Biomedical subjects

Maher Albitar

Publications and source records attributed to Maher Albitar.

At least 55 records · Page 3Linked to original sources

PubMed2004

Alemtuzumab: validation of a sensitive and simple enzyme-linked immunosorbent assay.

Alemtuzumab (MabCampath) is a humanized rat monoclonal antibody that targets the CD52 antigen. It has been approved for the treatment of patients with resistant chronic lymphocytic leukaemia (CLL). Measuring plasma/serum levels of alemtuzumab is important for optimizing the dosing and scheduling of therapy; however, current assays in serum or plasma, based on the capture of alemtuzumab using CD52, are complicated and difficult to adapt for high throughput testing. We developed a simple sandwich enzyme-linked immunosorbent assay (ELISA) to measure alemtuzumab that takes advantage of the remaining rat sequence in alemtuzumab. Using specific anti-rat immunoglobulin (Ig) antibodies (absorbed against human Ig), alemtuzumab levels were measured in the serum and plasma of patients treated with alemtuzumab. Levels were similar between plasma and serum samples, in fresh samples and samples stored at 4 degrees C for 24 h, but were significantly lower in samples stored at room temperature for 24h. The assay was successfully used to determine serum alemtuzumab pre- and post-treatment. This assay is simple and adaptable for high throughput testing, with a limit of detection of 0.05 microg/ml and a coefficient of variation of +/-12.5%. No false positivity was observed in >200 samples tested. This validated assay should help optimize the dosing and scheduling of alemtuzumab therapy. The underlying principles are also applicable to the measurement of other humanized antibodies using an appropriate anti-Ig.

Alemtuzumab↗

PubMed2004

Myelodysplastic syndrome: from morphology to biology.

Myelodysplastic syndrome is characterized by ineffective hematopoiesis manifesting as peripheral cytopenia, despite adequate or increased cellularity in bone marrow. Increased intramedullary apoptosis is thought to be the mechanism underlying this phenomenon. However, the mechanisms leading to this increased apoptosis remain largely unknown. Although less apoptosis is seen in more advanced disease with increased blasts, apoptosis remains the major characteristic feature of this disease and data suggest that all cases are biologically similar, irrespective of the blast count. Myelodysplastic syndrome is a highly aggressive disease that carries a poor prognosis, especially in symptomatic patients. New therapeutic agents that target histone deacetylation, DNA methylation, or angiogenesis show promise, but focused biologic and therapeutic studies are needed to improve the outcome of this disease.

Apoptosis↗

PubMed2003

Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia.

BACKGROUND: The objective of this study was to investigate the efficacy and safety of alemtuzumab, the humanized anti-CD52 monoclonal antibody, in patients with B-cell chronic lymphocytic leukemia and residual disease after chemotherapy. METHODS: Forty-one patients received alemtuzumab 3 times weekly for 4 weeks. The first 24 patients received 10 mg per dose, and the next 17 patients received 30 mg. All patients received infection prophylaxis during therapy and for 2 months after treatment. RESULTS: The overall response rate was 46%, including 39% of patients who received the 10 mg dose and responded versus 56% of the patients who received the 30 mg dose. The major reason for failure to respond was the presence of adenopathy. Residual bone marrow disease cleared in most patients, and 11 of 29 patients (38%) achieved a molecular disease remission. The median time to disease progression had not been reached in responders with a median follow-up of 18 months. Six patients remained in disease remission between 24-38 months after therapy. Infusion-related events were common with the initial doses, but all such events were NCI Common Toxicity Criteria Grade 1-2. Infections were reported to occur in 15 patients (37%), and 9 of these infections were reactivation of cytomegalovirus. Three patients developed Epstein-Barr virus positive, large cell lymphoma. Two patients had spontaneous resolution of the lymphoma and, in one patient, the lymphoma resolved after treatment with cidofovir and immunoglobulin. CONCLUSIONS: Alemtuzumab produced significant responses in patients with residual disease after chemotherapy. Bone marrow disease was eradicated more frequently than lymph node disease, and molecular disease remissions were achieved. A randomized trial comparing alemtuzumab with observation after chemotherapy is indicated.

Adult↗

PubMed2003

Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity.

