ALBERT

Description: Key Points Proteome-wide analysis of HTLV-1–infected T cells identified 17 biomarker proteins for the diagnosis of ATL or HAM/TSP patients.

Description: Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets

Description: Abstract 285 Background: KW-0761 is a defucosylated, humanized, monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CC chemokine receptor 4 (CCR4). CCR4 is expressed on the surfaces of cells comprising several T-cell malignancies such as ATL, peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). A phase I study of KW-0761 in patients with CCR4-positive ATL and PTCL demonstrated that 4 weekly intravenous infusions of KW-0761 were well tolerated up to 1.0 mg/kg and it showed encouraging clinical activity with an overall response rate (ORR) of 31.3% (4 of 13 ATL and 1 of 3 PTCL) in 16 patients (J Clin Oncol 2010;28:1591-8). Methods: A multicenter phase II study of KW-0761 has been conducted for relapsed patients with CCR4-positive ATL to evaluate its efficacy, pharmacokinetics (PK), safety and immunogenicity. Patients were planned to receive 8 weekly intravenous infusions of KW-0761 at 1.0 mg/kg. The primary endpoint was ORR. Objective responses were assessed after the 4th and 8th infusions of KW-0761 according to the response criteria for ATL (J Clin Oncol 2009;27:453-9) by each investigator and the independent efficacy assessment committee. The number of patients required was estimated to be 25, for 90% power to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold of ORR, based on the assumptions that the minimum required response ORR to a new drug for relapsed ATL is 5% and the expected ORR to KW-0761 is 30%. Results: Twenty-seven patients (12 males and 15 females) were enrolled and received KW-0761. The median age was 64 years (range: 49–83). The disease subtypes of ATL consisted of 14 acute-, 6 lymphoma-, and 7 chronic-types with unfavorable prognostic factors. Among the 27 patients enrolled, 14 patients (52%) completed the protocol treatment of 8 infusions. Eleven patients (41%) discontinued the protocol treatment because of progressive disease, and the remaining 2 discontinued because of skin rash or the concurrent colon tumor. The treatment-related grade (G) 2 or greater adverse events (AEs) were lymphopenia (96%), leukopenia (56%), skin rash (52%), neutropenia (33%), thrombocytopenia (26%), AST increase (26%), ALT increase (22%), hypoxemia (19%), anemia (15%), pruritus (15%), g-GTP increase (15%) and hypophosphatemia (15%). G2 or greater Infusion-related toxicities were observed in 22 of 27 patients (81%) including 1 G3, but immediately recovered after treatment with systemic steroids. Treatment-related severe AEs (SAEs) were observed in 5 patients, including a Stevens-Johnson syndrome (G3) and 4 skin rashes (each G3). All these AEs also improved by steroids. PK analysis demonstrated that Cmax and trough (C168h) after the 8th infusion was 38,853 ± 11,267 and 25,934 ± 10,193 ng/mL, respectively, and T1/2 after the 8th infusion were 457 ± 144 h. No anti-KW-0761 antibody has been detected. Among the 26 patients evaluable for efficacy, KW-0761 exhibited an ORR of 54% (14/26; 95% CI, 33 to 73) (acute: 6/14 patients, lymphoma: 3/6 patients, chronic: 5/6 patients) including 7 complete responses (CRs) (27%; 95% CI, 12 to 48) and 7 partial responses (PRs). These are remarkable results, considering that the ORR of relapsed or refractory patients with ATL to a single-agent chemotherapy has been reported to be low (7 to 39%). Response rates according to the affected disease lesion were 100% (13 patients, all CR), 71% (5 of 7 patients), and 38% (5 of 13 patients), respectively, for peripheral blood, skin, and lymph node disease. Conclusions: KW-0761 is a highly effective agent with acceptable toxicity profiles in relapsed patients with CCR4-positive ATL who have no standard therapies. A multicenter, randomized study for untreated ATL patients to compare mLSG15 (a dose-intensified multi-agent regimen, J Clin Oncol 2007;25:5458-64) + KW-0761 with mLSG15 alone has been initiated. Disclosures: Ogura: Kyowa Hakko Kirin Co Ltd: Consultancy. Akinaga:Kyowa Hakko Kirin Co Ltd: Employment.

