Lenalidomide and Eltrombopag for Treatment of Low- or Intermediate-Risk Myelodysplastic Syndrome: Result of a Phase II Clinical Trial

Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant hematopoietic stem cell disorders characterized by ineffective growth and differentiation of hematopoietic progenitors leading to cytopenias, and a variable risk of transformation to acute myeloid leukemia (AML; ref. 1). Thrombocytopenia is a serious complication of MDS and is associated with an increased bleeding risk and worse prognosis. Platelet transfusions have a short therapeutic effect and can trigger transfusion reactions (2). In addition, thrombocytopenia can prolong the time to the next cycle of treatments and lead to dose reductions that can further compromise the efficacy of MDS-directed therapy. At this time, there are no FDA-approved treatments that directly address thrombocytopenia in MDS.

The thalidomide analog lenalidomide (LEN) is an immunomodulatory drug (3) approved for the treatment of MDS with chromosome 5q deletion (del5q) as it has shown to induce disease remissions and transfusion independence in ∼50% of this population (4). For patients without del5q, LEN has been shown to reduce transfusion requirement in ∼25% of patients, but its use is limited by significant thrombocytopenia, and patients with platelet counts (PLTs) <50,000 k/μL have been excluded from these trials (5).

Eltrombopag (ELT) is an orally bioavailable small peptide thrombopoietin receptor (TPO-R) agonist that binds to the transmembrane domain of the TPO-R, inducing proliferation and differentiation of hematopoietic stem cells (6, 7). ELT has proven to be clinically effective increasing PLTs in MDS. ELT has additionally shown a therapeutic index in MDS in preclinical studies and trials evaluating its use in low and intermediate (low/int)-risk MDS (8, 9). ELT has also been shown to stimulate stem and progenitor growth via iron chelation thus providing a further rationale for use in iron overloaded MDS (6, 7, 10, 11). Furthermore, preclinical data have demonstrated that ELT can reverse the anti-megakaryopoietic effects of LEN in primary MDS patient samples without increasing the growth of the leukemic stem cells (10). Based on this rationale, we conducted a study to determine the safety and efficacy of the combination of eltrombopag and lenalidomide (ELT/LEN) in low/int-risk MDS (NCT01772420) with the hypothesis that it would reduce the incidence of LEN-induced thrombocytopenia thus enabling patients to tolerate the required duration of LEN therapy leading to higher rates of response.

Eligible patients were aged ≥ 18 years with a diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML; WBC ≤ 12,000/mL) of at least 3-month duration according to World Health Organization (WHO) criteria (12, 13) and International Prognostic Scoring System (IPSS) categories of low- or intermediate-1–risk disease (14). Patients either had symptomatic anemia untransfused with hemoglobin ≤ 10 g/dL in the 8 weeks before starting the study or had RBC transfusion dependence (i.e., ≥ 2 units/month) confirmed 8 weeks before starting the study and/or PLTs < 50,000/μL with hemoglobin > 10.0 g/dL. Patients must not have received prior therapy with LEN (for more than 2 months) nor ELT. The trial was conducted according to institutional guidelines and recognized ethical guidelines (Declaration of Helsinki). Institutional review boards or ethics committees at each site approved the protocol. Informed written consent was obtained from all study participants before participating in the trial.

In this Phase II multicenter, open-label trial, patients were assigned to one of the 2 arms based on their baseline PLT count: if patients had PLTs > 50,000 k/μL, they were assigned to Arm A; if they had PLTs < 50,000 k/μL, they were assigned to Arm B.

Patients in Arm A (PLTs > 50,000 k/μL) were started on LEN 10 mg daily for 21 days of a 28-day cycle. If their PLTs dropped to less than 50,000 k/μL during treatment, LEN was stopped, and ELT was started at a dose of 100 mg initially and titrated up (up to a maximum of 300 mg/day) to achieve a PLT count above 50,000 k/μL. Once a PLT count > 50,000 k/μL was achieved, that dose of ELT was continued for an additional 2 weeks. If a PLT count > 50,000 k/μL was maintained for 2 weeks, ELT was discontinued, and LEN restarted as a single agent. If PLTs fell < 50,000 k/μL a second time, then LEN was stopped, and ELT reinitiated at the dose that was last given to the patient. Once the PLTs were > 50,000 k/μL and maintained at this level for 2 weeks, LEN was started again, and this time given concurrently with ELT for all subsequent cycles.

