A prospective randomized trial of KRN8602 and cytosine arabinoside vs. daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. The KRN8602 Leukemia Study Group.

A prospective randomized study was conducted to compare the efficacy and toxicity of two anthracyclines for the treatment of patients with acute myelogenous leukemia (AML). Fifty-eight patients were randomized and received induction therapy consisting of cytosine arabinoside (AraC) 100 mg/m2/day for 7 days combined with either KRN8602 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride [KRN]) 15 mg/m2/day for 5 days (KRN/AraC group) or daunorubicin (DNR) 40 mg/m2/day for 3 days (DNR/AraC group). Complete remission rate was 78.6% (22/28) in the KRN/AraC group and 73.1% (19/26) in the DNR/AraC group. There was a higher incidence of nausea/vomiting and anorexia observed in the KRN/AraC group compared to the DNR/AraC group, while the incidence of other adverse effects (stomatitis, diarrhea, and infectious complications) were similar between both groups. No electrocardiogram (ECG) abnormalities were observed after treatment in the KRN/AraC group, while in the DNR/AraC group, one patient showed ECG abnormality and three patients exhibited either arrhythmia, heart failure, or tachycardia. Mental disorder was reported in two cases in the KRN/AraC group. These findings suggest that KRN/AraC is similar in effectiveness to DNA/AraC but more toxic in central nervous system and gastrointestinal symptoms and less toxic regarding cardiac function in patients with previously untreated AML.     

A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia

We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006.     

Intensified daunorubicin in induction therapy and autologous peripheral blood stem cell transplantation in postremission therapy (Double-7 protocol) for adult acute myeloid leukemia

To investigate whether an intensified dose of daunorubicin (DNR) in induction therapy and autologous peripheral blood stem cell transplantation (PBSCT) in the postremission period are effective treatments, we used a Double-7 protocol to treat adult patients with de novo acute myeloid leukemia (excluding M0 and M3). Induction therapy consisted of 40 mg/m2 of DNR intravenous drip infusion for 7 days and 200 mg/m2 of ara-C by continuous infusion for 7 days (7 + 7 DC regimen). Patients who achieved complete remission (CR) were given high-dose chemotherapy with autologous PBSCT in postremission therapy. Of the 22 assessable patients, 16 attained CR (73%). Disease-free survival (DFS) and overall survival (OS) at 3 years were 61.2% and 48.1%, respectively. Nine of the CR patients underwent PBSCT without therapy-related mortality. Patients in a favorable cytogenetic group (n = 7) attained 100% CR and long-term survival (71.4% DFS and 85.7% OS at 3 years). Thus, intensified DNR administration of 280 mg/m2 (40 mg/m2 per day for 7 days) in induction therapy for adult patients younger than 60 years of age might be optimal or at least comparable with the new anthracyclines such as idarubicin. In addition, autologous PBSCT in postremission therapy might improve DFS and OS, at least for patients in a favorable cytogenetic group, such as those with a t(8;21) abnormality.     

A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.     

A multicenter,open, non-comparative,phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine,and G-CSF as induction therapy in refractory acute myeloid leukemia - a report of the Polish Adult Leukemia Group (PALG)

OBJECTIVES: To evaluate the efficacy and toxicity of cladribine (2-chlorodeoxyadenosine, 2-CdA), cytarabine (Ara-C), and granulocyte-colony stimulating factor (G-CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study. METHODS: The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C2 g/m2, and G-CSF. In the case of partial remission (PR), a second CLAG was administered. Patients in complete remission (CR) received two consolidation courses based on HD Ara-C, mitoxantrone or idarubicine, with or without 2-CdA. RESULTS: Fifty-eight patients from 11 centers were registered; 50 primary resistant and eight early relapsed (CR1 < 6 months). CR was achieved in 29 (50%) patients, 19 (33%) were refractory, and 10 (17%) died early. Forty of 50 primary resistant patients received daunorubicin (DNR) and Ara-C as the first-line induction therapy (DA-7), 10 received additional 2-CdA (DAC-7). The CR rates after CLAG were 58% and 10%, respectively in each group (P = 0.015). Five of six patients with myelodysplastic syndrome (MDS)/AML achieved CR. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS, 1 yr) for the 58 patients as a whole, and the 29 patients in CR were 42% and 65%, respectively. Disease-free survival (DFS, 1 yr) was 29%. Only first-line induction treatment with DA-7 significantly influenced the probability of CR after CLAG. None of the analyzed factors significantly influenced DFS and OS. CONCLUSION: CLAG regimen has significant anti-leukemic activity and an acceptable toxicity in refractory AML. The addition of 2-CdA to the first-line induction treatment may worsen the results of salvage with CLAG. The high CR rate in patients with MDS preceding AML deserves further observation.     