Description: The nuclear factor-κB (NF-κB) transcription factors play important roles in cancer development by preventing apoptosis and facilitating the tumor cell growth. However, the precise mechanisms by which NF-κB is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-κB–inducing kinase (NIK) is overexpressed at the pretranslational level in adult T-cell leukemia (ATL) and Hodgkin Reed-Sternberg cells (H-RS) that do not express viral regulatory proteins. The overexpression of NIK causes cell transformation in rat fibroblasts, which is abolished by a super-repressor form of IκBα. Notably, depletion of NIK in ATL cells by RNA interference reduces the DNA-binding activity of NF-κB and NF-κB–dependent transcriptional activity, and efficiently suppresses tumor growth in NOD/SCID/γcnull mice. These results indicate that the deregulated expression of NIK plays a critical role in constitutive NF-κB activation in ATL and H-RS cells, and suggest also that NIK is an attractive molecular target for cancer therapy.

Description: Background: Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm developing in a minority of individuals infected with human T-cell leukemia virus type I (HTLV-I). Although the results of conventional chemotherapy remain unsatisfactory for the management of ATL, allogeneic hematopoietic stem-cell transplantation (allo-SCT) is emerging as a promising alternative which can provide long-term remission in selected patients. Methods: To evaluate the efficacy of allo-SCT for the treatment of ATL, data on 397 patients (pts) with ATL who had received allo-SCT between 01/1996 and 12/2005 were collected through JSHCT, JMDP and JCBBN. We analyzed pts who did not have a history of previous stem-cell transplantation; who received a T-cell-replete graft; who had data on age at transplantation, sex, donor type, stem-cell source, conditioning regimen, and graft-versus-host disease (GVHD) prophylaxis. A total of 363 pts, with a median age of 51 yrs (range, 18–79), 201 males and 162 females, fulfilled these criteria: 175 received bone marrow and/or peripheral blood from a related donor; 188 received marrow or cord blood from an unrelated donor. At the time of transplantation, 91 pts were in complete remission (CR) and 226 were not in CR. Risk factors which potentially affect the survival outcomes were analyzed using proportional-hazards models. Results: The median follow-up was 21.6 months (range, 1.5–102). The unadjusted 3-year overall survival, disease-associated mortality, and treatment-related mortality (95% confidence interval [CI]) for pts in CR at transplantation were 48% (35–59%), 16% (8–27%), and 35% (24–45%), respectively, while those for pts not in CR were 22% (16–29%), 35% (28–42%), and 41% (34–48%), respectively. Multivariable analyses revealed four significant factors which adversely affected survival: older recipient age (〉50 yrs)(adjusted hazard ratio [HR] 1.71; 95% CI, 1.24–2.38; P=0.001), male recipient (HR 1.46; 95% CI, 1.10–1.93; P=0.009), disease status other than CR (HR 2.21; 95% CI, 1.57–3.12; P

