Efficacy of Low Dose Clofarabine Plus Intermediate Dose Cytarabine In An Unselected AML Refractory/Relapsed Adult Population

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4349-4349
Author(s):  
Claudio Romani ◽  
Emanuele Angelucci ◽  
Barbara Scappini ◽  
Mario Petrini ◽  
Martina Pettinau ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Nucleoside Analogue ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Haematological Toxicity ◽  
Allogeneic Transplantation ◽  
Gemtuzumab Ozogamicin ◽  
Acute Myeloid

Abstract Abstract 4349 Advanced AML in adult patients is a difficult challenge for hematologists with several unsuccessful approaches attempted during the last years. We tested the combination of the new nucleoside analogue Clofarabine in association with Cytarabine in a consecutive series of adult patients with advanced acute myeloid leukemia. From April 2007 to April 2010, 29 unselected advanced disease (not M3) acute myeloid leukemia (AML) patients were included in this multicenter study. There were 14 female and 15 male. Median age was 44 years (range 22–65). Twenty patients were in second or more advanced relapse and 9 had refractory disease to one or more chemotherapy regimens. Patients were treated with one cycle of five days clofarabine 22,5 mg/m2/day together with five days cytarabine 1 g/m2/day. The low dose (22,5 mg/m2) clofarabine was selected because of the burden of therapy that our patients had already received. In 19 patients gemtuzumab ozogamicin 6 mg/m2 was added by Centre physician decision. Toxicity and remission status were defined according with WHO criteria. Partial remission was considered as improvement of peripheral blood count and reduction of bone marrow blasts > 50%). Toxicity: Grade IV haematology toxicity was recorded in all patients. Extra haematological toxicity was as follows: four patients presented ≥ grade III cutaneous toxicity, ten hepatic toxicity; three patients mucositis. Eight patients experienced a life threatening infection while in aplasia (six systemic septicemia and two pneumonia) which were ultimately fatal in four. Disease response: overall, 16 over 29 patients (55%) entered in complete remission (CR) and 4 in partial remission. Overall response rate was 69%. Outcome: over the sixteen patients who entered complete remission: 1 was lost at follow up, 1 relapsed, 1 was treated with azacitidine and 2 with another cycle of clofarabine. These three patients who received a not transplant intensification therapy are, so far, alive in complete remission. In eleven patients an allogeneic transplantation (with an unrelated or sibling donor) was performed as intensification therapy: to date, 8 of these 11 patients are alive in continuous complete remission after a median follow up of 6,5 months (2-36) while three died (two while in CR). Overall 11 (68%) of the 16 patients who entered into complete remission are alive and well. The new nucleoside analogue Clofarabine showed efficacy and synergism with cytarabine in treating AML. Even if 29/29 patients experienced grade IV haematological toxicity, infection rate was low and suitable considering the status of the disease. Extra haematological toxicity was acceptable and easily manageable. Considering the dismal outcome of these patients, we believe that intensification should be performed to allow a continuous complete remission. Indeed we were able to transplant 11/16 patients, eight of which maintained the complete remission after transplantation. Notably, 3 patients remained alive in complete remission out of a transplantation approach. It is not possible to draw any conclusion about the role, if any, of gemtuzumab ozogamicin. In summary, we showed that low dose clofarabine plus cytarabine because of efficacy and low extra-hematology toxicity could be a real bridge to allogeneic transplantation in these very poor risk pre-treated acute leukaemia patients. A longer follow up is awaited. Disclosures: Off Label Use: Clofarabine in refractpry/relapsed AML.

scholarly journals Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia

2010 ◽  
Vol 28 (11) ◽  
pp. 1856-1862 ◽  
Author(s):  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Daniel Jones ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Wild Type ◽  
Platelet Recovery ◽  
Probability Of Survival ◽  
Target Effect ◽  
Acute Myeloid

Purpose To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and Methods In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. Results Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. Conclusion Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

scholarly journals Clinical Outcomes Following Treatment with Gilteritinib or Quizartinib in Patients with Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Alexander E. Perl ◽  
Qiaoyang Lu ◽  
Alan Fan ◽  
Nahla Hasabou ◽  
Erhan Berrak ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 3 ◽  
Hematopoietic Stem ◽  
Travel Costs ◽  
Baseline Characteristics ◽  
Acute Myeloid

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

Maintenance with low-dose cytarabine for acute myeloid leukemia in complete remission

1992 ◽  
Vol 65 (2) ◽  
pp. 71-74 ◽  
Author(s):  
E. Archimbaud ◽  
B. Anglaret ◽  
X. Thomas ◽  
J. Jaubert ◽  
C. Sebban ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

scholarly journals Allogeneic transplantation for advanced acute myeloid leukemia: The value of complete remission

