Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Cost Evaluation Study of Management and Surveillance, and Review of the Recent USA and UK Guidelines

Abstract Introduction Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell lymphoma associated with textured breast implants, recently recognized by the revised WHO Classification. Recommended management for BIA-ALCL involves a multidisciplinary team (MDT) approach with breast surgery, haemato-oncology, pathology, radiology and oncoplastic input. Definitive management for the 'effusion-only' subset is surgical implant and capsule removal; systemic therapy is reserved for 'mass-forming' and 'advanced-disease' cohorts. Overall prognosis is excellent with the vast majority achieving remission. Although the diagnostic and treatment paradigm is established, post treatment surveillance and follow-up guidance varies widely (globally); over-utilisation of imaging tests compromises the patient pathway, impacts limited health-care resources and is associated financial burdens on patients and providers. Recently, newly published consensus guidelines (UK MHRA and USA NCCN clarify follow-up and surveillance imaging (Table 1). The aim of this study was to review our BIA-ALCL specialist centre institutional practise; to quantify the direct economic cost (EC) of imaging surveillance and indirect EC of outpatient clinic (OPC) assessment compared EC if recent guidelines were followed. The secondary aim is to highlight and raise awareness of the latest international guidance to promote the standardisation of practise. Methods A retrospective analysis of a prospectively maintained patient database between July 2015 to October 2019 was conducted, with Institutional Review Board Approval. Data collection included patient demographics, tumour subset, treatment, clinical and imaging surveillance. Follow-up and imaging undertaken for symptomatic concerns / non-BIA-ALCL related pathology was excluded. Imaging costs were calculated using UK NHS tariffs. Results Eleven patients were treated for BIA-ALCL during the study period, with a median age of 49 at diagnosis (range 30-82years). Patients were diagnosed with: effusion-only (n=7), effusion and mass (n=2), mass-only (n=2) subtypes, at a median time of eleven years from implant insertion (IQR 8-12). All patients underwent explantation and en-bloc capsulectomy, with 1 patient required neo-adjuvant (CHOP, Brentuximab) and 1 adjuvant (CHOP) therapy (CHOP. Surveillance with imaging and OPC detected no disease recurrence to date (overall median follow-up 38 months, IQR 12-47). Post treatment episodes of surveillance imaging or follow-up related to patient symptoms were excluded. 8 patients underwent surveillance imaging at our institute (Table 2). Total cost of imaging was £10,396 ($14,396) with a median cost of £1,953 ($2,705) per patient [IQR £526-2029 ($728-2,810)]. 7 patients had completed at least 24 months follow-up since surgery during the study period (Table 3), with 3 patients having not yet completed their follow-up period of two years. Of those with completed follow-up, the median OPC follow-up per patient was 48 months (IQR 38-52), median number of OPC was 7 (IQR 6-11) and the median cost of clinic review was £982 (IQR 804-1395). The surplus cost per patient compared with recommended follow-up was £118 ($164) [IQR £0-531 ($0-738)]. Conclusions Our data shows the variable BIA-ALCL surveillance practise pattern and the associated additional direct and indirect EC of unnecessary asymptomatic surveillance imaging, with an excessive number of follow-up OPC and period of clinical follow-up after complete remission. With no recurrence detected in our patient cohort to date, this data supports the new UK and updated USA NCCN Guidelines (extrapolated from data in other NHLs, and analogous to principles of the ASH Choosing Wisely Campaign) that routine post-treatment surveillance imaging should not be performed in BIA-ALCL patients. Routine asymptomatic post-treatment surveillance imaging is clinically unnecessary and potentially leads to a 'Cascade Effect' of further tests, with increased radiation exposure, excess costs and impact on limited health-care resources. We also support open-access follow-up for patients in remission, to reduce unnecessary follow up appointments. With UK and USA guidelines now available for BIA-ALCL, we support training and education of health-care professionals, global consensus guidelines and a registry, for this rare however increasingly recognised new entity. Figure 1 Figure 1. Disclosures Iyengar: Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: conference support; Janssen: Other: conference support, Speakers Bureau. Nicholson: Pfizer: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; BMS/Celgene: Consultancy; Novartis: Consultancy, Other: Conference fees. El-Sharkawi: Kyowa Kirin: Other: Ad boards; Beigene: Other: Ad boards; ASTEX: Other: Ad boards; Novartis: Other: Travel Support; Takeda: Honoraria; Roche: Honoraria; Janssen: Honoraria, Other: Ad boards; AstraZeneca: Honoraria, Other: Ad boards; AbbVie: Honoraria, Other: Travel Support, Ad boards. Tasoulis: BMJ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cunningham: Roche: Research Funding; Clovis Oncology: Research Funding; Celgene: Research Funding; Eli Lilly: Research Funding; Bayer: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; 4SC: Research Funding; AstraZeneca: Research Funding; MedImmune: Research Funding.

