are alive with no evidence of disease, while 2 (4%) patients are alive with disease. No deaths have occurred. Conclusion: The use of post-ASCT BV consolidation for pediatric patients with R/R HL is associated with a favorable safety and tolerability profile. In this cohort, the combination of salvage therapy, HD-chemotherapy/ASCT, and BV consolidation resulted in extremely promising outcomes and warrants further investigation in a prospective pediatric trial. Figure 1 Figure 1. Disclosures Leger: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbott Diagnostics: Research Funding. Roth: Merck: Consultancy; Janssen: Consultancy.

Download Full-text

The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma

Blood ◽

10.1182/blood.v124.21.673.673 ◽

2014 ◽

Vol 124 (21) ◽

pp. 673-673 ◽

Cited By ~ 6

Author(s):

Craig H. Moskowitz ◽

Auayporn Nadamanee ◽

Tamas Masszi ◽

Edward Agura ◽

Jerzy Holowiecki ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Hodgkin Lymphoma ◽

Salvage Therapy ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Frontline Therapy

Abstract Background For the past 20 years, high-dose therapy plus autologous stem cell transplant (ASCT) has been the standard of care for patients (pts) with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), providing a cure for approximately 50% of pts (Sureda 2005). Despite optimization of salvage chemotherapy, supportive care, and pt selection, improvements in outcomes post-ASCT have plateaued, likely due to disease progression (PD) in pts with pre-salvage therapy risk factors. The majority of pts with multiple risk factors will progress post-ASCT and novel therapy is urgently needed. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), and has an objective response rate of 75% in relapsed or refractory HL. The AETHERA trial was initiated to evaluate whether early treatment with brentuximab vedotin post-ASCT can prevent progression in pts with HL (ClinicalTrials.gov #NCT01100502). Methods The AETHERA trial is a phase 3, randomized, double-blind, placebo-controlled, multicenter study. Pts were enrolled in 1 of 3 high-risk categories: refractory to frontline therapy: 196 pts (60%), relapse <12 months after frontline therapy: 107 pts (33%), and relapse ≥12 months after frontline therapy with extranodal disease: 26 pts (8%). Pts were required to have obtained a CR, partial remission (PR), or stable disease (SD) to salvage therapy prior to ASCT. After ASCT, pts received brentuximab vedotin 1.8 mg/kg q3wk and best supportive care (BSC) or placebo and BSC for up to 16 cycles (approximately 12 months). Pts with PD were to discontinue study therapy and could request unblinding; these pts may have received subsequent brentuximab vedotin on another clinical trial or on-label in some regions. The primary endpoint is PFS per an independent review facility (IRF); additional endpoints include overall survival (OS) and safety/tolerability. Results A total of 329 pts were randomized at 78 sites in the United States and Europe. Of the 329 enrolled pts, 327 received study treatment. The median age was 32 years (range, 18–76) and 53% were male. The median number of prior systemic therapies (frontline and salvage) was 2 (range, 2–8); 47% of pts received more than 2 prior systemic therapies. Response to salvage therapy pre-ASCT was CR: 137 pts (42%), PR: 112 pts (34%), and stable disease (SD): 80 pts (24%). Prior to pre-ASCT salvage therapy, 106 pts (32%) had extranodal involvement and 87 pts (26%) had B symptoms. Prior to ASCT, 110 pts (33%) were PET negative, 116 pts (35%) were PET-positive and PET status was unknown for 103 pts (31%). Overall, 78% of pts had multiple risk factors for progression. All pts had completed or discontinued study treatment as of August 2013. The median number of treatment cycles was 15, and 159 pts (49%) received 16 cycles. Reasons for treatment discontinuation were: PD: 93 pts (28%), adverse event (AE): 61 pts (19%), patient decision: 15 pts (5%), and investigator decision: 1 pt (<1%). At the time of this analysis (June 2014), the median follow-up time from randomization was 24.4 mos (range, 0–43 mos). For the pooled study population at 24 mos, the Kaplan Meier estimates were 54% (95% CI: 47%, 60%) for PFS and 88% (95% CI: 84%, 91%) for OS. Of the 50 deaths, 8 occurred prior to PD. AEs of any grade in >15% of pts were peripheral sensory neuropathy (36%), upper respiratory tract infection (25%), neutropenia (24%), fatigue (21%), cough (19%), and pyrexia (17%). Grade 3 or higher AEs in ≥10 pts were neutropenia (20%), peripheral sensory neuropathy (6%), thrombocytopenia (3%), and peripheral motor neuropathy (3%). As assessed by a Standardised MedDRA Query, 144 pts (44%) had treatment-emergent events of peripheral neuropathy (PN). Grade 3 PN was reported for 23 pts (7%) and was mostly sensory; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in PN has occurred in 80% of pts with neuropathy events; the median time to resolution or improvement was 11.7 weeks (range, 0.1–128.0 weeks). Conclusions Based on analysis of blinded pooled efficacy data, the estimated 2-year PFS rate was 54% and the estimated 2 year OS rate was 88%. The most common reason for treatment discontinuation was disease progression. The primary analysis for the study will be performed in September 2014 and unblinded efficacy and safety data will be publicly presented for the first time at the conference. Figure 1 Figure 1. Disclosures Moskowitz: Genentech: Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Nadamanee:Gilead: Consultancy; Celgene: Consultancy; Spectrum: Research Funding; Seattle Genetics, Inc.: Research Funding. Masszi:Seattle Genetics, Inc.: Research Funding. Agura:Seattle Genetics, Inc.: Research Funding. Holowiecki:Seattle Genetics, Inc.: Research Funding. Abidi:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Chen:Seattle Genetics, Inc.: Research Funding. Stiff:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Gianni:Seattle Genetics, Inc.: Research Funding. Carella:Seattle Genetics, Inc.: Research Funding. Osmanov:Seattle Genetics, Inc.: Research Funding. Bachanova:Seattle Genetics, Inc.: Consultancy, Research Funding. Sweetenham:Seattle Genetics, Inc.: Honoraria, Research Funding, Speakers Bureau. Sureda:Takeda Pharmaceuticals International Co.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Huebner:Takeda Pharmaceuticals International Co.: Employment, Research Funding. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Hunder:Seattle Genetics, Inc.: Employment, Equity Ownership. Walewski:Seattle Genetics, Inc.: Research Funding; Takeda Poland: Consultancy, Travel expenses, Travel expenses Other.

