Refractory Anaplastic Large Cell Lymphoma Research Articles

Podcast on Emerging Treatment Options for Pediatric Patients with ALK-Positive Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumors.

Anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) are rare cancers observed predominantly in children and young adults. ALCL accounts for 10-15% of all pediatric non-Hodgkin lymphomas and is commonly diagnosed at an advanced stage of disease. In children, 84-91% of cases of ALCL harbor an anaplastic lymphoma kinase (ALK) gene translocation. IMT is a rare mesenchymal neoplasm that also tends to occur in children and adolescents. Approximately 50-70% of IMT cases involve rearrangements in the ALK gene. A combination of chemotherapeutic drugs is typically used for children with ALK-positive ALCL, and the only known curative therapy for ALK-positive IMT is complete surgical resection. Crizotinib, a first-generation ALK inhibitor, was approved in the USA in 2021 for pediatric patients and young adults with relapsed or refractory ALK-positive ALCL; however, its safety and efficacy have not been established in older adults. In 2022, crizotinib was approved for adult and pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT. This podcast provides an overview of ALK-positive ALCL and IMT. We discuss the current treatment landscape, the role of ALK tyrosine kinase inhibitors, and areas of future research.

Strategy for Pediatric Patients with Relapsed or Refractory Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma: A Review.

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody-drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL.

Characteristics and Outcomes of Chinese Children With Advanced Stage Anaplastic Large Cell Lymphoma: A Single-Center Experience.

PurposeTo evaluate the clinical characteristics and treatment outcomes of Chinese children with advanced stage anaplastic large cell lymphoma (ALCL) who were treated with the low-intensity APO regimen.MethodsClinical data from children newly diagnosed with advanced stage ALCL and treated with the APO regimen were reviewed.ResultsAltogether 22 eligible patients with advanced stage ALCL were recruited in this study. 18 (81%) patients achieved complete response (CR) after the initial induction, and 4 experienced relapse. Among patients with relapsed or refractory ALCL, CR was achieved in 3 (50%) who received the BFM95 R3/R4 regimen. Besides, 2 patients received the targeted therapy with crizotinib and were still alive. The 5-year OS and EFS rates were 82 ± 8.7% and 68.2 ± 9.4%%, respectively. According to our results, the elevated LDH level and bone marrow involvement were identified as the poor prognostic factors for EFS (p=0.035 and 0.048, respectively). During APO treatment, only 23% patients experienced grade 3-4 hematologic toxicity.ConclusionsIn this study, bone marrow involvement and elevated serum LDH levels were identified as the poor prognostic factors for EFS. In resource-limited regions, patients with advanced stage ALCL can also achieve comparable outcomes to those in high-income regions, and the BFM95 R3/R4 regimen can take the role of salvage treatment for patients with relapsed or refractory disease. Nonetheless, new therapeutic strategy is still needed.

Abstract ED01-02: Successes and failures of targeted drug development in pediatric tumors

