anti-CD30 Antibody-drug Conjugate Research Articles

Safety and Efficacy of Brentuximab Vedotin in Combination with AVD in Stage II-IV HIV-Associated Classical Hodgkin Lymphoma: Results of the Phase 2 Study, AMC 085

Safety and Efficacy of Brentuximab Vedotin in Combination with AVD in Stage II-IV HIV-Associated Classical Hodgkin Lymphoma: Results of the Phase 2 Study, AMC 085

A Phase I/II Trial of Brentuximab Vedotin (BV) Plus Rituximab (R) As Frontline Therapy for Patients with Immunosuppression-Associated CD30+ and/or EBV+ Lymphomas

A Phase I/II Trial of Brentuximab Vedotin (BV) Plus Rituximab (R) As Frontline Therapy for Patients with Immunosuppression-Associated CD30+ and/or EBV+ Lymphomas

Reducing the Burden of Chemoradiotherapy with the Combination of Brentuximab Vedotin and Rituximab with Reduced Toxicity Chemotherapy in Children, Adolescents and Young Adults with Newly Diagnosed Hodgkin Lymphoma

Background: Cure rates for newly diagnosed Hodgkin Lymphoma remain high through the combined use of chemoradiotherapy. (Hochberg/Cairo Cancer Journal 2018) However, this has resulted in significant adverse physical and psychosocial function that significantly impacts the quality of life among survivors, including cardiotoxicity, neurocognitive deficits, poor quality of life, and secondary malignancies. Pediatric cancer survivor studies have shown significant increases adverse health events following therapy throughout adulthood. Major risk factors for late effects include significant exposure to radiation, anthracyclines, cyclophosphamide, etoposide and bleomycin. (Bhakta et al Lancet 2017, Oeffinger et al NEJM 2006, Gibson et al Lancet Oncol 2018) Immunotherapy targeting the Reed Sternberg cell and tumor microenvironment, including regulatory B-cells, has potential to reduce the burden of traditional treatment. Brentuximab Vedotin, an anti-CD30 antibody-drug conjugate, and Rituximab, a chimeric anti-CD20 monoclonal antibody, have both shown efficacy in relapsed Hodgkin Lymphoma and Brentuximab has gained FDA approval in up front adult HL in combination with standard chemotherapy. (Younes et al JCO 2012, Younes et al Blood 2012, Connors et al NEJM 2018) We hypothesized that the addition of Brentuximab vedotin (Bv) and Rituximab (R) combined with risk adapted chemotherapy will be well tolerated and effective in children, adolescents and young adults with all stages of newly diagnosed Hodgkin lymphoma and will allow for the elimination of more toxic chemotherapies as well as need for radiation. Objectives: To evaluate the safety, tolerability and overall response rate of Brentuximab vedotin and Rituximab in combination with risk adapted chemotherapy in children, adolescents and young adults with newly diagnosed Hodgkin Lymphoma. Methods: Eligible patients 1-30 yrs with all stages of newly diagnosed classical Hodgkin Lymphoma. Patients were risk assigned as either Low (Stage IA, IIA, no bulk), Intermediate (Stage IA bulk/E, IB, IIA bulk, IIB or IIIA) and High Risk (Stage IB bulk/E, II bulk, IIIA bulk, IIIB, IV). Low risk patients were given 3 cycles of Brentuximab vedotin (1.2mg/kg) with Doxorubicin (25mg/m2), Vincristine (1.5mg/m2), Prednisone and Dacarbazine (375mg/m2) on Days 1 and 15. Intermediate and High Risk patients received 4 or 6 cycles of Brentuximab vedotin, Doxorubicin, Vinblastine, Dacarbazine and Rituximab (375mg/m2) on Days 1,2 and 15, 16. (Figure 1) Early response was measured by PET/CT scan. Slow responders, defined by lack of a complete metabolic response or <80% size reduction, received an additional 2 cycles of Bv-AVD-R for Intermediate Risk or Ifosfamide/Vinorelbine for High Risk. Involved Field RT was restricted to only patients with bulk disease with SER and those not in a CR at the end of therapy. Humoral and cellular immunity was measured upon completion of therapy. Results: Total enrolled = 33 patients. Median age = 15yr (range 4-23yr). Total 12 males, 21 females. Risk Assignment = 4 low, 17 intermediate, 12 high. Toxicity = 1 episode of Gr III mucositis, 1 episode of Gr III infusion reaction to Brentuximab vedotin, 2 episode Gr III peripheral neuropathy. All 33 patients achieved a complete response for a CR = 100%. Eighteen patients (58%) achieved a rapid early response. Four patients (only 12%) have required radiation therapy to date due to the presentation of bulky disease with a slow early response. Each of these patients was in CR prior to the start of radiation therapy. At a median follow-up of 18 months, the mean±SEM IgG level, CD19 and CD3 levels were 1097±63, 325±105, and 1273±290, respectively, all within normal range. Furthermore, none of the patients developed agammaglobulinemia or required hospitalization for systemic infection during or following treatment. The EFS and OS is 100% with a mean follow up time of 1320 days (= 44 months, range 3-80). (Figure 2) Conclusions: The addition of Brentuximab vedotin and Rituximab to combination risk adapted chemotherapy (without cyclophosphamide, etoposide or bleomycin) for newly diagnosed Hodgkin Lymphoma appears to be safe in children, adolescents and young adults. Our results show significant promise with a CR rate of 100%, 58% rapid early response and significant reduction in the use of toxic chemotherapy and radiation. The EFS/OS to date is 100% with a median follow up time of greater than 3.5 years. Disclosures Cairo: Osuka: Research Funding; Miltenyi: Other: MTA; Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau.

