CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: September 13, 2022
Expiration: September 12, 2023
Eunice S. Wang, MD:
Crenolanib is a second-generation pan-FLT3 TKI.1 It is similar to the second-generation FLT3 TKIs, gilteritinib and quizartinib, which have improved potency and specificity for mutant FLT3 over the first-generation FLT3 TKIs such as midostaurin and sorafenib. Unlike the first-generation TKIs, crenolanib is an effective and potent inhibitor of both FLT3‑ITD and the FLT3-TKD mutations in AML. Preclinical studies have demonstrated that crenolanib can overcome or exert activity against several mutations, which can confer resistance to TKIs.2
The long-term results of the multicohort phase II trial of crenolanib and 7+3 chemotherapy for adult patients with newly diagnosed FLT3-mutant AML were presented at ASCO 2022.3
Eunice S. Wang, MD:
The trial was designed to evaluate the safety and efficacy of combining crenolanib with standard 7+3 intensive chemotherapy in patients 18 years or older with newly diagnosed AML harboring activating FLT3 mutations, whether FLT3‑ITD, and/or FLT3-TKD mutations (NCT02283177). In general, patients (N = 44) received cytarabine dosed at 100 mg/m2/day plus either daunorubicin or idarubicin, based on the investigator’s choice. There were 2 cohorts of patients (cohorts A and B) in the study. In cohort A, patients (n = 28) received induction therapy with crenolanib in combination with cytarabine and daunorubicin with a reduced dose of daunorubicin for patients older than 60 years. In cohort B, patients (n = 16) received induction therapy with crenolanib in combination with cytarabine and idarubicin.
Crenolanib was started within 48 hours of completing 7+3 chemotherapy during induction and continued for up to 72 hours before the next chemotherapy. Reinduction therapy was allowed. All patients who achieved a CR or a CR with an incomplete platelet count recovery (CRi) received consolidation chemotherapy. Patients could receive up to 4 cycles of consolidation high-dose cytarabine. Crenolanib was also administered after the completion of consolidation chemotherapy and continued until the next chemotherapy cycle or until patients proceeded to undergo allogeneic hematopoietic stem cell transplantation (SCT). Maintenance crenolanib was given following consolidation or allogeneic hematopoietic SCT as monotherapy, continuously, daily for up to 12 months.
Eunice S. Wang, MD:
In total, 44 patients with a median age of 57 years (range: 19-75 years) were enrolled on the study. There were 29 patients 60 years or younger and 15 patients older than 60 years. An overwhelming majority of the patients—40 (91%)—had de novo AML and 15 (34.1%) patients had favorable-risk AML, while 13 (29.6%) and 16 (36.4%) patients had intermediate-risk and adverse-risk AML, respectively, according to the European LeukemiaNet (ELN) risk classification.
Eunice S. Wang, MD:
Among all 44 patients on the study, the overall postinduction composite CR (CRc) rate was 86%. Among all patients 60 years or younger (n = 29), the overall CRc was 90% vs 80% among those older than 60 years (n = 15). Of note, among 18 patients 60 years or younger who achieved an MRD-negative CR, the CR/CRi rate after first induction was 89% and the overall CRc rate was 89%. Among the 11 older patients older than 60 years who achieved MRD-negative CR, the CR/CRi rate after first induction was 45% with an overall CRc rate of 45%.
Eunice S. Wang, MD:
Overall, the CRc rate was 75% or higher regardless of age group, sex, baseline FLT3 mutation status, ELN risk category, baseline white blood cell counts, or mutation subgroup, except for the subgroup of patients with TP53-mutant AML where neither of the 2 patients harboring this mutation achieved CRc.
Eunice S. Wang, MD:
Of 18 patients 60 years or younger with available data by multiparameter flow cytometry, the majority (88%) were MRD negative following induction. Of the 16 patients with available data by local testing using polymerase chain reaction/next-generation sequencing (NGS), 88% were FLT3-negative following induction.
Eunice S. Wang, MD:
Overall, crenolanib plus 7+3 chemotherapy did not induce significant AEs, with the most common AEs being gastrointestinal, which is an on-target effect for the mechanism of action of crenolanib. In total, 38 of 44 (84%) patients were able to continue to receive crenolanib at the full dose during the induction phase.
Eunice S. Wang, MD:
With a median follow‑up of 45 months, the median event‑free survival (EFS) and OS in patients 60 years of age or younger were not reached. Among patients older than 60 years, the median EFS and OS were 7.9 months and 19.7 months, respectively. In the subgroup of younger patients (60 years or younger), 71.4% were alive at 3 years, whereas only 33.3% were alive in the subgroup of older patients (older than 60 years).