Abstract Eighty percent of children diagnosed with cancer are cured with multimodality therapy including cytotoxic chemotherapy. However, up to 40% of survivors of childhood cancer have at least one serious chronic medical condition as a consequence of curative therapy. Thus, patients, families, clinicians, researchers, and regulatory agencies enthusiastically endorse the development of targeted therapy to improve survival, decrease life threatening acute toxicity, and late effects of therapy for childhood cancer. Genomic characterization demonstrates that the tumor mutational burden in childhood cancers is low. For children with cancer a small number of drugs, such as NTRK inhibitors have had major unequivocal successes including initial regulatory approvals that include specific dosing in children. Other molecularly targeted drugs have achieved moderate success, however, many have failed despite strong pre-clinical rationale. As of June 2019, 25 drugs have been FDA approved for use in children with cancer including five tyrosine kinase inhibitors (3 BCR-ABL inhibitors and 2 NTRK inhibitors), and one mTOR inhibitor. A single drug, dinutuximab, was approved for a pediatric specific indication in high-risk neuroblastoma. This parallels recent European Medicines Agency authorizations that include indications for treating childhood cancer in 10 of 177 anti-cancer drug approvals. Similar to adults, the era of targeted therapies in children with cancer began with imatinib. Drugs targeting BCR-ABL in chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) in children include imatinib, dasatinib, and nilotinib. Point mutations in the kinase domain of the BCR-ABL fusion protein result in resistance to imatinib. Dasatinib, nilotinib, and ponatinib were developed to overcome resistance. Each has a specific role in caring for children with CML or Ph+ ALL. Ph-like ALL, a high-risk acute leukemia in children and young adults, is characterized by genomic alterations and activation of signaling pathways including JAK/STAT, amenable to inhibition tyrosine kinase inhibitors. The landmark age and histology agnostic global approval of larotrectinib and entrectinib was based on durable objective responses in patients with tumors harboring NTRK fusions enrolled on early phase clinical trials. Larotrectinib has produced dramatic objective responses in children and adults with cancer harboring NTRK fusions including a very rare cancer, infantile fibrosarcoma which is NTRK fusion positive in at least 95% cases. In addition to potent inhibition NTRK fusions, initial clinical trials of larotrectinib included adults and children as well as a pediatric appropriate formulation. Children with brain tumors harboring NTRK1,2,3 or ROS1 fusions have had rapid, durable objective responses to entrectinib. MAP kinase pathway aberrations occur in childhood cancer including rhabdomyosarcoma and brain tumors. Everolimus is approved for patients with subependymal giant cell astrocytoma. Dabrafenib and vemurafenib have produced durable objective responses in patients with pediatric low-grade glioma harboring BRAF V600E mutations. Selumetinib has been FDA approved for the treatment of plexiform neurofibromas in children with neurofibromatosis type 1 and may have activity in children and adolescents with solid tumors harboring MAP kinase aberrations. Overall, the success of MAP kinase inhibition in children with cancer has been modest, leading to consideration for combinatorial approaches. Crizotinib is approved for the treatment of ALK-positive metastatic NSCLC and has activity in children with refractory Anaplastic Large Cell Lymphoma (ALCL) and inflammatory myofibroblastic tumors, both associated with ALK fusions. Trials are ongoing to determine the activity of crizotinib and other ALK inhibitors in children with neuroblastoma with known translocations, mutations or amplifications in the ALK gene. Clinical trials of multi-targeted kinase inhibitors including cabozantinib, regorafenib, sorafenib and vandetanib have demonstrated activity in a variety of solid tumors. Clinical trials of these agents have been based on mechanistic rationale and pre-clinical evaluation rather than biomarker selection. Through large scale genomic sequencing efforts in the US and Europe actionable molecular alterations including mutations, amplifications and fusions have been identified in a variety of childhood cancers. Compared to cancers in adults, these molecular aberrations occur less frequently in most cancers in children. However, due to dramatic objective responses and the potential for improved response with decreased toxicity, efforts to evaluate and incorporate targeted agents into multimodality therapy for children with cancer remains a major focus. To date, multi-targeted kinase inhibitors and drugs that target fusion oncoproteins that are histology-agnostic oncogenic drivers in cancers that occur in both child and adults have been most successful. Understanding the characteristics of successful target- drug pairs is critically important to the prioritization of new drugs and clinical trials in children as well as the development of new therapies for pediatric specific targets. Citation Format: Elizabeth Fox. Successes and failures of targeted drug development in pediatric tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr ED01-02. doi:10.1158/1535-7163.TARG-19-ED01-02

Successful outcome with reduced-intensity condition regimen followed by allogeneic hematopoietic stem cell transplantation for relapsed or refractory anaplastic large-cell lymphoma.

We report a retrospective analysis of 38 patients (age ≤ 30years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72months (range, 35-96months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.

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.

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.

