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Key Studies in Hematologic Malignancies: Independent Conference Coverage of the 2021 ASCO Scientific Meeting
  • CME

Ian W. Flinn, MD, PhD
Shaji K. Kumar, MD
Eunice S. Wang, MD
Released: September 13, 2021

Leukemias

Enasidenib in High-Risk IDH2-Mutated MDS: Background

Eunice S. Wang, MD:
Approximately 5% to 10% of patients diagnosed with MDS have IDH2 mutations. Enasidenib is a selective oral inhibitor of the mutant IDH2 enzyme indicated as single‑agent therapy for R/R IDH2‑mutated AML. The response rate to enasidenib is approximately 40%, and median OS is 8.8 months in patients with IDH2-mutated AML.18

Patients with R/R MDS have a response rate of 53% and a median OS of 16.9 months with enasidenib.19 The current study evaluated the efficacy and tolerability of enasidenib as monotherapy or in combination with azacitidine in patients with higher‑risk IDH2‑mutated MDS.20

Enasidenib in High-Risk IDH2-Mutated MDS: Study Design

Eunice S. Wang, MD:
The study is an ongoing, multicenter, open‑label phase II trial and enrolled 25 hypomethylating agent (HMA)-naive patients with higher‑risk MDS/CMML or low blast count AML into arm A and 21 patients with R/R MDS after prior HMA therapy into arm B.20 Patients in arm A received azacitidine IV or SC at standard dosing on Days 1-7 and enasidenib 100 mg PO on Days 1-14 of 28‑day cycles. Patients in arm B received enasidenib 100 mg PO continuously on 28-day cycles.

The primary endpoint of the study was ORR defined by CR, marrow CR, PR, and hematologic improvement, with additional endpoints of safety and survival outcomes.

Enasidenib in High-Risk IDH2-Mutated MDS: Baseline Characteristics

Eunice S. Wang, MD:
The median age of patients was 73 years, although the frequency of patients 65 years of age and older was higher in patients assigned to receive enasidenib alone (86% vs 68%).20 Of note, 52% of patients in the monotherapy group were red blood cell transfusion dependent, and most patients (52%-68%) in each arm had high or very high risk disease by the Revised International Prognostic Scoring System.

Enasidenib in High-Risk IDH2-Mutated MDS: Efficacy

Eunice S. Wang, MD:
The combination of azacitidine and enasidenib induced a high ORR, with 84% of patients in the combination arm achieving some response, but enasidenib monotherapy induced an ORR in 43% of patients.20 The difference in ORR between the arms was largely the result of significantly higher molecular CR in the combination arm (44% vs 5%).

The time to first response was approximately 1 month in both arms, and time to best response was 1.6 months in the combination arm and 4.6 months in the enasidenib monotherapy arm. At a median of 12.6 months of follow-up, median OS was 32.2 months for azacitidine plus enasidenib and 21.3 months for enasidenib alone.

Enasidenib in High-Risk IDH2-Mutated MDS: Safety

Eunice S. Wang, MD:
Eight patients (17%) in this study developed differentiation syndrome, with a median time to onset of 1.4 months in patients receiving azacitidine plus enasidenib and 1.2 months in patients receiving enasidenib.20

Of the 6 patients who had grade 3 differentiation syndrome, 5 successfully received steroids, and the remaining patient received hydroxyurea and had AML progression. All patients with differentiation syndrome had leukocytosis, with a median white blood cell count of 28.3 x 109/L.

Enasidenib in High-Risk IDH2-Mutated MDS: Conclusions

Eunice S. Wang, MD:
This study confirmed the efficacy of azacitidine plus enasidenib in patients with IDH2‑mutant disease. In patients who had IDH2-mutated MDS, the combination of azacitidine and enasidenib led to an ORR of 84%, a marked improvement over the 43% ORR seen in patients receiving enasidenib monotherapy.20 Of note, enasidenib monotherapy was effective in patients with R/R MDS when used sequentially after HMA therapy.

The data suggest that the combination of IDH2 inhibitors and HMA therapies induce high responses in HMA-naive patients with higher‑risk MDS/CMML or low blast count AML. This approach should be further explored, particularly in patients who are older or who have high‑risk disease and are ineligible for stem cell transplant (SCT) or more aggressive treatment approaches.