The median OS for the entire patient population (n = 44) was not reached, and the cumulative incidence of relapse was 33.1%. Among patients 60 years or younger, the cumulative incidence of relapse was 13%. Of note, in this younger group of patients, there was no significant difference in the cumulative rate of relapse in those who underwent allogeneic hematopoietic SCT (12.5%) vs those who did not (14.3%).
Among patients who experienced relapse, no new FLT3 clones were acquired, and the majority of patients who experienced disease relapse (73%) did so without any evidence of FLT3-mutant disease at the time of recurrence.
Eunice S. Wang, MD:
This is one of the only available long‑term clinical trial results incorporating a potent FLT3 TKI in combination with intensive chemotherapy for younger and older patients with newly diagnosed FLT3-mutant AML. Of importance, high CRc rates ≥80% were observed regardless of age group with crenolanib plus intensive chemotherapy.
At the 2022 European Hematology Association meeting, data from the global, randomized, double-blind, placebo-controlled QuANTUM-First phase III trial of quizartinib plus induction and consolidation chemotherapy and as continuation therapy for 539 newly diagnosed patients aged 18 to 75 years with newly diagnosed FLT3-ITD–positive AML were presented.4 Compared with the global QuANTUM-First trial, this phase II trial of crenolanib plus 7+3 chemotherapy did not have a randomized control arm and much fewer patients were enrolled. Nevertheless, this small phase II study demonstrated that crenolanib is effective and the median OS was not reached even after a median follow-up of 45 months. In fact, the results with crenolanib may be comparable or even competitive with the results of the QuANTUM-First trial, which showed a median OS of 31.9 months with quizartinib vs 15.1 months with placebo (HR: 0.776; P = 0.0324) after a median follow-up of 39.2 months.3 Also, compared with the results of the phase I RATIFY trial of induction and consolidation chemotherapy plus midostaurin followed by maintenance midostaurin monotherapy for younger, newly diagnosed patients with AML, the CR rates observed in this phase II trial of crenolanib are more promising.5
Taken together, these studies suggest that, in the near future, midostaurin, a first-generation FLT3 TKI, may be replaced with 1 or both of these second-generation TKIs, crenolanib or quizartinib, based on the superior overall remission rates as well as improved EFS and OS data seen with these agents. In the next few years, it is anticipated that the field will be moving to this newer generation of TKIs for the treatment of FLT3-mutant AML in the first-line setting.
Eunice S. Wang, MD:
Clinical outcomes remain very poor for patients with AML harboring TP53 mutations.6 Patients with this particular genetic abnormality typically have disease that is refractory to all available first-line therapies or disease that recurs shortly after first‑line treatment, including venetoclax, azacitidine‑based therapies as well as intensive chemotherapy. The median OS for these patients is approximately 5-7 months.7
This has led to increased exploration of novel therapeutic approaches for patients with AML harboring TP53 mutations. A way to bypass the mechanisms of chemoresistance associated with TP53-mutant disease is to exploit other avenues to treat AML besides the conventional methods. A possible approach, which has garnered much interest in solid tumors as well as hematologic tumors, is immunotherapy. Available data with T‑cell checkpoint inhibition have been very disappointing, overall, in the treatment of myeloid malignancies. However, there is a lot of enthusiasm in looking at other pathways for myeloid malignancies, and 1 of these other pathways is to exploit the ability of host macrophages to identify and remove tumor cells.
Magrolimab is a monoclonal antibody that blocks CD47, an antigen that is overexpressed on AML cells and other cancer cells. The inhibition of CD47 causes macrophage‑mediated phagocytosis of tumor cells.8 The open-label, phase Ib trial investigated magrolimab alone or in combination with azacitidine as a frontline therapy for patients with AML (NCT03248479). At ASCO 2022, data from the AML expansion cohort of patients with disease harboring TP53 mutations were presented.9
Eunice S. Wang, MD:
Patients with previously untreated AML who are ineligible for or declined to receive standard induction therapy were enrolled on the study. The trial included dose evaluation and dose expansion phases. The study also included a dose expansion phase for patients with AML harboring TP53 mutations. Overall, 72 patients with TP53-mutated AML were included in the study.
Patients received intravenous magrolimab at a starting priming dose of 1 mg/kg, which was ramped up to 30 mg/kg weekly or biweekly as a maintenance dose. Azacitidine was administered at 75 mg/m2 on Days 1-7 of each 28-day cycle.
