Highlights und Publikationen der Studiengruppen beim 62. ASH Meeting

GMALL-Publikationen


2795
Interim Results of a Multicenter, Single-Arm Study to Assess Blinatumomab in Adult Patients (pts) with Minimal Residual Disease (MRD) of B-Precursor (BCP) Acute Lymphoblastic Leukemia (GMALL-MOLACT1-BLINA)

Die deutsche Studiengruppe für die ALL des Erwachsenen (GMALL) verfolgt den Ansatz, Blinatumomab bei Patienten mit molekularem Therapieversagen oder molekularem Rezidiv nach initialer Induktion und Konsolidation einzusetzen. Patienten mit MRD über 10-4 konnten in die Studie eingeschlossen werden. Nach einem Amendment wurden Patienten mit MRD über 10-3 nicht mehr eingeschlossen, da hierfür die zugelassene Medikation im Standard of Care verfügbar wurde. Die Rekrutierung wurde stattdessen bei Patienten mit MRD zwischen 10-4 und 10-3 beibehalten und auf Patienten mit MRD unter 10-4 ausgedehnt. Die letztgenannte Patientengruppe hat in der Primärbehandlung eine intermediäre Prognose, die keine Transplantationsindikation induziert; bei den betroffenen Patienten soll daher die Standardtherapie nach der Gabe von Blinatumomab fortgesetzt werden. Die Patienten erhielten bis zu vier Zyklen Blinatumomab. Nach einem Zyklus wurde das MRD-Ansprechen als primärer Endpunkt evaluiert. Patienten konnten dann auch einer SZT zugeführt werden.

60 Patienten mit einem medianen Alter von 44 Jahren waren evaluierbar. 81% der Patienten mit einem MRD-Niveau über 10-4 erreichten ein molekulares Ansprechen nach einem Zyklus, d.h. MRD unter 10-4 bzw. negativ. Ein komplettes molekulares Ansprechen wurde bei 67% der Patienten erreicht. Das MRD-Niveau bei Einschluß hatte keinen Einfluss auf das Ansprechen und auch andere Faktoren einschließlich des Alters spielten keine Rolle. Die Mehrzahl der Patienten wurde einer SZT zugeführt und die Mortalität war mit 13% relativ niedrig. Insgesamt traten 16 Rezidive auf – 8 davon unter Therapie bei Patienten mit unvollständigem Ansprechen. Bei einer medianen Nachbeobachtungszeit von 12 Monaten (1-38) war das mediane Überleben nicht erreicht. Nach zwei Jahren lag die Überlebenswahrscheinlichkeit bei 64%. Es deutete sich an, dass das Überleben bei Patienten mit höherem MRD-Niveau tendenziell etwas schlechter war (Tabelle). Auch Patienten mit unvollständigem Ansprechen oder Therapieversagen zeigten tendenziell ein ungünstigeres Überleben (Abbildung). Diese Ergebnisse unterstützen die Strategie, Blinatumomab bereits bei niedrigerem MRD-Niveau einzusetzen, wie dies in der GMALL-Studiengruppe empfohlen wird und nicht erst ab einem Niveau von 10-3, wie es die Zulassung vorsieht. Außerdem ist zu überlegen, ob eine rasche SZT und/oder eine Therapieumstellung bei Patienten mit unvollständigem MRD-Niveau sinnvoll wäre.


267
First Results of an Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Therapy Followed By a Conventional Chemotherapy Based Consolidation and Maintenance Therapy in Patients Aged 56 Years and Older with Acute Lymphoblastic Leukemia (INITIAL-1 trial)

Bei älteren Pateinten mit neu diagnostizierter ALL werden deutlich ungünstigere Ergebnisse als bei jüngeren Patienten erzielt. Das liegt unter anderem daran, dass ungünstige Prognosefaktoren mit dem Alter zunehmen, gleichzeitig die Mortalität und Morbidität hoch sind und auch häufiger Rezidive auftreten. Da es keine Optionen für eine weitere Intensivierung der Chemotherapie gibt, werden zunehmend neue, zielgerichtete Substanzen in der Primärtherapie älterer Patienten eingesetzt. Ein Konzept der GMALL besteht darin, die Chemotherapie-Induktion durch drei Zyklen Inotuzumab zu ersetzen. Der erste Zyklus ist etwas höher dosiert und enthält auch Dexamethason. Nach Abschluss der Induktionszyklen erhalten die Patienten eine Standard-Konsolidationschemotherapie und Erhaltungstherapie.

29 Patienten mit einem medianen Alter von 65 (56-80) Jahren waren evaluierbar. Alle Patienten erreichten eine CR wobei 2 Patienten die Induktion nach 1 bzw. 2 Zyklen wegen Toxizitäten beenden mussten. 17/23 untersuchten Patienten waren MRD-negativ. Bisher verstarben 2 Patienten in Remission und 2 Patienten entwickelten ein Rezidiv. 2 Patienten erhielten eine SZT. Die Überlebenswahrscheinlichkeit nach einem Jahr lag bei 82%. Die Therapie war insgesamt gut verträglich und auch in der nachfolgenden Konsolidationstherapie gab es keine auffälligen Toxizitäten. Bei der Toxizität der Inotuzumab-Therapie standen Hämatotoxizität und erhöhte Transaminasen im Vordergrund.


395
Molecular Subgroups of T Cell Acute Lymphoblastic Leukemia in Adults Treated According to GMALL Protocols

In der vorgestellten Arbeit charakterisierten wir eine Kohorte von 161 erwachsenen T-ALL-Patienten, die in Protokollen der GMALL-Studiengruppe behandelt wurden, auf mehreren molekularen Ebenen. Neben der Transkriptomanalyse mittels RNAseq wurde der Mutationsstatus mittels eines Genpanels von 206 Leukämie-assoziierten Genen sowie der Methylierungsstatus mittels 450k Chips analysiert. Im Fokus stand die Zuordnung der Proben zu molekularen Subgruppen, die im Wesentlichen auf der Überexpression von Onkogenen (TLX1, TLX3, HOXA, LYL1/LMO2, TAL1/LMO1, NKX2-1, TAL2) basieren. Dies konnte mittels RNAseq für 160 der 161 Patienten erfolgen. In ~50% der Fälle zeigte sich eine entsprechend zu Grunde liegende Treiberfusion. Die Subgruppenzuordnung zeigte eine gute Übereinstimmung mit Immunphänotyp sowie dem Methylierungsmuster. Bezüglich der Methylierung war insbesondere auffällig, dass die TAL1/LMO1-Subgruppe mit enthaltenen STIL-TAL1-Rearrangements eine globale Hypomethylierung aufwies. Bemerkenswerterweise zeigten ältere Patienten signifikant seltener ein TAL1/LMO1-Genexpressionsprofil und waren häufiger in der LYL1/LMO2- oder der HOXA-Subgruppe zu finden. Dies könnte zu unterschiedlichen Ansprechraten bei Kindern und Erwachsenen beitragen. Klinisch zeigte sich ein exzellentes Therapieansprechen für die TLX1-Subgruppe mit einer MRD-Negativität in 29 von 31 Patienten, welches sich in ein 5-Jahresüberleben von 93% übersetzte. Zusammen mit den wenigen Fällen der NKX2-1 Subgruppe bildeten diese Patienten eine prognostische günstige Gruppe, deren Wertigkeit auch in der ohnehin schon prognostisch guten thymischen T-ALL erhalten bleibt (93% 5-Jahres Überleben, p=0.02). Insgesamt unterstreicht die Arbeit den Stellenwert einer Transkriptomanalyse in der bislang größten publizierten Kohorte erwachsener T-ALL-Patienten im Rahmen der GMALL-Studiengruppe mit der Möglichkeit der Identifikation von molekularen Subgruppen.


2910
Molecular Subtypes with Distinct Clinical Phenotypes and Actionable Targets in Adult B Cell Precursor ALL Treatment According to GMALL Protocols

Charakterisierung molekularer Subgruppen und ihrer klinischen Phänotypen in einer GMALL Kohorte von Patienten mit B Vorläufer Akuter Lymphoblastischer Leukämie

Für die B Vorläufer Akute Lymphoblastische Leukämie (BCP-ALL) wurden inzwischen mehr als 20 unterschiedliche molekulare Treibersubgruppen mit ihren zugrundeliegenden genomischen Alterationen und Genregulationen identifiziert. Eine eingehende Charakterisierung der klinischen Phänotypen dieser heterogenen Landschaft fehlt bislang – insbesondere im Erwachsenenalter. In unserer vorgestellten Arbeit haben wir eine Kohorte von n=372 BCP-ALL Patienten mit Behandlung innerhalb von Protokollen der GMALL mittels Transkriptom-Sequenzierung charakterisiert. Basierend auf einem Abgleich mit unserer Multi-omics charakterisierten GMALL Referenzkohorte ließen sich 90% aller Patienten einer von 15 molekularen Treibersubruppen zuordnen. Am häufigsten wurden dabei Patienten mit Ph-postiver und Ph-like ALL identifiziert, gefolgt von DUX4-, KMT2A-, ZNF384- rearrangierter ALL und PAX5-plus ALL. Hinsichtlich des klinischen Phänotyps imponierten signifikante Unterschiede in der Alters- und Geschlechtsverteilung der molekularen Subtypen (jünger: ETV6-RUNX1-rearrangierte, Near haploid – High hyperdiploid (NH-HeH), PAX5-plus, DUX4-rearrangierte ALL / älter: KMT2A-rearrangierte, Low hypodiploid – Near triploid ALL; bevorzugt weiblich: DUX4- und KMT2A-rearrangiert ALL / bevorzugt männlich: Ph-like- und NH-HeH ALL). Insbesondere die Tatsache, dass das Geschlecht der Patienten die Selektion leukämogener Treiber in der BCP-ALL beeinflusst, war bisher noch nicht gezeigt worden. Hinsichtlich des Ansprechens auf die einheitliche GMALL-Induktionstherapie ergab die Quantifizierung der Minimalen Resterkrankung ein erwartet gutes Therapieansprechen der TCF3-PBX1 und NH-HeH ALL (n=8/8 und n=9/10 molekulare CR), während nur n=5/13 Patienten mit ZNF384-rearrangierter ALL eine molekular CR erreichten. Damit erscheint diese Subgruppe im Erwachsenenalter mit einem ungünstigen Risikoprofil assoziiert zu sein. Als mögliche biologische Grundlage konnten wir eine JAK/STAT Signalweg Aktivierung zeigen, die mit der ebenfalls eher prognostisch ungünstigen Ph-like ALL geteilt wird. Therapeutisch adressierbare Genfusionen fanden sind in n=13 Patienten (n=12 ABL-class Fusionen, n=1 ETV6-NTRK3). Unsere Arbeit zeigt, wie sich die molekulare Heterogenität der BCP-ALL Subtypen in heterogene klinische Phänotypen übersetzt. Sie bildet die Grundlag für eine weitere molekulare Charakterisierung aller Patienten innerhalb der laufenden GMALL08 Studie.



