Eltrombopag in Chronic Myelomonocytic Leukemia With Severe Thrombocytopenia. A Gfm Study

doi:10.21203/rs.3.rs-4113825/v1

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Eltrombopag in Chronic Myelomonocytic Leukemia With Severe Thrombocytopenia. A Gfm Study

https://doi.org/10.21203/rs.3.rs-4113825/v1

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published 12 Sep, 2024

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We conducted a multicenter single-arm phase II trial evaluating the oral thrombopoietin receptor agonist eltrombopag in chronic myelomonocytic leukemia (CMML) patients without blast excess and with platelets < 50 x10⁹/L.

CMML patients naïve of hypomethylating agents, with bone marrow blasts ≤ 5%, platelets < 50 x10⁹/L and with lower-risk disease received eltrombopag for at least 12 weeks including an 8-week titration. The primary endpoint was platelet response at 12 weeks (IWG 2006 criteria).

Twenty-nine patients were enrolled (median age 78 years). Median platelet count was 29 x10⁹/L. CPSS risk was low or intermediate-1 in 55% and 31% of patients respectively. RUNX1 was mutated in 56% of patients.

Eight patients dropped out the trial before 12 weeks (including 3 for early progression). A platelet response was achieved in 14 (48.3%, 95% CI 29.4–67.5) patients at 12 weeks, and in 21 (72.4%) at any time on study. Median response duration was 2.6 months, with 10 (34.5%) patients experiencing responses lasting ≥ 6 months. Grade 3 hepatobiliary adverse events occurred in 3 (10%) patients. Two-year progression-free and overall survival were 23% and 47%, respectively.

Carefully escalated eltrombopag induces frequent but transient platelet responses in CMML patients with thrombocytopenia.

Health sciences/Medical research/Drug development

Biological sciences/Cancer/Haematological cancer/Myelodysplastic syndrome

Chronic Myelomonocytic Leukemia

Thrombocytopenia

Eltrombopag

Chronic Myelomonocytic Leukemia (CMML) is the most frequent myelodysplastic/myeloproliferative overlap syndrome in adults ^1–3. Thrombocytopenia is frequent in CMML, occurring in 50–60% of patients, and is severe (platelet count < 50 x10⁹/L) in 10–30% of cases ^4–6. Thrombocytopenia leads to significant morbidity and mortality caused by bleeding ^{7, 8}, further aggravated in some patients by platelet dysfunction ^{9, 10}. Furthermore, CMML is often diagnosed in the elderly, with a median age at diagnosis around 70 years, and older age is an independent risk factor of bleeding in patients with thrombocytopenia ¹¹. Thrombocytopenia is also an independent predictor of increased risks of disease progression and transformation to AML ^12–14.

Management of thrombocytopenia is ill codified in CMML, with retrospective studies reporting anecdotal responses to steroids or danazol ². Transfusion support is resource consuming and has limited long-term efficacy due to immunization ¹⁵.

Eltrombopag is a small molecule, non-peptide, oral thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenic purpura (ITP) or acquired severe aplastic anemia ¹⁶. Eltrombopag has been shown to improve platelet counts in patients with lower-risk myelodysplastic syndrome ^17–19. In patients with higher-risk MDS or AML and/or with previous HMA failure, the objective response rate is modest, but eltrombopag nevertheless significantly decreases the incidence of clinically relevant thrombocytopenic and bleeding events ^20–23. Its activity in CMML with thrombocytopenia has been investigated in retrospective case series of up to eleven patients, ^24–26, or as part of a phase I MDS trial ²⁷. We report the results of a multicenter phase II study of single agent eltrombopag in CMML patients with thrombocytopenia (platelets < 50 x10⁹/L) and without blast excess.

Study design

This multicenter, open-label, single-arm, phase II clinical trial enrolled patients from 15 centers from August 2014 to September 2018. Patients received eltrombopag at a starting dose of 100 mg once daily (later amended to 50 mg/day based on safety concerns from ²⁷) for a minimum of twelve weeks. Eltrombopag dosing could be sequentially escalated every other week by 100 mg/day steps up to 300 mg/day or de-escalated by 50 mg/day steps from any starting dose in case of platelets > 400 x 10⁹/L or at the clinician’s discretion. The maximum eltrombopag dose was 150 mg/day for East Asian subjects.