The primary endpoints of the study were safety, tolerability, and CR rate.
Eunice S. Wang, MD:
Of the 72 patients with TP53-mutated AML, the median age was 73 years (range: 31-89 years). According to the World Health Organization AML classification, 10%, 34%, and 15% of patients had recurrent genetic abnormalities, myelodysplastic-related changes, and AML related to previous chemotherapy or radiotherapy, respectively. Besides TP53 mutations, TET2, DNMT3a and IDH1/2 mutations were found in 11%, 7%, and 4% of patients, respectively. In general, the study is largely for an older subset of patients with poor cytogenetic features and with an overwhelmingly adverse risk classification.
Eunice S. Wang, MD:
The overall safety and tolerability profile of magrolimab in combination with azacitidine was fairly manageable. The were no magrolimab-related serious AEs leading to death.
Eunice S. Wang, MD:
The most common AEs observed in patients were those related to the underlying disease with an increased risk of neutropenia, febrile neutropenia, thrombocytopenia, and anemia. In total, 19% of the patients experienced pneumonia (any grade). Gastrointestinal AEs, including constipation, diarrhea, nausea, and appetite loss, were mostly low grade.
A unique toxicity observed in patients receiving CD47-directed therapy is hemolytic anemia, which normally occurs after the administration of the first or second dose. It is thought that this toxicity results because these agents target the expression of CD47 on older red blood cells.10 In this study, there was no grade 5 anemia, but 26.4% of patients experienced grade 3 anemia.
Eunice S. Wang, MD:
The efficacy of the combination was very impressive in this poor prognostic group, with approximately 50% of patients achieving an overall response, including a CR rate of 33.3%, of which one half were MRD negative.
Approximately one third of the patients converted to red blood cell transfusion independence and 45.8% of the patients converted to platelet transfusion independence. Nine patients (12.5%) proceeded to undergo SCT.
The median DoR was an impressive 8.7 months (95% CI: 6.5-10.4 months) and the median OS was 10.8 months (95% CI: 6.8-12.8 months).
Eunice S. Wang, MD:
The study showed clear evidence of antileukemic activity with significant decreases in bone marrow blasts in the majority of patients from baseline.
Eunice S. Wang, MD:
The combination of magrolimab with azacitidine appears to be superior to the current standard of care of venetoclax plus azacitidine for these patients. This is clinically significant. In the subgroup analysis of patients in the randomized phase III VIALE-A trial, OS was not significantly improved with the addition of venetoclax to azacitidine in patients with AML harboring TP53 mutations.11
The data with magrolimab/azacitidine in 72 patients with TP53-mutated AML appeared to show a superior median OS of over 10 months, and a median DoR of 8.7 months, which allowed a handful of patients (n = 9) to proceed to undergo SCT. These phase Ib data are encouraging and have led to the initiation of the phase III ENHANCE‑2 trial evaluating first-line magrolimab plus azacitidine vs the physician’s choice of venetoclax in combination with azacitidine or intensive chemotherapy for previously untreated patients with AML harboring TP53 mutations (NCT04778397).
In addition, early data suggest that triplet therapy with magrolimab, venetoclax, and azacitidine may even be more effective, with CR rates in excess of 80% in very small numbers of patients.12 These results have led to the initiation of a competing phase III trial: ENHANCE‑3 (NCT05079230). The ongoing phase III ENHANCE-3 trial is investigating venetoclax plus azacitidine with or without magrolimab for patients with AML with and without TP53 mutations.
The results from the ongoing phase III ENHANCE-2 and ENHANCE-3 trials are eagerly anticipated.
Eunice S. Wang, MD:
Approximately 8% to 19% of patients with AML harbor oncogenic IDH2 mutations.13 The most common variants are R140Q (~75%) and R172K (~25%), and these variants differ based on function and prognostic relevance.13-17 Most of the published work on IDH2 mutations and their prognostic value is from newly diagnosed patients with AML.13-18 Currently, very little is known about the relevance of IDH2 mutations in R/R AML.