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Characteristics, Outcome and Pattern of Mutations in Patients with Follicular Lymphoma Who Progressed on BTK Inhibitors (Ibrutinib and acalabrutinib)

Blood ◽

10.1182/blood.v128.22.2975.2975 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2975-2975

Author(s):

Preetesh Jain ◽

Rashmi Kanagal-Shamanna ◽

Francis San Lucas ◽

Michael Wang ◽

Jorge E. Romaguera ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Post Treatment ◽

Advisory Committees ◽

Paired Samples ◽

Btk Inhibitors

Abstract Introduction: Acalabrutinib and ibrutinib are Bruton's tyrosine kinase (BTK) inhibitors, which have revolutionized the treatment of B-cell lymphoma/leukemias such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in frontline or relapsed refractory setting. Outcomes of patients with MCL and/or CLL who progressed on ibrutinib therapy are poor. Few reports have shown that ibrutinib resistant patients develop specific BTK mutations which confer resistance. We present the clinical and molecular data on patients with follicular lymphoma (FL) who have progressed on either ibrutinib based regimen or on acalabrutinib. Methods: We selected FL patients enrolled in clinical studies at our institution between 2013 and 2015 who discontinued acalabrutinib or ibrutinib for various reasons. Survival post ibrutinib discontinuation was calculated. We performed whole-exome sequencing on pre and post treatment (paired) samples of 3 FL patients (progressed on ibrutinib) using DNA extracted from formalin fixed paraffin embedded tissue samples. Library preparation and capture were performed using Agilent's SureSelect XT Human All Exon V4. Following capture the enriched libraries were pooled and sequenced in two Illumina HiSeq4000 lanes using a 75nt paired-end configuration. Results: Twenty of 55 patients discontinued treatment with BTK inhibitors; 5 came off from single agent acalabrutinib in relapsed refractory FL (RR-FL) while 15 came off from ibrutinib based regimen (4 as a single agent in RR-FL while 11 were treated with ibrutinib and rituximab in the frontline setting). These patients discontinued BTK inhibitor treatment, after a median of 2.8 months (range 0.9-22 months). Patients who received frontline ibrutinib (n=11), discontinued at a median of 2.8 months (0.9-22 months); previously treated patients discontinued BTK inhibitors at a median of 2.8 months (1.4-7.6 months). The reasons for discontinuation were as follows - 14 disease progression (3 on acalabrutinib and 11 on ibrutinib; 1 of them developed classical Hodgkin lymphoma), 2 non-responders (1 acalabrutinib and 1 ibrutinib) and 4 for other reasons (1 due to fatigue on acalabrutinib, 3 due to ibrutinib - 1 elevated liver enzymes, 1 asymptomatic atrial fibrillation another lost to follow up). Pre-treatment characteristics of the 16 patients who either progressed or were nonresponders to BTK inhibitors were - median age 59 years (range 41-75), 69% had stage 4 disease, 31% had FLIPI score of 3 or 4 and median LDH levels were 457 IU/L (range 290-754). Median follow up after discontinuation for all patients was 14.4 months (0-32 months). Eighteen patients (90%) were alive at the time of last follow up and 2 (10%) have died. Median survival (figure 1) of patients according to the causes of discontinuation was: not reached for both group of patients, those with other causes and those in progressive disease and/or non-responders. All 16 patients who progressed or not responded were treated with additional therapies. At the time of last follow up, 10/16 (62%) were responding to subsequent therapy - 5/10 (62%) achieved CR on lenalidomide-based therapies, 4/10 (40%), responded to chemoimmunotherapy and 1 patient responded to venetoclax-bendamustine and rituximab with CR. None were treated with PI3K inhibitors. WES studies showed EZH2 Y646 mutations in 2 of 3 FL patients in both pre and post treatment samples. Comparison of pre and post treatment samples on 3 patients showed multiple non-recurrent variants (2-12 per patient) in several genes in the post-treatment samples. These included DNMT3A R882H, NOTCH2 A3D and MLL E765G, all of which were noted in the post treatment sample of the patient that progressed to CHL. None of the other detected variants have been implicated in cancer. Of note, none of the samples showed BTK mutations despite adequate coverage. Conclusions: In contrast to other B-cell malignancies such as CLL and MCL, we observed that almost all FL patients who progressed on BTK inhibitors were salvageable by alternate therapies. Absence of BTK gene mutations in paired samples of 3 patients who progressed on ibrutinib suggests alternate mechanisms of drug resistance. Figure 1 Outcomes of patients with follicular lymphoma after discontinuing acalabrutinib and/or ibrutinib based regimen according to the cause of discontinuation Figure 1. Outcomes of patients with follicular lymphoma after discontinuing acalabrutinib and/or ibrutinib based regimen according to the cause of discontinuation Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Research Funding; Onyx: Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; BeiGene: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding. Oki:Novartis: Research Funding. Westin:Spectrum: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees. Fowler:Gilead: Research Funding; Jannsen: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; TG Therapeutics: Consultancy.

