High-dose Cytarabine And Mitoxantrone Research Articles

Multicentre, Open Label, Randomized Phase III Study of Cpi-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 60 years) with Relapsed / Refractory Acute Myeloid Leukemia (AML) - Armada 2000 (AML003) Trial

Multicentre, Open Label, Randomized Phase III Study of Cpi-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 60 years) with Relapsed / Refractory Acute Myeloid Leukemia (AML) - Armada 2000 (AML003) Trial

Safety Study of Salvage Chemotherapy High-Dose Ara-C/Mitoxantrone (HAM) and Type I FLT3-TKI Crenolanib in First Relapsed/Primary Refractory AML

Background: High-dose cytarabine and mitoxantrone (HAM) have been used as salvage chemotherapy in patients (pts) with relapsed/refractory AML. Mitoxantrone is less cardiotoxic than other anthracyclines and can be tolerated in older pts. Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with promising single-agent activity in multiply relapsed/refractory FLT3+ve AML. Crenolanib has a half-life of 6-8 hrs and does not accumulate after chronic dosing. We here report data from the first 8 pts with primary relapsed or refractory AML treated with HAM followed by crenolanib.Design: Pts with AML and/or prior MDS regardless of FLT3 status (wild-type or mutant) were enrolled in this study. Eligible pts must have progressed on or be refractory to their first line AML therapy. Pts were treated with HAM (cytarabine 1.0 g/m2/d for d1-6 and mitoxantrone 10 mg/m2 for d1-3) followed by crenolanib 100 mg TID, starting from d8 continuously for a maximum of 49d per cycle (2 cycles of treatment were allowed). Older pts (≥60 yr) or pts who had prior SCT or who required a second induction cycle received lower dose of HAM (cytarabine 0.5 g/m2/d for d1-6 and mitoxantrone 8 mg/m2 for d1-3). Pts in remission following salvage induction were eligible to proceed to allo SCT.Results: 8 pts (4 males, 4 females) with first relapsed or primary refractory AML have been enrolled and received HAM followed by crenolanib. The median age on study was 64 (range 36-78) with 6/8 pts ≥ 60yr and 3 pts older than 70yr. 3/8 pts came on study with FLT3 activating mutations, including ITD (2 pts) and D835 (1 pt). 7/8 pts had de novo AML, and 1 had prior-MDS after receiving prior chemotherapy for ovarian cancer. 3/8 pts were primary refractory to first line therapy with the remaining 5 pts having relapsed following response to first line therapy. Pt demographics are summarized in Table 1.8 pts received 1 cycle of salvage treatment with HAM followed by continuous daily crenolanib (100 mg TID). 6 pts were evaluable for responses with a complete remission rate of 67% (2 CR, 2 CRi), including 2 pts who were refractory to front line chemotherapy. 2 of 3 pts with FLT3 activating mutations (1 with ITD and 1 with D835) achieved complete remission with complete count recovery; the third pt (FLT3-ITD) had 10% residual blasts after 1 cycle of induction, and is currently planned for transplant.Crenolanib with salvage chemotherapy was well-tolerated in all 8 pts administered full dose crenolanib (100 mg TID) following HAM. No crenolanib dose reductions were required in any of the 8 pts during induction; however crenolanib was held for intercurrent illnesses, such as C. difficile diarrhea. 2 events of grade 1 ALT/AST elevation were noted during salvage treatment with HAM, but did not cause delays in the initiation of crenolanib. Moreover, the addition of crenolanib did not cause any further elevation of ALT/AST in these 2 pts and no dose reductions or holds were required. Only 1/8 pts showed an elevation in total bilirubin, this event was a transient grade 2 elevation attributed to concomitant medication for fever and returned to normal within 3-5d with no intervention required.Conclusions: Full-dose crenolanib was well-tolerated when given sequentially with HAM in an older pt population (median 64 yrs) with primary relapsed/refractory AML. Four pts achieved CR/CRi following 1 cycle of HAM/crenolanib, including 2 pts with WT FLT3 and 2 pts with FLT3 activating mutations (1 ITD, 1 D835). This trial has been expanded to allow combination of full dose crenolanib with other standard salvage chemotherapies, including MEC (mitoxantrone, etoposide, cytarabine) and FLA(G)-IDA (fludarabine, cytarabine, idarubicin w/ or w/o G-CSF). A phase III is initiated combining crenolanib and salvage chemotherapies in first relapse or primary refractory AML pts with FLT3+ve activating mutations. [Display omitted] DisclosuresIyer:Genentech: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Incyte: Research Funding; Arog: Research Funding; Celgene: Research Funding. Karanes:Arog: Research Funding. Eckardt:Arog: Employment, Equity Ownership.

Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia.

We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.

High Efficacy and Significantly Shortened Neutropenia Of Dose-Dense S-HAM As Compared To Standard Double Induction: First Results Of a Prospective Randomized Trial (AML-CG 2008)

BackgroundFor curative treatment of younger patients with acute myeloid leukemia (AML) double induction with two cycles of intensive cytarabine/ anthracycline based chemotherapy 21 days apart is the current standard of care. In the prospective randomized AML-CG 2008 trial we asked question whether current results could be improved on by a dose-dense regimen (S-HAM – Sequential High-dose cytArabine and Mitoxantrone) in which the interval between cycles was minimized to 3 days. A prior large one-armed study (AML-CG 2004) had demonstrated a high antileukemic efficacy and shortened neutropenia of the S-HAM regimen as compared to a historical control of standard double induction treatment. The first clinical results of the randomized comparison are presented here. MethodsAll patients with first diagnosis of a de-novo or secondary AML (excluding APL) that were deemed fit for intensive induction chemotherapy by their treating physician were eligible for this study. Younger patients in the standard arm were treated with one cycle of TAD-9 (standard dose cytarabine and daunorubicine 60mg/m2 for 3 days) and a mandatory second cycle of HAM (high dose cytarabine and mitoxantrone) starting at day 21. Elderly patients were treated with one cycle of HAM followed by a second cycle of HAM only in case of residual leukemia in the day 16 bone marrow aspirate. Patients in the experimental arm all received S-HAM (two sequential cycles of high-dose cytarabine on days 1+2, mitoxantrone days 3+4) with a 3 days interval. Patients in the age cohort 60 – 69 could be allocated to the “younger” or “elderly” cohort according to their biological fitness at the discretion of the treating physician. However high-dose cytarabine dosages were allocated according to chronological age with patients <60 years receiving 3g/m2 cytarabine per dose and patients 60+ years receiving 1g/m2. The primary endpoint was the overall response rate (i.e. CR + CRirate), secondary endpoints were duration of critical neutropenia, overall survival amongst others. Postremission treatment consisted of recommended early allogeneic transplantation in high risk patients and conventional postremission treatment according to the AML-CG standard (one cycle of TAD-9 consolidation followed by up to 3 years of maintenance treatment) in patients with low risk disease. Results396 patients were randomized into the study with an age range of 18 to 86 years (median 58). The 387 evaluable patients (184 standard, 203 experimental) were well balanced according to their clinical characteristics, cytogenetics, molecular genetics and overall risk profile. For the primary endpoint a higher ORR of 77% for S-HAM could be found as compared to 72% in the standard arm which was however not significant because a 15% difference had been postulated for the study. Non-hematological toxicities did not show any significant differences. However this was in clear contrast to hematological toxicities: Importantly the duration of critical neutropenia was highly significantly reduced by more than 2 weeks from 45 days (standard) to 29 days (S-HAM) counted from day 1 of treatment. Similarly critical thrombocytopenia was reduced by 13 days from 46 days to 33 days. The early death (ED) rate between both arms was identical between both arms. However a subgroup analysis demonstrated a significantly reduced ED rate in patients receiving 1g/m2 S-HAM as compared to all other treatment groups. The respective ED rates for the various time intervals (always counted from day d1 of treatment) for the 1g/m2S-HAM group were as follows: Interval d1-14 1%, d1-30 3%, d1-60 5%, d1-90 10%. Data for overall survival will be available in November 2013. ConclusionThe dose-dense induction regimen S-HAM was highly feasible in patients up to the 8th age decade. The antileukemic efficacy was high with an ORR of 77% for the whole group of unselected patients. As compared to standard double induction dose-dense S-HAM reduced critical neutropenia by more than two weeks. Moreover the subgroup of patients receiving the 1g/m2 S-HAM regimen experienced the lowest ED rate ever reported in the AML-CG trials. This underlines that in contrast to our general expectations the concept of dose-density is able to combine high antileukemic efficacy with significantly reduced haematological toxicity in AML, characterising this approach as first candidate for the next standard arm for future trials of the study group. Disclosures:Lengfelder:TEVA/ Cephalon: Research Funding.

Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16)

AbstractPatients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) and inv(16)/t (16;16) subtypes requires intensification remained to be determined. In the 2 successive studies (AML-BFM-1998 and AML-BFM-2004), 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study AML-BFM-1998 but not in AML-BFM-2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n = 78) compared with without HAM (n = 53): OS 92% ± 3% versus 80% ± 6%, plogrank0.047, EFS 84% ± 4% versus 59% ± 7%, plogrank0.001, and CIR 14% ± 4% versus 34% ± 7%, p(gray)0.006. These differences were not seen for inv(16) (n = 43 and 46, respectively): OS 93% ± 4% versus 94% ± 4%, EFS 75% ± 7% versus 71% ± 9% and CIR 15% ± 6% versus 23% ± 8% (not significant). The subtype t(8;21), but not inv(16), was an independent predictor of worse outcome without HAM reinduction. Based on our data, a 5-year OS of > 90% can be expected for CBF-AML, when stratifying t(8;21), but not inv(16), patients to high-risk chemotherapy, including HAM reinduction.

Preventive CNS Irradiation with 12 Gy Compared to 18 Gy: Results of Studies AML-BFM 98 and 2004.

Abstract 483The importance of preventive CNS irradiation (CNS-RT) for disease control in childhood acute myeloid leukemia (AML) is unclear. Results of study AML-BFM 87 revealed an increased risk for relapse when CNS-RT was omitted in CNS negative patients (Creutzig, J Clin Oncol 11, 1993). With the aim to reduce the risk for late effects associated with CNS-RT, we evaluated a dose reduction for CNS-RT by comparing the effect of a reduction of the standard dose of 18 Gy to 12 Gy in a randomized prospective way in the AML-BFM 98 and 2004 trials. Methods:To achieve a power of 80% for non-inferiority (range 11%) 240 patients per group were required, which could only be achieved by randomization over two study periods (7/1998 - 4/2009). Patients:Out of a total number of 1,202 study patients, 471 were not eligible for randomization (126 patients with Down syndrome, 138 patients who did not achieve remission or died/relapsed during the first 140 days before irradiation, 97 patients with initial CNS involvement and 110 patients who were assigned to stem cell transplantation [SCT]). Out of the 731 eligible patients, 241 refused randomization. Thus, a total of 490 children and adolescents <18 years with de novo AML were randomized to receive 12 Gy (n = 248) or 18 Gy (patients between 15 and 24 months: 15 Gy) (n = 242). Eighteen of the randomized patients did not receive radiotherapy. Four of the patients randomized to 12 Gy were treated with 18 Gy, and 15 patients randomized to 12 Gy received 18 Gy. Since this was a non-inferiority study, the analysis was performed for patients as treated (12 Gy n=251, 18 Gy n=221). Therapy:Treatment regimens of study AML-BFM 98 (see Creutzig, J Clin Oncol 24, 2006) and AML-BFM 2004 were largely similar. AML-BFM 2004: AIE (cytarabine, idarubicin and etoposide) or ADxE (Dx = liposomal daunorubicine) followed by HAM (high-dose cytarabine and mitoxantrone) and subsequently, two short therapy cycles with medium and high-dose cytarabine and anthracyclines. Intensification and maintenance were as in study -98. Allogeneic SCT from a family donor was restricted to high-risk patients. Intrathecal cytarabine was given 12 times in addition to CNS-RT. Results:The patient characteristics were similar in both randomized groups. Five-year survival (OS), event-free survival (EFS) and relapse rate (cumulative incidence) were similar in patients who received 12 Gy or 18 Gy (80%±3% vs. 77%±3%, 68%±3% vs. 60%±4%, 30%±3% vs. 36%±4%, respectively. The lower limit of the one-sided confidence interval for the difference in 5-years pEFS (7%) was 0.004. There were 7 relapses with CNS involvement (1 in the 12 Gy group, incidence 0.4% and 6 in the 18Gy group, incidence 3%, p=0.04). Secondary leukemias occurred in 1 and 3 patients, respectively. The analysis for patients treated as randomized (12 Gy n=229, 18 Gy n=216) was comparable. Conclusion:Our results demonstrate that there is no disadvantage for patients irradiated with a reduced CNS dose of 12 Gy regarding OS, EFS and rate of relapse. Due to intensification of chemotherapy, results in the AML-BFM studies improved considerably since study -87. Since the results of other international pediatric AML studies indicate that prophylactic CNS-RT does not improve outcome in the context of current chemotherapy regimen and because intensified chemotherapy elements with improved CNS efficiency such as high-dose cytarabine and liposomal daunorubicin have been introduced in our treatment schedule after study -87, we intend to replace CNS-RT by inclusion of triple intrathecal therapy in the next trial in order to reduce irradiation related long-term sequelae. Disclosures:No relevant conflicts of interest to declare.