Enasidenib is an oral, small-molecule inhibitor of mutant IDH2, and it is approved by the FDA for the treatment of patients with R/R AML harboring an IDH2 mutation.19 IDHENTIFY is a phase III trial of enasidenib vs conventional care in older patients with AML harboring IDH2 mutations (NCT02577406). At ASCO 2022, the subgroup analysis of efficacy and safety results of the IDHENTIFY trial in patients with AML harboring specific IDH2 mutational variants was reported.20,21
Eunice S. Wang, MD:
The IDHENTIFY trial enrolled older patients with IDH2-mutated de novo or secondary AML who had previously received 2 or 3 therapies for AML. In total, 319 patients 60 years or younger were randomized to receive either enasidenib monotherapy (n = 158) or investigator’s choice of conventional care treatment azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or best supportive care (n = 161). The conventional care regimen was preselected before randomization. The goal of the study was to determine whether enasidenib offered any advantage over azacitidine, cytarabine, or best supportive care in older patients with AML, and the primary endpoint was OS.
In the initial analysis previously presented for the entire patient population, the trial did not meet its primary endpoint and demonstrated no significant difference between enasidenib and conventional care regimens.22 Hence, the data presented at ASCO 2022 was a subgroup analysis of patients with AML harboring specific IDH2 mutational variants: R140 and R172.20,21
Eunice S. Wang, MD:
The baseline characteristics were fairly well balanced between treatment arms, even when analyzed by the specific IDH2 mutational variants.
Eunice S. Wang, MD:
In the subgroup of patients with the R140 IDH2 variant, there was no significant difference in the median OS, which was 5.7 months in each treatment arm (HR: 0.93; 95% CI: 0.70-1.24; P = .612). However, the data demonstrated significant differences in other efficacy outcomes, including ORR, which was 36.5% with enasidenib vs 11.4% with the conventional care regimens (odds ratio: 4.3; 95% CI: 2.2-8.6; P <.0001). The CR rate was also significantly higher with enasidenib compared with conventional care regimens at 18.3% vs 3.5% (P = .0005). The median time to treatment failure (TTF) was significantly longer with enasidenib vs conventional care regimens at 4.3 months vs 1.6 months (HR: 0.63; 95% CI: 0.48-0.83; P <.001).
Eunice S. Wang, MD:
In the subgroup of patients with the R172 IDH2 variant, the benefits were more pronounced. There was a significant improvement in the median OS in favor of enasidenib compared with the conventional care regimens at 14.6 vs 7.8 months (HR: 0.59; 95% CI: 0.35-0.98; P = .039). The ORR was an impressive 51.2% with enasidenib compared with 6.7% with conventional care regimens (odds ratio: 15.0; 95% CI: 3.9-56.9; P <.0001). The CR rate was 37.2% vs 4.4% with enasidenib and conventional care regimens, respectively (P = .0001). Also, the median TTF was significantly longer with enasidenib vs conventional care regimens at 7.5 vs 2.2 months (HR: 0.30; 95% CI: 0.19-0.49; P <.001).
Eunice S. Wang, MD:
The median treatment duration was substantially longer with enasidenib (142 days) compared with conventional care regimens (36 days). There were no significant differences in the toxicities experienced by patients in both IDH2 variant groups.
Eunice S. Wang, MD:
These results suggest that the selective use of enasidenib for patients with R/R AML who have failed multiple previous lines of therapy may play an important role in treatment outcomes.
Patients harboring the R172 IDH2 mutation may be particularly more likely to experience a prolonged OS with enasidenib as opposed to those with AML harboring the R140 IDH2 mutation. At present, it is not clear whether there will be a redefinition of patients with R/R AML who would be eligible to receive enasidenib. Certainly, however, the results from this subgroup analysis have clinical implications and can be used to predict the response to targeted treatment with enasidenib.
Eunice S. Wang, MD:
MRD positivity is associated with an increased risk of relapse and poor prognosis in patients with AML in cytomorphologic CR before allogeneic hematopoietic cell transplantation (alloHCT).23,24 It is known that all patients with AML who achieve a CR are not equal, and as a result of non‑standardized MRD testing approaches, patients who achieve MRD negativity by any method, whether it be by molecular or flow cytometric analysis, have a much better prognosis than those who are MRD positive. The lack of standardization of MRD testing approaches and unknowns regarding the generalizability of single-center data are some of the reasons why MRD testing has not been widely adopted in the management of patients with AML. The Pre-MEASURE trial evaluated the utility of central pre-alloHCT MRD testing by NGS in patients with AML.25
Eunice S. Wang, MD:
Pre-MEASURE is a retrospective multisite analysis of 1075 patients with AML in their first CR (CR1) who underwent first alloHCT from 2013 to 2017. All patients had archived blood samples collected within 100 days pre-alloHCT. The study used samples reported to the Center for International Blood and Marrow Transplant Research as harboring FLT3, NPM1, IDH1, IDH2, and/or KIT mutations pre-alloHCT. There were 2 cohorts: initial series (cohort 1) and the validation series (cohort 2).
