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© 1999 American Society for Clinical Oncology Topotecan and Cytarabine Is an Active Combination Regimen in Myelodysplastic Syndromes and Chronic Myelomonocytic LeukemiaFrom the Departments of Leukemia and Molecular Hematology, and Division of Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Department of Hematology, Singapore General Hospital, Singapore. Address reprint requests to Miloslav Beran, MD, PhD, DVM, Department of Leukemia, Box 61, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; emailmberan{at}notes.mdacc.tmc.edu
PURPOSE: To evaluate the efficacy and safety of the combination of topotecan and cytarabine in patients with myelodysplastic syndromes (MDSs) and chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: Fifty-nine patients with MDSs and 27 with CMML were enrolled. They were either previously untreated (66%) or had received only biologic agents (14%) or chemotherapy with or without biologic agents (20%). Treatment consisted of topotecan 1.25 mg/m2 by continuous intravenous infusion daily for 5 days and cytarabine 1.0 g/m2 by infusion over 2 hours daily for 5 days. Prophylaxis included antibacterial, antifungal, and antiviral agents. At a median follow-up of 7 months, all 86 patients were assessable for response and toxicity. RESULTS: Complete remission (CR) was observed in 48 patients (56%; 61% with MDSs, 44% with CMML; P = .15). Similar CR rates were observed for patients with good-risk and poor-risk MDS (70% and 56%, respectively). The treatment effectively induced CR in patients with a poor-prognosis karyotype involving chromosomes 5 and 7 (CR, 71%) and secondary MDSs (CR, 72%). Fifty-four patients received one induction course, 25 patients received two, and the rest received more than two. The median number of continuation courses was two. The median overall duration of CR was 34 weeks (50 weeks for MDSs and 33 weeks for CMML). The median survival was 60 weeks for MDS and 44 weeks for CMML patients. CR and survival durations were longer in patients with refractory anemia with excess blasts (RAEB). Grade 3 or 4 mucositis or diarrhea was observed in three patients each. Fever was observed in 63%, and infections in 49% of patients. Six patients (7%) died during induction therapy. CONCLUSION: Topotecan and cytarabine induced high CR rates in unselected patients with MDSs and CMML, particularly among patients with poor-prognosis cytogenetics and secondary MDSs. Topotecan-cytarabine is an active induction regimen in MDS and CMML patients, is well tolerated, and is associated with a low mortality rate.
MYELODYSPLASTIC syndromes (MDSs) and chronic myelomonocytic leukemia (CMML) are a heterogeneous group of clonal disorders of the bone marrow with ultimately dismal outcome and no generally accepted standard of care. Ineffective hematopoiesis and maturation defects are the dominant features of MDSs.1,2 Management of MDS is hampered by its heterogeneous nature and highly variable clinical course; survival ranges from a few months to many years.3-13 The French-American-British (FAB) classification of MDS subtypes relies on the morphologic characteristics and the percentage of immature cells in the bone marrow and the peripheral blood.2 High-risk MDSs include refractory anemia with excess blasts (RAEB), which accounts for 30% to 35% of MDS cases and is associated with a median survival of 6 to 12 months, and RAEB in transformation (RAEBt), which accounts for 25% of cases of MDS and is associated with a median survival of 9 months or less.4-13 Although at times it is considered a variant of MDS,2 CMML differs biologically and clinically from MDSs, mainly because of its proliferative rather than dysplastic features and frequent extramedullary involvement.14-17 CMML shares clinical features with Philadelphia chromosome–negative myeloproliferative disorders.18-20 The median survival of CMML is 8 to 30 months.17,20 Currently, there is no consensus on management of high-risk MDSs. Supportive measures, such as blood-product transfusions and antibiotics, are still considered by many to be the standard care; other approaches are often considered investigational. Results with hematopoietic growth factors,21-23 low-dose chemotherapy with agents such as cytarabine,24-26 and combination antileukemic-type chemotherapy26-38 remain unsatisfactory. The excessive toxicity of most of the effective drug combination regimens remains a major concern. Clearly, there is a need to discover new therapeutic agents or strategies for the treatment of MDS. One such agent is topotecan, a semisynthetic derivative of camptothecin. Like other camptothecin derivatives, topotecan targets DNA topoisomerase I, an enzyme that is present in cells in concentrations relatively independent of the stage in the cell cycle. Topotecan stabilizes the complex formed between topoisomerase I and DNA, leading to DNA strand breakage and cell death.39-41 Topotecan is active in patients with solid tumors; myelosuppression is the dose-limiting side effect, and nonhematologic side effects are generally mild.42,43 Topotecan has also shown activity in patients with relapsed acute leukemia resistant to conventional therapies.44-46 Recently, topotecan has been shown to induce complete remission (CR) in high-risk MDS subcategories and CMML.47,48 Cytarabine is another drug effective against MDSs and the most active agent against acute myelogenous leukemia (AML). Cytarabine demonstrated activity in MDS and CMML, producing CR rates of 15% to 20% when used in a low-dose, extended schedule.24-26 However, virtually all patients treated with low-dose cytarabine relapse. In contrast, high-dose cytarabine has been reported to produce durable CRs.49 Topotecan and cytarabine act through different cytotoxic mechanisms, and their actions may be potentially synergistic. The purpose of this study was to evaluate the activity of the combination of topotecan and cytarabine in patients with advanced MDS or CMML. In addition, we hoped to improve response rates, especially in patients with poor prognostic features.