Cytoreduction with hydroxyurea was recommended in patients with a WBC count > 30 x10⁹/L and mandatory if > 50 x10⁹/L and continued until resolution of hyperleukocytosis or study discontinuation due to progressive disease per protocol criteria. Concomitant use of erythropoiesis stimulating agents was not allowed. The platelet transfusion policy was aligned with recommendations from the French health authorities, i.e., in case of platelet count < 10 x10⁹/L or higher in case of fever, infection, hypertension, mucositis or other bleeding-prone lesion, or brutal fall of platelet counts over the last 72 hours. The transfusion threshold could be as high as 50 x10⁹/L in case of active bleeding.

In patients deriving clinical benefit, eltrombopag was to be continued at the effective dose up to 24 months in the absence of major toxicity (including arterial or deep-vein thrombotic event and treatment-emergent AEs grade ≥ 3 according to NCI CTCAE version 4.0 not recovering to grade ≤ 2 with adequate dosing delay), loss of efficacy or disease progression. Patients were followed at least 6 months after the last administration of eltrombopag.

Eligibility criteria

Eligible patients were 18 years or older, with a confirmed diagnosis of CMML according to WHO 2010 criteria ²⁸, bone marrow blasts ≤ 5%, a platelet count < 50 x10⁹/L on two successive blood counts in the 2 weeks before inclusion and lower risk disease. Lower risk was defined in patients with myelodysplastic CMML (MD-CMML, WBC < 13 x10⁹/L) as a low or intermediate-1 risk according to IPSS ²⁹, and in patients with myeloproliferative CMML (MP-CMML, WBC ≥ 13 x10⁹/L) as at most one of the following criteria derived from Wattel et al ³⁰: clonal cytogenetic abnormality other than t(5;12)(q33; p13), absolute neutrophil count > 16 x10⁹/L, Hb < 100 g/L and documented extramedullary localization other than splenomegaly. Of note, although the study protocol initially allowed the accrual of higher risk patients (MD-CMML: IPSS intermediate-2 or high, MP-CMML: two or more of the above-mentioned criteria) provided they previously failed hypomethylating agents, no such patient was accrued in the present study. Other relevant eligibility criteria included a performance status ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale and adequate renal and liver functions. Patients eligible for allogeneic hematopoietic cell transplantation (allo-HCT), those with hepatitis C infection, splenomegaly > 16 cm by ultrasound or CT scan, grade ≥ 2 myelofibrosis, clinically relevant thromboembolic risk factor or prior cancers (except in situ cervix carcinoma, limited basal cell carcinoma, or other tumors if not active during the last 3 years) were excluded.

Endpoints and assessments

The primary endpoint was platelet response (hematological improvement – platelet lineage [HI-P]) after 12 weeks, according to International Working Group (IWG) 2006 criteria ³¹. Secondary endpoints were major and minor platelet response at 12 weeks according to the 2000 IWG criteria ³², duration of platelet response, evolution of bleeding symptoms and of platelet transfusions. Other secondary endpoints included overall (OS) and progression-free (PFS) survival and eltrombopag safety according to NCI CTCAE v4.0.

Platelet transfusion dependency was defined by the transfusion of any number of platelet units during the 8 weeks before accrual. Disease progression was defined as a > 50% increase of bone marrow blasts from baseline or best response to > 5% blasts, or by a significant increase of myeloproliferative features, as previously defined (doubling of WBC count, new extramedullary disease including palpable splenomegaly or increase of palpable splenomegaly to > 5 cm below costal margin) ^{30, 33}.