ASH-Highlight für die AML

458
Remission and Survival after Single Versus Double Induction with 7+3 for Newly Diagnosed Acute Myeloid Leukemia: Results from the Planned Interim Analysis of Randomized Controlled SAL-Daunodouble Trial

Background
Double induction using two subsequent 7+3 regimens of cytarabine plus anthracycline is commonly performed in AML patients with an adequate performance status in order to maximize dose intensity upfront. However, for patients with a good early response at day 15 of first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle.

Aims
In order to answer the question if good responders of the first 7+3 induction could be spared a second induction cycle, we set up randomized-controlled SAL DaunoDouble trial. The study prospectively assesses the outcome of patients with a good early response with respect to the number of induction cycles (single versus double). We assumed non-inferiority of single induction in terms of complete remission (CR/CRi) rate, based on a margin of 7.5%. Here, we present the results of the planned interim analysis.

Methods
Patients (pts) 18-65 years with newly diagnosed AML, normal cardiac and organ function received a first induction cycle with seven days of cytarabine plus three days of daunorubicin (“7+3”). Response assessment in bone marrow was done on day 15 after the initiation of chemotherapy and confirmed by central review. A blast count <5% was defined as good response. Pts with good response were randomized to receive a second induction cycle (arm D) or no second induction cycle (arm S). Primary endpoint was CR/CRi after completion of induction, secondary endpoints were RFS, and OS.

Results
Between 2014 and 2020, 624 evaluable pts were enrolled and received the first induction cycle with 7+3. A marrow blast clearance below 5% on day 15 was achieved in 298 pts (48%), providing eligibility for randomization. Of these patients, 150 were randomized into arm S and 148 into arm D, respectively. Median age was 52 years, 92% had de novo AML, NPM1 mutation was present in 53%, FLT3-ITD in 25% of pts. Favorable, intermediate and adverse risk (ELN 2017) were present in 56%, 34% and 10% of pts, respectively. CR/CRi rates at the end of induction were 86% after single induction and 85% after double induction. The CR/CRi rates in 224 pre-defined per-protocol pts were 88% versus 91%, resulting in a CR difference of 3% (95%-CI -0.047-0.111; p for non-inferiority test 0.145). After a median follow-up time of 24 months, RFS was slightly but not significantly lower after single induction with a 3-year RFS of 53% versus 64% (HR 1.4, p=0.125), whereas no differences were seen in 3-year OS, with a of rate of 74% versus 75% (HR 1.1, p=0.645) after single versus double induction.

Conclusion
The interim analysis results show that in good responders, the difference between CR rates after single versus double induction was even smaller than the predefined 7.5% margin, suggesting a trend for non-inferiority of single induction, although statistical significance was not reached. The trial continued recruitment. These findings suggest that in good responders, it may be safe to omit a second induction cycle if a second cycle poses a high risk.

Figure. CR + CRi, RFS and OS after randomization to single versus double induction.

 

Publikationen der AMLSG


111
Escalated Dosing Schedules of CC-486 Are Effective and Well Tolerated for Patients Experiencing First Acute Myeloid Leukemia (AML) Relapse: Results from the Phase III QUAZAR AML-001 Maintenance Trial

INTRODUCTION
: Standard intensive induction chemotherapy (IC) for AML leads to complete remission (CR) in 60%–80% of patients aged ≤ 60 years and in 40%–60% of patients aged > 60 years. However, about two-thirds of patients relapse after frontline therapy, and most relapses occur within the first 18 months (Yilmaz, Blood Cancer J, 2019).
Effective post-induction AML maintenance treatment should decrease the risk of relapse by suppressing growth of residual leukemic cells. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules (> 7 days per 28-day treatment cycle) to sustain therapeutic activity. In the phase III international, randomized, double-blind QUAZAR AML-001 trial (NCT01757535), CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients with AML in first remission following IC, who were not candidates for hematopoietic stem cell transplant (HSCT) (Wei, ASH 2019, LBA-3). Patients initially received CC-486 or placebo for 14 days per 28-day cycle, but patients identified as having early AML relapse with 5–15% blasts in peripheral blood or bone marrow could receive an escalated 21-day/cycle dosing schedule at investigators’ discretion.

OBJECTIVE: Evaluate clinical outcomes in patients in QUAZAR AML-001 who relapsed with 5–15% blasts on-study who then received escalated 21-day dosing of study drug.

METHODS: Eligible patients were aged ≥ 55 years, with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤ 3, and had achieved a first CR or CR with incomplete blood count recovery (CRi) after IC ± consolidation. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to receive CC-486 300 mg or placebo once-daily on days 1–14 of repeated 28-day treatment cycles. CR/CRi status was assessed centrally every 3 cycles; patients who exhibited signs of relapse in hematology parameters at routine clinic visits (conducted every 2 weeks) could have an unscheduled bone marrow test to confirm AML relapse. Patients who developed 5%–15% blasts in blood or bone marrow could receive study drug for 21 days/cycle at the investigator’s discretion. Treatment could continue until >15% blasts, unacceptable toxicity, or HSCT.

RESULTS: In all, 472 patients were randomized to CC-486 (N=238) or placebo (N=234). During the course of the study, 91 patients (CC-486, n=51 [21%]; placebo, n=40 [17%]) were identified as having early AML relapse with 5–15% blasts and were assigned to receive a 21-day/cycle dosing schedule. Median time to dose escalation of CC-486 was 9.2 months (range 1.0–52.7) and of placebo was 6.0 months (0.5–19.3). Median number of 21-day dosing cycles was 2.0 in both the CC-486 (range 1–45) and placebo (1–16) arms, but proportionally more patients in the CC-486 arm received > 3 escalated dosing cycles (CC-486, 43%; placebo, 18%). Among 78 evaluable patients with ≥ 5% blasts in the most recent bone marrow on or before day 1 of 21-day dosing, 23% (10/43) of patients in the CC-486 arm and 11% (4/35) of patients in the placebo arm regained CR/CRi (< 5% blasts in bone marrow; central review) while receiving an escalated dosing regimen. Among all patients who received escalated dosing schedules, median OS from the time of randomization was 22.8 months in the CC-486 arm vs. 14.6 months in the placebo arm (hazard ratio [HR] 0.66 [95% CI 0.42, 1.0]; P = 0.073), and 1-year survival rates were 80.4% vs. 59.5%, respectively (+20.9% [2.1, 39.7]).

The most common adverse events first reported during 21-day dosing were febrile neutropenia (CC-486, 24%; placebo, 3%), thrombocytopenia (22% and 23%), anemia (22% and 20%), and neutropenia (20% and 10%) (Table). A similar proportion of patients in each arm (CC-486, 31%; placebo, 35%) first experienced a grade 3 or grade 4 adverse event while receiving escalated dosing. CC-486 dose-escalation did not lead to detrimental effects on patient-reported quality of life measures (as assessed by the FACIT-Fatigue and EQ-5D-3L instruments) vs. placebo.

CONCLUSIONS: An escalated 21-day CC-486 dosing regimen was well tolerated and resulted in restoration of remission in approximately one-fourth of patients. Hematologic adverse events first reported during escalated dosing in both treatment arms may be due in part to disease relapse. A 21-day CC-486 dosing schedule could be considered for patients who experience AML relapse with ≤ 15% blasts.


275
Next-Generation Sequencing (NGS)-Based Measurable Residual Disease (MRD) Monitoring in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication (FLT3-ITD+ AML) Treated with Additional Midostaurin

Background: FLT3-ITD occurs in ~25% of adult AML patients (pts) and is associated with poor prognosis. MRD monitoring is of high prognostic relevance, but restricted to certain AML subtypes. FLT3-ITD represents an attractive target for MRD monitoring in particular in pts treated with a tyrosine kinase inhibitor. FLT3-ITD MRD monitoring is hampered by the broad heterogeneity of ITD length and insertion site (IS). NGS may overcome these limitations offering the opportunity for MRD monitoring in FLT3-ITD+ AML.

Aims: To validate our recently established NGS-based FLT3-ITD MRD assay in a defined cohort of FLT3-ITD+ AML pts treated within the AMLSG16-10 trial (NCT01477606) combining intensive chemotherapy with midostaurin followed by midostaurin maintenance and to evaluate the prognostic impact of FLT3-ITD MRD monitoring.

Methods: Using FLT3-ITD paired-end NGS (Illumina MiSeq) with a variant allele frequency (VAF) sensitivity of 10-4-10-5 (Blätte et al., Leukemia 2019), 227 bone marrow (BM) and 17 peripheral blood samples from 61 FLT3-ITD+ AML pts were analyzed at diagnosis (Dx), after two cycles of chemotherapy (Cy2), at the end of treatment (EOT), and during 3-6 months follow-up (FU). All pts achieved complete remission (CR) after Cy2. Allogeneic hematopoietic cell transplantation in first CR was performed in 40 (66%) pts. Mutational status for NPM1 and DNMT3A was available for all pts (NPM1mut, n=48; DNMT3Amut, n=33; NPM1mut/DNMT3Amut, n=31), and NPM1mut MRD data for 41 pts.