Phase I clinical study of brentuximab vedotin (SGN-35) involving children with recurrent or refractory CD30-positive Hodgkin\u2019s lymphoma or systemic anaplastic large cell lymphoma: rationale, design and methods of BV-HLALCL study: study protocol

BackgroundHodgkin’s lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) are the two most common tumors expressing CD30. Internationally, a clinical study that is being conducted involving adults with recurrent or refractory HL or ALCL suggests efficacy of brentuximab vedotin (SGN-35). Pediatric patients should be given medicines that have been appropriately evaluated for their use. In the past, however, new approved drugs have been used for pediatric patients without the confirmation of safety and efficacy in pediatric patients. Therefore, it is important to examine the safety and efficacy of SGN-35 in Japanese children.MethodsPhase I clinical study of SGN-35 involving children with recurrent or refractory CD30-positive Hodgkin’s lymphoma or systemic anaplastic large cell lymphoma (BV-HLALCL study) is being conducted for pediatric patients in order to evaluate the safety, feasibility and preliminary clinical effectiveness of brentuximab vedotin. SGN-35 is intravenously administered on Day 1 of each cycle (21 days/cycle). The dose of SGN-35 is calculated based on the body weight at the baseline. The primary endpoint is dose limiting toxicity and incidence of adverse events. The secondary endpoints are pharmacokinetics, response rate, complete remission rate, response duration, progression-free survival and event-free survival. The reduction rate of tumor will be calculated according to revised response criteria for malignant lymphoma for measurable tumor. Six pediatric patients will be enrolled in this study.DiscussionThis study aims to expand indication of SGN-35 in Japan by assessing its safety and efficacy in pediatric patients.Trial registrationJMACCT ID: JMA-IIA00229. Registered on 17 Nov 2015.

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

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

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

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

ALK kinase domain mutations in primary anaplastic large cell lymphoma: consequences on NPM-ALK activity and sensitivity to tyrosine kinase inhibitors.

ALK inhibitor crizotinib has shown potent antitumor activity in children with refractory Anaplastic Large Cell Lymphoma (ALCL) and the opportunity to include ALK inhibitors in first-line therapies is oncoming. However, recent studies suggest that crizotinib-resistance mutations may emerge in ALCL patients. In the present study, we analyzed ALK kinase domain mutational status of 36 paediatric ALCL patients at diagnosis to identify point mutations and gene aberrations that could impact on NPM-ALK gene expression, activity and sensitivity to small-molecule inhibitors. Amplicon ultra-deep sequencing of ALK kinase domain detected 2 single point mutations, R335Q and R291Q, in 2 cases, 2 common deletions of exon 23 and 25 in all the patients, and 7 splicing-related INDELs in a variable number of them. The functional impact of missense mutations and INDELs was evaluated. Point mutations were shown to affect protein kinase activity, signalling output and drug sensitivity. INDELs, instead, generated kinase-dead variants with dominant negative effect on NPM-ALK kinase, in virtue of their capacity of forming non-functional heterocomplexes. Consistently, when co-expressed, INDELs increased crizotinib inhibitory activity on NPM-ALK signal processing, as demonstrated by the significant reduction of STAT3 phosphorylation. Functional changes in ALK kinase activity induced by both point mutations and structural rearrangements were resolved by molecular modelling and dynamic simulation analysis, providing novel insights into ALK kinase domain folding and regulation. Therefore, these data suggest that NPM-ALK pre-therapeutic mutations may be found at low frequency in ALCL patients. These mutations occur randomly within the ALK kinase domain and affect protein activity, while preserving responsiveness to crizotinib.

