Topoisomerase I inhibitors in the treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia.
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Antineoplastic Agents↗
Biomedical subjects
M Beran
Publications and source records attributed to M Beran.
Allogeneic transplantation: a therapeutic option for myelofibrosis, chronic myelomonocytic leukemia and Philadelphia-negative/BCR-ABL-negative chronic myelogenous leukemia.
The role of allogeneic transplantation for myeloproliferative diseases other than chronic myeloid leukemia is not well established. In all, 20 patients with a median age of 51 years underwent allogeneic hematopoietic stem cell transplantation (HSCT) for myelofibrosis (n=5), chronic myelomonocytic leukemia (CMML) (n=8) and Philadelphia (Ph) chromosome-negative/BCR-ABL-negative chronic myeloid leukemia (CML) (n=7) in our institution. Patients who developed acute leukemia prior to HSCT were excluded from this analysis. A total of 15 patients received related and five patients received unrelated donor transplants. One patient failed to engraft. After a median follow-up of 17.5 months, actuarial survival at 2 years was 47% (95% CI 2%-67%), and disease-free survival 37% (95% CI 17-58%). Allogeneic transplantation may provide a therapeutic option for patients with myelofibrosis, CMML and Ph chromosome-negative/BCR-ABL-negative CML.
Adult↗
Metastatic gastric adenocarcinoma following allogeneic stem cell transplantation in a patient with acute myelogenous leukemia.
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Adenocarcinoma↗
Opportunities for Trisenox (arsenic trioxide) in the treatment of myelodysplastic syndromes.
Arsenic trioxide (ATO) has a long history of efficacy as an antileukemic agent. However, with the advent of modern therapy, it had been relegated to a historical footnote. In the 1990s, investigators in China reported that ATO was safe and had dramatic efficacy in patients with acute promyelocytic leukemia (APL). Preclinical investigations indicate that the biological targets of this novel drug extend to a variety of malignancies other than APL and include induction of apoptosis, nonterminal differentiation, and suppression of proliferation and angiogenesis. The myelodysplastic syndromes (MDSs) present a particular therapeutic challenge. Ineffective hematopoiesis predominates in patients with low-grade prognostic scores. The survival of those patients with high-grade disease is compromised by a high risk of leukemia transformation. Although a number of therapeutic options have been investigated, none has emerged as being broadly efficacious and having an acceptable toxicity profile. No drug has yet received approval by the Food and Drug Administration for this indication. Biologic features of MDS, which include accelerated apoptotic potential, limited maturation capacity, and medullary neovascularity, create a strong scientific rationale for the investigation of ATO in MDS. This report describes the history and scientific basis for ATO treatment of hematologic malignancies, enumerates the potential benefits of ATO in MDS, and discusses the direction of ongoing trials of this novel antineoplastic agent.
Antineoplastic Agents↗
Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia.
Resistance to purine analogs is emerging as a major problem in the management of patients with chronic lymphocytic leukemia (CLL). Most of these patients have already been exposed to and have become refractory to alkylating agents. To define the natural history of fludarabine (Fludara) refractory patients with CLL, we reviewed the response to first salvage therapy of 147 patients who were refractory to Fludara or had a remission less than six months in duration after a Fludara-containing regimen. Thirty-three (22%) patients responded to their first salvage attempt. However, the median survival was only 10 months. Responders survived significantly longer than non-responders. The most effective salvage regimens were combinations of purine analogs and cyclophosphamide. Patients still possibly sensitive to alkylating agents had a superior response than alkylating agent resistant or naive patients. Subsequent salvage therapy was administered to 61 patients. The most promising results noted in the group were transplantation and the use of Campath-1H antibody. The major morbidity and cause of death were associated with infections. The probability of infection was most strongly associated with the response to salvage therapy. Gram-positive organisms were most commonly associated with infection. However, gram-negative bacilli or opportunistic infection such as fungi, Pneumocystis carinii, acid-fast bacilli and legionella were prominent causes of infection. Fludara-refractory patients are a poor prognosis group and need more effective therapeutic regimens and well-designed infection prophylactic regimens.
Adult↗
Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts.