Results: At Dx we identified 191 ITDs; median length was 45 nucleotides (range, 9-194) and median VAF 0.279% (range, 0.006-90.21). Of the 191 ITDs, 133 (70%) located in the juxtamembrane domain (JMD) and 58 (30%) in the tyrosine kinase domain-1 (TKD1). There was no correlation of VAF with length or IS, whereas ITD size correlated with IS: the more C-terminal the IS, the longer the ITD (Rho=0.51; p<.001). Total ITD VAF per pt was in median 34.3% (range, 0.007-90.21) and correlated positively with white blood cell count (WBC, Rho=0.314; p=.021) and lactate dehydrogenase serum level (LDH, Rho=0.274; p=.04), and inversely with the number of ITDs (Rho=-0.265; p=.04). Most pts (67%) exhibited >1 ITD at Dx (median 2; range, 1-16). Categorizing pts according to IS as JMDsole (46%), JMD/TKD1 (34%), and TKD1sole (20%) revealed that JMD/TKD1 pts exhibited more ITD subclones (p<.001) and a lower total VAF at Dx (p=.03). There were no correlations with any other clinical or genetic features.
Pts’ total ITD VAF significantly decreased after Cy2 and at EOT (median log10 reduction: 4.4 and 4.7; p<.001, each), and MRD negativity (MRD-) was achieved in 67% and 87% of pts, respectively. According to subgroups, pts with JMDsole or TKD1sole showed deeper MRD reduction compared to JMD/TKD1 pts after Cy2 (4.6 vs 4.7 vs 3.7 log10; p=.06) and at EOT (4.8 vs 4.8 vs 4.0 log10; p=.02) but this did not result in a significant difference in achievement of MRD-. Concurrent NPM1mut was of favorable impact for log10 VAF reduction (median, 4.7 for DNMT3Amut/NPM1mut vs 4.6 for NPM1mut vs 2.8 others; p=.003) and MRD- (77 vs 76 vs 31%; p=.01) after Cy2, but exerted no impact at EOT. Correlating NPM1mut and FLT3-ITD MRD course revealed a positive correlation after Cy2 (Rho=0.327; p=.03), but not at EOT (Rho=0.250; p=.10), likely due to the higher sensitivity of the real-time quantitative PCR-based NPM1mut MRD assay.
Median follow-up was 3.4 years (95% CI, 2.6-4.6). Survival analyses with respect to cumulative incidence of relapse (CIR; n=60) and overall survival (OS; n=61) revealed significantly lower CIR for total VAF at Dx >34.3% (p=.03), a VAF reduction >4.7 log10 (MR4.7) at EOT (p=.001), and for MRD- pts at EOT (p=.001). There was no impact on OS. In preliminary exploratory Cox regression (n=48), including BM blasts, WBC, LDH, age, and NPM1mut as covariables, MRD- at EOT was the only consistent favorable variable for CIR (HR, 0.1; p=.001) and OS (HR, 0.27; p=.03). During FU, 5/8 (63%) MRD+ pts at EOT became MRD- and 4/53 (8%) MRD- pts converted to MRD+ resulting in consecutive relapse in 2 pts.

Conclusion: In this first cohort of FLT3-ITD+ AML pts treated with intensive chemotherapy and midostaurin in the prospective AMLSG16-10 trial we could demonstrate that FLT3-ITD NGS-based MRD monitoring is feasible and represents a promising tool to evaluate therapy response and identification of pts at a higher risk of relapse. Further analysis of the study cohort is ongoing.


391
Molecular Landscape and Prognostic Impact of FLT3 Internal Tandem Duplication Insertion Site in Acute Myeloid Leukemia (AML): Results from the Ratify Study (Alliance 10603)

Introduction: Internal tandem duplications of the FLT3 gene (FLT3-ITD), present in ~25% of newly diagnosed adult acute myeloid leukemia (AML), are associated with poor prognosis, in particular in cases of high mutant to wild-type allelic ratio (AR) and/or insertion site (IS) in the beta1-sheet.

Aims: To investigate the relationship between ITD IS and patient (pt) outcome, Roche 454 next generation sequencing (NGS) was performed in 452/555 (81.4%) FLT3-ITD positive pts enrolled into the RATIFY trial (NCT00651261).

Results: NGS identified 908 ITDs with up to 9 ITDs/pt; 242 (53.5%) pts exhibited ≥2 ITD clones (2 ITDs, 29%; 3 ITDs, 12.8%; 4 ITDs, 5.3%; 5 ITDs, 4%; 6 ITDs, 0.7%; 7 ITDs, 1.5%; 9 ITDs, 0.2%). Median ITD-size was 45 nucleotides (range, 6-246); all ITDs were in-frame with direct head-to-tail orientation. Molecular characterization revealed the majority (70.8%, n=643) of IS within JMD, whereas 29.2% inserted 3´ of JMD, predominantly in the beta1-sheet of TKD1 (27.5%, n=250). In the 242 pts featuring multiple ITD clones, 698 concurrent IS were delineated with coexistent IS within JMD-Z being the most frequent interaction (41.5%) followed by JMD-Z and beta1-sheet (20.2%), within beta1-sheet (12.2%), by JMD-Z and hinge region (11.5%), by beta1-sheet and hinge region (5.5%), and within the hinge region (4.8%). ITD size strongly correlated with IS, in that the more C-terminal the IS, the longer the inserted fragment (P<0.001).

FLT3-ITD IS, categorized as (i) JMDsole (n=251, 55.5%), (ii) JMD/TKD1 (n=117, 25.9%), and (iii) TKD1sole (n=84, 18.6%) were not associated with differences in clinical characteristics, but with genetic features: JMDsole was positively correlated with NPM1mut (P=.029), inversely with the NPM1wt/FLT3-ITDlow genotype (P<.001), and showed higher AR, determined by both Genescan and NGS (P<.001, each). Pts with JMD/TKD1 more frequently were FLT3-ITDlow (AR ≤0.5) (P<.001) and had more ITD subclones (P<.001).

Complete remission (CR) was achieved in 274/452 (60.6%) pts. Regression model including the 3 categorized IS groups revealed NPM1mut as a favorable marker for achievement of CR (OR, 2.16; P=.001), while WBC (OR, 0.83; P=.009) and number of ITDs (OR, 0.80; P=.035) predicted for a lower CR rate. The 3 IS groups had no impact on CR achievement.

The estimated median follow-up of the 452 pts was 60.6 months (95% CI, 57.7-63.6). Survival analysis according to categorized IS groups showed that pts exhibiting insertion exclusively in TKD1 had significantly inferior OS (P=.032) compared to the other 2 groups. In multivariate Cox models for OS and CIR, including allogeneic hematopoietic stem-cell transplantation in CR1 (HCT) as time-dependent covariate, FLT3-ITD IS in TKD1sole (compared to JMDsole: HR, 1.61; P=.014, and compared to JMD/TKD1: HR, 2.17; P=.004), WBC (HR, 1.12; P=.010), and age (HR, 1.02; P=.029) were unfavorable factors for OS, whereas NPM1mut (HR, 0.58; P<.001) and HCT (HR, 0.45; P<.001) were both favorable. For CIR, FLT3-ITD IS in TKD1sole (compared to JMDsole: HR, 2.14; P=.002), WBC (HR, 1.18; P=.002), and NGS-based AR (HR, 1.16; P=.007) were associated with higher risk of relapse, whereas HCT (HR, 0.51; P=.007) reduced risk of relapse significantly; treatment with midostaurin had no impact on OS and CIR in the whole cohort. Cox regression models on OS and CIR according to the 3 IS subgroups revealed for the TKD1sole group HCT (HR, 0.29; P=.005 and HR, 0.24; P=.015) as the only significant factor for improved OS and CIR, whereas WBC (HR, 1.38; P=.008 and HR, 1.32; P=.026) were of adverse impact for both endpoints. Within the JMDsole group, NGS-based AR (HR, 1.18; P=.006 and HR, 1.43; P<.001) and multiclonality (HR, 1.29; P=.022 and HR, 1.43; P=.047) were negative on both OS and CIR, and age (HR, 1.02; P=.024) on OS only, whereas treatment with midostaurin (HR, 0.56; P=.005 and HR, 0.56; P=.034) and NPM1mut (HR, 0.47; P<.001 and HR, 0.47; P=.006) were of beneficial impact on both endpoints. A significant beneficial effect for HCT was also observed for CIR (HR, 0.48; P=.040). The only significant factor for the JMD/TKD1 group was HCT (HR, 0.18; P=.018) associated with improved OS.

Conclusions: In this cohort of 452 FLT3-ITD mutated AML pts treated within the RATIFY trial the negative prognostic impact of TKD1 IS was confirmed. A beneficial effect of midostaurin was only found for patients with JMDsole IS. In this subset, NPM1mut also exerted a strong beneficial effect.


625
Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant IDH1 AML: Results from Matched Comparisons to Historical Controls

Background: A European Marketing Authorization Application for ivosidenib (IVO) is currently under review for the indication of mutant isocitrate dehydrogenase 1 (mIDH1) R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) in adult patients (pts) who have received ≥ 2 prior regimens, including ≥ 1 standard intensive chemotherapy (IC) regimen, or are not candidates for IC and have received ≥ 1 prior non-intensive regimen. IVO is an oral, potent, targeted inhibitor of mIDH1 and was approved by the FDA for the treatment of mIDH1 R/R AML in 2018, and in newly diagnosed AML in adults ≥ 75 years of age or pts ineligible for IC in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study.

Aims: To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, UK, and Spain.

