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CLINICAL STUDIES
Eligibility And Efficacy CriteriaThe major eligibility criteria in the three studies were similar with the exception of age restrictions. MSKCC study was limited to patients <= 60 years, while the U.S. Multicenter Trial and SEG included adult patients >= 18 years and >= 15 years, respectively. Within the studies the two arms were comparable at entry with regard to: sex, age, FAB classification, performance status, infection status, bleeding, WBC, platelets, hemoglobin, and cytogenetics, where performed. Specific patient characteristics are summarized on Table 13. The MSKCC study excluded patients with prior myelodysplastic syndrome while the other two studies permitted patients with an antecedent hematologic disorder. Table 14 provides data on presence of antecedent hematologic disorders, along with baseline values of white blood cell (WBC) counts, platelets, and hemoglobin. All patients, as randomized, were considered in evaluating the results of these trials. Therefore, these studies evaluated the "intent to treat" sample and not a selected "evaluable" patient sample.[10] Results from these statistical analyses represent conservative outcomes. Those who achieved complete remission * and were eligible, underwent bone marrow transplantation (BMT). Of the 22 patients treated with IDA/Ara-C who have undergone BMT, 19 have had allogeneic BMT and three patients received an autologous BMT. Of the 12 BMT patients treated with DNR/Ara-C, ten received allogeneic BMT, while two received an autologous transplant.Table 15 summarizes the study protocols and patients who have undergone BMT.[10] All patients not achieving complete remission were considered failures, including all early deaths. Those patients not responding after one cycle and not receiving a second course for various reasons, were also considered failures.[10]
* CR: normocellular or sightly hypocellular bone marrow <= 5% blasts, WBC > 3000/µ or granulocyte count > 2000/µL, platelets > 100,00/µL. One study (MSKCC) required CRs to last at least 4 weeks to be so classified.
SurvivalIn the MSKCC study the proportion of patients alive on the IDAMYCIN® arm was greater than that of patients receivinq daunorubicin at any time followinq randomization. (See Chart 1). The median lenqth of survival was 16.7 and 14.3 months for IDAMYCIN and daunorubicin, respectively. After 18 months, the probability of survival was 48% on the IDAMYCIN arm and only 28% on the daunorubicin arm. What's more, the tails of these two curves become clearly divided, favoring IDAMYCIN. Overall average survival time was nearly 65% longer on the IDAMYCIN arm than on the daunorubicin arm, with a hazard ratio of 1.65, and a statistically significant* difference (P > 0.05).[10] Upon completion of the MSKCC study 15 of 65 Patients (23%) on the IDAMYCIN arm remained disease-free (alive and without any relapse), and 10 of them (15%) have been in complete remission for more than 2 years. In contrast, on;y 9 of 65 patients (14%) on the daunorubicin arm remained disease free, and 2 of these patients (3%) have been in complete remission for more than 2 years. Censoring bone marrow transplant (BMT) patients the MSKCC survival curves (shown in Chart 2) show a clear difference favoring the IDAMYCIN arm. Median survival for these patients was 16.1 and 13.5 months for IDAMYCIN and daunorubicin, respectively. The Pvalue remains statistically significant (P< 0.05) and the hazard ratio suggests that survival time with IDAMYCIN is nearly 67% longer than with daunorubicin. *All P values in survial data havebeen determined by log rank test.
The U.S. Multicenter Trial survival curve significantly favors the IDAMYCIN® arm, with the length of median survival 12.9 months for IDAMYCIN and 9.2 months for daunorubicin. Patients treated with IDAMYCIN survived approximately 40% longer compared to those receiving daunorubicin (hazard ratio of 1.40). After 18 months of therapy, the survival probability was 35% on the IDAMYCIN arm, yet only 23% on the daunorubicin arm. The difference in overall survival is statistically significant, with P < 0.05. Median survival rates with or without BMT in this trial, favored IDAMYCIN over daunorubicin as shown in Chart 4. When adjusted for age, the results were consistently favoring IDAMYCIN. (See Table 17.) Patients 18 to 50 years of age assigned to the IDAMYCIN arm survived about 80% longer compared with those randomized to the daunorubicin arm.
