ALBERT

Description: Recently, several novel prognostic factors have been identified; their significance has been demonstrated in selected patient (pt) populations and retrospective analyses. As a group, previously treated pts with CLL likely have their respective, relevant prognostic factors for clinical endpoints, which may be further impacted by treatment (Rx). We prospectively evaluated the significance of newer prognostic factors: FISH abnormalities (abn) (Vysis CLL panel), IgVH mutation status, ZAP70 expression (flow & immunohistochemistry), CD38 expression (≥30%); as well as traditional factors: conventional cytogenetic analysis perfomed on bone marrow metaphases, age, sex, # prior Rx, refractoriness to alkylating agents (ALK) or fludarabine (FLU), absolute lymphocyte count (ALC), HGB, PLT, β-2 microglobulin (B2M), ALB, LDH, creatinine, and Alk Phos as independent predictors for survival in previously treated pts. The group included 473 previously treated pts seen at M.D.Anderson (10/03–8/07), who were evaluated by bone marrow sampling with conventional and FISH cytogenetic analyses, and the new and traditional prognostic factors described above. The median (range) age was 63yrs(31–87) and # prior Rx was 2(1–13). Other characteristics were: 43% Rai high-risk; 35% FLU-refractory; and 39% ALK-refractory; 74% unmutated IgVH; 54% ZAP70+ (flow); 76% ZAP70+ (IHC); and 68% CD38+. FISH results were: 22% del 17p13, 21% del 11q22, 10% +12, and 48% del 13q14 or no abn by the hierarchical classification. Conventional cytogenetic analysis of bone marrow metaphases demonstrated 25% with a complex karyotypic abn (〉1 cell with 〉1 chromosome abn), 58% diploid, 17% with single clonal abn (〉1 cell with 1 abn). Of the 100 pts with complex karyotypic abn, 50% had del 17p13, 28% del 11q22, 6% +12, 9% del 13q14, and 7% had no abn by FISH. Survival was measured from the time of prognostic factor characterization (FISH). The median follow-up time was 10mo(0–47). Univariate analyses identified the following significant (p≤.01) predictors for shorter survival: advanced age, # prior Rx, Rai high-risk, ALK- or FLU-refractory, FISH del 17p13; complex karyotypic abn (Figure 1), unmutated IgVH, high ALC, low HGB, low PLT, high B2M, low ALB, high LDH, and high Alk Phos. Multivariate analysis produced the following model with the following significant (p

Description: The availability of new and active agents for treatment of patients with CLL has led to an evolution in treatment from single-agent to combination regimens, resulting in improved response rates and possibly survival. The focus in developing new treatment regimens is to attain as high a complete remission (CR) rate as possible and to eliminate residual disease in bone marrow. The FCR regimen has significant activity in both chemotherapy-naïve and previously treated patients with CLL. Historic comparisons suggest a survival advantage for previously treated patients treated with FCR compared with F or FC. We combined alemtuzumab (A) with FCR to enhance the potentiation of mAb and chemotherapy in a phase II clinical trial for previously treated patients with CLL. The CFAR regimen consists of C-250mg/m2 day 3–5; F-25mg/m2 days 3–5; A-30mg days 1,3,5, and R-375–500mg/m2 day 2, each 28 days for 6 intended cycles. Methylprednisone 125 mg on day 1 and hydrocortisone 100 mg on days 2, 3, 5 were given with each course for mAb premedication. Allopurinol 300 mg daily was given for tumor lysis prophylaxis. Antibiotic prophylaxis was TMP-SMX DS twice daily 2–3 days/week and valacyclovir or valgancyclovir through all 6 cycles and 2 months after completion of treatment. Blood CMV antigen was monitored before each course. To date, 66 patients have been enrolled. There are 44 evaluable patients; 35 were male, 24 had Rai high-risk disease, the median # of prior treatments was 4 (1–9), 36% were fludarabine-refractory, 91% received prior R, 20% prior A, 16% had prior FC, and 48% had prior FCR. Pre-treatment karyotype of bone marrow cells was done in 38, 17 had complex abnormalities (7=17p-; 7=11q-); 16 were diploid. The median age=58yrs(41-79), ALC=428k/μL(.04–320), HGB=11.9g/dL(8.2–15.4), PLT=126k/μL(14–349), and β2m=4.5mg/L(2.5–11.3). The CR, PR, and OR rates for the 44 patients were 27%, 38%, and 65%, respectively. There were 2 early deaths and 2 could not be evaluated for response. Higher CR and OR rates were seen in fludarabine-sensitive patients. Higher OR but not CR rate was seen in earlier-stage patients. Elimination of minimal residual disease by flow cytometry (

