scholarly journals Correlation of CD123 Expression Level with Disease Characteristics and Outcomes in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 459-459 ◽  
Author(s):  
Adam J. Lamble ◽  
Lisa Eidenschink Brodersen ◽  
Todd A. Alonzo ◽  
Jim Wang ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Oncology Group ◽  
Standard Chemotherapy ◽  
Molecular Alterations ◽  
Disease Characteristics ◽  
Study Population ◽  
Childhood Aml ◽  
Children And Young Adults ◽  
Acute Myeloid

Introduction: Despite maximally intensified chemotherapy, cure rates remain suboptimal for children and young adults with acute myeloid leukemia (AML). As CD123 (IL3RA) is expressed on the majority of AML cells, it is a promising immunotherapeutic target. Increased CD123 expression has been linked to high-risk disease characteristics in adult AML, but clinical implications for childhood AML are less well-defined. Methods: The Children's Oncology Group AAML1031 phase 3 trial (NCT01371981) tested the efficacy of the addition of bortezomib to standard chemotherapy in a randomized fashion. A total of 1400 children and young adults were enrolled on study. All diagnostic specimens were centrally and prospectively evaluated for the expression of CD123 by multi-dimensional flow cytometry (MDF) at Hematologics, Inc. Patients were stratified to either a low-risk (LR) or high-risk (HR) arm of the therapy based on cytogenetic and molecular alterations and end-of-induction (EOI) minimal residual disease (MRD) measured by MDF. LR patients received four cycles of chemotherapy, while HR patients received 3 courses of chemotherapy followed by best allogeneic hematopoietic stem cell transplantation (HSCT). Patients with high allelic ratio FLT3-ITD enrolled on arm C received sorafenib in combination with standard chemotherapy followed by HSCT. Here we provide data on expression of CD123 across all patients and correlate this expression with disease characteristics and clinical outcomes. Results: Surface CD123 expression on AML cells was available for 1040 patients, and expression level varied significantly across the study population with a median CD123 molecules per cell of 1300 (range 120-13,100 molecules per cell). For analysis, the study population was divided into quartiles (n=260 each) based on CD123 expression levels. Significant variation in cytogenetic/molecular characteristics was observed across the four quartiles, where those with highest CD123 expression had a lower prevalence of t(8;21), inv(16), and CEBPA mutations (p<0.001 for all) and higher prevalence of KMT2A rearrangements and FLT3-ITD mutations (p<0.001 for both) (Figure 1A). CD123 expression quartile was not significantly different among those in morphological complete remission (CR) (p=0.278) or MRD negative (bone marrow < 0.1%) (p=0.182) at EOI. Evaluation of outcome parameters across the four quartiles demonstrated that those in lower CD123 expression quartiles 1, 2 and 3 (Q1-3) had similar relapse risk (RR), event-free and overall survival (EFS and OS). However, those with the highest CD123 expression (Q4) had a significantly higher RR (53% vs. 39%, p<0.001), lower EFS (49% vs. 69%, p<0.001), and lower OS (32% vs 50%, p<0.001) (Figure 1B) in comparison to Q1-3. These differences were maintained within the protocol-defined LR cohort, as those with LR disease but high CD123 expression (Q4) had worse RR, EFS, and OS versus those in Q1-3 (p<0.001 for all) (Figure 1C). Given the observed association of CD123 expression with known risk groups, we performed a multivariable Cox regression analysis of all prognostic factors, including cytogenetic/molecular risk group, age, MRD status, and FLT3-ITD status, which demonstrated that high CD123 expression was independently associated with worse OS (HR 1.54, 95% CI 1.21-1.96, p<0.001) (Figure 1D). Conclusions: CD123 expression is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. Patients with highest CD123 surface expression are more likely to have HR genetic alterations and a paucity of LR features. Further, despite similar induction remission rates, those with high CD123 expression had inferior clinical outcomes compared to patients with lower CD123 expression. However, despite an association with HR features, expression of CD123 appears to be independently associated with therapeutic response given that outcome differences were maintained in multivariate regression analysis. This suggests that CD123 expression may provide additional prognostic information, as highlighted by the inferior outcomes in LR patients that had high CD123 expression. In pediatric and young adult patients with the highest risk disease, the higher CD123 expression represents a valuable therapeutic target in the development of immunotherapies for childhood AML. Disclosures Eidenschink Brodersen: Hematologics, Inc: Employment. Pardo:Hematologics, Inc: Employment. Tasian:Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte Corportation: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership.

CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group

2021 ◽  
Author(s):  
Adam J. Lamble ◽  
Lisa Eidenschink Brodersen ◽  
Todd A. Alonzo ◽  
Jim Wang ◽  
Laura Pardo ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Molecular Alterations ◽  
Disease Characteristics ◽  
High Risk Disease ◽  
Childhood Aml ◽  
Acute Myeloid

PURPOSE Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial ( NCT01371981 ). MATERIALS AND METHODS AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels. RESULTS The study population was divided into CD123 expression–based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations ( P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations ( P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis. CONCLUSION CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.

scholarly journals Real World Outcomes of Liposomal Daunorubicin and Cytarabine Versus 7+3 in Patients with Secondary Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Ellen Madarang ◽  
Jillian Lykon ◽  
Nina Nguyen ◽  
Justin M. Watts ◽  
Terrence J Bradley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Committees ◽  
Liposomal Daunorubicin ◽  
Secondary Acute Myeloid Leukemia ◽  
Study Population ◽  
Patient Groups ◽  
Acute Myeloid ◽  
Count Recovery

Introduction: Liposomal daunorubicin and cytarabine (CPX-351) was approved based on data which showed improved overall survival (9.56 v 5.95 months; p = .003) and remission rates (47.7% v 33.3%; p = .016) compared to conventional cytarabine and daunorubicin (7+3) chemotherapy in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients receiving CPX-351 had prolonged time to neutrophil and platelet count recovery compared to 7+3, which was not associated with adverse outcomes (Lancet et al, JCO 2018). Based on these data, our center adopted CPX-351 as a first-line agent in this patient population. Considering the significant cost differences and delays in count recovery, we conducted a comparison of outcomes in patients who received CPX-351 versus 7+3 at our center. Methods: The objective of this study was to compare efficacy and safety of CPX-351 versus 7+3 in patients with sAML. Primary outcome was response rate as defined by CR or CRi. Secondary outcomes included duration of neutropenia, incidence of invasive fungal infections (IFIs), and number of patients proceeding to allogeneic hematopoietic cell transplant (HCT). Patients with sAML receiving induction with 7+3 (daunorubicin dosed at 60 or 90 mg/m2 per treating physician's discretion) or CPX-351 from July 2014 to April 2020 were reviewed. Secondary AML was defined as: AML with a history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), AML with myelodysplasia-related changes, or therapy-related AML. Patients with prior myeloproliferative neoplasms, myelofibrosis, or FLT3 mutations were excluded. Patient characteristics were summarized using descriptive statistics (TABLE 1) including mean for continuous measures and proportions and frequencies for categorical measures. The association between continuous variables and patient groups were assessed using ANOVA or Student's t-test. The associations between categorical variables and patient groups were evaluated using Chi-square test. Results: Over the study period, 65 patients with sAML received induction therapy with either CPX-351 (n = 31) or 7+3 (n = 34). Of these, 61 patients had an evaluable bone marrow biopsy at count recovery. The data is summarized in Table 2. The response rates (CR or CRi) were no different (36% 7+3 vs 36% CPX-351, p = 0.958) among the study population. Longer duration of neutropenia was observed with CPX-351 (33 days 7+3 vs 47 days CPX-351, p = 0.026). More patients in the 7+3 arm proceeded to allogeneic HCT; however, this was not statistically significant (59% 7+3 vs 39% CPX-351, p = 0.105). In an efficacy subgroup analysis of patients with TP53 mutation, there was no difference in response rates (33% 7+3 vs 11% CPX-351, p = 0.224). There was no difference in IFI between the groups (38% 7+3 vs 42% CPX-351, p = 0.761). Upon further analysis of IFI characteristics, there was no difference in choice of mold-active vs non mold-active prophylaxis (ppx) and the incidence of IFIs (40% mold ppx vs 39% non-mold ppx, p = 0.91). Patients with baseline neutropenia prior to induction did not have increased risk of IFIs (65% 7+3 vs 74% CPX-351, p = 0.626). Additionally, there were no between group differences in incidence of IFIs in patients who were neutropenic prior to induction. Conclusions: In the evaluable dataset of patients receiving 7+3 or CPX-351, there was no difference in CR/CRi rate between the two subgroups. There was a longer duration of neutropenia in the CPX-351 group without increased incidence of IFI. However, we report a higher incidence of IFI compared to the study population in Lancet et al (18% Lancet vs 40% Miami) despite appropriate anti-fungal prophylaxis, which may be due to patient selection on the clinical trial, demographic differences (e.g., age, ethnicity), or locoregional environmental factors. In our population, a greater percentage of patients who received 7+3 proceeded to allogeneic HCT. While this study was not powered to detect a significant difference between the two regimens and these findings require validation in larger cohorts, they do not support superior outcomes in patients who receive CPX-351. Data on differences in hospital costs will also be presented. Future directions include a larger multi-center real-world analysis to evaluate patient outcomes, safety, and the financial implications of these two regimens. Disclosures Watts: Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptevo Therapeutics: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees.