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Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Blood ◽

10.1182/blood-2019-130633 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2865-2865

Author(s):

Sudhakiranmayi Kuravi ◽

Janice Cheng ◽

Kishore Polireddy ◽

Gabrielle Fangman ◽

Roy A Jensen ◽

...

Keyword(s):

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Advisory Board ◽

Advisory Committees ◽

Apoptotic Protein ◽

Large Cell Lymphoma ◽

Alk Positive

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

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Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽

10.1182/blood-2019-122393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2898-2898

Author(s):

Vania Phuoc ◽

Leidy Isenalumhe ◽

Hayder Saeed ◽

Celeste Bello ◽

Bijal Shah ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Fdg Pet ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study

Blood ◽

10.1182/blood.v126.23.1518.1518 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1518-1518 ◽

Cited By ~ 1

Author(s):

Jackie Vandermeer ◽

Allison M Winter ◽

Ajay K. Gopal ◽

Ryan D. Cassaday ◽

Brian T. Hill ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

First Line ◽

Advisory Committees ◽

First Line Therapy

Abstract Introduction Among patients with aggressive B-NHL who fail RCHOP, about half respond to standard salvage regimens and may proceed to curative-intent, transplant-based therapy. However, whether pts failing more intensive regimens such as dose-adjusted, infusional EPOCH benefit from standard salvage regimens is unclear. We hypothesized that such patients comprise a higher-risk cohort, facing inferior response rates and outcomes using standard salvage regimens. We undertook a collaborative study to assess response rates and survival among pts failing EPOCH for aggressive B-NHL, to inform patient management and design of clinical trials in this setting. Methods Pharmacy records and institutional databases were queried, identifying pts receiving EPOCH over the last 10 years at the University of Washington/SCCA and the Cleveland Clinic Foundation, for combined analysis. Under IRB approval, patient characteristics, histology, outcome with EPOCH, time to EPOCH failure, response to salvage, and overall survival were analyzed. Diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, B-cell-lymphoma unclassifiable, HIV-associated B cell lymphoma, and transformed B cell non-Hodgkin lymphoma were included. Pts receiving <2 cycles EPOCH, or who had inadequate follow-up (<3 months), were excluded. Failure of EPOCH was defined as failure to respond or progression during therapy, need for initiation of salvage therapy, or death during therapy of any cause. Adverse events or treatment change due to toxicity were not included in the definition of failure. JMP 11 was used to generate kaplan-meier survival estimates. Results 124 pts with aggressive B-NHL receiving EPOCH were identified. 54 had not relapsed, and among 70 remaining da-EPOCH failures, 37 met the above inclusion criteria. Median age was 55. 27% were female, and 23 received EPOCH as first-line therapy. All but 3 received rituximab with EPOCH. Histologies were primarily DLBCL in 22/37 (60%) and BCL-U in 12/37 (32%) carrying a MYC translocation; most of these harbored additional translocations in BCL2 and/or BCL6 (10/12). However, data regarding MYC rearrangement was not available for all pts. 2 had HIV-associated B-NHL and 3 had PMBCL. With 18 months follow up, the median time to EPOCH failure was 5 months. Only 3 EPOCH failures occurred late (>12 months). Median OS from the date of EPOCH failure was 10 months (Figure 1). Those receiving EPOCH as first-line therapy (23) had a median OS of 14 months from EPOCH failure, as opposed to 4 months for those receiving EPOCH as salvage therapy (log-rank p=.01). Salvage chemotherapy regimens after EPOCH were diverse, and generally ineffective; 6/28 (21%) regimens produced a response (Table 1). Among patients failing EPOCH within a year, platinum-containing salvage (RICE/RDHAP) was effective in only 2/13 patients (15%). 