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. 2017 Jun 27;8(45):79073-79086.
doi: 10.18632/oncotarget.18674. eCollection 2017 Oct 3.

Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis

Francesca Palandri  1 , Giuseppe Alberto Palumbo  2 , Massimiliano Bonifacio  3 , Mario Tiribelli  4 , Giulia Benevolo  5 , Bruno Martino  6 , Elisabetta Abruzzese  7 , Mariella D'Adda  8 , Nicola Polverelli  9 , Micaela Bergamaschi  10 , Alessia Tieghi  11 , Francesco Cavazzini  12 , Adalberto Ibatici  13 , Monica Crugnola  14 , Costanza Bosi  15 , Roberto Latagliata  16 , Ambra Di Veroli  17 , Luigi Scaffidi  3 , Federico de Marchi  4 , Elisa Cerqui  8 , Barbara Anaclerico  18 , Giovanna De Matteis  19 , Marco Spinsanti  1 , Elena Sabattini  1 , Lucia Catani  1 , Franco Aversa  14 , Francesco Di Raimondo  2 , Umberto Vitolo  5 , Roberto Massimo Lemoli  10 , Renato Fanin  4 , Francesco Merli  11 , Domenico Russo  9 , Antonio Cuneo  12 , Maria Letizia Bacchi Reggiani  20 , Michele Cavo  1 , Nicola Vianelli  1 , Massimo Breccia  16
Affiliations

Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis

Francesca Palandri et al. Oncotarget. .

Abstract

In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk (p=0.024), large splenomegaly (p=0.017), transfusion dependency (p=0.022), platelet count <200×109/l (p=0.028), and a time-interval between MF diagnosis and RUX start >2 years (p=0.048). Also, patients treated with higher (≥10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (p=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (p<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results.

Keywords: myelofibrosis; predictive factors; response; ruxolitinib; splenomegaly.

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Conflict of interest statement

CONFLICTS OF INTEREST MT has acted as consultant and received honoraria from Novartis, BMS and ARIAD. MBo declares research funding from Novartis. GAP, FDR and AC report personal fees and non-financial support from NOVARTIS, from null, outside the submitted work.

Figures

Figure 1
Figure 1
Proportion of patients treated with different doses of ruxolitinib over time, after stratification according to ruxolitinib starting doses (A: 5 mg BID; B: 10 mg BID; C: 15 mg BID; D: 20 mg BID). Percentages are calculated on evaluable patients at each time point. Ruxolitinib starting doses were mainly administered according to prescribing information (i.e.: 5 mg BID if platelet between 50 and 99 ×109/l, 15 mg BID if platelet between 100 and 199 ×109/l, 20 mg BID if platelet ≥ 200 ×109/l).
Figure 2
Figure 2. Spleen response
A baseline splenomegaly palpable at <5 cm was not eligible for spleen response. (A) Evaluable patients with a baseline spleen palpable between 5 and 10 cm below left costal margin. Spleen response: 100% decrease (not palpable spleen). (B) Evaluable patients with a baseline spleen palpable >10 cm below left costal margin. Spleen response: ≥50% decrease in palpable spleen length. (C) Best percent change from baseline in palpable spleen length at any time. Each bar represents data from an individual patient.
Figure 3
Figure 3
Univariate (A) and multivariable (B) logistic regression models of baseline factors predictive for spleen response at 6 months in patients treated with ruxolitinib. The area under the ROC curve was 0.69 and the H-L test reported a p value of 0.79. IPSS: International Prognostic Score System. TSS: Total Symptom Score. Fibrosis was evaluated according to the European Consensus Grading System [33].
Figure 4
Figure 4. Landmark analyses by spleen response at 6 months
A 6-month time after the initiation of therapy was selected as a landmark for conducting the analysis of survival by response. Only patients alive at 6 months were included in the analysis, separated into two response categories according to whether they have had a spleen response at that time-point. (A) Unadjusted survival rate calculated with Kaplan-Meier. Survival probability at 3 years from ruxolitinib start was 77.9% in patients achieving a spleen response at 6 months (blue line, n=114) and 68.4% in patients without a spleen response (yellow line, n=213) (Log-rank, p=0.034). (B) Overall survival estimation adjusted for IPSS score (HR: 1.47, 95% CI: 0.87–2.49, p=0.151). The dashed line on the x-axis represents the 6-months landmark point. SR: spleen response. NR: no response.
Figure 5
Figure 5
Univariate (A) and multivariable (B) logistic regression models of baseline factors predictive for symptoms response at 6 months in patients treated with ruxolitinib. The area under the ROC curve was 0.70 and the H-L test reported a p value of 0.47. IPSS: International Prognostic Score System. TSS: Total Symptom Score.
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