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Background: We recently showed that the combination of ATRA and arsenic trioxide (ATO) is at least not inferior and possibly superior to standard ATRA and chemotherapy (CHT) in the front-line ...management of low/intermediate risk APL (Italian-German APL 0406 trial; Lo-Coco et al., NEJM 2013). We report herein on the extended and final series of 276 patients (162 were in the previous report) with the last case being enrolled into the study in January 2013.
Methods: The APL0406 study was a prospective, open-label, randomized intergroup trial conducted by the Italian GIMEMA and the German SAL and AMLSG study groups. Eligible patients were adults aged 18-<71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10x109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally developed by the MD Anderson Cancer Center group, or the Italian AIDA2000 protocol (Estey et al., Blood 2006 and Lo-Coco et al., Blood 2010). Patients in the ATRA-ATO arm received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in the ATRA-CHT arm received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based consolidation together with ATRA and low dose CHT and ATRA for maintenance. The primary study objective was EFS at 2 years.
Results: A total of 254 patients were evaluable for response to induction. CR was achieved in 122/122 (100%) in the ATRA-ATO versus 128/132 (97%) in the ATRA-CHT arm (P=0.12). Four patients died during induction in the ATRA-CHT arm. After a median follow-up of 36 months (range 1-75 months), the 2-year EFS was 98% and 84.9% in the ATRA-ATO and ATRA-CHT groups respectively (P= 0.0002), The 2-year cumulative incidence of relapse (CIR) rate was 1.1% and 9.4%, respectively (P=0.005) and, finally, the 2-year overall survival (OS) rate was 99.1% vs. 94.4% (P=0.01) for ATRA-ATO vs ATRA-CHT, respectively.
Conclusions: The data on this extended cohort demonstrate a significantly augmented survival benefit coupled to a higher antileukemic efficacy provided by ATRA-ATO as compared to ATRA-CHT, in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting.
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Platzbecker:Teva: Honoraria. Off Label Use: Presentation includes off-label use of arsenic trioxide (ATO) in front-line management of APL. ATO is currently approved in treatment of relapsed APL in the US and Europe. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Lübbert:Cephalon / TEVA: Travel support Other. Link:TEVA: Consultancy, Speakers Bureau. Radsak:Celgene: Research Funding. Döhner:TEVA: Research Funding. Schlenk:TEVA: Research Funding, Speakers Bureau. Lo-Coco:TEVA: Honoraria; Lundbeck: Honoraria.
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Introduction
Aberrant DNA methylation is a common feature of acute myeloid leukemia (AML) and increases with age. DNMT inhibitors such as Azacitidine (AZA) can induce meaningful responses and ...remissions in AML as monotherapy. The combination of AZA with standard chemotherapy (7+3) has not been tested in a randomized trial.
Patients and study design
The AML-AZA trial compared AZA directly followed by standard induction therapy, AZA followed by standard consolidation, and further Azacitdine maintenance with standard induction and consolidation without AZA in older patients with AML. All patients received standard Cytarabine (100 mg/sqm) and Daunorubicin (60 mg/sqm) induction (“7+3”) and up to two cycles of intermediate dose Cytarabine (1 g/sqm q12hr days 1, 3, 5) as consolidation therapy. AZA (75 mg/sqm for 5 days) preceded each therapy cycle in the AZA arm. In addition, AZA maintenance for up to 1 year was also scheduled for patients in the AZA arm. 105 patients were randomized to receive AZA plus Cytarabine plus Daunorubicin as induction therapy (AZA + 7+3) and 109 patients to receive 7+3 only (control group). Median age was 70 years in both treatment arms. Patient cohorts were well balanced with regard to blast counts in bone marrow, secondary versus de novo AML and molecular genetics risk group. More patients in the AZA + 7+3 arm (39/105; 37.1%) than in the control group (25/109; 22.9%) showed high risk cytogenetics (p=0.057). Event free survival (EFS) was the primary end point. Secondary endpoints were overall survival (OS), complete remission (CR) rate, toxicity and different treatment response according to molecular markers.
