United States Cutaneous Lymphoma Consortium Research Articles

Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC

AbstractThe number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Epi-O-02 - International Cutaneous Lymphomas Pandemic Section (ICLYPS) analysis of CTCL outcomes during COVID-19

At the onset of the COVID-19 pandemic, the United States Cutaneous Lymphoma Consortium (USCLC) and the European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Task Force (EORTC-CLTF) developed emergency guidelines for the management of patients with cutaneous lymphomas (CLs) during the pandemic. These emergency protocols were intended to ensure patient safety and called for dose modifications, treatment delays and treatment interruptions as necessary to minimize exposure risks to COVID-19. Because there are no established maintenance protocols for CLs, the impact of such delays or interruptions on disease outcomes was not known. The ISCL created an International Cutaneous Lymphomas Pandemic Section (ICLYPS) to collect data from the institutions around the world to assess the impact of these changes on patients’ outcomes and to determine if these measures were effective in preventing infection. We summarize the outcomes from a preliminary cohort of patients from Brazil, Greece, Italy, Spain, Switzerland, the UK and the US. Actively managed patients with an established diagnosis of CL from March to October 2020 were included according to the Institutional Protection of Human Subjects guidelines at the respective centers. We included 149 patients in this retrospective review. The average age was 61.88 years (range: 22–95). 2 patients (1.3%) had diagnoses of CD30+ lymphoproliferative disorders (LyP and pcALCL), 112 (75.2%) had mycosis fungoides (MF), and 35 (23.5%) had Sézary syndrome (SS). 77 patients (68.7%) had stages IA–IIA MF, 23 (20.5%) had Stage IIB MF, 6 (5.4%) had stage III MF, and 41 (27.5%) had Stage IV disease, of which 6 had Stage IV MF (5.4%) and 35 had SS (23.5%). Treatment was delayed for more than half (53.0%) of the patients for a mean of 3.2 months (range: 10 days to 10 months). Treatment delay was associated with a significant risk of disease relapse or progression across all stages (65.8% vs 32.9%, p<0.00001). During follow up, 6 patients (4%) died due to disease progression, including 3 patients with Stage IIB MF, one with Stage IVB MF, and two with SS. Twenty-eight patients (18.8%) had a confirmed COVID-19 infection during the capture period. Two of these cases were definitive hospital-acquired infections following prolonged hospital admission, while the remaining contracted the virus through community exposures. There were no outpatient office-acquired infections. Three of the 26 patients who contracted COVID-19 died of the infection (2 SS and 1 LyP, mean age: 80, range: 66–89). The ICLYPS analysis has revealed that treatment interruptions and delays during the COVID-19 pandemic resulted in significantly worse outcomes in patients with CLs as compared to those who did not experience treatment interruptions. No outpatient office-acquired infections were reported in this extensive review, and patients with CLs who developed COVID-19 did not do worse than expected according to their risk factors. Effective safety measures and protocols can prevent transmission of COVID-19 at physicians’ offices. Interruption of therapy leads to negative clinical outcomes and should be avoided, especially in the setting of advanced disease, as the risk of contracting COVID-19 in the outpatient setting did not outweigh the risk of morbidity and mortality due to disease progression. Ensuring continuity of treatment and maintenance therapy appears to be critical to avoiding life-threatening disease progression.

Tre-P-21 - Extracorporeal photopheresis during the COVID-19 pandemic: experience in Argentina

Background:Patients with primary cutaneous lymphoma receive immunosuppressive therapy for long term disease control. Both cutaneous lymphoma and immunosuppressive treatment can contribute to the development of more severe COVID-19 complications. The real challenge during the COVID-19 pandemic remains the management of the advanced and aggressive forms of cutaneous lymphomas, including late-stage mycosis fungoides (MF) and Sézary syndrome (SS). Extracorporeal photopheresis (ECP) is one of those treatments. ECP is considered high risk therapy according to the United States Cutaneous Lymphoma Consortium recommendations for treatment of cutaneous lymphomas during the COVID-19 pandemic because it may require travel to the clinic or hospital.Methods:In this cross-sectional retrospective study, data of patients with MF or SS who received ECP treatment were collected. ECP consisted of a two-session cycle every two to four weeks. In our group we did not carry out prophylactic interruption of the therapy, once started. In patients with stable disease (SD) or partial response (PR), ECP was administered every 4 weeks, until a 6-week maximum interval was reached, and the response maintained. During the study period, the frequency of treatments was decreased, especially for patients with severe comorbidities and/or older age. The associated therapy was considered individually, depending on the extension of the disease, comorbidities, and adverse effects of each agent.Results:16 patients with cutaneous lymphoma received ECP (9 (56%) with SS and 7 (44%) with MF). Their median age at diagnosis was 63 (57–67) years. The median number of treatments before ECP was 2 (1–3), which was typically either phototherapy or systemic corticosteroids. Regarding the associated treatment during ECP and pandemic, INF and retinoids were the first-choice treatments. In the MF group 3 patients (2 PR and 1 relapse) required additional therapy with acitretin and topic corticosteroids. In the SS group 5 patients (1 PR, 3 progressive disease and 1 relapse) received concomitant t treatment with INF alfa 2b, bexarotene and electron beam; the relapsed patient underwent mono chemotherapy. Three patients were infected with SARS-CoV-2, all of them were from the SS group, the contagion was outside the hospital environment. Two of the patients who developed COVID infection died.Conclusion:For patients with advanced forms of LCCT, who usually have multiple risk factors for a severe course of SARS-CoV-2 infection therapy. The critical patient subset includes those with advanced disease, who require treatment with polychemotherapy, ECP and checkpoint inhibitors. Treatment decisions should be made on an individual basis. In our experience, the continuous use of ECP during the pandemic did not increase the risk of contagion.