Less Toxicity by Optimizing Chemotherapy, but Not by Addition of Granulocyte Colony-Stimulating Factor in Children and Adolescents With Acute Myeloid Leukemia: Results of AML-BFM 98

To improve prognosis in children with acute myeloid leukemia (AML) by randomized comparisons of (1) two short consolidation cycles versus the Berlin-Frankfurt-Muenster (BFM) -type biphasic 6-week consolidation and (2) the prophylactic administration of granulocyte colony-stimulating factor (G-CSF) versus no G-CSF. Further, therapy for standard risk patients was intensified by addition of a second induction, HAM (high-dose cytarabine and mitoxantrone). Four hundred seventy-three patients younger than 18 years with de novo AML were enrolled in trial AML-BFM 98. Patients received five courses of intensive chemotherapy, cranial irradiation, and 1-year maintenance therapy. Four hundred eighteen patients (88%) achieved remission. Compared with trial AML-BFM 93, early deaths decreased from 7.4 to 3.2% (P = .005), and 5-year overall survival increased from 58% to 62% (log-rank P = .03). Both types of consolidation therapy led to similar outcome (event-free survival, 51% v 50%), but in the two-cycle arm, treatment duration was shorter (median duration, 15 days), and treatment related mortality was lower (five v nine patients). G-CSF shortened neutropenia, but did not reduce the rate of severe infections. Intensification of induction therapy did not improve prognosis of standard-risk patients (event-free survival, 62% v 67%). Overall results were improved by neither the administration of G-CSF nor by cycle therapy; however, the latter was easier to perform. Compared with study AML-BFM 93, therapy intensification with HAM in standard-risk patients did not result in improved prognosis. Future treatment designs have to balance intensification of treatment with higher toxicity, improve supportive care, and to consider alternative treatment strategies.

Acute Megakaryoblastic Leukemia in Children without Down's Syndrome.

