Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia

Angiogenesis plays an important role in solid tumors and hematologic malignancies. The prognostic significance of angiogenic factors in adult acute lymphoblastic leukemia (ALL) remains ambiguous. We therefore analyzed the impact of angiogenic factor levels on overall survival of newly diagnosed adult ALL patients. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-1 receptor alpha (IL-1Ralpha), IL-6, IL-8, VEGF receptors VEGFR1 and VEGFR2, and thrombopoietin (TPO) were measured in plasma samples of 95 patients by enzyme-linked immunosorbent assay (ELISA). In a univariate Cox proportional hazards model, higher levels of IL-1Ralpha, IL-8, VEGFR1, and VEGFR2 were predictive of poor survival. In contrast, higher levels of VEGF were predictive of longer survival, and higher levels of bFGF suggested a similar trend (P = .09). The multivariate model simultaneously included VEGF (relative risk [RR] for death, 8.01; P = .001 for levels less than or equal to 19.5 pg/mL), IL-1Ralpha (RR, 5.12; P = .007 for levels greater than 373 pg/mL), and VEGFR2 (RR, 4.01; P = .04 for levels greater than 8222 pg/mL) as independent factors for survival. Of interest is the association of high levels of VEGF with good prognosis and higher levels of VEGF receptors with poor outcome. These data reflect the complexity by which angiogenic factors may affect the clinical behavior of patients with ALL, and this complexity should be considered in any therapeutic strategy incorporating antiangiogenic agents.     

Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy

Pretreatment characteristics and outcome of patients treated with induction regimens containing high-dose ara-C (HiDAC) at M. D. Anderson Cancer Center refractory to 1 cycle of induction were compared with similar patients achieving a complete response (CR). Among 1597 patients treated with HiDAC-based induction from 1995 to 2009, 285 were refractory to 1 cycle. Median age was 59 years (range, 18-85 years). Induction regimens included HiDAC with anthracyclines (n = 181; 64%) or HiDAC with nonanthracycline chemotherapy (n = 104; 36%). Refractory patients were older (median age, 59 vs 56 years; P < .001), more likely with unfavorable cytogenetics (P < .001) and antecedent hematologic disorder (P < .001), and had a higher presentation white blood cell count (P = .04), but not a higher incidence of FLT3 mutations (P = .85), than those achieving CR. Forty-three patients (22%) responded to salvage (35 CR and 8 CR without platelet recovery). With a median follow-up of 72 months (range, 27-118 months) in responders, 11 are alive. Nineteen patients (7%) were alive and in CR for at least 6 months, including 9 who underwent allogeneic stem cell transplantation. On multivariate analysis, severe thrombocytopenia, leukocytosis, increasing marrow blast percentage, unfavorable cytogenetics, and salvage not including allogeneic stem cell transplantation were associated with a worse survival. Alternative strategies are needed for these patients.     

Pilot study of bortezomib for patients with imatinib-refractory chronic myeloid leukemia in chronic or accelerated phase

BackgroundProteasome inhibitors are anticancer compounds that disrupt the proteolytic activity of the proteasome and lead to tumor cell growth arrest and apoptosis. Bortezomib is a proteasome inhibitor that is currently approved for use in multiple myeloma (MM) and mantle-cell lymphoma. It induces apoptosis of chronic myeloid leukemia (CML) cells in vitro, but the activity of bortezomib in patients with imatinib-resistant CML is unknown.MethodsWe conducted a pilot trial to evaluate the activity of single-agent bortezomib in CML. Seven patients with imatinib-refractory CML were treated with bortezomib at a dose of 1.5 mg/m² on days 1, 4, 8, and 11 every 3 weeks.ResultsThe median number of cycles received was 2. No patient had a hematologic or cytogenetic response. Three patients had a temporary decrease in basophil counts associated with therapy with bortezomib. Six patients experienced grade 3/4 nonhematologic toxicities.ConclusionBortezomib had minimal efficacy and considerable toxicity in patients with imatinib-refractory CML. Further studies should focus on alternative approaches to using proteasome inhibitors in the treatment of CML, such as in combination with tyrosine kinase inhibitors (TKIs) or as a strategy to eradicate leukemic stem cells.     