Description: Abstract 4299 Background Adult T-cell leukemia/lymphoma (ATLL) has a poor prognosis because of its chemo-resistance. Many chemotherapeutic regimens have been created but none of them have shown sufficient results. We proposed allogeneic stem cell transplantation (allo-SCT) for ATLL patients and showed an improved survival rate. However, relapse or progression of ATLL is one of the major limiting factors of survival in post SCT patients. Aims In order to establish a better treatment strategy for poor responders after SCT for ATLL, we analyzed the outcome of relapse or progression cases after allo-SCT. We paid special attention to the graft versus ATLL (GvATLL) effect. Methods There were 37 ATLL patients in which allo-SCT was performed in Imamura Bun-in Hospital (IBH) from June 1998 to April 2009. Twenty-eight cases survived over 100 days after SCT. Sixteen of the 30 patients relapsed. Using data in medical records of IBH, we analyzed transplant characteristics and the outcome of these 17 patients retrospectively. Results Disease status at SCT was CR in 2 patients, 2 PR, 5 SD, and 7 PD. Eight patients received conventional stem cell transplantation (CST) and the other seven patients received reduced-intensity stem cell transplantation (RIST). Fourteen patients in 17 obtained remission (10 CR and 5 PR), but the remaining 2 did not (1 SD and 1 PD) after SCT. The sites of relapse or progression in 17 were skin in 10 patients, 8 peripheral blood, 7 lymph node, 3 central nervous system, and 1 bone. All patients discontinued immunosuppressants after relapse or progression. Eleven patients obtained remission. Especially, in 5 out of 11 patients, remission was obtained only by discontinuation of immunosuppressants (graft-versus-ATLL effect), and the time to remission after discontinuation of immunosuppressants was between 1 to 14 days. Twelve patients were complicated with acute GVHD (grade I-IV). Twelve patients died after SCT. The causes of death were disease progression of ATLL in 5 patients, 3 acute GvHD, 3 infectious complications, and 1 interstitial pneumonia. Four patients who were complicated with acute GvHD survived over 3 years. Discussions Ten patients out of 17 experienced relapse or progression as skin lesion, and 8 patients out of 10 achieved re-remission. It suggests that skin lesion can be a warning sign of ATLL relapse. Since various types of clinical entities, such as ATLL relapse, GvHD, or drug eruption, can manifest as skin lesion after SCT, we strongly recommend to do skin biopsy aggressively to clarify the diagnosis. Ten patients out of 17 achieved re-remission (5 of them achieved only after the discontinuation of immunosuppressant), and 2 patients out of 5 attained long-term survival. This fact raises the possibility that GvATLL effect play a role in controlling exacerbation of ATLL. By focusing on the 5 cases that obtained re-remission only with discontinuation of immunosuppressant, 4 cases showed GvATLL effect prior to GvHD, and one patient experienced fatal grade IV GvHD, respectively. These outcomes suggest that immunosuppressant should be resumed in response to the signs of GvHD deterioration. Relapse/progression cases shows poor survival rate compared with non-relapse ones (60% vs 20% P=0.0028). Although re-remission was highly achieved, this fact suggested that countermeasure against GvHD or re-relapse are indispensable for long-term survival. Summary/conclusions Skin was a major site of relapse or progression after SCT in ATLL patients. A certain number of patients obtained remission only by the discontinuation of immunosuppressants. Four patients survived more than 3 years with their complication of acute GVHD. These results suggest that the GvATLL effect after SCT exists and plays an important role in longer survival for poor responders of post allo-SCT in ATLL patients. Disclosures: No relevant conflicts of interest to declare.

Description: The addition of rituximab to CHOP (CHOP-R) chemotherapy has resulted in an improved outcome for patients with DLBCL and has recently been shown to diminish the prognostic impact of several recognized biomarkers. S-phase kinase-associated protein 2 (Skp2) is a proto-oncogene that has been shown to be expressed in a number of tumors. We have reported that Skp2 expression in tumor cells is an unfavorable prognostic factor in DLBCL. In the present study, we investigated the significance of Skp2 expression in the patients with DLBCL treated with CHOP or CHOP-R. DLBCL patients (333 cases) were entered into this study, based on the availability of paraffin blocks for interpretable immunohistochemistry for all antigens (CD10, Bcl-6, MUM1, Bcl-2, Skp2). All patients were treated with either CHOP (201) or CHOP-R (132) from 1996 to 2005, and were diagnosed as having DLBCL at the twenty different hospitals. All specimens were histopathologically reviewed before entering into this study. Their clinical characteristics, including either the IPI or R-IPI factors, were evenly matched. The median follow-up of living patients was 3.7 and 2.1 y for CHOP vs CHOP-R, respectively. DLBCL were assigned to GCB subtype (40.8%: 136/333) or non-GCB subtype (59.2%: 197/333) based on the method of Hans et al., Blood 103: 275–82 (2004), with similar distribution in both treatment groups. Expression of bcl-6 (p