Download Full-text

Autologous Stem Cell Transplant Outcome in Classic Hodgkin Lymphoma Patients in the Era of Post-Transplant Brentuximab Vedotin Consolidation

Blood ◽

10.1182/blood-2021-154492 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3935-3935

Author(s):

Shanee Chung ◽

Jennifer White ◽

Cynthia L. Toze ◽

Heather J. Sutherland ◽

David Sanford ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Median Number ◽

Salvage Chemotherapy ◽

Brentuximab Vedotin ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Classic Hodgkin Lymphoma

Abstract Introduction: Patients newly diagnosed with classic Hodgkin lymphoma (CHL) have over 80% chance of remission with first-line chemotherapy, such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regime. However, 10-40% of patients relapse eventually and require salvage therapy. High-dose therapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory CHL, offering a cure rate of around 50%. This may be further improved to around 60% with post-transplant consolidation with brentuximab vedotin (BV). Post-SCT BV consolidation has been offered to all patients, regardless of the risk group, in British Columbia since late 2015. We set out to review the ASCT outcome in CHL patients in the recent decade at our institution. Methods: All adult patients who received ASCT for relapsed or refractory CHL between July 2011 and June 2020 were included in this retrospective analysis. Information pertaining to their demographics, disease characteristics, treatment history, transplant details, clinical outcomes and post-relapse therapy was obtained by review of electronic data. The data cut-off date was June 28, 2021. Survival outcomes were censored at the last known clinic visit for patients without relapse or death during follow up. Survival analysis was performed using Kaplan-Meier survival function and log-rank test. Pearson's chi-square test and ANOVA were used for comparison between cohorts. The statistical program used was Stata® version 16.1 (Texas, USA). Results: 114 patients underwent ASCT for relapsed/refractory CHL. Bulky disease and extranodal involvement were seen in 11% and 40% respectively at relapse. Looking at the 'high risk criteria' as defined in the AETHERA trial: 45/114 (40%) patients had primary refractory CHL, 21/114 (18%) had relapsed within 12 months of completing the front-line chemotherapy and 15/114 (13%) had relapsed beyond one year of completing initial treatment but with an extranodal disease. The most commonly used salvage chemotherapy regime was GDP (gemcitabine, dexamethasone, cisplatin; 111/114; 97%). 10/114 (9%) patients received BV after failing salvage chemotherapy pre-SCT. The median number of lines of therapy pre-SCT was two (range 2-5). 94/108 (98%) had a chemosensitive disease with 35/108 (32%) achieving complete remission. 6/108 (6%) patients had a progressive disease at the time of SCT. For the transplant, all patients had a peripheral blood stem cell source and the conditioning regime was either Carmustine/Etoposide/Cytarabine/Melphalan (76%) or Etoposide/Melphalan (24%). After median follow up of 62.2 months, 50/114 (44%) patients relapsed with median relapse-free survival of 20.2 months (range 0.9 - 113.5) and 16/114 (14%) died. The direct cause of death was lymphoma progression in all but three patients (PJP pneumonia, pulmonary fibrosis, traumatic subdural hematoma). Whereas only 4/51 (8%) patients (2 without relapse) received post-SCT BV consolidation via a compassionate access program between July 2011 and October 2015 (cohort 1), 45/63 (71%) patients (33 in remission) received routine BV consolidation between November 2015 and June 2020 (cohort 2). In cohort 2, 44% had primary refractory CHL compared to 33% in cohort 1 but the number of 'low risk' patients was similar at 29% (Table 1). The most common reason for no post-SCT BV consolidation in cohort 2 was patient refusal (7/18; 40%). Other causes included BV pre-SCT, early disease progression and patient comorbidities. Only 9/42 (21%) patients with available data in cohort 2 completed the planned 16 cycles of BV consolidation. The median number of cycles was 10.5 (range 1-16). The most common reasons for early termination of BV consolidation were peripheral neuropathy (22/33; 67%) and disease progression (9/33; 27%). There was no statistically significant difference in PFS or OS demonstrated between the two cohorts (Graphs 1, 2). Conclusion: After median follow up of 5 years, 86% of patients remain alive and 56% are alive in remission. In British Columbia, post-SCT BV consolidation has been widely adopted with over 70% of patients receiving at least one cycle since late 2015. Successful completion of post-SCT BV consolidation is, however, limited by a high rate of treatment-limiting peripheral neuropathy. Relapse-free survival benefit of routine post-SCT BV consolidation is not demonstrated in this single-centre cohort. Figure 1 Figure 1. Disclosures White: Novartis: Honoraria. Sutherland: Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Amgen: Consultancy. Sanford: Abbvie: Membership on an entity's Board of Directors or advisory committees; Stellar: Membership on an entity's Board of Directors or advisory committees. Abou Mourad: Amgen: Consultancy; Paladin: Consultancy; Pfizer: Consultancy. Song: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria.