Retrospective comparison of clofarabine versus fludarabine in combination with high-dose cytarabine with or without granulocyte colony-stimulating factor as salvage therapies for acute myeloid leukemia

We recently reported that clofarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (GCLAC) produced a 46% complete remission rate in relapsed/refractory acute myeloid leukemia. GCLAC differs from FLAG by substitution of clofarabine for fludarabine, raising the question of the relative efficacy of these two regimens. We compared GCLAC given at the University of Washington Medical Center/Fred Hutchinson Cancer Research Center to fludarabine and cytarabine (FA) and FLAG given at MD Anderson Cancer Center. Independent multivariate analyses conducted at both institutions showed that after accounting for duration of first complete remission, salvage number, age, and cytogenetics, GCLAC was associated with a higher complete remission rate (odds ratio 9.57, P<0.0001) and longer survival (mortality hazard ratio 0.43, P=0.0002). Despite the retrospective nature of the analyses, GCLAC may be superior to FA/FLAG, particularly in patients with short duration of first complete remission or unfavorable cytogenetics.     

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.     

A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome

BACKGROUND:

Ezatiostat is a glutathione analog prodrug glutathione S‐transferase P1‐1 (GSTP1‐1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate‐1 risk myelodysplastic syndrome (MDS).

METHODS:

Patients were randomized by 1 stratification factor—baseline cytopenia (anemia only vs anemia with additional cytopenias)—to 1 of 2 extended dosing schedules. Multilineage hematologic improvement (HI) responses were assessed by International Working Group 2006 criteria.

RESULTS:

Overall, 11 of 38 (29%) red blood cell (RBC) transfusion‐dependent patients had HI‐Erythroid (HI‐E) response. The median duration of HI‐E response was 34 weeks. Multilineage responses were observed. There was 1 cytogenetic complete response in a del (5q) MDS patient. An important trend was the effect of prior therapy on response. A 40% HI‐E rate (6 of 15 patients) was observed in patients who had prior lenalidomide and no prior hypomethylating agents (HMAs), with 5 of 11 (45%) patients achieving significant RBC transfusion reduction and 3 of 11 (27%) achieving transfusion independence. A 28% HI‐E rate (5 of 18 patients) was observed in patients who were both lenalidomide and HMA naive, with 4 of 8 (50%) patients achieving clinically significant RBC transfusion reductions. Most common ezatiostat‐related adverse events were grade 1 and 2 gastrointestinal including: nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%).

CONCLUSIONS:

Ezatiostat is the first GSTP1‐1 inhibitor shown to cause clinically significant and sustained reduction in RBC transfusions, transfusion independence, and multilineage responses in MDS patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS. Cancer 2012. © 2011 American Cancer Society.     

Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS

BACKGROUND:

Activating mutations in RAS are frequently present in patients with acute myeloid leukemia (AML), but their overall prognostic impact is not clear.

METHODS:

A retrospective analysis was performed to establish the clinical characteristics of patients with RAS‐mutated (RAS^mut) AML, to analyze their outcome by therapy, and to describe the proteomic profile of RAS^mut compared with wild‐type RAS (RAS^WT) AML.

RESULTS:

Of 609 patients with newly diagnosed AML, 11% had RAS^mut. Compared with RAS^WT, patients with RAS^mut AML were younger (median age, 54 years vs 63 years; P = .001), had a higher white blood cell count (16K mm^?3 vs 4K mm^?3 ; P < 0.001) and bone marrow blast percentage (56% vs 42%; P = .01) at diagnosis, and were less likely to have an antecedent hematologic disorder (36% vs 50%; P = .03). The inv(16) karyotype was overrepresented in patients with RAS^mut and the ?5 and/or ?7 karyotype was underrepresented. RAS mutations were found to have no prognostic impact on overall survival or disease‐free survival overall or within cytogenetic subgroups. There was a suggestion that patients with RAS^mut benefited from cytarabine (AraC)‐based therapy. Proteomic analysis revealed simultaneous upregulation of the RAS‐Raf‐MAP kinase and phosphoinositide 3‐kinase (PI3K) signaling pathways in patients with RAS^mut.