Patients in Arm B (PLTs < 50,000 k/μL at baseline) were started on ELT at a dose of 100 mg initially and titrated up to achieve PLTs > 50,000 k/μL. The dose titration included dose increments of 100 mg to a maximum dose of 300 mg/day. Once PLTs > 50,000 k/μL was achieved, that dose of ELT was continued for an additional 2 weeks. If PLTs > 50,000 k/μL was maintained for 2 weeks, ELT was discontinued and LEN was started, following the treatment algorithm described for patients in Arm A.

During study, patients that were started on Arm B (PLTs < 50,000 k/μL) were permitted to stay on ELT alone if they achieved a hematologic response on ELT by the 2006 International Working Group (IWG) Criteria (Supplementary Table S1) or if their baseline hemoglobin was > 10.0 g/dL and didn't decrease while on study drug (Fig. 1).

The study's primary objectives were to evaluate the rate of hematologic improvement (HI) as per the 2006 MDS IWG criteria (Supplementary Table S1; ref. 15) and to evaluate the safety and tolerability of the ELT and LEN treatments, including the risk of bleeding, thrombotic events, leukemic transformation, and any other adverse events. Secondary objectives were to assess the number of clinically significant bleeding events, pathologic bone marrow cytogenetic response assessment for complete or partial response based on IWG criteria (15), bone marrow morphologic response (complete response and partial response), duration of hematologic improvement, and time to attain hematologic improvement.

The data cut-off date was September 22, 2021. For baseline characteristics analyses we used Fisher exact test or Kruskal–Wallis test as appropriate. All the efficacy analyses were conducted in the intention-to-treat (ITT) population. Fisher exact test was used to compare responses based on MDS 2006 IWG Criteria (Supplementary Table S1; ref. 15) between low- and intermediate-risk MDS per the IPSS and the Revised IPSS (IPSS-R), and to compare responses among cytogenetic and somatic mutations. We used the Wilcoxon signed-ranked test to compare platelet responses between responders and nonresponders. For survival analysis, we plotted Kaplan–Meier curves and used the log-rank test to calculate significance.

When designing the study, it was calculated that a maximum of 52 patients would be enrolled in the study. On the basis of Simon's optimal two-stage design, an early stopping rule for lack of efficacy was implemented as follows. After the first 25 patients were enrolled and evaluated for response, the trial would be terminated early if fewer than 7 patients responded to treatment. If 7 or more responses were observed, the trial would continue until a total of 52 patients were evaluated. At the end of the trial, the treatment would be considered efficacious and worthy of further study if 17 or more patients responded of 52 patients.

The data generated in this study are available upon request from the corresponding author.

From April 2013 through January 2020, 52 patients were enrolled (Fig. 2): 28 to Arm A (PLTs > 50,000 k/μL), and 24 to Arm B (PLTs < 50,000 k/μL). Among those enrolled, 8 patients received treatment for < 6 weeks. Six patients withdrew consent and received < 6 weeks of treatment, 4 on ELT and 2 on LEN. One patient assigned to ELT never started treatment and 1 patient died of sepsis and received < 4 weeks of LEN.

The mean age of the patients was 71 years (range 34–93), mean age of patients on ELT was 68 years, 74 for patients on LEN, and 73 for patients on ELT/LEN. Seventy-one percent of the patients were men. Fifty-six percent of the patients were White, 17% Black, 21% Hispanic, and 4% Asian. Forty-nine (94%) patients had MDS and 3 (6%) CMML. One (2%), 24 (46%), and 27 (52%) patients had very low–risk, low-risk, and intermediate-risk disease, respectively, by IPSS-R criteria. Thirty (58%) patients were treatment-naïve and 21 (40%) had received ≥ 1 line of treatment, including erythropoiesis-stimulating agents and hypomethylating agents (HMA; Table 1; Supplementary Table S2). One patient had received LEN for < 2 months prior to enrollment; all patients were ELT-naïve. The median dose of ELT administered to the patients was 200 mg.