9 patients did not receive any salvage, most of whom died or proceeded to palliative measures and/or hospice care. Conclusions A relatively low overall response rate (21%) was observed in this retrospective analysis of patients failing EPOCH. Analogous to early RCHOP failure in the CORAL study, those failing EPOCH within a year may face inferior outcomes with platinum-based salvage therapy. While combined from two institutions, our data represent a modest sample size and require confirmation. If verified, examination of mechanisms of resistance to EPOCH, and selecting EPOCH failures for clinical trials of novel targeted therapies and transplant-based approaches, may prove critical. Table 1. Salvage Therapy for REPOCH failures Regimen: response/total number treated Notes Response to any salvage: 6/28 (21%) Some patients received more than 1 chemo salvage; responses were tabulated per regimen. RICE: 4/12 2/3 alive post transplant(1 auto 1 allo; 1 declined transplant and survived; 1 died) RDHAP: 1/6 Gemcitabine-based: 0/5 HyperCVAD (Part A and/or B): 1/5 Survivor had CNS only relapse, received regimen B and transplant 9- received no systemic treatmen; most died or proceeded to palliative measures and/or hospice Figure 1. Figure 1. Disclosures Gopal: Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Emergent/Abbott: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Consultancy, Honoraria; BioMarin: Research Funding; Piramal: Research Funding; Janssen: Consultancy; Millenium: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding. Hill:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Till:Roche/Genentech: Research Funding; Pfizer: Research Funding.

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Long-Term Responders after Brentuximab Vedotin: Experience on 57 Patients with Relapsed and Refractory Hodgkin and Anaplastic Large Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2725.2725 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2725-2725 ◽

Cited By ~ 1

Author(s):

Pier Luigi Zinzani ◽

Letizia Gandolfi ◽

Beatrice Casadei ◽

Cinzia Pellegrini ◽

Alessandro Broccoli ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cell Lymphoma ◽

Large Cell ◽

Median Number ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Large Cell Lymphoma

Abstract Brentuximab vedotin (BV) is an antibody drug-conjugate targeting CD30 linked to monomethyl auristatin E. Several studies have shown the efficacy of BV in patients with refractory or relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). We reviewed our clinical database to evaluate the long-term efficacy of this treatment. From July 2009 to February 2015, 57 patients were treated with BV in our Institute: 43 with a diagnosis of HL and 14 with sALCL. Thirty-six were males and 21 were females, with a median age of 33 years (range 16-77). All of them had been heavily pretreated before BV with a median number of previous therapies of 3 (range 2-10). Thirty-nine had refractory disease and 18 were relapsed. Autologous stem cells transplantation had failed in 30 patients. BV was administered at a dosage of 1.8 mg/mq, every 21 days, for a maximum of 16 cycles. The median number of cycles was 8 (range 2-16); 13 patients completed the entire schedule. The best overall response rate was globally 57,8% (33 of 57 patients), including 25 (43.8%) complete responses (CR): 18 with HL and 7 with sALCL. At present, 20/25 (80%) patients are still in continuous CR (CCR) with a median follow up of 9 months (range 3-41): 10 of them have consolidated the response with a stem cell transplantation (SCT) (4 auto-SCT and 6 allo-SCT) and 10 patients have remained in CR without any other therapy after BV. Among these long-term responders without any consolidation (7 patients with HL and 3 with sALCL), the median follow-up is 12 months (range 3-37); in particular there are 3 patients in CCR after at least 24 months. The global overall survival rate at 68 months is 71% (no patients with sALCL dead) and the median overall survival has not been reached yet. The global progression-free survival rate at 48 months is 30%, the median is achieved at 11,7 months. Toxicity was primarily neurological with peripheral sensory symptoms (30%) and motor neuropathy (5%); the majority was grade 3 in severity (8 patients). This study confirms the safety and the high efficacy of BV that can be considered an effective treatment in patients with relapsed or refractory HL or sALCL. This drug can induce a durable complete response representing a "bridge" to auto-SCT or allo-SCT. However our data show a subset of patients that can be considered "long-term responders", who have remained in CCR without any consolidation after BV. Disclosures Zinzani: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Honoraria; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria.