The investigators examined the prognostic value of MRD detection by NGS, in correlation with the presence of specific mutations, on relapse rate, nonrelapsed mortality, relapse-free survival (RFS), and OS.
Eunice S. Wang, MD:
In the initial series (cohort 1), results from 454 patients were analyzed. The baseline characteristics of the patients in the initial series were fairly representative of patient characteristics for an overall general population of patients with AML.
Eunice S. Wang, MD:
In cohort 1, the primary focus was on specific mutations detected by NGS-MRD pre-alloHCT, including FLT3-ITD, FLT3-TKD, NMP1, KIT, and IDH1/2 mutations.
Eunice S. Wang, MD:
In cohort 1, the detection of MRD prior to alloHCT was prognostic and specific gene mutations had different implications in terms of clinical outcomes, including RFS, relapse rate and OS.
Eunice S. Wang, MD:
MRD detection by NGS for FLT3-ITD mutation–positive and NPM1 mutation–positive AML was associated with poor clinical outcomes with respect to the risk of relapse (P <.0001) and OS (P <.0001). However, the detection of residual IDH1 or IDH2 mutations was not associated with increased relapse risk, potentially because these mutations do not contribute in a meaningful way to subsequent aggressive relapse. This, however, is yet to be definitively ascertained.
Eunice S. Wang, MD:
MRD testing by NGS was prognostic in patients aged younger than 60 years (P <.0001) as well as those aged older than 60 years (P <.0001). Also, the conditioning regimen was prognostic for OS (P <.0001).
Eunice S. Wang, MD:
The risk of relapse was significantly higher in patients who received reduced-intensity conditioning (RIC) with a non-melphalan agent (RIC-other) compared with those who received RIC with melphalan in MRD-negative patients (P = .015) and MRD-positive patients (P = .002). In particular, the OS was significantly improved with RIC with melphalan compared with RIC-other in MRD-positive patients (P = .012). However, in MRD-negative patients, there was no significant difference in OS with RIC-other compared with RIC with melphalan.
Eunice S. Wang, MD:
Pre-MEASURE demonstrates that not all mutations at the time of AML diagnosis and remission carry the same prognostic significance. So, in terms of MRD detection according to mutational status, it is important to recognize that only some mutations have prognostic utility, while others are irrelevant. These results also suggest that there may be some relationships between the intensity of the conditioning regimen and the subsequent outcomes in patients who undergo alloHCT. The caveat is that these are early results that require further validation in additional patients. Nonetheless, these results could help to set a baseline for the standardization of MRD detection with respect to the presence or absence of some of these mutations for prognostication purposes in AML in the near future.
As higher remission rates are achieved with targeted therapies and novel combination approaches, the ability to reliably detect MRD and be able to predict those patients who will need additional therapy vs those who will not will become increasingly important for the appropriate development and use of targeted and nontargeted therapies.
Eunice S. Wang, MD:
In older patients with ALL, the median OS is low at 5-10 months and complicated by the presence of more aggressive disease and underlying pre-existing comorbidities that preclude curative treatments.26,27 In older, unfit patients who are newly diagnosed with Philadelphia chromosome (Ph)–negative B‑cell ALL, a regimen consisting of inotuzumab ozogamicin (INO), a CD22-directed antibody-drug conjugate, in combination with mini-hyper-CVD has earned a significant amount of interest among clinicians as an upfront treatment.27 The addition of blinatumomab, an anti-CD19/CD3 bispecific monoclonal antibody, to INO and mini-hyper-CVD may deepen responses, reduce the need for chemotherapy, and avoid the toxicities associated with chemotherapy. It may even result in improvements in treatment-related mortality in this patient population.26
Updated results from the phase II trial evaluating INO plus mini-hyper-CVD with or without blinatumomab in older adults with newly diagnosed Ph-negative B-cell ALL were reported at ASCO 2022.28
Eunice S. Wang, MD:
Patients (N = 80) aged 60 years or younger with newly diagnosed Ph-negative B-cell ALL were enrolled on the open-label phase II study. All patients received mini-hyper-CVD for up to 8 cycles. Initially, INO was given in fractionated doses for 4 cycles. Rituximab was added for patients with CD20-positive disease with prophylactic intrathecal chemotherapy for the first 4 cycles. Responding patients received mercaptopurine/vincristine/methotrexate/prednisone (POMP) maintenance for up to 3 years.