Molecular genetics

Targeted sequencing of a 36-gene panel (list in Supplementary Table 1) was done using Ion AmpliSeqT Custom Panel Primer Pools to perform multiplex PCR. Library preparation included addition of indexed paired-end adaptors (NEXTflex, Bioo Scientific) to sequence in an Illumina MiSeq flow cell using the onboard cluster method, as paired-end sequencing (2x250 bp reads) (Illumina, San Diego, CA). Briefly, PCR amplicons after Fupa digestion were end-repaired, extended with an 'A' base on the 3'end, ligated with indexed paired-end adaptors (NEXTflex, Bioo Scientific) using the Bravo Platform (Agilent), amplified by PCR for 6 cycles and purified with AMPure XP beads (Beckman Coulter). Standard (CPSS) and molecular (CPSS-mol) CMML Prognostic Scoring Systems were computed post hoc ^{6, 34}.

Statistical analyses

The sample size was determined using Flemming’s single-stage Phase II design ³⁵. Considering a HI-P rate below 10% would imply lack of efficacy, a sample of at least 24 patients had to be recruited to detect a response rate greater than 35% with 90% power and a type I error rate at 5% (two-sided test). Following a pre-planned futility interim analysis after 12 enrolled patients ³⁶, the sample size was readjusted as requested by the data and safety monitoring board to reach a statistical power of 95% - to a total of 30, with each analysis to be performed at the 2.5% level.

Summary statistics are reported, namely numbers and percentage for qualitative data and median with inter-quartile range (IQR) and range for quantitative data. Outcome analysis used the modified intent-to-treat population, where only consent withdrawals were excluded. Clopper and Pearson exact confidence interval (CI) of the primary endpoint was computed, considering dropouts as non-responders, with comparison to the control rate of 10% based on the exact binomial test. Censored data were plotted using the non-parametric Kaplan-Meier estimator with 95% confidence intervals. Prognostic factors of OS and PFS were investigated using Cox proportional hazard models. Models assumptions were checked using statistical test and graphical diagnostics based on the scaled Schoenfeld residuals for proportional hazards ³⁷ and spline smoothing of residuals for the log-linearity assumption. Statistical analyses were done using R version 4.2.1 (https://www.R-project.org/). The study datasets are available from the corresponding author on reasonable request.

Study oversight

The study protocol and amendments were approved by the CPP Ile-de-France X ethics committee and the French Health Authority (Agence Nationale de Sécurité du Médicament et des Produits de Santé). The amended study protocol (including safety assessment procedures) is available as supplement online. All patients provided written consent. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, the guidelines for Good Clinical Practice of the International Conference on Harmonization, European directives and national legislation on clinical trials. A data and safety monitoring board oversaw the trial, assessing safety and efficacy, and recommended completion of accrual after the planned interim analysis, but increasing the sample size to improve study power (see supra). The study is registered on EudraCT (2013-001779-19) and clinicaltrials.gov (NCT02323178).

Study population

From August 2014 to September 2018, 40 patients were screened and 30 were enrolled in 13 centers. Screening failed due to bone marrow blast excess upon central morphology review (n = 5), platelet counts increasing above 50 x109/L (n = 4) and transient monocytosis (n = 1). One patient withdrew his consent before beginning study treatment, leaving 29 patients (21 males, 8 females) in the modified intent to treat (ITT) population.

Baseline clinical and biological characteristics are summarized in Table 1. Median age at inclusion was 78 years (IQR, 74–83; range 65–93). All patients had CMML-1 per WHO 2010 criteria ²⁸, with a median bone marrow blast count of 3 (IQR 2–4; range 0–5). Nine (31%) patients had MP-CMML and 20 (69%) MD-CMML. The CONSORT diagram of the study is provided in Fig. 1A.

Table 1

Study population.
Parameters	N (%) or median (range)
	n = 29
Age, years	78 (64–92)
Sex
Male	21 (72)
Female	8 (28)
Performance Status (ECOG scale, n = 27)
0	11 (41)
1	14 (52)
2	2 (7)
CMML subset (WHO 2010)
CMML-1	29 (100)
CMML-2	0 (0)
CMML-MD	20 (69)
CMML-MP	9 (31)
Bone marrow blasts, %	3 (0–5)
Peripheral blasts, %	0 (0–2)
WBC (G/L)	9 (3.9–27.6)
Hemoglobin (g/dL)	12.8 (8.3–15.1)
Platelets (G/L)*	29 (13–59)
Platelet transfusions
Dependent	12 (41)
Independent	17 (59)
Platelet transfusions over the last 8 weeks (n = 12)	1 (1–6)
CPSS
Low	16 (55)
Intermediate-1	9 (31)
Intermediate-2	3 (10)
High	0 (0)
Not evaluable**	1 (4)
Previous Therapy
No	18 (62)
Yes	11 (38)