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Breast Implant Associated-Anaplastic Large-Cell Lymphoma (BIA-ALCL): Data Based on the Lymphoma Study Association (LYSA) Registry. Promising Results of Brentuximab Vedotin Combined with Cyclophosphamide, Doxorubicin and Prednisone (BV-CHP) As First Line Treatment for Patient Requiring Chemotherapy

Blood ◽

10.1182/blood-2021-150478 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1387-1387

Author(s):

Fabien Le Bras ◽

Jean Marc Schiano De Colella ◽

Lucie Oberic ◽

Emmanuel Itti ◽

Thua-Ha Dao ◽

...

Keyword(s):

Breast Cancer ◽

Research Funding ◽

Clinical Presentation ◽

Cell Lymphoma ◽

Breast Implant ◽

Large Cell ◽

Histological Subtype ◽

Tumor Mass

Abstract Background: Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is a rare form of T-cell lymphoma arising adjacent to a breast implant, recently recognized as a provisional entity in the 2017 revised World Health Organization (WHO) lymphoma classification. The pathogenesis of this entity remains elusive even if gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent. ECHELON 2 trial (Horwitz S et al. The Lancet 2019) has set BV-CHP as a new standard of treatment for CD30-positive peripheral T-cell lymphoma, mainly in systemic ALCL patients (pts) but not in BIA-ALCL. Our objective is to describe a series of pts with BIA-ALCL included in the LYSA registry focusing on the use of BV CHP as front-line chemotherapy for patient requiring chemotherapy. Methods: since 2016, a national multidisciplinary meeting has been implemented by the French Cancer Agency to better define therapeutic strategies for newly diagnosed cases after histologic confirmation. Meanwhile, BIA-ALCL registry was funded by the LYSA to collect ambispectively, in France and more recently in Belgium, patient clinical data including reasons for breast implantation, implant manufacturer, treatment and outcome. Results: from 2009 to 2021 , 85 pts (73 in France and 12 in Belgium) gave their informed consent to participate to the registry. Median age was 57 years (range 29-82) at diagnosis. In 39 out of 85 pts (45.9%) the first implant followed a mastectomy for breast cancer. In this analysis, only implants in the breast(s) where the lymphoma occurred have been considered. Five pts (5.9%) had bilateral lymphoma and 80 pts had unilateral lymphoma (35 left side and 45 right side), 35 pts were implanted once (41.2%), 35 twice (41.2%) and 15 pts (17.6%) 3 times or more. The median period between first implant and BIA-ALCL diagnosis was 12.2 years (range 4.1-40.5), and 7 years (range 0.2-25.4) from last implant to diagnosis. The clinical presentation was seroma in 64 pts (75.3%), breast tumor mass with or without seroma in 18 pts (21.1%) and 3 pts were diagnosed without any mass or seroma (1 contiguous lymph node involvement, 2 in the context of systematic implant removal). The two main clinical presentation (i.e. seroma and tumor mass) were most often correlated with the two distinct histological subtypes (in "situ/mixed" (n=62) or "infiltrative" (n=21)). For 2 pts, histological subtype was not available. The majority of pts were Ann Arbor stage I-II (n=65, 76.5%), and 18 (21.2%) pts were stage IV. Stage was unknown in 2 pts. Considering available information, almost all patients had at least one silicone-filled (n=76) and at least one textured implant (n=85) with Biocell texturation (n=61, 71.8%). No patient had only smooth implant. Implant removal with total capsulectomy was performed in 66 patients and 25 underwent chemotherapy based on CHOP or CHOP-like (4 to 6 cycles) chemotherapy regimens (n=13), BV-CHP (6 cycles) (n=10) and others (n=2). Among the patients receiving chemotherapy, CR was obtained in 21 pts (84%) and in 2 pts failed to respond (8%). Among the patients treated with BV-CHP, 8 pts achieved CR (80%) and 2 pts were not yet evaluated at the time of analysis. No limiting toxicity was noted. After a median follow-up of 28.6 months, 78 pts are alive and free of evolutive disease and 8 are lost to follow up. Seven pts died, either from lymphoma progression alone (n=2) or associated with concomitant active breast cancer (n=2), one from breast cancer alone, one from lung epidermoid cancer and one due to myocardial infarction. Patients with an "infiltrative" histological subtype have a significantly worse outcome with a 2y-PFS of 73.8% vs 96.7% for other subtypes ("in situ/mixed subtypes") (p=0.0039, HR=5.3) and a 2y-OS of 78.7% vs 100% (p=0.0022, HR=8.5). With a median follow-up of one year, the 10 patients treated with BV-CHP are alive and free of evolutive disease at the time of analysis. Conclusions: We report on the basis of a limited series of patients that 6 cycles of BV-CHP provide an excellent disease control in patients with BIA-ALCL requiring chemotherapy. Confirmation of these results on a larger series of patients with a longer follow-up is needed. Such observation provides basis for a prospective trial in order to determine if treatment with BV-CHP could be installed as a standard of care for higher risk patients with BIA-ALCL, as those presenting with tumor mass and /or infiltrative subtype. Disclosures Le Bras: Novartis: Honoraria; Celgene BMS: Research Funding; Takeda: Honoraria, Research Funding; Kite Gilead: Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Bonnet: Roche: Consultancy. André: AbbVie: Other: Travel/accomodation/expenses; Roche: Other: Travel/accomodation/expenses, Research Funding; Johnson & Johnson: Research Funding; Celgene: Other: Travel/accomodation/expenses; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Takeda: Consultancy, Research Funding. Haioun: Amgen: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding.

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Imatinib +/- Brentuximab Vedotin Induces Sustained Complete Remission in Chemotherapy-Resistant Anaplastic Large Cell Lymphoma Expressing PDGFR

Blood ◽

10.1182/blood-2019-129955 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4037-4037

Author(s):

Philipp Bernhard Staber ◽

Christoph Kornauth ◽

Ines Garces de los Fayos Alonso ◽

Wilhelm Woessmann ◽

Wolfram Klapper ◽

...

Keyword(s):

Stem Cell ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Large Cell Lymphoma ◽