Forty-two patients had available testing for somatic mutations; at baseline, 36 of 42 patients (86%) were identified with somatic variants in genes recurrently mutated in myeloid malignancies. The most commonly mutated genes were TET2 (36%), SF3B1 (36%), ASXL1 (27%), RUNX1 (19%), SRSF2 (17%), and BCOR (14%).

As per IWG criteria, the overall response rate (ORR) in the ITT population was 35% (18/52). Thirteen (25%) patients achieved HI in erythrocytes (HI-E), 9 (17%) patients had platelet HI (HI-P), 7 (13%) patients had bilineage responses, and 3 (6%) achieved complete remission (CR) as per IWG criteria (15).

Twenty-one patients received ELT monotherapy, among these ORR was 33.3% (7/21), with 29% achieving HI-P, and 24% achieving bilineage responses with 1 CR. In this group, patients with PLTs < 20,000 k/μL had an ORR of 45% (5/11), with HI-P of 45%, and patients with PLTs between 20 to 50,000 k/μL had an ORR of 22.2% (2/9), with HI-P of 11.1%.

Sixteen patients received LEN monotherapy, 1 patient had del5q, ORR was 38% (6/16). All of the responders on LEN monotherapy achieved HI-E. Fifteen patients received both ELT and LEN, ORR was 33.3%, 20% achieved HI-E and 20% HI-P with 13% achieving bilineage responses and 2 CRs (Table 2).

Of the 27 (52%) patients who were RBC transfusion–dependent (RBC-TD), 29.6% (8/27) achieved RBC-TI. Fifty percent (5/10) of patients on LEN, 20% (2/10) on ELT, and 14% (1/7) on ELT/LEN achieved RBC-TI, respectively.

Of the ELT/LEN group, 11 patients initially received LEN and were given ELT after developing thrombocytopenia. Of these patients, 3/11 (30%) had an objective response and 2 of them had a CR: 1 is depicted in Fig. 3 and the other didn't require LEN reintroduction because the patient responded on ELT alone with improvement in hemoglobin.

Our trial included 2 patients with human immunodeficiency virus (HIV)-positive MDS, who had undetectable viral loads before starting the study. Both achieved sustained CRs, 1 with ELT alone and 1 with the combined use of ELT and LEN. The second patient developed thrombocytopenia while on LEN and was then started on ELT. ELT treatment led to improvements in both thrombocytopenia and anemia and resulted in transfusion independence (Fig. 3).

The median time to response was 8 weeks (range 6–12.4) for ELT alone, 12 weeks (range 2.4–16) for LEN alone, and 8 weeks (range 2–20) for ELT/LEN combination. The median duration of response was 40 weeks for ELT (range 8–ongoing), 41 weeks (range 25–ongoing) for LEN, and 88 weeks (range 8.3–ongoing) for ELT/LEN as of the last follow-up. There was no statistical difference when comparing responses between patients with low-risk MDS and intermediate-risk MDS based on IPSS or IPSS-R, no difference among race/ethnicity, as well as no difference in responses based on baseline cytogenetic or somatic mutations (Supplementary Tables S3 and S4).

Nonresponders had a median overall survival (mOS) of 315 days, versus not reached in responders (P = 0.0036; Supplementary Fig. S1). The ELT group had a mOS of 410 days, the LEN group had a mOS of 603 days, and the ELT/LEN group of 528 days. There was no difference in OS across groups. (Supplementary Fig. S2)