Starting with patient 50, INO was given in fractionated doses in each of 4 cycles followed by 4 cycles of blinatumomab in the consolidation phase followed by maintenance therapy with 12 cycles of POMP and 4 cycles of blinatumomab.
Eunice S. Wang, MD:
The median age of the patients was 68 years (range: 60-87 years), with 30 (38%) of the patients aged 70 years or older. All patients had disease expressing both CD19 and CD22 at the time of diagnosis.
Eunice S. Wang, MD:
With a median long-term follow-up of 55 months, the patient disposition and rate of veno-occlusive disease were highly encouraging. Of note, veno-occlusive disease occurred in 6 patients only, with 1 event after SCT.
Eunice S. Wang, MD:
Among 74 evaluable patients, 73 (99%) achieved an overall response, with 89% achieving a CR and 9% achieving a CR with partial hematologic recovery or CRi. By Day 21 of cycle 1, 80% of the patients were MRD negative by flow cytometry and 94%, overall, were MRD negative at any time point.
Eunice S. Wang, MD:
The OS outcome was highly encouraging, with a 5-year OS rate of 47% in all patients. The highest 5-year OS rate of 69% was observed in patients aged 60-69 years with nonpoor cytogenetic risk.
Eunice S. Wang, MD:
The clinical significance of this study is in the extremely high ORRs as well as the highest 5-year OS rate that has ever been seen in this older patient population. This regimen, which includes a low-intensity chemotherapy backbone and 2 targeted agents may soon become the new standard of care for the treatment of older patients with newly diagnosed Ph-negative B-cell ALL.
Certainly, there are limitations regarding the interpretation of these results in that the data are from a single center, and these results will need to be recapitulated in other academic centers to determine whether these astonishingly high ORR and OS rates can be replicated. However, many are increasingly looking at this mini‑hyper-CVD backbone added to targeted therapies as an approach that gives older patients with newly diagnosed Ph-negative B-cell ALL the greatest survival benefit in the current era.
Studies through cooperative groups are planned to address this question in a randomized trial on which newly diagnosed patients with Ph‑negative B-cell ALL will receive this regimen vs other standards of care to facilitate the approval and use of the mini-hyper-CVD plus INO plus blinatumomab regimen as a standard of care in the next few years.
Eunice S. Wang, MD:
Ponatinib is a pan–BCR-ABL TKI with demonstrated activity against the BCR-ABL T315I mutation, which is a common mechanism of TKI resistance in Ph-positive ALL.29 The combination of ponatinib with hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) previously demonstrated a 3-year EFS rate of 70% in patients with newly diagnosed Ph-positive ALL.30 Also, in patients with Ph-positive ALL, blinatumomab previously demonstrated activity as a monotherapy in the R/R setting and in combination with dasatinib in the newly diagnosed setting.31,32
The results from a phase II trial of ponatinib in combination with blinatumomab for patients with Ph-positive ALL were presented at ASCO 2022.33
Eunice S. Wang, MD:
In total, 55 patients with newly diagnosed or previously treated Ph-positive ALL or lymphoid accelerated phase/blast phase chronic myeloid leukemia (CML) were enrolled on the single-arm, phase II study. All patients received treatment in 3 phases: induction, consolidation, and maintenance. All patients received 30 mg daily of ponatinib in cycle 1, which was reduced to 15 mg daily once the patient achieved a complete molecular response (CMR). All patients received up to 5 cycles of blinatumomab. After the completion of blinatumomab, ponatinib was continued for ≥5 years. All patients also received 12 doses of intrathecal chemotherapy. The primary endpoints were CMR rate, RFS, EFS, and OS.
Eunice S. Wang, MD:
The patient population was somewhat younger, with a median age of 57 years (range: 22-83 years) in patients with newly diagnosed Ph-positive ALL, 38 years (range: 24-61 years) in patients with R/R Ph-positive ALL, and 69 years (range: 29-82 years) in patients with or without lymphoid accelerated phase/blast phase CML.
Eunice S. Wang, MD:
The overall CR/CRi rates across all patient groups were impressive. The CR/CRi rate in all patients was 93% with a CRi rate of 7%. The CR/CRi rate was 96%, 92%, and 83% in the subgroups of patients with newly diagnosed Ph-positive ALL, R/R Ph-positive ALL, and CML, respectively. Very few early deaths occurred among patients with newly diagnosed Ph-positive ALL (n = 1) and no early deaths occurred in the population of patients with R/R Ph-positive ALL or those with CML.