Description: Invariant natural killer T (iNKT) cells are unique T cells that regulate the immune response to microbes, cancers, and autoimmunity. We assessed the characteristics of iNKT cells from persons infected with human T-lymphotropic virus type 1 (HTLV-1). Whereas most infected persons remain asymptomatic carriers (ACs) throughout their lives, a small proportion, usually with high equilibrium proviral loads,develop 2 diseases: HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). We demonstrated that the frequency of iNKT, NK, and dendritic cells in the peripheral blood of HAM/TSP and ATL patients is decreased. We also observed an inverse correlation between the iNKT cell frequency and the HTLV-1 proviral load in the peripheral blood of infected persons. Notably, in vitro stimulation of peripheral blood cells with α-galactosylceramide led to an increase in the iNKT cell number and a subsequent decrease in the HTLV-1–infected T-cell number in samples from ACs but not HAM/TSP or ATL patients. Our results suggest that iNKT cells contribute to the immune defense against HTLV-1, and iNKT-cell depletion plays an important role in the pathogenesis of HAM/TSP and ATL. Therefore, iNKT cell–based immunotherapy may be an effective strategy for preventing these HTLV-1–associated disorders.

Description: Background: KW-0761 produced by POTELLIGENT ® technology is a defucosylated humanized IgG1 monoclonal antibody against CC chemokine receptor 4 (CCR4). Fucose is demonstrated to be the most critical IgG1 oligosaccharide component for antibody-dependent cellular cytotoxicity (ADCC) activity and KW-0761 composed of defucosylated IgG1 exhibits an enhanced ADCC activity. Previous studies revealed that CCR4 was overexpressed on tumor cells from 88% of pts with ATL and 38% of pts with PTCL unspecified (PTCL-U), and its expression was associated with poor prognosis. CCR4 was also expressed in cutaneous T-cell lymphoma (CTCL) such as mycosis fungoides (MF) and Sezary syndrome, especially its large cell transformant. These results suggest that CCR4 could be a realistic therapeutic target for ATL, CTCL and PTCL-U. Methods: A multicenter phase I study of KW-0761 has been conducted for relapsed pts with CCR4-positive ATL or PTCL to evaluate its safety, pharmacokinetics (PK), immunogenicity and efficacy. Pts were planned to receive 4 weekly intravenous infusions of KW-0761 at 0.01, 0.1, 0.5, and 1.0 mg/kg. A dose-limiting toxicity (DLT) was defined as any of the following adverse events: ≥ grade (G) 4 hematologic toxicities except for lymphopenia, ≥ G4 acute infusion reaction/cytokine release syndrome or tumor lysis syndrome, or ≥ G3 other non-hematologic toxicities. Plasma KW-0761 levels were assessed in all pts enrolled. Response was assessed by standard response criteria for NHL by each investigator. Results: As of August 18, 2008, 13 pts including 6 males and 7 females (11 ATL, 1 PTCL-U, 1 MF) were treated with KW-0761 at 0.01 (N=3), 0.1 (N=4), 0.5 (N=3) and 1.0 mg/kg (N=3). Median age was 62 years (range 46 – 69). KW-0761 was well tolerated without any DLT. ≥ G2 toxicities included: hematologic: lymphopenia (G4: N=2, G3: N=6, G2: N=3), neutropenia (G3: N=2, G2: N=3), eosinophilia and thrombocytopenia (G2: N=1, each); and non-hematologic: herpes zoster (3 months after the 4th dosing, G3: N=1), acute infusion reaction/cytokine release syndrome (G3: N=1, G2: N=4), constipation, rash, prolonged QTc, ALT increase, CRP increase, and pain of lymph node (G2: N=1, each). One pt enrolled at 0.1 mg/kg was withdrawn due to early disease progression. PK analysis showed that Cmax at 0.01 and 1.0 mg/kg after the 4th dosing were 324 ± 57 and 43469 ± 3819 ng/mL, respectively, and C168h at 0.01 and 1.0 mg/kg after the 4th dosing were 152 ± 12 and 21900 ± 3880 ng/mL, respectively. T1/2 at 0.01 and 1.0 mg/kg after the 4th dosing were 244 ± 117 and 554 ± 125 h, respectively. No anti-KW-0761 antibody has been detected. Complete response (CR) was observed in one ATL pt (0.1 mg/kg) with the disappearance of abnormal blood cells and skin disease, and in one PTCL-U pt (1.0 mg/kg) with the disappearance of abnormal blood cells, skin disease and enlarged lymph node. Overall, investigator-assessed responses for 13 enrolled pts were 31% including 2 CRs, 2 PRs (ATL at 0.01, and 0.1 mg/kg) and 4 SDs (ATL at 0.01, 0.1 and 1.0 mg/kg). Conclusions: KW-0761 was tolerable across a wide range (0.01 – 1.0 mg/kg) and had clinical activity in relapsed CCR4-positive ATL or PTCL. KW-0761 is a promising new antibody therapy for ATL and PTCL. Patient accrual is ongoing and the updated results will be presented.