Study Design Patients were enrolled on this study from May 1996 through September 1998. Patients with RAEB or RAEBt were randomly assigned to the topotecan plus cytarabine arm or to one of four other arms of induction therapy used for AML and MDSs: (1) fludarabine, cytarabine, and idarubicin alone, (2) these three drugs plus granulocyte colony-stimulating factor, (3) these three drugs plus trans-retinoic acid, or (4) these three drugs plus granulocyte colony-stimulating factor and trans-retinoic acid.50,51 All patients with CMML were treated with topotecan and cytarabine.
Eligibility Criteria
Eligibility criteria included age older than 15 years; diagnosis of advanced MDS (RAEB, RAEBt, or CMML); a performance status of less than 3 on the Zubrod scale; adequate liver function (bilirubin level
Therapy
Supportive Care
During and up to 2 days after chemotherapy, patients received antiemetic prophylaxis. Thereafter, occasional nausea was managed at the discretion of the attending physician. Diarrhea was managed conservatively according to its severity with either loperamide or opiates administered orally. Mucositis was managed supportively. When fever requiring IV antibacterial antibiotics (
Evaluation Before and During Therapy Patients younger than 55 years who achieved CR and had an HLA-identical sibling were offered the option of allogeneic BMT. All other patients who achieved CR were eligible to continue receiving chemotherapy every 4 to 8 weeks at the discretion of the treating physician. At maximum, six courses were given. The topotecan dose was reduced by 25% for grade 2 toxicity and by 50% for grade 3 or 4 toxicity.
Criteria for Response
Statistical Considerations
Eighty-six patients received 134 induction cycles of topotecan and cytarabine. All patients completed the study; no patients were withdrawn because of side effects or for other reasons. All patients were assessable for response at the time of this report, including 59 patients with MDSs (25 with RAEB and 34 with RAEBt) and 27 patients with CMML. Patient characteristics are listed in Table 1. The median age was 64 years (range, 21 to 80 years), and 48% of patients were 65 years of age or older. Sixty-nine percent of patients were men. There was large variation in the duration of disease before enrollment onto the study. The median length of abnormal blood counts before enrollment onto the study was 3.5 months (range, 0 to 139 months) for the study group overall, 1 month (range, 0 to 96 months) for patients with MDSs, and 7 months (range, 0 to 139 months) for patients with CMML (Table 1). Chromosome 5 or 7 abnormalities were present in 21 patients, trisomy 8 in nine patients, and other abnormalities in 13 patients. Three patients presented with inv16 or t(8,21). A normal karyotype was present in 40 patients. Sixty-eight patients (79%) had primary MDSs or CMML, and 18 patients (21%) had a history of prior malignancy and were classified as having secondary MDSs (Table 1).