Results
Overall, 214 of 216 planned patients were enrolled into the AML-AZA trial. Due to a higher number of severe adverse events (SAE), AZA administration was stopped after recruitment of 214 patients whereas chemotherapy was continued as planned. Percentages of patients in the AZA arm with AZA doses as initially planned were as follows: 99% for first induction cycle, 72% for the second induction cycle. AZA as maintenance therapy for at least one cycle was delivered to 18% of patients in the AZA group. At least one SAE occurred in 51% of AZA + 7+3 patients compared to 31% of 7+3 patients (p=0.005). Cardiac disorders with CTCAE grade 3-5 occurred more frequently in the AZA + 7+3 arm (n = 15) than in the 7+3 arm (n = 6) (not significant). Leukopenia was prolonged by one day (median 23 vs 22 days) in the AZA + 7+3 group (p=0.043), whereas time of thrombocytopenia was not different. The early death rates at 30, 60 and 90 days did not differ significantly between treatment groups. Efficacy analyses were performed on an intention-to-treat basis. Median EFS as the primary endpoint was 6 months in both treatment arms (p=0.96). Median OS was 16 months for patients treated with AZA + 7+3 and 21 months for 7+3 (p=0.35). Median relapse free survival was 12 months in both treatment arms (p=0.95). 48 of 100 patients (48%) in the AZA + 7+3 arm achieved complete remission (CR) after induction therapy versus 57 of 109 patients (52%) in the 7+3 arm (p=0.58). DNMT3A exon 23 mutations were detected in 30 out of 162 analyzed patients. Exploratory analyses were performed to detect a potential interaction between AZA + 7+3 response and DNMT3A mutation status. Trends for improved EFS and OS were noted for AZA + 7+3 treatment in DNMT3A mutated patients.
Conclusion
AZA as addition prior to standard induction and consolidation chemotherapy does not prolong EFS and OS in unselected older AML patients and it is more toxic. However, a trend towards better efficacy in patients with DNMT3A mutation was observed and should be further explored.
Müller-Tidow:Celgene: Honoraria, Research Funding. Thiede:AgenDix GmbH: Equity Ownership, Research Funding; Illumina: Research Support, Research Support Other. Kiehl:Roche: Membership on an entity’s Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding. Ehninger:GEMoaB GmbH: Consultancy, Patents & Royalties.
In newly diagnosed acute myeloid leukemia, immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pre-therapeutic ...risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed acute myeloid leukemia undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based firstline therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months, p=.42) nor in the TriNetX cohort (7.5 vs. 7.2 months, p=.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed acute myeloid leukemia might be a safe option for selected patients, provided that close clinical monitoring is performed.
Long-term engraftment after stem cell transplantation is dependent on pluripotent hematopoietic stem cells capable to multi-lineage reconstitution. The engraftment and prolonged repopulation of B ...lymphoid progenitor cells is dependent on pluripotent hematopoietic stem cells. We have recently shown that a high number of B-cell progenitors is detectable in the bone marrow from patients both after allogeneic PBSCT and after allogeneic BMT. The percentage of CD19/CD10+ pro-B/pre-B cells showed a high variability and ranged from 0 to 98% of all B-lymphocytes. Interestingly, no difference in numbers of precursor B-lymphocytes between BM recipients and PBSC recipients was found. In micro-satellite analysis, both in PBSC and in BM recipients the B cell precursors were derived exclusively from the donor. To identify predictors of B lymphopoiesis in the bone marrow after stem cells transplantation, a stepwise, multiple regression analysis was performed. The stem cell source, BM or PBSC, the occurrence of GVHD, the conditioning with or without TBI and whether ATG was given, were entered as categorical variables. Time point of BM sampling after transplantation, age of the donor and the recipient, the quantity of stem cell transplanted and the T cell content of the BM sample served as continuous variables. Time elapsed after transplantation (p=0.002) and severe GVHD (aGVHD grade III/IV or extensive cGVHD) (p=0.036) could be identified as parameters with an independent influence on the percentage of B cell precursors. The highest percentage of precursor B cells was found during the first year after transplantation, unless severe GvHD was present, leading to neglible precursor B-cells. This hyperactive B lymphopoiesis in the first year after transplantation contrasts to low circulating B cell counts. Finally, it could be formally demonstrated, that G-CSF mobilized PBSC contain hematopoietic stem cells capable of long-term reconstitution of the B cell compartment.
Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The
corepressor
and its homolog, the
, have been reported to be rare but recurrent mutations in AML. Previously, smaller ...studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML.
and
mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were
,
and
. Mutated
and loss-of-function mutations of
were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of
had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005-2.134),
= 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163-3.117),
= 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990-2.258),
= 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of
regarding risk stratification in AML, which may influence treatment allocation.
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Despite a high complete hematologic remission (CHR) rate with imatinib-based therapy, the prognosis of elderly patients (pts.) with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) ...is poor, primarily due to relapse. Nilotinib (Tasigna®) is a potent ABL kinase inhibitor (TKI) approved for treatment of chronic and accelerated phase CML, but data on its efficacy in Ph+ ALL are limited. To study the activity of ABL-TKI in the front-line setting, the EWALL (European Working Group for Adult ALL) has developed a joint chemotherapeutic protocol for first-line therapy of elderly Ph+ ALL pts. (aged 55 years or more) that serves as a platform for the addition of targeted therapeutic agents. This chemotherapy backbone was used to test the efficacy and safety of the addition of nilotinib in elderly patients with newly diagnosed Ph+ ALL in a European, investigator-initiated trial.
Male or female pts. > 55 years with Ph+ and/or BCR-ABL1 positive ALL were eligible if they had not been previously treated except with corticosteroids, single dose vincristine or three doses of cyclophosphamide, had a WHO performance status of 0-2, adequate organ function and had signed written informed consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of all participating centres. The trial was registered under NCT01528085. After a pre-phase with dexamethasone (Dex) 10 mg/m² d-7 to d-3 (cyclophosphamide 200mg/m² i.v. d-3 to d-1 optional), nilotinib was administered at 400 mg BID starting with induction therapy and given continuously thereafter. During induction, nilotinib was combined with IV injections of vincristine (VCR) 1 mg and Dex 40 mg on 2 days (20 mg over 70y), repeated weekly for 4 weeks. Consolidation cycles consisted of nilotinib 400 mg BID, methotrexate 1000 mg/m² IV d1 (500 mg/m² over 70y) and asparaginase 10,000 UI/m² IV d2 (5,000 UI/m² over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m²/12h IV d1, d3, d5 (500 mg/m² over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of nilotinib, 6-MP QD and methotrexate once weekly over 1 month every other month, and Dex/VCR in 2 month intervals for up to 24 months of treatment. The primary end-point is the rate of pts. without an event (defined as relapse, death, SAE or study treatment discontinuation) at 12 months, secondary endpoints include the rate of CHR after induction, death during induction or in CHR, event free (and overall survival, the rate of major (MMR) or complete molecular response (CMR) defined by BCR-ABL/ABL ratios < 0.1% and < 0.001%, respectively.
As of August 2014, 47 pts. (21 male, 26 female) have been enrolled. Median age is 66 years (55-85 years), twelve pts. are older than 70 years of age. To date, 43 pts. are evaluable for safety and 36 pts. are evaluable for efficacy. The CHR rate is 97% (35 of 36 pts. evaluable for response), one patient was refractory (3%). No patient died during induction therapy. With a median follow-up of 211 days, 31 of 35 evaluable pts. are in CCR and four pts. relapsed, two of whom had discontinued study treatment to undergo allogeneic SCT. 13 of the 36 pts. with documented induction response have discontinued study treatment prematurely, primarily because of transfer to allogeneic SCT (n=7), as explicitly permitted by the protocol. Six pts. discontinued for various other reasons. Eight of 35 CR pts. have completed the consolidation cycles and have entered maintenance phase, five pts. have completed protocol therapy. The rate of complete molecular remission (CMR) after induction (32 pts. evaluable) was 30%, with 2 pts. having undetectable BCR-ABL1 transcripts. During consolidation, 13 of 31 pts. (42%) had a CMR, and BCR-ABL transcripts were undetectable in 9 of 31 pts. (29%). Tolerability has been acceptable, with thirty-four SAEs reported so far, 11 during induction (of 43 pts.), 16 during consolidation (of 37 pts.), 6 during the maintenance phase and one following study discontinuation. Infectious events and neutropenic fever predominated, individual SAEs included metabolic, cardiovascular, neurologic, renal and hepatic events.
In conclusion, nilotinib in conjunction with chemotherapy according to the EWALL-PH-02 protocol is well tolerated and highly effective with a 97% CR in elderly pts. with newly diagnosed Ph+ ALL. Molecular response rates are high and MRD levels in responding pts. continue to decrease with time.