New Therapies in T-cell Lymphoma

T-cell lymphomas represent 10–12% of all patients with non-Hodgkin lymphoma (NHL) in the Western world. When cutaneous T-cell lymphoma (CTCL) is excluded, peripheral T-cell lymphoma—not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL) represent the overwhelming majority of patients in this population. These diseases remain a great challenge to treat. They are characterized by an aggressive presentation, extranodal disease, paraneoplastic phenomena, and resistance to standard chemotherapeutics. With the rapid development of new molecular gene profiling techniques, it is highly likely that these diseases will be subclassified by molecular abnormalities in the future. An evolving understanding of the tumor molecular pathogenesis will undoubtedly lead to further novel targeted therapies. Immunoconjugates, such as brentuximab vedotin (BV), have provided outstanding responses in relapsed, refractory CD30-positive ALCL. Histone deacetylase (HDAC) inhibitors have shown activity in PTCL and are potentially synergistic with proteasome inhibitors. Denileukin diftitox is an interesting recombinant DNA fusion protein linking fragments of the diphtheria toxin to interleukin-2 (IL-2) that is tested in clinical trials. Crizotinib, a highly specific anaplastic lymphoma kinase (ALK) inhibitor, has shown great promise in small number of patients with ALK-positive ALCL; the future of patients with this disorder looks very promising. Biomarker-driven chemotherapeutics is becoming a critical part of the state-of-the-art treatment in early- and late-phase clinical trials. It is crucial that future trials include sensible biomarker-based designs when future treatments are used in these challenging disorders.

Crizotinib as Salvage and Maintenance With Allogeneic Stem Cell Transplantation for Refractory Anaplastic Large Cell Lymphoma

The NPM-ALK fusion protein is found in ALK(+) anaplastic large cell lymphomas harboring the t(2;5) chromosomal translocation. Patients harboring ALK translocations typically have an excellent prognosis with conventional chemotherapy and a reported 5-year survival rate of 70%. Although most patients with ALK(+) anaplastic large cell lymphoma have a good prognosis, some patients do not respond to standard therapies. In patients with refractory anaplastic large cell lymphoma who can achieve remission, allogeneic stem cell transplant is a potentially curative option. This article describes a patient with refractory ALK(+) anaplastic large cell lymphoma who experienced a complete response to the ALK inhibitor crizotinib and then underwent an allogeneic stem cell transplant followed by crizotinib maintenance therapy.

Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin

Despite the relative success of chemotherapy for Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), novel therapeutic agents are needed for refractory or relapsed patients. Targeted immunotherapy has emerged as a novel treatment option for these patients. Although unconjugated anti-cluster of differentiation (CD)30 antibodies showed minimal antitumor activity in early clinical trials, development of antibody–drug conjugates (ADCs) appears promising. Brentuximab vedotin is an ADC composed of an anti-CD30 antibody linked to a potent microtubule-disrupting agent monomethyl auristatin E (MMAE). It has the ability to target CD30-positive tumor cells and, once bound to CD30, brentuximab vedotin is internalized and MMAE is released to induce cell cycle arrest and apoptosis. In two Phase II trials, objective response was reported in 75% and 86% of patients with refractory or relapsed HL and systemic ALCL, respectively, with an acceptable toxicity profile. Based on these studies, the US Food and Drug Administration (FDA) granted accelerated approval of brentuximab vedotin in August 2011 for the treatment of refractory and relapsed HL and ALCL. We review the key characteristics of brentuximab vedotin, clinical data supporting its therapeutic efficacy, and current ongoing trials to explore its utility in other CD30-positive malignancies.

Pancreatitis In Patients Treated With Brentuximab Vedotin: A Previously Unrecognized Serious Adverse Event

BackgroundBrentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. MethodsFollowing a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial (NCT01476410), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. ResultsEight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in Table 1. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. ConclusionThis is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures:Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens:Seattle Genetics : Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy. Hamlin:Seattle Genetics : Consultancy, Honoraria. Coiffier:Millennium Pharmaceuticals : Consultancy. Engert:Millennium Pharmaceuticals : Consultancy. Moskowitz:Seattle Genetics : Research Funding. Ghosh:Millennium Pharmaceuticals : Membership on an entity's Board of Directors or advisory committees. Petrich:Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon:Seattle Genetics : Research Funding. Winter:Seattle Genetics : Research Funding.