Methods:
Individual pt data from Arm 1+ of the AG120-C-001 study (n = 159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n = 127) and the RWD (n = 148). A medical review was conducted to identify Arm 1+ IVO pts in the AG120-C-001 study and HC pts who fell within the proposed EU indication. Treatment with IVO was compared with the most recent therapy received by HC pts. HC pts treated with IC as their most recent therapy were excluded, as IVO pts, based on the AG120-C-001 study’s eligibility criteria, were not considered candidates for IC. Propensity score-based matching/weighting methods were used to adjust for imbalances in baseline prognostic factors between the 2 cohorts (optimal full matching and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 6 baseline prognostic factors for estimation of propensity scores (age, history of hematopoietic stem cell transplantation, number of prior regimens for AML, nature of AML, cytogenetic risk, and primary refractory status). Balance between populations was assessed pre- and post-match via comparison of (weighted) standardized differences (SDs) for each covariate. Time-to-event data were summarized via Kaplan–Meier (KM) estimators with 2-sided 95% confidence intervals (CI). Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HR) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Complete remission (CR) rates were also compared between IVO pts and RWD non-IC HC pts (AMLSG pts were excluded as the response data did not allow for identification of CRs distinct from other response types).

Results: One hundred and nine IVO pts and 60 HC pts fell within the proposed EU indication. The IPTW-matched dataset was selected for analysis, as it more strongly minimized the absolute weighted SDs between cohorts as compared with optimal full matching, with all SDs < 0.05. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with IVO compared with 2.9 mo (95% CI: 1.9, 4.5) in the HC pts. The HR for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favor of IVO (p < 0.0001). There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1).

Conclusion: IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population.


692
CC-486 Prolongs Survival for Patients with Acute Myeloid Leukemia (AML) in Remission after Intensive Chemotherapy (IC) Independent of the Presence of Measurable Residual Disease (MRD) at Study Entry: Results from the QUAZAR AML-001 Maintenance Trial

BACKGROUND: In newly diagnosed AML, high remission rates are typically achieved with IC, but the response is often transient, and detectable residual disease in the bone marrow post-chemotherapy is predictive of early relapse. Emerging data show that the identification of ≥ 0.1% MRD by multiparameter flow cytometry (MFC) in patients with AML in remission after IC is an important prognostic marker that may help guide treatment (Tx) decisions. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to prolong drug exposure over the Tx cycle. In the QUAZAR AML-001 Maintenance Trial, Tx with CC-486 300 mg QD for 14 days/28-day Tx cycle was associated with significantly improved overall (OS) and relapse-free survival (RFS) vs. placebo (PBO) in patients (pts) with AML in first remission after induction chemotherapy ± consolidation. Samples for MFC were obtained prior to randomization and serially throughout the study to assess the impact of MRD on OS and RFS, and to evaluate rates of conversion from MRD positivity (+) to negativity (–) in the CC-486 and PBO arms.

METHODS: Eligible pts aged ≥ 55 years with AML were randomized 1:1 to CC-486 300 mg or PBO within 4 months of achieving first complete remission (CR) or CR with incomplete blood count recovery (CRi). MFC assessments of bone marrow aspirates were performed centrally at screening; at cycles 3, 6, 9, 12, 15, 18, 21, 24, 30, and 36; and as clinically indicated. Samples were analyzed with a panel of 22 cell surface markers using an MRD+ cutoff of ≥ 0.1% (per ELN MRD guidelines). For pts MRD+ at baseline (BL; ie, at randomization), an MRD response was defined as achievement of MRD– for ≥ 2 consecutive assessments. MRD– duration was calculated from the time of randomization (for pts MRD– at BL) or from the first of ≥ 2 consecutive MRD– tests (for pts MRD+ at BL), until the last MRD– assessment (for pts who became MRD+) or Tx discontinuation. OS, RFS, and MRD– durations were estimated using Kaplan-Meier methods. Multivariate (MV) Cox regression analyses were performed to evaluate the association of BL MRD status (MRD+ vs. MRD–) and randomized Tx arm (CC-486 vs. PBO) with OS and RFS.

RESULTS: The MRD-evaluable cohort comprised 463/472 randomized pts (98.1%; CC-486, n=236; PBO, n=227) who had samples available for evaluation at BL and at ≥ 1 post-BL visit. At BL, 43% of pts (n=103) in the CC-486 arm and 50% (n=116) in the PBO arm were MRD+. Overall, BL characteristics were similar between MRD+ and MRD– pts: median ages were 69 (range 55–84) and 68 (55–86) years, respectively; 84% and 88% had intermediate-risk cytogenetics at diagnosis; 52% and 46% of pts had an ECOG PS of 0; and 79% and 82% received ≥ 1 cycle of consolidation after induction.

CC-486 Tx resulted in improved OS from time of randomization compared with PBO in pts who were either MRD+ (median 14.6 vs. 10.4 mo, respectively; HR 0.69 [95%CI 0.51, 0.93]) or MRD– (median 30.1 vs. 24.3 mo; HR 0.81 [0.59, 1.12]) at BL. Median RFS was also extended with CC-486 vs. PBO for both MRD+ (7.1 vs. 2.7 mo, respectively; HR 0.58 [95%CI 0.43, 0.78]) and MRD– pts (13.4 vs. 7.8 mo; HR 0.71 [0.52, 0.98]). In MV analyses, BL MRD status (MRD+ vs. MRD–) was significantly associated with OS (HR 1.85; P < 0.0001) and RFS (HR 2.04; P < 0.0001), and CC-486 showed a significant Tx benefit vs. PBO on both OS (HR 0.74; P = 0.0067) and RFS (HR 0.63; P < 0.0001) independent of MRD status at BL (Figure).

The median duration of MRD negativity was extended with CC-486 vs. PBO: 11.0 vs. 5.0 mo, respectively (HR 0.62 [95%CI 0.48, 0.78]). Tx with CC-486 also resulted in a higher rate of MRD response (MRD+ to MRD–) vs. PBO: 37% vs. 19%, respectively. Among MRD responders, 9/38 patients (24%) in the CC-486 arm achieved MRD negativity > 6 mo after randomization, compared with only 1/22 patients (5%) in the PBO arm.

CONCLUSIONS: The QUAZAR AML-001 Maintenance Trial was the first prospective, randomized trial to include long-term longitudinal assessment of MRD in older patients with AML in remission. In both treatment arms, MRD+ status (≥ 0.1%) after induction ± consolidation was associated with significantly shorter OS and RFS compared with MRD– status. Approximately one-fourth of MRD responders treated with CC-486 achieved MRD negativity > 6 mo after study entry, suggesting that CC-486 could induce MRD negativity after prolonged MRD+ status. Maintenance Tx with CC-486 substantially improved OS and RFS independent of MRD status at BL.


1036
CC-486 Improves Overall Survival (OS) and Relapse-Free Survival (RFS) for Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC), Regardless of Amount of Consolidation Received: Results from the Phase III QUAZAR AML-001 Maintenance Trial

BACKGROUND: Approximately 40–60% of older patients (pts) with AML achieve complete remission (CR) with IC. Factors influencing the use of consolidation after induction include disease-related considerations, extent of hematopoietic recovery, pt fitness, and physician and pt preference. Most older pts who achieve AML remission will experience disease relapse despite consolidation therapy (Schlenk, Haematologica, 2018). In the phase III, randomized, double-blind QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent, was shown to significantly prolong OS and RFS vs. placebo (PBO) in pts with AML in first remission following induction ± consolidation. Prior to study entry, the use of consolidation chemotherapy and number of consolidation cycles was at the discretion of the treating physician, with study eligibility not contingent on the use of consolidation.

OBJECTIVE: Assess survival outcomes in the QUAZAR AML-001 trial in pt subgroups defined by number of consolidation courses received before study entry.

METHODS: Eligible pts were aged ≥55 years with newly diagnosed AML, intermediate- or poor-risk cytogenetics, and ECOG PS ≤3. Within 4 months (mo) of attaining first CR or CR with incomplete blood count recovery (CRi), pts were randomized 1:1 to CC-486 300 mg or PBO QD for 14 days per 28-day treatment (Tx) cycle.

OS and RFS were compared among pts who received no consolidation (“No Consolidation”), 1 cycle of consolidation (“1 Consolidation”), or ≥2 cycles of consolidation (“≥2 Consolidations”). For these analyses, “induction” and “consolidation” defined regimens received before and after, respectively, the reported date of first CR/CRi. OS was defined as the time from randomization to death, and RFS as time from randomization to relapse or death. Kaplan-Meier OS/RFS estimates were compared for CC-486 vs. PBO using log-rank test. Hazard ratios (HRs) and 95% CIs were generated using a stratified Cox proportional hazards model. These analyses were not powered sufficiently to determine statistical significance.

RESULTS: 472 pts were randomized to CC-486 (N=238) or PBO (N=234). Most pts (80%) received consolidation before study entry. The No Consolidation cohort comprised 94 pts (20%; CC-486 52, PBO 42), the 1 Consolidation cohort comprised 212 pts (45%; CC-486 110, PBO 102), and the ≥2 Consolidations cohort comprised 166 pts (35%; CC-486 76, PBO 90), including 19 pts (CC-486 6, PBO 13) who received 3 consolidation cycles. Common agents used for consolidation were cytarabine (377/378 pts), idarubicin (95/378), and daunorubicin (37/378). While most pts received 1 induction, 97 pts received ≥2 induction courses; of them, 21 (CC-486 14, PBO 7) did not receive consolidation and 76 (CC-486 43, PBO 33) received ≥1 consolidation cycle.