Ottmann:Novartis: Consultancy, Honoraria, Research Funding. Ribera:Novartis: Research Funding. Rousselot:Novartis: Research Funding.
In a up-front randomized study, 939 adult patients up to the age of 60 years received a double induction therapy. One course of MAV (mitoxantrone 10 mg/m2 days 4–8, cytarabine 100 mg/m2 continuous ...infusion days 1–8, etoposide 100 m g/m2 days 4–8) was followed by one cycle of MAMAC (cytarabine 1 g/m2, every 12h days 1–5; amsacrine 100 mg/m2 days 1–5). Patients with intermediate risk cytogenetic (IRCG) and a HLA matched sibling received an allogeneic transplantation, those with poor risk cytogenetic (PRCG) were intended to be transplanted from a sibling or unrelated donor. All AML patients without an available donor received the randomly assigned first postremission therapy (PRT) mitoxantrone combined with intermediate-dose cytarabine (I-MAC; total dose 12 g/m2) or high-dose cytarabine (H-MAC; total dose 36 g/m2). As second PRT, patients with t(8;21) received an additional cycle of chemotherapy. An autologous transplantation was scheduled for IRCG and PRCG without an allogeneic donor. The CR rate was 88% for patients with t(8;21), with IRCG 71%, and 50% with PRCG. The 5-year-survival was 21% (95% CI: 16–27%) in the PRCG, 40% (95% CI: 36–45%) in the IRCG and 74% (95% CI: 60–88%) in the t(8;21) group. No difference was observed between the I-MAC and the H-MAC group. In a multivariate analysis, a significant (p<.01 for each parameter) better overall survival was observed in patients under the age of 37 years, blast count <10% at day 15, high myeloperoxidase positivity, low CD34 expression, WBC <15*10^9/L, thrombocytes >50*10^9/L, and IRCG compared to PRCG. The relapse incidence was higher in patients without an allogeneic donor, a Flt3 mutant/wildtype ratio > 0.8 or PRCG. A risk score build out of the sum of the individual hazard ratios (SHR) was able to discriminate two groups for the IRCG with a marked difference in the 5-year-survival (low SHR: 55% 95% CI: 48–62%; high SHR: 33% 95% CI: 28–38%) was well as for the PRCG group (low SHR: 44% 95% CI: 32–56%; high SHR: 13% 95% CI: 7–18%). The risk score identified in this large patient cohort may allow individual tailoring of therapeutic interventions in future AML trials.
Highlights • A clofarabine-based salvage therapy combined with early allogeneic HSCT in patients with relapsed or refractory AML provides good long-term results. • Comorbidity evaluation based on the ...HCT-CI and ECOG score provided prognostic information on OS and thus showing the feasibility and clinical relevance of comorbidity evaluation at the time of diagnosis of relapsed or refractory AML.
High-dose chemotherapy with autologous stem cell rescue can result in autotransplantation of tumor cells. A possible approach to reduce tumor cell contamination is the positive selection of CD34+ ...PBPC, but this might be associated with a prolonged recovery time as well as an increased risk of infectious complications because of the loss of committed progenitor cells. To investigate this aspect, we compared two sequentially treated cohorts of high-risk breast cancer patients. Both groups received the same high-dose chemotherapy regimen followed by autologous peripheral stem cell transplantation. Group I received CD34+-selected blood progenitor cells, and group II received nonselected blood progenitor cells. We compared these two identically treated groups with regard to recovery time, need for blood products, infectious complications, need for antibiotic treatment, and length of the transplantation-related hospital stay. We found a prolonged recovery time for neutrophils up to 0.5 x 10(9)/L (14 days in the selected group/10 days in the nonselected group) and platelets up to 30 x 10(9)/L (29/12 days), associated with an increased requirement for RBC transfusions (5/3 U) and platelet transfusions (10/2 U). The rate of severe infectious complications (2/0), the need for nonprophylactic antibiotic treatment (15/10), and the length of the hospital stay (25/21 days) in group I were also increased. We conclude that positive selection of PBPC should not be used routinely until randomized studies show a clear long-term benefit of using CD34+-selected stem cell products in breast cancer patients.
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