Download Full-text

Outcome of Hodgkin Lymphoma after Progression Following Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.2994.2994 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2994-2994

Author(s):

Joseph M. Connors ◽

Alina S Gerrie ◽

Maryse M Power ◽

Kerry J Savage

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Single Agent ◽

Progression Free Survival ◽

Brentuximab Vedotin ◽

Primary Objective ◽

Initial Diagnosis ◽

Cell Transplant ◽

Free Survival

Abstract 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. Disclosures Connors: Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding.

Download Full-text

Allogeneic Stem Cell Transplantation for Refractory Acute Myeloid Leukemia in Pediatric Patients: The UK Experience

Blood ◽

10.1182/blood.v126.23.4404.4404 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4404-4404

Author(s):

Patricia M O'Hare ◽

Giovanna Lucchini ◽

Michelle Cummins ◽

Paul Veys ◽

Mike Potter ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Allogeneic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Pediatric Patients ◽

Refractory Disease ◽

Free Survival ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid ◽

Refractory Aml

Abstract INTRODUCTION The prognosis for children with refractory acute myeloid leukemia (AML) treated with chemotherapy is dismal and data on the outcome after allogeneic haematopoietic stem cell transplant (SCT) are scanty with reported leukemia free survival (LFS) rates of 10-20%. Thus there is significant controversy about whether SCT is appropriate in such patients (pts). We performed a retrospective, national study to analyse outcomes and prognostic factors for children undergoing SCT for refractory AML in the UK. METHODS A retrospective analysis of all pts <18 years of age reported to the BSBMT registry who received their first allogeneic SCT between 2000-2012 for refractory AML (ie >5% blasts in the bone marrow (BM) or proven extramedullary disease (EM) was performed. Source data verification (SDV) was performed to ensure pts were indeed refractory. The primary end-point was 5 year LFS. Secondary end-points were Relapse Rate (RR), Treatment Related Mortality (TRM), Graft Versus Host Disease (GVHD) and Overall Survival (OS). The Kaplan Meyer method was used to estimate survival data and Fisher's exact and Mantel-Cox Log Rank tests were used to compare disease- transplant- and survival-related variables. RESULTS Following SDV, a total of 44 pts from 13 centres were included in the study. The median age at SCT was 11.5 yrs and the median number of prior lines of chemotherapy was 3. The median time from diagnosis to SCT was 197 days. 23 pts had primary refractory AML and 21 had relapsed refractory AML. 12 pts showed adverse risk cytogenetics, 26 standard risk and 6 favourable. EM disease was documented in 5 pts. 42 children had >5% myeloid blasts in the BM immediately prior to conditioning and refractory disease was confirmed by cytogenetics/molecular genetics in 23. 2 pts were in BM remission but had frank EM disease. 38 pts (86%) received myeloablative conditioning (14 TBI based) and 6 (14%) had reduced intensity conditioning (RIC). In vivo T cell depletion was used in 25 pts. 15 pts (35%) were transplanted from an HLA identical family donor, 15 from a matched unrelated donor and 14 (32%) a mismatched donor. BM was used as the stem cell source in 18 (41%), peripheral blood in 20 (46%) and cord blood in 6 cases (14%). Median follow up was 4 years 10 months. 5 pts never achieved engraftment and had disease progression. The remaining 39 pts engrafted at a median of 15 days post-SCT. 30 pts (68%) achieved a complete remission (CR) following SCT. TRM at 1 year was 18% (5 infections, 1 cardiac failure, 1 GVHD-related). Acute GVHD occurred in 23 pts and was severe (grade ≥III) in 8 (19%). The incidence of chronic GvHD was low (1 limited, 2 extensive). Relapse was the major cause of treatment failure and occurred in 17 pts (39%) at a median 2.3 months post SCT. At last follow-up, 18 pts remain alive and in continuous complete remission (CCR). In this cohort, the 5 year OS and LFS were both 43% (95%CI 31-61%) (Figure1). Outcomes in pts with primary refractory disease (9/23, 39% in CCR) and those with relapsed refractory AML (9/21, 43% in CCR) were equivalent. Outcome for pts with cytogenetic confirmation of refractory disease was not statistically different (7/23, 30% in CCR) from the overall group. Pts transplanted with ≤30% blasts in the BM had improved outcomes (5-year LFS 52% vs 27%, p= 0.05). Likewise, the development of aGVHD of any grade was associated with a significantly better LFS (5-year LFS 56% vs 30%, p= 0.05). Cytogenetics including monosomy 7 (n=7) and molecular risk classification did not translate into a significant prognostic factor for relapse. Since RIC was used in only 6 pts, the impact of the intensity of conditioning cannot be determined. CONCLUSIONS This is the largest series of outcomes for SCT for refractory paediatric AML reported to date. Our data indicate that for selected pts, particularly those with a lower disease burden, SCT offers a realistic chance of salvage in both primary refractory and relapsed refractory AML (5 year LFS 43%) with acceptable toxicity. The association of aGVHD with improved LFS suggest a possible role in engineering a graft-versus-leukemia effect in this patient group. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Prophylactic Rh and Kell Antigen Matching Significantly Decreases Rates of Alloimmunization in Transfusion Dependent MDS Patients

Blood ◽

10.1182/blood.v124.21.4297.4297 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4297-4297 ◽

Cited By ~ 2

Author(s):

Aliza Saskin ◽

Yulia Lin ◽

Richard A. Wells ◽

Martha Lenis ◽

Alex Mamedov ◽

...