Variable loss of CD30 expression by immunohistochemistry in recurrent cutaneous CD30+ lymphoid neoplasms treated with brentuximab vedotin

Brentuximab vedotin is a monoclonal anti-CD30 antibody-drug conjugate that has been used to treat a variety of CD30+ neoplasms. The phenomenon of antigen loss has been observed in patients treated with the anti-CD20 antibody rituximab. This study seeks to assess for antigen loss in the setting of recurrent CD30+ neoplasms treated with brentuximab vedotin. We report nine cases of persistent/recurrent cutaneous CD30+ lymphoid neoplasms that demonstrated variable CD30 expression after treatment with brentuximab vedotin. Cases include MF (n = 6), cutaneous T-cell lymphoma, not otherwise specified (n = 1), and anaplastic large cell lymphoma (ALCL), both primary (n = 1) and systemic (n = 1). Immunohistochemical staining revealed decreased CD30 expression following brentuximab vedotin therapy in seven of nine cases. In these seven cases, the pre-treatment percent of tumor cells staining for CD30 ranged from 10% to 100% (mean 50.0%, SD 27.8%), compared to 5% to 50% (mean 14.5%, SD 14.8%, P = 0.003) at recurrence. This case series highlights the finding that CD30 positivity can be variable in recurrences after treatment with anti-CD30 antibodies. This serves to raise awareness of the phenomenon of antigen loss after treatment with brentuximab vedotin and underscores the utility of performing multiple biopsies and/or employing molecular diagnostic techniques in patients with recurrent/persistent disease.

Abstract CT104: A Phase I open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies

Abstract Background: Sutro’s cell-free antibody production system was used to generate STRO-001, a novel CD74 targeting antibody drug conjugate. CD74 is expressed on B cells throughout differentiation and is an attractive target for treatment of B cell malignancies (Zhao et al, J Path Clin Res, Jan 2019). STRO-001 demonstrates potent cytotoxicity in non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) cell lines and anti-tumor activity in xenograft models. Toxicology studies demonstrate dose-dependent B-cell depletion and reversible hematologic toxicity when STRO-001 is administered at up to 10 mg/kg (Solis et al, Proc AACR 2018, Abs 742). Methods: This study (NCT03424603) is a first-in-human Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), recommended phase 2 doses (RP2D) and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies (MM and NHL) who are refractory to, or intolerant of, all therapy known to provide clinical benefit. STRO-001 is given to all patients on study via intravenous infusion on Day 1 and Day 15 of each cycle until disease progression. Dose limiting toxicities are assessed in the first cycle (Days 1-28) of dose escalation. In Part 1, 2 cohorts (1 for MM and 1 for NHL) will enroll 30 patients each to determine the MTD and RP2D for expansion while Part 2 will enroll 4 dose expansion cohorts based on disease subtypes (MM, diffuse large B cell, mantle cell and follicular lymphomas). Efficacy will be evaluated per MM-specific or NHL-specific criteria. Key inclusion criteria include relapsed or relapsed/refractory disease, adequate bone marrow and renal function, and ability to comply with treatment, testing and pharmacokinetic (PK) schedules. NHL patients must have at least one measurable lesion. Key exclusion criteria include leukemic manifestations of lymphoma, need for ongoing anti-coagulants or immunotherapy including systemic corticosteroids and a history of CNS involvement. Samples will be collected to assess the PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US at the following sites: Medical College of Wisconsin, City of Hope, UCSF, Rocky Mountain Cancer Centers, Texas Oncology, Virginia Cancer Specialists, Winship Cancer Institute of Emory University, and the Willamette Valley Cancer Institute and Research Center. Citation Format: Nirav N. Shah, Amrita Y. Krishnan, Nina D. Shah, John M. Burke, Jason M. Melear, Alexander I. Spira, Jonathan L. Kaufman, Jonathon B. Cohen, Ruben Niesvizky, Leslie L. Popplewell, Saurabh Chhabra, Jeff P. Sharman, Thomas G. Martin, Shannon L. Matheny, John P. Leonard, Arturo Molina. A Phase I open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT104.