According to the karyotype-associated classification of MDS,29 43 patients (50%) had favorable disease (diploid, t(8,21); inv16), and 43 patients (50%) had unfavorable disease (-5/-7,+8 complex abnormalities). When the 59 patients with MDSs were classified according to the International Prognostic Scoring System (IPSS),12 12 patients (22%) had intermediate-risk 1 disease, 20 (36%) had intermediate-risk 2 disease, and 23 (41%) had high-risk disease. Of the 27 patients with CMML, 14 (52%) had between 5% and 30% blasts in the marrow; by analogy to chronic myeloid leukemia, these patients could be considered to have disease in accelerated phase or transformation. Fifty-seven patients (66%) were previously untreated, 12 (14%) had received biologic agents, and 17 (20%) had received one course of chemotherapy with or without biologic agents.
Response
CR was observed in 61% of patients with MDSs (95% CI, 47% to 73%). The CR rate was 80% for RAEB (95% CI, 59% to 93%) and 47% for RAEBt (95% CI, 30% to 66%) (Table 4). The CR rate was 44% (95% CI, 25% to 65%) in patients with CMML (P < .015) (Table 4). Further analysis of CMML responses by the stage of disease showed that 62% of patients with 5% or fewer blasts in the bone marrow (chronic phase) had CR, but the CR rate was 29% in patients with more than 5% blasts in the marrow (accelerated phase) (Table 4).
CR rates were similar for patients with poor-prognosis karyotypes (25 of 43, 58%) and patients with good-prognosis karyotypes (23 of 43, 53%). Among patients with MDSs, there was no significant difference in CR rates between patients with a good risk (age 70 years or younger and < 1 month history of abnormal blood counts [14 of 20, 70%]) and patients with a poor risk (22 of 39, 56%) (Table 4). Similar CR rates were also seen in patients with platelet counts lower than 30 x 109/L and patients with platelet counts higher than 30 x 109/L (61% and 53%, respectively) (Table 4). The CR rate as a function of the time between diagnosis and treatment is shown in Table 4. For patients in whom this interval was less than 1 month, the CR rate was 64% for MDS patients and 50% for CMML patients. Table 4 also lists the CR rates for patients for whom this interval was 1 to 3 months, 4 to 6 months, and more than 6 months. Within each disease category, the differences were comparable and not statistically significant. These results suggest that, in our limited number of patients, the duration of disease before treatment did not have a major impact on CR rate (Table 4). Similar CR rates were noted in patients with primary and secondary MDSs/CMML. In primary disease, 35 (52%) of 68 patients achieved CR, whereas in secondary MDSs, 13 (72%) of 18 patients achieved CR. A breakdown of responses by FAB subcategory and prior malignancy is listed in Table 5. Finally, the responses of 55 patients with RAEB/RAEBt were evaluated according to their assignment to IPSS categories.12 CR rates obtained in intermediate-risk 1, intermediate-risk 2, and high-risk categories were not statistically different (Table 6).
Serial Marrow Studies and Cytogenetic Studies in CR Bone marrow karyotype was studied in all patients. In 19 patients with abnormal karyotype, follow-up information after treatment was available. In 13 patients (68%), complete cytogenetic conversion with disappearance of the abnormal karyotype was observed in CR. In one of these patients with the 20q abnormality, the clone persisted in CR and a gradual shift toward a diploid pattern was seen during three subsequent courses of maintenance therapy.
In the remaining six patients, CR was associated with major improvement in the relative representation of the diploid clone and decrease of the abnormal clone below 10% in two patients. Interestingly, in four patients with multiple clones, the remission status was karyotypically characterized by elimination of some clones and persistence of others along with a diploid population, suggesting different importance of various abnormal clones in the re-establishment of normal hematopoiesis in CR.
Length and Intensity of Continuation of Therapy in CR Eighty-five maintenance courses (70%) were given on a 5-day schedule to 37 patients. With this schedule, the median dose of topotecan per course was 0.75 mg/m2 per day given by continuous infusion for 5 days (range, 0.37 mg/m2/d to 1.5 mg/m2/d). The median dose of cytarabine was 0.75 g/m2/d for 5 days (range, 0.25 g/m2/d to 1.0 g/m2/d). The median topotecan dose per course represented 60% of the induction dose, and the median cytarabine dose per course represented 75% of the induction dose. Thirty-six maintenance courses (30%) were given on a 3-day rather than a 5-day schedule to 11 patients. For all courses, the topotecan dose was 1.25 mg/m2/d for 3 days (3.75 mg/m2/course), and the cytarabine dose was 1.0 mg/m2/d for 3 days (3 g/m2/course). This represented 60% of the induction doses of both drugs. Because of the wide variation in the age and condition of the patients, the intensity of maintenance therapy varied widely. The first maintenance dose was reduced in all patients. The second or subsequent courses were further reduced in 13 of 31 patients. Comparison of the duration of CR and survival revealed no differences in the 3-day versus 5-day maintenance groups.