Description: Interleukin-1 (IL-1) has recently been reported to play an important role in acute myelogenous leukemia (AML) blast proliferation. We therefore investigated the effect of soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) on the growth of AML bone marrow blast progenitors from 25 patients. In the AML blast colony culture assay, sIL-1R and IL-1RA inhibited blast colony-forming cell replication in a dose-dependent fashion, at concentrations ranging from 10 to 500 ng/mL (sIL-1R) and 10 to 1,000 ng/mL (IL-1RA), and their inhibitory effect was partially reversed by IL-1 beta. A similar inhibitory effect was also noted with the use of anti-IL-1 beta neutralizing antibodies. When AML blast progenitors were grown either in the presence of fetal calf serum (FCS) alone or with one of the following: phytohemagglutinin leukocyte-conditioned medium (PHA-LCM), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), or stem cell factor (SCF), addition of 100 ng/mL sIL-1R or IL-1RA inhibited blast colony formation by 3% to 96% and 2% to 97%, respectively. In sharp contrast, neither of these IL-1- inhibitory molecules significantly inhibited proliferation of normal marrow hematopoietic progenitors. Lysates of 2 x 10(7) low-density AML marrow cells were tested for intrinsic IL-1 beta content using an enzyme-linked immunoadsorbant assay (ELISA). Samples from five of six patients showed high concentrations (ranging from 501 to 2,041 pg), whereas 2 x 10(7) cells from two normal marrow aspirates yielded 54.6 pg of IL-1 beta. AML blast colony-forming cells from all six patients were inhibited by sIL-1R, IL-1RA, or both. Incubation of nine samples of AML low-density cells with either sIL-1R or IL-1RA reduced GM-CSF concentrations in cell lysates, and supernatants from nine (P less than .01) and six samples (P less than .037), respectively, and G-CSF concentration in lysates from six of nine samples (P less than .03), and in supernatants from five of six samples (P less than .06) when studied by ELISAs. Our data implicate IL-1 in AML blast proliferation and suggest the potential benefits of using IL-1-inhibitory molecules in future therapies for AML.

Description: Interleukin-1 (IL-1) has recently been reported to play an important role in acute myelogenous leukemia (AML) blast proliferation. We therefore investigated the effect of soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) on the growth of AML bone marrow blast progenitors from 25 patients. In the AML blast colony culture assay, sIL-1R and IL-1RA inhibited blast colony-forming cell replication in a dose-dependent fashion, at concentrations ranging from 10 to 500 ng/mL (sIL-1R) and 10 to 1,000 ng/mL (IL-1RA), and their inhibitory effect was partially reversed by IL-1 beta. A similar inhibitory effect was also noted with the use of anti-IL-1 beta neutralizing antibodies. When AML blast progenitors were grown either in the presence of fetal calf serum (FCS) alone or with one of the following: phytohemagglutinin leukocyte-conditioned medium (PHA-LCM), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), or stem cell factor (SCF), addition of 100 ng/mL sIL-1R or IL-1RA inhibited blast colony formation by 3% to 96% and 2% to 97%, respectively. In sharp contrast, neither of these IL-1- inhibitory molecules significantly inhibited proliferation of normal marrow hematopoietic progenitors. Lysates of 2 x 10(7) low-density AML marrow cells were tested for intrinsic IL-1 beta content using an enzyme-linked immunoadsorbant assay (ELISA). Samples from five of six patients showed high concentrations (ranging from 501 to 2,041 pg), whereas 2 x 10(7) cells from two normal marrow aspirates yielded 54.6 pg of IL-1 beta. AML blast colony-forming cells from all six patients were inhibited by sIL-1R, IL-1RA, or both. Incubation of nine samples of AML low-density cells with either sIL-1R or IL-1RA reduced GM-CSF concentrations in cell lysates, and supernatants from nine (P less than .01) and six samples (P less than .037), respectively, and G-CSF concentration in lysates from six of nine samples (P less than .03), and in supernatants from five of six samples (P less than .06) when studied by ELISAs. Our data implicate IL-1 in AML blast proliferation and suggest the potential benefits of using IL-1-inhibitory molecules in future therapies for AML.

Description: Syndecan-1 (sCD138) is a transmembrane heparan sulfate-bearing proteoglycan expressed in epithelial cells as well as hematopoitic cells that demonstrate plasmacytioid differentiation. CD138 is believed to play a role in cell-cell and cel-matrix interaction. A soluble form of CD138 (sCD138) has been reported to be elevated in multiple myeloma. Higher levels of sCD138 have been reported to correlate with poor outcome in myeloma. While some cells in patients with chronic lymphocytic leukemia (CLL) can demonstrate plasmacytoid differentiation, CD138 is usually not expressed in B-cell CLL. We investigated the levels of circulating sCD138 in the plasma of 104 patients with CLL and correlated these levels with clinical behavior. sCD138 levels were elevated in patients with CLL as compared with normal control subjects (median, 52.8, range: 13.4-252.7 ng/mL) (P53 ng/mL) had significantly shorter survival than those with mutated IgVH and lower levels of sCD138. Similarly, patients with unmutated IgVH but high levels of sCD138 (〉53 ng/mL) had significantly shorter survival than those with lower levels of sCD138 and unmutated IgVH (P=0.007). When CLL patients were dichotomized into 2 groups according to the median level of sCD138, there was significant positive correlation with age, platelet count, male sex, white cell count, and sCD23 level (all P