A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors

SummaryPurpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter. Patients with stable disease or better were eligible to continue treatment until disease progression, unacceptable toxicity, or study closure. Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study. The most common CD30 positive solid tumors were testicular cancer and mesothelioma. Both subtypes had more than one patient with an objective response. The median duration of BV exposure was 6.1 weeks. The disease control rate, defined as achieving stable disease or better at any point during the study, was 55%. The objective response rate was 11%, with a median duration of response of 2.92 months. The most common adverse events reported were fatigue (57%), nausea (33%), and decreased appetite (32%). Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients.

Existing and Emerging Therapies for Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by an infiltration of malignant monoclonal T lymphocytes into the skin. Mycosis fungoides (MF), the most common subtype, and the rarer Sézary syndrome (SS), are considered the classical forms of CTCL, which, because of a varying presentation and lack of genetic and immunophenotypical markers, can often have a delayed diagnosis. With skin-directed topical treatment being the mainstay of therapy in the early stages, there is an absence of long-term curative therapies for advanced disease. Recent insight into the pathogenesis of CTCL has identified new potential therapeutic targets including the monoclonal antibody therapies, brentuximab vedotin and mogamulizumab. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, received extended approval by the US FDA in 2017 to include primary cutaneous anaplastic large-cell lymphoma and CD30-expressing MF. Mogamulizumab, an anti-CCR4 antibody, received FDA approval in 2018 for relapsed or refractory MF and SS. Further targets and therapies continue to be investigated, including the monoclonal antibody therapy alemtuzumab, an anti-CD52 antibody, and the immune checkpoint blockade therapies, pembrolizumab and nivolumab. These new and emerging targets and therapies may lead to a promising broadening of CTCL treatment options in the future.

Abstract A028: Memory stem T-cells expressing an optimized CD30-specific chimeric antigen receptor (CAR) efficiently eradicate peripheral T-cell lymphoma in vivo

Abstract Peripheral T-cell lymphomas (PTCL) represent the most aggressive form among non-Hodgkin lymphomas with a very poor prognosis (5-year survival of 30%), demanding innovative novel treatment strategies. Adoptive immunotherapy with chimeric antigen receptor (CAR) T-cells has demonstrated its therapeutic potential in advanced B-cell hematologic malignancies. However, its application to PTCL remains a formidable challenge mainly due to a lack of truly tumor-specific antigens that are not expressed on normal T-cells. Anaplastic large T-cell lymphomas (ALCL) and several other subtypes of PTCL express CD30, which is also expressed by activated normal T-cells but no other healthy tissues. Indeed, brentuximab-vedotin, an anti-CD30 antibody-drug conjugate, has shown some clinical efficacy in PTCL and ALCL patients although duration of responses is short in the majority of cases. Here, we developed a refined CD30-CAR T-cell approach to target CD30+ PTCL as a potential novel therapeutic strategy. We selected a novel targeting domain that is unaffected by soluble CD30 protein (Nagata S et al., Clin Cancer Res 2002) to prevent blockade of the CD30-CAR. Moreover, we optimized the therapy by using memory stem T-cells (TSCM) to promote engraftment and persistence of CD30-CAR T-cells after transfer.TSCM were generated with CD3/CD28 costimulation in presence of IL-7, IL-15 and IL-21 (Alvarez C et al., J Transl Med 2016). On day 2 of culture, cells were transduced with a third-generation lentiviral vector encoding the CD30-41BBz-EGFRt CAR. The cell line Karpas 299 (ALCL) was used as tumor model. Cytotoxicity assay was performed at 24 hours and the tumor cell death was detected by luminiscence. Mice were injected with Karpas 299 tumor cells (2x10^6 cells/mice; iv) and were treated with CD30-CAR TSCM (1x10^7 cells/mice; iv) when the tumor was established (day 10). Mice were followed daily for survival. The presence of CD30-CAR TSCM in lymphoid organs and their expression of immune checkpoint molecules (i.e., TIM-3, LAG-3) were analyzed at the end of the in vivo study by flow cytometry. TSCM were the most prevalent T-cell subset at day 10 of culture (84±3.1% of total cells), and the CD30-CAR expression was 82.8±1.0% in CD4+ TSCM and 85.2±2.0% in CD8+ TSCM. Although CD30 protein was detected in a fraction of activated T-cells in culture, CD30-CAR TSCM could be expanded ex vivo (CD4+ CD30-CAR TSCM: 96.0±3.2 fold expansion; CD8+ CD30-CAR TSCM: 109.0±4.2 fold expansion). CD30-CAR TSCM conferred specific cytolytic activity against Karpas 299 cells in vitro (tumor cell death 5:1 (effector:target) ratio: 70.2±5.1% vs. 0% with untransduced TSCM; p<0.001), which was not blockade by soluble CD30 protein. CD30-CAR TSCM were able to eliminate T-cell lymphoma in vivo (60% survival vs 0% control; p=0.001). In addition, CD30-CAR T-cells (>80% of detected CD4+ and CD8+ T-cells) were still present in lymphoid organs (bone marrow, spleen and lymph nodes) of surviving mice at 50 days after infusion. Tumor-bearing mice also showed CD30-CAR T-cells in their lymphoid organs (80% of total CD4+ and CD8+ T-cells) and in the tumor (67.5% of detected T-cells). Interestingly, a high expression of exhaustion markers TIM-3 (74%±6.8%) and LAG-3 (34%±9.7%) were found on those tumor-infiltrating lymphocytes (TILs). Collectively, our data demonstrate that TSCM cells can be efficiently transduced and ex vivo expanded with a novel CD30-CAR and confer potent antitumor efficacy against CD30+ PTCL in vitro and in vivo, with a potential improvement of the therapy using an immune checkpoint blockade for either TIM-3 or LAG-3. Our findings suggest the potential to improve outcome of patients with CD30+ PTCL through adoptive therapy with CD30-CAR modified T-cells. Citation Format: Laura Escribà-Garcia, Carmen Alvarez-Fernández, Ana Carolina Caballero, Rydzek Julian, Einsele Hermann, Jorge Sierra, Michael Hudecek, Javier Briones. Memory stem T-cells expressing an optimized CD30-specific chimeric antigen receptor (CAR) efficiently eradicate peripheral T-cell lymphoma in vivo [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A028.