Keyword(s):

Risk Factors ◽

Median Time ◽

Research Funding ◽

Median Number ◽

Transfusion Practice ◽

Blood Group Antigens ◽

Red Cell ◽

Free Survival ◽

Potential Risk Factors

Abstract Background: 40-80 % of patients with myelodysplastic syndrome (MDS) become transfusion dependent during their disease course and are at risk for the development of alloimmunization. Red blood cell (RBC) alloantibodies can make finding compatible blood for transfusion more difficult, expensive and time consuming. Allommunization rates of approximately 30-47% have been reported in patients with sickle cell disease and the transfusion of RBCs prophylactically matched for Rh antigens E and C, and K antigens reduced the rate of alloimmunization from 3% to 0.5% per unit (Vichinsky et al, 2001). In 2007, our hospital instituted a policy of transfusing prophylactic Rh and K matched blood to MDS patients. The objectives of this study were to compare the rates of alloimmunization in MDS patients who received prophylactic Rh and K matched blood compared to those that did not and identify potential risk factors for alloimmunization. Methods: 193 Transfusion dependent MDS patients were identified out of 387 patients registered and prospectively followed in a local MDS registry. Transfusion dependence was defined as the receipt of at least 1 unit of PRBC every 8 weeks for a minimum of 16 weeks. Records of transfusions received up to May 1, 2014 were collected from blood bank databases of the hospitals at which patients were transfused. Patients were classified according to whether phenotyping had been performed, the location of transfusions (transfused only at our institution, transfused only at an outside institution or transfused at both sites) and whether prophylactic Rh (E, C antigens) and K matched blood was transfused. Data were descriptively analyzed and we conducted univariate and multivariate logistic regression using p< 0.05 as statistically significant to identify risk factors for alloimmunization. Results: 176 MDS patients with complete transfusion records are included, 73 transfused at Sunnybrook, 92 transfused in community hospitals and 11 at both. The median age was 72 yrs (range 22-89), 60% were male, and 8%, 43% and 27% had very low, low and intermediate risk R-IPSS scores respectively. Median follow up was 2.9 years (IQR 1.6-5) 3.49 SD). Blood groups O, A, B, AB and O were 45%, 38%, 15% and 2% respectively, while 85% were RhD+. The median time from diagnosis until first transfusion was 4 months (IQR: 0.2-14), with 51 patients having received at least 1 transfusion prior to diagnosis at a median time of 0.9 months. 4.5% had a pre-existing allo-antibody at time of MDS diagnosis. With a median follow up from diagnosis of 3 years (IQR:1.6-5)), the median number of RBC units transfused was 38 (IQR: 15-98)) and 36 (20%) patients developed new alloantibodies (median 2 (IQR (1-2.5) alloantibodies). The median number of RBC units until first allo antibody was 13.5 units (range 0-121) and 1.25 years from diagnosis (95% CI:0.4-2.1). The majority of the alloantibodies were in the Rh (n=28) and K (n=14) groups (80%) and co-existed 27% of the time. More patients transfused at our hospital received prophylactic Rh K matched blood sometimes or always (60% versus 26%) and rates of allo-immunization were decreased by 65% (absolute rate of alloimmunization 10% versus 29%). By multivariate analysis analysis, number of rbc transfused (p<.0001), receiving prophylactic phenotype matched blood (p=.0008) and location of transfusions (Sunnybrook versus elsewhere (p=.03)) were independent risk factors for alloimmunization. Conclusions: 20-30% of RBC transfusion dependent MDS patients will become allo-immunized to clinically significant blood group antigens, the majority being Rh and K antigens. The practice of phenotyping at baseline and prophylactically transfusing Rh and Kell matched blood decreases rates of alloimmunization up to 65% and should be strongly considered for routine transfusion practice in centres that treat MDS. Table 1. All Patients (n=176) Sunnybrook (n=73) Community(n=92) Ever phenotyped 45% 64% 28% Phenotyped before 1st transfusion 20% 38% 8% Developed allo-antibodies 20% 10% 29% Received prophylactic Rh K matched blood (developed alloantibodies) Never Sometimes Always 58% (16%) 24% (42%) 18% (6%) 40% (3%) 23% (23%) 37% (7%) 74% (22%) 22% (60%) 4% (0%) Figure 1. Allo Antibody free survival according to number of red cell units transfused in patients that developed an allo-antibody Figure 1. Allo Antibody free survival according to number of red cell units transfused in patients that developed an allo-antibody Disclosures Wells: Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Buckstein:Celgene: Research Funding.

Download Full-text

Vinorelbine, Paclitaxel, Etoposide, Cisplatin and Cytarabine (VTEPA) Is An Effective Salvage Therapy for Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL) but Not for R/R Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood.v118.21.1628.1628 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1628-1628 ◽

Cited By ~ 1

Author(s):

Rajni Sinha ◽

Nassoma King ◽

Pareen J Shenoy ◽

Mary Jo Lechowicz ◽

Kevin Bumpers ◽

...

