Phase 2 Study of Lenalidomide Maintenance for Patients with High-Risk Acute Myeloid Leukemia in Remission

Abstract

New drug combinations have led to significant improvements in remission rates for patients with acute myeloid leukemia (AML). However, many patients with high-risk AML who respond to initial treatment and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes. In this phase II trial, we evaluated the efficacy of lenalidomide maintenance in patients with high-risk AML, who have achieved first or second remission after induction chemotherapy and at least one consolidation cycle and who are not candidates for immediate ASCT. Lenalidomide was given at 10–20 mg orally daily on days 1–28 of a 28-days cycle for up to 24 cycles. A total of 28 patients were enrolled in this study with a median age of 61 years (range, 24–87). The median number of cycles was 8 (range, 1–24). Ten (36%) patients completed 24 months of maintenance treatment. With a median follow-up of 22.3 months (range, 2–55), 12 (43%) patients relapsed after a median of 3 months (range, 0.7–23). The median duration of remission for all patients was 18.7 months (range, 0.7–55.1). The 2-year OS and RFS from time of enrollment were 63% and 50%, respectively. Overall, lenalidomide was well tolerated; Serious adverse events of grade 3 or 4 were observed in 13 (46%) patients including rash (n=5), thrombocytopenia (n=4), neutropenia (n=4), fatigue (n=2). Lenalidomide is a safe and feasible maintenance strategy in high-risk AML patients who are not candidates for ASCT, with beneficial effects in patients with negative measurable residual disease.

INTRODUCTION

Acute myeloid leukemia (AML) is a clonal myelopoietic stem cell disorder characterized by the accumulation of malignant clones of myeloid lineage in the bone marrow and peripheral blood.^{1, 2} New drug combinations and higher intensity therapy have led to a significant steady increase in survival rates of AML patients in the last two decades.^{3, 4} However many patients with high-risk AML, especially older adults who respond to initial standard induction/consolidation chemotherapy will eventually relapse with very poor outcomes.^5–8 Currently, allogeneic stem cell transplantation (ASCT) remains the best post-remission therapy in both intermediate and poor-risk genetics when the relapse incidence is expected to be greater than 35%.^{5, 9, 10} Nonetheless, multiple factors may preclude AML patients in remission to undergo ASCT that include age, comorbidities, performance status, or toxicity of prior therapy. Alternative approaches using a long-term lower intensity maintenance treatment to prolong remission duration and survival has been of great interest in the management of AML, but it is not yet considered as part of standardized treatment.¹¹ Multiple studies evaluating post-consolidation maintenance therapy using different agents such as low dose chemotherapy or hypomethylating agents failed to provide convincing evidence to incorporate maintenance into therapeutic strategy of AML.^11–14 Recently, CC-486, an oral form of 5-azacytidine, when used as maintenance treatment in AML patients who were in remission post induction chemotherapy showed encouraging results with improvement in both relapse-free survival (RFS) and overall survival (OS).¹⁵ Perhaps, newer therapies employing different mechanisms of action including immune modulation and alteration of intracellular signaling may be ideal for maintaining longer remission control and potential cure. Lenalidomide has been shown to enhance NK cell cytotoxicity, cytokine secretion and immune synapse formation to favor anti-leukemia immunity.^16–18 Such reconstitution of AML immune surveillance with lenalidomide in the maintenance setting could translate into long-term disease control and a higher cure rate. The aim of this phase II trial is to evaluate the efficacy and safety of low intensity, continuous dosing of lenalidomide in patients with high-risk AML who have responded to induction/consolidation chemotherapy and are not immediate candidates for ASCT.