Eunice S. Wang, MD:
In the subgroup of patients with R/R Ph-positive ALL, preliminary data suggest that 6 of 14 patients proceeded to undergo hematopoietic SCT. In the subset of patients with newly diagnosed Ph-positive ALL, 32 of 35 patients have ongoing responses without undergoing hematopoietic SCT.
Eunice S. Wang, MD:
Across all subgroups of patients, the median OS has not been reached, and the 2-year OS rate was 93%, 61%, and 60% in patients with newly diagnosed Ph-positive ALL, R/R Ph-positive ALL, and CML, respectively. The 2-year EFS rate was 93%, 42%, and 33% in patients with newly diagnosed Ph-positive ALL, R/R Ph-positive ALL, and CML, respectively.
Eunice S. Wang, MD:
These results show that in the population of patients with Ph‑positive ALL, both in the newly diagnosed and R/R settings, it is possible to achieve extremely high ORRs and OS rates at 2 years without ever using conventional chemotherapy. This regimen, consisting only of a TKI (ponatinib) and an anti-CD19/CD3 bispecific antibody, may open the door for the consideration of nonchemotherapy regimens in patients with Ph-positive ALL or lymphoid accelerated phase/blast phase CML.
Again, this study is limited by the fairly small numbers of patients on the trial and by the fact that it is a phase II trial performed at a single center. There are planned cooperative group studies to examine chemotherapy‑free regimens in these disease settings for younger and older patients.
Eunice S. Wang, MD:
Asciminib is a first-in-class STAMP inhibitor, which targets a myristoyl site of the BCR‑ABL protein.34,35 It is the only TKI targeting this specific mechanism of action in patients with BCR‑ABL mutation–positive myeloid malignancies.
The phase III ASCEMBL trial is evaluating asciminib vs bosutinib in previously treated CML-CP (NCT03106779). Primary analysis of results from the ASCEMBL trial after a median follow-up of 14.9 months, demonstrated superior efficacy and favorable safety with asciminib compared with bosutinib.35,36 These results led to the recent FDA approval of asciminib for the treatment of patients with Ph-positive CML-CP who have previously received ≥2 TKIs. Also, based on the results of the multicenter phase I CABL001X2101 trial, asciminib received FDA approval for adults with Ph-positive CML-CP harboring the BCR-ABL T315I mutation (NCT02081378).
Long-term safety and efficacy data from ASCEMBL for patients who have been followed for a median of 2.3 years (16.5 months of additional follow-up since primary analysis) were reported at ASCO 2022.37
Eunice S. Wang, MD:
ASCEMBL is a multicenter, open‑label, randomized phase III trial for adult patients with CML-CP who are resistant or intolerant to ≥2 TKIs. Patients who are intolerant to previous TKI therapy with BCR-ABL1IS >0.1% were allowed on the study. Patients with CML-CP harboring the T315I or V299L BCR-ABL mutations were not eligible for enrolment on the study. Randomization was stratified by major cytogenetic response status at baseline. Patients (N = 233) were randomly assigned to receive either asciminib (n = 157) or bosutinib (n = 76) for up to 96 weeks after the last dose or 48 weeks after the last patient switched to asciminib, depending on which was longer. The primary endpoint was the MMR rate at Week 24.
Eunice S. Wang, MD:
Updated results at 96 weeks reveal that 84 (53.5%) patients on the asciminib arm remain on treatment, whereas only 15 (19.7%) patients on the bosutinib arm remain on treatment. Of note, 72 (45.9%) patients had discontinued asciminib, whereas 61 (80.3%) patients had discontinued bosutinib at Week 96. The most common reason for the discontinuation of treatment was the lack of efficacy that occurred in 38 (24.2%) patients on the asciminib arm vs 27 (35.5%) patients on the bosutinib arm. AEs leading to discontinuation occurred in only 11 (7%) patients on the asciminib arm compared with 19 (25%) patients on the bosutinib arm.
Eunice S. Wang, MD:
At Week 96, 37.6% of patients on the asciminib arm achieved an MMR compared with only 15.8% of patients on the bosutinib arm (P = .001). The cumulative incidence of an MMR at Week 96 was 41.2% on the asciminib vs 22.6% on the bosutinib arm.