Toxicity
Severe gastrointestinal toxicity was infrequent. Grade 3 or 4 mucositis was seen in three patients (3%). Grade 3 or 4 diarrhea was noted in three patients (3%). With the prophylactic use of antiemetics, mostly mild (grade 1 or 2) nausea was observed during and a few days after chemotherapy in 31 patients (36%); severe nausea was noted in only two patients. The onset of mucositis and diarrhea was commonly seen at the end of the first week of therapy, and resolution of both mucositis and diarrhea usually occurred during the second week. Only occasionally did patients require parenteral fluids or parenteral nutrition as a consequence of gastrointestinal side effects (Table 7). Alopecia of various degrees was common, occurring in 100% of patients. Skin rash was noted in 25 patients (29%) and was severe in two. Surprisingly, neurotoxicity was observed in only two patients and consisted of short periods of confusion in one patient and involuntary movements in the other patient. Both resolved spontaneously. Other nonhematologic side effects occurred in six patients (Table 7). Eighty-three patients had pretreatment bilirubin levels of 1.5 mg/100 mL or lower, and one patient had a pretreatment bilirubin level of 1.7 mg/100 mL. Increase above 1.7 mg/100 mL was noted in two patients but without undue consequences in both cases. Increase in the creatinine level above 1.5 mg/100 mL or increase of at least 100% of pretreatment values was noted in 33 (38%) of 86 patients. Deterioration of kidney function to a degree requiring dialysis was observed in four patients; all had received concomitant nephrotoxic agents (antibiotics/antifungals). All patients required RBC and platelet support.
Mortality
Hematologic Recovery
Duration of Responses and Survival
Patients with a poor-prognosis karyotype had shorter median CR duration (26 weeks) and survival (42 weeks) than patients with a good-prognosis karyotype in whom the median CR duration was 51 weeks and median survival was 60 weeks. Because of the small number of patients in each group, these differences were not statistically significant (Fig 3). Comparison of CR duration between patients with normal karyotype (diploid patients) and patients with any chromosomal abnormalities showed CR duration of 51 weeks for patients with favorable cytogenetics and 26 weeks for the unfavorable group (Fig 3A). The survival times for 43 favorable cytogenetic patients and 43 unfavorable patients were 60 weeks and 42 weeks, respectively (P = .674; Fig 3B).
With a median follow-up of 7 months, 22 patients (46%) had a relapse (eight of 20 with RAEB, eight of 16 with RAEBt, and six of 12 with CMML). Overall, 29 patients (34%) have died, five in CR (Table 2). The median disease-free survival time was 50 weeks for RAEB, 31 weeks for RAEBt, and 34 weeks for CMML. In MDS groups stratified according to karyotype, the median disease-free survival was 41 weeks for the good-prognosis subgroup and 25 weeks for the poor-prognosis subgroup. The differences were not statistically significant.