Keyword(s):

Stem Cell ◽

Salvage Therapy ◽

Research Funding ◽

B Cell Lymphoma ◽

Electrolyte Imbalance ◽

Stage Iii ◽

High Dose ◽

Cell Transplant ◽

Refractory Disease ◽

Relapsed Disease

Abstract Abstract 1628 Introduction: Historically, relapsed DLBCL and HL has been associated with a high cure rate with salvage regimens followed by high dose chemotherapy and stem cell transplant (ASCT). However, patients (pts) who relapse early following upfront chemotherapy and pts who fail to respond to salvage have a poor overall response rate (ORR) with additional salvage regimens and a poor prognosis even when consolidated with ASCT (von Tresckow & Engert, 2011; Gisselbrecht et al., 2010). At present there is no standard therapy in the third-line setting for pts with DLBCL and HL. We designed a regimen: vinorelbine (30mg/m2) & paclitaxel (175mg/m2) given on day 1; etoposide (100mg/m2) & cisplatin (20mg/m2) given on days 2–5; and cytarabine (2000mg/m2) on days 4 and 5 (VTEPA) for treatment of lymphoma pts with 1° refractory disease or relapse following salvage. In phase 1, VTEPA was safe with a 33% ORR following 1 cycle (Lonial et al, 2006). Design and Methods: To examine the effectiveness of VTEPA, we conducted an IRB approved retrospective review of consecutive cases of relapsed/refractory DLBCL and HL identified from our database from 1999–2011. All pts had evidence of primary refractory disease or stable or progressive disease following first line salvage therapy. Responses following salvage VTEPA were retrospectively assessed using International Working Group Criteria (JCO 1999) for all pts. Responding pts proceeded to ASCT. Survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Results: 74 pts (44 DLBCL and 30 HL) with a median age at diagnosis of 30 years (range 18–63) for HL and 49 years (range 20–68) for DLBCL were included. 67% of HL pts had primary refractory disease and 33% of pts had relapsed disease; 60% were stage III/IV at diagnosis. 75% of DLBCL pts had primary refractory disease and 25% of pts had relapsed disease; 73% stage III/IV. Pts received a median of 2 prior therapies (range 1–4). 63% pts with HL received prior salvage therapy with ifosfamide, carboplatin, and etoposide (ICE) and 13% with other regimens. 16 pts with HL received 1 cycle of VTEPA, 13 received 2 cycles and 1 pt received 3 cycles of VTEPA. 70% pts with DLBCL had received prior salvage therapy with rituximab (R) + ICE and 16% received other salvage regimens. 32 pts with DLBCL received 1 cycle of R-VTEPA and 12 pts received 2 cycles. The most common reported grade 3/4 toxicities were pancytopenia (97%), nausea/vomiting (58%), fatigue (30%), infectious complications (26%), diarrhea (24%), electrolyte imbalance (19%), and mucositis (16%). 70 pts (43 DLBCL and 27 HL) were evaluable for response. The ORR for DLBCL pts was 44% (9% CR and 35% PR) while that for HL pts was 70% (26% CR and 44% PR, p=0.04). 4 DLBCL pts had treatment related mortality. 34 pts went on to collect ≥2 × 106 CD34+ cells/kg; 3 pts had inadequate stem cell collection. In 23 pts collection was not attempted, and 14 pts collected stem cells prior to R+/−VTEPA. 37 pts (47%) went onto planned ASCT, and 4 pts underwent allogeneic transplantation. The PFS at 2 years for pts with HL was 68% vs. 49% for pts with DLBCL (p<0.001, Figure 1). Similarly the OS at 2 years for pts with HL was 79% vs. 41% for pts with DLBCL (p<0.001, Figure 2). Conclusions: Treatment with VTEPA for heavily pretreated relapsed/refractory HL and DLBCL pts is feasible with manageable side effects, a high ORR, and permits transplantation for nearly ½ of pts. Nevertheless, outcomes for pts with refractory DLBCL is exceedingly poor compared to refractory pts with HL treated with the same approach. While there remains a great need for novel agents to aid DLBCL pts who are chemotherapy and R refractory, the favorable PFS and OS for relapsed/refractory HL pts suggest VTEPA is a promising salvage regimen for this disease. Disclosures: Sinha: Celgene: Research Funding. Kaufman:Millenium; Onxy; Novartis; Keryx: Research Funding; Merk, Celgene: Research Funding. Flowers:Spectrum: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Celgene: Consultancy; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy.

Download Full-text

Brentuximab Vedotin (SGN-35) in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies without Prior High-Dose Chemotherapy and Stem Cell Transplantation.

Blood ◽

10.1182/blood.v120.21.2743.2743 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2743-2743 ◽

Cited By ~ 1

Author(s):

Achim Rothe ◽

Stephanie Sasse ◽

Helen Goergen ◽

Dennis A. Eichenauer ◽

Andreas Lohri ◽

...

Keyword(s):