Cancer ◽  
2017 ◽  
Vol 123 (11) ◽  
pp. 2025-2034 ◽  
Author(s):  
Daniel J. Weisdorf ◽  
Heather R. Millard ◽  
Mary M. Horowitz ◽  
Parvinder S. Hyare ◽  
Richard Champlin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Allogeneic Transplantation ◽  
Acute Myeloid

Early Allogeneic Hematopoietic Cell Transplantation during Induction Chemotherapy in High-Risk Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2299-2299 ◽  
Author(s):  
Gerhard Ehninger ◽  
Uwe Platzbecker ◽  
Christian Thiede ◽  
Thomas Illmer ◽  
Ulrich S. Schuler ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Minor Response ◽  
Cytogenetic Aberrations ◽  
Acute Myeloid

Objectives: In patients with acute myeloid leukemia and high-risk cytogenetic aberrations or minor response to the first cycle of induction chemotherapy (IC) the probability of achieving a sustained complete remission is low. Thus early treatment intensification may be warranted in order to achieve long-term disease control. We performed a prospective trial to evaluate whether reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors can be performed during the aplastic phase of IC in patients with poor-risk AML. Methods: Seventeen patients (n=17) aged between 17 and 63 years (median 45) with acute myeloid leukemia and high-risk cytogenetic aberrations (n=14, complex, inv3 or t(3;3), t(3;5), −7 or del 7q, +8) or more than 10 % marrow blasts on day 15 after the first cycle of IC (n=3) were included so far. During aplasia a median of thirteen days (range 7–35) after the first (n=8) or second (n=9) cycle of IC patients received 5 x 30 mg/m2 fludarabine i.v. combined with either 8 mg/kg busulfan p.o. (n=4) or 150 mg/m2 melphalan iv. (n=13) followed by allogeneic G-CSF mobilized peripheral blood stem cells (PBSC, n=16) or bone marrow (n=1) from related (n=7) or unrelated (n=10) donors. Nine out of seventeen patients were not in complete remission before conditioning therapy was started. Patients with unrelated grafts received antithymocyte globulin (4 x 10 mg/kg ATG Fresenius). GvHD prophylaxis was performed with cyclosporine A (CSP). Results: All patients engrafted (ANC > 0.5 Gpt/l on day 11, range 8–19, platelets > 50 Gpt/l day 15, range 11–32) and went into remission. Acute GvHD grade II-IV occurred in 8 patients and extensive chronic GvHD was documented in 5 patients with a follow-up of > 100 days. Two patients died while being in remission from infectious complications associated with acute (n=1) or chronic (n=1) GvHD and two patients died during relapse eight and twelve months after PBSC. With a median follow-up of 15 months (range 1–65) thirteen out of seventeen patients (76 %) are alive and in remission. Conclusion: Early allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in AML patients with either poor risk karyotype or minor response to the first induction cycle.

Practically All Patients with Acute Myeloid Leukemia (AML) in Continuous Complete Remission for 3 Years or More Are Cured of Their Disease: The ECOG Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 132-132
Author(s):  
Justin M Watts ◽  
Lynette Zickl ◽  
Mark R Litzow ◽  
Selina M Luger ◽  
Hillard M Lazarus ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Late Relapse ◽  
Published Data ◽  
High Dose ◽  
Acute Myeloid