Baseline characteristics (eg, CR / CRi after IC, ECOG PS, cytogenetic risk at diagnosis) were generally similar among Tx arms and cohorts. Median (range) ages of pts in the 0 / 1 / ≥2 Consolidation cohorts were 71 (58–84), 68 (55–86), and 67 (55–82) years, respectively. In the No Consolidation cohort, median OS from the time of randomization with CC-486 vs. PBO was 23.3 vs. 10.9 mo, respectively (HR 0.55 [95%CI 0.34, 0.89]), and median RFS was 8.4 vs. 3.9 mo (0.55 [0.34, 0.88]) (Figure A). In the 1 Consolidation cohort, median OS was 21.0 vs. 14.3 mo with CC-486 vs. PBO, respectively (HR 0.75 [95%CI 0.55, 1.02]), and median RFS was 10.0 vs. 4.7 mo (0.72 [0.53, 0.99]) (Figure B). In the ≥2 Consolidations cohort, median OS was 28.6 mo with CC-486 vs. 17.6 mo with PBO (HR 0.75 [95%CI 0.50, 1.11]), and median RFS was 13.0 vs. 6.1 mo (0.59 [0.41, 0.87]) (Figure C).

CONCLUSIONS: CC-486 was associated with consistent survival benefits vs. PBO regardless of number of prior consolidation cycles. Use of consolidation was generally associated with nominal improvements in OS and RFS within each Tx arm; however, in the CC-486 arm, median OS for pts who did not receive consolidation was similar to those who received 1 consolidation cycle (23.3 and 21.0 mo, respectively). Results should be interpreted with caution, as these cohorts were not prospectively defined and the study was not powered to detect significant differences between subgroups. Nevertheless, these data clearly suggest that older pts with AML in first remission after induction can benefit from CC-486, regardless of their fitness to receive consolidation or the number of consolidation cycles received before starting CC-486.


1037
Comparative Results of Azacitidine and Decitabine from a Large Prospective Phase 3 Study in Treatment Naive Patients with Acute Myeloid Leukemia Not Eligible for Intensive Chemotherapy

Background: Prognosis of elderly (≥65 years of age) patients (pts) with acute myeloid leukemia (AML) remains dismal with a substantial proportion being deemed unfit for intensive chemotherapy. Monotherapy with the hypomethylating agents azacitidine (AZA) or decitabine (DEC) has been the de facto standard of care for the treatment of chemotherapy-ineligible AML pts although both AZA and DEC did not improve median OS compared to low-dose cytarabine (LDAC) or physician choice, respectively, in phase III trials. No clinical trials comparing AZA and DEC head-to-head in AML exist. Here, we present a subgroup analysis of pts enrolled in the phase III ASTRAL-1 trial (NCT02348489) who were randomized to the AZA or DEC control arm.

Methods: ASTRAL-1 randomized 815 treatment-naïve AML pts ineligible for intensive chemotherapy in a 1:1 ratio to either guadecitabine or treatment-choice (TC) of AZA, DEC, LDAC (NCT02348489). Study protocol and results have been presented previously (Fenaux, EHA 2019). Briefly, adult (≥18 years of age) pts with newly-diagnosed AML ineligible for intensive chemotherapy based on age of 75 years or older, major organ comorbidities, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-3 were eligible for enrollment. Exclusion criteria included prior treatment with AZA or DEC, extramedullary central nervous system AML, inability to tolerate treatment in the TC arm, or refractory congestive heart failure, uncontrolled active infection, or advanced pulmonary disease. Pts were pre-selected to receive either AZA, DEC, or LDAC with subsequent 1:1 randomization to either guadecitabine or TC in the respective arm. Patients treated with standard doses and schedules of AZA or DEC within the TC arm were included in the subgroup analysis presented here. Co-primary outcomes were rates of complete response (CR) and median, 1-year, and 2-year overall survival (OS) as defined by the International Working Group response criteria for AML. Composite CR (CRc) was defined as the composite of CR, CR with incomplete platelet count recovery (CRp), and CR with incomplete cell count recovery (CRi).

Rates of CR among pts treated with AZA and DEC were compared using Fisher’s exact test. Survival outcomes were compared using log-rank tests to compare the hazard ratio for death among the AZA and DEC treated pts. Subgroup analyses for OS stratified by patient and disease characteristics were performed.

Results: 815 patients were enrolled in the ASTRAL-1 trial across 144 sites in 24 countries with 171 and 167 pts being randomized to and treated with AZA and DEC in the TC arm of the trial, respectively. Baseline patient and disease characteristics were well-balanced between the AZA and DEC-treated pts (Table 1). The median number of treatment cycles was 6 (range [R]: 1-31) in the AZA arm and 5 (R: 1-34) in the DEC arm. There was no statistically significant difference in the co-primary endpoint of CR with 30 pts (17.5%) in the AZA and 32 pts (19.2%) in the DEC arm achieving CR (p=0.78). The rate of CRc (CR + CRp + CRi) was comparable among AZA and DEC-treated patients with 22.2% (38 out of 171 pts) and 25.1% (42 out of 167 pts), respectively (Table 2). Median OS between AZA and DEC-treated pts was similar with 8.7 months and 8.2 months in the two arms, respectively (hazard ratio [HR] for death: 0.97; 95% CI: 0.77-1.23; p=0.81). One-year and 2-year OS was comparable in both groups with 39% and 15% in the AZA arm and 32% and 14% in the DEC arm, respectively. Median OS estimates in clinically or genetically-defined patient subgroups were similar between AZA and DEC-treated pts. Serious adverse events leading to death occurred more frequently in the AZA arm compared with DEC (AZA: 38% vs 26% with DEC; p=0.02).

Conclusion: Outcomes in treatment-naïve AML pts ineligible for intensive chemotherapy treated with AZA or DEC in the randomized phase III ASTRAL-1 trial are comparable with CR rates of 17.5% and 19.2% and median OS of 8.7 months and 8.2 months, respectively. No patient, disease, or molecular characteristics predicted a higher likelihood of response to either AZA or DEC. Safety in this frail patient population was comparable to prior trails of HMAs in AML and no major safety differences between AZA and DEC were detected although fatal serious adverse events tended to be higher in the AZA-treated cohort.


1043
Higher Dose of CPX-351 Is Associated with Prolonged Hematologic Recovery: Results from an Interim Safety Analysis of the Randomized, Phase III AMLSG 30-18 Trial

Background: CPX-351, a liposomal formulation of daunorubicin and cytarabine in the fixed molar ratio (1:5), is approved for the treatment of adult patients (pts) with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML (t-AML). To explore the potential benefit of CPX-351 in a broader indication, we initiated a randomized phase III study of CPX-351 vs „3+7“ in pts ≥18 years (yrs) of age with AML and intermediate or adverse genetics according to 2017 European LeukemiaNet (ELN) risk categorization (AMLSG 30-18, NCT03897127). In the younger pts (18-60 yrs) we sought to investigate a higher dose of CPX-351. We here report data from an interim safety analysis for this higher CPX-351 dose.

Methods: Pts are randomized to receive first induction cycle (ind 1) with either CPX-351 or daunorubicin + cytarabine („3+7“: daunorubicin 60 mg/m2 on days 1, 2, 3 + cytarabine 200 mg/m2 on days 1-7); in pts aged 18-60 yrs (performance status 0-1) CPX-351 is given at a dose of 55 mg/m2 daunorubicin/125 mg/m2 cytarabine (125 U/m²; 1 U/m2=0.44 mg/m2 daunorubicin/1 mg/m2 cytarabine; days 1, 3, 5); pts >60 yrs receive the standard dose CPX-351 100 U/m² (days 1, 3, 5). There was no age-adapted dosing in the control arm. For induction cycle 2 (ind 2), pts on the CPX-351 arm receive the same dosage on day 1+2 only; pts on the control arm receive intermediate-dose cytarabine + daunorubicin (both in age-adapted dosing). Continuous assessment for safety is performed for two endpoints: 60-day mortality with a maximally tolerated rate (MTR) of 15%; and hematologic recovery times with i) neutropenia 4° and / or ii) thrombocytopenia 3° or 4° after each ind lasting longer than day 42 after start of treatment cycle (without evidence of persistent leukemia) with a MTR of 25%. Median hematologic recovery times were analyzed using Kaplan-Meier estimates, p-values are mentioned in a descriptive manner (log-rank test).

Results: As of July 20, 2020, 36 patients have been randomized to the study (CPX-351, n=19; „3+7”, n=17) with following characteristics: de novo AML, n=27, secondary or t-AML, n=9; median age 60.5 yrs (range 47-75; ≤60 yrs, n=18; >60 yrs, n=18); intermediate and adverse risk genetics were found in 7 and 10 pts, respectively (not available yet, n=19). On the CPX-351 arm, 9 of 19 pts were ≤60 yrs of age and received the higher CPX-351 dose. So far, 36 pts received ind 1, 25 pts ind 2. Overall, the median time to neutrophil recovery with absolute neutrophil count (ANC) >0.5 G/l was longer in the CPX-351 arm compared to the „3+7” arm: 39 vs 28 days (p=0.07) after ind 1, and 26.5 vs 19 days after ind 2 (p=0.06; table 1). Time to platelet recovery >50 G/l was significantly prolonged in the CPX-351 arm after ind 1 (40 vs 26 days; p<0.0001), currently not after ind 2 (33 and 18 days; p=0.35). When comparing the higher dose (125 U/m²; pts 18-60 yrs) with the standard CPX-351 dose (100 U/m², pts >60 yrs), the median time to neutrophil recovery after ind 1 was significantly longer with the higher dose (40 and 31 days, respectively; p=0.03); after ind 2 median times were 38 and 20.5 days (p=0.26); platelet recovery (>50 G/l) was also significantly delayed after ind 1 with the higher compared to the standard CPX-351 dose (median 43 vs 32 days; p=0.002); platelet recovery after ind 2 was after a median of 38.5 and 26.5 days, respectively (p=0.17). There was no treatment-related death (60-day mortality 0%) in both arms. So far, 6 of the 9 pts (67%) treated with the higher CPX-351 dose reached the safety endpoint of persisting neutropenia (n=4) or thrombocytopenia (n=5) during ind beyond day 42. The MTR was exceeded for thrombocytopenia (0.63; 95% confidence interval (CI) [0.31; 0.86]), but not for neutropenia (0.50; 95% CI [0.22; 0.78]). Overall, there were 18 serious adverse events (SAEs); among the most frequent SAEs were infections and fever in neutropenia (n=10).

