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ASH 2019: Leukemias
Leukemias: Key Trials From ASH 2019

Released: February 03, 2020

Expiration: February 01, 2021

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In this commentary I discuss the most clinically relevant studies from the 2019 ASH annual meeting for the treatment of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Impact of Time From Diagnosis to Treatment on AML Prognosis
Data reported by Rollig and colleagues from a German AML registry representing 46 treatment centers demonstrated, for the first time, that the turnaround time from diagnosis to initiation of therapy for patients with AML need not be 24 hours or less, as is current practice. The study recruited 2263 patients with a diagnosis of an acute nonpromyelocytic myeloid leukemia who received intensive induction chemotherapy and had a minimum follow-up of 12 months. The investigators found that there was no difference in clinical outcomes, specifically early mortality or OS, regardless of whether patients initiated therapy after 0-5 days, 6-10 days, 11-15 days, or more than 15 days. The same outcomes were seen in younger and older patients with AML, as well as in patients presenting with or without an elevated white blood cell count. One of the most common questions in current clinical practice is whether a clinician can wait for results of pending cytogenetic and molecular characterization of disease before starting therapy in fit patients with newly diagnosed AML. Many international guidelines have recommended that these tests be done within a short time frame of 3-5 days so as not to adversely affect treatment outcome, but in reality, these results can often take much longer. Now we have data suggesting that it is safe and does not adversely affect outcomes to wait up to 15 days or longer to initiate intensive induction therapy in younger fit patients with newly diagnosed AML.

AG221‑AML‑005: Enasidenib Plus Azacitidine for IDH2-Mutant AML
The reason we want to take that time to conduct cytogenetic and molecular analyses is to enable us to tailor treatment for AML based on the presence of actionable mutations. This next study demonstrates the potential therapeutic benefits of that approach. AG221-AML-005 was a randomized phase I/II study performed by DiNardo and colleagues to assess whether it is appropriate to use the targeted IDH2 inhibitor enasidenib in combination with azacitidine for treatment of patients with newly diagnosed IDH2‑mutant AML, as compared with treatment with azacitidine alone. Results show a significantly higher ORR (the primary endpoint) and CR rate with the addition of enasidenib to azacitidine therapy for these patients. Although there was no difference in OS between the 2 groups, use of enasidenib with azacitidine resulted in a nonstatistically significant trend to increased event‑free survival (EFS) of 17.2 months vs 10.8 months with azacitidine alone. This study prompts the question of whether a combination approach will become the new standard of care vs hypomethylating agent (HMA) therapy or enasidenib alone for the treatment of patients with IDH‑mutant AML moving forward in the newly diagnosed setting.

FLAG‑IDA Plus Venetoclax for AML
Although venetoclax plus low-dose chemotherapy has become the new standard for older unfit patients with newly diagnosed AML, it is uncertain if BCL-2 inhibition can successfully be combined with intensive induction chemotherapy. Here, Aboudalle and colleagues evaluated the efficacy of adding venetoclax to filgrastim, fludarabine, idarubicin, and cytarabine (FLAG-IDA) induction and consolidation chemotherapy followed by venetoclax maintenance therapy in newly diagnosed and patients with relapsed/refractory (R/R) AML. In this single-center phase Ib/II trial, the authors noted extremely high CR rates, with an ORR of 70% to 75% in 26 patients with R/R AML, and 93% in 14 patients with newly diagnosed AML. These data are significant in that this is the first phase Ib/II study showing that venetoclax can safely be given with standard upfront induction chemotherapy, albeit with a dose reduction of cytarabine to 1.5 g/m2. No significant increase in treatment-related mortality, specifically from infections, was observed. The question remains whether venetoclax can safely be added to other intensive chemotherapy regimens other than FLAG-IDA, and whether these combinations will result in improvements in long-term outcomes (EFS and OS) as compared with chemotherapy alone. If demonstrated in future clinical trials, venetoclax plus intensive chemotherapy may become the new standard of care in place of standard 7+3‑based induction and consolidation.