Non-hematologic grade 3–4 treatment-related adverse events were few, including G3 hyperbilirubinemia (2%), G3 transaminitis (2%), G3 bleeding (4%), G4/5 pneumonia (2%), G3 febrile neutropenia (2%) for ELT, and G3 hyperbilirubinemia (4%), G3 transaminitis (4%), G3 rash (4%), G3 arthralgia (2%), G4 pneumonia (2%), G3/4 febrile neutropenia (4%), G3 atrial fibrillation (2%), pericarditis (2%) for LEN (Table 3). Two patients had major bleeding events who were on ELT (upper GI bleed and right arm hematoma). There were 4 deaths, 3 attributable to infectious complications and 1 to gallbladder cancer. One patient who received ELT had a reversible increase in peripheral blasts (up to the highest level of 14%) during an episode of acute cholecystitis, and 1 patient had development of marrow fibrosis after 6 years of ELT. Five patients discontinued treatment due to side effects. Of the 3 patients on ELT who discontinued treatment, 1 patient discontinued treatment due to a combination of G2 headache, G2 dizziness, G2 blurry vision, and G2 abdominal pain; 1 patient because of development of moderate bone marrow fibrosis; and 1 patient due to a G3 hematoma. Of the 2 patients on LEN who discontinued treatment, 1 was due to a G2 facial rash, and 1 due to G2 abdominal pain and G2 diarrhea.

Although thrombocytopenia is a serious and potentially fatal complication in patients with MDS, there are no current FDA-approved agents that directly address this problem. Several studies have shown the efficacy and safety of ELT in patients with MDS. A randomized, single-blinded, and controlled Phase II study in patients with low-risk MDS, found ELT to be well tolerated and clinically effective (8). A second single-agent Phase II study in patients with low- and intermediate-risk MDS corroborated this result (9). Both of these studies used ELT up to a maximal dose of 150 mg/day. A multicenter, randomized, placebo-controlled, double-blind study showed a good safety profile of ELT in high-risk MDS and AML at doses up to 300 mg daily (16). Attempts to overcome therapy-induced thrombocytopenia in MDS with combination therapy have been tried and have unfortunately failed so far. The addition of ELT to standard-of-care treatment with HMAs showed worsening of thrombocytopenia in the Phase III, randomized SUPPORT trial suggesting potential adverse pharmacodynamics in combination with HMAs (17). On the basis of the prior success of ELT in MDS, we designed a study that combined treatment of ELT with LEN, with the hypothesis that it would reduce the incidence of LEN-induced thrombocytopenia thus enabling patients to tolerate the required duration of LEN therapy leading to higher rates of response.

We determined that 29% of patients who received ELT monotherapy in our study achieved hematologic improvement in platelets with a median duration of response of 40 weeks, similar to the previously mentioned Phase II, placebo-controlled study in patients with low/int-risk MDS that showed significant improvement in PLTs, 47% versus 3% favoring the treatment arm (8). We additionally observed that patients on ELT monotherapy achieved bilineage responses (24%) which are similar to results of the prior clinical trial by Vicente and colleagues (9) These bilineage and trilineage responses on ELT monotherapy have also been seen in prior clinical trials in patients with severe aplastic anemia, such as the trial by Desmond and colleagues that showed an ORR of 40%, including tri- and bilineage responses, and suggest stimulatory activity at the hematopoietic stem and progenitor level (6, 18). Furthermore, in the group of patients that received ELT and LEN either in combination or sequentially, we observed an ORR of 33%, with 20% achieving HI-P and 20% HI-E with tolerable safety signals. Finally, our LEN monotherapy group had similar responses to prior studies with LEN in low/int-risk disease (4). These responses are also comparable with other treatment modalities for symptomatic lower-risk MDS patients, such as HMAs, which have a 30% response rate (19), or luspatercept, which has a similar response rate in MDS with ring sideroblasts (RS; ref. 20). In addition, this trial included 2 patients with well-controlled HIV who were able to tolerate and respond to treatment, which is an indicator that this patient population shouldn't be excluded from clinical trials.

The toxicity profile in our study was comparable with that in previous studies (4, 8, 9). A concern with ELT has been the potential progression to higher-risk MDS and AML seen in clinical trials with other TPO-R agonists, such as romiplostim, which has led to the discontinuation of clinical trials because of a rise in blast counts (21, 22). But ELT has shown that it does not stimulate leukemic cell growth in in vitro preclinical studies with leukemia cell lines, and furthermore, it inhibits the proliferation of AML cell lines (7, 10, 11), potentially due to its ability to chelate intracellular iron and inhibit the TET mutant clones (6, 23). In our study, 1 patient had a transient increase in peripheral blasts; however, we did not have any patients with progression to AML.