Impact Of Induction Regimen and Consolidative Stem Cell Transplantation In Patients With Double Hit Lymphoma (DHL): A Large Multicenter Retrospective Analysis

▪ BackgroundDHL are high-grade B-cell lymphomas (BCL) characterized by dual gene rearrangements (RA) of MYC and either BCL2 or BCL6. Outcomes are typically dismal, particularly when treated with R-CHOP, as compared to those observed in patients (pts) with similar histologies without dual RA. Few reports have evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation (SCT). We sought to evaluate the role of intensive induction as well as SCT, and to investigate predictors of outcome in DHL. MethodsThis study was an IRB-approved retrospective analysis across 15 centers. Cases were diagnosed between 2000-2012 as aggressive BCL harboring RA, by FISH, of MYC along with RA of BCL2 and/or BCL6. Pts were treated with either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE. Survival was estimated using Kaplan Meier method, and comparisons made with log rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazard regression. ResultsOne hundred six pts were analyzed. Median age at diagnosis was 60; 59% were male. The majority had DHL characterized by RA of MYC and BCL2 (77%); the remainder showed RA of MYC and BCL6 (10%), or all three (12%). History of indolent lymphoma was present in 29 pts (27%). The most common histology was DLBCL in 56 pts (53%), followed by BCL unclassifiable (BCLU) in 45 (42%), and Burkitt-like in 5 (5%). Thirty six pts (33%) received R-CHOP, 33 (31%) R-EPOCH, and 28 (36%) R-Hyper-CVAD or CODOX-M/IVAC. Fourteen pts (13%) were consolidated with SCT (n=1 allo and n=13 auto SCT); all were treated with intensive induction. Three additional pts underwent SCT in partial remission or progressive disease following R-CHOP induction. The median PFS and OS for the entire cohort were 8.8 mo and 12 mo, respectively (Table 1); of the 24 pts (23%) alive and without progression, median follow-up was 19 mo. R-EPOCH was superior in achieving complete response (CR) compared with R-CHOP (P 0.01), and trended towards significance compared with pts receiving other intensive induction (P 0.07). Additionally, primary refractory disease, observed in 37 pts (34.5%), occurred less frequently in pts receiving R-EPOCH compared to R-CHOP (P .005) or other intensive regimens (P 0.03); induction regimen did not impact OS in patients not receiving SCT (P 0.7; Fig 1). SCT in first remission was associated with improved OS (P 0.02), and PFS (P 0.006) compared with induction alone. However, among pts achieving CR, SCT was not associated with improved OS compared with observation (P 0.22; Fig 2). Pts with prior history of indolent NHL did not fare worse than those with de novo DHL (P 0.5). No difference in OS was observed based on histology (P 0.2). The following factors were evaluated in MVA: prior indolent lymphoma, histological subtype, IPI>/=3, primary refractory disease, type of induction (R-CHOP vs intensified), and consolidative SCT. Only primary refractory disease (P<0.0001) predicted for inferior OS. Consolidative SCT did not improve OS on MVA (P 0.13).TreatmentN^CR1 Achieved (%)Primary Refectory Disease (%)PFS (mo)OS (mo)Entire Cohort*10657 (53.7)37 (34.9)8.812R-CHOP3316 (48.8)15 (45.5)7.712R-CHOP w/ SCT30 (0)2 (66.6)8.813.1R-EPOCH2819 (67.8)5 (17.9)9.211.6R-EPOCH w/ CR1 SCT55 (100)0 (0)1212R-Hyper CVAD155 (33.3)8 (53.3)811R-Hyper CVAD w/ CR1 SCT66 (100)0 (0)22.621R-CODOX-M/IVAC62 (33.3)4 (66.6)46.4R-CODOX-M/IVAC w/ CR1SCT11 (100)0 (0)15.415.4 [Display omitted] [Display omitted] ConclusionsIn this analysis of DHL, primary refractory disease was the primary predictor of OS. Pts achieving CR did not appear to benefit from consolidative SCT, though our analysis was limited by the fact that pts receiving SCT are often highly selected (for chemosensitivity, age, comorbidities) and in this study, by the low number of pts receiving SCT. R-EPOCH was associated with a decreased rate of primary refractory disease compared to other regimens, and increased rate of CR compared to R-CHOP, but the lack of clear survival benefit suggests that relapsed disease offsets early benefit. Our analysis confirms the generally poor outcomes for pts with DHL, though a subset with chemosensitive disease has an improved prognosis, likely due to favorable disease biology. Further investigation on the role of SCT and of novel agents is needed for this high-risk population.^Three patients untreated, one received multiple regimens Disclosures:Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Petrich:Genetech: Consultancy, Honoraria. Fenske:Seattle Genetics : Consultancy, Honoraria. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Evens:Seattle Genetics: Consultancy, Honoraria; Millennium: Consultancy, Honoraria, Research Funding; Ziopharm, Inc: Research Funding; Celgene: Consultancy, Honoraria.