PURPOSE: Therapeutic selectivity is one of the most important considerations in cancer chemotherapy. The design of therapeutic strategies to preferentially kill malignant cells while minimizing harmful effects to normal cells depends on our understanding of the biological differences between cancer and normal cells. We have previously demonstrated that certain agents generating reactive oxygen species (ROS) such as 2-methoxyestradiol (2-ME) preferentially kill human leukemia cells without exhibiting significant cytotoxicity in normal lymphocytes. The purpose of the current study was to investigate the biochemical basis for such selective anticancer activity. METHODS: Flow cytometric analyses were utilized to measure intracellular O(2)(-) levels and apoptosis. MTT assays were used as indicators of cellular viability. Western blot analysis was used to measure the expression of antioxidant enzymes in cancer and normal cells. RESULTS: Malignant cells in general are more active than normal cells in the production of O(2)(-), are under intrinsic oxidative stress, and thus are more vulnerable to damage by ROS-generating agents. The intrinsic oxidative stress in cancer cells was associated with the upregulation of SOD and catalase protein expression, likely as a mechanism to tolerate increased ROS stress. The increase in SOD and catalase expression was observed both in primary human leukemia cells and in primary ovarian cancer cells. Both malignant cell types were more sensitive to 2-ME than their normal counterparts, as demonstrated by the significant accumulation of O(2)(-) and subsequent apoptosis. The administration of ROS scavengers in combination with 2-ME prevented the accumulation of O(2)(-) and abrogated apoptosis induction. CONCLUSIONS: O(2)(-) is an important mediator of 2-ME-induced apoptosis. The increased oxidative stress in cancer cells forces these cells to rely more on antioxidant enzymes such as SOD for O(2)(-) elimination, thus making the malignant cells more vulnerable to SOD inhibition than normal cells.

2-Methoxyestradiol↗

PubMed2003

Relative increase in leukemia-specific DNA in peripheral blood plasma from patients with acute myeloid leukemia and myelodysplasia.

Using loss of heterozygosity (LOH) and X-chromosome inactivation, we compared peripheral blood (PB) plasma with bone marrow (BM) cells in detecting genomic abnormalities in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We detected LOH in the PB plasma of all 45 patients who had cytogenetically documented chromosomal abnormalities (5q-, 7-, +8, 17-, or 20-). BM cells from the same patients showed LOH in 89% of patients with MDS and 70% of patients with AML. Posttherapy samples from 16 of these patients demonstrated complete concordance between LOH and cytogenetics in detecting residual disease in 15 samples. Of the 16 samples, 4 showed LOH in plasma with normal BM morphology. Using X-chromosome inactivation, clonality was detectable in 19 (73%) of 26 BM samples, whereas all PB plasma samples showed clonality. These data support the conclusion that PB plasma is enriched by tumor-specific DNA and can replace BM cells for studying genomic abnormalities.

Adult↗

PubMed2003

The clinical significance of soluble CD86 levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Levels of the soluble form of CD86 (sCD86) are elevated in a proportion of patients with leukemia. Although it is a potential modulator of antitumor responses, the significance of sCD86 in patients with hematologic malignancies is unknown. METHODS: The authors evaluated sCD86 levels by enzyme-linked immunosorbent assay in patients with acute myeloid leukemia (AML) (n = 57 patients) and patients with myelodysplastic syndrome (MDS) (n = 40 patients) and analyzed the relation between sCD86 levels and various clinical parameters. RESULTS: Levels of sCD86 were elevated (> 2.32 ng/mL) relative to normal donors (0.22-2.32 ng/mL; n = 51 patients) in 25% of patients with AML and in 27% of patients with MDS. Patients with AML who had elevated sCD86 levels had significantly lower complete remission (CR) rates compared with patients with AML who had normal sCD86 levels. In multivariate analysis using sCD86 as a continuous variable and including the interaction of age and sCD86 as a variable, sCD86 was a significant prognostic factor (P = 0.014) independent of cytogenetics. Further analysis demonstrated that, in patients with AML age 60 years and younger, but not in patients older than 60 years, elevated sCD86 levels were associated with significantly shorter survival (P = 0.04). There was no correlation between sCD86 levels and CR rates or survival in patients with MDS. CONCLUSIONS: The presence in patients with AML of elevated levels of circulating sCD86 were associated with lower CR rates and poor survival. The prognostic significance of sCD86 was independent of cytogenetics but was modulated by age, in that it was independently significant only in younger patients. The results suggest that sCD86 may play a role in modulating immune responses associated with the progression of AML.