CONCLUSIONS:

RAS mutations in AML may delineate a subset of patients who benefit from AraC‐based therapy and who may be amenable to treatment with inhibitors of RAS and PI3K signaling pathways. Cancer 2012. © 2012 American Cancer Society.     

Cytogenetic profile of patients with acute myeloid leukemia and central nervous system disease

BACKGROUND:

Acute myeloid leukemia (AML) infrequently involves the central nervous system (CNS). This study was undertaken in patients with AML to determine whether cytogenetic findings predict CNS involvement.

METHODS:

The medical records of 1354 patients with AML who were treated at The University of Texas MD Anderson Cancer Center between January 2000 and December 2008 were reviewed. Forty patients (3%) had CNS involvement at time of presentation or disease recurrence, of whom 37 had conventional cytogenetics performed on bone marrow aspirate material. Demographics, treatment, and status at last follow‐up were collected.

RESULTS:

Eleven patients (30%) had a diploid karyotype, and 14 patients (38%) had complex cytogenetics. Only 5 of the 40 patients had CNS disease at diagnosis, and the remaining patients had CNS disease at relapse. Patients who developed CNS disease were younger (P = .019), had a higher white blood cell (WBC) count at diagnosis (P = .001), had higher lactate dehydrogenase level (LDH) levels (P < .0001), and had higher percentages peripheral blast cells (P = .024) at diagnosis compared with the rest of the population. In addition, patients with CNS disease had higher rates of chromosome 16 inversion (P < .001), chromosome 11 abnormality (P = .005), and trisomy 8 (P = .02) and had a tendency toward complex cytogenetics (P = .2) compared with the control group (patients who had AML with no CNS involvement).

CONCLUSIONS:

Patients with AML and CNS disease often had higher LDH levels and WBC counts at diagnosis, and they often presented with chromosome 16 inversion and chromosome 11 abnormalities. The current study indicated that the overall survival of patients with AML who had CNS involvement is poor. Cancer 2012;. © 2011 American Cancer Society.     

Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia

BACKGROUND: From 20% to 30% of patients with acute promyelocytic leukemia (APL) who are treated with all-trans retinoic acid (ATRA) develop recurrent disease. Arsenic trioxide (ATO) is an effective agent for the salvage of patients with recurrent APL, and gemtuzumab ozogamicin (GO) has shown activity in patients with APL. METHODS: The authors investigated the efficacy of a combination of ATO, ATRA, and GO in 8 patients with APL in first recurrence (7 patients with hematologic recurrences and 1 patient with a molecular recurrence). All patients had received previous treatment with ATRA either alone or in combination with other agents. Patients received ATO 0.15 mg/kg intravenously until they achieved a bone marrow complete remission (CR). Once in CR, patients received consolidation with ATO, ATRA, and GO for 10 months. Patients then received maintenance with idarubicin, ATRA, 6-marcaptopurine, and oral methotrexate for 11 months. RESULTS: All 7 patients who had hematologic recurrences achieved CR after a median of 39 days (range, 21-56 days). After a median follow-up of >/=36 months (range, 4-55 months), 6 patients remained alive in CR, and 2 patients died in CR. Six of 8 patients remained in second CR that was longer than their first CR. All 7 evaluable patients achieved molecular remission. There were no grade 3 or 4 extramedullary toxicities. Two patients died, 1 secondary to a complication of metastatic lung adenocarcinoma, and the other of sepsis. CONCLUSIONS: The combination of ATO, ATRA, and GO was effective and may achieve durable remissions in patients with APL in first recurrence. It should be considered as an effective alternative to allogeneic or autologous transplantation.