Phase Ib/II of Ivosidenib and Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies: Background

Eunice S. Wang, MD:
IDH mutations promote leukemogenesis and increase BCL-2 dependency, and have been identified in approximately 20% of patients with AML.21-23 Preclinical models suggest that IDH1/2 mutations may enhance susceptibility of aberrant myeloid cells to the BCL-2 inhibitor venetoclax. Ivosidenib is an IDH1 inhibitor with demonstrated efficacy as a monotherapy for R/R and ND AML.24-25

This is an interim analysis of safety and efficacy from a currently enrolling phase Ib/II dose-escalation study of ivosidenib and venetoclax with or without azacitidine in patients with ND or R/R IDH1‑mutant myeloid malignancies.26

Phase Ib/II of Ivosidenib and Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies: Study Design

Eunice S. Wang, MD:
This phase Ib/II study has a 3 x 3 dose-escalation/de-escalation design and is enrolling adult patients with ND AML, R/R AML, advanced MDS, or myeloproliferative neoplasms (MPN) with a documented IDH1R132 mutation.26

Patients in all 4 treatment arms receive ivosidenib 500 mg PO QD continuously starting on Day 15 of cycle 1 and venetoclax 400 mg or 800 mg daily on Days 1-14 of each 28-day cycle. The third and fourth cohorts of patients also receive azacitidine 75 mg/m2 daily on days 1-7 of each cycle.

The primary objectives are safety, tolerability, maximum tolerated dose (MTD), and ORR in the expansion cohort. Secondary objectives include OS, event-free survival (EFS), and pharmacokinetics. The current analysis includes data from the first 3 cohorts, as the fourth cohort is still enrolling.

Phase Ib/II of Ivosidenib and Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies: Baseline Characteristics

Eunice S. Wang, MD:
The median age of enrolled patients was 67 years; 13 patients (52%) had ND AML, 8 (32%) had R/R AML, and 4 (16%) had MDS or MPN.26 In total, 13 patients (52%) were classified as adverse risk by European LeukemiaNet guidelines.

Phase Ib/II of Ivosidenib and Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies: Safety

Eunice S. Wang, MD:
Four cases of IDH differentiation syndrome were reported among the 25 enrolled patients: 2 in the cohort receiving ivosidenib plus venetoclax 400 mg, 1 in the cohort receiving ivosidenib plus venetoclax 800 mg, and 1 in the cohort receiving triplet therapy.26 One study death was reported due to pneumonia.

Phase Ib/II of Ivosidenib and Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies: Efficacy Outcomes

Eunice S. Wang, MD:
Four patients (67%) in the ivosidenib plus venetoclax 400-mg arm achieved composite CR vs 6 (100%) in the ivosidenib plus venetoclax 800-mg arm and 11 (85%) in the arm receiving ivosidenib, venetoclax 400 mg, and azacitidine.26 A CR was achieved in 3 patients (50%) in each of the doublet therapy arms and 7 patients (54%) in the triplet therapy arm. The difference in the composite CR rate was influenced by 1 patient (17%) achieving a CRi in each of the doublet arms.

Median OS was impressive: 9 months in patients receiving ivosidenib plus venetoclax 400 mg and not yet reached in patients receiving ivosidenib plus venetoclax 800 mg or patients receiving triplet therapy. Median DoR also was impressive; patients receiving ivosidenib and venetoclax 400 mg had a median DoR of 13 months vs 7 months in patients receiving ivosidenib and venetoclax 800 mg, and NR in patients receiving triplet therapy.

Phase Ib/II of Ivosidenib and Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies: Subgroup Outcomes

Eunice S. Wang, MD:
Improved survival correlated with MRD negativity. Patients with AML who achieved MRD negativity had a 12‑month OS of 100% vs 33% in patients who remained MRD positive (P = .0052).26 The OS rate at 12 months was 50% for patients with R/R AML, 76% for patients with ND AML, and 100% for patients with MDS or MPN. Overall, 71% of patients were alive at 12 months.

Phase Ib/II of Ivosidenib and Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies: Conclusions

Eunice S. Wang, MD:
These data are limited by the small number of enrolled patients but suggest that the combination of ivosidenib and venetoclax is highly effective in patients with IDH1-mutated disease and can be safely administered.26 The addition of azacitidine may further improve outcomes, particularly in patients with R/R disease. Moving forward, these combination regimens may be employed in different patient subgroups to further improve outcomes in the ND and R/R disease settings.

Ven + Aza vs Aza for tAML or AML From Antecedent MDS/CMML: Background

Eunice S. Wang, MD:
Patients with sAML arising from therapy, MDS, or CMML have a poorer prognosis compared with patients with primary AML.27 These patients frequently have a complex karyotype or TP53 mutations, which make them particularly challenging to treat.