Efficiency of phototherapy in patients with mycosis fungoides: preliminary results of a comparative non-randomized study

Clinical reasoning. There is a need to optimize the use of UV-B-311 nm and PUVA-therapy in patients with mycosis fungoides to determine the duration of the treatment regimen, the number of sessions per week, and ultraviolet irradiation regimen.&#x0D; Goal of research. Evaluation of the effect of the type and duration phototherapy on efficacy in patients with mycosis fungoides.&#x0D; Principle. A comparative, non-randomized study of the effectiveness of phototherapy in patients with mycosis fungoides in the early stages. Evaluation of the effectiveness of UV-B-311 nm and PUVA therapy was performed using the BSA index (area of skin lesions) and Modified Severity-Weighted Assessment Tool (mSWAT), as well as according to the criteria proposed by the International Society for Skin Lymphomas (ISCL), the European Organization for the Study and Cancer Treatment (EORTC) and United States Cutaneous Lymphoma Consortium (USCLC).&#x0D; Results. The study included 14 patients with mycosis fungoides, 5 of whom received treatment with UV-B-311 nm, 9 PUVA therapy. A strong correlation was found between the duration of UV-B-311 nm therapy with mSWAT delta (R = 0.90; p = 0.038) and BSA delta (R = 0.90; p = 0.038), while similar correlation was not found in the PUVA-therapy group (mSWAT (R = 0.24; p = 0.527); BSA (R = 0.09; p = 0.823)). When comparing the effectiveness of therapy between the treatment group UV-B-311 nm and PUVA therapy, delta mSWAT and BSA at the 20th procedure, delta mSWAT and BSA after the end of therapy did not have a statistically significant difference between the UVB-311 nm and PUVA groups.&#x0D; Conclusion. Statistically significant correlation was found between the number of procedures and the effectiveness of therapy In the UV-B-311 nm group. An increase in the number of PUVA therapy procedures (after 20) does not lead to a statistically significant increase in the effectiveness of treatment. Additional research is needed to increase the level of evidence of the results and develop optimal phototherapy regimens.

Efficiency of phototherapy in patients with mycosis fungoides: preliminary results of a comparative non-randomized study

Clinical reasoning. There is a need to optimize the use of UV-B-311 nm and PUVA-therapy in patients with mycosis fungoides to determine the duration of the treatment regimen, the number of sessions per week, and ultraviolet irradiation regimen.&#x0D; Goal of research. Evaluation of the effect of the type and duration phototherapy on efficacy in patients with mycosis fungoides.&#x0D; Principle. A comparative, non-randomized study of the effectiveness of phototherapy in patients with mycosis fungoides in the early stages. Evaluation of the effectiveness of UV-B-311 nm and PUVA therapy was performed using the BSA index (area of skin lesions) and Modified Severity-Weighted Assessment Tool (mSWAT), as well as according to the criteria proposed by the International Society for Skin Lymphomas (ISCL), the European Organization for the Study and Cancer Treatment (EORTC) and United States Cutaneous Lymphoma Consortium (USCLC).&#x0D; Results. The study included 14 patients with mycosis fungoides, 5 of whom received treatment with UV-B-311 nm, 9 PUVA therapy. A strong correlation was found between the duration of UV-B-311 nm therapy with mSWAT delta (R = 0.90; p = 0.038) and BSA delta (R = 0.90; p = 0.038), while similar correlation was not found in the PUVA-therapy group (mSWAT (R = 0.24; p = 0.527); BSA (R = 0.09; p = 0.823)). When comparing the effectiveness of therapy between the treatment group UV-B-311 nm and PUVA therapy, delta mSWAT and BSA at the 20th procedure, delta mSWAT and BSA after the end of therapy did not have a statistically significant difference between the UVB-311 nm and PUVA groups.&#x0D; Conclusion. Statistically significant correlation was found between the number of procedures and the effectiveness of therapy In the UV-B-311 nm group. An increase in the number of PUVA therapy procedures (after 20) does not lead to a statistically significant increase in the effectiveness of treatment. Additional research is needed to increase the level of evidence of the results and develop optimal phototherapy regimens.

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Managing HRQL in patients with CTCL: Physician responses from the 2018 USCLC Workshop

Introduction: The 2018 United States Cutaneous Lymphoma Consortium (USCLC) workshop focused on assessing and improving health-related quality of life (HRQL) for patients with cutaneous lymphoma.