It has been unclear whether regimens containing topotecan + ara-C (TA) or fludarabine + ara-C (FA) +/- idarubicin are superior to regimens containing idarubicin + ara-C (IA) without either fludarabine or topotecan for treatment of newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or RAEB. Of 1279 patients treated here for these diagnoses between 1991 and 1999, 322 received IA regimens, 600 FA regimens, and 357 TA regimens. All regimens used ara-C doses of 1 to 2 gm/m(2)/d, given by continuous infusion in IA, and over 2 to 4 hours in FA and TA. Complete remission (CR) rates were lower with FA (55%) and TA (59%) than with IA (77%). Both event-free survival (EFS) in CR and survival were shorter: median EFS in CR (95% confidence interval) was 63 weeks (range, 55-76 weeks) for IA, 40 (range, 31-46 weeks) for FA, and 36 (range, 27-44 weeks) for TA; median survival was 77 weeks (range, 57-88 weeks) for IA, 30 (range, 27-35 weeks) for FA, and 41 (range, 35-50 weeks) for TA. These trials were not randomized, and patients with worse prognoses were disproportionately given the FA and TA regimens. Nonetheless, after accounting for prognosis the FA and TA regimens remained highly significantly associated with lower CR rates, shorter EFS in CR, and shorter survival. Accounting for possible effects of individual trials within each of the IA, FA, and TA groups did not alter these findings. It is unlikely that, as given here, either FA or TA is, in general, superior to IA, highlighting the need for new treatments.
Anemia, Refractory, with Excess of Blasts↗
High-dose chemotherapy in high-risk myelodysplastic syndrome: covariate-adjusted comparison of five regimens.
BACKGROUND: Antileukemic chemotherapy has been used for two decades to treat high-risk myelodysplastic syndrome (refractory anemia with excess of blasts [RAEB] and RAEB in transformation into acute leukemia [RAEB-t]) patients. Because the results of standard regimens have been disappointing, high-dose chemotherapeutic regimens were investigated recently. In the absence of randomized trials, the relative merits of various treatment regimens are unknown. METHODS: The authors analyzed the outcome for 394 newly diagnosed patients treated between 1991 and 1999 with five regimens consisting of intermediate- or high-dose cytosine arabinoside (A) in combination with idarubicin (I), and introduced cyclophosphamide (C) and the new agents fludarabine (F) and topotecan (T) into new combinations with A. In addition to defining the role of high-intensity chemotherapy in the overall outcome for patients with RAEB-t and RAEB, the authors determined the relative merits of the five regimens (IA, FA, FAI, TA, and CAT), accounting for the nonrandom distribution of the prognostic covariates. RESULTS: The overall complete response (CR) rate of 58% was significantly associated with karyotype, performance status (PS), treatment in the laminar air flow room, duration of antecedent hematologic disorder and age, but not French-American-British or International Prognostic Scoring System risk categories. Multivariate analysis did not identify statistically significant differences in CR rates obtained with each regimen. Induction death rates increased with age with all but the TA regimen; they were lowest with TA (5.4%) and highest with FAI (20.7%), and these differences were significant in patients older than 65 years. The trend for time to death was the same as for time to recurrence in all groups. Multivariate analysis of time to death identified treatment regimen (FA, FAI, and CAT), cytogenetic status (-5/-7), increasing age, and PS greater than 2 as significant independent unfavorable prognostic factors. After prognostic variables were accounted for, survival with IA treatment remained superior to that of FA and FAI but comparable to TA, and CR duration was only marginally shorter with FA. Landmark analysis showed the overall survival of responders to be superior to that of nonresponders, the difference remaining significant after adjustment for prognostic covariates. CONCLUSIONS: Although the newer regimens did not improve outcome, TA and CAT produced results comparable to those of IA and may be considered treatment alternatives. The TA regimen was particularly effective in RAEB patients and could be delivered safely, with low induction mortality. Our results indicated that although CR seemed associated with survival advantage, innovative post-remission managements represent a challenge because improvement in outcome is not likely to come from intensified therapy.
Aged↗
High-dose liposomal daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia.