The gold standard regimen to treat older, unfit patients with AML remains venetoclax plus azacitidine based on data from the phase III VIALE‑A trial.28 In a pooled analysis presented at ASCO 2021, investigators evaluated the efficacy and safety of venetoclax plus azacitidine vs azacitidine alone in a subset of patients with tAML or AML developing from antecedent MDS or CMML.29

Ven + Aza in sAML: Study Design

Eunice S. Wang, MD:
All patients were treatment naive and ineligible for intensive chemotherapy.29 Patients with prior exposure to HMAs, history of MPNs, or favorable-risk cytogenetics were excluded, and patients with antecedent MDS or CMML were included. The key evaluated outcomes were CR/CRi, CR/CR with partial hematologic recovery, DoR, and OS.

Ven + Aza in sAML: Baseline Characteristics

Eunice S. Wang, MD:
In total, 40 patients had tAML, and 85 patients had antecedent MDS/CMML.29 Among patients with tAML, 18 patients (58%) who received venetoclax plus azacitidine had poor-risk cytogenetics at baseline vs 6 patients (67%) who received azacitidine alone. Of the patients with antecedent MDS/CMML, 19 patients (32%) who received venetoclax plus azacitidine had poor-risk cytogenetics at baseline vs 13 patients (50%) who received azacitidine alone.

Ven + Aza in sAML: Response Rates, DoR, OS

Eunice S. Wang, MD:
Response data were encouraging, with 19 patients (61.3%) who had tAML achieving CR/CRi with venetoclax plus azacitidine vs 1 patient with azacitidine alone.29 Similarly, 39 patients (66.1%) with antecedent MDS/CMML achieved CR/CRi with venetoclax plus azacitidine vs 7 patients (26.9%) with azacitidine alone.

Median OS trended toward improvement with combination therapy vs monotherapy, with tAML patients having a median OS of 16.4 months with combination therapy vs 11.1 months with monotherapy (HR: 0.64; 95% CI: 0.27-1.53; P = .31). In patients with antecedent MDS/CMML, median OS was 15.9 months with combination therapy vs 10.1 months with monotherapy (HR: 0.57; 95% CI: 0.33-1.00; P = .05). These numbers reflect the overall CR/CRi rates and are similar to the median survival benefit seen for all patients enrolled in the VIALE‑A trial.

Ven + Aza in sAML: CR/CRi Response by Subgroup

Eunice S. Wang, MD:
Among patients with TP53 mutations, venetoclax plus azacitidine treatment resulted in a 50% to 60% CR/CRi rate, which was encouraging.29 There also was evidence that patients with intermediate-risk cytogenetics had increased benefit from combination therapy: In patients with tAML, 92% of patients with intermediate-risk cytogenetics achieved CR/CRi vs 44% of patients with poor-risk cytogenetics, and patients who had antecedent MDS/CMML and intermediate-risk cytogenetics had a 70% rate of CR/CRi vs 58% in patients with poor cytogenetic risk.

Ven + Aza in sAML: Safety

Eunice S. Wang, MD:
Venetoclax plus azacitidine was associated with an increased rate of grade ≥3 febrile neutropenia and leukopenia, but otherwise there was no evidence of additional safety concerns with combination therapy over monotherapy.29

Ven + Aza in sAML: Conclusions

Eunice S. Wang, MD:
Venetoclax plus azacitidine appears to be effective regardless of the cause of sAML, and the benefit paralleled what was seen in the overall patient population in the VIALE‑A trial.29 Moving forward, healthcare professionals will need to consider these data when determining whether patients with sAML would benefit more from venetoclax plus azacitidine than 7 + 3 induction therapy. Clinical trials of venetoclax plus azacitidine in younger patients with sAML are ongoing. The treatment of sAML after HMA therapy, as well as patients with p53 mutant disease in conjunction with complex karyotype, remains suboptimal. Further studies to address whether these patients would benefit from receiving alternate therapy or clinical trial agents for their disease are still needed.