Phase II Trial of CH5424802 (alectinib hydrochloride) for Recurrent or Refractory ALK-Positive Anaplastic Large Cell Lymphoma

Introduction: Anthracycline-based combination chemotherapy is a standard first-line treatment for anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) both in adults and children, which results in favorable clinical outcomes. However, a standard therapy has not been established for recurrent or refractory diseases. Because many treatment options, such as hematopoietic stem cell transplantation, are available, patients with diseases that are resistant to conventional chemotherapies have particularly poor prognosis. Brentuximab vedotin, an anti-CD30 antibody drug conjugate, has improved the prognosis of recurrent or refractory ALCL; however, other types of novel agents have not yet been investigated. ALK inhibition could be a promising therapeutic strategy for ALK-positive malignancies. Therefore, this study aimed to determine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with recurrent or refractory ALK-positive ALCL.Methods: In this open-label, phase II trial, patients with recurrent or refractory ALK-positive ALCL diagnosed by histological examination were eligible. Other major inclusion criteria were as follows: age >6 years, ECOG performance status 0-2, at least one measurable lesion, and preserved organ functions. Alectinib 300 mg was administered orally twice a day (600 mg/day). Patients who weighed <35 kg were administered reduced doses of alectinib, i.e., 150 mg twice a day (300 mg/day). The primary endpoint was the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints were pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events (AEs). All patients who received at least one dose of alectinib were evaluated for responses and toxicities. We expected that a response rate of 85% and a statistical power of 79% could be obtained for 10 patients with an alpha level of 0.05 (one tailed). This study is registered in UMIN-CTR (UMIN 000016991).Results: Ten patients were enrolled in the study from May 2015 to November 2017. The median age was 19.5 (range, 6-70) years. Of 10 patients, 8 were administered alectinib 600 mg/day and 2 were administered with 300 mg/day. Objective tumor responses were documented in 8 of 10 patients (80%; 90% confidence interval: 56.2-95.9), with CR in 6 and PR in 2 according to the independent review committee. Two patients underwent stem cell transplantation after alectinib treatment. Five patients continued to take alectinib at the data cut-off. One-year overall survival and progression-free survival rates were 70.0% and 58.3% (Fig), respectively. Three patients died owing to disease progression. A severe AE was observed in 1 patient (grade 3 acute pharyngitis). Grade 4 AEs were observed in 1 patient (neutropenia). Common AEs observed were diarrhea in 2 patients, upper respiratory infection in 3, elevated alkaline phosphatase in 3, and maculopapular rash in 4. No unexpected AEs were experienced. The mean steady state peak concentration of alectinib was 479.5, 676.7, and 391.1 ng/mL in patients aged <15 years administered 300 mg/day, those aged <15 years admisnitered 600 mg/day, and those aged >15 years administered 600 mg/day, respectively. The mean time to reach the peak concentrations was 4, 4, and 5 h, respectively.Conclusion: Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who progressed on standard chemotherapy. This study demonstrated similar pharmacokinetic profiles between pediatric and adult patients. Therefore, alectinib could be a suitable treatment for both pediatric and adult patients with recurrent or refractory ALK-positive ALCL. [Display omitted] DisclosuresSekimizu:Eli Lilly and Company: Speakers Bureau. Kada:Bayer Yakuhin, Ltd: Membership on an entity's Board of Directors or advisory committees. Nagai:HUYA Bioscience International: Research Funding; Bayer Yakuhin Ltd.: Research Funding; Esai Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Roche Ltd.: Honoraria; SymBio Pharmaceuticals Limited: Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi K. K.: Honoraria; Mundipharma K.K.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Abbvie G. K.: Research Funding.