BACKGROUND: Liposomal encapsulation of daunorubicin (DaunoXome, DNX; Nexstar Pharmaceutical, Boulder, CO) changes the pharmacology profile to increase delivery to tumor sites and decrease toxicity. The authors investigated the effect of daunorubicin in combination with ara-C in patients with refractory or recurring acute myelogenous leukemia (AML). PATIENTS AND METHODS Sixty-two patients with refractory or recurring AML received escalating doses of daunorubicin of 75, 100, 125, or 135 mg/m(2) daily for 3 days together with ara-C 1 g/m(2) intravenous continuous infusion daily for 4 days. RESULTS: Eighteen patients (29%) achieved a complete remission (CR) and 7 (11%) a hematologic improvement (i.e., met all criteria for CR except for platelet count < 100 x 10(9)/L) for an overall response rate of 40%. The dose-limiting toxicity was mucositis in 4 in 9 (44%) patients treated at the 150 mg/m(2) dose level, but minimal at 125 mg/m(2) (2 of 32, 6%) or 135 mg/m(2) (1 of 13, 8%). Cardiotoxicity Grade 2 was observed in 4 patients (6%) and Grade 3 or higher in 4 patients (6%). The median CR duration was 63 weeks, and overall survival rate was 25 weeks, with 28% patients alive after 1 year. CONCLUSIONS: The combination of DNX (or liposomal daunorubicin) and ara-C has significant antileukemia activity with acceptable toxicity. Further studies are warranted to investigate the role of high-dose anthracyclines in frontline AML therapy.
Adult↗
Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia.
PURPOSE: To assess the efficacy of combination therapy with fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) based on data suggesting in vitro synergistic activity of the two agents. PATIENTS AND METHODS: A total of 128 patients with CLL were treated with fludarabine 30 mg/m(2) intravenously daily for 3 days and cyclophosphamide at either 500 mg/m(2) daily for 3 days (n = 11), 350 mg/m(2)/d for 3 days (n = 26), or 300 mg/m(2) daily for 3 days (n = 91). The cyclophosphamide dose was decreased because of myelosuppression in the early part of the study. Patients were divided into four groups based on the expectation for response to single-agent fludarabine, including previously untreated patients, patients previously treated with alkylating agents, patients successfully treated with alkylating agents and fludarabine but relapsing, and patients refractory to fludarabine with or without alkylating agents. RESULTS: Fludarabine and cyclophosphamide produced > or = 80% response rates in all patients not refractory to fludarabine at the start of therapy as well as a 38% response rate in patients who were refractory to fludarabine. The complete remission (CR) rate was 35% in previously untreated patients, which was not significantly different from the CR rate in historical control patients treated with single-agent fludarabine. However, residual disease assessed by flow cytometry occurred in only 8% of previously untreated patients achieving CR, and median time to progression has not been reached after a median follow-up of 41 months. The main complication of therapy was related to myelosuppression and infection. Neutropenia to less than 500 x 10(9)/L was noted in 48% of patients who received cyclophosphamide 300 mg/m(2). Pneumonia or sepsis occurred in 25% of patients, and fever of unknown origin occurred in another 25%. Pneumonia or sepsis were significantly more frequent in patients who were refractory to fludarabine at the start of combination chemotherapy. CONCLUSION: Fludarabine and cyclophosphamide seem to have a significant advantage over single-agent fludarabine in the salvage setting. Although the CR rate was not increased in previously untreated patients, residual disease detected by flow cytometry was rare and remission durations seemed to be prolonged in this subset. Myelosuppression and infection remain the most significant complications of therapy in CLL.
Adult↗
Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia.
PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m(2)/d (3.6 mg/m(2)/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined. RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m(2)/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m(2). Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease. CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.
Acute Disease↗
Clinical relevance of Flt1 and Tie1 angiogenesis receptors expression in B-cell chronic lymphocytic leukemia (CLL).
Angiogenesis, a complex process tightly controlled by several molecules including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) along with their receptors, plays a major role in the growth and metastasis of solid tumors. The expression and production of VEGF and bFGF have been documented in numerous solid tumors and hematopoietic neoplasms. Having recently shown increased expression of cellular VEGF in the leukemic cells of patients with chronic lymphocytic leukemia (CLL) we decided to investigate the expression of angiogenic receptors Flt1 and Tie1. Levels of Tie1 and Flt1 proteins were measured in leukemic cells from 231 patients with B-cell CLL using Western blot analysis and solid-phase radioimmunoassay (RIA). A strong correlation was found between Flt1 and Tie1 levels and white blood cell count (WBC) and absolute lymphocyte counts. Levels of Flt1 but not Tie1 correlated with levels of cellular VEGF. Interestingly, Tie1 correlated well with Rai stage (P=0.04). Flt1 and Tie1 did not correlate with survival, although when we evaluated the patients with early disease (Rai stage 0-II), higher levels of Tie1 but not of Flt1 correlated with worse survival. These data suggest that Tie1 plays a role in the early stages of B-cell CLL and as the disease progresses, the tumor cells become independent from the effects of Tie1. Further studies are now needed to dissect the mechanisms responsible for this phenomenon.