The Addition of Bortezomib to Standard Chemotherapy for Pediatric Acute Myeloid Leukemia Has Increased Toxicity without Therapeutic Benefit: A Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 899-899 ◽  
Author(s):  
Richard Aplenc ◽  
Soheil Meshinchi ◽  
Lillian Sung ◽  
Todd A. Alonzo ◽  
Jessica Pollard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Oncology Group ◽  
Standard Chemotherapy ◽  
Free Survival ◽  
Risk Patients ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction: Despite the very high intensity of current chemotherapy regimens for children with acute myeloid leukemia (AML), approximately 50% of patients will experience disease relapse. New therapeutic strategies to improve clinical outcomes have centered on improving the efficacy of standard chemotherapy with novel agents such as gemtuzumab and other agents designed to augment standard chemotherapy. Bortezomib, a proteasome inhibitor, is one such agent. The Children's Oncology Group (COG) Phase III clinical trial AAML1031 tested the hypothesis that the addition of bortezomib to standard chemotherapy would improve treatment outcomes in pediatric patients with newly diagnosed AML. Methods: The COG AAML1031 trial randomized patients younger than 30 years of age with de novo AML to either standard chemotherapy (Arm A) or standard chemotherapy with bortezomib (Arm B). Patients with high allelic ratio FLT3 ITD were offered enrollment on a standard chemotherapy plus sorafenib (Arm C, n = 102) and are excluded from this efficacy analysis. All patients received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE). Risk stratification occurred at the end of ADE induction and was based on the presence of high risk cytogenetic/molecular markers and/or minimal residual disease (MRD) >0.1% determined by multidimensional flow cytometry. Low risk patients received three additional courses of chemotherapy consisting of a second course of ADE, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. High risk patients received a second course of cytarabine/mitoxantrone, a third course of cytarabine/etoposide, and then allogeneic stem cell transplant (SCT) from the best available donor. Bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each cycle with one dose de-escalation to 1 mg/m2 allowed for dose limiting toxicity. Results: A total of 1097 patients were randomized to either standard therapy (Arm A, n = 542) or standard chemotherapy with bortezomib (Arm B, n = 555). No statistically significant differences in sex, age, race, ethnicity, WHO classification, initial blast count, or initial CNS status was observed between arms. Remission induction rate did not differ between treatment arms 89% vs 91%, p = 0.457. MRD was negative in 75% of patients on both treatment arms at the end of Induction I and mean MRD measures did not differ significantly: 2.8% vs 1.9%, p = 0.247. For all patients, event free survival (EFS) and overall survival (OS) at 3 years were 44.4% ± 3.8% and 60.6% ± 4.4%. EFS was not significantly different between Arms A and B (44.0% ± 5.2% vs 44.6% ± 5.6%, p = 0.285) (Figure 1). Likewise, OS was similar between arms (59.0 ± 6.7 vs 62.2 ± 6.0, p = 0.732) (Figure 1). One year cumulative treatment related mortality (TRM) was 14.6 ± 9.3 and 10.8 ± 7.5, p = 0.49 for Arms A and B, respectively. No significant differences were seen in OS, disease-free survival, and TRM from the end of Induction I in low and high risk groups. Cox proportional hazards analysis demonstrated that initial WBC count at diagnosis was the only consistently identified risk factor for OS, DFS, and TRM. Targeted toxicity monitoring identified increased toxicity risks in Arm B for peripheral neuropathy (Induction I/II), dose reductions (all chemotherapy courses), and PICU admissions (Induction I/II) and Intensification I). Serial monitoring of cardiac ejection fraction/shortening fraction in all patients did not demonstrate a clinically meaningful difference in drop in ejection fraction/shortening fraction by treatment arm. No other consistent differences in targeted toxicity rates were identified. Conclusions: The addition of bortezomib to standard chemotherapy increased toxicity but did not improve EFS or OS in children with newly diagnosedAML Consequently, bortezomib should not be used in children with de novo AML in combination with standard chemotherapy. Future work will evaluate the role of intensifying Induction II therapy for patients with high risk AML, further refine risk stratification, and define a more optimal role for allogeneic donor SCT in pediatric AML. Figure 1 Figure 1. Disclosures Loken: Hematologics: Employment, Equity Ownership.