Adolescent↗

PubMed2003

Transient down-modulation of CD20 by rituximab in patients with chronic lymphocytic leukemia.

Lymphoid cells in most patients with chronic lymphocytic leukemia (CLL), when treated with rituximab, become CD20-. This is thought to be due to masking of CD20 by rituximab. We used specific antimouse immunoglobulin antibodies to detect rituximab on the surface of CLL lymphocytes and we demonstrate that rituximab is rarely detectable after therapy. Only 3 of 65 patients with CLL had rituximab detectable on their lymphocytes after rituximab therapy despite the fact that most had no detectable CD20 expression. In vitro mixing of CLL or Raji cells with rituximab demonstrated that rituximab was detectable on the surface of cells due to its binding to CD20. However, the addition of plasma led to the down-modulation of CD20 expression, and the rituximab became undetectable. This down-modulation of CD20 protein expression was associated with a down-modulation of CD20 mRNA. CLL cells that lost their CD20 expression regained CD20 expression after 24 hours in culture. These data suggest that rituximab therapy leads to a substantial but transient down-modulation of CD20 expression and that negativity for CD20 in cells from patients treated with rituximab is not necessarily due to CD20 masking. The importance of this down-modulation in the efficacy of current therapy with rituximab needs further investigation.

Antibodies, Monoclonal↗

PubMed2003

Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders.

BACKGROUND: Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl, bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). METHODS: The authors investigated the efficacy of imatinib in patients with these disorders. Forty-eight patients with AML (n = 10), MDS (n = 8), myelofibrosis (n = 18), atypical chronic myeloid leukemia (CML; n = 7), chronic myelomonocytic leukemia (CMML; n = 3), or polycythemia vera (n = 2) were treated with imatinib 400 mg daily. RESULTS: None of the patients with AML or MDS responded. Among patients with myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had erythroid hematologic improvement, and 1 had improvement in platelet count. One patient with atypical CML had erythroid hematologic improvement. Both patients with polycythemia vera needed fewer phlebotomies (from 2-3 per year to none during the 8 months of therapy and from 3-6 per year to 1 during 9 months of therapy). None of the three patients with CMML responded. Treatment was well tolerated. The side effects were similar to those observed in patients with CML. CONCLUSIONS: Within these small subgroups of disease types, single-agent imatinib did not achieve a significant clinical response among patients with AML, MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on polycythemia vera are promising and deserve further investigation. Responses among myelofibrosis patients were minor. Therefore, a combination treatment regimen including imatinib may be more effective.

Adult↗

PubMed2003

Anagrelide and imatinib mesylate combination therapy in patients with chronic myeloproliferative disorders.

PURPOSE: The tyrosine kinase inhibitor imatinib mesylate inhibits the function of the Bcr-Abl oncoprotein associated with Philadelphia-positive chronic myelogenous leukemia (CML). Anagrelide suppresses megakaryocyte proliferation and differentiation. The objectives of this study were to investigate the feasibility and safety of imatinib mesylate and anagrelide combination therapy in patients with Ph-positive CML or chronic myeloproliferative disorders (MPD) with persistent thrombocythemia. METHODS: This study was a retrospective review of all available records of patients with chronic MPD presenting to the M.D. Anderson Cancer Center between October 1998 and May 2002, treated with imatinib mesylate combined with anagrelide. RESULTS: Of 22 patients identified, 18 had Ph-positive CML (chronic phase, 16 patients; accelerated phase, 2 patients), 1 had agnogenic myeloid metaplasia (AMM), 2 had essential thrombocythemia (ET) and 1 had MPD transformed into refractory anemia with excess blasts (RAEB). The median age was 57 years (range 26-82 years). The median dose of imatinib mesylate administered was 400 mg (range 300-800 mg) and the median dose of anagrelide was 1.5 mg (range 0.5-4.0 mg). Imatinib mesylate and anagrelide combination therapy was feasible and tolerable. Of the 18 patients with Ph-positive CML, 15 in chronic phase and 1 in accelerated phase achieved a complete hematologic response (CHR), and 9 of the 18 achieved cytogenetic response (complete in 8 patients). No responses were noted in patients with AMM, ET or MPD transformed into RAEB. CONCLUSIONS: The combination of imatinib mesylate and anagrelide was safe and was associated with an 89% CHR rate in patients with CML in chronic phase and persistent thrombocythemia.

Adult↗

PubMed2003

Telomerase activity is prognostic in pediatric patients with acute myeloid leukemia: comparison with adult acute myeloid leukemia.

BACKGROUND: Significantly elevated telomerase activity (TA) has been found in samples from patients with almost all malignant hematologic diseases. The impact of elevated TA on the course of pediatric patients with acute myeloid leukemia (P-AML) is unknown. METHODS: Using a modified polymerase chain reaction-based, telomeric repeat-amplification protocol assay, the authors measured TA in bone marrow samples from 40 patients with P-AML and, for comparison, in 65 adult patients with AML (A-AML), excluding patients with French-American-British M3 disease. The results were correlated with patient characteristics and survival. RESULTS: TA in patients with P-AML was significantly lower compared with TA in patients with A-AML (P = 0.005). Patients who had P-AML with low TA had a projected 5-year survival rate of 88%, whereas patients who had P-AML with high TA had a projected 5-year survival rate of 43% (P = 0.009). Conversely, patients who had A-AML with very high TA (upper quartile) had significantly longer survival compared with patients who had A-AML with lower TA (P = 0.03). There was no correlation between complete remission rate or disease free survival and TA in P-AML or A-AML. In the A-AML group, when patients were separated by cytogenetic findings (poor prognosis vs. others), it was found that TA was significantly lower in patients with a poor prognosis, but the prognostic value of TA was not independent of cytogenetic status. CONCLUSIONS: The current results suggest, that for patients with P-AML, bone marrow TA is a highly significant prognostic factor.

Acute Disease↗

PubMed2003

Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome.

The hallmark of myelodysplastic syndrome (MDS) is enhanced apoptosis in myeloid, erythroid, and megakaryocytic cells in the bone marrow leading to ineffective hematopoiesis. Recent studies suggested that immunological and microenvironmental factors play a role in the pathophysiology of this disease. We report a significant increase in apoptosis in bone marrow B lymphocytes in MDS as compared to that found in acute myeloid leukemia and healthy controls. Furthermore, we demonstrate that patients with refractory anemia with excess blasts in transformation (RAEB-T) had apoptosis levels in lymphocytes similar to those seen in other subtypes of MDS. Our findings suggest that the alterations in B lymphocytes in the form of increased apoptosis can be seen in MDS and support the concept that immune modulation plays a role in the pathophysiology of MDS.

Apoptosis↗

PubMed2003

Clinical relevance of the expression of the CD31 ligand for CD38 in patients with B-cell chronic lymphocytic leukemia.

BACKGROUND: CD31 (platelet endothelial cell adhesion molecule-1 [PECAM-1]) is the ligand for CD38, a transmembrane glycoprotein that is expressed on the surface of leukemic cells in many patients with B-cell chronic lymphocytic leukemia (B-CLL). In a previous study, the authors showed that CD38 expression was correlated with a poor prognosis in patients with B-CLL. In the current study, blood samples from patients with B-CLL were examined to identify CD31 surface marker expression, and CD31 expression was correlated with several other known prognostic variables, including CD38. METHODS: Using flow cytometry, peripheral blood samples from 120 patients with B-CLL were analyzed for CD31 and CD38 expression on CD19 positive leukemic B cells. RESULTS: Thirteen of 120 patients (11%) had CD31 expression on < 20% of their B cells, and the remaining patients had various levels of CD31 expression. The median expression of CD31 was 76% of leukemic, CD19 positive cells. Levels of CD31 expression were not correlated with survival outcomes or with any of the known prognostic parameters when all patients were considered. Patients who had high CD38 expression (>or= 20%), as expected, had significantly shorter survival (P = 0.001) compared with patients who had low CD38 expression (< 20%). However, in patients with low CD38 expression, a subgroup with low CD31 expression (< 76%) had significantly longer survival compared with the survival for the entire group (P = 0.0001). Moreover, the survival pattern of patients with low CD38 expression and high CD31 expression was not significantly different from the survival pattern seen in patients with high CD38 expression. CONCLUSIONS: CD31 expression further defined a subgroup of patients with B-CLL who had a different survival outcome. Defining the interaction between CD31 expression and CD38 expression in patients with CLL will require further exploration.

ADP-ribosyl Cyclase↗

PubMed2003

Phase II study of SU5416--a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor--in patients with refractory myeloproliferative diseases.