Description: Prognostic factors are tools to address heterogeneity in clinical behavior and survival in patients with disease. They are particularly relevant for patients with malignancy, including chronic lymphocytic leukemia (CLL). There is striking heterogeneity in overall survival (OS) of patients with CLL as well as in response to treatment, time to treatment failure (TTF), and time to progression (TTP) following response. Serum β2 microglobulin (β2M) has previously been reported to correlate with OS and TTP in patients with CLL. We performed a retrospective analysis of 659 Rx-naïve and 1062 previously treated patients with CLL enrolled on clinical trials from 5/74 to 7/05 at MD Anderson Cancer Center evaluating for predictors for response to treatment, amount of treatment given, incidence of myelosuppression, TTF, TTP in responders, and OS. Univariate analysis was performed, then significant factors were used to develop multivariate models for these endpoints. Groups were analyzed separately. The clinical factors evaluated included: age, Rai stage, # nodal sites, liver and spleen size, β2M, WBC, ALC, HGB, PLT, serum LDH, Cr, ALB, CD38 expression, and serum Ig levels, and refractoriness to alkylating agents and fludarabine and # prior treatments for previously treated patients. In the Rx-naïve group, characteristics (median and range) were as follows: age=57 yrs(17–86); β2M=3.3 mg/L(1.1–16.4); WBC=74.7k/μL(2.1–552); ALC= 63k/μL(1–512); HGB=12.7 g/dL(5.7–18.7); PLT=156 k/μL(8–450); LDH=545 IU/L(103–3600); and IgG=754 mg/dL(45–5000). Patients with Rai stage 0=28; Rai I-II=402; and Rai III-IV=196. In the previously treated group, characteristics (median and range) were as follows: age=61 yrs(25–83); β2M= 4.4 mg/L(1.4–59.4); WBC= 43 k/μL(.6–953); ALC=36 k/μL(0–829); HGB=11.4 g/dL(3.8–17.6); PLT= 121 k/μL(2–703); LDH=597 IU/L(21–4739); and IgG=586 mg/dL(14–5000). Patients with Rai stage 0=37; Rai I-II=392; and Rai III-IV=563. Multivariate models identified the following predictors (p

Description: Patients (pts) with CLL have diverse clinical features, including time to first treatment (Rx), response to Rx, remission duration, and outcomes with salvage Rx. We identified serum beta-2 microglobulin (B2M) of 4 mg/L or greater as a high-risk feature, predicting for lower complete remission (CR) rate and shorter progression-free survival (PFS), with frontline chemoimmunotherapy. For pts

Description: The clinical course for patients with chronic lymphocytic leukemia (CLL) is remarkably variable. Patient characteristics have been correlated with meaningful clinical endpoints such as time to treatment, response to treatment, progression-free survival, and overall survival (OS) for patients with CLL. Identification of such characteristics enables informed discussion about timing of treatment, treatment options, and can provide insight into the basic biology of the disease. The Rai staging system identifies risk groups for survival based on characteristics in untreated patients. However, within each stage there is still heterogeneity in survival. In addition to factors used in clinical staging, several other characteristics have been correlated with survival including: age, gender, pattern of marrow infiltration, lymphocyte doubling time, presence of prolymphocytes, presence of chromosome abnormalities, elevated serum levels of beta-2 microglobulin (ß-2M), thymidine kinase, and soluble CD23, IgVH mutation status, and expression of ZAP70 and CD38 by leukemia cells. Alone, each of these independent prognostic factors, including stage, has limited utility in predicting overall survival. A nomogram is a graphic representation of a statistical model with scales for calculating the cumulative affect of weighted variables on the probability of a particular outcome. The strength of using nomograms is that they combine multiple independent variables to predict an outcome and enable appreciation of the prognostic weight of each variable. They are useful in counseling patients and in developing expectations for clinical trials as well as identifying patients "at risk" who should be targeted for aggressive therapy or investigational approaches. We retrospectively evaluated 1607 chemotherapy-naive and 1602 previously treated patients with CLL that presented to MD Anderson Cancer Center to identify independent characteristics that could be used to predict OS. Based on significant characteristics identified in univariate analyses, a multivariate model was developed for OS for each patient group. Characteristics evaluated included age, gender, Rai stage, performance status (PS), # of affected node sites, WBC count, absolute lymphocyte count (ALC), HGB, PLT, ALB, serum alkaline phosphatase (AP) and LDH, % BM lymphocytes, spleen and liver size, ß-2M, # of prior therapies and refractoriness to fludarabine for previously treated patients. Univariate and multivariate analyses identified several patient characteristics at presentation that predicted for overall survival for each patient group. The final multivariate Cox proportional hazards model included the following characteristics for chemotherapy-naive patients: age, ALC. LDH, β2M, Rai stage, and # of involved lymph node groups. For previously treated patients, the final multivariate Cox hazards model included the following significant characteristics: β2M, # prior Rx, age, IgM, PLT, and HGB. Nomograms were constructed for each group using the respective significant characteristics to estimate 2-, 5-, and 10-year survival probability and median survival time. These prognostic model may help patients and clinicians in decision-making as well as in clinical research and design of clinical trials. Nomograms are powerful tools for predicting important clinical endpoints including survival, for counseling patients, and developing and analyzing clinical trials.