Richard Quek

Combination mTOR and IGF-1R Inhibition: Phase I Trial of Everolimus and Figitumumab in Patients with Advanced Sarcomas and Other Solid Tumors

Purpose: Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG2 anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated. Experimental Design: Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1. Results: No DLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17–300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab. Conclusions: Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation. Clin Cancer Res; 17(4); 1–9. ©2010 AACR.

Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma

UNLABELLED The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic-activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. SIGNIFICANCE Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs.

High SUV uptake on FDG–PET/CT predicts for an aggressive B-cell lymphoma in a prospective study of primary FDG–PET/CT staging in lymphoma

BACKGROUND Data assessing the role of positron emission tomography (PET)/computed tomography (CT) imaging in lymphoma staging is still being accumulated and current staging is based primarily on CT. This study aims to compare the value of PET/CT over conventional CT and bone marrow biopsy (BMB) in the initial evaluation of patients with lymphoma. METHODS Data on 122 patients with PET/CT scans as part of their initial staging were prospectively collected and reviewed. All patients had complete staging, including BMB. RESULTS Among the 122 patients, 101 had non-Hodgkins lymphoma (NHL) and 21 had Hodgkins lymphoma (HL). Compared with conventional CT, PET/CT upstaged 21 (17%) cases [B-cell non-Hodgkins lymphoma (B-NHL), 12; T-cell non-Hodgkins lymphoma (T-NHL), 3; HL, 6]. Of significance, in 13 patients with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-avid splenic lesions, four had normal CT findings. A maximum FDG uptake of >10 standardized uptake value (SUV) seems to significantly correlate with an aggressive B-cell lineage (odds ratio 2.47, 95% confidence interval 2.23-2.70). Overall, PET scan was concordant with BMB results in 108 (89%) and discordant in 14 (11%) cases. In HL, our data show that PET scan and marrow results agreed in 19 of the cases (90%), being concordantly negative in 18 cases and concordantly positive in one, giving a negative predictive value (NPV) of 100%, sensitivity of 100% and specificity of 90%. Of note, all 13 with early-stage HL had negative PET/CT scan and BMB. In NHL, all 17 cases of T-NHL had concordant PET and BMB results. In patients with aggressive B-NHL, BMB and PET/CT agreed in 58 patients (92%) and disagreed in five (8%), while the corresponding rates in indolent B-cell lymphoma were 14 (67%) and seven patients (33%), respectively. All seven were falsely negative. CONCLUSIONS PET/CT upstages 17% of cases and detects occult splenic involvement. This may have potential therapeutic and prognostic implications. SUV >10 may predict for an aggressive histology. Except for indolent B-NHL, our data show that PET scans have a good overall NPV in excluding lymphomatous bone marrow involvement. This is particularly true of early-stage HL, suggesting that BMB may be safely omitted in this group.

The relationship of hepatitis B virus infection and non‐Hodgkin’s lymphoma and its impact on clinical characteristics and prognosis

Aim of the study:  This study aims to evaluate the association between hepatitis B virus (HBV) and lymphoma and to characterize HBV‐related lymphomas. The efficacy of prophylactic lamivudine on HBV reactivation was also evaluated.

Prognostic factors in patients with diffuse large B cell lymphoma: Before and after the introduction of rituximab

This study attempted to evaluate the usefulness of the International Prognostic Index (IPI) as a prognostic model in patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin and prednisolone) chemotherapy. We compared 279 patients with DLBCL. Among them, 183 received CHOP while 96 received R-CHOP. Results showed that there were no statistically significant differences between the two groups of patients in terms of both the patient and the lymphoma characteristics. The estimated 2-year survival was significantly higher among patients treated with R-CHOP compared to CHOP alone (85.6% vs. 64.7%, P = 0.004). Both the IPI and age-adjusted IPI were less useful as prognostic models in patients receiving R-CHOP compared to CHOP. In the multivariate analysis, age ≥ 60, elevated serum LDH, low serum albumin and advanced stages of disease were each independently associated with decreased survival in patients treated with CHOP. In contrast, among those treated with R-CHOP, only male sex and advanced stage of disease were each independently associated with decreased survival. Using these two factors, patients treated with R-CHOP could be separated into three prognostic groups with 5-year estimated survival ranging from 47% to 100% (P < 0.0001). In summary, we can conclude that with the significant improvement in survival following the use of rituximab, the relevance of previously recognized prognostic factors has to be reassessed and re-evaluated.