Acute megakaryoblastic leukemia (AMKL) in children without Down's syndrome occurs in less than 10% of childhood AML. Data on clinical presentation, immunological and genetic features and treatment strategies are rare.Between 6/1987 and 7/2003 89 children with AMKL (m=46; f=43) were treated according to the AML-BFM trials 87 (n=19), 93 (n=39) and 98 (n=31). AML FAB M7 was centrally confirmed by immunophenotyping (n=86) or immunohistology (n=3). The median age at diagnosis (1.5 yrs) was significantly lower compared to other children with AML (total group n=1,149; median age 7.8 yrs; p<0.004). The percentage of AMKL in the AML-BFM trials was 6%. Children with AMKL presented with anemia (93%), thrombocytopenia (88%) and hepatomegaly (83%). Hyperleukocytosis (> 100,000/μl) was less frequent (13%) compared to other AML subtypes (21%; p<0.0001). Immunophenotyping revealed the co-expression of stem cell antigens such as CD34 (61%) and CD117 (82%), myeloid antigens (CD33/CD13) and megakaryocytic antigens (CD41/CD42/CD61). The aberrant expression of CD7 (92%) was significantly increased (other AML subtypes 29%; p<0.0001). Cytogenetics revealed several aberrations such as t(1;22) (14%), monosomy 7 (12%) and trisomy 8 or 21 (7%), but mostly not isolated.The complete remission rate increased from 58% in study AML-BFM 87 to 77% and 83% in AML-BFM 93 and 98 (p<0.05), respectively. The outcome of all children with AMKL was as follows: 5-year event-free survival (EFS) 40±5%; disease-free survival (DFS) 49±6%; overall survival (OS) 42±6%. Compared to children with high risk (HR)-AML (n=714) treated in the AML-BFM studies, the EFS was similar (40±6% vs. 43±2%; p= 0.44). Due to poor response to relapse treatment, the OS tended to be inferior (AMKL 44±6% vs. HR-AML 52±2%; p=0.13).The treatment intensification in AML-BFM 93 and 98 with high-dose cytarabine and mitoxantrone (HAM) as second induction resulted in a significantly improved EFS (46±6%), DFS (58±7%) and OS (49±6%) compared to AML-BFM 87 (11±7%, 18 ±12%. 21±9%; p<0.009).There was no significant difference of outcome between children treated with chemotherapy only (n=54) or allogeneic stem cell transplantation (alloSCT) in 1st CR (n=13 ) DFS 50±7 vs 37±14; p=0.49; OS 54±7 vs 43±15%; p=0.47).Considering gender, age, WBC, blast percentage, immunophenotype or cytogenetic subgroup (available n=74; 83%) no prognostic factor could be identified. Children with poor response (n=19) or relapse (n=33) had a very unfavorable outcome. Only 5 of these children survived. Two children stayed alive in CR after relapse chemotherapy (follow-up 12.8 and 11.3 years), two after alloSCT (follow-up 1.4 and 2.4 years) and one child was alive with disease after alloSCT and relapse (follow-up 0.6 years). In conclusion, in children with AMKL intensive chemotherapy enabled a remission rate and a long-term survival comparable to other childhood HR-AML. AlloSCT seemed not to improve outcome. Therefore new approaches for the treatment of AMKL in children are needed.

It's moving day: factors affecting peripheral blood stem mobilization and strategies for improvement

It's moving day: factors affecting peripheral blood stem mobilization and strategies for improvement

Successful collection of peripheral blood progenitor cells in patients with acute myeloid leukaemia following early consolidation therapy with granulocyte colony‐stimulating factor‐supported high‐dose cytarabine and mitoxantrone

We evaluated the feasibility of collecting peripheral blood progenitor cells (PBPC) in patients with acute myeloid leukaemia (AML) following two cycles of induction chemotherapy with idarubicin, cytarabine and etoposide (ICE), and one cycle of consolidation therapy with high-dose cytarabine and mitoxantrone (HAM). Thirty-six patients of the multicentre treatment trial AML HD93 were enrolled in this study, and a sufficient number of PBPC was harvested in 30 (83%). Individual peak concentrations of CD34+ cells in the blood varied (range 13.1-291.5/microl; median 20.0/microl). To reach the target quantity of 2.5 x 10(6) CD34+ cells/kg, between one and six (median two) leukaphereses (LP) were performed. The LP products contained between 0.2 x 10(6) and 18.9 x 10(6) CD34+ cells/kg (median 1.2 x 10(6)/kg). Multivariate analysis showed that the white blood cell count prior to HAM and the time interval from the start of HAM therapy to reach an unsupported platelet count > 20 x 10(9)/l were predictive for the peak value of CD34+ cells in the blood during the G-CSF stimulated haematological recovery. In 16 patients an intraindividual comparison was made between bone marrow (BM) and PBPC grafts. Compared to BM grafts, PBPC grafts contained 14-fold more MNC, 5-fold more CD34+ cells and 36-fold more CFU-GM. A CD34+ subset analysis showed that blood-derived CD34+ cells had a more immature phenotype as indicated by a lower mean fluorescence intensity for HLA-DR and CD38. In addition, the proportion of CD34+/Thy-1+ cells tended to be greater in the PBPC grafts. The data indicate that sufficient PBPC can be collected in the majority of patients with AML following intensive double induction and first consolidation therapy with high-dose cytarabine and mitoxantrone.