Efficacy of liposomal daunorubicin and cytarabine as reinduction chemotherapy in relapsed acute lymphoblastic leukaemia despite expression of multidrug resistance-related proteins

The treatment of relapsed adult acute lymphoblastic leukaemia (ALL) is frequently unsuccessful with current chemotherapy regimens, and often there is an overexpression of multidrug resistance (MDR)-related proteins. Liposomal encapsulation makes daunorubicin (DNR) less sensitive to the efflux effect of P-glycoprotein (PGP), and in vitro data indicate that liposomal-encapsulated DNR (Daunoxome-DNX) is more toxic than DNR against ALL cell lines. In this study, we assessed the in vivo and in vitro efficacy and toxicity of DNX plus cytarabine (Ara-C) as reinduction chemotherapy in 25 relapsed ALL patients (pts). The expression of MDR-related proteins (PGP, MRP1 and LRP) was also analysed. Of the 25 pts, 12 were males and 13 females; median age was 32 yr (range 18-58). Six cases were ALL T and 19 ALL B; eight pts were Ph+ (32%), and nine Bcr-Abl+ (36%). The expression of MDR-related proteins, and DNR and DNX retention and induction of apoptosis in leukaemic cells were evaluated in all cases. Seventeen of 25 (68%) pts were at first relapse and eight (32%) at second or subsequent relapse. The DNX was given in a dose of 80 mg/m(2)/d (days 1-3) in 11/25 pts (44%) and in a dose of 100 mg/m(2)/d (days 1-3) in 14/25 pts (66%). In all pts, Ara-C was administered in a dose of 2 g/m(2) (days 1-5). Twenty pts (80%) achieved a complete remission (CR) and two (8%) entered a partial remission (PR) for an overall response (OR) rate of 88% (22/25), with a tolerable toxicity and without significant cardiotoxicity. Before the start of DNX therapy, 18/25 (72%) cases overexpressed at least one MDR-related protein compared with 9/25 (36%) cases with MDR overexpression at diagnosis (P = 0.01). Taking into account the small number of cases, the response rate was not affected by MDR expression and the in vitro results also showed a higher uptake and apoptotic cell death by DNX compared with DNR. Twelve pts subsequently underwent allogeneic bone marrow transplantation (11 unrelated donor BMT, and one sibling BMT). The overall survival was 39% after 12 months. These data show the efficacy (OR rate 88% and CR rate 80%) of DNX plus Ara-C as reinduction therapy in very poor-risk ALL pts and the response rate seems not to be affected by MDR overexpression. Moreover, the high rate of remissions and the good clinical tolerance in heavily pretreated pts suggest a promising role of DNX in ALL chemotherapy regimens.     

Liposomal daunorubicin (DaunoXome) for treatment of poor-risk acute leukemia

Toxicity limits the use of anthracyclines in elderly sick patients and in heavily pretreated patients. Since the liposomal preparation of daunorubicin (DNR) (DaunoXome, or DNX) is expected to be less toxic than conventional DNR, we tested DNX combined with high-dose arabinosyl cytosine (HDAC) in 42 adult poor-risk acute leukemia patients. Thirty-one patients had acute non-lymphocytic leukemia (ANLL). Of these, 12 patients were newly diagnosed but were not eligible for standard induction treatment, 13 were in first relapse, and 6 were in second or subsequent relapse. Eleven patients had acute lymphocytic leukemia (ALL), in first (eight cases) or second (three cases) relapse. DNX was given i.v. in three doses of 80 or 100 mg/m(2) each (days 1-3) by a 60-min infusion in glucose 5%, followed by a 4-h infusion of HDAC 2 g/m(2) (days 1-5). Among 31 ANLL patients there were 16 (51%) complete remissions (CR), 5 deaths during induction, and 10 failures. Among 11 ALL patients there were 10 CRs and 1 failure. The response rate was not affected by the overexpression of MDR-related proteins (PgP, MRP-1, and LRP). Non-hemopoietic toxicity was negligible, with no intestinal toxicity and only one case of gram-negative bacteremia. We conclude that DNX, in combination with HDAC, is an effective treatment for poor-risk adult AL. Because of the low non-hematologic toxicity, it can be used to reinduce remission in poor-risk patients who are candidates for allogeneic bone marrow transplantation. The high CR rate observed in ALL requires confirmation.     

Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer

Pegase 03 is a multicenter prospective randomized phase III trial evaluating the impact of first-line high-dose chemotherapy (HDC) with stem cell support on overall survival (OS), disease-free survival (DFS) and response rate in 308 patients with histologically proven metastatic breast cancer responding to induction therapy. Eligible patients received four induction cycles with FEC 100 (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)). Patients with objective response (N=179) were randomized to one cycle of HDC (cyclophosphamide 6000 mg/m(2) and thiotepa 800 mg/m(2) (CHUT)) and stem cell support (N=88), or no further treatment (N=91). All patients were observed until disease progression or death. One toxic death occurred after CHUT. Other toxicities were manageable. The response rate at 3 months was higher in the intensification arm: 82.7% (25.3% complete response (CR)) versus 59.2% (14.1% CR) (P=0.0002). Median follow-up was 48 months. Median DFS was 11 and 6.6 months in the intensification and the observation arms, respectively (P=0.0001). There was no survival difference: 33.6 versus 27.3% OS at 3 years (P=0.8) and 22.9 versus 22.3 months median time to relapse in the intensification and observation arms, respectively. In this randomized trial, HDC with CHUT improved DFS but not OS, corroborating findings from earlier trials.     

Randomized comparison of fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex during and after consolidation therapy for elderly patients with acute myeloid leukemia: the JALSG GML200 Study

We conducted a multicenter prospective randomized study to compare a fixed-scheduled induction therapy with a response-oriented individualized induction therapy for elderly patients with acute myeloid leukemia (AML). Newly diagnosed AML patients, aged between 65 and 80, were randomly assigned to receive fixed or individualized induction. Both groups received daunorubicin (DNR) 40?mg/m(2) for 3?days and behenoyl cytarabine (BHAC) 200?mg/m(2) for 8?days. In the individualized group, bone marrow biopsy was done on days 8 and 10, and according to the cellularity and blast ratio, the patients received additional DNR and BHAC for two to four more days. All patients achieving complete remission (CR) were randomized a second time to determine whether they would receive ubenimex. CR was obtained in 60.1?% of the fixed group and 63.6?% of the individualized group. Predicted 4-year relapse-free survival (RFS) was 9?% for the fixed group and 18?% for the individualized group. There were no statistically significant differences in CR and RFS between the fixed and individualized groups. In the ubenimex group, prolonged RFS was observed. Notably, gender was a prognostic factor in this study, as 102 female patients had a significantly higher CR rate (72.5 vs. 54.3?%, p?=?0.0048) and better OS (24 vs. 14?% at 4?years, p?=?0.018), compared with 140 male patients.     

High-dose cytosine arabinoside and daunorubicin postremission therapy in adults with de novo acute myeloid leukemia