METHODS

Study Design and Participants

Adult patients with high-risk AML who have achieved first or second complete remission (CR1 or CR2) after induction chemotherapy and at least one consolidation cycle within 12 months of enrollment and who are not candidates for immediate ASCT were enrolled in this phase 2 trial. High-risk features for AML included adverse cytogenetics, FLT3 mutation, a prior myeloid neoplasm (myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN)), secondary AML (s-AML), presence of significant dysplasia in the bone marrow, therapy-related AML, primary refractory AML (requiring more than 1 cycle of intensive induction chemotherapy to achieve first CR), or persistent measurable “minimal” residual disease (MRD) (detected by cytogenetics, molecular markers, or flow cytometry) at any point after initial induction chemotherapy. Eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or less, adequate hepatic and renal function (serum bilirubin ≤ 1.5 the upper limit of normal (ULN) and serum creatinine ≤ 2.5 × ULN) and an adequate bone marrow reserve (absolute neutrophil count (ANC) > 0.5 × 10⁹/L, platelet count ≥ 30 × 10⁹/L). Patients were excluded if they had a diagnosis of acute promyelocytic leukemia or core binding factor leukemia with the following cytogenetics: inv(16), t(16;16), t(8;21), an active infection not controlled with antibiotics; clinical evidence of grade 3 or 4 heart failure, as defined by the New York Heart Association criteria, uncontrolled hypertension and active cardiovascular comorbidities; active CNS disease; or previous treatment with lenalidomide or documented hypersensitivity to any components of the study program. All study participants were able to comply with the requirements of the REMS ^® program.

All patients were enrolled consecutively and gave written informed consent. The study was done in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Treatment Plan

This is a single arm, open label phase II clinical trial evaluating low intensity, continuous dosing of lenalidomide in patients with high-risk AML who have responded to induction/consolidation therapy and are not immediately candidates for ASCT. Patients are initially treated with the standard frontline chemotherapy regimen, followed by a number of consolidation cycles that the primary physician considers adequate. Patients after either completion of standard courses of consolidation or after inability to complete further treatment based on physician’s judgment (ie. Performance status, comorbidities, recurrent infections,..) were enrolled in this trial. Patients were treated continuously with lenalidomide 10 mg orally daily on days 1–28 of a 28-days cycle. After cycle 1, stepwise dose escalations to 20 mg daily were allowed in patients who were tolerating their dose and had presence of minimal residual or morphologically detectable disease. Treatment was continued during the duration of the study, up to 24 months unless patient had evidence of clinically significant treatment failure, clinically significant disease progression, unacceptable toxicity, treatment with stem cell transplantation, or if the investigator determined that discontinuation was in the best interest of the patient.

Clinical Endpoints

The primary endpoint was to assess RFS of patients with AML treated with lenalidomide maintenance therapy after achieving remission, calculated from the beginning of treatment until relapse or death. Secondary endpoints included OS, duration of remission, and safety profile of lenalidomide maintenance. CR was defined as the presence of fewer than 5% blasts in the bone marrow, with more than 1 × 10 ⁹/L neutrophils and more than 100 × 10 ⁹/L platelets in the peripheral blood. Relapse was defined by recurrence of more than 5% myeloblasts in a bone marrow aspirate unrelated to hemopoietic recovery or by the presence of extramedullary disease. Duration of continuous CR was calculated from the date of enrollment until relapse. OS was calculated from the time of treatment initiation until death from any cause (censored at last follow-up date).

Statistical methods

Patients’ characteristics were summarized using descriptive statistics including median (range) for continuous variables and frequency (%) for categorical variables. The Kaplan-Meier method was used to estimate RFS, OS and duration of remission. All statistical analysis were carried out in GraphPad prism version 8.

The study is registered at Clinicaltrials.gov, number NCT02126553.

RESULTS

Baseline characteristics

Between January 2015 and May 2019, 28 patients were enrolled in this phase II study and were treated with lenalidomide as single agent maintenance. Baseline patient and disease characteristics are summarized in Table 1. The median age was 61 years (range, 24–87), and 50% were males. All patients were in CR at the time of enrollment, with 25 (89%) patients in CR1 and 3 (11%) in CR2. Patients started lenalidomide maintenance after a median of 8.8 months (range, 4–19.3 months) from the start of induction chemotherapy, and a median of 5.8 months (range, 2.4–12 months) from first or second remission date. Patients had a median of 4 prior consolidation cycles (range, 1–10), detailed in Table 1 below. High-risk features at the time of enrollment were as follows (some are overlapping): 7 (25%) patients with history of prior myeloid neoplasm, 15 (54%) with persistent MRD, 7 (25%) adverse mutational profile, 6 (21%) adverse cytogenetics (including complex cytogenetics (n=2), monosomal (n=3), t(4;11) (n=1)), 3 (11%) CR2 status, 2 (7%) t- AML and 2 (7%) primary refractory disease.