Median platelet count at screening was 29 x10⁹/L (IQR, 21–43; range 13–59). Twelve (41%) were dependent on platelet transfusions, with a median of 1 (range 1–6) platelet transfusions over the previous 8 weeks. One (3%) and four (14%) had bleeding symptoms (all grade 1) at inclusion or within the first two weeks on treatment, respectively.

CPSS risk was low in 16 (55%) patients, int-1 in 9 (31%) patients, int-2 in 3 (10%) patients and unknown (missing cytogenetics) in 1 (4%). Centralized genetics was done in 27 patients (included 2 with missing SETBP1 data). TET2 was the most frequently mutated gene (93%) followed by RUNX1 (56%), SRSF2 (37%), ASXL1 (33%), PHF6 (17%) and EZH2 (15%) (Fig. 1B). CPSS-mol was low in 5 (17%) patients, intermediate-1 in 4 (14%) patients, intermediate-2 in 13 (45%) patients, high in 2 (7%) patients and not known in the remaining 5 (17%) patients. Eleven (38%) patients had received at least one previous therapy including erythropoiesis-stimulating agents (n = 2), hydroxyurea (n = 2), corticosteroids (n = 6), intravenous immunoglobulin (n = 3) and danazol (n = 1).

Eltrombopag was initiated at 100 mg/day in 16 patients and at 50 mg/day in the remaining 13 patients following protocol amendment. Eight (28%) prematurely dropped out the trial before the 12-week evaluation, due to early disease progression (n = 3), early death (deterioration in general condition, n = 1), newly diagnosed pancreatic cancer (n = 1), toxicity (n = 1, grade 3 hypocalcemia) and lack of efficacy according to the investigator (n = 2).

Primary endpoint: Platelet response at 12 weeks

Fourteen (48.3%, 95% CI, 29.4–67.5%) patients achieved a platelet response [HI-P] at 12 weeks per IWG 2006 criteria, thus meeting the study primary endpoint (p < 0.0001). Of note, all the 14 patients met the IWG 2000 criteria for major platelet response, without any additional minor responder with those criteria (Table 2). The median dose of eltrombopag at the 12-week visit was 175 mg per day (range 50–300 mg/day) across the 22 patients, 100 mg/day (range 50–300 mg/day) among the 14 IWG 2006 responders and 225 mg/day (range 50–300 mg/day) in the 8 evaluable non-responders.

Table 2

Response and response duration
Response	N (%) or median (95% CI)
Platelet Response at twelve weeks (IWG2006)
No Response	15 (52)
Response	14 (48)
Platelet Response at twelve weeks (IWG2000)
No response	15 (52)
Major Response	14 (48)
Minor Response	0 (0)
Platelet Response at any time (IWG2006)
No Response	8 (28)
Response	21 (72)
Platelet Response at any time (IWG2000)
No response	5 (18)
Major Response	12 (41)
Minor Response	12 (41)
Median duration of response, months
IWG 2006 criteria	2.6 (1.1–11.6)
IWG 2000 criteria	3.2 (2.3–8.8)