Brentuximab Vedotin in CD30+ Lymphomas

Monoclonal antibodies (mAb) have become an effective treatment strategy for hematologic malignancies. CD30 is a rational target for therapy due to its limited expression on normal tissues and the strong and uniform expression on malignant cells in classical Hodgkin’s lymphoma (cHL) and anaplastic large-cell lymphoma (ALCL). Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, utilizes the targeting properties of mAb to deliver a cytotoxic agent inside the malignant cell. Brentuximab vedotin has significant clinical activity in patients with relapsed or refractory cHL and relapsed or refractory ALCL, and has the potential to represent a significant advance in modern oncology.

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

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

Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study

Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30. The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL. Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion. The primary end point of the study was overall objective response rate as assessed by independent central review. Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. The median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 adverse events in ≥ 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%). Brentuximab vedotin induced objective responses in the majority of patients and CRs in more than half of patients with recurrent systemic ALCL. Targeted therapy with this CD30-directed antibody-drug conjugate may be an effective treatment for relapsed or refractory systemic ALCL and warrants further studies in front-line therapy.

Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology Group phase I consortium study.

9500 Background: Genetic aberrations in the anaplastic lymphoma kinase (ALK) gene are found in anaplastic large cell lymphoma (ALCL), neuroblastoma (NB) and other tumors.Crizotinib,a small molecule inhibitor of ALK and c-Met, is active in non-small cell lung cancers (NSCLC) harboring an ALK translocation. We performed a phase 1 dose-escalation and pharmacokinetic (PK) trial of crizotinib in patients (pts) with refractory solid tumors and ALCL. Methods: Crizotinib was administered bid without interruption in 28 day cycles using the rolling-six design. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2/dose) have been evaluated (A1). Pts with confirmed ALK fusion proteins, mutations or amplification (A2) could enroll at one dose level lower than part A1 and those with NB could enroll on a separate stratum (A3). PK studies were performed on day 1 and at steady state (SS). ALK genomic status in tumor tissue was evaluated and qPCR was used to measure NPM-ALK fusion transcript in bone marrow and blood samples of ALCL pts. Results: 70 pts were enrolled, 57 fully evaluable for toxicity, [median (range) age 9.9 yrs (1.1–21.3)]: 29 on A1, 18 on A2, and 10 on A3. In A1, 2/7 pts developed DLT (grade 3 dizziness, grade 5 intra-tumoral hemorrhage) at 215 mg/m2 and 1/6 pts developed DLT (grade 4 liver enzyme elevation) at 365 mg/m2. In A2, 1 grade 4 DLT (neutropenia) occurred at 165 mg/m2; in A3, no DLTs occurred. Mean (±SD) Cave (=AUC0-12h/12h) of crizotinib at SS was 466±114 ng/mL at 215 mg/m2/dose (n=5), 443±121 ng/mL at 280 mg/m2/dose (n=8), and 720±230 ng/mL at 365mg/m2/dose (n=4). Response data for pts with ALCL (six at 165 mg/m2, two at 280 mg/m2) approved for release by the Data Safety Monitoring Committee demonstrates 7/8 (88%) complete response (CR) rate to date. RT-PCR data for 6 of these pts at 57 time points was obtained and will be described. In addition, 2 pts with NB have had CRs, one with a documented ALK mutation. One patient with an inflammatory myofibroblastic tumor and one with NSCLC had PRs. Conclusions: Inhibition of ALK in pediatric pts with ALK-driven tumors occurs with minimal toxicity and is associated with objective anti-tumor activity.