Table 1.

Baseline Characteristics of all patients

Total N=28	N(%), median [range]
Age- years	61 [24–87]
Male gender	14 (50%)
Induction regimen
Cytarabine + Anthracycline (3+7)	9 (32)
Cytarabine + Anthracycline + Nucleoside Analog	12 (43)
CPX-351	4 (14)
Hypomethylating Agent + venetoclax	3 (11)
No. of Consolidation courses	4 (1–10)
Consolidation regimen
High dose cytarabine	4 (14)
Cytarabine + Anthracycline + Nucleoside Analog	17 (61)
CPX-351	4 (14)
Hypomethylating Agent + venetoclax	3 (11)
High-risk feature AML category
MRD persistence	15 (54%)
Adverse cytogenetics	6 (21%)
Prior myeloid neoplasm (MDS-MPN)	7 (25%)
Prior hypomethylating agent treatment	4 (14%)
AML with myelodysplastic changes	4 (14%)
Adverse molecular profile	7 (25%)
Second remission	3 (11%)
Primary refractory	2 (7%)
Therapy-related AML	2 (7%)
Prior stem cell transplantation	2 (7%)
Molecular Profile
FLT3-ITD /D835	2 (7%)
IDH1/IDH2	7 (25%)
DNMT3A	7 (25%)
NPM1	6 (21%)
NRAS/KRAS	5 (18%)
TET2	5 (18%)
TP53	2 (7%)
RUNX1	1 (3%)
ASXL1	1 (3%)
Cytogenetics
Diploid	16 (57%)
Complex (>2 abnormalities)	2 (7%)
Monosomal	3 (11%)
KMT2A rearranged, t(4;11)	1 (4%)
Miscellaneous	6 (21%)

Efficacy and Survival outcomes

Of patients who started lenalidomide, 27 patients (96%) are off treatment. Ten (36%) patients completed 24 months of maintenance treatment, and one patient is still receiving lenalidomide on study. Treatment discontinuation was due to disease relapse in 12 patients (43%) and toxicity in 5 patients (18%). Overall median treatment duration was 8 cycles (range, 1–24).

With a median follow-up of 22.5 months (range, 2.6–55), 12 (43%) patients relapsed after a median of 3 months (range, 0.7–23); of them, 7 patients had sAML (n=5) or t-AML (n=2). None of the patients who completed 24 months of treatment relapsed after a median follow-up of 16 months (range: 0–32.7) from discontinuation. The median duration of remission for all patients was 18.7 months (range, 0.7–55.1). The median duration of remission for patients who started lenalidomide within 6 months of remission (N=15) was 4.5 months, versus 25.7 months for those who started lenalidomide beyond 6 months of remission (N=13). Among the patients who entered the trial within 6 months of CR, 3 patients had MRD positive disease at time of enrollement and 7 patients had sAML or tAML. The 2-year OS and RFS from time of enrollment were 63% and 50%, respectively (figure 1, A-B). The median OS and RFS in patients with sAML (n=7) or t-AML (n=2) was only 6.7 and 2.5 months respectively versus not yet reached in patients with other high-risk categories (p<0.0001) (figure 2, A-B). Furthermore, at the time of lenalidomide initiation, 5 (18%) patients had detectable MRD with a median of 0.1% of aberrant blasts (range, 0.02–1.6%) detected by multiparametric flow cytometry. Of them, four patients relapsed within 3.7 months (range, 1.2–5.7), and one received ASCT due to persistent MRD and continues in remission.

Figure 1. Kaplan Meier curves for overall survival (Panel A) and relapse-free survival (Panel B) of all enrolled patients.

Kaplan-Meier curves for (A) OS and (B) RFS of all enrolled patients. OS indicated overall survival; RFS, relpase-free survival.

Figure 2. Kaplan Meier curves for overall survival (panel A) and Relapse-free survival (panel B) by risk groups (secondary or therapy related AML versus other high risk groups).

Kaplan-Meier curves for (A) OS and (B) RFS by risk groups (sAML or tAML vs other high risk groups). OS indicated overall survival; RFS, relpase-free survival; sAML, secondary acute myeloid leukemia; tAML, therapy-related acute myeloid leukemia.