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: Background

Eunice S. Wang, MD:
MRD status following intensive induction and consolidation chemotherapy for AML is now well established as a key prognostic factor independently predicting OS, relapse-free survival (RFS), and transplant outcomes. However, it is unclear whether MRD status is similarly prognostic in patients receiving a lower-intensity upfront regimen such as venetoclax plus azacitidine. This study examined the clinical significance of MRD status in treatment-naive older and/or unfit patients with AML enrolled on the VIALE‑A phase III trial. These patients were ineligible for standard induction therapy due to age (75 years and older) and/or comorbidities and were randomized to receive venetoclax plus azacitidine or azacitidine alone as upfront therapy.28,30

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: Study Design

Eunice S. Wang, MD:
MRD response was defined as ≤1 residual leukemic blast per 1000 leukocytes.30 Bone marrow aspirates were collected at screening, the end of cycle 1, and after every 3 cycles thereafter until CR/CRi was confirmed. MRD analysis was performed centrally by multiparameter flow cytometry using integrated leukemia‑associated immunophenotypes and different-than-normal procedures. In this study, MRD status was evaluated in association with key outcomes (CR/CRi, DoR, EFS, and OS) in patients receiving venetoclax plus azacitidine on clinical trial.

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: Baseline Characteristics

Eunice S. Wang, MD:
The baseline characteristics of patients were similar regardless of MRD status, with a similar frequency of patients having de novo AML and sAML.30 Frequency of molecular mutations also were approximately equivalent, apart from a higher frequency of NPM1-mutated disease in patients with MRD <10-3.

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: DoR

Eunice S. Wang, MD:
Results showed that MRD status was highly predictive for DoR, with 81.2% of patients with a CR/CRi and MRD <10-3 having a durable response at 12 months compared with 46.6% of patients with MRD ≥10-3. At 18 months, these numbers were 69.6% and 33.5%, respectively.30 Median DoR was NR in patients with MRD <10-3 and was 9.7 months in patients with MRD ≥10-3. All of these differences were statistically significant.

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: EFS

Eunice S. Wang, MD:
Similar data were achieved for EFS. Patients with MRD <10-3 had a median EFS that was NR compared with 10.6 months in patients with MRD ≥10-3.30 Significant differences favoring MRD negativity also were seen at 12 and 18 months.

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: OS

Eunice S. Wang, MD:
Of importance, survival curves also significantly differed based on MRD status. At 12 months, 94.0% of patients with MRD <10-3 were alive compared with 67.9% of patients with MRD ≥10-3. At 18 months, these numbers were 84.6% vs 50.1%, respectively.30 The median OS in patients with MRD <10-3 was NR compared with 18.7 months in patients with MRD ≥10-3. Achievement of MRD <10-3 was highly associated with OS (HR: 0.285; P <.001), as was high cytogenetic risk (HR: 2.062; P = .004).

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: Time to MRD Response

Eunice S. Wang, MD:
The investigators also evaluated the frequency of patients who achieved MRD <10-3 after subsequent therapy.30 By the end of cycle 1, 25% of patients with CR/CRi had MRD <10-3. By the end of cycle 4, an additional 27% of patients in CR had MRD <10-3. After 7 cycles, a further 27% of patients reached this threshold, and after cycle 7, all remaining patients in CR/CRi had achieved MRD <10-3.

These data must be interpreted with some caution because patients no longer in remission were removed from subsequent analysis, thereby accounting for 100% of patients being MRD negative after 7 cycles. Nevertheless, these data do suggest that additional rounds of venetoclax plus azacitidine may induce deeper responses in some patients, and these MRD-negative responses still correlate with OS.

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: Safety

Eunice S. Wang, MD:
Patients had similar rates of grade ≥3 AEs regardless of MRD status, with neutropenia, febrile neutropenia, and thrombocytopenia being the most common.30

MRD Status and Prognosis With Ven + Aza in Treatment-Naive AML: Conclusions

Eunice S. Wang, MD:
This study found that MRD status is predictive of DoR, EFS, and OS in patients with previously untreated AML ineligible for intensive induction therapy who received venetoclax plus azacitidine in the VIALE-A trial.30 MRD status in those patients achieving CR/CRi was a further indicator of long‑term outcome in each treatment group. Some patients who did not initially achieve MRD <10-3 and received subsequent cycles of venetoclax plus azacitidine later achieved MRD <10-3 if they remained in CR/CRi. Future clinical trials using a venetoclax plus azacitidine backbone could therefore consider the use of MRD status as a surrogate marker of DoR, EFS, and OS.

In the clinic, we can continue to feel confident that MRD status is prognostic in patients receiving venetoclax plus azacitidine. Many of my patients who are on therapy wish to stop therapy with venetoclax plus azacitidine after a few cycles, and I think these data will help convince them to continue therapy, particularly if they remain MRD positive. For patients who are MRD negative, they can be reassured that they are doing well. One challenge for these patients is figuring out how long to give venetoclax and azacitidine, and with which drugs. These MRD data promise to add valuable information to this discussion. 