In the SEG study, median survival was 10.8 months for patients treated with IDAMYCIN® and 9.1 months for those treated with daunorubicin. Patients lived an average of 14% longer having been on the IDAMYCIN arm than those on the daunorubicin arm. This difference is not statistically significant IP = 0. 3 81. As shown in Chart 6, these results were similar in patients who received BMT. The survival curves of the SEG study may have been more dramatically different, as demonstrated in the other trials, had intensive maintenance therapy not been given. The incidence of death in complete remission during the maintenance phase was considerably higher on the IDAMYCIN arm than on the daunorubicin arm. In two randomized trials, IDAMYCIN proved to be superior to daunorubicin in terms of overall survival. This difference was statistically significant in two of three U.S. studies. Table 17 shows the breakdown of median survival by two important factors; age and WBC at baseline.
Complete RemissionThe complete remission (CR) rate was higher on the IDAMYCIN®arm than on the daunorubicin arm in all three randomized trials. In two of the trials the difference was statistically significant (P < 0.05). (See Table 18.) Following the first induction course in the MSKCC study 54% of patients on the IDAMYCIN arm achieved CRs, whereas only 29% of those treated with daunorubicin did. After the second course, the CR rate on the IDAMYCIN arm increased to 78% and the CR rate of the daunorubicin arm became 58%. The difference in the overall CR rates is statistically significant with P < 0.05. If less stringent criteria (see eligibility and efficacy criteria) were used (if the definition of CR was exclusion of the second BM examination), the CR rate would have risen to 86% and 66%, respectively. Resistant disease (persistant blasts) was the reason for failure in 57% ~8/14~ and 74% (20/27) of the nonresponding patients randomized to receive IDAMYCIN and daunorubicin, respectively. In the U.S. Multicenter trial, after the first induction course, 52% of patients entered a CR on the IDAMYCIN arm, compared to 38% on the daunorubicin arm. After the second course, the CR rate increased to 67% with IDAMYCIN and 58% with daunorubicin (P = 0.18). Resistant disease was the reason for failure in 18% (6/31) and 47% (22/47) of the nonresponding patients randomized to receive IDAMYCIN and daunorubicin, respectively. Following the first induction course in the SEG trial, 53% of patients on the IDAMYCIN arm achieved a CR compared with 43% of the patients on the daunorubicin arm. After the second course, the CR rate increased to 68% (IDAMYCIN) and 55% (daunorubicin) with a statistically significant difference favoring IDAMYCIN (P < 0.05). Resistant disease was the reason for failure in 31% (11/35) and 43% (23/54) of nonresponding patients randomized to receive IDAMYCIN and daunorubicin, respectively. Overall patients treated on the IDAMYCIN arm achieved higher CR rates than patients on the daunorubicin arm in all three trials, and the difference was statistically significant in two of these studies. Table 19 shows a breakdown of CR rates by age and WBC count at baseline.
In the MSKCC study, the median duration of remission was 3 weeks longer on the IDAMYCIN® arm than on the daunorubicin arm (9.6 mo v 8.9 mo). (See Chart 7.) In the U.S. Multicenter Trial, the median duration of remission was 1 month longer on the IDAMYCIN arm than on the daunorubicin arm (9.4 mo v 8.4 mo, P < 0.05). (See Chart 8.) In the SEG study, the median duration of remission was 7.5 months longer on the IDAMYCIN arm than on the daunorubicin arm (18.8 mo v 11.3 mo). (See Chart 9.) To conclude, the median durations of remission were consistently longer on the IDAMYCIN arm in all three studies.