Objective Response ◽

Progression Free Survival ◽

Median Number ◽

High Dose Chemotherapy ◽

Brentuximab Vedotin ◽

High Dose ◽

Refractory Disease ◽

Free Survival ◽

Prior Chemotherapy ◽

Initiation Of Therapy

Abstract Abstract 2743 Background: Based on the impressive results of two pivotal phase II trials, the CD30 targeting antibody-drug conjugate brentuximab vedotin (SGN-35) was approved for the treatment of relapsed Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) by the Food and Drug Administration (FDA) in 2011. Recently, we reported the experience of the German Hodgkin Study Group (GHSG) with brentuximab vedotin as single agent in 45 patients suffering from refractory or relapsed CD30-positive HL. In this cohort with a median age of 35 years and a median number of four prior chemotherapy regimens, overall survival (OS) and progression-free survival (PFS) at 12 months were 83% (95%-CI: 72%-95%) and 43% (95%-CI: 28%-58%), respectively. Interestingly, 10 of 17 patients considered very high-risk (59%) who had primary refractory disease or early relapse and refractory disease prior to brentuximab vedotin treatment, achieved an objective response, which was comparable to the overall response rate of 60% for the whole cohort (Rothe et. al., Blood, July 2012). Since very limited data is available on relapsed or refractory HL patients who received brentuximab vedotin without prior high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), we have expanded our analysis. Methods: Since March 2010, the GHSG and associated centres have treated patients with refractory or relapsed HL or relapsed ALCL with brentuximab vedotin. In addition to six patients included in our previous analysis, we identified 10 further patients who had not undergone prior HDCT and SCT and were treated with brentuximab vedotin. All patients had histologically confirmed CD30-positive lymphoma and were treated within a named patient program (NPP). All participants gave written informed consent in accordance with the Declaration of Helsinki. Patients received a 30-minute infusion of brentuximab vedotin dosed at 1.8mg/kg body weight every three weeks. Response was defined according to the revised response criteria for malignant lymphoma. Overall survival (OS) was defined as the time from the initiation of therapy to death from any cause. Progression-free survival (PFS) was measured from initiation of therapy to progression, relapse, or death from any cause. Results: In total, 16 patients with HL (n=14) or ALCL (n=2) with a median age of 48.5 years and a median number of three prior chemotherapy regimens were analyzed. Reasons for ineligibility for HDCT and autologous SCT prior to treatment with brentuximab vedotin were refractory disease (n=11), comorbidity (n=4) and unknown reasons (n=1). Treatment with brentuximab vedotin resulted in an objective response in 11 patients (69%), including five complete remissions. Noteworthy, six of the 11 patients with chemotherapy refractory disease and all four patients with significant comorbidity achieved an response. Six patients received a consolidating HDCT followed by autologous (n=4) or allogeneic (n=2) SCT after brentuximab vedotin treatment. OS and PFS at 12 months were 68% (95%-CI: 40%-95%) and 22% (95%-CI: 0%-48%), respectively. Conclusion: This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in patients with heavily pre-treated CD30-positive malignancies. Moreover, we present the first data indicating therapeutic efficacy of brentuximab vedotin as reinduction therapy in chemotherapy-refractory HL and ALCL patients before HDCT and ASCT. Disclosures: Engert: Millenium The Takeda Oncology Company: Honoraria.

Download Full-text

Overall Survival Benefit for Patients with Relapsed Hodgkin Lymphoma Treated with Brentuximab Vedotin After Autologous Stem Cell Transplant

Blood ◽

10.1182/blood.v120.21.3701.3701 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3701-3701 ◽

Cited By ~ 5

Author(s):

Meghan S. Karuturi ◽

Sally Arai ◽

Robert W. Chen ◽

Ajay K. Gopal ◽

Lei Feng ◽

...

Keyword(s):

Clinical Trial ◽

Stem Cell ◽

Randomized Clinical Trial ◽

Research Funding ◽

Brentuximab Vedotin ◽

Categorical Variables ◽

Cell Transplant ◽

Time To Event ◽

Free Survival ◽

Duration Of Response

Abstract Abstract 3701 Background: Salvage chemotherapy and autologous stem cell transplantation (ASCT) in the management of relapsed or refractory Hodgkin's lymphoma (HL) results in prolonged disease-free survival in only around 50% of patients (pts). Median survival following relapse from ASCT is estimated at 2.4 years, with poor outcomes in those experiencing relapse or progressive disease within one year from ASCT (Horning 2008 et al). Recently, a pivotal multicenter Phase 2 trial investigated the efficacy of brentuximab vedotin (BV) in pts with recurrent HL following ASCT. The study demonstrated an overall response rate of 75% and median duration of response of 6.7 months. Furthermore, 34% of patients achieved a complete response (CR), with a median progression free survival of 29 months (mos). Whether treatment with BV renders an OS benefit in pts with relapsed or refractory disease after ASCT remains to be determined. Objective: 1) To compare OS in pts with relapsed HL after receiving ASCT in a cohort of 102 HL pts treated with BV, with 756 pts from 6 international centers before the introduction of BV. 2) To evaluate predictors of durable CR in pts treated with BV. Methods: Kaplan-Meier method was used to depict time-to-event outcomes, including OS. The Chi-square test was used to evaluate the association between two categorical variables and log-rank test to compare time-to-event endpoints among pt groups. Based on the univariate proportional hazard model, we examined whether certain variables (sex, stage at diagnosis, number of prior treatments, and time to CR) were predictors of CR duration in pts receiving BV. Results: In the non-randomized comparison between those with relapsed-refractory HL following ASCT who received BV and those who did not, pts were well matched by age, with a relatively higher percentage of females treated on the pivotal study. Dates of progression from ASCT ranged from 1996–2009 in the BV group and 1981–2003 in the international cohort. Median follow-up after ASCT for the censored observations of pts who received BV and those in the international cohort was 49.4 and 58.8 mos. The difference in median OS was statistically significant (p<0.0001) between those receiving BV and those not exposed to the drug (91.49 vs. 27.99 mos). Improvement in OS was irrespective of time to relapse from ASCT, despite previous studies noting a higher risk of recurrence in pts relapsing within 12 mos of ASCT (Sureda 2005 et al). Neither age nor sex was found to impact OS. In the subgroup analysis of pts achieving a CR with BV, univariate analysis of duration of CR and PFS uncovered no significant factors, while only stage of disease at initial diagnosis had a significant effect on OS (P=0.0004). Disease status characterized as relapsed vs. refractory had borderline significance with a positive impact on OS (P=0.0581). No significant associations were noted between the variables and duration of response post BV stratified into periods of less or greater than 12 mos. However, among those pts who experienced a duration of CR greater than 12 mos, 81.8% (n=18) had an initial CR after receiving ≤ 4 doses of BV, compared with 58.3% entering CR after receiving > 4 doses. Conclusions: While the impact of BV on OS can only be determined through a randomized clinical trial, our analysis indicated that treatment with BV in pts with relapsed/refractory HL following ASCT is associated with prolonged OS when compared with historical control patients. Those who achieve a rapid CR with BV may also have a longer duration of response. A randomized clinical trial is ongoing to evaluate prospectively the efficacy of BV following ASCT. Disclosures: Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding; Celgene: Consultancy. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ramchandren:Seattle Genetics, Inc.: Speakers Bureau. Forero-Torres:Seattle Genetics: Research Funding. Moskowitz:Seattle Genetics: Speakers Bureau. Connors:Seattle Genetics, Inc.: Research Funding. de Vos:Seattle Genetics: Speakers Bureau. Engert:Takeda: Honoraria, Research Funding; Millennium: Honoraria, Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Morschhauser:Takeda: Honoraria. Younes:Seattle Genetics: Honoraria.