Eunice S. Wang, MD:
Across all endpoints, asciminib demonstrated superior clinical activity compared with bosutinib. The percentage of patients who achieved BCR-ABLIS ≤1%, MR4 and MR4.5 rates at Week 96 were significantly higher with asciminib compared with bosutinib.
Eunice S. Wang, MD:
AEs leading to discontinuation occurred much less with asciminib (7.7%) vs bosutinib (26.3%). Similarly, AEs leading to dose adjustments or interruptions occurred less with asciminib (42.3%) vs bosutinib (64.5%).
Gastrointestinal AEs including diarrhea, nausea, and vomiting occurred at a higher frequency with bosutinib compared with asciminib. All-grade and grade ≥3 thrombocytopenia and anemia were more frequent in the asciminib arm compared with the bosutinib arm. However, more patients on the bosutinib arm experienced dermatologic toxicities (rash). The median duration of exposure to asciminib was 23.7 months (range: 0-46.2 months) compared with 7.0 months (range: 0.2-43.3 months) on the bosutinib arm.
Eunice S. Wang, MD:
Of note, the incidence of arterial occlusive events experienced by patients on both arms of the study was relatively low considering that twice as many patients were randomly assigned to the asciminib arm compared with the bosutinib arm. On the asciminib arm 8 patients experienced arterial occlusive events vs only 1 patient on the bosutinib arm. The arterial occlusive events on the asciminib arm included myocardial ischemia, coronary artery disease, ischemic stroke, and mesenteric artery embolism/thrombosis. The only arterial occlusive event experienced on the bosutinib arm was acute coronary syndrome.
Eunice S. Wang, MD:
Thrombocytopenia, neutropenia, and anemia mostly occurred within the first 6 months of treatment with asciminib, with some persistence beyond 18 months of presentation. Conversely, most nonhematologic AEs with asciminib occurred during the first 6 months of therapy and rarely persisted beyond the initial period of presentation.
Eunice S. Wang, MD:
The long‑term follow-up data of the ASCEMBL trial continued to favor asciminib over bosutinib in terms of treatment efficacy, rate of treatment discontinuation, and incidence of AEs. These data validate the clinical utility of asciminib in this patient population and support current ongoing trials examining asciminib in the frontline setting (NCT05143840).
The current FDA approval of asciminib is for patients who have failed 2 or more previous TKIs, but we will need to wait and see how this agent is sequenced in terms of how clinicians choose when and where to use asciminib. Of note, previous studies have shown that patients receiving asciminib can overcome resistance to BCR-ABL1–directed therapies, but its use may lead to the development of other mutations based on its unique mechanism of action.38 So, where asciminib optimally fits in the treatment algorithm for patients with R/R CML-CP is still unclear.
In the current era, there are many TKIs available for patients with CML-CP. The selection of specific TKIs in the community or academic practice often depends on individual patients and the underlying pre-existing medical conditions. Where asciminib fits and whether it will be used preferentially over the other available TKIs, based on its safety profile and/or its mutational profile in terms of the development of resistance, still remains to be seen.
Eunice S. Wang, MD:
Overall, at ASCO 2022, results from studies of multiple novel targeted approaches for the treatment of acute and chronic leukemias were presented. In AML, data supporting the use of newer-generation FLT3 inhibitors, CD47-targeted immunotherapy, and the importance of specific IDH2 mutations in the selection of enasidenib over conventional care regimens were presented.3,9,20,21 There was also an important study looking at molecular NGS-MRD and specific mutations with prognostic utility as we move potentially forward with this NGS-MRD as a new standard of care in guiding the selection and treatment of patients with AML in the future.25
In adult patients with Ph-negative ALL, the studies on the further development and incorporation of INO and blinatumomab into the frontline treatment setting demonstrated impressive response rates.28 This study also suggests that intensive chemotherapy can now be reduced or even eliminated as targeted therapies replace and supplant conventional chemotherapy regimens for the first time for the treatment of adults with ALL. Similarly, a combination of targeted therapies using blinatumomab and ponatinib elicited high activity in patients with Ph-positive ALL.33
Finally, the novel BCR‑ABL TKI asciminib, which targets a novel site of the BCR‑ABL protein, was further validated in a long-term follow-up analysis.37 Unlike the other BCR‑ABL–directed agents that are currently available, asciminib has the potential to open up new avenues to treat patients with CML-CP, and it will be interesting to see whether asciminib moves forward into the frontline setting.
In summary, overall, ASCO 2022 emphasized the importance and, in some cases, the superiority and efficacy of targeted therapies, in general, for the treatment of both acute and chronic leukemias.
Back