A Phase II Study of Brentuximab Vedotin Plus Adriamycin and Dacarbazine without Radiation in Non-Bulky Limited Stage Classical Hodgkin Lymphoma

BACKGROUNDABVD with or without radiation is standard therapy for limited stage HL, but carries risks of bleomycin-lung injury and radiation toxicity. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate which is highly active in relapsed classical HL. We previously combined BV with AVD in limited stage non-bulky classical HL which resulted in a high CR rate, but at the cost of increased neutropenia, neutropenic fever, and neuropathy, likely related to the overlapping toxicity profile with vinblastine. Similar toxicity findings were also observed with BV-AVD in advanced stage classical Hodgkin lymphoma. We therefore evaluated BV plus AD (BV-AD) without radiation therapy for non-bulky stage I-II classical HL with the goal of reducing toxicity and maintaining high rates of inducing CR. METHODSThis is a multicenter single arm open label phase 2 study. Patients received BV 1.2 mg/kg plus standard dose adriamycin and dacarbazine on days 1 and 15 of each 28 day cycle. GCSF prophylaxis was not included. Patients received 4 or 6 cycles of BV-AD based on the results of an interim PETCT scan performed following cycle 2. PET negativity was defined as Deauville scores 1-3. Patients in CR on interim PETCT received 4 total cycles of therapy; patients in PR completed 6 cycles. The primary endpoint is complete response rate (CRR) at end of treatment. A sample size of 34 was required to detect an end of treatment CRR of 95% with 91% power and alpha error of 0.09. RESULTS34 patients were enrolled. Median age is 36 (range 18-63). Stage is IA (3), IB (1), IIA (29) and IIB (1). Risk is classified per the GHSG criteria as early unfavorable in 47%, and favorable in 53%. The interim CR rate is 94%. Accordingly, 32 interim PET negative patients (94%) received 4 total cycles of therapy, and 2 interim PET positive patients (6%) received 6 total cycles of therapy. No patients received consolidative radiation therapy, per protocol. The primary endpoint of end of treatment CR rate is 100%. At a median follow-up of 15 months, the FFS, PFS and OS are all 100%. The most common adverse events of any grade are nausea (79%), peripheral sensory neuropathy (56%), fatigue (50%), constipation (38%), alopecia (35%) and neutropenia (24%). Most toxicities were low grade, with only 15% of subjects experiencing any grade 3 toxicity, and there were no grade 4 or 5 toxicities. Specifically, 2 patients had grade 3 neutropenia, and 1 patient each had grade 3 nausea/vomiting, pneumonia and thromboembolic event. Peripheral sensory neuropathy was grade 1 in 17 patients, and grade 2 in 2 patients. There were no cases of neutropenic fever. CONCLUSIONSBV-AD for 4-6 cycles induces high interim and end of treatment CR rates of 94% and 100%, respectively, allowing 4 total cycles of therapy in most patients. The PFS, FFS and OS are all 100% at last follow up. Toxicity appears mild and notable for a low incidence of neutropenia, alopecia, and moderate peripheral neuropathy. This promising regimen avoids bleomycin, vinblastine, radiation and primary GCSF prophylaxis with resultant low toxicity and preserved high efficacy rates in patients with early favorable and early unfavorable non-bulky limited stage classical Hodgkin lymphoma. Follow up for this trial is ongoing. [Display omitted] DisclosuresAbramson:Merck: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board.

Resistance to Inotuzumab Ozogamicin in a B-ALL Patient with TET2 and DNMT3A Mutations and Myeloid Lineage Switch