BACKGROUND: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with myeloproliferative disorders (MPD), including agnogenic myeloid metaplasia (AMM), chronic myeloid leukemia in blastic phase (CML-BP), and chronic myelomonocytic leukemia (CMML). VEGF is a soluble, circulating, angiogenic molecule that acts through receptor tyrosine kinases (RTK), including VEGF receptor 2 (VEGFR-2). SU5416 is a small-molecule RTK inhibitor (RTKI) that targets VEGFR-2, c-kit, and fms-related tyrosine kinase Flk2. METHODS: Adult patients with advanced CMML, AMM, CML-BP, or other BCR-ABL negative MPD were entered on a multicenter, Phase II study. RESULTS: Thirty-two patients (19 patients with BCR-ABL negative MPD, 6 patients with CMML, 4 patients with CML-BP, and 3 patients with AMM) with a median age of 66 years (range, 29-85 years) received SU5416 145 mg/m(2) twice weekly intravenously for a median of three 4-week cycles (maximum, 12 cycles). Drug-related Grade 3-4 toxicities included acute abdominal pain (13%), bone pain (9%), infusion-related dyspnea (9%) or headache (6%), fatigue (6%), diarrhea (3%), and catheter site reactions (3%). Eleven patients (34%) did not receive a second cycle of therapy (6 patients had progressive disease, 3 because of adverse events; 2 patients withdrew due to lack of response). One patient with AMM achieved a partial response. Eight patients received more than 6 months of therapy. CONCLUSIONS: SU5416 had minimal clinical activity in patients with MPD. Long-term administration of a twice-weekly, hyperosmolar, intravenous solution containing polyoxyl 35 castor oil was difficult. More tolerable RTKI may be worthy of further investigation in patients with MPD.

Adult↗

PubMed2003

Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia.

BACKGROUND: Therapy for patients with Richter syndrome (RS) or fludarabine-refractory chronic lymphocytic leukemia (CLL) is unsatisfactory. A Phase II study was conducted to evaluate an alternating combination cytotoxic regimen given with rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) in these patients. METHODS: Fludarabine-refractory CLL was defined as failure to respond to most recent prior fludarabine-containing regimen. Patients received up to six cycles of fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone (hyper-CVXD) plus rituximab and GM-CSF alternating with methotrexate and cytarabine plus rituximab and GM-CSF. Response, toxicity, and survival data were compared with data from prior therapy with hyper-CVXD alone in this patient group. RESULTS: Forty-nine patients with RS (n = 30 patients) or refractory CLL (n = 19 patients) were treated on study. Nine patients (18%) achieved a complete remission, and 11 patients achieved a partial remission (22%), for an overall objective response (OR) rate of 41%. With a median follow-up of 7.5 months and a maximum follow-up of 15.2 months, the 12-month failure free survival (FFS) rate was 27%, and the overall survival (OS) rate was 39%. Nine patients (18%) died during the first cycle of therapy, and two patients (4%) died during the second cycle. There were no significant differences between the rates of OR, OS, and FFS in the current study and those obtained with hyper-CVXD alone on a prior study. CONCLUSIONS: The study regimen had activity and significant toxicity in patients with RS or fludarabine-refractory CLL. It was not clearly better compared with hyper-CVXD alone in this patient population.

Adult↗

PubMed2003

In vitro activity of dimethylarsinic acid against human leukemia and multiple myeloma cell lines.

PURPOSE: Arsenic trioxide (As(2)O(3)), an inorganic arsenic compound, has recently been approved for the treatment of relapsed or refractory acute promyelocytic leukemia. However, systemic toxicity associated with As(2)O(3) treatment remains a problem. Inorganic arsenic is detoxified in vivo by methylation reactions into organic arsenic compounds that are less toxic. METHODS AND RESULTS: We investigated the antiproliferative and cytotoxic activity of dimethylarsinic acid (DMAA), an organic arsenic derivative and major metabolic by-product of As(2)O(3), against a panel of eight leukemia and multiple myeloma cell lines. As(2)O(3) was tested in comparison. In clonogenic assay, the average concentration of DMAA that suppressed cell colony growth by 50% was 0.5-1 m M, while for As(2)O(3) it was on average 1-2 microM. At those concentrations DMAA and As(2)O(3) had significantly less effect on colony growth of normal progenitor cells. Cytotoxic doses of DMAA and As(2)O(3) in 3-day trypan blue dye exclusion assay experiments were similar to doses effective in clonogenic assay. Assessment of apoptosis by annexin V assay revealed a high rate of apoptosis in all cell lines treated with DMAA and As(2)O(3), but significantly less effect on normal progenitor cells. DMAA, unlike As(2)O(3), had no effect on the maturation of leukemic cells. CONCLUSIONS: DMAA exerts differential antiproliferative and cytotoxic activity against leukemia and multiple myeloma cells, with no significant effect on normal progenitor cells. However, concentrations of DMAA needed to achieve such efficacy are up to 1000 times those of As(2)O(3). Evaluation of novel organic arsenic that would combine the high efficacy of As(2)O(3) and the low toxicity of DMAA is warranted.