Standardization of regimens in Narrowband UVB and PUVA in early stage mycosis fungoides: position paper from the Italian Task Force for Cutaneous Lymphomas.

UV-based (PUVA and narrowband UVB) phototherapy is broadly and commonly used in the treatment of Cutaneous T-cell Lymphomas (CTCL), yet unfortunately, the evidence for the efficacy of these treatments is based only on case series or prospective but non-randomized studies. Therefore, no internationally approved guidelines exist and no standardization of schedules has been proposed. Recently, consensus guidelines have been published by the United States Cutaneous Lymphoma Consortium. The aim of this study was to review the biological and clinical evidences on PUVA and NB-UVB in CTCL and to critically evaluate acceptability and feasibility of these guidelines in the real-life setting from the perspective of the Cutaneous Lymphoma Task Force of the Italian Lymphoma Foundation (Fondazione Italiana Linfomi, FIL).

Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium

Ultraviolet light (UVL) is a long established treatment for mycosis fungoides (MF) and Sézarysyndrome (SS), subtypes of cutaneous T-cell lymphoma (CTCL). Treatments have traditionally included broadband, narrowband ultraviolet B light (UVB) and psoralen plus ultraviolet A light photochemotherapy (PUVA), but more recently, treatment options have expanded to include UVA1 and excimer laser. UVL is used either as monotherapy or as an adjuvant to systemic therapy, demonstrating efficacy in many cases that equal or surpass systemic medications. Despite its utility and duration of use, the current practice of using UVL guidelines for psoriasis to treat patients with MF/SS is problematic because the goals of prolonging survival and preventing disease progression are unique to CTCL compared to psoriasis. We sought to develop separate guidelines for phototherapy for MF/SS for both clinical practice and for clinical trials. Literature review and cutaneous lymphoma expert consensus group recommendations. This paper reviews the published literature for UVB and UVA/PUVA in MF/SS and suggests practical standardized guidelines for their use. New standardization of phototherapy. These guidelines should allow the comparison of results with phototherapy in MF/SS acrossdifferent stages of patients, centers, and in combination with other agents in practice and in clinical trials.

Epstein-Barr Virus Kinase-Targeted Therapy for Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder

Abstract BACKGROUND: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare complication of solid organ transplant, with no standard therapy. Epstein-Barr virus (EBV) is ubiquitous making the virus a candidate therapeutic target. For virus targeted therapy to be effective, antiviral agents must be phosphorylated by lytic-phase kinases BXLF1 and BGLF4. We hypothesized that lytic kinases would be constitutively expressed in PCNS-PTLD and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based regimens in patients who often have impaired organ function and poor performance status. METHODS: We investigated the safety and efficacy of EBV-kinase targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS-PTLD. Patients with biopsy-proven PCNS-PTLD following solid organ transplantation were eligible for treatment. Immune suppression was reduced in all patients prior to treatment. Induction therapy consisted of 14 days of AZT 1500 mg IV BID, GCV 5 mg/kg IV BID, dexamethasone 10 mg IV BID and rituximab 375 mg/m2 once weekly for four weeks. Maintenance antiviral therapy was initiated on day 15 with valganciclovir 450 mg and AZT 300 mg, both twice daily. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of BGLF4 and BXLF1 by in situ hybridization or immunohistochemistry. To test the hypothesis that expression of EBV kinases conferred sensitivity to antiviral therapy, 293T cells were transfected with cDNAs (or control vectors) encoding for full length BXLF1 and/or BGLF4. Transiently transfected cells were tested for expression by immunoblot and drug sensitivity to AZT/GCV was performed by MTS and flow cytometry assays. RESULTS: Twelve patients (7 M, 5 F) with a median age of 49 were treated from 1998-2014. Transplant history included kidney (N=11), pancreas (N=2), and liver (N=1). Histology data included diffuse large B-cell lymphoma (N=7) and grade III lymphomatoid granulomatosis (N=5). EBV positivity (EBER-ISH) and CD20 expression were documented in all cases. All patients completed induction therapy. Median follow-up time and median duration of maintenance therapy were 28 months (range 2 - 143). The mean progression free survival (PFS) was 33.8 months. Overall response rate (ORR) was 83.3%. Eight patients achieved a complete response (CR) within a median time of 2 months (range 0.75 – 6 months). Two patients had a partial response (PR) with an average time to response of 1.25 months. Two patients (2/12) had progressive disease (PD). Causes of death included septic shock (n=3), pulmonary embolism (n=1), and poor functional status requiring hospice (n=1). One patient had PD at the time of death. Median overall survival (OS) was 29 months (range 2 – 143 months). Grade 3-4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=2), and neutropenia (N=5). Toxicity in the maintenance phase was generally reversible with holding therapy. Three patients required discontinuation of AZT during maintenance treatment for transfusion-dependent anemia persisting after holding AZT for 7 days or neutropenia coinciding with systemic infection. One patient had AZT discontinued due to nausea and vomiting that led to acute kidney injury. Evaluation of BXLF1, BGLF4 and LMP1 was completed in 7 patients and found to be positive in all cases. LMP1 and kinase expression occurred in mutually exclusive regions of the tumor. Expression of BXLF1 and BGLF4 led to enhanced sensitization of 293T cells to antiviral-induced growth inhibition and apoptosis. CONCLUSIONS: EBV-kinase targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be effective treatment for patients with EBV+ PCNS-PTLD. We demonstrated durable responses without disease recurrence and minimal toxicity. Expression of BXLF1 and BGLF4 kinases provides a mechanistic rationale for an antiviral approach to this disease and an attractive option to replace high dose chemotherapeutic regimens with less toxic targeted therapy in patients with compromised transplant organ function. A multi-center phase II trial is in development to further investigate this regimen in patients with immune deficiency-related CNS EBV-LPD. Figure 1 Figure 1. Disclosures Porcu: Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees.

Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

▪IL2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) are two members of the Tec family of non-receptor tyrosine kinases which are essential mediators of intracellular signaling in both normal and neoplastic T and natural killer (NK)-cells. ITK-deficient mice display alterations in T cell receptor (TCR) responses including proliferation, cytokine production and activation of downstream pathways, and these defects are exacerbated by RLK deficiency. Given their critical roles, inhibitors of ITK and RLK have therapeutic potential in a number of human autoimmune diseases, inflammatory conditions, and malignancies. Specific inhibitors targeting both ITK and RLK have not been reported and until very recently it has been challenging to develop specific inhibitors with clinical potential given the homology to many other human kinases. Targeting cysteine residues within the ATP binding pocket of kinases is a safe and effective way to design and optimize highly potent and selective kinase inhibitors. In this study, we describe preclinical mechanism of action studies of a novel covalent ITK/RLK inhibitor, PRN694, which covalently binds to cysteine moieties 442 of ITK and 350 of RLK and blocks their kinase activities.We undertook the design of highly selective ITK/RLK inhibitors using a combination of tailored covalency and structure-based design. Molecular modeling and a synthetic feasibility assessment led to the prioritization of several small focused compound libraries. The structure-based medicinal chemistry optimization of one such library culminated in the identification of PRN694. The in vitro selectivity and potency of PRN694 against a panel of 250 kinases revealed only small number of kinase targets, and in a microfluidic kinase assay, PRN694 exhibited high selectivity and potency against ITK and RLK with IC50 values of 0.3 nM and 1.3 nM, respectively. This selectivity was validated in Jurkat T cells with mutated ITK or overexpressed RLK. As expected, PRN694 suppressed a variety of downstream TCR pathways including nuclear activation of NFAT1 and cytoplasmic PLCγ1 and IKBα in TCR-activated Jurkat cells expressing wild type ITK. However, when the covalent binding site for PRN694 was removed, using ITK-C442A, this suppressive effect was lost, indicating specific covalent interaction with ITK. Furthermore, we demonstrated that only PRN694 was able to ablate TCR-induced activation in Jurkat cells which stably express RLK in addition to ITK. These data confirmed that PRN694 was a dual inhibitor of ITK and RLK and could block downstream TCR-activation in T-cells that express both complementary TEC-kinases. In vitro cellular assays also confirmed that PRN694 could prevent TCR or Fc receptor (FcR) - induced cellular and molecular activation in primary T or NK cells, inhibit TCR-induced T-cell proliferation without direct cytotoxicity, and block pro-inflammatory cytokine (including IL-2, TNFα, and IFNγ) release as well as activation of Th17 cells. Additionally, in vivo assays demonstrated durable pharmacodynamic effects of PRN694 on ITK. At 1 hour, 6 hour and 14 hour time points, the percentages of ITK occupancy were 98%, 95% and 54% respectively, and the concentrations of PRN694 in the plasma were 1530 ng/ml, 359.3 ng/ml and 14.8 ng/ml respectively.Further, we examined potential therapeutic applications of PRN694 in the treatment of T-cell leukemias or T-cell driven inflammation. Our results demonstrated an effective blockade of TCR stimulation by PRN694 in the HH cutaneous T-cell lymphoma cell line and primary T-cell prolymphocytic leukemia (T-PLL) cells, suggesting a potential clinical application of this compound in the treatment of T-cell leukemias. ITK and RLK play a critical role in T-cell driven inflammation. Therefore, we also tested the effect of PRN694 on an oxazolone induced delayed type hypersensitivity (DTH)reaction using a well-established in vivo model of inflammation driven by cell-mediated immunity, and found that PRN694 treatment significantly inhibited the DTH reaction.In conclusion, we designed and characterized a novel covalent ITK/RLK inhibitor, PRN694, which has direct therapeutic potential for the treatment of T or NK cell related diseases including inflammation, autoimmune diseases, and malignancy. DisclosuresPorcu:Actelion: Honoraria; Infinity: Research Funding; Seattle genetics: Research Funding; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity’s Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity’s Board of Directors or advisory committees. Bradshaw:Principia Biopharma: Employment, Equity Ownership. Owens:Principia Biopharma, Inc: Employment, Equity Ownership. Brameld:Principia Biopharma: Employment, Equity Ownership. Funk:Principia Biopharma Inc.: Employment, Equity Ownership. Hill:Principia Biopharma: Employment. Johnson:Principia Biopharma: Research Funding. Dubovsky:Principia Inc.: Research Funding.

Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, Shows Activity in Patients with Relapsed/Refractory T-Cell Lymphoma

Introduction: Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are uncommon lymphoid malignancies. Approved agents in the relapsed setting have overall response rates (ORR) in the range of 25-35%. Phosphoinositide-3-Kinases (PI3K) are pivotal in cell signaling and regulate multiple cellular functions relevant to oncogenesis. PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes with distinct roles in T-cell function. PI3K-δ and PI3K-γ are central to the growth and survival of certain T-cell malignancies and inhibition of PI3K is a therapeutic strategy for PTCL and CTCL. Duvelisib (IPI-145), an oral inhibitor of PI3K-δ and PI3K-γ, was studied in a phase 1 trial in hematologic malignancies with disease-specific expansion cohorts at the maximum tolerated dose (MTD). Responses were seen in a substantial number of patients with relapsed or refractory PTCL and CTCL.Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered twice daily (BID), continuously in 28-day cycles. Patients with relapsed or refractory leukemia or lymphoma received doses ranging from 8 mg to 100 mg BID. A disease-specific cohort at the MTD included PTCL and CTCL patients. The pharmacodynamics of duvelisib were assessed by early positron-emission tomography (PET) in a subset of patients and in serum through evaluation of a panel of cytokines, chemokines, and matrix metalloproteinase.Results: Thirty-three patients with TCL (17 CTCL, 16 PTCL) received duvelisib primarily at the MTD of 75 mg BID (25 mg, n=1; 50 mg, n=1; 60 mg, n=4; 75 mg, n=25; 100 mg, n=2). The median age was 64 years (range: 34-86), and the median number of prior therapies was 4 (range: 1-11). The median time from last prior therapy to first dose of duvelisib was 1.05 months (range: 0.2-36). Thirty-one patients were evaluable for efficacy, with an ORR of 42% (13/31). The ORR in PTCL was 47% (7/15, 2 complete responses [CR], 5 partial responses [PR]) and in CTCL 38% (6/16, 6 PR). The median time to response was 1.9 months (range: 1.5-3.8). Median overall survival (OS) was 36.4 weeks (95% CI: 18.6, –) for patients with PTCL. The median OS was not yet reached for patients with CTCL. The median number of treatment cycles was 3.1 (range: 0.5-12.5), with 14 (42%) on treatment ≥4 cycles (16 weeks).Pharmacodynamic results showed that within 8 days of starting treatment with duvelisib, modulation of serum cytokines and chemokines known to play a role in leukocyte migration and support the tumor microenvironment was observed. Furthermore, a reduction in standard uptake value (SUV) from baseline was observed in 6/11 patients evaluated by PET at Cycle 1 Day 22. (All 6 patients with reduction in SUV received duvelisib ≥60 mg BID).Twenty-six (79%) patients had adverse events (AEs) ≥Grade 3, with the most common (≥10%) being increased ALT/AST (n=12, 36%), rash (combined terms) (n=7, 21%), and neutropenia (n=5, 15%). Ten (30%) patients discontinued treatment due to an AE, with the most common (>1 patient) being increased ALT/AST [n=5 (4 CTCL, 1 PTCL), 15%]. Three TCL patients died on treatment or within 30 days of the last dose of duvelisib, one due to disease progression, one who declined supportive therapy, and one due to HSV pneumonia (patient was not receiving HSV prophylaxis).Conclusions: Duvelisib has shown clinical activity in patients with relapsed/refractory TCL (ORR 42%, including 2 CR) with an acceptable safety profile that supports continued assessment in this heavily pretreated patient population. The preliminary results support further evaluation of duvelisib in patients with TCL, including additional studies in both CTCL and PTCL to determine the optimal dose and identify appropriate combination therapy. DisclosuresHorwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum-Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Off Label Use: ipi-145 is not an approved drug. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Allen:Infinity Pharmaceuticals: Employment. Kelly:Infinity Pharmaceuticals: Employment. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau.

Clinical Activity of Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, in Patients Previously Treated with Ibrutinib