Conclusion: The higher dose of CPX-351 administered in pts 18-60 yrs of age led to significantly prolonged hematologic recovery times during ind 1 and 2 exceeding the MTR for thrombocytopenia without treatment-related death. Based on the prolonged hematologic recovery, the protocol will be amended, in that the CPX-351 dose for ind in pts 18-60 yrs of age is reduced to the current Package Insert for CPX-351 44 mg/m2 daunorubicin / 100 mg/m2 cytarabine (100 U/m²). Data on hematologic response as well as on measurable residual disease using multi-parameter flow cytometry will be presented.


1077
Harmony Alliance Provides Novel Insights into Acute Myeloid Leukemia Based on a Pan-European NGS Data Collection

Background: To fully capture the molecular heterogeneity underlying hematologic malignancies (HMs), large cohorts need to be analyzed to unravel the impact of genetic aberrations on treatment outcome. In accordance, we have built a large “Big Data for Better Outcome” platform for HMs within the HARMONY Alliance, a pan-European private-public partnership that aims to put together over 100000 cases of AML, ALL, CLL, MM, MDS, NHL, and pediatric HMs.

Aims: We report first results of our “proof-of-principle” AML study based on the first 4986 AML cases comprised in the HARMONY platform.

Methods: First, we implemented a de facto anonymization and a data harmonization process using the Observational Medical Outcomes Partnership (OMOP) common data model to include AML into our “Big Data for Better Outcome” platform. For data analysis, we have implemented gene-gene interaction analyses for co-occurrence and mutual exclusivity, a hierarchical Dirichlet process for class discovery, and a Bradley-Terry analysis to estimate clonal evolution. Finally, to assess the effects of genomic data on clinical outcome, i.e. rates of remission, relapse and survival, we have fitted prognostic multistage models.

Results: The proof-of-principle analysis was based on patients (pts) with combined clinical and molecular information available. Male to female ratio was 53% vs. 47%, and the median age was 52 (18-91) years. The ELN 2017 risk groups were well represented (favorable: 27%, intermediate: 41%, adverse: 32%), and 43% of pts were treated with an allogeneic stem cell transplantation (alloSCT), whereas 57% of pts received conventional consolidation. Known patterns of co-occurrence and mutual exclusivity were confirmed by gene-gene interaction analysis. For example, we could provide additional evidence for the co-occurrence of RUNX1 mutations with aberrations in SRSF2, SF3B1, and STAG2, genes involved in splicing processes. Examining the variant allele frequency (VAF) of mutations using a Bradley-Terry analysis, we could further refine the model of clonal evolution and generate additional evidence that epigenetic driver mutations in genes affecting DNA methylation (e.g. DNMT3A, TET2, IDH1/2) are earlier events than mutations in histone modifying enzymes (e.g. KMT2D, EZH2, ASXL1, EP300), which usually occur later. With regard to the detection of outcome relevant mutational patterns, an unsupervised cluster genomic aberration based analysis allowed the subcategorization of “distinct” ELN risk groups, such as cases harboring an inv(16). In this core binding factor AML subclass, different inv(16) outcome cohorts could be delineated based on mutational patterns characterized by either NRAS mutations, or KRAS, KIT, FLT3-ITD and CBL mutations. Similarly, supervised outcome analyses could indicate the power of mutations to predict overall survival (OS) following an alloSCT. Our results confirmed that many patients with high-risk genotypes, such as e.g. patients harboring a TP53 mutation, do only benefit little from an alloSCT (median OS of 90 days without alloSCT vs. 382 days following alloSCT, p<0.001). However, distinct higher risk genotype constellations, such as DNMT3A in combination with PTPN11 mutations, can have a much larger survival benefit from an alloSCT (median OS 427 days without alloSCT vs. 1493 days following alloSCT, p=0.027). Finally, we could investigate FLT3-TKD mutations in n=190 cases, and define FLT3-TKD mutant AML with concomitant NPM1 mutation as “favorable” intermediate risk ELN genotype.

Summary/Conclusion: Results the HARMONY AML proof-of-principle study clearly demonstrate the benefit in combining OMOP harmonized data sets within a Pan-European “Big Data for Better Outcome” platform. In accordance, the HARMONY Alliance proves that big data sets might enable us to significantly improve individual patient outcomes and thus to further individualize patient management. By the time of the ASH Annual Meeting we will present the data of our ongoing analyses, which will included findings of a validation data set comprising additional molecularly well-defined AML cases that are currently submitted to the HARMONY platform.


1943
Molecular Characterization of Clinical Response and Relapse in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib and Azacitidine

Background: Acute myeloid leukemia (AML), a hematologic malignancy characterized by clonal expansion of abnormal myeloid progenitors, is a disease exhibiting a dynamic mutational landscape over time. Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6–10% of patients (pts) with AML. Ivosidenib (IVO) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed/refractory (R/R) AML and newly diagnosed (ND) AML in adults ≥ 75 years (yrs) of age or with comorbidities precluding intensive induction chemotherapy (IC). In an ongoing phase 1b study (NCT02677922), 23 pts (11 male; median age 76 yrs [range 61–88]) with mIDH1 ND AML received IVO 500 mg daily and subcutaneous azacitidine (AZA) 75 mg/m2 on Days 1–7 in 28‑day cycles. As of 19Feb2019, median number of treatment cycles was 15 (range 1–30); 10 pts remained on treatment. Overall response rate (complete remission [CR] + CRi [incomplete neutrophil recovery] + CRp [incomplete platelet recovery] + morphologic leukemia-free state [MLFS]) was 78% (18/23): including CR in 61% (14/23) and CR with partial hematologic recovery (CRh) in 9% (2/23). mIDH1 clearance assessed in bone marrow mononuclear cells (BMMCs) by BEAMing digital PCR (detection limit 0.02–0.04%) was observed in 11/16 pts (69%) with CR/CRh, including 10/14 (71%) with CR.

Aim: Characterize clonal evolution and resistance in pts with mIDH1 ND AML treated on study with IVO + AZA.

Methods: The secondary efficacy endpoint of CRh was sponsor derived and defined as CR with absolute neutrophil count > 0.5 X 109/L and platelets > 50 X 109/L. Bulk DNA sequencing (DNA-seq, 1400-gene ACE Extended Cancer Panel, 2% variant allele detection limit ) was performed on BMMCs and/or peripheral blood mononuclear cells (PBMCs). Single-cell (sc) targeted DNA-seq was performed on PBMCs using a microfluidic platform (Tapestri®) with a 20-gene AML panel capable of detecting rare subclones down to 0.1%.

Results: To identify mechanisms of acquired resistance, longitudinal bulk DNA-seq was analyzed for 22/23 pts, including 5 pts with available samples at relapse or disease progression (3 CR and 1 MLFS with morphological relapse; 1 CRh with disease progression). Mutations not detected at baseline but emerging during therapy were categorized into canonical biological pathways (Table). Emerging mutations were observed in 9/22 (41%) pts, including 4 with multiple mutations. 3/22 (14%) pts had emerging IDH2 mutations, with concurrent rise in plasma 2-hydroxyglutarate (2-HG) levels. Within the relapse/progression cases, emerging mutations were observed in 4/5 pts, including 3 where the emerging mutation appeared to be the predominant mutation at relapse/progression (2 CR pts with IDH2 mutations, and 1 CRh pt with a TET2 mutation). To date, from the bulk DNA-seq analysis, no emergence of an IDH1 second-site or receptor tyrosine kinase pathway (FLT3, KRAS, NRAS, PTPN11) mutation has been observed. To further evaluate clonal evolution of clinical response and disease progression, scDNA-seq was performed, with data available for 15 pts (10 CR, 2 CRh, 1 MLFS, and 2 stable disease), including end-of-study time points for 5 relapse/progression pts. In the 2 relapsed pts with an emerging IDH2 mutation observed by bulk DNA-seq, 1 had a minor IDH2 clone present at baseline that expanded independently from IDH1 during therapy (Fig). In a separate case, a subclonal baseline PTPN11 clone evolved to gain both RUNX1 and IDH2 mutations, becoming the predominant clone at relapse. In 2 other cases, scDNA-seq data showed that non-IDH1 clones were selected from baseline clones ancestral (TP53 n = 1) to or emerged separate from mIDH1 (TET2 n = 1). Clonal architecture and evolution from additional pts will be presented.

Conclusion: IVO + AZA combination treatment in IC-ineligible ND AML led to deep and durable molecular remissions. Although the dataset is small, IDH2 clones appeared to expand or emerge separate from the IDH1 clone, with no observation of an IDH1 second-site mutation to date. Understanding patterns of emerging mutations/pathways at relapse will allow for comparison with mIDH1 R/R AML and ND AML pts treated with IVO monotherapy. These results underline the importance of mutational testing, particularly at progression to determine optimal salvage therapy. Potential combination or sequential therapies should be evaluated prospectively in future clinical trials.


2807
Activity of Decitabine (DAC) Combined with All-Trans Retinoic Acid (ATRA) in Oligoblastic AML: Subgroup Analysis of a Randomized 2x2 Phase II Trial

Background:
DNA-hypomethylating agents are providing a very well-accepted backbone for non-intensive combination treatment of AML/MDS patients (pts), and an in vivo synergism has been demonstrated for the azacitidine+venetoclax combination in the VIALE-A trial (DiNardo et al., EHA 2020). The DAC+ATRA combination also resulted in an improved response rate and survival compared to DAC without ATRA (DECIDER trial, Lübbert et al., J. Clin. Oncol. 2020), also in pts with prior hematologic disorder (mostly MDS); no benefit was seen when valproic acid (VPA) was added to DAC (2x2 factorial design). In a previous study, we had investigated the outcome of elderly pts with oligoblastic AML (i.e. with 20-30% bone marrow blasts, defined as MDS RAEBt according to the French-American-British classification) treated with either DAC or best supportive care within the EORTC 06011 phase III trial (Becker et al., Ann. Hematol. 2015), observing a median overall survival (OS) of 8.0 months (mths) in DAC-treated RAEBt pts. We now hypothesized that the outcome of pts with oligoblastic AML may be improved by the addition of ATRA to DAC. Therefore, in the present exploratory subgroup analysis, pts from the DECIDER cohort with 20-30% bone marrow blasts were analyzed for clinical outcome.