Actuarial Analysis↗
Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase.
The objective of the study was to investigate the toxicity and efficacy of cyclic combination therapy offered to patients with Ph-positive CML having a sub-optimal response to IFN-alpha. Patients in early chronic phase CML were treated with IFN-alpha at 5MU/m(2) daily. Patients who did not achieve cytogenetic response after 6 months of IFN-alpha therapy, or Ph-suppression to less than 35% Ph-positive cells (partial cytogenetic response) after 12 months of therapy were offered cyclic intensive chemotherapy every 6 months, with IFN-alpha maintenance between cycles. The initial 3 cycles included daunorubicin, vincristine, cytosine arabinoside (ara-C) and prednisone (DOAP). Later cycles were given with cyclophosphamide replacing daunorubicin (COAP). Of 74 patients treated, 61 (82%) achieved complete hematologic response (CHR): 51 (69%) had a cytogenetic response, which was major (Ph < 35%) in 31 (42%), and complete in 23 (31%). Fifty-five patients (74%) achieved CHR by 6 months of therapy, 38 (69%; 51% of total) with a cytogenetic response - 13 (24%) had a major cytogenetic response. Seventeen patients received at least 1 course of DOAP therapy. Median survival of the overall cohort of patients was 120 months. With a median follow-up of 145 months (103+ to 155+ months), 40 patients (54%) have died. The median duration of cytogenetic response was 35 months (range 3 to 149+ months) and the estimated 10-year cytogenetic response rate was 37%. A durable complete cytogenetic response was observed in 16 patients (20%) with a median duration of 139+ months (range 12+ to 149+ months), 11 of them (15%) are now off IFN-alpha therapy for a median of 57+ months (range 12+ to 128+ months). The projected 10-year survival was 50% for the study group versus 35% for 208 patients who received other IFN-alpha based regimens at the MD Anderson Cancer Center (p<.01). In conclusion, the addition of intensive chemotherapy may improve survival in patients with CML who have not obtained an adequate cytogenetic response on an IFN-alpha-based regimen.
Actuarial Analysis↗
High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia.
Vascular endothelial growth factor receptor-2 (VEGFR-2), also termed KDR, is a high-affinity vascular endothelial growth factor (VEGF) receptor. VEGFR-2 plays a role in de novo blood vessel formation and hematopoietic cell development. Recently, we found that chronic lymphocytic leukemia (CLL) cells express high levels of VEGF. Therefore, we sought to investigate the role of VEGFR-2 in CLL. Using Western blot analysis, we first determined that VEGFR-2 is present in peripheral blood CLL cells. We then quantified the cellular levels of VEGFR-2 protein using a solid-phase radioimmunoanalysis in peripheral blood cells from 216 patients with CLL. As control, we used peripheral blood mononuclear cells (PBMNCs) from 31 hematologically normal individuals. The median of VEGFR-2 levels detected in the control samples was assigned a value of 1.0, and VEGFR-2 protein levels were normalized to the control median value. The median level of VEGFR-2 in CLL cells was 1.57. Patients with VEGFR-2 levels higher than 1.57 had elevated lymphocyte counts, severe anemia, elevated beta(2)-microglobulin and advanced-stage disease. Elevated VEGFR-2 levels were also associated with statistically significantly shorter survival (35.4 versus 60.1 months; P < 0.01). Our data indicate that cellular VEGFR-2 levels may serve as a prognostic factor in CLL. Further studies should investigate the biological implications of these findings and the effect of the interaction between VEGF and VEGFR-2 on CLL cell proliferation.
Anemia↗
Effects of signal transduction inhibitor 571 in acute myelogenous leukemia cells.