QUAZAR AML-001 Multivariate Analysis: Background

Eunice S. Wang, MD:
Although 40% to 60% of older patients with AML achieve CR with intensive chemotherapy, 80% to 90% of these patients subsequently relapse.31-35 Predictors of relapse include age, performance status, poor‑risk cytogenetics, and MRD positivity.

Oral azacitidine (formerly known as CC‑486) is an HMA with a distinct pharmacokinetic/pharmacodynamic profile from parenteral and systemic azacitidine that allows for extended dosing.36 Oral azacitidine is FDA approved for the treatment of adults with AML who achieve CR/CRi following intensive induction chemotherapy but cannot complete intensive curative therapy, including allogeneic SCT.37

The current study, QUAZAR AML-001, used multivariate analysis to identify predictors of survival with oral azacitidine among patients with AML in remission following intensive chemotherapy.38-39

Aza vs Placebo in High-Risk AML (QUAZAR AML-001): Study Design

Eunice S. Wang, MD:
The QUAZAR AML‑001 study is an ongoing randomized, double‑blind, placebo‑controlled phase III trial of oral azacitidine vs placebo in 472 patients 55 years of age and older with AML and intermediate- or poor‑risk cytogenetics.39 All patients had achieved CR/CRi after intensive chemotherapy with or without consolidation and were ineligible for transplant.

Patients in the oral azacitidine group received 300 mg PO on Days 1-14 every 4 weeks. The same schedule was used for the placebo group. Patients were assessed for response every 3 cycles, and treatment was adjusted based on response. Patients who achieved CR or CRi continued therapy. Those with evidence of progression (ie, 5%-15% bone marrow blasts) had the option for treatment escalation (receiving oral azacitidine or placebo on Days 1-21 of each cycle). All patients continued treatment until death, withdrawal of consent, study end, or loss to follow up. Patients with ≥15% bone marrow blasts discontinued treatment.

The primary endpoint was OS, and the key secondary endpoint was RFS.

QUAZAR AML-001 Multivariate Analysis: Methods

Eunice S. Wang, MD:
The multivariate analysis used Cox proportional hazard models to estimate the relative impact of treatment arm and key baseline characteristics on OS and RFS.39 Baseline covariates included age, sex, cytogenetic risk, MRD status, and number of consolidation cycles.

QUAZAR AML-001 Multivariate Analysis: Final OS Multivariate Model

Eunice S. Wang, MD:
The final OS multivariate model confirmed that patients benefited from oral azacitidine vs placebo (HR: 0.70; 95% CI: 0.56-0.88; P = .0016).39 MRD status, cytogenetic risk, and age were significant independent predictors of improved OS. After controlling for all baseline characteristics, oral azacitidine remained a significant independent predictor of improved OS.

QUAZAR AML-001 Multivariate Analysis: Final RFS Multivariate Model

Eunice S. Wang, MD:
The final RFS multivariate model also confirmed that patients significantly benefit from oral azacitidine vs placebo (HR: 0.59; 95% CI: 0.47-0.73; P <.0001).39 MRD status, cytogenetic risk, number of consolidation cycles, and prior MDS diagnosis were significant predictors of improved RFS. Oral azacitidine remained a significant independent predictor of improved RFS after controlling for all baseline factors.

QUAZAR AML-001 Multivariate Analysis: Conclusions

Eunice S. Wang, MD:
Multivariate analysis of the QUAZAR AML‑001 study further showed that oral azacitidine reduced mortality risk by 30% and the risk of relapse by 41% in patients with AML in remission following intensive chemotherapy.39 These data support the continued use of oral azacitidine in this setting. Baseline MRD positivity and adverse cytogenetic risk were predictive of reduced OS and RFS in this patient population and should be taken into consideration when counselling patients about this treatment. I would use these data to reassure patients with baseline characteristics such as intermediate‑risk cytogenetics that they might benefit from the use of oral azacitidine. However, patients who have poor cytogenetic risk or are MRD positive may need to be monitored more closely, as they would be expected to have a worse prognosis. If available, my preference for these patients may be to consider a clinical trial option.