Patients and Methods:
Key inclusion criteria: newly diagnosed pts >60 years (yr), unfit for induction with non-M3 AML (WHO, de novo or after antecedent hematologic disorder [AHD], therapy-associated [t]AML), ECOG performance status (PS) 0-2. Treatment: DAC 20 mg/m2 day 1-5 (treatment arms A/B/C/D), ATRA p.o. day 6-28 (arms C/D), VPA p.o. continuously from day 6 (arms B/D), of each 28-day course (repeated until relapse/progression, prohibitive toxicity, withdrawal or death). Key endpoints: objective response rate (ORR): CR/CRi/PR, overall (OS) and event-free survival (EFS). Sample size calculation was based on the primary endpoint ORR, assuming an ORR of 25% in arm A (Lübbert et al., Haematologica 2012). For a power of 80% (test in this phase II study at 1-sided alpha=0.1) for an increase of ORR to 40% with ATRA or VPA, 176 pts were necessary, planned sample size 200. Between 12/2011 and 2/2015, 200 pts were randomized and treated. Efficacy analyses were performed in the intention-to-treat (ITT) population. ATRA was investigated by comparing arms C+D vs arms A+B, VPA by comparing arms B+D vs arms A+C, ORR was analyzed with logistic regression estimating odds ratios (OR), OS/EFS with Cox regression estimating hazard ratios (HR), each with 95% confidence intervals (CI), and presented with descriptive two-sided p values of the tests of no treatment effect. Central hematopathologic review (blinded as to treatment arms) was conducted by an independent morphologist.

Results:
In 56/200 pts of the DECIDER cohort, bone marrow blasts were 20-30% (median, 25%). The number of pts in the randomized arms were: 13 in arm A, 21 in arm B, 9 in arm C, 13 in arm D. Baseline pt characteristics were as follows: male 77%, median age: 75 yr (range 61-88), median WBC: 3400/µl (range 500-52,600), adverse genetics (ELN 2010) present in 25%, ECOG 2 in 13%, comorbidities (HCT-CI) ≥ 3 in 48%, AHD in 68%, tAML in 11% (only slight random imbalances across randomized treatment arms). A median of 5 DAC courses were administered (per arm: 2/5/11/4). Six pts attained a CR, 7 pts a CRi, and 1 pt a PR, resulting in an ORR of 25% (arm A: 7.7%, arm B: 28.6%, arm C: 33.3%, arm D: 30.8%, respectively). Effect on ORR of ATRA vs no ATRA (31.8 vs 20.6%): OR 1.85, CI [0.54,6.37], p=0.33; and of VPA vs no VPA (29.4 vs 18.2%): OR 1.93, CI [0.51,7.24], p=0.33. With 40 deaths out of 56 pts, median OS was 9.5 mths (arm A: 7.6 mths, arm B: 8.9 mths, arm C: 37.2 mths, arm D: 11.2 mths, respectively). Effect on OS of ATRA vs no ATRA (12.5 vs 7.6 mths median OS): HR 0.47, CI [0.24,0.94], p=0.032 (after adjustment for PS, HCT-CI, WBC, LDH, genetic risk: HR 0.42, CI [0.19,0.90], p=0.025); and of VPA vs no VPA (10.0 vs 8.4 mths median OS): HR 0.99, CI [0.51,1.92], p=0.98: A comparable benefit on EFS of ATRA vs no ATRA (but not VPA vs no VPA) was observed.

Conclusion:
In elderly pts with oligoblastic AML ineligible for induction chemotherapy, the addition of ATRA, but not VPA, to DAC resulted in a clinically meaningful survival benefit; OS of pts receiving DAC without ATRA was very similar to that observed in a previous study. It is tempting to speculate that the combination of an HMA with a retinoid such as ATRA may also be active in MDS pts with excess of blasts.


2896
Mutational Landscape of Relapsed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)

Background: Acute myeloid leukemias (AML) with rearrangements of core-binding factor (CBF) complex genes (CBF-AML), comprising t(8;21) and inv(16) subgroups, are considered as diseases with favorable outcome. Nevertheless, CBF-AML relapse rates remain high, with ~40% of patients (pts) relapsing after standard intensive chemotherapy.

Aim: To dissect the biology of relapse in CBF-AML, we performed whole exome sequencing (WES) in a large cohort of 101 cases at the time of diagnosis and for 47 cases also at the time of relapse.

Methods: All pts were treated either with standard chemotherapy or with standard chemotherapy and kinase inhibitor dasatinib within clinical trials of the German-Austrian AML Study Group (AMLSG). Using the Nextera Rapid Capture Exome kit (Illumina) we performed WES of paired diagnostic (dx), remission and relapse samples of 47 pts, namely 21 pts with t(8;21) and 26 pts with inv(16). RNAseq was performed in 18 of these pts using the Ribo Zero RNA-sequencing kit (Illumina). To better define genomic signatures related to CBF-AML relapse, we included WES data previously published by our group (Faber et al. Nat Genet 2016). This set comprised dx samples of 8 t(8;21) and 10 inv(16) pts who relapsed as well as a control group of 20 t(8;21) and 16 inv(16) CBF-AML pts, who did not experience relapse.

Results: For the new cohort, WES sequencing of 47 pts was performed with a mean coverage of 127-fold. In t(8;21), we identified a median of 3.5 mutations exclusively present at dx (range: 0-8), 11.6 mutations persistent from dx to relapse (range: 4-19), and 4.0 mutations gained at relapse (range: 2-7). For the inv(16) subgroup a median of 2.0 mutations were dx specific (0-7), 6.0 mutations persisted during tumor evolution (3-26) and 2.5 were gained at relapse (0-9). As previously reported, the spectrum of genes affected by mutations showed little overlap between t(8;21) and inv(16), except for commonly affected ‘signaling’ genes such as KIT, RAS, FLT3 and epigenetic players such as TET2. In total, in t(8;21) we identified 94 relapse-specific mutations or mutations displaying a strong increase in variant allele frequency (VAF) at relapse, and 63 of such relapse-specific alterations in inv(16) pts. In addition to the previously reported RUNX1 and cohesin complex gene mutations showing an increase in VAF at relapse, we found recurrent novel relapse-specific mutations in LAMC3, which occurred exclusively in the t(8;21) subgroup affecting 9% of pts. In inv(16), recurrent mutations in the tumor suppressor gene WT1 occurred in 12% of pts, either acquired at relapse or already present at dx as a minor subclone. Remarkably, mutations in relapsed t(8;21) pts often affected genes involved in PI3K-AKT and in cell cycle regulation pathways. In the inv(16) relapse group, in addition to dysregulation of the MAPK signaling pathway, we found several non-recurrent mutations in genes involved in ribosomal RNA metabolism, like in PRNAD1.

Conclusion: Our WES sequencing results already provide first insights into the molecular composition and mechanisms underlying relapse in CBF-AML which often affect pathways linked to proliferation, such as PI3K-AKT and MAPK signaling. While we are currently validating additional hits, updated results will be provided at the ASH meeting, which will also address combinatorial mutation patterns underlying chemotherapy resistance in t(8;21) and inv(16) positive AML.


ASH-Highlight für die CML

LBA-4
Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs)

Introduction: Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. BOS, an ATP-competitive TKI, has shown clinical efficacy in pts who received ≥2 TKIs and in newly diagnosed CML, in prospective clinical trials. We asked if asciminib could provide superior efficacy to BOS beyond 2nd line, based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 study.

Methods: Adults with CML-CP previously treated with ≥2 TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Randomization was stratified by major cytogenetic response (MCyR; Ph+ metaphases ≤35%) status at baseline. Pts intolerant of their most recent TKI were eligible if they had BCR-ABL1IS >0.1% at screening (19 pts with BCR-ABL1IS <1% enrolled). Pts with treatment failure (per 2013 European LeukemiaNet recommendations) on BOS are permitted to switch to asciminib per investigator judgement. Pts with known bosutinib-resistant T315I or V299L mutations were excluded. The primary endpoint was major molecular response (MMR) rate at 24 wks. We report primary efficacy and safety results from ASCEMBL (cutoff: May 25, 2020).

Results: A total of 233 pts with CML-CP was randomized to receive asciminib 40 mg BID (n=157) or BOS 500 mg QD (n=76). Fewer pts on asciminib discontinued their last TKI due to lack of efficacy and fewer received ≥3 prior lines of TKI therapy (Table 1). At cutoff, treatment was ongoing in 97 (61.8%) and 23 (30.3%) pts, respectively; the most common reason for treatment discontinuation was lack of efficacy (asciminib, 33 [21.0%] pts; BOS, 24 [31.6%]) (Table 1). Lack of efficacy was most frequently BCR-ABL1 >10% or Ph+ >65% after 6 months of therapy (asciminib 10.8%, BOS 25.0%). Among the 24 pts who discontinued BOS due to lack of efficacy, 22 switched to asciminib. At baseline, ≥1 BCR-ABL1 mutation was present in 12.7% pts on asciminib (most common: F359C/V) and 17.1% on BOS (most common: M244V, F317L). Median duration of follow-up was 14.9 months from randomization to cutoff. Median duration of exposure was 43.4 wks (range, 0.1-129.9) for asciminib and 29.2 wks (range, 1.0-117.0) for BOS; median relative dose intensity was 99.7% (87-100) and 95.4% (74-100).