A total of 149 consecutive de novo AML patients aged 50 years or less (median age = 37 years) were enrolled in this prospective multicenter trial initiated in May 1985. All patients received the same induction and early consolidation therapy with daunorubicin (DNR), cytosine arabinoside (Ara-C), and etoposide (DAV). High-dose Ara-C/DNR therapy included Ara-C at 3 g/m², in 12 doses (HD-Ara-C/DNR I) and eight doses (HD-Ara-C/DNR II), followed by DNR 30 mg/m² for 3 days. A complete remission (CR) was achieved in 104 (70%) patients; 61 complete responders received at least one cycle with HD-Ara-C/DNR. If those patients who were transplanted in first CR (n=26), were not considered, the median relapsefree-survival (MRFS) of the remaining 78 patients was 15 months, with a probability of relapse-free survival (RFS) at 116 months of 30% (95% CI, 20–40%) after a median follow-up of 95 months. The MRFS of the HD-Ara-C/DNR consolidated patients was 25 months, with a probability of RFS at 116 months of 37% (95% CI, 24–50%). If all patients who were transplanted (n=44) were not considered, the median survival time (MST) was 18 months with a probability of being alive at 118 months of 24% (95% CI, 16–33%). MST of the HD-Ara-C/DNR consolidated patients was 58 months with a survival probability of 46% (95% CI, 31–60%) at 118 months. Prognostic factor analysis did not reveal any significant influence of age, sex, FAB subtype, white blood cell count, hemoglobin level, thrombocyte count, LDH, or response to the first induction course on RFS of the HD-Ara-C/DNR consolidated patients. In summary, HD-Ara-C/DNR consolidation can improve the long-term outcome of a subgroup of de novo AML patients. Further improvement of the outcome seems to depend on the identification of patients with an inferior outcome under that strategy who might benefit from alternative treatment strategies.     

The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients

Fludarabine in addition to cytosine-arabinoside (ARA-C) increases the accumulation of ARA-C-5'-triphosphate (ARA-CTP), which is responsible for the cytotoxic effect in leukemic blasts. In a randomized phase 3 trial, patients with high-risk myelodysplastic syndrome (MDS) (n = 91) or elderly patients with acute myeloid leukemia (AML) (n = 43) were randomized to receive 2 induction courses consisting of ARA-C (2 g/m2 days 1 through 5) and granulocyte colony-stimulating factor (G-CSF) (filgrastim, 5 microg/kg) during and after chemotherapy with or without fludarabine (25 mg/m2, days 1 through 5) (FLAG versus AG). Consolidation consisted of daunorubicin (45 mg/m2, days 1 through 3) and ARA-C (200 mg/m2, days 1 through 7). Complete remission (CR) rate following AG was 65% versus 71% with FLAG (P =.49). Overall survival (OS) at 24 months was 24% for AG treatment and 39% for FLAG (P =.32). Event-free survival (EFS) at 2 years was 10% and 19% (P =.31) for the AG and FLAG treatments, respectively. Platelet and granulocyte recovery times after the second cycle were prolonged in the FLAG treatment group. Grades 3 to 4 neurotoxicities were more often reported in the FLAG arm (14% versus 3%, P =.03), whereas no significant differences in other toxicities were observed. In a cohort of patients, the in vivo accumulation of ARA-CTP in leukemic cells was determined. Although ARA-CTP accumulation in leukemic cells after FLAG was enhanced, clinical outcome in terms of CR rate, OS, EFS, and disease-free survival (DFS) was not significantly improved by combining fludarabine with ARA-C.     

Long-term results of the UHKT-911 study of adult patients under 65 years of age with de novo acute myeloid leukemias without favorable karyotypes