Comparative analysis of extra-nodal NK/T-cell lymphoma and peripheral T-cell lymphoma: significant differences in clinical characteristics and prognosis

Aim: We aimed to compare the frequencies, clinical characteristics, and prognostic factors of peripheral T‐cell lymphoma (PTCL) vs. extra‐nodal natural killer (NK)/T‐cell lymphoma and to characterize the subtypes of extra‐nodal NK/T‐cell lymphoma. Methods: We reviewed 97 consecutive patients with PTCL and extra‐nodal NKT lymphoma from 2000 to 2006. During this period, a total of 780 patients with malignant lymphomas were treated in our center. The diagnostic criteria used were based on the WHO classification system of malignant lymphomas. Results: Extra‐nodal‐NK/T‐cell lymphoma and PTCL comprised 5.0% (39/780) and 7.4% (58/780) of all cases. Of the PTCL cases, histology was PTCL‐NOS in 25, anaplastic large cell in 11, angioimmunoblastic T cell in 18 and other subtypes in four patients. Compared with PTCL, extra‐nodal NK/T‐cell lymphoma was associated with a significantly inferior rates of complete remission (33% vs. 53%, P = 0.05) and 3 yr overall survival (29.5% vs. 47.5%, P = 0.003). On multivariate analysis, extra‐nodal NK/T‐cell histology was independently associated with decreased survival. Further analysis into this subtype showed the nasal variant (n = 25) differed significantly from extra‐nasal variant (n = 14) in terms of stage at presentation (stages III/IV, 36% vs. 79%), international prognostic index scores (high intermediate or high IPI scores, 24% vs. 64%), complete remission rates (48% vs. 7%), and median survival (10 months vs. 1 month, P < 0.0001). Conclusions: Extra‐nodal NK/T‐cell lymphoma was associated with a poorer prognosis compared with PTCL and is likely to comprise two distinct variants with different clinical behavior and prognosis.

Gastrointestinal Stromal Tumor: A Clinical Overview

Gastrointestinal stromal tumor (GIST) is a disease that was poorly understood historically. In the last decade, it has undergone a major transformation, sparked by the landmark discovery of the central role of activating KIT mutations in its pathogenesis and recognition of KIT protein expression (CD 117) as a reliable diagnostic marker of disease. The introduction and subsequent US Food and Drug administration approval of imatinib mesylate in the treatment of metastatic or unresectable GIST in February 1, 2002 has thrust this hitherto little known disease into the center stage of oncology, and GIST has served as a model for rationally designed drug trials in the field of cancer therapeutics since.

Effects of Sorafenib on Intra-Tumoral Interstitial Fluid Pressure and Circulating Biomarkers in Patients with Refractory Sarcomas (NCI Protocol 6948)

Purpose Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density. Patients and Methods Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1–2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP). Results In 15 patients accrued, the median TTP was 45 days (range 14–228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1α and decreased sVEGFR-2 levels. Increased plasma SDF1α and decreased sVEGFR-2 levels on day 28 correlated with disease progression. Conclusions Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series. Trial Registration ClinicalTrials.gov NCT00330421

JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Late‐onset neutropenia following RCHOP chemotherapy in diffuse large B‐cell lymphoma

Rituximab has been associated with the development of late‐onset neutropenia (LON). As only heterogeneous studies have been conducted, its incidence and clinical course remain unclear. We aim to: (1) study the incidence and clinical relevance of WHO grade 3/4 LON in a uniform group of patients with diffuse large B‐cell lymphoma (DLBCL) in complete remission following curative rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) chemotherapy; (2) ascertain predictive factors for LON. The 121 eligible patients identified from our prospectively maintained database were followed up for occurrence of WHO grade 3/4 LON. The clinical course of LON was documented, and its relationship with patient‐ and tumor‐related factors was analyzed. With a median follow‐up of 883 days (range, 265–1762), 13.2% had developed LON of grade 3/4. The median time to neutrophil nadir was 129 days (range, 39–277). The median time to recovery was 69 days (range, 3–349) and occurred in all except two patients. Only one episode of nonlife threatening bacterial culture‐positive urinary tract infection and pulmonary tuberculosis, both occurring in the same patient was documented. Results of Fischers exact test revealed that age, stage, LDH level, ECOG, marrow involvement, and hematologic parameters did not predict for LON development. WHO grade 3/4 LON is not infrequent in patients with DLBCL receiving RCHOP. Even so, it is reassuring that LON is self‐limiting and unassociated with life‐threatening infection. A watchful waiting approach is appropriate in majority of patients who develop LON following RCHOP. Am. J. Hematol., 2009.