ZUMA-3: Background

Eunice S. Wang, MD:
Changing topics, I would now like to discuss an important study in acute lymphoblastic leukemia (ALL). Relapse occurs following initial treatment in up to 50% of adults with B-cell ALL.40 Prognosis following first salvage is poor and worsens with each therapy line.41 Currently, the only CAR T-cell therapy approved for ALL is tisagenlecleucel, but this is indicated only for patients up to 25 years of age who have B-cell ALL that is refractory or in second or later relapse.42

Brexucabtagene autoleucel is an autologous CD19-targeted CAR T-cell therapy that is FDA approved to treat R/R mantle cell lymphoma (MCL).43 In perhaps the most important abstract presented at ASCO 2021, results from the phase II ZUMA-3 trial presented by Shah and colleagues44 now report the efficacy and safety of CAR T-cell therapy with brexucabtagene autoleucel in adult—rather than pediatric—patients with R/R B-cell AML.

ZUMA 3: Brexucabtagene Autoleucel in R/R B-cell ALL Study Design

Eunice S. Wang, MD:
ZUMA-3 was a multicenter, open-label trial that treated 71 adults with R/R ALL with brexucabtagene autoleucel at the recommended phase II dose of 1 x 106 cells/kg.44 Patients received a conditioning regimen of fludarabine and cyclophosphamide prior to CAR T-cell therapy. Of the enrolled patients, 57 received conditioning chemotherapy, and 55 went on to receive CAR T‑cells. CAR T‑cells were successfully manufactured in 92% of patients, so this was not a limiting factor. The median time from leukapheresis to CAR T‑cell delivery was 13 and 14.5 days in the United States and Europe, respectively.

The primary endpoint was CR/CRi by central assessment, and secondary endpoints included MRD negativity, DoR, RFS, OS, and safety. The current analysis reports these results at a median follow-up of 16.4 months.

ZUMA-3: Baseline Characteristics

Eunice S. Wang, MD:
Patients enrolled on this study ranged between 19 and 84 years of age, with a median of 40 years of age.44 Of note, 47% of patients had received ≥3 prior lines of therapy. In total, 45% of patients had previously received blinatumomab, 22% had received inotuzumab ozogamicin, and 42% had received allogeneic SCT. In addition, 78% were R/R to ≥2 prior systemic therapy lines, and 22% had primary refractory disease. The bone marrow blast burden in these patients was extremely high, with a median of 65.0% at screening and 59.0% at preconditioning after bridging chemotherapy. Overall, these patients had very poor prognosis disease and would not be expected to survive very long with any standard therapies.

ZUMA-3: Response

Eunice S. Wang, MD:
Despite having poor prognostic markers and heavily pretreated disease, a remarkable 70.9% of patients achieved CR/CRi, with 56.4% achieving CR and 14.5% achieving CRi.44 In addition, MRD negativity was achieved in 97% of responding patients. The median time to CR/CRi was 1.1 months and median DoR was 12.8 months, regardless of subsequent allogeneic SCT. In total, 31% of patients who achieved CR/CRi were in ongoing remission without allogeneic SCT at data cutoff.

ZUMA-3: Survival

Eunice S. Wang, MD:
The median OS in patients with CR/CRi was NR vs 2.4 months in patients without CR/CRi.44 The median RFS was 14.2 months in patients with CR/CRi vs 0 months in patients without CR/CRi. 

ZUMA-3: Safety

Eunice S. Wang, MD:
All patients experienced an AE, with 95% experiencing pyrexia, 67% experiencing hypotension, and 53% experiencing anemia.44 In total, 10 patients (18%) had grade 5 AEs, and 2 of these deaths were related to brexucabtagene autoleucel treatment (brain herniation and septic shock). In addition, 34 patients (62%) had grade 4 AEs.

ZUMA-3: CRS and Neurologic Events

Eunice S. Wang, MD:
In total, 49 patients (89%) developed any-grade CRS, with 13 patients (24%) developing grade ≥3 CRS.44 The median time to onset was 5 days, with a median duration of 7.5 days. There were no grade 5 CRS events. Any-grade neurological events occurred in 33 patients (60%), and 14 patients (25%) had grade ≥3. The median time to onset was 9 days and median duration was 7 days. As mentioned, grade 5 brain herniation related to CAR T-cell therapy occurred in 1 patient.