Description: Introduction: KW-0761 is a defucosylated humanized IgG1 monoclonal antibody against CC chemokine receptor 4 (CCR4). Previous studies revealed that CCR4 was over-expressed on tumor cells from 88% of pts with ATLL and 38% of pts with PTCL. CCR4 expression was associated with unfavorable prognosis in both diseases. These evidences suggest that CCR4 could be a reasonable molecular target for treatment of CCR4-positive ATLL and PTCL. KW-0761 exerted very potent ADCC but not CDC against cultured ATLL cell lines using normal effecter cells. KW-0761 also exhibited potent ADCC against freshly isolated ATLL cells using the auto-effecter cells. Methods: KW-0761 is being investigated in a Phase I, single-agent, dose-escalation, multicenter study for relapsed or refractory pts with ATLL or PTCL after undergoing the initial chemotherapy. Eligible pts were required to express CCR4 on their tumor cells by FCM and/or IHC. This phase I trial was designed to evaluate toxicity, pharmacokinetics (PK), immunogenicity and anti-tumor activity. Toxicity was evaluated by NCI CTCAE (v3.0). Pts were planned to receive four weekly intravenous injections of KW-0761 at the doses of 0.01, 0.1, 0.5 and 1.0 mg/kg. Results: As of August 10, 2007, 6 pts (1 PTCL and 5 ATLL) have been treated with KW-0761 at the dose of 0.01 (N=3) and 0.1 mg/kg (N=3). Three pts were evaluable for toxicity, PK, immunogenicity and 4 pts were evaluable for anti-tumor activity. KW-0761 was well tolerated with no dose-limiting toxicities. Reversible grade (G) 3 toxicities were lymphocytopenia and herpes zoster. G1-2 adverse events were; rash, constipation, nausea, EF decrease, neutropenia, thrombocytopenia, eosinophilia, lymphocytopenia, ALP increase and QT prolongation. In one leukemic ATLL pt with swollen lymph nodes (LNs) treated at 0.01 mg/kg, peripheral ATLL cells disappeared and the LNs were decreased in size, attaining PR. In another leukemic ATLL pt with skin involvement treated at 0.1 mg/kg, peripheral ATLL cells disappeared and the skin achieved PR by Physicians Global Assessment of Clinical Conditions (PGA). One ATLL pt with skin and bone involvement at 0.01 mg/kg showed SD. Preliminary PK analysis at 0.01 mg/kg showed that Cmax and T1/2 after the 4th dosing was 323.7 56.7 ng/ml and 244 117 hrs, respectively. KW-0761 did not exhibit immunogenicity at 0.01 mg/kg. Conclusions: Preliminary phase I data warrant further investigations of KW-0761, a first-in-class humanized anti-CCR4 antibody, against CCR4-positive peripheral T-cell malignancies including ATLL. Patient accrual is ongoing and the updated results will be presented at the meeting.