STI571 is a 2-phenylalaminopyrimidine derivative that inhibits c-abl, Bcr-Abl, and platelet-derived growth factor receptor tyrosine kinases. Recently, inhibition of stem cell factor (SCF)-induced c-kit phosphorylation and cell proliferation by STI571 was reported in the human myeloid cell line MO7e. Because approximately 70% of acute myelogenous leukemia (AML) cases are c-kit positive, we evaluated in vitro effects of STI571 on c-kit-positive cell lines and primary AML blast cells. At concentrations >5 microM, the drug marginally inhibited SCF-independent proliferation of cell lines and most of AML blasts. Treatment of AML cells with cytarabine and STI571 showed synergistic effect at low concentrations. Western blotting analysis documented a distinct band of M(r) 145,000 specific for c-kit in cell lines and in AML samples. There was no correlation between the level of the c-kit expression evaluated by Western blotting and percentage of c-kit-positive blasts as measured by flow cytometry. Neither in cell lines nor in primary AML cells, c-kit autophosphorylation was detectable under standard growth conditions. SCF-induced phosphorylation of c-kit in MO7e cells was inhibited by STI571. In a c-kit-positive AML-4 cell line, as well as in AML samples, c-kit phosphorylation was not induced by SCF exposure, suggesting that in these cases, the receptor could not be functionally activated. In conclusion, with the exception of MO7e, SCF did not induce phosphorylation of c-kit, and cell proliferation was not modulated in the presence of STI571. We did not detect any SCF-independent c-kit phosphorylation in our experimental systems. Consequently, STI571 exerted only a limited inhibitory effect on the cell growth.
Benzamides↗
Report of an international working group to standardize response criteria for myelodysplastic syndromes.
Standardized criteria for assessing response are essential to ensure comparability among clinical trials for patients with myelodysplastic syndromes (MDS). An international working group of experienced clinicians involved in the management of patients with MDS reviewed currently used response definitions and developed a uniform set of guidelines for future clinical trials in MDS. The MDS differ from many other hematologic malignancies in their chronicity and the morbidity and mortality caused by chronic cytopenias, often without disease progression to acute myeloid leukemia. Whereas response rates may be an important endpoint for phase 2 studies of new agents and may assist regulatory agencies in their evaluation and approval processes, an important goal of clinical trials in MDS should be to prolong patient survival. Therefore, these response criteria reflected 2 sets of goals in MDS: altering the natural history of the disease and alleviating disease-related complications with improved quality of life. It is anticipated that the recommendations presented will require modification as more is learned about the molecular biology and genetics of these disorders. Until then, it is hoped these guidelines will serve to improve communication among investigators and to ensure comparability among clinical trials. (Blood. 2000;96:3671-3674)
Disease Progression↗
Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia.
Strong evidence exists for an association between high vascular endothelial growth factor (VEGF) levels and poor prognoses in patients with solid tumors and acute leukemia. Using Western blot analysis and solid-phase radioimmunoassay, we measured cellular VEGF levels in B-cell chronic lymphocytic leukemia (CLL) samples from 225 patients and correlated these levels with disease characteristics and prognoses. The median VEGF level in CLL samples was 7.26 times the median level detected in normal peripheral blood mononuclear cells. Patients with lower levels of VEGF protein showed a trend toward shorter survival (P =.07). However, in a subgroup of CLL patients with good prognoses or early-stage disease (Rai stages 0-II, Binet stages A,B; beta2-M </= 2.8 mg/dL), lower levels of VEGF were associated with shorter survival times. For the entire group of patients, no correlation was found between VEGF levels and beta2-M levels or Rai and Binet stage. Most samples from patients with CLL expressed the 43-kd VEGF isoform in addition to the commonly expressed 45-kd isoform. It remains to be seen whether the expression of the 43-kd isoform is responsible for this reversed correlation with outcome. (Blood. 2000;96:768-770)
Adult↗
Differences between refractory anemia with excess blasts in transformation and acute myeloid leukemia.
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Acute Disease↗
Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias.
Leukemic blasts from patients with acute phase chronic myeloid leukemic and refractory acute myeloid leukemia are highly resistant to a number of cytotoxic drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria toxin (DT) with a (G4S)2 linker (L), expressed and purified the recombinant protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3 receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative cell lines based on assays of cytotoxicity using thymidine incorporation, growth in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to 680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming colonies in semi-solid medium (colony-forming units leukemia) > or =10-fold in 4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and 3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors (colony-forming unit granulocyte-macrophage) from five different donors treated and assayed under identical conditions showed intermediate sensitivity with three- to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic progenitors from a number of acute phase CML patients suggests that this agent could have therapeutic potential for some patients with this disease.
DNA Replication↗