Pdgfr Alpha

Background. Anaplastic lymphoma kinase positive systemic anaplastic large cell lymphoma (ALK+ ALCL) represents an aggressive T-cell malignancy that primarily affects children and younger adults. Upon treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens its prognosis is relatively favourable compared to other aggressive T-cell lymphomas, however, the rare event of disease reoccurrence remains particularly challenging. ALCL is CD30 positive, and mono treatment with brentuximab vedotin (BrV) can achieve long term remissions in only few relapsed patients not receiving consolidating stem cell transplantation (Pro B. et al. Blood 2017). A subset of ALCL patients express platelet derived growth factor receptor (PDGFR) alpha or beta in their tumour cells which is induced by ALK via AP-1 transcription factor activation. We previously demonstrated that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib is an effective treatment concept for ALK+ ALCL in experimental mouse models (Laimer D. et al. Nature Med. 2012). Here we aimed to assess the prognostic value of PDGFR expression and to probe the clinical value of its targeting by imatinib in ALK+ ALCL patients. Methods. The impact of PDGFR expression to predict clinical outcome was analyzed in samples of 98 ALK+ ALCL patients included in the studies NHL-BFM 90, 95 and ALCL99 between 1992 and 2006. Six patients (age 18-45) with chemo-refractory ALK+ ALCL were prospectively treated with imatinib plus (4) or minus (2) BrV. 33% (2/6) had previously received salvage treatment with stem cell transplantation (SCT). Three of the patients had been enrolled in a prospective single-arm study combining imatinib and BrV, a trial that was terminated due to poor patient recruitment (AGMT ALCL1 trial, EudraCT No.: 2013-003505-26, supported by Takeda®). PDGFR alpha and beta expression analyses were performed on tumour samples of treated patients. Results. ALK+ ALCL patients with high PDGFR expression on tumor cells (n=11) had a significantly lower event-free survival rate (EFS) at 5 years compared to patients with no or low expression (n=87) (27±13% versus 70±5%, respectively, p<0.001, figure 1a). Four of the six patients with relapsed/ refractory ALK+ ALCL responded to imatinib +/- BrV with a rapid metabolic complete remission (CR). At a median clinical follow-up of 52 months (range 20 to108) all responding patients demonstrated an ongoing CR without SCT even after imatinib was discontinued with an average time on imatinib of 49 weeks (range 32 to 130; figure 1b). Half (2/4) of responding patients received no or only 1 infusion of BrV; both non-responding patients had received BrV. Importantly, despite the few patients that could be prospectively treated, PDGFR expression status had a significant impact on clinical course. All patients (4/4) who expressed either PDGFR alpha or beta in tumour cells and in the lymph node microenvironment responded with an ongoing metabolic CR, whereas the two patients whose lymphoma cells had negative PDGFR expression failed to respond (EFS: 4 versus 210 weeks, p = 0.018; figure 1c). Conclusions. 1) PDGFR expression is a poor risk factor in ALK+ ALCL. 2) Imatinib alone or in combination with BrV overcomes chemo-resistance conferred by PDGFR expression. 3) Imatinib treatment can be discontinued with ongoing CR. 4) These observations suggest that PDGFR expressing ALK+ ALCL patients might benefit from early treatment with imatinib. Disclosures Staber: Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Mayerhoefer:Siemens: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Greil:Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ratiopharm: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; GSK: Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Boehringer Ingelheim: Honoraria; Mundipharma: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Imatinib - bcr-abl Inhibitor

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Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update