Download Full-text

FDG-PET Adapted Sequential Therapy With Brentuximab Vedotin and Augmented ICE Followed By Autologous Stem Cell Transplant For Relapsed and Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.2099.2099 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2099-2099 ◽

Cited By ~ 5

Author(s):

Alison Moskowitz ◽

Heiko Schoder ◽

John F. Gerecitano ◽

Paul Hamlin ◽

Steven M. Horwitz ◽

...

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Salvage Therapy ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Genetics Research ◽

Grade 3

Abstract Background Pre-transplant FDG-PET (PET) normalization is the strongest predictor of outcome following autologous stem cell transplant (ASCT) for patients with relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) (Moskowitz, AJ. Blood. 2010 Dec 2;116(23):4934-7). Due to its high efficacy in ASCT failures, we aimed to determine whether brentuximab vedotin (BV) can replace ICE (ifosfamide, carboplatin, etoposide) salvage therapy, increase rate of PET normalization, and enhance referral to ASCT for patients (pts) who fail front-line HL therapy. Here we present our phase II study evaluating a novel salvage strategy for rel/ref HL, an intent-to-treat study of PET-adapted sequential therapy with BV and augmented ICE (augICE) prior to ASCT. Methods Patients with rel/ref HL who have failed 1 prior regimen are enrolling on this phase II clinical trial. Patients receive weekly brentuximab vedotin (BV) administered at 1.2mg/Kg IV weekly for 3 weeks on and 1 week off for 2 cycles, followed by PET. Patients who achieve normalization of PET (Deauville 2 or less) proceed to ASCT. Patients with PET scores of Deauville 3 or higher receive 2 cycles of augICE prior to consideration for ASCT. Results 41 of planned 46 patients have enrolled; 34 pts completed salvage therapy, of whom 33 proceeded to ASCT. 28 pts are at least 90 days post-ASCT and represent the focus of this report. These 28 pts include 20 (71%) males, 21 (75%) pts with primary refractory or relapse within 1 year of initial treatment, 11 (39%) with B symptoms at enrollment and 11 (39%) with extranodal disease. Median number CD34+ cells/kg collected were 7.44x 10^6 (2.96 - 31.43x10^6). Disease status prior to ASCT was CR (Deauville 2) for 27 pts and PR (Deauville 3) for 1 pt. Salvage therapy for pts in CR prior to ASCT include BV alone (9), BV followed by augICE (16), and BV followed by augICE (with Deauville 4 response) followed by involved field radiation to achieve CR (2). The 1 patient in PR prior to ASCT received BV followed by augICE. Conditioning regimens included BEAM (9), CBV( 9), and high dose chemoradiotherapy (10). Early (within 90 days) transplant-related toxicities include grade 2 pneumonitis (3pts) and grade 3 acute kidney injury (1pt); late toxicities include grade 3 esophageal stenosis (1pt), grade 3 acute kidney injury (1pt), and 1 death (7 months post ASCT) due to progressive multifocal leukoencephalopathy. After a median follow-up of 9.5 months post-ASCT (range 3.3-15.6 months), 2 of 28 pts have progressed (at 2.7 and 4.3 months post ASCT respectively). One achieved a second CR with BV and proceeded to allogeneic stem cell transplant (alloSCT); the second achieved near CR following GND (gemcitabine, vinorelbine, Doxil) and proceeded to alloSCT. Conclusion PET-adapted sequential salvage therapy with BV followed by augICE produces high CR rates, adequate stem cell collection, and facilitates referral to ASCT for virtually all pts. Updated results will be presented at the meeting. Disclosures: Moskowitz: Seattle Genetics: Research Funding. Off Label Use: Brentuximab vedotin is approved for treatment of Hodgkin lymphoma following failure of 2 multi-agent regimens or autologous stem cell transplant. This study is evaluating the use of brentuximab vedotin in the pre-transplant setting for Hodgkin lymphoma. Schoder:Seattle Genetics: Research Funding. Hamlin:Seattle Genetics : Consultancy, Honoraria. Horwitz:Millennium: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Moskowitz:Seattle Genetics: Research Funding.