Background: Immunologic therapies targeting lineage-specific antigens such as CD22 and CD19 can improve outcome in patients with B cell acute lymphoblastic leukemia (B-ALL). The presence of mixed lineage leukemia (MLL) gene rearrangements highlights a subset of B-ALL patients with increased risk of treatment failure after inotuzumab ozogamicin (INO), an anti-CD22 antibody-drug conjugate. In some MLL-rearranged cases, a switch of hematopoietic lineage from B-ALL to acute myeloid leukemia (AML), has been associated with resistance to lymphoid-targeted therapies. In AML, founder clones harboring mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) can persist during remission as reservoirs of treatment resistance. We therefore hypothesized that B-ALL can arise in the setting of a founding CHIP clone and undergo lineage switch under the selection pressure of B cell restricted therapy.Case Description: A 65-year-old female presented with two weeks of easy bruising, fatigue, and 54% circulating blasts. Flow cytometry was consistent with B-ALL that was positive for CD19, CD22, and aberrant CD15. Cytogenetics confirmed the presence of a t(4;11) (q21;q23) MLL rearrangement. The patient received intensive induction with dose-adjusted Larson regimen and morphologic complete remission was confirmed on Day 36. No residual disease was detectable by multiparametric flow cytometry. During consolidation (Day 136), a relapse of CD19+ CD22+ B-ALL was observed in the blood and marrow and treatment with INO was initiated. Despite rapid initial clearance of circulating disease, peripheral blasts were again observed on Day 167. At this time, flow cytometry demonstrated myeloblasts (positive for CD13, CD33, and CD117, but negative for CD19 and CD22), with no evidence of the previous lymphoblast population. The AML was refractory to multiagent salvage chemotherapy.Results: We evaluated the lineage-specificity and clonal dynamics of somatic genetic alterations using targeted gene panel sequencing at 5 timepoints during the course of treatment, compared to results from cytogenetic analysis and flow cytometry. At the time of initial diagnostic evaluation, we identified somatic mutations in DNMT3A (p.Q696*) and TET2 (p.L1209P). Variant allele fractions (VAFs) were 44% and 48%, respectively, suggesting they were both present at high abundance in the leukemic clone.TET2 and DNMT3A mutations are most commonly found in individuals with myeloid neoplasms and CHIP and are not frequently observed in those with B-ALL. We therefore asked whether these mutations preceded the MLL rearrangement in the leukemia clonal hierarchy by comparing their abundance at diagnosis to their abundance during MRD-negative clinical remission. We observed persistence of the DNMT3A (VAF = 13% and 10%) and TET2 (VAF = 8% and 6%) mutations during remission (Day 39, Day 82), while the MLL rearrangement was undetectable at both remission timepoints.We next evaluated the clonal relationship between the myeloid relapse after INO treatment and the initial B-ALL. In the AML phase, we again observed DNMT3A and TET2 mutations at high VAFs (>40%), as well as a PTPN11 p.A72T mutation (VAF 15%) and tetrasomy 8 that were undetectable at prior timepoints. A new TP53 p.R249T mutation was detected at the time of clinical progression after salvage chemotherapy, despite clearance of the PTPN11 mutated subclone. Cytogenetic analysis at diagnosis, first relapse, and second relapse confirmed MLL rearrangement t(4;11)(q21;q23).Conclusion: These results provide molecular evidence that primordial founder clones may persist during clinical remissions in MLL-rearranged leukemia and enable lineage switching upon relapse. More broadly, this case suggests that somatic mutations found in CHIP and other potentially pre-neoplastic states could confer increased risk of clonal escape from lineage-restricted therapies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: A Subgroup Analysis from the Phase 3 Echelon-1 Study

Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: A Subgroup Analysis from the Phase 3 Echelon-1 Study

Chemoimmunotherapy with Inotuzumab Ozogamicin Combined with Mini-Hyper-CVD, with or without Blinatumomab, for Newly Diagnosed Older Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: Results from a Phase II Study

Chemoimmunotherapy with Inotuzumab Ozogamicin Combined with Mini-Hyper-CVD, with or without Blinatumomab, for Newly Diagnosed Older Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: Results from a Phase II Study

Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Inotuzumab ozogamicin for the treatment of acute lymphoblastic leukemia.

Therapy for adult acute lymphoblastic leukemia (ALL) with multiagent cytotoxic chemotherapy has not been as successful as that for pediatric patients. The advent of targeted monoclonal antibodies against common cell surface antigens (i.e. CD19, CD20, and CD22) has resulted in improved outcomes without additional toxicities. Inotuzumab ozogamicin is an anti-CD22 antibody–drug conjugate approved for the treatment of relapsed or refractory B-cell precursor ALL. It improved outcomes compared with standard salvage chemotherapy. Its combination with low-intensity chemotherapy in the relapse setting and in frontline elderly patients is promising.

Outcome of patients with relapsed or refractory anaplastic large cell lymphoma who have failed brentuximab vedotin.

Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate that is highly effective in patients with relapsed/refractory anaplastic large cell lymphoma (ALCL). However, survival outcomes following suboptimal response or subsequent relapse are not well known. We conducted a multicenter study analyzing outcomes of patients with relapsed/refractory ALCL who have received BV with a secondary focus on survival after progression following BV. A total of 56 patients were treated with BV for relapsed or refractory ALCL. The overall response rate to BV was 73% with complete response (CR) rate of 46%. The median failure-free survival and overall survival (OS) after BV were 15.5month and not reached, respectively. The median duration of response was 27.6months in patients who achieved CR by BV, while the median OS of those who did not achieve CR by BV was 9.5months. There was no significant difference in OS between those who underwent stem cell transplant (SCT) and those who did not in patients who achieved CR after BV. However, if patients were in PR after BV, SCT was associated with significantly longer OS. Thirty patients experienced progressive disease on BV or required a subsequent treatment. The median OS after BV failure was 2.9months with 2-year OS of 27.1%. There were seven long-term survivors (≥12months) following failure. After an adequate response to subsequent salvage therapy, five patients underwent subsequent SCT (three allogeneic and two autologous), four of which were long-term survivors (17+, 25+, 32+, and 50+ months). In conclusion, BV failure is associated with a poor outcome in patients with ALCL, which defines a small but important group with unmet need. SCT may have benefit in patients with relapsed/refractory ALCL who failed BV.

