Nelarabine (506U78) is a soluble pro-drug of 9-␤-D-arabinofuranosylguanine (ara-G), a deoxyguanosine derivative. We treated 26 patients with T-cell acute lymphoblastic leukemia (T-ALL) and 13 with T-cell lymphoblastic lymphoma (T-LBL) with nelarabine. All patients were refractory to at least one multiagent regimen or had relapsed after achieving a complete remission. Nelarabine was administered on an alternate day schedule (days 1, 3, and 5) at 1.5 g/m 2 /day. Cycles were repeated every 22 days. The median age was 34 years (range, 16-66 years); 32 (82%) patients were male. The rate of complete remission was 31% (95% confidence interval [CI], 17%, 48%) and the overall response rate was 41% (95% CI, 26%, 58%). The principal toxicity was grade 3 or 4 neutropenia and thrombocytopenia, occurring in 37% and 26% of patients, respectively. There was only one grade 4 adverse event of the nervous system, which was a reversible depressed level of consciousness. The median disease-free survival (DFS) was 20 weeks (95% CI, 11, 56), and the median overall survival was 20 weeks (95% CI, 13, 36). The 1-year overall survival was 28% (95% CI, 15%, 43%). Nelarabine is well tolerated and has significant antitumor activity in relapsed or refractory T-ALL and T-LBL. (Blood. 2007;109:5136-5142)

IntroductionThe SET protein is a potent physiologic inhibitor of protein phosphatase 2A (PP2A) 1 that was isolated from a chromosomal rearrangement at 9q34 in a patient with acute undifferentiated leukemia. 2 The SET protein is overexpressed in chronic myelogenous leukemia (CML) cells, and SET protein levels are further elevated during blast crisis. 3 SET overexpression in CML cells correlates with decreased PP2A activity. 3 This indicates that many of the SET oncogenic activities may be manifest through inhibition of PP2A. PP2A plays a role in many cellular processes, including cell cycle regulation, cell proliferation, apoptosis, development, cytoskeleton dynamics, cell motility, and stem cell self-renewal. 4 In addition, PP2A is a critical tumor suppressor gene that regulates multiple important oncogenic signal transduction pathways. [5][6][7] PP2A inhibition is essential for cell transformation and tumor formation, 8,9 but overexpression of PP2A inhibitory proteins in chronic lymphocytic leukemia (CLL) has not been reported.Of the nearly 84 000 annual cases of leukemia in the Western world, B-cell CLL is the most common, accounting for ϳ 30% of adult leukemia cases. 10 Characterized by accumulation of monoclonal mature B cells, 11 the CLL clinical course is heterogeneous, with some patients experiencing an aggressive course that demands early treatment and others experiencing long survival without disease-related symptoms or ever requiring treatment. 11 Aberrant apoptosis in CLL cells correlates with arrest either in the G 0 or early G 1 phases of the cell cycle. 12,13 This defective apoptosis in CLL cells is partly the result of aberrant signaling through the Akt kinase and the ERK MAPK pathways, in which phosphorylated-Akt is necessary for survival of the leukemia cells. 14,15 The observation of aberrantly activated Akt and downstream pathways in CLL cells also suggests that the normal regulator of these pathways, PP2A, is unable to perform its normal role.We thus sought to determine whether SET is overexpressed in CLL cells relative to normal B cells. We found that SET is significantly overexpressed in CLL cells and related non-Hodgkin lymphoma (NHL) cell line cells. In freshly isolated CLL patient samples, higher cellular levels of the SET correlated with more aggressive disease requiring earlier treatment. Antagonism of SET using shRNA-mediated knockdown or pharmacologic antagonism with novel cell-permeable SET antagonist peptides induced apoptosis, reduced cellular levels of Mcl-1, and caused death of CLL and NHL cells, but normal B cells were scarcely affected by SET antagonism. We also found that pharmacologic SET antagonism in vivo inhibited growth of B-cell NHL tumor xenografts in SCID mice. Methods GeneralAll reagents were from Sigma-Aldrich unless noted otherwise. Anti-SET antibody was from Santa Cruz Biotechnology. Anti-␤-actin, total c-Myc, pS62 c-Myc, and Mcl-1 were from Abcam. All primary antibodies were used at a 1:1000 dilution, except for ␤-actin, which was used at 1:10 000. All secondary ...

Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.

Purpose Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) –specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial. Patients and Methods Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control. Results Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients. Conclusion Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials.

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BACKGROUNDAfrican‐American patients have been under‐represented in oncology clinical trials. Better understanding barriers to African‐American participation may help increase the accrual of African‐American patients onto clinical trials.METHODSTwo hundred eighteen patients with malignant disease (72 African‐American patients and 146 white patients) were recruited from the Duke Cancer Clinic and from Duke Oncology Outreach Clinics (DOORS). Patients were interviewed using a standardized survey. Questions included patients' knowledge of cancer, religious/spiritual beliefs, satisfaction with medical care, knowledge of clinical trials, reasons for participating or refusing to participate in a clinical trial, financial/transportation issues, and demographic factors, such as age and education. Data on attitudes and belief were analyzed for group differences between African‐American patients and white patients as well as between patients who were treated at the Duke Cancer Clinic and patients who were treated at DOORS clinics.RESULTSWillingness to participate in a clinical trial depended on both race and clinic site. Forty‐five percent of white patients, compared with 31% of African‐American patients, were willing to participate in a clinical trial (P = 0.05). white and African‐American patients who were treated at the Duke Cancer Clinic were more willing to participate in a trial compared with their counterparts who were treated at DOORS clinics (47% vs. 37%, respectively; P = 0.09). The greatest differences between groups (African‐American patients vs. white patients and Duke Cancer Clinic patients vs. DOORS patients) were education and income: Much greater percentages of African‐American patients and DOORS patients did not complete high school and had annual incomes < $15,000. In addition, more African‐American patients than white patients believed that God would determine whether they would be cured or would die from their disease. In a multivariate analysis, education, income, and belief that God would determine the patient's outcome also were correlated with a decreased willingness to participate in clinical trials.CONCLUSIONSFactors associated with religion, education, and income, rather than race, may be major barriers to clinical trial participation. Interventions that target education and income may increase the recruitment of African‐American oncology patients onto clinical trials. Cancer 2003;97:1499–506. © 2003 American Cancer Society.DOI 10.1002/cncr.11213

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Purpose Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC). Experimental Design In dose escalation, ensartinib was administered at doses of 25−250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were allowed. Results Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related Grade 3-4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60% and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI naïve patients was 80% and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC.