Sequential High-dose Cytarabine Research Articles

Peripheral Blood Absolute Lymphocyte Count at Diagnosis As a New Prognostic Factor in Acute Myeloid Leukemia with t(8;21) Patients

Background: The recurrent translocation t(8;21) represents approximately 12% of adult AML cases, and it involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, which generates an AML1-ETO fusion protein. Previous studies have shown that t(8;21) AML with AML1-ETO fusion has a high complete remission rate with standard chemotherapy and a prolonged survival when sequential high-dose cytarabine is administered. However, prognosis of AML with t(8;21) is heterogeneous. Method: In order to under the relationship between clinical characteristics and prognosis, we retrospectively analyzed data of 68 t(8;21) AML patients who diagnosed at the two centers of South Korea between November 2005 and September 2016. Results: Median age was 56 (range, 17 to 82) and median follow up duration was 99.8 months (range, 278 to 150.8). Among 65 patients who achieved CR after induction therapy, 24 patients (37%) received allogeneic stem cell transplantation (allo-SCT). The median absolute lymphocyte count (ALC) at diagnosis was 2,093 × 106/L (range, 400-7,200), with higher ALC (≥ 2,205 x 106/L) being detected in 31 (45.6%) patients. Higher ALC at diagnosis was defined by an ALC cut-off of ≥ 2,205 x 106/L determined by receiver operating characteristic analysis and this cutoff value discriminated (in terms of sensitivity and specificity) between survival and death (area under curve [AUC] = 0.740, P = 0.001). In univariate analysis, lower CD19 expression (≥ 35%), higher BM blast (≥ 55%) and higher ALC at diagnosis were significantly associated with poor overall survival (OS) and leukemia-free survival (LFS) rate. The 5-year OS and the 5-year LFS of patients with higher ALC were 26.2% and 26.7%, respectively, while those of patients with lower ALC were 83.9 % and 73.6%, respectively. Of note, when we analyzed OS of 139 patients with normal karyotype according to ALC, there was not significant difference of survival rate and the 5-year OS of higher ALC in normal karyotype AML patients was 21.2%. Both groups according to ALC in t(8;21) AML patients were comparable for age, sex and clinical features at diagnosis as well as the proportion of patients who received allo-SCT. WBC count (> 20,000 x 109/L), ANC (> 1,500 x 106/L), additional cytogenetic abnormality, and C-kit mutation at diagnosis have not significant impact on survival. Minimal residual disease (MRD) after the first consolidation therapy did not affect the survival rate. Interestingly, among the patients who achieved CR after induction therapy, patients in higher ALC group showed MRD after the first consolidation therapy with higher incidence (91.3% vs. 60.6%, P = 0.012). In multivariate analysis, higher BM blast (HR 3.97, P = 0.004) and higher ALC (HR 11.59, P < 0.001) remained independent prognostic factors for poor OS rates. Higher BM blast (HR 4.42, P = 0.001) and higher ALC (HR 7.37, P < 0.001) were also independent factors for worse LFS rates. Conclusion: Higher ALC was a significant prognostic factor for LFS and OS in AML patients with t(8;21). Further study for the correlation of ALC and the mechanism of adverse prognosis are needed. Disclosures No relevant conflicts of interest to declare.

Clinical Impact of an Accurate Genetic Characterization of Older Acute Myeloid Leukemia Patients: A Report from the Northern Italy Leukemia Group (NILG) Randomized Trial 02/06

IntroductionIn acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287).Patients and MethodsFive hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation.ResultsThe characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P<0.0001), while 3-years DFS was 73%, 28% and 13% (P<0.0001) (Figure 1A). According to the presence or absence of a MDS/MPN signature at diagnosis, 5-years OS was 11% vs 41% (P=0.0001) while 3-years DFS was 12% vs 49% (P<0.0001) (Figure 1B). AlloHSCT was associated with a significant benefit in terms of 5-years OS (57% vs 25%, P=0.0162) and DFS (53% vs 26%, P=0.0363) (Figure 1C). As expected, age had also an impact, with patients aged 60-64 years performing better than patients aged ≥65 years (5-years OS 38% vs 13%, P=0.003; 5-years DFS 43% vs 10%, P=0.002).ConclusionsOlder AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment. [Display omitted] DisclosuresCattaneo:GILEAD: Other: Advisory Board. Cortelezzi:janssen: Consultancy; novartis: Consultancy; abbvie: Consultancy; roche: Consultancy. Rambaldi:Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia\u2014a phase 3 study

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = “dose-dense”) and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = “standard”). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CRi) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)—P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)—P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

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.

Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG

Chemomodulation of cytarabine by fludarabine has been attributed with a higher antileukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, of which 281 were evaluable) were randomly assigned to SHAI (cytarabine, 1 g/m(2) bid, days 1-2 and 8-9 (3 g/m(2) for patients ≤ 60 years with refractory AML or ≥ 2nd relapse); idarubicin 10 mg/m(2) daily, days 3-4 and 10-11) or F-SHAI (SHAI with fludarabine, 15 mg/m(2), 4 h before cytarabine). Although complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time to treatment failure from 2.04 to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic stem cell transplantation, with a significantly higher number of patients in CR or incomplete remission in the F-SHAI group (22 vs 10%, P<0.01). In conclusion, fludarabine has a beneficial, although moderate, impact on the antileukemic efficacy of high-dose cytarabine-based salvage therapy for relapsed and refractory AML.

Post Transplant Lymphoproliferative Disorders: Risk, Classification, and Therapeutic Recommendations

Post transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease that may occur in recipients of solid organ transplants (SOT) and hematopoietic stem cell transplant. The risk of lymphoma is increased 20-120% compared with the general population with risk dependent in part on level of immune suppression. In addition, recent data have emerged, including HLA and cytokine gene polymorphisms, regarding genetic susceptibility to PTLD. Based on morphologic, immunophenotypic, and molecular criteria, PLTD are classified into 4 pathologic categories: early lesions, polymorphic, monomorphic, and classical Hodgkin lymphoma. Evaluation by expert hematopathology is critical in establishing the diagnosis. The aim of therapy for most patients is cure with the concurrent goal of preservation of allograft function. Given the pathologic and clinical heterogeneity of PTLD, treatment is often individualized. A mainstay of therapy remains reduction of immune suppression (RI) with the level of reduction being dependent on several factors (e.g., history of rejection, current dosing, and type of allograft). Outside of early lesions and/or low tumor burden, however, RI alone is associated with cure in a minority of subjects. We approach most newly-diagnosed polymorphic and monomorphic PTLDs similarly using frontline single-agent rituximab (4weeks followed by abbreviated maintenance) in conjunction with RI. Frontline combination chemotherapy may be warranted for patients with high tumor burden in need of prompt response or following failure of RI and/or rituximab. Due to chemotherapy-related complications in PTLD, especially infectious, we advocate comprehensive supportive care measures. Surgery or radiation may be considered for select patients with early-stage disease. For PTLD subjects with primary CNS lymphoma, we utilize therapeutic paradigms similar to immunocompetent CNS lymphoma using high-dose methotrexate-based therapy with concurrent rituximab therapy and sequential high-dose cytarabine. Finally, novel therapeutic strategies, especially adoptive immunotherapy, should continued to be explored.

Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG

AbstractDose density during early induction has been demonstrated to be one of the prime determinants for treatment efficacy in acute myeloid leukemia (AML). The German AML Cooperative Group has therefore piloted a dose-dense induction regimen sequential high-dose AraC and mitoxantrone followed by pegfilgrastim (S-HAM) in which 2 induction cycles are applied over 11 to 12 days instead of 25 to 29 days as used in conventional double induction, thereby increasing dose density 2-fold. Of 172 de novo AML patients (excluding acute promyelocytic leukemia), 61% reached a complete remission, 22% a complete remission with incomplete peripheral recovery, 7% had persistent leukemia, 10% died (early death) resulting in an overall response rate of 83%. Kaplan-Meier estimated survival at 2 years was 61% for the whole group (patients with unfavorable karyotypes, 38%; patients with favorable karyotypes, 69%; patients with intermediate karyotypes, 75%) after S-HAM treatment. Importantly, the compression of the 2 induction cycles into the first 11 to 12 days of treatment was beneficial for normal hematopoiesis as demonstrated by a significantly shortened duration of critical neutropenia of 31 days compared with 46 days after conventionally timed double induction. (European Leukemia Trial Registry LN_AMLINT_2004_230.)

Sequential high-dose cytarabine therapy in combination with asparaginase in acute myeloid leukemia

Between 1984 and 1987 14 patients with acute non-lymphocytic leukemia were treated with sequential high-dose cytosine arabinoside in combination with asparaginase. Twelve patients were suffering from refractory leukemia; in these patients complete remissions were achieved in 58%. The efficacy of this schedule was much better in patients with substantial leukemia cell reduction due to antecedent conventional therapy and no more than 25% blast cells in the bone marrow. In this subgroup complete remissions were achieved in 75% and 86% respectively, taking into account only the completed treatment courses. Beside the well-known side-effects such as alopecia, nausea, vomiting and hepatotoxicity, we observed an increase in severe infections. Three patients died of pulmonary mycosis.