The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.

We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio ≥2.0, or average number of FGFR1 signals per tumor cell nucleus ≥6, or the percentage of tumor cells containing ≥15 FGFR1 signals or large clusters ≥10%) was detected at a frequency of 16% and low-level amplification (as defined by ≥5 FGFR1 signals in ≥50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials.

The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overex-pressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon-(IFN-) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138 human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autolo-gous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lympho-cytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignan-cies provided a tumor antigen-specific antibody is available. (Blood. 2006;107: 1955-1962)

Because nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) express CD20, rituximab may be used as a nonmutagenic treatment option to avoid late toxicities in this rather indolent entity. Between 1999 and 2004, the German Hodgkin Study Group (GHSG) investigated the activity of rituximab (375 mg/m 2 in 4 doses) in a phase 2 trial in 21 relapsed or refractory NLPHL patients. The initial diagnosis of NLPHL was confirmed in 15 of the 21 enrolled patients by reference pathology. The remaining cases were reclassified as Hodgkin lymphoma transformed to T-cell rich B-cell lymphoma (TCRBCL; n ‫؍‬ 2) or CD20 ؉ classical Hodgkin lymphoma (cHL; n ‫؍‬ 4). In NLPHL patients the overall response rate was 94%, including 8 complete remission (CR) and 6 partial remission (PR IntroductionNodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of Hodgkin lymphoma (HL) and has a typical immunophenotype of the malignant cell population (CD30 Ϫ CD15 Ϫ CD20 ϩ ) as compared with cHL (CD30 ϩ CD15 ϩ CD20 Ϫ ). 1,2 NLPHL can resemble T-cell rich B-cell lymphoma (TCRBCL) 3 and often presents in early stages with an indolent course and excellent prognosis. 4,5 Early-stage NLPHL patients treated with chemotherapy are more likely to die from secondary malignancies and cardiovascular disease compared with primary neoplasm. 1 The slow disease progression and the CD20 ϩ tumor cells in NLPHL prompted us to evaluate rituximab in a phase 2 clinical trial. 6 Here we report the 7-year follow-up of this trial showing that single agent rituximab has substantial and longlasting antitumor effects in NLPHL and CD20 ϩ classical Hodgkin lymphoma (cHL) patients when given at standard doses. MethodsPatients were enrolled between 1999 and 2004 at 17 different centers. Eligibility criteria included NLPHL at first or higher relapse or progressive disease after at least one standard regimen. In addition, at least 30% of tumor cells had to stain positive for CD20. All histologic slides were reviewed by an independent expert panel consisting of 6 reference pathologists. Patients received 4 weekly infusions of standard dose rituximab at 375 mg/m 2 . The study was approved by the institutional review board at each study site, and written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. Remission status according to the International Workshop Criteria was checked 4 weeks after the end of treatment, and then every 3 months for 2 years, every 6 months until the fifth year, and once a year later on. Time-to-progression (TTP) and overall survival (OS) were analyzed using the Kaplan-Meier method. A complete description of the design of this phase 2 multicenter study was reported elsewhere. 6 Results and discussionInitially, 21 patients with NLPHL (19 males, one female) were included. The diagnosis of NLPHL was confirmed in 15 (71%) of these patients by expert reference pathology. The remaining patients were either reclassified as HL transformed to TCRBCL (n ϭ 2) or CD20-positive cHL (n ϭ 4) and...