scholarly journals Venetoclax in Combination with High-Dose Chemotherapy Is Active and Well-Tolerated in Children with Relapsed or Refractory Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 178-178
Author(s):  
Seth E Karol ◽  
Thomas Alexander ◽  
Amit Budraja ◽  
Stanley Pounds ◽  
Kristin E Canavera ◽  
...  
Keyword(s):  
Stock Options ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Complete Response ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Children And Young Adults ◽  
Acute Myeloid ◽  
Refractory Aml ◽  
Count Recovery

Introduction: Venetoclax (VEN) is a potent and selective inhibitor of BCL-2. It has demonstrated activity in adults with acute myeloid leukemia (AML) in combination with low-dose cytarabine (&lt;100mg/m2/day) and hypomethylating agents. Here, we report safety and activity of VEN in combination with intermediate- and high-dose cytarabine with or without idarubicin in children and young adults with relapsed or refractory AML. Methods: VEN was given daily for 28 days and chemotherapy was started on day 8, or earlier in cases of disease progression. Dosages of VEN and chemotherapy were escalated separately using a rolling-six design. Response to the VEN window was determined using total peripheral blood blast count or, in a subset of patients, bone marrow blast percentage as determined by flow-cytometry based minimal residual disease (MRD). Pharmacokinetics of VEN both as a single agent and in combination with chemotherapy were measured in a subset of patients treated at the maximum tolerated combination dose of VEN. Response to therapy was determined using bone marrow evaluation between days 29-50 of therapy. All patients received antimicrobial prophylaxis, typically with levofloxacin and micafungin. Azoles were prohibited during VEN administration. Results: Thirty-six patients aged 2-22 years were enrolled. All dose levels were tolerated. The recommended phase 2 dose of VEN in combination with high-dose cytarabine with or without idarubicin was 360 mg/m2 daily (max 600mg). One patient (treated with 240mg/m2 of VEN and intermediate-dose cytarabine) experienced a dose-limiting toxicity due to delayed count recovery and one patient died of recurrent colitis (at dose level 3) which first occurred during prior therapy and was deemed unrelated to VEN. Patients experienced a mean of 2.4 non-hematologic grade 3+ toxicities, with infections including culture-negative febrile neutropenia, sepsis, and colitis the most common toxicities. Patient-reported quality of life was similar at study entry and at the completion of cycle 1 and was within normal limits in most patients. Among 22 patients receiving VEN with high-dose cytarabine ± idarubicin, 14 (64%) achieved a complete response (CR) or complete response with incomplete count recovery (CRi). Response to the VEN window was associated with end of cycle 1 response; 13/15 (87%) patients with a greater than 80% reduction in peripheral blasts achieved a partial response (PR; 3) or CR/CRi (10). In contrast, only 8/15 (53%) patients with less than an 80% reduction in blasts responded to combination therapy (7 CR, 1 PR). Window response to VEN was associated with BH3 dependence as determined by cytochrome c release from leukemia cells in a flow-cytometry based assay. 5 of the 6 (83%) patients with primary BCL-2 dependence had a &gt;80% reduction in blasts; the single patient with a poor response had a change to BCL-XL dependence at the end of cycle 1. In contrast, 4 of the 6 (66%) patients with primary BCL-XL dependence had a &lt;80% reduction in blasts; the 2 patients with a &gt;90% reduction had secondary BCL-2 dependence. None of the 4 patients with FLT3-ITD or point mutations responded as determined by end of cycle 1 marrow. VEN levels were consistent across weights and ages and similar to levels seen in adults. The levels were similar between patients who did and did not receive idarubicin (mean AUC24 38.3 ± 32.7 vs. 47.3 ± 22.9 μg•h/mL). Conclusion: VEN combined with high-dose cytarabine or high-dose cytarabine and idarubicin was well tolerated and effective in children and young adults with relapsed or refractory AML. Enrollment continues to refine estimates of response rate. VEN window response is associated with BH3 dependence and end of cycle 1 response rates. Targeting BCL-XL or FLT3 may improve response to combination therapy. Table Disclosures Karol: Abbvie: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study.. Alexander:AbbVie: Other: travel funding. Salem:AbbVie: Employment, Other: Stock/stock options. Palenski:Abbvie: Employment, Other: Stock/ stock options. Opferman:AbbVie: Research Funding. Rubnitz:AbbVie: Research Funding.