Updated combined analysis of two phase II studies of brentuximab vedotin in patients with mycosis fungoides and Sézary syndrome

Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate with activity against mycosis fungoides (MF) and Sézary syndrome (SS). We pooled the updated data of 2 open-label single-arm phase II BV trials in relapsed/refractory MF/SS patients with a spectrum of CD30 expression (0-100% by skin IHC) with the aim to analyze the clinical activity profile in a larger combined cohort. We defined ORR4, ORR6, and ORR12 as objective responses lasting at least 4, 6, 12 months respectively, without initiation of new therapy or PD. MSWAT90 (near CR/CR) was defined as >90% reduction in mSWAT. The two trials had similar study design. Seventy-four patients (MDACC 38, Stanford 36) were included with 92% MF; 14 (19%) stage IB/IIA, 60 (81%) advanced stage (34 IIB, 25 IV); 53% LCT, 42% F-MF; median prior systemic treatments 3. ORR was 57% (42/74) with median time to response of 9 (4–40) weeks. The ORR4 was 49% (36/74), ORR6, 32% (24/74), and ORR12 12% (9/74). Greater improvement in mSWAT was observed in patients with ORR4, ORR6 and ORR12. Although the CR rate was only 5%, the mSWAT90 was 30% (21/74) and was associated with ORR4 and ORR6, p < 0.0001 and p = 0.0001 respectively. While patients with CD30 status at screening >5% had higher ORR, a notable response was still observed in those with <5% expression (63% vs 46%) (p = 0.17). Median time to next systemic treatment (TTNT) of n = 74 was 41 weeks with no significant difference observed by CD30 status >5% vs <5%, p = 0.68. At 1 and 3 years, KM estimates for PFS showed 58% and 23%. The most common related adverse events were peripheral neuropathy 65% (23% G 1, 39% G 2, 3% G 3/4), fatigue 36%, nausea 28%, alopecia 22%, neutropenia 20%, and rash 22%. BV demonstrates high ORR in patients with relapsed/refractory MF/SS with many patients achieving near CR+CR (mSWAT90) in the skin and durable responses. Notable clinical activity was observed in patients with very low CD30 expression levels.

Brentuximab vedotin in Hodgkin lymphoma and anaplastic large-cell lymphoma: an evidence-based review.

Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) account for ~10% and 2%–3% of all cases of lymphoid neoplasms, respectively. Up to 30% of patients with HL are refractory or relapse after first-line therapy, and elderly patients with HL represent a subgroup of patients with suboptimal responses to the currently available treatments. Five-year overall survival for ALCL patients is 50%–80% with conventional chemotherapy. Therefore, new therapeutic approaches are needed for these groups of patients. Brentuximab vedotin is a chimeric IgG1 anti-CD30 antibody–drug conjugate that has all the features that are necessary to make a substantive difference with the standard therapies in patients with HL and ALCL: a novel mechanism of action, single-agent activity, non-cross-resistance, and safety both in the relapsed-refractory and in the front-line setting. This review provides an update of the results of the most relevant clinical trials including brentuximab vedotin for patients with HL and ALCL conducted to date.

Abstract 835: TRPH-222, a novel anti-CD22 antibody drug conjugate (ADC), has significant anti-tumor activity in NHL xenografts and reduces B cells in monkeys

Abstract CD22 is a cell surface protein with expression restricted to mature B lineage cells. It is highly expressed on a wide range of B cell malignancies including NHL (non-Hodgkin's lymphoma), DLBCL (diffuse large B cell lymphoma), follicular lymphoma and MCL (mantle cell lymphoma). CD22 is a clinically validated target for an antibody-drug conjugate (ADC) with approval in B cell acute lymphoblastic leukemia (B-ALL). In contrast, in NHL CD22 targeted ADCs have been limited clinically due to a poor therapeutic index. Subsequently the ADC field has focused on stable and site-specific conjugation of payloads for increased therapeutic index. TRPH-222 comprises an anti-CD22 antibody site-specifically modified at one site per heavy chain to express formylglycine (FG), allowing site-specific conjugation of a maytansinoid payload, a protease-insensitive spacer, and a functional group for coupling to an aldehyde on antibody FG residues. This SMARTAG™ site specific non-cleavable conjugation enforces a maximum drug to antibody ratio (DAR) of 2 with high stability enabling an improved therapeutic index. Studies described here characterize the anti-tumor activity of TRPH-222 in human NHL xenograft models and evaluate the pharmacodynamic effects in peripheral B cells. In WSU-DLCL2 xenografts once weekly intravenous (IV) dosing with either 3 or 10 mg/kg TRPH-222 reduced tumor volume by 100% after 28 days, as did a once every three-week 10mg/kg dose. In SU-DHL-2 and SU-DHL-4 xenograft models, TRPH-222 resulted in dose- and schedule-dependent anti-tumor activity with 91% and 100% tumor growth inhibition respectively at 10 mg/kg once weekly dosing. In the Granta-519 xenograft model, weekly 10 mg/kg dosing resulted in 87% tumor growth inhibition and also significantly inhibited tumor growth following escape from R-CHOP. Cross-species assessment of TRPH-222 binding revealed that TRPH-222 bound to immobilized human but not rat CD22. Similarly, TRPH-222 bound strongly to human and monkey peripheral B cells whereas no binding was observed to rat B cells. The pharmacodynamic effects of TRPH-222 on circulating rat and monkey B cell levels were evaluated following either a single (rat) or repeat (monkey) IV doses of TRPH-222 up to either 60 mg/kg or 50mg/kg respectively. In rats, TRPH-222 did not result in a reduction in absolute B cell numbers in any of the treatment groups. In contrast, B cells in cynomolgus monkey were reduced up to 70% from baseline in peripheral blood at all doses evaluated. In conclusion, the studies reported here demonstrate that TRPH-222 has significant anti-tumor activity in all NHL lymphoma models tested and has activity following R-CHOP escape. TRPH-222 demonstrated a CD22-mediated pharmacodynamic effect in monkeys that was consistent with target binding. IND-enabling safety studies are currently ongoing with TRPH-222 to support clinical development in 2018. Citation Format: Ann P. Maclaren, Nancy Levin, Henry Lowman. TRPH-222, a novel anti-CD22 antibody drug conjugate (ADC), has significant anti-tumor activity in NHL xenografts and reduces B cells in monkeys [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 835.