Safety

Adverse events are listed in Table 2. All patients were evaluable for safety. Serious adverse events of grade 3 or 4 occurred in 13 patients (46%) including rash (n=5), thrombocytopenia (n=4), neutropenia (n=4), fatigue (n=2), dyspnea (n=1), stroke (n=1), febrile neutropenia (n=1), nausea (n=1), and vomiting (n=1). Ten (36%) patients continued on 10 mg dosing, 2 (7%) had successfully increased the dose to 15 mg daily, 12 (43%) had dose reduction to 5 mg daily mainly due to rash (n=5), thrombocytopenia (n=3), neutropenia (n=2), nausea (n=1), and diarrhea (n=1). Five patients (18%) discontinued treatment because of adverse events after a median of 7 cycles (range: 1–20); three (11%) patients discontinued due to recurrent rash despite dose reduction, one discontinued because of grade 2 dyspnea attributed to interstitial lung disease and one discontinued after one cycle of treatment due to stroke. After a median follow-up of 10.8 months (range: 6.6–22.4) after drug discontinuation, none of the patients relapsed.

Table 2.

Treatment related toxicities regardless of causality

Adverse Event	Any grade	Grade 1–2	Grade 3	Grade 4
Rash	12 (43%)	7 (25%)	5 (18%)	0 (0%)
Pruritus	7 (25%)	7 (25%)	0 (0%)	0 (0%)
Fatigue	6 (21%)	4 (14%)	2 (7%)	0 (0%)
Neutropenia	4 (14%)	0 (0%)	0 (0%)	4 (14%)
Thrombocytopenia	4 (14%)	0 (0%)	2 (7%)	2 (7%)
Diarrhea	5 (18%)	5 (18%)	0 (0%)	0 (0%)
Nausea/Vomiting	5 (18%)	3 (11%)	2 (7%)	0 (0%)
Febrile neutropenia	2 (7%)	1 (3%)	1 (3%)	0 (0%)
Increased Transaminases	2 (7%)	2 (7%)	0 (0%)	0 (0%)
Myalgias	2 (7%)	2 (7%)	0 (0%)	0 (0%)
Dizziness	2 (7%)	2 (7%)	0 (0%)	0 (0%)
Headache	2 (7%)	2 (7%)	0 (0%)	0 (0%)
Dyspnea	1 (3%)	0 (0%)	1 (3%)	0 (0%)
Stroke	1 (3%)	0 (0%)	1 (3%)	0 (0%)

DISCUSSION

In this phase II clinical trial, we assessed the clinical activity of single agent lenalidomide maintenance in high-risk AML ineligible for ASCT. We found that lenalidomide maintenance is effective and well tolerated and observed that lenalidomide was not effective in eradicating persistent measurable residual disease. Adverse events related to lenalidomide were manageable with dose reductions. Main causes of discontinuation were due to disease progression, which occurred in 43% of patients, followed by toxicities in 18% of patients. None of the patients discontinued the drug for significant hematologic toxicities. In our study, the median OS was not reached and median RFS was 23 months, exceeding the historical outcomes of high-risk AML not undergoing ASCT. This RFS surpassed our own historical experience for similar high-risk patients treated at our institution and not receiving ASCT – whether they had received higher intensity therapy (median RFS: 10 months) or lower intensity therapy (median RFS: 8 months) to achieve a remission. The median duration of remission was 17.3 months, which was longer than reported duration of CR1 of 9.4 months in patients who relapsed without a prior ASCT.¹⁹ Patients with sAML or t-AML had significantly shorter remission duration and OS with lenalidomide maintenance compared to those with non-secondary AML. This subgroup remains a challenging subset with extremely poor outcomes without receiving ASCT, and warrants exploration of newer therapeutic strategies.