QUAZAR: CC-486 as Maintenance Therapy in First-Remission AML in Older Patients
Two important studies presented at the 2019 ASH annual meeting questioned the long‑held belief that there is no role for maintenance therapy for the treatment of patients with AML. The QUAZAR AML‑001 study by Wei and colleagues was a multicenter, randomized, placebo‑controlled, double‑blind phase III study examining the role of oral azacitidine for this indication. In this study, 472 older individuals with newly diagnosed or secondary AML, who had achieved CR following standard induction and consolidation chemotherapy, were randomized to receive either oral azacitidine (also known as CC‑486) or placebo for 12 months. The results of this study demonstrated a statistically significant improvement in median OS of almost 10 months for those patients receiving CC‑486 as maintenance therapy over placebo. Although increased gastrointestinal adverse events were reported with CC-486, the overall toxicity of this agent was manageable. This is the first trial ever to demonstrate that a maintenance strategy of any kind following intensive induction chemotherapy is beneficial to newly diagnosed patients with AML. The only caveat to this study is the fact that this maintenance strategy only applies to patients with intermediate-risk to high-risk AML unable to undergo stem cell transplantation (SCT). We eagerly await the decision on whether oral azacitidine receives regulatory approval to become part of the standard upfront therapy of these patients in the next 6-12 months.

ECOG‑ACRIN E2906: Decitabine Maintenance Therapy for Older Patients With AML
This is the second study to demonstrate the therapeutic benefit of an HMA as maintenance therapy for patients with AML. The ECOG‑ACRIN E2906 study presented by Foran and colleagues randomized 120 older patients with newly diagnosed AML who had achieved first CR or CR with incomplete neutrophil recovery after induction and consolidation chemotherapy to receive either monthly decitabine (dosed at 20 mg/m2 on Days 1-3) every month or observation for 1 year. After a median follow-up of 49.8 months, there was no significant difference in disease‑free survival (DFS; the primary endpoint) between arms. However, there was a trend for improved OS in patients receiving the decitabine maintenance, with an HR of 0.69 (95% CI: 0.43-1.09; 1‑sided P = .06). Patients who had FLT3‑ITD disease did not appear to benefit from decitabine maintenance.

Taken together with the QUAZAR trial, both of these studies suggest that the specific HMA may not be as important in the maintenance setting, but rather it is the routine administration of HMA therapy for 12 months that may benefit in prolonging OS in this population of patients not proceeding to SCT for AML. The question remains which HMA would be preferred. Obviously, oral azacitidine (CC-486) may be simpler for patients to receive on a routine basis than IV decitabine, but the 3 days/month schedule may also offer advantages. It remains to be seen if there is any significant difference in adverse events between the 2 HMAs. At present, it appears that either HMA could be considered and that maintenance therapy may become standard therapy for these patients.

Patients With R/R AML After First‑line Venetoclax Plus HMA
Given the growing prevalence of upfront venetoclax and HMA therapy for patients with newly diagnosed AML, it is important to understand the clinical outcomes of individuals treated with this regimen. Data were presented by Maiti and colleagues describing the outcomes of 41 patients with newly diagnosed AML or untreated secondary AML enrolled on 2 clinical trials of venetoclax plus either decitabine or azacitidine who developed R/R disease after an initial response. Despite the fact that these patients were treated at a major academic center, the median OS in this population was only 2.4 months, and the response to subsequent salvage therapy after failing first‑line treatment was almost universally disappointing. This study is significant in confirming that this subset of older patients with AML whose disease fails to respond to first-line venetoclax plus HMA have a dismal prognosis. These patients primarily had AML characterized by complex karyotype, secondary or therapy‑related AML, and mutations in TP53, NRAS/KRAS, TET2, ASXL1, or DNMT3A. The take-home point is that patients with AML with these baseline characteristics should be strongly considered for enrollment on a clinical trial to avoid the poor outcomes associated with failure of venetoclax and HMA induction therapy.