Summary Of Foreign Controlled StudiesTwo multicenter, randomized, controlled studies have been started in Europe to compare IDAMYCIN®/Ara-C to daunorubicin/Ara-C in the treatment of adult AML. The first study, designed and performed by the GIMEMA group, began in Italy in October 1984, and was completed inJune 1987.[46] The second study, designed and performed by the BGMT group, was started in France in April 1987, and is still ongoing. Both studies are limited to patients > 55 years of age, and the study designs are shown in Table 20. Some of the results of these studies are summarized in Table 21. In the GIMEMA study, after the first course of therapy, 30% (37/124) achieved a CR with IDAMYCIN and 20% (25/125) achieved a CR with daunorubicin. Though the overall CR rates were only slightly different in the two arms 30% (37/124) of the responders on the IDAMYCIN arm achieved a CR after one course, compared with only 20% (25/125) of the responders on the daunorubicin arm. This difference was statistically significant (P < 0.05). After the second course, the overall CRs were 40% on the IDAMYCIN arm and 39% on the daunorubicin arm. Resistant leukemia was the reason for treatment failure in 23% (17/74) of the patients on the IDAMYCIN arm and in 51 % (39/76) of those on the daunorubicin arm. In terms of early deaths, 8% of patients on the IDAMYCIN arm and 7% of patients on the daunorubicin arm died before response could be evaluated. There were fewer hypoplastic deaths in the daunorubicin arm as compared to the IDAMYCIN arm (14% v 29%). It can be speculated that these results were due to the lack of appropriate supportive care at some of these institutions. Overall survival was influenced by these early deaths; the median length of survival for the IDAMYCIN arm was 2.2 months, with 117 patients (94%) who died and 7 patients being censored; the length of survival for the daunorubicin arm was 5.0 months, with 119 patients (95%) who died, and 6 being censored. No statistically significant differences were detected between the groups with respect to the duration of survival. (See Chart 10) Remission duration with IDAMYCIN was longer than with daunorubicin, although the difference was not statistically significant. The median duration was 9.01 months on the IDAMYCIN arm and 7.86 months on the daunorubicin arm. Relapse-free survival time was slightly longer on the IDAMYCIN arm than on the daunorubicin arm (9.84 mo v 9.34 mo). In the BGMT trial, the results are still preliminary. In terms of CR rates to date, 72% of patients achieved complete remission on the IDAMYCIN arm and 65% on the daunorubicin arm. Resistant disease was the reason for failure in 30% (6/20~ of nonresponding patients randomized on the IDAMYCIN arm and 67% (16/24~ of those nonresponders on the daunorubicin arm. The relapse rate was somewhat higher in those treated with daunorubicin, since 24 patients who achieved a CR with this drug relapsed, whereas only 18 patients who achieved a CR with IDAMYCIN relapsed. There are 26 patients in continuous CR on the IDAMYCIN arm and 17 on the daunorubicin arm. (See Chart 11)
Response rates, as shown in Table 23, vary from 18% to 29% in the AML patients. These were the rates expected considering that they were for relapsed and refractory patients 10 CRs in these and other patients refractory to or relapsed following previous anthracycline therapy,[10] of cross-resistance between other anthracyclines and IDAMYCIN.[47,48] The trials noted were also important since they were the first evidence for the activity of IDAMYCIN in adult AML.
Summary Of Foreign Uncontrolled StudiesForeign uncontrolled studies in AML, most with small numbers of patients had response rates varying from 0% to 40%, with an overall CR rate of approximately 16%. These studies are listed in Table 24. In most studies, IDAMYCIN® was given on a daily x 3 basis, with a total dose per course ranging from 15 to 40 mg/m². Only at the higher range did this compare with the other trials reported previously.The response rate observed in these uncontrolled European trials does not appear to be substantially different from that observed in the U.S. uncontrolled studies of relapsed and refractory patients.
Safety Profiles Of U.S. Controlled StudiesClinical and laboratory disturbances are expected with anthracycline and Ara-C treatment of AML. These adverse events include infection, bleeding, nausea and vomiting, diarrhea, mucositis, fever, neurologic disturbances, anorexia, skin reactions, and hair loss. Table 25 shows the total incidence and the most severe toxicity (Grade 3 or 4) of induction adverse events. There were no statistically significant differences in the incidence or severity of the adverse events seen. Rare unexpected toxicities were reported with IDAMYCIN® including bullous erythrodermatous rash of the palms and soles, similar to that seen with high-dose Ara-C and intestinal perforation (in some cases related to instrumentation).