Introduction: Duvelisib (IPI-145) belongs to an emerging class of therapeutic small molecule kinase inhibitors that target B-cell receptor (BCR) signaling pathways important in various lymphoproliferative disorders. Duvelisib, a novel oral inhibitor of PI3K-δ,γ, has shown clinical activity across a range of hematologic malignancies in an ongoing Phase 1 study.Some patients (pts) treated with ibrutinib (IBR), a BCR inhibitor that targets Bruton’s tyrosine kinase (BTK), have had disease progression and various mechanisms of IBR resistance have been characterized. Since the mechanism of action of duvelisib differs from IBR, duvelisib was evaluated in a subset of pts previously treated with IBR enrolled in an ongoing Phase I study.Methods: The study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, and activity of orally administered duvelisib twice daily in 28-day cycles. Pts with relapsed/refractory (R/R) hematologic malignancies were enrolled, including pts previously treated with IBR with R/R chronic lymphocytic leukemia (CLL) and aggressive B-cell NHL (aNHL including DLBCL and Richter’s transformation [RT]). Pharmacodynamic studies in CLL pts with measurable disease in the peripheral blood (PB) included flow cytometry to evaluate whether duvelisib inhibits the phosphorylation of AKT (pAKT) at S473 and the CLL cell proliferation index via measurement of Ki67. DNA sequencing on malignant PB cells was performed to determine the mutation status of BTK and other genes involved in hematologic malignancies. Clinical responses were based on IWCLL (2008) criteria and revised IWG (2007) criteria as applicable.Results: Twelve pts previously treated with IBR were enrolled (R/R CLL, n=6; aNHL, n=6 [DLBCL=2; RT=4]) and received IPI-145 at 25 mg BID (n=2) or 75 mg BID (n=10). The median age in R/R CLL pts was 58 years (y) (42-76), 67% were male, 100% had ≥3 prior systemic therapies, the median time from prior therapy to first dose of duvelisib was 0.34 months (mo) (0.0-1.6), and 67% started duvelisib within 2 wks of last dose of IBR. The median age in R/R aNHL pts was 62 y (36-81), 67% were male, 50% had ≥3 prior systemic therapies, a median time from last prior therapy to first dose of duvelisib of 0.74 months (0.2-3.7), and 50% started duvelisib within 3 weeks of last dose of IBR.With a median of 4.1 treatment cycles (range 3.0-9.2) in the R/R CLL pts and 2.5 treatment cycles (range 1.8-5.4) in R/R aNHL pts, the safety profile in these pts previously treated with IBR appears consistent with all pts (n=206) with advanced hematologic malignancies receiving duvelisib. The best response observed in R/R CLL pts includes 1 partial response (PR) and 5 stable disease (SD). Of these 6 pts, 2 pts (1 PR, 1 SD) remain on duvelisib for 8 and 9 months, respectively, and 4 pts have discontinued treatment (progressive disease [PD], n=3; physician decision, n=1). The best response observed in R/R aNHL pts included 2 PRs, 1 SD, 2 PD, and 1 not evaluated [NE]. Three pts remain on duvelisib (1 PR, 1 SD, 1 NE) for 3-5 mo and 3 pts have discontinued treatment (progressive disease, n=2; AE, n=1).The median baseline proliferative index (Ki67) in R/R CLL pts previously treated with IBR (n=5) was substantially higher (22.2% vs 3.8%) than in non-IBR exposed R/R CLL pts (n=23). Across both R/R CLL populations, Ki67 was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state); however, the effect was more pronounced in non-IBR treated pts. Despite this apparent difference in baseline proliferative index, the IBR previously treated pts with measureable disease in PB (R/R CLL=5), including 3 pts with a known IBR-resistance mutation in BTK (2 with C481S, 1 with C481F) demonstrated reductions of pAKT that were observed within 1 hour of duvelisib treatment and sustained through 24 hours postdose. This pAKT pharmacodynamic response was consistent with results in R/R CLL pts not previously treated with IBR (n=35).Conclusions: Pharmacodynamic data demonstrates duvelisib inhibits pAKT in R/R CLL pts, including those with an IBR-resistance mutation in BTK, and is consistent with duvelisib having a non-overlapping MOA with IBR. Baseline Ki67 data suggest a more aggressive clinical phenotype in R/R CLL pts who progress on IBR compared to those without previous IBR treatment. Early evidence of clinical activity and a tolerable safety profile suggest additional studies of duvelisib in pts who have progressed on IBR are warranted. DisclosuresPorcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: IPI-145. Flinn:Infinity Pharmaceuticals: Consultancy. Kahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum-Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Oki:Infinity Pharmaceuticals: Research Funding. Byrd:Pharmacyclics, Genentech: Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Ni:Infinity Pharmaceuticals: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment.

Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Introduction: Signaling via PI3K-δ and PI3K-γ has distinct and complimentary effects on malignant B-cells and nonmalignant immune cells important in tumor immunity, and on the tumor microenvironment involved in the support and maintenance of B-cell neoplasms, including chronic lymphocytic leukemia (CLL). Duvelisib (IPI-145), a novel targeted oral PI3K-δ,γ inhibitor, is in development for the treatment of hematologic malignancies. An ongoing Phase 1 study has demonstrated substantial clinical activity in patient (pts) with relapsed/refractory (R/R) CLL, including those with poor prognostic risk factors.Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity of duvelisib administered in pts with advanced hematologic malignancies. Pharmacodynamic (PD) studies included peripheral blood (PB) flow cytometry to evaluate whether duvelisib inhibits phosphorylation of AKT (pAKT) and proliferation (Ki67) in CLL cells and serum sampling to evaluate modulation of cytokines and chemokines important for tumor microenvironment signaling. Genomic DNA was isolated from PB at baseline for Sanger sequencing of IGHV and next-generation sequencing of TP53. Following dose escalation, expansion cohorts enrolled CLL pts at 25 and 75 mg BID (MTD). Response was based on IWCLL (2008) criteria.Results: The median age of the R/R CLL pts (n=54) was 66 y (range 42-82), 78% of whom were male. Forty-four (81.5%) pts received ≥3 prior systemic therapies. The median time from prior therapy to first dose of duvelisib was 3.5 mo (range 0-39.1). Baseline cytopenias ≥ Grade 2 were neutropenia (41%), thrombocytopenia (31%) and anemia (26%). Of the pts with baseline tests for mutations associated with poor CLL prognosis, 49% (23/47) had TP53mut and/or cytogenetic (del)17p and 89% (31/35) had an unmutated IGHV.Duvelisib dosed at 25 mg BID provided an optimal biologic effect based on maximum pAKT inhibition in CLL cells (<24 hrs after a single dose) and reductions in serum cytokines and chemokines (by Cycle 1 Day 8) known to contribute to CLL growth and survival. In addition, median CLL cell proliferation index (Ki67) was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state). These PD effects were similar at higher doses (75 mg BID). On-target lymphocytosis had a rapid onset (maximum mean absolute lymphocyte count [ALC] by Cycle 1 Day 8) across the dose range evaluated (8 to 75 mg BID), returning to baseline (mean ALC) by Cycle 4 Day 1 (12 wks on treatment). In pts with baseline CT assessments, 83% (38/46) achieved >50% reduction in adenopathy by CT scan. The best overall response rate (ORR) by IWCLL criteria was 55% in 49 evaluable pts, including 1 complete response (CR) and 26 partial responses (PR). There were 21 pts with stable disease and 1 pt with progressive disease. Median time to response was 1.9 mo (range 1.7-8.3). The ORR was similar irrespective of dose (52%, ≤25 mg BID [n=29]; 60%, 75 mg BID [n=20]), or the presence of TP53mut/(del)17p (48% [n=23], including 1 CR) or unmutated IGHV (52%, n=31).Treatment emergent adverse events (AEs, all causality) were similar across the dose range and were predominantly Grade 1-2. With a median of 7.3 treatment cycles (range 1.0-30.8), the most common AEs ≥Grade 3 (≥10%, all causality) were transient cytopenias (neutropenia [31%] and thrombocytopenia [11%]), febrile neutropenia (15%), and pneumonia (11%). The most common reasons for treatment discontinuation were AEs (31%) and disease progression (24%).Conclusions: Pharmacodynamic studies in this ongoing investigation indicate duvelisib, an oral PI3K-δ,γ inhibitor, modulates pAKT in CLL cells, chemokines/cytokines involved in CLL cell survival, and CLL cell proliferation index (Ki67). Early resolution of lymphocytosis and objective lymph node responses suggest survival signals from the tumor microenvironment are affected by inhibition of PI3K-δ,γ pathways. Duvelisib continues to demonstrate clinical activity, with a best ORR of 55% (IWCLL) in a heavily pretreated R/R CLL population, including pts with poor prognostic features. The overall safety profile is generally well tolerated, consistent with underlying disease and suggests a favorable benefit-risk profile in this R/R CLL population. These results support the further development of duvelisib monotherapy, and a randomized Phase 3 study in pts with R/R CLL is ongoing. DisclosuresKahl:Infinity Pharmaceuticals: Consultancy, Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum: Consultancy, Honoraria, Research Funding. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau. Porcu:Actelion (e), Cutaneous Lymphoma Foundation (h), United States Cutaneous Lymphoma Consortium (h), Infinity (d), Celgene (d), : Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment. Flinn:Infinity Pharmaceuticals: Consultancy.

The Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) Demonstrates Broad and Durable Clinical Activity in Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL)

Background: The nuclear export protein, XPO1 is overexpressed in all types of malignant lymphoma. The SINE selinexor (KPT-330) is a slowly reversible XPO1 antagonist that forces the nuclear retention and activation of over 10 tumor suppressor proteins (TSP) such as p53, IkB, FOXO and p21. In addition, selinexor inhibits the nuclear export and the translation of oncogenic mRNAs such as c-myc and Bcl-XL levels. Together these effects result in apoptosis of cancer cells in preclinical models of both T- and B- cell NHL. In DLBCL cell lines (n=10), selinexor induced potent cytotoxicity against both germinal center (GCB) and nonGCB including those with high MYC and/or BCL2/6 protein levels. Methods: Selinexor was administered orally for 4-10 doses in a 28-day cycle in this phase 1 study. Serial tumor biopsies were performed. Response evaluation was performed in cycle 1 and 2 and then every 2 cycles. All pts had heavily pretreated NHL with documented progressive disease (PD) on study entry. Results: 58 pts (34 males 24 females; median age 62 yrs; ECOG PS 0/1/2: 19/35/4; median prior regimens: 3) received selinexor across 13 dose levels (3 to 80 mg/m2). The recommended Phase 2 dose is 60 mg/m2 based on results across all Phase 1 studies. Grade 3/4 events (>5%) include thrombocytopenia (31%), neutropenia (22%), fatigue (10%), and anemia (7%). The most common Grade 1/2 AEs were: nausea (66%), anorexia (47%), fatigue (40%), and vomiting (40%) that were manageable with supportive care and were seen less frequently following cycle 1. Increases in XPO1 mRNA levels were observed at all doses and sustained for 4-48 hours, supporting twice weekly dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reductions, and apoptosis induction of cancer cells. Objective responses were observed in all classes of NHL studied (Table 1). An objective response rate (ORR) of 31% was observed across all NHL types. An ORR of 40% was observed in pts with rel/ref aggressive B-NHL (DLBCL, Follicular NHL grade 3b (FLgrd3b) and transformed NHL) at doses ³60 mg/m2 vs an ORR of 33% at 23-50 mg/m2 and 25% at ²20 mg/m2. Across all NHL types, time to best response was delayed, including 5 complete responses (CR) (4 in DLBCL and 1 T-NHL). Nine pts out of 34 have remained on therapy for >6-23 months without clinically significant cumulative toxicities or major organ dysfunction. Conclusions: Selinexor treatment is generally well tolerated with supportive care and can be given over a prolonged period. Durable single agent activity in pts with heavily pretreated NHL has been observed. Phase 2 studies in DLBCL, Richter’s transformation and T-NHL of single agent selinexor as well as in combination with other agents including CD20 antibodies are expected to begin in the near future.Abstract 396. Table 1Cancer TypeSelinexor Dose (mg/m2)N*ORR (%)CR (%)PR (%)SD (%)PD (%)WC/NE (%)Aggressive B-NHL (DLBCL, FLgrd3b, Transformed)≤2041 (25%)–1 (25%)1 (25%)2 (50%)–20 – 50217 (33%)4 (19%)3 (14%)5 (24%)6 (29%)3 (14%)≥60*104 (40%)–4 (40%)4 (40%)–2 (20%)Follicular & Other Indolent NHL≤304–––4 (100%)––≥3542 (50%)–2 (50%)1 (25%)–1 (25%)Mantle Cell Lymphoma≤3021 (50%)–1 (50%)1 (50%)––≥352––––1 (50%)1 (50%)T-Cell Lymphoma≤304–––2 (50%)–2 (50%)≥3511 (100%)1 (100%)––––Richter’s Transformation≤3031 (33%)–1 (33%)2 (67%)––≥3531 (33%)–1 (33%)––2 (67%)TOTAL5818 (31%)5 (9%)13 (22%)20 (34%)9 (16%)11 (19%)* First pt in this population was dosed on 23-July-2012ORR=Objective Response Rate; CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease; WC=Withdrew Consent; NE=Non-Evaluable DisclosuresByrd:Pharmacyclics, Genentech: Research Funding. Porcu:Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity’s Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity’s Board of Directors or advisory committees. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Flinn:AstraZeneca: Research Funding. Kukreti:Celgene: Honoraria. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therpeutics: Employment. Shacham:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership. Carlson:Karyopharm Therapeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity’s Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therpeutics: Employment, Equity Ownership.

Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia

Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia

Major achievements of the EORTC Cutaneous Lymphoma Task Force (CLTF)

This article describes the achievements of the Cutaneous LymphomaTask Force (CLTF) over the recent decade in their goal to optimize classification and response criteria and establish new treatment options for patients suffering from cutaneous T-cell lymphomas (CTCL). Collaborative work with the International Society of Cutaneous Lymphoma (ISCL) and the United States Cutaneous Lymphoma Consortium (USCLC) has led to publication of pivotal manuscripts proposing revised staging proposals for Mycosis fungoides (MF)/Sézary syndrome (SS) and also non MF/SS primary cutaneous lymphomas as well as the recent publication of a proposal for defining endpoints in MF/SS.

Cutaneous T-Cell Lymphomas: A Review of New Discoveries and Treatments

Treatment regimens of patients with CTCL vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients. Unfortunately, other than allogeneic HCT, there are no potential curative therapies for CTCL. Clinical trials are currently underway to identify new therapies to improve quality of life for patients, and researchers are hard at work to identify novel pathways and genes for prognostication and as targets for therapies. Importantly, collaborative clinical trials to enhance rates of accrual need to be conducted, and improved interpretation of data via standardizing end points and response criteria should be an emphasis. Recently, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) met to develop consensus guidelines to facilitate collaboration on clinical trials. These proposed guidelines consist of: recommendations for standardizing general protocol design; a scoring system for assessing tumor burden in skin, lymph nodes, blood, and viscera; definition of response in skin, nodes, blood, and viscera; a composite global response score; and a definition of end points. Although these guidelines were generated by consensus panels, they have not been prospectively or retrospectively validated through analysis of large patient cohorts.

Clinical End Points and Response Criteria in Mycosis Fungoides and Sézary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer

Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.

The United States Cutaneous Lymphoma Consortium (USCLC)

The United States Cutaneous Lymphoma Consortium (USCLC)