Abstract Abstract 132 Late relapse in acute myeloid leukemia (AML) has been infrequently studied and variably defined in the literature. Two series have shown that late relapse of AML ≥5 years after first complete remission (CR1) is uncommon, with rates of 1.19–3% (Medeiros et al, Leuk Lymphoma 2007; Verma et al, Leuk Lymphoma 2010). We searched the long-term data available on 784 adults (<60 years-old) who were treated on 1 of 4 ECOG clinical trials (E3483, PC486, E3489, or E1900) and achieved CR1 for reports of late relapse (defined as recurrence of AML ≥3 years after CR1). Median follow-up for the 553 patients last known alive was 11.1 years. The longest median follow-up was 17.2 years on trial PC486. Outcomes We found that 11 patients (1.4%) relapsed late; of these, 2 were treated on E3483, 1 on PC486, 5 on E3489, and 3 on E1900. Seven patients with late relapse died from their disease and 4 were living at last known follow-up. Only 1 patient (0.13%) had recurrence of AML ≥5 years after achieving CR1. It is possible that more late relapses will occur on E1900 (a more recent study with ongoing follow-up). All of these trials except E3483 treated some patients with autologous hematopoietic cell transplantation (autoHCT) as part of post remission therapy. On PC486, no post remission consolidation chemotherapy was administered before autoHCT. Ninety-eight total patients on E3489 and PC486 received autoHCT, and there were no late relapses; on E1900, 2 of the 141 patients treated with autoHCT developed late relapse. No patients who underwent allogeneic (allo) HCT in CR1 experienced late relapse on any of the 4 clinical trials. Nine of the 11 patients with late relapse did not undergo HCT; of these, 5 were consolidated with high-dose cytarabine, 2 received maintenance with low-dose cytarabine and 6-thioguanine, and 2 received unknown post remission therapy. Of the 3 patients with late relapse on E1900, 2 received standard-dose and 1 high-dose daunorubicin with induction. Conclusions Across all 4 trials, only 2 of the 239 patients (0.8%) treated with post remission autoHCT experienced late relapse of AML (≥3 years after CR1), which reinforces previously published data that late relapse after autoHCT is uncommon (Cassileth et al, J Clin Oncol 1993). Furthermore, of the 35 patients treated with autoHCT on PC486, 11 relapsed early and no patients relapsed late, suggesting that post remission chemotherapy may not be necessary before autoHCT. Based on this large AML cohort of nearly 800 patients with long-term follow-up, patients who remain in CCR for at least 3 years have a very low risk of relapse and can be considered cured of their disease. Moreover, given that recurrent AML was extremely rare after 5 years or more of CCR (<0.2%), the risk of therapy-related AML from contemporary induction and post remission strategies including HCT appears to be minimal. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy and Safety of Decitabine in Combination with G-CSF, Low-Dose Cytarabine and Mitoxantrone in Pediatric Refractory and Relapse Acute Myeloid Leukemia and MDS-Raebt

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5175-5175
Author(s):  
Liyan Fan ◽  
Aili Chen ◽  
Yixin Hu ◽  
Peifang Xiao ◽  
Jun Lu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Pediatric Patients ◽  
Efficacy And Safety ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Acute Myeloid

Abstract Background: It is difficult for pediatric refractory and relapse acute myeloid leukemia (RR-AML) and MDS-RAEB/RAEBT patients to achieve complete remission (CR) and these patients develop recurrence and die of either disease progression or associated complications. The CAG regimen (cytarabine, aclarubicin and G-CSF) has been widely used in treating patients with MDS-EB and AML-MRC in Asia. Likely, Short term CAG derived regimens called low dose induction therapy, MAG regimen (Mitoxantrone for 3 doses, cytarabine and G-CSF for 10 days) also showed efficacy in De Novo AML. However, MAG regimen showed less efficacy in RR-AML and MDS-5(5q-). Purpose: To evaluate the clinical efficacy and safety of low-dose decitabine in combination with low-dose MAG regimen (D-MAG regimen) in the treatment of RR-AML and MDS-RAEB/RAEBT. Method A total of 17 patients with MDS-RAEB/RAEBT and RR-AML((2 cases of MDS-RAEB, 3 cases of MDS-RAEBT, 10 cases for refractory AML, and 2 cases for relapse AML) from June 2017 to April 2018 in our center were included in the retrospective study. All the patients were treated with decitabine of 20 mg/m2 for 5 days and followed by 10 days of MAG regimen (cytarabine of 10mg/m2 q12h for 10 days, mitoxantrone of 5 mg/ m2.d for 3 days, and G-CSF of 5μg/kg.d for 10 days),called D-CAG regimen. After two cycles of induction chemotherapy, the patients who obtained CR received consolidation chemotherapy or hematopoietic stem cell transplantation (HSCT). Results Among a total of 17 patients, the median age was the median age was 102 months (32-200 months) and 64.71 % of them were male. Characteristic features of these patients were illustrated in Table 1. Only 2 cases died of severe lung infection due to continuous agranulocytosis who had been received high dose induction therapy (Daunorubicin of 50mg/M2.d for 3 days, cytarabine of 100mg/m2 q12h for 10 days, and Etoposide of 150mg/m2.d for 5 days) for 2 cycles with poor physical condition before D-MAG. In the other 15 cases, 10 of them had complete remission (CR) after the first course of treatment, 4 cases were partial remission (PR), 1 case with a high blast cells at 25% indicated a poor response to D-MAG, and the effective rate was 93.3%. Among 4 children with PR, one case reached CR after the second courses of treatment. The most common adverse reactions in all children were hematological toxicity, grade III-IV. Liver damage was found in 2 cases, grade I and grade II respectively. There were 3 cases of oral side reactions, 1 case in grade I and 2 cases in grade II. The gastrointestinal reactions in all children were grade I - II. By July 2018, the median follow-up was 11 months (7-16months). Among 15 patients after D-MAG, 11 patients received HSCT. The twelve-month survival rate was 88.24% and the median leukemia-free survival (LFS) was 11 months. Conclusion The low-dose decitabine in combination with Low-dose MAG regimen improved CR rate for pediatric patients with MDS-RAEB and RR- AML, and is a promising treatment for pediatric patients with MDS/RR-AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Double Priming Induction Regimen for Acute Myeloid Leukemia with Inferior PS Among Resource Limited Areas