Table 26 lists the duration of myelosuppression following induction therapy. This data indicates comparable duration of aplasia between IDAMYCIN®/Ara-C and daunorubicin/Ara-C therapies.
Table 27 addresses chanqes in selected laboratory tests including bilirubin, SGOT, and alkaline phosphatase representing measurements of liver function; and, BUN and creatinine representing measurements of renal function during induction. The physiological disturbances associated with AML and its treatment are reflected in the considerable incidence of disturbance of hepatic and renal function occurring with both IDAMYCIN and daunorubicin therapies.
Spontaneously reported adverse events greater than 5% in the U S. Multicenter Trial are listed in Table 28. It is difficult to determine the relationship of reported experiences with therapy administered. There does not appear to be any significant difference in the incidence of any of these adverse events with regard to the treatment group.
Following consolidation, the average severity of elevations in bilirubin level was greater with IDAMYCIN®/Ara-C than with daunorubicin/Ara-C. The greatest shift though wa in the grad 1-2 elevations. Grade 3-4 elevations occurred at a similar frequency, as seen in Table 29. The duration of aphasia, defined as the number of days with a WBC < 1000/mm³ and/or a platelet count < 50,000/mm³, was significantly longer during the consolidation phase for the idarubin patients compared to daunorubicin-treated patients in each of three U.S. trials.
Table 30 documents the overall incidence and Grade 3 or 4 toxicit of expected adverse events for the consolidation phase of the studies. There were differences in the incidence and average severity of infection and in the average severity of mucositis, with patients on the IDAMYCIN®/Ara-C arm experiencing somewhat greater toxicity.
The changes in left ventricular e jection fraction (LVEF) and the frequency of congestive heart failure (CHF) as a function of increasing dose of anthracycline, are listed in Table 31. There were no marked differences between the treatments with respect to the mean change from baseline in the LVEF, nor in the number of patients who experienced a decline in LVEF gradecl as moderate or severe. Congestive heart failure is difficult to assess since symptoms of CHF frequently accompany fluid overload resulting from blood transfusions, antibiotic infusions, and continuous infusions of chemotherapeutic agents.
All on-study deaths are summarized in Table 32. The severity of AML and its treatment, account for the tact that approximately 20% of patients treated with either IDAMYCIN® or daunorubicin died during induction therapy. Death was generally associated with infection or bleeding due to the absence of normal blood cells. There were five deaths on the IDAMYCIN/Ara-C arm and one on the daunorubicin/Ara-C arm during the intensive maintenance phase of the SEG study. This phase was then discontinued.
SummaryThree open label randomized U.S. trials in previously untreated adult AML patients, had 277 patients randomized to receive IDAMYCIN®/Ara-C and 297 patients randomized to receive daunorubicin. The treatments were comparable with respect to major baseline prognostic variables. The median duration of survival was longer for patients on IDAMYCIN/Ara-C than for those on daunorubicin/Ara-C. This difference was statistically significant in two of three studies. Survival for IDAMYCIN patients was longer than for daunorubicin patients in each of the age strata. In each study, proportionately more patients randomized to receive IDAMYCIN/Ara-C achieved a complete remission than those receiving daunorubicin/Ara-C. The difference was statistically significant in two of the three studies. In two of the three studies, more patients on IDAMYCIN/Ara-C than on daunorubicin/Ara-C achieved a remission after one induction course. The median duration of remission was longer for IDAMYCIN than for daunorubicin treated patients. This difference was statistically significant in one trial. There were no ma jor differences in clinical or laboratory safety parameters nor in cardiac toxicity during the induction phase of the studies. The incidence of induction deaths was similar for the two treatments.
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