scholarly journals A Phase II of Combination D aunorubicin and Cytarabine (A ra-c) and Nilotinib (TA signa) (DATA) in Patients Newly Diagnosed with Acute Myeloid Leukemia and KIT Expression: Interim Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3808-3808
Author(s):  
Aref Al-Kali ◽  
Raoul Tibes ◽  
Jeanne Palmer ◽  
Hassan B Alkhateeb ◽  
Pamela Atherton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase Ii Study ◽  
Newly Diagnosed ◽  
Standard Chemotherapy ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive form of blood cancers with a wide range of response and relapse rates using standard chemotherapy regimen (commonly known as 7+3). Several genes (FLT3, IDH1, RAS) have been targeted using small molecule tyrosine kinase inhibitors with encouraging results. The stem cell receptor tyrosine kinase KIT is expressed more than 10% in the blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-apoptotic effects (Domen and Weissman 2000). AML with high KIT expression is associated with poorer outcome (Del Poeta, Venditti et al 2003). Goals: To study the efficacy and safety of combination 7+3 and nilotinib in patients (pts) with AML and KIT expression. Primary goal is to determine the complete response (CR) rate; while secondary goals include 2-year overall survival (OS) and disease free survival (DFS) in addition to safety of DATA regimen. Methods: A single arm, Phase II study, enrolled pts at Mayo Clinic (MN and AZ). Appropriate IRB was obtained and study was registered (NCT 01806571). Pts were enrolled if they were newly diagnosed with AML with KIT (CD117) expression of 20% or higher on myeloblasts by flow cytometry. KIT mutations were allowed if present. Nilotinib 300 mg twice daily was given on days 4-14 of induction and consolidation; and continuous daily maintenance therapy for up to 2 years. Cytarabine 100 mg/m2/day continuous IV x7 days plus daunorubicin 60 mg/m2 IV daily x3 days were used for induction , while consolidation used standard cytarabine 3 gm/m2 twice daily days 1, 3, 5 for a total of 4 cycles. This is a Simon 1-stage design with a safety analysis after enrolling 12 pts, and an interim analysis after enrolling 18 out of 43 pts. If 11 or fewer pts achieve complete remission, the regimen will be considered ineffective. Results: Eighteen pts have been enrolled between July 2013 and July 2015, 17 of which have baseline data. Median age was 58 years (range 24-65) with 76.5% being male. Median laboratory findings include hemoglobin of 9.3 gm/dL, platelets of 52 x109, and white blood count of 7.0 (0.5-125). Cytogenetics were normal in 41% of the pts. Favorable cytogenetics were seen in 2 pts (inv 16). FLT3 testing was done on 15 pts and was positive in 27%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed no pathogenic mutation. Median number of cycles was 3 (range 1-7). Six pts had treatment delays, with 2/13 (15%) delays being due to non-hematologic toxicities. No delays or missed doses affected cytarabine and daunorubicin administration. Out of 15 pts evaluable for response, 12 (80%) achieved CR (or CR with incomplete platelet recovery). Six of the 12 pts (50%) who achieved remission needed a second induction on protocol. Two out of 15 did not respond (did not get re-induction on protocol). One pt died before disease assessment due to liver failure (G5, had only one dose of nilotinib and toxicity was attributed to daunorubicin). Of the 14 pts having at least 1 bone marrow biopsy, the overall CR rate was 86%. Five (33%) pts proceeded to allogeneic stem cell transplant, all are alive and none were able to initiate protocol nilotinib maintenance therapy. Only 2 out of 12 (17%) pts relapsed after achieving CR, one was secondary AML from myelodysplastic syndrome with complex karyotype and the other was therapy-related AML with t(9;11). Only 2 (11%) pts died at time of report. Thirteen pts were evaluated for adverse events (AE). Six pts had G4 non-hematological AEs. Five of 12 G4 AEs were related to infection, 2 were electrolyte imbalances, and 2 were heart failures. Most common G3 non-hematological AEs were febrile neutropenia (53%), hypophosphatemia (23%), hyperglycemia (23%), and hypertension (23%). In agreement with the favorable outcomes, the molecular target validation revealed that nilotinib treatment down-regulates the expression of KIT, Sp1, DNA methyltransferase (DNMT) 1, DNMT3a and DNMT3b. Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Interim results show an acceptable safety profile in the first 12 evaluable pts with most common AE being infection as expected. Thirty day mortality is acceptable (7%). DATA regimen has encouraging CR rates of 80% (intent to treat) and 86% in assessed pts, with half of the pts who achieved remission requiring 2 cycles of induction. Relapse rate seems to be low at 17%. We will continue accrual until all pts accrued for final results. Disclosures Al-Kali: Celgene: Research Funding. Off Label Use: This is a Phase II study of combination nilotinib to standard chemotherapy in patients diagnosed with AML.. Tibes:TetraLogic Pharmaceuticals: Research Funding.

Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Makowka ◽  
Verena Stolp ◽  
Karoline Stoschek ◽  
Hubert Serve
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Therapy Response ◽  
Secondary Resistance ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Slow Progress ◽  
Molecular Aberrations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

Sign in / Sign up

Export Citation Format

Share Document