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5173-5173
Author(s):  
Stephen Liang ◽  
Siliang Chen ◽  
Xiaoli Huang ◽  
Zheyuan Qin ◽  
Sanbin Wang
Keyword(s):  
Quality Of Life ◽  
Acute Myeloid Leukemia ◽  
Pilot Study ◽  
Subcutaneous Injection ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Grade 3 ◽  
Acute Myeloid

Abstract The treatment options for patients with acute myeloid leukemia (AML) under inferior performance status (i.e. senior patients, MDS transformed AML, and patients with proven invasive fungal disease) are limited. The conventional "3+7" (idarubicin plus cytarabine) induction for those patients can be either too toxic, which leads to higher mortality rate, or requires prolonged recovery time thus raise medical cost. And the delay of consolidation may compromise outcome thus cause early relapse in such patients. Giving the rationale from the designing art of CPX-351, the prolonged IV time requirement for cytarabine, as well as mini-transplantation for AML treatment, at least in part, reflects the philosophy of a longer exposure to the chemo agent can be a more effective treatment approach for leukemia. On the other hand, the D-CAG protocol, which indicated an encouraging result for elderly patients with AML, indicated effectiveness of the strategy with reduced intensity. However, the cyto-toxic effect of decitabine with standard dose (20mg/m2) could still lead to severe treatment adverse events (AEs) thus raise the need of optimization of D-CAG regimen for patients with inferior PS. When considering the low dose hypo-methylation agent (HMA) can trigger the innate immunity response, the unique effect of homoharringtonine, as well as the effectiveness of CAG, we designed this DHCAG protocol following the principle of "longer exposure, lower intensity preceded by priming" and observed an unexpected excellent outcome with high CR rate, low induction failure and treatment mortality, as well as a higher cost effective value for patients with AML, when compared to "3+7" protocol, whom under inferior PS. From March 2016 - January 2018, we initiated this pilot study and investigated the safety and efficiency of this DHCAG protocol in patients with AML under poor PS. We enrolled 25 patients and administer the regimen as followings: i) G-CSF: 5μg/kg used when WBC <20×10^9/L at day 0-14 subcutaneous injection; ii) Decitabine: 6mg/m2 at day 0, 3, 6, 9, 12 iv drip; iii) Aclarubicin: 6mg/m2 at day 1-8 iv drip; iv) Homoharringtonine: 1mg/m2 at day 9-14 iv drip ( at day 9, if WBC >1*10^9/L then increase the dosage of homoharringtonine to 2mg/m2); iv) Cytarabine:10mg/m2 q12h at day 1-14 subcutaneous injection (if WBC >20*10^9/L then increase to 100mg/m2 by 24h CIV, or 50mg/m2 q12h by subcutaneous injection). The primary end point was complete hematologic remission, defined as a bone marrow blast cells ≤5%, Neutrophils in peripheral blood ≥1.0X109 /L, hemoglobin≥90g/L, and platelets ≥100X109/L and no any evidence of extramedullary leukemic infiltration; Secondary end points included numbers of adverse events, length of hospital stay, medical costs, and quality of life as measured with the use of the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire. Among the 25 patients in the study, 23 completed the induction therapy. And 21/25 patients had a hematologic complete remission after a median time of 19 days. Once complete remission had occurred, all 21 patients received post-remission treatment for another 5 cycles of DHCAG. Median follow-up was 14 months (range, 8 to 19) by June 2018. Interestingly, regardless of grade 3-4 myelo-suppression occurred all of our patients during induction, eight patients did not experienced grade 3-4 myelo-suppression during the following cycles. The median hospital stay is 22 days. The median of total medical costs for induction was $9,815 (range, $5,053 to $16,336) vs $14,705 for "3+7" induction protocol (history control. Data unpublished). Patients resumed their usual lifestyle during post-remission therapy, and their quality of life was rated as nearly normal on the FACT-G questionnaire. At the time of the last follow-up, seven patients had had a hematologic relapse. The results of our pilot study, in which we tested a priming based, low dose and longer exposure in 25 patients with AML under poor PS, showed that the treatment was safe, effective, and economical. A prospective multicenter, randomized trial comparing DHCAG with IA is now under way in China. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3895-3895
Author(s):  
Hannah Asghari ◽  
Dasom Lee ◽  
Yehuda E. Deutsch ◽  
Onyee Chan ◽  
Najla Al Ali ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Group ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

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