The presence of MRD, defined as persistent leukemic clones below the detection level of routine microscopy, is not only an independent prognostic marker of higher risk of relapse and shorter survival, but also a tool to indicate the need for pre-emptive treatments.^20–22 Half of our patients had persistent MRD post-induction chemotherapy, but only 5 patients were MRD positive at time of enrollment. The median duration to relapse on treatment was 3.7 months, which was similar to the expected time to relapse of 3–6 months in MRD-positive patients. Lenalidomide appeared to provide greater benefit in MRD-negative patients, suggesting that it may be less effective in eradicating measurable residual disease but effective at controlling relapses in settings of even lower disease burden below the limits of detection. Similar findings were reported in the UK NCRI AML trial, where 5-azacitidine maintenance did not show a survival benefit including all participants; however, it only improved the 5‐year OS of MRD-negative patients compared to others (40.5% vs 13.5%; P = .003).²³ The goal MRD eradication with novel therapeutic intervention prior to initiation of long-term lenalidomide maintenance, therefore, may be an optimal strategy to maintain long-term remissions in high risk patients.

Lenalidomide maintenance was previously tested in clinical trials either alone or in combination with hypomethylating agents including different treatment schedules and patient population. In a phase 1 dose escalation study conducted by the Australasian Leukemia and Lymphoma Group (ALLG), escalated doses of lenalidomide 10–40 mg were given for 2 consecutive 28-days cycles, followed by continuous administration of 10 mg daily for 12 months to adult AML patients who achieved CR post induction chemotherapy regardless of risk of relapse.²⁴ A total of 28 patients were included, with a median age of 54 (range 18–65) years. The reported 12- and 24‐month OS were 97% and 91%, respectively, and the 12- and 24‐month risk of relapse in whole population were 18% and 26%, respectively. Sequential administration of 5-azacitidine and lenalidomide as maintenance treatment in elderly high risk AML in CR1 was tested by the French Innovative Leukemia Organization (FILO). After a median follow-up of 38 months, the median DFS and OS were 7.9 and 10 months respectively. This trial failed to show any beneficial advantage of the combination in patient’s outcomes, especially that most of patients relapsed while on maintenance treatment.²⁵ In another Australian trial including 40 patients with AML in CR receiving the combination of 5-azacitidine and lenalidomide, the reported median DFS and OS for patients in CR1 were 12 and 20 months respectively. ²⁶

Currently, there are few options for maintenance treatment in AML. The QUAZAR AML-001 trial was the first randomized trial using oral hypomethylating agent (CC-486) that demonstrated a clinically significant improvement in both OS and RFS in patients with AML in first remission following induction chemotherapy.¹⁵ In this trial, patients were randomized to either CC-486 300 mg one daily for 14 days every 28 days or placebo. The majority of patients were in CR1 (79%) and had intermediate cytogenetics (85%). At a median follow-up of 41 months, the median OS and RFS were improved in the CC-486 arm compared to placebo (median OS: 24.7 vs 14.8, HR=0.69 95%CI: 0.55–0.86, p=0.0009; median RFS: 10.2 vs 4.8 months, HR=0.65 95%CI: 0.52–0.81, p=0.0001). These compare favorably to our data, in a cohort where 21% of the patients had adverse karyotype.

In conclusion, our study shows that single agent lenalidomide was feasible and potentially effective in prolonging remissions in patients with adverse biologic features at baseline who are not able to pursue additional consolidation chemotherapy and/or ASCT. Most of relapsing patients (75%) did so within 6 months of lenalidomide initiation, and none of the patients relapsed after completing 24 months of treatment. This is indicative that patients who remain in remission beyond 6 months are more likely to achieve long-term remission with lenalidomide maintenance; and persistent MRD contributes to relapse. Although lead time bias is one of the limitations of this trial, most of patients with sAML or tAML (7/9 patients) started lenalidomide within 6 months of remission date, and had short remission duration on lenalidomide. Other limitations of this study are the number of enrolled patients, which highlight the challenges of enrolling on a trial of AML maintenance, and the heterogeneity of induction/consolidation regimens that patients received prior to starting lenalidomide maintenance.

The optimal duration of maintenance treatment in AML can also be debated. In the QUAZAR AML-001 trial, oral CC-486 was given indefinitely until disease progression or unacceptable toxicities. Longer duration of lenalidomide maintenance until disease progression might be problematic, especially due to increased incidence of secondary hematologic and solid malignancies as seen in patients with multiple myeloma with lenalidomide maintenance therapy.²⁷ A novel combination approach worth investigating is lenalidomide in addition to CC-486 in order to further improve CR duration and ultimately OS. Comparative trials should be conducted to further determine the additional benefit of lenalidomide maintenance treatment in AML.