Cacodylic Acid↗

PubMed2003

SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes.

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.

Acute Disease↗

PubMed2003

Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes.

BACKGROUND: Gemtuzumab is used to treat patients with previously untreated or recurrent acute myelogenous leukemia (AML). The fludarabine and cytarabine (ara-C) regimen is active in these patients. Resistance to gemtuzumab is associated with blast multidrug resistance (MDR). The objectives of this study were to evaluate the efficacy and toxicity of a combination regimen of gemtuzumab, fludarabine, ara-C, and the MDR modifier (cyclosporine [CyA]) in patients with previously untreated AML, refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEBT). METHODS: The MFAC regimen was comprised of gemtuzumab (Mylotarg trade mark ) (6 mg/m(2) intravenously [i.v.] on Day 1); fludarabine and ara-C (15 mg/m(2) and 0.5 g/m(2), respectively, twice daily on Days 2-6); and CSA (6 mg/kg loading dose before gemtuzumab, followed by 16 mg/kg continuous i.v. infusion on Days 1 and 2). RESULTS: Fifty-nine evaluable patients were treated: 39 patients (66%) had AML and 20 patients (34%) had RAEB/RAEBT. Their median age was 57 years (range, 27-76 years). The MFAC regimen induced complete remission (CR) in 27 patients (46%) and CR with incomplete platelet recovery (CRp) in 1 patient (2%). The median survival period is 8 months. At 12 months, the survival rate is 38% and the event-free survival rate in patients with CR/CRp is 27%. Infections complicated 38% of the courses of chemotherapy. Grade 3/4 toxicity included hyperbilirubinemia in 31% and transaminitis in 7% of the patients. Four patients (7%) developed hepatic venoocclusive disease (VOD). CONCLUSIONS: The MFAC regimen may merit further study in patients with AML if measures to avoid and/or treat VOD can be incorporated into the regimen.

Adult↗

PubMed2003

A randomized trial of liposomal daunorubicin and cytarabine versus liposomal daunorubicin and topotecan with or without thalidomide as initial therapy for patients with poor prognosis acute myelogenous leukemia or myelodysplastic syndrome.

BACKGROUND: Because angiogenesis may play a role in the pathogenesis of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), and thalidomide (Th) has shown significant anti-angiogenic activity, this study was designed to investigate the potential role of Th in the treatment of patients with AML and MDS and the possible role of a non-ara-C-containing regimen. METHODS: Adults with AML or high-risk MDS and cytogenetic abnormalities other than inv (16), t(8;21), -Y or -X were randomized to receive liposomal daunorubicin (DNX) and ara-C (DA) or DNX and topotecan (DT). Within each arm, patients were randomized to receive chemotherapy alone (DA or DT) or with thalidomide (DATh or DTTh). Vascular endothelial growth factor (VEGF) plasma levels and microvascular density was measured before and after therapy. Eighty-four patients (median age, 65 years; range, 27-84 years) were treated. RESULTS: None of 11 patients treated with DT or DTTh responded and these arms were closed. Seventeen of 37 patients treated with DA and 15 of 36 treated with DATh achieved an early complete remission. Median complete response duration was 38 and 34 weeks (P = 0.57) and median survival 35 and 28 weeks (P = 0.15), respectively. Patients with high pretreatment VEGF levels had an inferior survival. There was no significant difference in the changes in VEGF levels or microvascular density after treatment in patients who did versus those who did not receive thalidomide. CONCLUSIONS: The authors concluded that thalidomide in combination with chemotherapy does not result in clinical benefit in patients with AML or high-risk MDS.

Adult↗