MMR rate at 24 wks was 25.5% with asciminib and 13.2% with BOS, meeting the primary objective. The between-arm common treatment difference for MMR at 24 wks, after adjustment for MCyR status at baseline, was 12.2% (95% CI, 2.19-22.3: 2-sided P=.029). Among those pts who achieved MMR, median time to MMR was 12.7 wks and 14.3 wks with asciminib and BOS, respectively. At 24 wks, more pts on asciminib (17 [10.8%] and 14 [8.9%]) than on BOS (4 [5.3%] and 1 [1.3%]) achieved deep molecular response (MR4 and MR4.5, respectively). CCyR rate at 24 wks was 40.8% with asciminib vs 24.2% with BOS. Preplanned subgroup analysis showed that the MMR rate at 24 wks was superior with asciminib than BOS across most major demographic and prognostic subgroups, including in pts who received ≥3 prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline cytogenetic response (Figure).

Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively. The proportion of pts who discontinued treatment due to AEs was lower with asciminib (5.8%) than BOS (21.1%). Grade ≥3 AEs and AEs requiring dose interruption and/or adjustments were reported less frequently with asciminib than BOS (Table 2). Most frequent grade ≥3 AEs (occurring in >10% of pts in any treatment arm) with asciminib vs BOS were thrombocytopenia (17.3%; 6.6%), neutropenia (14.7%; 11.8%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). On-treatment deaths occurred in 2 pts (1.3%) on asciminib (ischemic stroke and arterial embolism, 1 pt each) and 1 pt (1.3%) on BOS (septic shock).

Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs.

zur ASH-Pressemitteilung: Asciminib Found Safe and Effective for Hard-to-Treat Chronic Myeloid Leukemia


Publikationen der Deutschen CML-Allianz


46
Bosutinib (BOS) Versus Imatinib for Newly Diagnosed Chronic Phase (CP) Chronic Myeloid Leukemia (CML): Final 5-Year Results from the Bfore Trial

Introduction:
BOS is approved for patients (pts) with Philadelphia chromosome–positive (Ph+) CML resistant/intolerant to prior therapy and pts with newly diagnosed Ph+ CP CML. Approval of first-line BOS was based on the primary results from the phase 3 BFORE trial, which showed superior efficacy vs imatinib (IMA) in the modified intent-to-treat (ITT) population (pop; Ph+ with e13a2/e14a2 transcripts) after ≥12 mo of follow-up. We report the final efficacy and safety results from the BFORE trial after 5 y of follow-up.

Methods: In the open-label BFORE trial (NCT02130557), 536 pts with newly diagnosed CP CML were randomized 1:1 to receive BOS (n=268) or IMA (n=268; 3 untreated), both at 400 mg once daily. Efficacy was assessed in the ITT pop (all randomized pts). Long-term secondary endpoints included duration of response (DOR), on-treatment event-free survival (EFS) and overall survival (OS). Safety was assessed in the safety pop (all treated pts). This final analysis was based on an April 17, 2020 last pt last visit (June 12, 2020 database lock), 5 y (240 weeks) after the last enrolled pt.

Results: At study completion in BOS and IMA arms, respectively, 59.7% and 57.4% were still on treatment, 86.6% and 86.2% completed 5 y on study. Median duration of treatment and time on study was 55.2 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 394 (39–583) vs 400 (189–765) mg/d. Cumulative major molecular response (MMR) rate by 60 mo was higher with BOS vs IMA (73.9% vs 64.6%), as was cumulative molecular response (MR)4 (58.2% vs 48.1%) and MR4.5 rate (47.4% vs 36.6%; Table). Among evaluable pts, more pts in the BOS arm achieved BCR-ABL1 ≤10% at 3 months (Table); cumulative MMR by 60 mo was higher in pts with transcripts ≤10% vs >10% in both treatment arms (BOS, HR 2.67 [95% CI, 1.90–3.75]; IMA, HR 3.12 [2.19–4.45]). Pts in the BOS arm achieved responses earlier than pts in the IMA arm; cumulative incidence function for MMR, MR4 and MR4.5 was higher with BOS vs IMA (HR [95% CI]: MMR 1.34 [1.10–1.64], MR4 1.34 [1.07–1.69], MR4.5 1.41 [1.09–1.83]). Among responders, duration of MMR was similar for BOS and IMA (Table). Superior MRs with BOS vs IMA were consistent across Sokal risk groups, with the greatest difference seen in pts with high Sokal risk (Table). On-treatment transformations to accelerated/blast phase (AP/BP) occurred in 6 (AP 3; BP 3) BOS- and 7 (AP 6; BP 1) IMA-treated pts. No transformation occurred after the 24-mo follow-up. In all, 18 BOS- vs 25 IMA-treated pts had EFS events. There were no differences in EFS between treatment arms; cumulative incidence of on treatment progression/death at 60 mo was 6.7% for BOS vs 9.3% for IMA (Table). The 60-mo OS rates were similar (94.5% and 94.6%; Table); 14 BOS- and 14 IMA-treated pts died during the study period: 3 and 4 were CML-related, 0 and 1 were due to adverse events (AEs) related to study treatment.

The most common reasons for permanent discontinuation were AEs (25.0% vs 12.5%) and lack of efficacy (4.9% vs 16.2%). Treatment-emergent AEs (TEAEs) occurred in 98.9% of pts in each arm; most common (>30%) were diarrhea (75.0%), nausea (37.3%), thrombocytopenia (35.8%) and increased alanine aminotransferase (ALT; 33.6%) with BOS, and diarrhea (40.4%), nausea (42.3%) and muscle spasms (30.6%) with IMA. Most TEAEs occurred during the first year of treatment. Grade 3/4 TEAEs occurred in 73.5% of BOS- vs 57.0% of IMA-treated pts; most common (>5%) were increased ALT (20.9%) and lipase (13.4%), thrombocytopenia (14.2%), increased aspartate aminotransferase (10.4%), diarrhea (9.0%) and neutropenia (7.5%) with BOS, and neutropenia (13.6%), thrombocytopenia (6.0%), anemia (5.7%) and increased lipase (5.7%) with IMA. No individual AE led to discontinuation in >5% of pts. The most frequent AEs leading to permanent treatment discontinuation were increased ALT (4.9%) with BOS vs thrombocytopenia (1.5%) with IMA; 1.5% vs 1.1% of pts discontinued due to diarrhea.

Conclusions: At 5 y, first-line BOS continued to show superior efficacy vs IMA; BOS-treated pts achieved earlier and deeper molecular response. An improvement in MR with BOS was demonstrated across Sokal risk groups, with the greatest benefit vs IMA observed in Sokal high-risk pts. Long-term AEs were generally manageable, and consistent with previous reports and the known safety profiles of both drugs. These results confirm the use of BOS as a standard of care in pts with newly diagnosed CP CML.


647
Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Introduction: The use of 2G TKIs in patients with CP-CML who have failed ≥1 2G TKIs is not associated with durable responses; there is limited clinical evidence to support that switching to alternate 2G TKI therapy improves long-term clinical outcomes for these patients. Patients with resistant and intolerant CP-CML with substantial prior 2G treatment demonstrated deep, lasting responses to PON in the pivotal PACE trial. A post hoc modeling analysis of the data from PACE suggested a relationship between dose and safety events (including arterial occlusive events [AOEs]). The OPTIC trial was designed to prospectively evaluate response-based PON dosing regimens with the aim of optimizing its efficacy and safety in patients with CP-CML; the interim analysis (IA) demonstrated clinically manageable safety and AOE profiles with response-based PON dosing regimens. The combined PACE and OPTIC trials comprise the largest patient population in a post-2G TKI setting. We present the efficacy and safety outcomes of these patients over time.

Methods: PACE (NCT01207440) evaluated PON in patients with refractory CML or Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). OPTIC (NCT02467270) is a multicenter, randomized Phase 2 trial characterizing the safety and efficacy of PON over a range of 3 starting doses (45, 30, or 15 mg/day); patients with CP-CML receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR-ABL1IS. Data from patients with CP-CML in PACE (n=254) and the 45-mg starting dose cohort (45 mg→15 mg) in OPTIC (n=92) who have been treated with ≥1 2G TKI are presented; OPTIC data are from the IA. Efficacy data includes molecular responses (measured using polymerase chain reaction and performed at the same central lab for both studies) and survival outcomes over time. Safety data, including treatment-emergent AOE rates following adjudication, are also presented.

Results: A combined 350 PON-treated patients from the PACE and OPTIC trials who have received ≥1 prior 2G TKI were analyzed; efficacy results are summarized in Table 1. The ≤1% BCR-ABL1IS response rates increased over time and ranged from 42% to 52% in the OPTIC IA 45-mg starting dose cohort and in PACE. Progression-free survival and overall survival were 52% and 73%, respectively, in PACE (up to 5 years) and 81% and 93%, respectively, at the OPTIC IA (up to 2 years) (Table 1). Serious treatment-emergent adverse event (AE) and AOE rates (including exposure-adjusted AOE rates) were lower in OPTIC IA with a response-adjusted dosing regimen compared with PACE (Table 2). Propensity score analyses comparing AOE incidence among all patients in OPTIC vs PACE demonstrate that the relative risk for adjudicated AOEs is 64% lower in OPTIC when compared with PACE after adjusting for baseline differences, duration of exposure, and total PON dose received. Analyses on responses by mutation status also will be presented.

Conclusions: In this analysis, comprising the largest patient population of CP-CML patients in a post-2G TKI setting, ponatinib shows high response rates and robust survival outcomes in patients who have failed 2G TKIs. With the response-adjusted dosing regimen in OPTIC (starting at 45 mg and reducing to 15 mg upon response), efficacy outcomes were consistent with that of PACE, while the overall incidences of AOEs and serious treatment emergent-AEs were lower; exposure-adjusted AOEs during the first 2 years were also lower. The ongoing OPTIC study is also evaluating lower starting doses of ponatinib (30 and 15 mg) and primary analysis of this study will provide a refined understanding of the benefit:risk profile of the 3 starting doses of ponatinib in CP-CML patients.