Platelet response beyond 12 weeks

With a median follow-up of 40 months, the 29 patients received eltrombopag for a median of 15 weeks (IQR, 10–32; range 2-105 weeks) at a median dose of 200 mg/day (range 50–300 mg/day). Eighteen patients continued eltrombopag beyond the 12-week initial evaluation, including the 14 responders at 12 weeks and an additional 4 patients with platelet improvement below the IWG 2006 defined response threshold. Overall, 21 patients (72.4%, 95% CI 52.8–87.3%) achieved an IWG 2006 platelet response at any time on study, including 3 with transient responses starting before 12 weeks but lost at 12 weeks, and 4 with a response starting after 12 weeks. Across those 21 patients, the median time to first response was 14 days and response duration was 2.6 months (95% CI, 1.1–11.6 months, Fig. 2A). Loss of response was caused by decrease in platelet counts alone (n = 12) or with platelet transfusion requirement (n = 6), or due to disease progression or death (n = 3). Overall, any-time responders (n = 21) received a median of 23 weeks of eltrombopag (IQR, 13–39; range 5–104 weeks). In 9 (43%) of those 21 responders, response was prolonged for a median 5.9 weeks (IQR 3.7–9.0, range 1.6–63.0) beyond eltrombopag withdrawal. At any time during study, 24 patients experienced a platelet response according to IWG 2000 criteria (82.7%, 95% CI, 64.2–94.1%) including 12 major and 12 minor responses. Median duration of IWG 2000 response was 3.2 months (95% CI, 2.3–8.8 months). Among the 12 patients with baseline PLT-TD, 6 patients achieved PLT-TI for a median of 19.6 weeks (IQR, 5.9–82.2; range 2.7–252.0). Nineteen (66%) patients required platelet transfusions at any time on study (including 9 of the 12 patients with baseline PLT-TD), with a median of 0.8 platelet transfusion per month (IQR, 0.4–3.2) until last transfusion. During study duration, a total of 37 bleeding events occurred in 16 patients (median 1 per patient, IQR, 1–3; range 1–6), including 27 grade 1, 4 grade 2, 5 grade 3 and 1 grade 4 bleeding event. Eleven of these events (including 10 grade 1 and 1 grade 3) occurred while patients were responding. Of note, no improvement of myeloproliferative features was noted in the 9 MP-CMML accrued. Reasons for eltrombopag withdrawal were lack or loss of response (n = 6), toxicity (n = 4), disease progression (n = 5), transient peripheral blast increase not meeting criteria for disease progression (n = 1), death (n = 2), investigator’s decision (n = 1) and protocol deviation (n = 1) while one patient was still on eltrombopag at the end of the study.

Progression and survival

During follow-up, 16 patients had disease progression including 5 patients transforming to AML, and 23 died. Progression, transformation to AML and death occurred on study while patients were exposed to eltrombopag in 8, 0 and 2 patients respectively. Causes of death were disease progression (n = 7) other malignancies (n = 2), cardio-respiratory events (n = 3), infection (n = 4), bleeding (n = 4) and others (n = 3). Two-year PFS was 23% (95% CI, 12–46%, Fig. 2B) and 2-year overall survival (OS) was 47% (95% CI 32–70%, Fig. 2C). Considering death as a competing risk, 2-year cumulative incidence of transformation to AML was 15% (95% CI 4–30%) and 2-year cumulative incidence of progression was 49% (95% CI 29–66%).

Predictors of response or progression

Platelet response at 12 weeks did not differ between patients with MD-CMML (n = 11, 55%) and those with MP-CMML (n = 3, 33%, p = 0.43), and in patients with (n = 8, 67%) or without baseline PLT-TD (n = 6, 35%, Fisher test p = 0.14). Neither CPSS (low/int-1: n = 8/16, 50%, int-2/high, n = 5/12, 42% p = 0.72) nor CPSS-mol (low/int-1 n = 4/9, 44%; int-2/high n7/15, 47%, p = 1) had any significant impact on response. There was no impact of individual recurrently mutated gene status on the probability of response (Fig. 1B). Notably, 6 of 15 RUNX1 mutated patients achieved an HI-P. Neither baseline hemoglobin level (p = 0.20) nor SRSF2 status (p = 0.44) predicted response. Finally, there was no evidence of any difference in the cumulative incidence of progression (p = 1.00) or of AML transformation (p = 0.61) beyond 12 weeks between patients achieving HI-P at twelve weeks and non-responders. Among the 28 patients alive at 12 weeks, there was no difference in OS between the 14 patients responding at this date and the remaining 14 patients (p = 0.39).

Safety

Grade ≥ 2 adverse events occurred in 23 patients during the first 12 weeks of eltrombopag, including 8 patients experiencing grade ≥ 2 adverse events (Table 3). The full list of grade ≥ 2 events is summarized in Supplementary Table 2. The most frequent grade ≥ 2 events included abdominal pain, constipation and diarrhea. Arthritis, fatigue and heart failure occurred in 4 patients each, including 3 cases of grade 3 hepatobiliary AEs and 3 grade 3 heart failures.