ZUMA-3: Association Between CAR T-Cell Expansion and Efficacy/Safety

Eunice S. Wang, MD:
Expansion of CAR T‑cells in the blood was associated with ongoing remission (P = .0002), CR/CRi (P <.0001), and MRD negativity (P = .027).44 The median time to peak CAR T-cell levels was 15 days after infusion, and CAR T-cells were detectable at 12 months in 1 of 12 patients with evaluable samples. Patients with the most robust CAR T‑cell expansion had a higher risk of grade ≥2 CRS vs grade ≤1 (P = .0018) and grade ≥3 neurological events vs grade ≤2 (P = .043).

ZUMA-3: Conclusions

Eunice S. Wang, MD:
In summary, results from phase II stage of the ZUMA-3 trial show that a single infusion of CD19 CAR T-cells (brexucabtagene autoleucel) in adults with heavily pretreated R/R B-cell ALL produces high rates of response that are impressively durable.44 At a median follow-up of 16.4 months, CR/CRi was achieved in 70.9% of patients with a median DoR of 12.8 months, even in the 31% of patients who received no subsequent allogeneic SCT. Median OS was 18.2 months. Of note, the current standard of care therapies for relapsed B-cell ALL in adults (blinatumomab, inotuzumab) result in median OS lasting 6-8 months. The safety profile of brexucabtagene autoleucel was consistent with previous studies of CD19-directed CAR T-cell therapies. Most AEs occurred early and were reversible.

These data from ZUMA‑3 are expected to support the potential FDA approval of brexucabtagene autoleucel in this patient population. If so and if brexucabtagene autoleucel becomes commercially available, I think it will quickly become the standard of care in adult patients with R/R B-cell ALL, particularly for individuals whose disease relapses post-SCT or who have primary refractory disease.

Additional studies are needed to determine where CAR T-cell therapy should fit into the treatment regimen and identify potential predictors of response. When to use blinatumomab or inotuzumab ozogamicin vs CAR T-cell therapy also still needs to be determined. Due to increasing use of inotuzumab ozogamicin and blinatumomab in upfront induction and consolidation, CAR T‑cell therapy also could become a first‑line regimen at the time of relapse for patients who previously received these other agents as part of upfront therapy.

OPTIC: Background

Eunice S. Wang, MD:
I’d like to end my analysis with a discussion of a highly clinically relevant abstract for treatment of patients with chronic myeloid leukemia (CML).

Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) designed to inhibit BCR‑ABL1IS with or without single resistance mutations, specifically the T315I mutation, which confers resistance to all other commercially available TKIs.45

In the phase II PACE trial, ponatinib conferred deep, durable responses in patients with chronic-phase CML (CP-CML) resistant/intolerant to second-generation TKI therapy.46-47 However, arterial occlusive events (AOEs) emerged as AEs of special interest, and a post-hoc analysis suggested a relationship between the dose of ponatinib and AOEs.47-48

The OPTIC trial evaluated a novel, response-based dose-reduction strategy for ponatinib. The current study reports the primary analysis of this trial based on a median follow-up of 32 months.49

OPTIC: Ponatinib in CP-CML Resistant/Intolerant to TKIs: Study Design

Eunice S. Wang, MD:
OPTIC is an ongoing randomized phase II dose‑optimization trial of ponatinib in 283 adults with CP-CML resistant or intolerant to ≥2 prior TKIs or who are BCR-ABL1IS T315l mutation positive.49 Patients were randomized to receive a daily dose of 45 mg, 30 mg, or 15 mg of ponatinib. Patients receiving 45 mg or 30 mg who achieved ≤1% BCR-ABL1IS had their ponatinib dose reduced to 15 mg/day. Further dose reduction was allowed to 10 mg/day for AEs for all patients receiving the 15 mg/day dose. Patients received treatment for up to 24 months.

The primary endpoint was ≤1% BCR-ABL1IS at 12 months. Key secondary endpoints included major molecular response rate at 12 and 24 months, and safety.

OPTIC: Baseline Characteristics

Eunice S. Wang, MD:
Cardiovascular risk factors were evenly distributed across cohorts; 23% to 28% of patients had arterial hypertension, 3% to 7% had diabetes mellitus, and 15% to 20% had hyperlipidemia.49 Across cohorts, 40% to 46% of patients received 2 prior TKIs, and 51% to 60% had received ≥3 TKIs. T315I mutations were present in 22% to 27% of patients.

