ALBERT

Description: The prognosis of older adults with acute myeloid leukemia (AML) has not improved over the last three decades, despite the improvement in the outcome of younger adults during this same time due to the use of hematopoietic stem cell transplantation and intensive cytarabine consolidation. Older adults can not tolerate intensive therapy due to poor performance status, impaired organ function, and comorbid illnesses. Tipifarnib is an oral farnesyl transferase inhibitor with activity in the treatment of myelodysplastic syndrome (MDS) and high-risk AML patients. The primary objective of study S0432 was to test whether any of four different regimens of tipifarnib is sufficiently effective and tolerable therapy for previously untreated AML in patients of age 70 or over to warrant phase III study. Patients could not be considered candidates for, or must have declined, conventional induction chemotherapy. Patients had to have adequate renal and hepatic function, and the white blood cell (WBC) count had to be less than 30,000/cmm at the time of registration. Eligible patients could have a history of MDS, but could not have received AML induction chemotherapy or stem cell transplantation. Patients were randomized to receive either 600 mg or 300 mg of tipifarnib twice daily for either 21 consecutive days or 7 days every other week. Cycles were repeated every 28 days until disease progression or unacceptable toxicity. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) were to receive three additional cycles and then discontinue therapy. Patients achieving partial remission (PR) or with stable disease could continue treatment until progression of AML. If none of the first 15 patients on an arm achieved CR, CRi or PR, then accrual to that arm would be closed. However, all 4 treatment arms continued to full accrual. Three hundred forty-eight patients were registered between September 15, 2004 and February 15, 2006. Eighteen patients were excluded from analysis due to diagnosis other than AML, WBC above 30,000/cmm, no protocol therapy, and incorrect regimen administered. The median age in each arm was 78 years. The following are the treatment regimens: arm 1, 600 mg twice daily for 21 days; arm 2, 600 mg twice daily for 7 days every other week; arm 3, 300 mg twice daily for 21 days; arm 4, 300 mg twice daily for 7 days every other week. Responses were seen in each of the treatment arms with acceptable toxicities. The most common grade 3 or 4 adverse events were fatigue, febrile neutropenia, and infection in each treatment arm. However, the CR + CRi rates were less than 20% in each treatment arm, suggesting that further investigation of any of these regimens of tipifarnib is not warranted. Identification of predictors of response to tipifarnib, to further define the population of elderly AML patients most likely to benefit from this agent, should be investigated. Arm 1 Arm 2 Arm 3 Arm 4 CR 8% 4% 11% 1% CRi 5% 6% 4% 5% Fatal toxicity 8% 4% 2% 0% One year survival 14% 25% 28% 14%

Description: It is well known that, with advancing age, diseases and clinical procedures are associated with increased morbidity and mortality. This increasing vulnerability in the elderly with acute myeloid leukemia has been documented in a previous report of a study of a group of patients enrolled in five Southwest Oncology Group (SWOG) studies (Appelbaum, et al., Blood, 2006 May 1;107(9):3481-6). The authors of that study observed that the frequency of unfavorable risk cytogenetics was significantly elevated in patients over the age of 75. In this study we have examined the nature of cytogenetic changes over the entire adult life span in greater detail. We included the same patient population noted above plus additional AML patients with eligible cytogenetics data registered on a cytogenetics ancillary study SWOG 8750/9007, including a recent treatment study with subjects over the age of 70 years (S0432). A total of 1069 patients from 10 SWOG therapeutic clinical trials of previously untreated AML were included in this analysis. The abnormalities detected in this study are consistent with the emergence of increased genomic instability in the malignant clone. We observed an increasing frequency of complex karyotypes in the older subjects. For each 10 years increase in age there was a 16% increase (95% confidence interval 14%–19%) in the average number or abnormalities per individual, which was statistically significant (Poisson regression model, P

Description: Outcome of adult acute lymphoblastic leukemia (ALL) continues to be poor, and parameters to better discriminate patients with distinct prognosis are necessary. In studies comparing global gene expression differences between normal hematopoietic cells (whole bone marrow, peripheral blood, CD34+, and CD22+ sorted populations) and ALL cells using microarrays we found that the B-ALL cells showed evidence of increased expression of Connective Tissue Growth Factor (CTGF). The median log 2 transformed signal intensity of CTGF was 4.26 (range 3.95–4.76) in normal hematopoietic cells, and 6.59 (range: 3.85–10.62) in all leukemic samples; this difference in signal intensity is equivalent to a 5-fold increase in median expression of CTGF in leukemic cells. Therefore, we hypothesized that expression level of CTGF may have prognostic significance in adult ALL. Using real-time RT-PCR assays for CTGF we examined the expression of CTGF in 79 diagnostic ALL patients from SWOG protocol S9400 (28 bone marrow and 51 peripheral blood samples). Patients with L3 ALL were excluded from the study. The median age of patients was 35 (range 17–64), with the median WBC 23,400/ul (range 600–396,600), and peripheral blood blasts 56% (range: 0–98). Fifty patients had B-ALL (63%), 13 (16%) had T-ALL and lineage was unknown for 16 (20%). When treated as a continuous variable in a logistic regression model, the level of CTGF expression was significantly associated with inferior OS and DFS (p=0.007 and p=0.0012, respectively). When controlled for WBC and cell lineage, the association of CTGF with OS and DFS remained statistically significant. We then sub-grouped the ALL patients into three equal groups (tertiales) based on CTGF expression. This subgroup analysis found that the OS for patients in the highest tertile (highest CTGF expression) was approximately 11% (95% CI 0–24) at 5 years, as compared to 42% (95% CI 23–61) and 58% (95% CI 38–78) for patients with middle and low CTGF expression respectively (figure). In sub-analysis of patients with B-lineage ALL (n=50), the association of CTGF expression with OS and DFS was still statistically significant (p=0.009 and p=0.005) when treated as a continuous variable. This report is an example where a gene expression study detected a gene differentially expressed in leukemia, with clear clinical value. Moreover, this is the first report that correlates the level of expression of CTGF with outcome in ALL patients. We are actively pursuing the biological and clinical significance of CTGF in other ALL patients and model systems. Figure Figure

Description: We compared the gene expression profile of adult acute lymphoblastic leukemia (ALL) to normal hematopoietic and non-ALL samples using oligonucleotide arrays. Connective tissue growth factor (CTGF) was the highest overexpressed gene in B-cell ALL compared with the other groups, and displayed heterogeneous expression, suggesting it might have prognostic relevance. CTGF expression was examined by quantitative reverse transcriptase–polymerase chain reaction (QRT-PCR) on 79 adult ALL specimens. CTGF expression levels were significantly increased in ALL cases with B-lineage (P 〈 .001), unfavorable cytogenetics (P 〈 .001), and blasts expressing CD34 (P 〈 .001). In a multivariate proportional hazards model, higher CTGF expression levels corresponded to worsening of overall survival (OS; hazard ratio 1.36, for each 10-fold increase in expression; P = .019). Further studies are ongoing to confirm the prognostic value of CTGF expression in ALL and to investigate its role in normal and abnormal lymphocyte biology.