Abstract 2853: Development of novel preclinical models of secondary resistance to the anti-CD37 antibody drug conjugate (ADC) IMGN529/DEBIO1562 in diffuse large B-cell lymphoma (DLBCL)

Abstract Background: CD37 is a membrane protein expressed almost exclusively in cells of the immune system (Bertoni &amp; Stathis, Blood 2016). The IMGN529/DEBIO1562 ADC consists of an anti-CD37 antibody conjugated via a thioether-based linker to the cytotoxic anti-microtubule agent maytansinoid DM1. IMGN529/DEBIO1562 has shown preclinical (Deckert et al., Blood 2013; Gaudio et al., ASH 2016) and clinical antilymphoma activity (Stathis et al., ASH 2014). A better understanding of the resistance mechanisms could lead to rational combination strategies to prevent development of resistance and enhance efficacy. Hence, we generated DLBCL cell lines with secondary resistance to IMGN529/DEBIO1562. Materials and Methods: IMGN529/DEBIO1562 resistance was generated through chronic treatment of cell lines for over 6 months. Proliferation of acquired stable resistance was tested by MTT assay (72 hrs) in resistant and parental cells after 2 weeks of drug-free culture. Multidrug resistance phenotype (MDR1 expression by real-time PCR) was ruled out. Resistant and parental cells underwent transcriptome profiling by RNA-seq and whole-exome sequencing (WES). CD37 surface expression was determined by FACS. Results: The activate B-cell like SU-DHL-2 and the germinal center B-cell type SU-DHL-4 DLBCL cell lines were exposed to increasing concentrations of IMGN529/DEBIO1562 starting from IC50s for several months until they acquired resistance to the compound. Two SU-DHL-2 and 2 SU-DHL-4 resistant cell lines were obtained. In parallel, both cell lines were cultured upon the same conditions with no drug exposure (parental). SU-DHL-2 and SU-DHL-4 resistant lines showed IC50s that were approximately 10-fold higher than parental counterpart while maintaining a sensitivity similar to parental cells when exposed to the free DM1 toxin. CD37 expression was lost at both protein and mRNA levels in SU-DHL-2 resistant cells, and this appeared due to an homozygous deletion affecting the CD37 gene locus at 19q13.33, as identified by WES. CD37 loss was also associated to changes of the recently described CD37 signatures in DLBCL patients (Xu-Monette et al., Blood 2016). Besides the CD37 gene loss, the populations of resistant SU-DHL-2 cells shared 25 somatic mutations in genes coding for extracellular matrix components, protein kinases and transcription factors. The SU-DHL-4 resistant cells, which did not lose CD37 expression, harbored 48 shared mutations affecting kinases, cytokines, transcription factors and oncogenes and were enriched in specific pathways at RNA-seq. Conclusions: We presented two novel DLBCL models of secondary resistance to the anti-CD37 ADC IMGN529/DEBIO1562. These models, apparently driven by different biologic processes, will help in clarifying mechanisms of resistance to the drug and developing combination therapeutic approaches. Citation Format: Alberto J. Arribas, Luciano Cascione, Luca Aresu, Eugenio Gaudio, Andrea Rinaldi, Chiara Tarantelli, Murodzhon Akhmedov, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Francesco Bertoni. Development of novel preclinical models of secondary resistance to the anti-CD37 antibody drug conjugate (ADC) IMGN529/DEBIO1562 in diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2853.