The treatment regimen described in this report was developed to improve the response rates and response duration in patients with MDSs and CMML, particularly in patients with a poor prognosis for survival predicted by cytogenetic abnormalities.28,29,38 In addition, it was hoped that this treatment regimen would be well tolerated. Its activity as a single agent in refractory AML44,45 and in MDSs47,48 supports the use of topotecan, which has a unique mechanism of action, in combination with cytarabine. In phase I studies, topotecan demonstrated activity in patients with acute leukemia.44,45 In our study, the overall response rate was 19% in 27 patients with refractory or relapsed acute leukemia who received topotecan as a 5-day continuous infusion.44 Encouraging results were observed in a phase II study of 47 patients with MDS (n = 22) or CMML (n = 25) who received topotecan 2 mg/m2/d as a continuous infusion daily for 5 days.47 The main side effects in this trial were severe mucositis and diarrhea at the maximum-tolerated dose of 10 mg/m2 per course. CRs were observed in 31% of patients with high-risk MDSs and in 28% of patients with CMML.47 Of particular interest was the observation that topotecan seemed to preferentially affect the abnormal cytogenetic clones; conversion to a diploid karyotype occurred in patients in CR. These results were later confirmed in an extension of this study to include 60 patients.48 Cytarabine is the most active agent in the treatment of AML, and in the present study, cytarabine in combination with topotecan was shown to be an active regimen associated with low mortality in patients with high-risk MDSs or CMML. In particular, this regimen produced CR in a high proportion of patients with a poor-prognosis karyotype. Optimal management of high-risk MDSs remains controversial, and treatment approaches other than supportive care are often considered investigational. Results from a number of small, mostly retrospective pilot studies suggest that combination chemotherapy might have a role in high-risk MDSs.27,29-31,34-37,53,54 In these studies, combination chemotherapy in MDSs produced a pattern of response similar to that seen in elderly patients with AML. However, the CRs were of short duration, and the treatment was associated with high mortality even in a presumably selected patient population. Because there have been no studies of chemotherapy versus no treatment in patients with MDSs or CMML, the impact of chemotherapy on the natural history of these diseases and on survival has not yet been conclusively demonstrated. The high frequency of primary resistance and the high relapse rate in MDSs and CMML seen in early studies of chemotherapy for these diseases, particularly in patients with poor-prognosis karyotypic abnormalities, were suggestive of drug resistance. In this study, the combination of continuous-infusion topotecan with short concomitant infusions of high-dose cytarabine proved to be an effective and well-tolerated regimen, equally effective in inducing CR in poor-prognosis and good-prognosis MDSs. Compared with single-agent topotecan therapy, the combination of topotecan and cytarabine almost doubled the CR rate (from 31% to 56%) and significantly reduced the incidence of severe gastrointestinal complications (from 20% to < 5%) because of the lowered topotecan dose (from 10 mg/m2 to 6.25 mg/m2 per course). Whether the concomitant use of both drugs was optimal in terms of the therapeutic results is unknown. Some preclinical studies suggested that sequencing may be important in topotecan-containing drug combinations, particularly when this drug is combined with topoisomerase II–active drugs (Vey et al, manuscript submitted for publication).55-57 Our pilot randomized study comparing sequential use of etoposide and topotecan in relapsed acute leukemia patients failed to show any differences in activity; topotecan followed by etoposide was the more toxic regimen, which is consistent with data from animal models (Vey et al, manuscript submitted for publication). Similarly, it is not known whether continuous-infusion topotecan is more effective than short-infusion topotecan. With regard to toxicity, Rowinsky et al46 reported results that suggested a lower response of acute leukemias to daily-times-five bolus schedules than to continuous infusion but similar toxicity between the two dosing methods. The studies of Seiter et al58 and Rowinsky et al46 suggested that an equitoxic daily dose of short-infusion topotecan is two to four times that given as continuous infusion on a 5-day schedule. The present study was designed to increase response rates and survival in patients with high-risk MDSs and CMML. It further aimed to evaluate response in subcategories of patients stratified according to various potentially clinically useful criteria. Because the heterogeneity of these disorders most likely has a strong affect on the risk-benefit assessment of any treatment modality, this analysis by subcategories, albeit composed of a limited number of patients, represented an important part of the study. The first observation was that response differed between patients with CMML and those with RAEB or RAEBt. It has been noted previously that CMML had a slightly lower response rate to single-agent topotecan than MDSs,47,48 which suggests a higher activity of topotecan in MDSs. Although the addition of cytarabine increased the overall CR rate from 27% to 44% (P = .2) in CMML and from 31% to 66% in MDSs (P = .003), response differences persisted, which might reflect differences in the biology of CMML and MDSs. In our previous studies, duration of the antecedent hematologic disorder was a negative prognostic factor for response to chemotherapy. Keating et al59 first reported that the responses of patients with AML developing on the background of MDSs were inversely related to the