In conclusion, in a Phase II multicenter, open-label trial, we observed that treatment with ELT and LEN is effective at achieving hematologic improvement in a portion of patients with lower-risk MDS and is well tolerated. Moreover, ELT can lead to single-agent and bilineage responses. The conclusions are limited by non-randomized trial design, small sample size, and the inability to account for clonal evolution. Further larger, prospective, and controlled studies are needed to better define the role of ELT as well as combinatorial strategies with ELT in the treatment of patients with low/int-risk MDS.

A. Yacoub reports personal fees from Incyte, Pfizer, Novartis, Servier, CTI Pharma, Pharmaessentia, AbbVie, Apellis, Gilead, and Notable Labs outside the submitted work. J. Berdeja reports grants and personal fees from Bristol Myers Squibb during the conduct of the study. J. Berdeja also reports grants from 2Seventy Bio, AbbVie, Acetylon, Amgen, C4 Therapeutics, CARsgen, Cartesian, Celularity, EMD Serono, Fate Therapeutics, Genentech, GlaxoSmithKline, Ichnos Sciences, Incyte, Karyopharm, Lilly, Novartis, Poseida, Sanofi, Teva, and Zentalis; grants and personal fees from Bluebird Bio, Celgene, CRISPR Therapeutics, Janssen, and Takeda; and personal fees from Kite Pharma, Legend Biotech, and Secura Bio outside the submitted work. I. Mantzaris reports personal fees from Kite Pharma outside the submitted work. K. Gritsman reports grants from Celgene and GlaxoSmithKline during the conduct of the study; in addition, K. Gritsman reports research funding for unrelated projects from iOnctura, Societe Anonym, and ADC Therapeutics. U. Steidl reports grants from GlaxoSmithKline and Bayer; personal fees from Celgene, Pieris Pharmaceuticals, Novartis, Pfizer, and Trillium Therapeutics; grants and personal fees from Aileron Therapeutics and Vor Biopharma; and grants, personal fees, and other support from Stelexis Therapeutics outside the submitted work. B. Will reports grants from Novartis Pharma and Life Biosciences, as well as personal fees from Novartis Pharma outside the submitted work. A. Shastri reports research funding from Kymera Therapeutics, consultancy fees from Janssen, advisory board fees from Rigel Pharmaceuticals and Kymera Therapeutics, and honorarium from NACE. A. Verma reports grants from Bristol Myers Squibb and Novartis during the conduct of the study. A. Verma also reports research funding from GlaxoSmithKline, Bristol Myers Squibb, Janssen, Incyte, MedPacto, Celgene, Novartis, Curis, Prelude, and Eli Lilly and Company; compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, Bakx Therapeutics, and Celgene; and equity ownership in Throws Exception Clinstreet and Stelexis Therapeutics. No disclosures were reported by the other authors.

J.D. Gonzalez-Lugo: Data curation, formal analysis, investigation, writing–original draft, writing–review and editing. S. Kambhampati: Project administration, writing–review and editing. A. Yacoub: Project administration, writing–review and editing. W.B. Donnellan: Project administration, writing–review and editing. J. Berdeja: Project administration, writing–review and editing. P. Bhagat: Project administration. K. Fehn: Project administration. C. Remy: Project administration. S. Jasra: Writing–review and editing. M. Kazemi: Writing–review and editing. K. Pradhan: Data curation, formal analysis. M. Kim: Conceptualization, formal analysis. I. Mantzaris: Writing–review and editing. R.A. Sica: Writing–review and editing. N. Shah: Writing–review and editing. M. Goldfinger: Writing–review and editing. N. Kornblum: Writing–review and editing. K. Gritsman: Writing–review and editing. I. Braunschweig: Writing–review and editing. U. Steidl: Supervision, writing–review and editing. B. Will: Supervision, writing–review and editing. A. Shastri: Conceptualization, supervision, funding acquisition, writing–original draft, writing–review and editing. A. Verma: Conceptualization, resources, data curation, supervision, funding acquisition, methodology, writing–original draft, project administration, writing–review and editing.

This work received financial support from Novartis and Bristol Myers Squibb.

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