OPTIC: ≤1% BCR-ABL1IS at 12 Months (Primary Endpoint), PFS, and OS

Eunice S. Wang, MD:
The primary endpoint of ≤1 BCR-ABL1IS at 12 months was achieved by 44.1% of patients receiving the 45-mg → 15-mg regimen, 29.0% of patients receiving the 30-mg → 15-mg regimen, and 23.1% of patients receiving the 15-mg regimen.49

Among patients with T315I mutations who received the 45-mg → 15-mg regimen, 60% achieved ≤1 BCR-ABL1IS vs 25% in the 30-mg → 15-mg regimen and 11% in the 15-mg regimen.

Median PFS was NR for the 45-mg → 15-mg and 30-mg → 15-mg regimens and was 45.6 months with the 15-mg regimen. The 36-month median OS was nearly identical among the cohorts, ranging from 89% to 92%.

OPTIC: ≤1% BCR-ABL1IS by 6, 12, and 24 Months and Median Dose Intensity

Eunice S. Wang, MD:
The 45-mg → 15-mg regimen conferred the best and fastest response, with 40.9% of patients achieving ≤1% BCR‑ABL1IS by 6 months compared with 29.0% of patients in the 30-mg → 15-mg regimen and 20.9% of patients in the 15-mg regimen.49

OPTIC: Effects of Dose Reduction on Response

Eunice S. Wang, MD:
Of the 73 patients who received 45--mg and 30-mg doses of ponatinib and were subsequently dose reduced to 15 mg after achieving ≤1% BCR‑ABL1IS, 75% maintained their response.49

OPTIC: Effects of Dose Re-escalation on Response

Eunice S. Wang, MD:
Most patients who lost molecular response and re‑escalated their ponatinib dose subsequently regained their response safely.49 Among 13 patients receiving the 45-mg → 15-mg regimen who had dose re-escalation, 8 patients (61.5%) regained ≤1% BCR‑ABL1IS in a median of 3.9 months. Of the 5 patients receiving the 30-mg → 15-mg regimen who dose re-escalated, 4 patients (80.0%) regained ≤1% BCR‑ABL1IS in a median of 4.2 months.

OPTIC: Safety

Eunice S. Wang, MD:
The most common TEAEs were thrombocytopenia, hypertension, headache, and increased lipase.49

AEs did not appear to be more frequent with the 45-mg → 15-mg regimen compared with the other regimens, as the rate of any-grade TEAE ranged from 93.6% to 100% across groups. The incidence of treatment-emergent AOEs was only 6%.

OPTIC: Conclusions

Eunice S. Wang, MD:
The take-home message of the OPTIC trial is that it appears to be safe to start with the 45-mg ponatinib dose and subsequently dose reduce to 15 mg upon response. The incidence of treatment-related AOEs was only 6%, and careful dose adjustment allowed ponatinib to be administered safely and with high efficacy.49 In patients at higher risk for AOEs, I think a starting dose of 30 mg or 15 mg is acceptable but will result in lower initial response rates. These data support the routine and safe use of ponatinib for those patients with CP-CML with prior treatment resistance (ie, failed ≥2 prior TKIs or with the T3151 mutation).

ASCO Leukemias 2021: Summary

Eunice S. Wang, MD:
At ASCO 2021, we saw many advances for the treatment of leukemias. We saw the integration of IDH1 and IDH2 inhibitors into combination treatment regimens for patients with IDH1/IDH2‑mutant AML and MDS. Regimens combining 2‑3 agents including targeted IDH inhibitors, venetoclax, and/or HMAs were highly effective and well tolerated, and may be the way of the future for the treatment of IDH‑mutant disease. The QUAZAR study showed the benefit of oral azacitidine across patients with different baseline prognostic factors following intensive chemotherapy who were unable to continue with intensive approaches. Continued administration of venetoclax/azacitidine improves MRD negativity rates over time, and MRD status may serve as an important biomarker for future studies using the venetoclax/azacitidine backbone, given it is an important predictor of DoR, EFS, and OS in these patients.

For ALL, we saw pivotal data supporting the use of CAR T-cell therapy in adults with poor-risk R/R ALL post-SCT and in the primary refractory setting. I look forward to future research and debates about where CAR T-cell therapy should fit with currently available agents.

In CML, ponatinib can now safely be incorporated into the treatment regimen for patients with therapy-resistant disease. Although the highest response rates with ponatinib were observed at a starting dose of 45 mg, patients can rapidly de‑escalate to 15 mg to minimize AEs during long‑term use while maintaining treatment response.

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Supported by educational grants from
AbbVie
AstraZeneca
Bristol-Myers Squibb
GlaxoSmithKline
Novartis Pharmaceuticals Corporation
Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc.
Sanofi Genzyme

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