duration of the antecedent hematologic disorder preceding AML. Similarly, response rates of patients with more advanced MDSs, ie, RAEBt, tended to be higher than those of patients with RAEB.28 In the present study, these factors were not predictive for response. In particular, the lack of correlation between the duration of the disease and the response rate may be of importance for therapeutic decision making because it implies that delaying chemotherapy does not necessarily compromise the initial response. This information must be verified in a larger patient population and correlated with the duration of response and survival as well. This study did not require an observation period to evaluate the stability of the MDS status. Consequently, some patients were treated immediately after diagnosis was established. This approach might have skewed the study to include more aggressive subsets of MDSs, ie, patients who would progress into AML within a few months of the diagnosis. The observation that, after failing one induction course of chemotherapy, only a small fraction of patients achieves complete CR with a second course argues against such an approach and favors change of management, although the median duration of CRs in both groups was comparable (limited number of patients). Currently two courses of chemotherapy might be recommended to select responders for continuation therapy. The usefulness of the risk-oriented prognostic classification of MDSs (and a subpopulation of CMML)12 for the assignment of patients to various therapeutic options is presently unknown. General validity of the classification must be tested cautiously, particularly because, as shown by our data,13 its application to patient populations at various institutions may result in appreciable differences in the expected survival within each category. It is, therefore, of interest that in 38 MDS patients treated with topotecan and cytarabine, there were no significant differences in CR rates between the three highest IPSS categories. The survival was best, however, in the intermediate-risk 1 category and worst in the high-risk category. How does the topotecan-cytarabine combination regimen compare with other combination chemotherapy regimens? In the case of a single-arm study, comparison is best made to historical controls at the same institution. Such comparison for MDSs (RAEB and RAEBt) is summarized in Table 8, which lists the M.D. Anderson Cancer Center's historical results with regimens containing high-dose cytarabine with fludarabine and/or idarubicin. When comparing the results, ideally, adjustment for significant covariate prognostic factors known to influence response should be made. Also, consecutive patients should be entered onto each trial. Nonetheless, the data in Table 8 suggest lack of significant differences in the overall CR rate between topotecan plus cytarabine and other regimens; the same applies for CR duration. The most significant difference is in the low mortality rate with topotecan and cytarabine (Table 8).
Our recent analysis of the outcome of 530 consecutive patients with AML, RAEBt, or RAEB treated at M.D. Anderson Cancer Center with intensive antileukemic chemotherapy demonstrated that outcome was worst in patients with complex chromosomal abnormalities involving chromosome 5 or 7.28 The overall CR rate in this group was 45%.28 Therefore, this subgroup may benefit from new investigational regimens. In the present study, the combination of topotecan and cytarabine produced improvement in these patients, at least in CR rates. Unfavorable karyotypic changes are frequently found in secondary MDSs, the incidence of which seems to be increasing; thus, patients with secondary MDSs may also benefit from this new drug combination. An important question is whether topotecan adds to the activity of high-dose cytarabine, which is considered themost active single agent in AML. The effectiveness of high-dose cytarabine as a single agent for both induction and maintenance chemotherapy has not been studied in MDSs, except in a pilot study by Preisler et al60 in AML secondary to MDS. However, a trial of single-agent, high- and intermediate-dose cytarabine was conducted at the M.D. Anderson Cancer Center in 151 patients with untreated AML and MDSs.49 The results of that study can be compared with those of the present study under the assumption that RAEB, RAEBt, and AML respond identically to AML-type chemotherapy.28 Without covariate adjustment and with apparently more unfavorable disease in the topotecan-cytarabine study (higher median age, higher frequency of the 5 or 7 karyotype), the CR rate was higher in the topotecan-cytarabine study than in the cytarabine only study (74% v 64%; P = .23). The most significant differences were in patients with abnormalities in chromosome 5 or 7 (80% v 26%; P = .002), which indicated that topotecan increased the efficacy of high-dose cytarabine in inducing remission. Outcome of primarily resistant and relapsed patients was dismal. Reinduction with intensive chemotherapy, predominantly with anthracycline-containing regimens, was attempted in 16 relapsed and 19 primarily resistant patients. Only one short CR was obtained with idarubicin plus high-dose cytarabine. Failures were associated with either deaths during reinduction, predominantly caused by infection, or deaths in untreated patients during supportive care. Although the results presented in this report are promising in terms of CR rates, longer follow-up is necessary for evaluation of the survival benefit. The major challenge at present is the development of innovative and relatively nontoxic maintenance strategies intended to prolong disease-free survival.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 mg/100 mL) and renal function (creatinine level 
[FAV CG]) and poor-prognosis karyotype (unfavorable cytogenetics, 