Table 3

**Safety profile.** Grade 2–4 adverse events occurring in at least X patients or grade 5 events occurring in any number of patients.
AE	Total	Grade 2	Grade 3	Grade 5
Abdominal pain	4	2	2	0
Constipation	4	4	0	0
Diarrhea	4	4	0	0
Arthritis	4	2	2	0
Fatigue	4	3	1	0
Heart failure	4	1	3	0
Gastrointestinal pain	3	3	0	0
Nausea	3	3	0	0
Arthralgia	3	3	0	0
Back pain	3	2	1	0
Weight loss	3	3	0	0
Hepatobiliary, Other	3	0	3	0
Hypertension	3	3	0	0
General, other	1	0	0	1
Cognitive disturbance	1	0	0	1
Adult respiratory distress syndrome	1	0	0	1

Our study reports the largest prospective trial of eltrombopag in CMML patients with thrombocytopenia. It is also the first to focus on HMA-naïve patients without blast excess. The study met its primary endpoint, with a platelet response rate of 48% at 12 weeks, significantly higher than the null hypothesis of a 10% response rate. These patients were receiving a median dose of eltrombopag of 100 mg/day at the 12-week evaluation. When considering platelet responses occurring at any time, this response rate increased to 72%. Responses could be obtained across the CMML spectrum, regardless of CPSS (or CPSS-mol) risk, including in patients with myeloproliferative CMML or those with baseline platelet transfusion dependence. Platelet increase was rapid, with a median 14 days from eltrombopag onset to response, but responses were mostly transient, lasting a median 2.6 months and no response was notable on other lineages. However, 9 patients had prolonged (> 6 months) platelet responses.

Though immune thrombocytopenia can occur in CMML ^{38, 39}, the mutational profile of our study population was suggestive of central thrombocytopenia in most cases, with 56% of patients harboring RUNX1 mutations, a master regulator of megakaryopoiesis and independent predictor of thrombocytopenia in CMML ^{12, 40}. The median dose required to achieve response at 12 weeks of 100 mg/day is also higher than that required to improve platelet counts in ITP ¹⁶, though we cannot formally rule out that improvement of an immune-mediated thrombocytopenia may have underpinned platelet response in some patients, as previously reported ²⁵.

Our study used MDS IWG 2006 criteria to define platelet response as primary endpoint ³¹. Of note, these are similar to those defining platelet response in the more recent MDS/MPN response criteria ⁴¹ or in the updated 2018 IWG criteria for MDS ⁴². The less stringent IWG 2000 response captured some additional minor responses ³². Importantly, studies of eltrombopag in patients with advanced MDS/AML showed that a reduction in clinically significant thrombocytopenic events could be obtained despite a low objective platelet improvement rate.

The response rate in our study is close to the ~ 50% response rate reported in selected HMA-naïve lower-risk MDS patients, but responses and eltrombopag exposure were more prolonged in MDS patients than in our cohort ^{17–19, 26}. This difference likely reflects both a difference in the mechanisms of thrombocytopenia (e.g. RUNX1 mutations were detected in 7% of lower-risk MDS patients treated by Vicente et al., compared to 56% in our study)¹⁹ and in the safety profile of eltrombopag in MDS versus CMML.

Elevated liver enzymes have been highlighted as a dose-limiting toxicity for eltrombopag ¹⁶. Our study implemented careful titration and a specific liver function management plan to mitigate this risk. Three patients experienced grade 3 hepatobiliary adverse events, two of which led to study discontinuation. Other adverse events leading to drug discontinuation included electrolyte disorders related to diarrhea in one case, and acute kidney failure caused by urolithiasis in another case. The causality of eltrombopag in these two latter events is unclear.