Blood ◽

10.1182/blood.v118.21.443.443 ◽

2011 ◽

Vol 118 (21) ◽

pp. 443-443 ◽

Cited By ~ 9

Author(s):

Ranjana H. Advani ◽

Andrei R. Shustov ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership

Abstract Abstract 443 Background: Systemic anaplastic large cell lymphoma (sALCL) is a T-cell non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30. sALCL accounts for 2–5% of all cases of NHL; approximately 40–65% of patients experience recurrent disease after frontline treatment with few effective treatment options. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); updated results of this trial are presented. Methods: Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of efficacy was based on objective response assessments per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patients were enrolled between June 2009 and May 2010 at 22 clinical sites in the US, Canada, and Europe. Results: 58 patients with a median of 2 prior therapies (range 1–6) were treated; 57% were male and the median age was 52 years (range 14–76). Seventy-two percent of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission (CR) or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the objective response rate (ORR) was 86%, the CR rate was 57%, and 97% of patients had a reduction in tumor volume postbaseline. At the time of this updated analysis (data cut May 2011), all but 2 patients had discontinued treatment with brentuximab vedotin; the median number of treatment cycles was 7 (range 1–16). The median duration of objective response was 13.0 months (range 0.1–19.1+) and the median duration of response for patients achieving a CR was 17.1 months (range 0.7–19.1+). Median progression-free survival (PFS) was 14.6 months and median overall survival was not yet reached. Per investigator assessment, the median PFS with brentuximab vedotin was significantly longer than the median PFS achieved with the most recent prior therapy (20.0 months vs. 5.9 months; P value <0.001). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity, regardless of baseline disease characteristics, tumor burden, or prior treatment history. Responses were particularly noteworthy in patients who had never responded to any previous therapy (n=13); in this subgroup of patients, 10 achieved an objective response (77%) and 4 a CR (31%). After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The most common adverse events observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Most AEs in the study were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined in a Standardised MedDRA Query; no Grade 4 events were observed. In patients with neuropathy, 79% (26 of 33) have experienced resolution or some improvement and the median time to resolution or improvement was 13.3 weeks (range 0.3–48.7). Conclusions: Durable complete remissions were achieved with brentuximab vedotin, and treatment was associated with manageable toxicity, in patients with relapsed or refractory sALCL. Approximately half of the responding patients (24 of 50) continued in remission at the time of this analysis; updated results of efficacy and long term safety will be presented at the meeting. Based on the results from this study, a trial evaluating the safety of brentuximab vedotin administered in sequence and in combination with multiagent chemotherapy was initiated and is currently ongoing in frontline sALCL. Disclosures: Advani: Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Shustov:Millennium: Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Brice:Roche: Honoraria; Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Cephalon: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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The Survival Outcome of the Patients with Relapsed/Refractory Anaplastic Large-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2738.2738 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2738-2738 ◽