Dasatinib Plus Blinatumomab for Ph-Positive ALL
Now, we turn to management of ALL. Chiaretti and colleagues presented the results of a multicenter, phase II study evaluating the combination of dasatinib and blinatumomab for upfront treatment of adults with newly diagnosed B-precursor Philadelphia chromosome (Ph)–positive ALL. This regimen is unique in omitting all cytotoxic chemotherapy drugs from the regimen, consisting of 84 days of dasatinib plus prednisone, followed by dasatinib with blinatumomab for a maximum of 5 cycles. The primary endpoint was complete molecular remission (CMR) or measurable residual disease (MRD) negativity after 2 cycles of dasatinib and blinatumomab. Overall, almost two thirds of patients (60.4%) achieved this endpoint. After a median follow-up of 14 months, OS was 95.2%, with 24.0% of the 63 patients proceeding to subsequent allogeneic SCT. Although the treatment was well tolerated overall, some patients, particularly those with mutations in IKZF1 and ABL1, did less well and may not be ideal candidates for this treatment. In addition, among the 6 patients who relapsed, 3 had extramedullary disease, which may be another consideration when deciding whether to use this regimen in this patient population.

Hyper‑CVAD and Ponatinib in Ph-Positive ALL
Short and colleagues reported long‑term results of a single-arm phase II study of the combination of hyper‑CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus the TKI ponatinib in patients with newly diagnosed or R/R (up to 2 prior chemotherapy regimens) Ph‑positive ALL. In the later phase of this study, patients received ponatinib 45 mg/day during an intensive phase of eight 21-day cycles, followed by dose reduction due to toxicity to ponatinib 30 mg/day for cycle 2 and 15 mg/day after CMR in subsequent cycles. All patients received maintenance ponatinib with vincristine and prednisone, all patients achieved both a CR and a complete cytogenetic remission, and 86% achieved a CMR. After a median follow-up of 44 months, the 3‑year EFS rate was 78% and the 5‑year EFS rate was a very impressive 74%. These outstanding results, even in patients who did not proceed to allogeneic SCT, suggest that the highly potent TKI ponatinib plus induction chemotherapy may actually negate the need for SCT in some patients with Ph‑positive disease. Given the mortality rate of 20% to 30% with allogeneic SCT, these results are provocative in suggesting that if one achieves CMR with upfront hyper‑CVAD/ponatinib, it may not be necessary to pursue allogeneic SCT in first remission for Ph-positive ALL until the time of relapse.

Blinatumomab vs Chemotherapy as Post Reinduction Therapy for Younger Patients With Relapsed B-Cell ALL
Brown and colleagues reported follow-up results from COG AALL1331, a multicenter, open‑label phase III study in which 208 younger patients (aged 1‑30 years) with first relapsed, intermediate-risk or high-risk B-cell ALL were randomized to receive blinatumomab and dexamethasone followed by blinatumomab alone vs a chemotherapy‑based regimen. After a median of 1.4 years of follow-up, patients who received blinatumomab-based therapy as opposed to chemotherapy alone experienced significant improvements in DFS and OS. Moreover, those individuals who received cytotoxic chemotherapy had significantly higher rates of adverse events, including febrile neutropenia, infection, sepsis, and mucositis. In September 2019, the data and safety monitoring committee recommended closure of the chemotherapy arm with crossover to the blinatumomab arm based on the significant differences in safety and efficacy between the 2 arms. In almost every clinical efficacy parameter measured, including OS, DFS, MRD‑negative disease, and bridging to transplant, the use of blinatumomab-based therapy was associated with improved efficacy and improved safety over chemotherapy alone. These data are compelling in suggesting that the use of cytotoxic chemotherapy in this setting should be discouraged in place of using immunotherapy‑based approaches such as blinatumomab.

M16‑106: Venetoclax and Navitoclax for R/R ALL
Despite the above data, treatment options for R/R ALL remain poor. The M16-106 trial was an open‑label, dose-escalation phase I study reported by Lacayo and colleagues examining the combination of the BCL-2 inhibitor venetoclax with a novel BCL-X inhibitor, navitoclax, together with chemotherapy, in 45 adult and pediatric patients with R/R ALL and lymphoblastic lymphoma. Researchers added navitoclax on the theory that it may overcome resistance mechanisms and synergistically promote the antileukemic activity of venetoclax. Overall, 22 of the 45 (49%) patients responded to therapy, with a lower response rate of 39% in patients with T‑cell ALL and a higher rate (67%) in patients with lymphoblastic lymphoma. Treatment was generally well tolerated, with few discontinuations or dose reductions. These outcomes are significant, given that this was a very heavily pretreated population with few other treatment options. In the future, perhaps we will see this regimen as a first salvage regimen for such patients or perhaps upfront for the treatment of high-risk ALL and other lymphoid malignancies.

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