Transient circulating blast increases have been attributed to TPO receptor agonists in MDS, though these drugs do not seem to increase the long-term risk of disease progression ^{18, 21, 43}. In a phase I study including 7 CMML patients with previous HMA failure, including 5 with ≥ 10% bone marrow blasts, Ramadan et al. reported development of leukocytosis and/or increase in circulating blasts in five cases during the first cycle, raising concerns regarding the use of eltrombopag in that high risk population ²⁷. These results prompted us to reduce the starting dose from 100 mg to 50 mg per day, since 6 of those 7 patients received 100 mg or higher as starting eltrombopag dose. Despite this precaution, 3 patients progressed during the first 12 weeks of eltrombopag, and an additional 5 patients discontinued eltrombopag because of disease progression beyond the 12-week visit. The 12- and 24-month cumulative incidence of progression in the study population were 34% (95% CI, 18–52) and 49% (95% CI, 29–66) respectively. Though our study excluded patients with blast excess, thrombocytopenia itself remains an independent poor prognostic factor in CMML ^12–14, and the CPSS-mol risk was intermediate-2 or high in 15 of 24 evaluable patients (62.5%) in this study. Therefore, the contribution of eltrombopag exposure to disease progression in our study remains unclear but cannot be ruled out.

Our study has some limitations. It was a single-arm trial, and such a design does not support a causal interpretation as an effect of the treatment. Moreover, it relied on, knowledge external to the trial to estimate the outcome of the trial population, and one cannot exclude that the assumed 10% rate of response was too low. The high observed response rate is however far from this assumption.

Overall, these results suggest that careful use of eltrombopag may be considered in CMML patients with platelets < 50 x109/L and without blast excess, not as a long-term therapy, but rather to mitigate a transient situation, such as bleeding symptoms or planned surgery. In this case, our results advocate for an initial dose of 50 mg per day with careful titration monitoring blood counts and liver function tests and considering response unlikely to occur beyond the dose of 200 mg per day. Further studies of eltrombopag as long-term therapy in lower-risk CMML patients may only be envisaged in the context of clinical trials accounting for gene mutations to stratify patient risk. Alternative strategies to improve platelet counts need also be investigated in this disease, where both central and peripheral causes of thrombocytopenia may be intricated ⁴⁴.

Acknowledgments. The authors thank all participating patients and investigators. They are indebted to GFM staff for study management and site research associated for data collection. The authors would like to thank the SIRIC InsiTu : Comprendre les cancers : de l’inflammation à la tumeur (INCa-DGOS-INSERM-ITMO Cancer_18008). The study was funded by Novartis Pharma AG. However, Novartis was not involved in study design, conduct, analysis and was not involved in this publication.

Author contribution. RI, PF and SC designed the study. FR and RI interpreted the study results and drafted the manuscript. AWP and SC performed statistical analyses. FC and RS managed the study and supervised data collection. RI, BG, ST, TB, NV, JMTD, PP, AT, MD, JD, LL, LA and PF accrued patients. ND and ES performed genetic analyses. DL performed central morphology review. All authors reviewed the manuscript and approved its final version.

Competing Interest Statement. RI has consulted for Amgen, BMS/Celgene, CTI Biosciences (now Sobi) Daiichi-Sankyo, Gilead, Jazz, Karyopharm, Stemline Therapeutics (now Menarini) and Syndax, and received research funding from Abbvie and Janssen, none of which is related to the present work. LL has consulted for Amgen, BMS/Celgene, GSK, Incyte, Novartis and Pfizer, none of which is related to the present work. The other authors declare no conflict of interest.

Funding Sources. The study was funded by Novartis Pharma AG. However, Novartis was not involved in study design, conduct, analysis and was not involved in this publication.

This study has been presented in part at the 2017 and 2020 Annual Meetings of the American Society of Hematology.

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Eltrombopag in Chronic Myelomonocytic Leukemia With Severe Thrombocytopenia. A Gfm Study

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Abstract

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INTRODUCTION

PATIENTS AND METHODS

Study design

Eligibility criteria

Endpoints and assessments

Molecular genetics

Statistical analyses

Study oversight

RESULTS

Study population

Primary endpoint: Platelet response at 12 weeks

Platelet response beyond 12 weeks

Progression and survival

Predictors of response or progression

Safety

DISCUSSION

DECLARATIONS

REFERENCES

Additional Declarations

Supplementary Files

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