Cited By ~ 1

Author(s):

Dai Chihara ◽

Michelle A. Fanale ◽

Mansoor Noorani ◽

Jason R Westin ◽

Loretta Nastoupil ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Survival Outcome ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Large Cell Lymphoma

Abstract Purpose: We assessed the survival outcome of patients with anaplastic large cell lymphoma (ALCL) who experienced disease progression or relapse after first line and subsequent therapy. We sought to evaluate the impact of brentuximab vedotin (BV), and survival outcome of patients with ALCL who experienced progression after BV. Patients and Methods: A total of 176 patients (74 ALK+, 102 ALK-) initially diagnosed between 1999 and 2014 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) after the progression/relapse following first-line chemotherapy (PFS1 and OS1), after first salvage therapy (PFS2 and OS2) and after second salvage therapy (PFS3 and OS3) were calculated. Outcome was separately analyzed according to the ALK status focusing on the use of BV. Results: The median age of the patients was 50 (range: 18-89). With a median follow up of 64 months, 111 patients (38 ALK+, 73 ALK-) experienced progression/relapse after the first-line therapy, of which 4 ALK- patients were post upfront stem cell transplant (SCT). Thirty and 15 patients eventually underwent autologous and allogeneic SCT after salvage chemotherapy, respectively. The median PFS1 and OS1 in patients with ALK+ALCL and ALK-ALCL were 8.4 and 28.5 months, and 13.1 and 47.7 months, respectively. In patients with ALK+ALCL, the median PFS1, PFS2 and PFS3 were 53.6, 5.2 and 2.3 months, respectively. The median OS1, OS2 and OS3 were not reached, 47.3 and 6.1 months, respectively. In patients with ALK-ALCL, the median PFS1, PFS2 and PFS3 were 12.9, 3.0 and 2.0 months, respectively. The median OS1, OS2 and OS3 were 54.3, 10.8 and 5.8 months, respectively. Interestingly, there were no significant difference in PFS2 between ALK+ALCL and ALK-ALCL. However, OS2 was significantly longer in patients with ALK+ALCL, suggesting possibly continued chemosensitivity of recurrent ALK+ALCL. A total of 30 patients received BV in 1st salvage (15 patients) and after 2nd salvage (15 patients).The use of BV at 1st salvage was associated with significantly longer PFS2 and OS2 both in patients with ALK-ALCL but not with ALK+ALCL likely due to small number of cases. Mutivariate analysis adjusting baseline PIT risk factors and the duration of the response to first line therapy revealed that use of BV (at any point in the salvage setting) is significantly associated with longer OS2 (HR: 0.43, 95%CI: 0.23-0.80). Overall, 12 patients experienced relapse/progression after BV treatment. The median OS after BV failure was 1.4 months (95%CI: 0.5-9.5 months) (Figure). Summary: Survival outcome for relapsed/refractory patients with ALK+ and ALK- patients is improved with BV. However, survival outcome after BV failure is very poor. A new treatment strategies to consolidate or maintain the response after BV and to develop more safe and better therapeutic options are needed. Figure 1. Figure 1. Disclosures Fanale: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Westin:Spectrum: Research Funding. Nastoupil:Celgene: Honoraria; Genentech: Honoraria; AbbVie: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Wang:Celgene: Research Funding.

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