Download Full-text

Phase 1/2 Study Of Brentuximab Vedotin In Pediatric Patients With Relapsed Or Refractory (R/R) Hodgkin Lymphoma (HL) Or Systemic Anaplastic Large-Cell Lymphoma (sALCL): Preliminary Phase 2 Data For Brentuximab Vedotin 1.8 Mg/Kg In The HL Study Arm

Blood ◽

10.1182/blood.v122.21.4378.4378 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4378-4378 ◽

Cited By ~ 8

Author(s):

Franco Locatelli ◽

Kathleen A Neville ◽

Angelo Rosolen ◽

Judith Landman-Parker ◽

Nathalie Aladjidi ◽

...

Keyword(s):

Abdominal Pain ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Pediatric Patients ◽

Phase 1 ◽

Brentuximab Vedotin ◽

Phase 2 ◽

Free Survival ◽

Grade 3 ◽

Preliminary Phase

Abstract Background Brentuximab vedotin is a CD30-targeted antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Pivotal phase 2 studies reported the efficacy and manageable toxicities of the drug, leading to its approval by the US FDA for use in adult patients with R/R HL and R/R sALCL in 2011. Data for brentuximab vedotin in children with these lymphomas are currently limited but promising. This ongoing phase 1/2 prospective, open-label, multicenter study is the first clinical trial of brentuximab vedotin conducted exclusively in pediatric patients with R/R HL or R/R sALCL (NCT01492088). The phase 1 portion established the recommended phase 2 dose (RP2D) of brentuximab vedotin in pediatric patients with R/R HL or R/R sALCL as 1.8 mg/kg every 3 weeks (Q3wk), and complete response (CR) and partial response (PR) were reported in 88% of patients at the RP2D. Here, we report preliminary phase 2 response, safety and PK findings for the HL patients receiving the RP2D. Methods The phase 2 portion aimed to enroll 15 response-evaluable HL patients at the RP2D, including those R/R HL patients treated at the RP2D in phase 1 (phase 2 data for the sALCL patients are not reported here). The phase 2 primary objective was overall response rate (ORR; CR + PR) at the RP2D; secondary objectives were time to progression, time to response, duration of response, event-free survival, progression-free survival, overall survival, to characterize PK, to further evaluate safety, and to determine immunogenicity of brentuximab vedotin. Patients with R/R HL aged 5 to<18 years, with measurable disease, who were in their second or later relapse, had failed chemotherapy, and were ineligible for, refused, or previously received stem cell transplant, received brentuximab vedotin 1.8 mg/kg by IV infusion Q3wk for up to 16 cycles until progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses will be assessed both by the investigators and independent review facility per IWG revised response criteria for malignant lymphoma; investigator responses are reported here. Blood samples for PK analysis were collected on day 1 (all cycles) immediately before and 5 minutes after the infusion and on prespecified days during cycles 1, 2, and 8. Results 16 patients with R/R HL received at least 1 dose of brentuximab vedotin at the RP2D; median age was 15 years (range, 8–18); 56% were male; Ann Arbor stage at initial diagnosis was 44% stage II, 6% stage III, 44% stage IV, and 6% unknown; median time from initial diagnosis was 16.7 months (range, 0–38) and 50% had B symptoms at baseline. At data cut-off (June 20, 2013), patients had received a median of 3 cycles of treatment (range, 1–16); 10 (63%) patients had discontinued treatment due to: progressive disease (n=7), AEs (n=2), and allogeneic transplant (n=1). Response data were available for 14 patients at data cut-off. The ORR was 64% (95% confidence interval [CI]: 35, 87); 3 (21%; 95% CI: 5, 51) patients achieved CR and 6 (43%; 95% CI: 18, 71) achieved PR. Reponses were typically observed at C2. 12 of 16 (75%) patients had ≥1 AE, and 7 (44%) had grade ≥3 AEs. The most common (>1 patient) AEs were nausea (38%), pyrexia (31%), neutropenia, paresthesia (each 19%), abdominal pain, upper abdominal pain, constipation, decreased appetite, diarrhea, hepatotoxicity, hypokalemia, leukopenia, myalgia, pharyngitis, and vomiting (each 13%). 7 serious AEs (SAEs) occurred in 5 patients; 4 SAEs in 3 patients were considered related to brentuximab vedotin: grade 3 hepatotoxicity and grade 3 febrile neutropenia (n=1); grade 3 anaphylaxis (n=1); and grade 3 pneumonia (n=1). One patient died on C2D4 of unrelated cardiac arrest due to progressive mediastinum enlargement (disease progression). 2 (13%) patients discontinued, 1 due to grade 3 hepatotoxicity on C1D13 and 1 due to grade 3 peripheral neuropathy on C8D4. Preliminary PK data show that brentuximab vedotin remained detectable in the blood just prior to the next infusion over the treatment period; thus, patients remain exposed to brentuximab vedotin from cycle to cycle. Conclusions Brentuximab vedotin 1.8 mg/kg Q3wk (RP2D) was generally well tolerated in pediatric patients with R/R HL and demonstrated preliminary evidence of activity, with an ORR to date of 64%, including 21% CR. The phase 2 portion is ongoing in pediatric patients with R/R HL and R/R sALCL. Disclosures: Off Label Use: Brentuximab vedotin for the treatment of pediatric patients with relapsed or refractory Hodgkin lymphoma. Franklin:Millennium: The Takeda Oncology Company: Research Funding. Fasanmade:Millennium: The Takeda Oncology Company: Employment, Equity Ownership, Research Funding. Wang:Millennium: The Takeda Oncology Company: Employment. Sachs:Millennium: The Takeda Oncology Company: Employment. Mauz-Koerholz:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees.

Download Full-text