Between February 1991 and April 1994 induction chemotherapy of 32 adult consecutive patients under 65 years with de novo acute myeloid leukemias (AML) was started in the study UHKT-911. They were 19 women and 13 men, aged 18-63 (median 44) years. Their AML were classified according to the FAB classification: 3 M0, 3 M1, 9 M2, 14 M4, 3 M5. Induction chemotherapy consisted of 1-2 cycles with 3-4 doses of daunorubicin (DNR) 45 mg/m2/d i.v. and 14 doses of cytosine arabinoside (Ara-C) 200 mg/m2 per 3-h infusion every 12 hours. After the treatment patients, not being in complete remission, got the HD cycle with 10 high-doses of Ara-C 2000 mg/m2 per 3-h infusion every 12 hours i.v. and DNR 45 mg/m2/d i.v. on days 4 and 5, then the EMi cycle composed of etoposide 100 mg/m2/d i.v. for 5 days and mitozantrone 10-12 mg/m2/d i.v. on days 1, 3 and 5. Complete remission (CR) was achieved in 25 of 32 (78%) patients after 1-3 cycles. Five patients died between days 5 and 24 of treatment of infections, two patients were resistant to 4 cycles of induction therapy and survived 8.4 and 13.5 months. Three patients chose allogeneic bone marrow transplantation in their 1st CR from their relatives. Two of them have been living in CR for 115 a 110 months since diagnosis, the third died of sepsis on the day 52 after transplantation. Two patients in CR died of infections after their 2nd. consolidation cycle. Twenty patients in CR completed 2-4 consolidation cycles (1-3 HD, 1 EMi). Median of their CR duration was 17.8 (2-117) months. Relapse appeared in 12 cases after 4.4-34.8 (median 12.5) months, 8 patients (6 women and 2 men, aged 29-63 years) have remained longer than 5 years in their 1st. CR. Cytogenetic examination of their bone marrow showed a normal karyotype in 4 cases, 1x 46,XX,del(1)(p32p34), 1x 46,XX,16p+, 1x 47,XX,+mar, 1x 46,XX,del(5)(q22q33). After 62 months in CR a pancytopenia with dysplastic bone marrow changes developed in one of them, probably a secondary myelodysplastic syndrome, lasting for further 33 months. Event-free survival at 5 years was 27.5% (8/29 patients), significantly better (p = 0.046) against 7.5% (3/40) patients treated without HD cycles in the years 1982-1987. The same difference was observed in 7.5-year overall survival (p = 0.036) between the two studies, when 3 of 6 patients 60-64 years old remain in their 1. CR.     

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.     

Retrospective study of acute myelogenous leukemia in elderly patients: treatment and outcome of 83 consecutive patients

We retrospectively analyzed treatments and outcomes for 83 acute myelogenous leukemia (AML) patients aged 60 years or more (median age 71) admitted to our hospital between August 1984 and January 1998. Complete remission was achieved in 36% of 78 patients who received anti-leukemic therapy, and median overall survival was 227 days. In addition to abnormal karyotypes involving chromosome 5 or 7, administration of less than 120 mg/m2/course of daunorubicin (DNR) during the initial treatment phase was an unfavorable prognostic factor for both CR and survival. Only 41% of all patients received 120 mg/m2/course of DNR or more, and had a significantly higher CR rate (56%) and longer survival, with a median of 389 days. It was suggested that intensive chemotherapy was effective for selected elderly AML patients who were relatively younger and had good performance status, although the number of such patients was limited in our study.     

Unrelated donor bone marrow transplantation using a chemotherapy-only preparative regimen for adults with high-risk acute myelogenous leukemia

Limited data are available for adults undergoing unrelated donor (URD) BMT for AML using chemotherapy-only preparative regimens. Previous studies incorporated irradiation, included adults and children, and excluded secondary leukemia. Herein we report long-term outcomes for adults with poor-prognostic AML receiving a novel regimen of busulfan (16 mg/kg), cytarabine (8,000 mg/m(2)), and cyclophosphamide (120 mg/kg) (BAC), followed by URD BMT. From June 1995 through October 2001, 45 adults were enrolled. Adverse features included unfavorable cytogenetics (49%), secondary AML (47%), leukemia at transplant (42%), and extramedullary disease (16%). At time of BMT, 23 were in remission (12 CR1) while 22 had leukemia. Four (9%) died early. Acute and chronic GVHD rates were 44 and 67%, respectively. Seventeen (38%) were disease-free 52 months post-BMT; 13 were leukemia-free (eight CR1) at transplant. Eleven relapsed. Three-year DFS and OS were 42 and 46%, respectively. DFS and OS were longer, and relapses less, for those in CR at time of BMT. Secondary leukemia, cytogenetics, cell dose, and GVHD did not influence outcome. In poor-risk AML, BAC provided cytoreduction comparable to reported TBI-containing regimens, when administered for URD BMT. With decreasing treatment-related mortality, it is justified to proceed early to URD BMT for patients with poor prognostic features.     

The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.     

Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study

A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance courses were given every 4 wk or every 8 wk.     

High-dose hydroxyurea in the treatment of poor-risk myeloid leukemias

The aim of the study was to evaluate the antileukemic effectiveness and toxicity of high-dose hydroxyurea (HHY) and to assess its acute toxicity. Between August 1997 and October 1998, 12 consecutive adult patients (>18 years) with high-risk acute myeloid leukemia (AML) (four patients in first early relapse, seven patients with secondary AML, and one patient with de novo AML concomitant to a lymphoproliferative disorder) were enrolled to receive a single course of HY (100 mg/kg per day) until bone marrow aplasia or for a maximum of 30 days. Of the 12 patients, 5 (41.6%) achieved complete remission (CR), 1 achieved partial remission (PR), 4 were resistant to treatment, and 2 died during induction from infection. No patient with relapsed AML achieved CR, while it was achieved by five of eight patients with secondary AML at diagnosis; five of six MDR1+ patients achieved CR. As concerns follow-up of the CR patients, one did not receive any further treatment and died in CR from pulmonary aspergillosis, and one with a concomitant chronic lymphocytic leukemia (CLL) received two courses of FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor) regimen with disappearance of the clonal Ig rearrangement, but relapsed after 11 months and died from pneumonia. The remaining three patients were consolidated with two courses of high-dose cytosine arabinoside (AraC), followed by peripheral blood stem cell transplantation (PBSCT) in one patient. One of them relapsed after 3 months, while the other two are still in continuous complete remission (CCR) after 16 and 28 months, respectively. This study has demonstrated the safety and efficacy of HHY in inducing CR in AML patients with unfavorable prognosis. Despite the small number of patients, these encouraging results warrant further studies.     

High-dose daunorubicin as liposomal compound (Daunoxome) in elderly patients with acute lymphoblastic leukemia

Elderly acute lymphoblastic leukemia (ALL) is a rare condition associated with low complete remission (CR) rate and short survival. In order to improve these results, we evaluate the efficacy and toxicity of Daunoxome, a liposomal daunorubicin, exhibiting toxicity profile and pharmacokinetic indices better than standard daunorubicin. In total, 15 consecutive patients with nonmature ALL were enrolled on a prospective phase II study. No exclusion was made because of older age, poor performance status and organ dysfunctions. Median age was 69 years; performance status resulted >/=2 in nine patients (60%), six patients (40%) were bcr-abl positive and two-thirds of the patients had comorbidities. Induction therapy consisted of vincristine, Daunoxome and dexamethasone. Patients in CR received one or two consolidation cycles of cyclophosphamide, cytarabine and topotecan followed, in patients achieving CR, by a two-year rotating maintenance course including vincristine, Daunoxome, cyclophosphamide and prednisone. In all, 11 patients (73%) achieved CR, three patients (20%) died early during the induction phase and one patient (7%) had resistant disease. Five patients (33%) relapsed after 5-21 months. With a median follow-up of 20 months, disease free survival (DFS) and overall survival (OS) at 2 years were 36 and 38%, respectively. Major toxicity included myelosuppression and infection. Our experience demonstrates that a high dose of daunorubicin as liposomal compound can be safely administered in elderly ALL, exhibiting high antitumor activity. Our therapeutic program shows evidence of benefit in DFS and OS.     

The GIMEMA ALL 0183 trial: analysis of 10-year follow-up

We report the 10-year follow-up of the GIMEMA ALL 0183 trial.
From 1983 to 1987, 358 adults with acute lymphoblastic leukaemia (ALL) were entered into this trial, which included a mild induction, an early intensive consolidation, a post-consolidation phase randomized in conventional maintenance (arm A) and in more intensive regimen (arm B). CNS prophylaxis did not include CNS irradiation. The overall complete remission (CR) rate was 79.3% (284/358); 212 patients were randomized (110 in arm A and 102 in arm B).
The median overall CR duration was 20 months and the median overall survival (OS) 21 months; both curves reach a plateau after 6 years; at 10 years 25% of patients were projected to be in long-term remission and survivors. The median disease-free survival (DFS) was 17 months, at 10 years 27% and 28% of patients were DFSs in arm A and in arm B respectively.
In multivariate analysis age, WBC count and L2 FAB subtype were found to significantly influence OS and DFS. With regard to our previous report OS appears to linearly correlate with initial WBC count and age (P=0.0002 and P=0.042 respectively).
195 (68.7%) patients relapsed (only 25 had isolated CNS). The overall second CR rate was 56.5%; 23 patients underwent transplantation (12 BMT and 11 ABMT). Post-relapse survival was found to be influenced by the duration of first CR.