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In: The Lancet Haematology, Elsevier BV, Vol. 7, No. 10 ( 2020-10), p. e737-e745

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(20)30251-9

Language: English

Publisher: Elsevier BV

Publication Date: 2020

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5464-5464

Abstract: Background: Comorbidities and body mass index (BMI) are significantly associated with outcome in patients (pts) who receive continue treatment with tyrosine kinase inhibitors (TKIs), such as in Ph+ leukemias. Ruxolitinib (RUX) is the first JAK1/2 inhibitor that may induce spleen/symptom responses and improve quality of life in pts with myelofibrosis (MF). Up-to-date, no data are available on the impact of comorbidities and BMI on pts treated with RUX. Aims: To evaluate the impact of comorbidities and BMI on responses, overall survival (OS) and maintenance of RUX dose in a large cohort of pts. Methods: Data were extracted from an electronic database that included retrospective data on pts treated before January 2015 in 16 Italian Hematology centers. Response to RUX was evaluated according to IWG-MRT criteria. BMI was calculated at the time of start of RUX and classified according to WHO criteria. Comorbidities were recorded at the time of start of RUX and classified according to the Charlson Comorbidity Index (CCI). Overall survival (OS) was calculated from the date of RUX start to the time of death or to last follow-up, whichever came first. Results: Between June 2011 and Apr 2016, 289 pts with PMF (52.6%), or PET-MF (17%) or PPV-MF (30.4%) were treated with RUX in participating Centers. At RUX start, median age was 68.4 years (range 39-89) with a male prevalence (56.4%); International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.6%), intm-2 (45.3%), high (39.1%). Transfusion dependence and spleen enlargement were present in 26.6% and 96.9% of pts, respectively (69.6% with spleen≥ 10 cm). Median total symptom score (TSS) was 20 (range 0-70). JAK2V617F was present in 80.3% of 234 evaluable pts. Median follow-up from MF diagnosis was 3.8 yr (range 0.3-29.6) and median RUX exposure was 20 months (3-56.2). Overall, comorbidities were evaluable in 275 pts. CCI stratification showed the absence of comorbidities in 100 pts (36.4%), one comorbidity in 63 pts (22.9%) and two or more in 112 pts (40.7%). Compared to pts with CCI 〈 2, pts with CCI ≥2 were more frequently: male (66.1% vs 49.1%, p=0.005), ≥65y (74.1% vs 54%, p=0.001), at intm2/high IPSS risk (90.2% vs 81%, p=0.03) and transfusion-dependent (36.6% vs 20.2%, p=0.003). Notably, the percentage of pts starting RUX 〉 2y from MF diagnosis was lower if CCI≥2 (33.9% vs 54%, p=0.001). Higher CCI did not correlate with lower spleen response (achieved by 45.2% vs 34.7%, p=0.09), TSS response (90.1% vs 83.2%, p=0.11), and higher incidence of RUX-induced anemia (Hb 〈 10 g/dl in pts with baseline Hb ≥10 g/dl) (48% vs 41%, p=0.33). RUX starting and titrated doses at 12-wks were similar in the two groups (p=0.44 and p=0.81, respectively). OS was significantly higher in pts with CCI 〈 2 (96.7% vs 87.8% at 2 yr, p 〈 0.001). After stratification according to CCI (below or above 2) and the achievement of a spleen response, both factors remained significantly associated with survival. Indeed, in pts with CCI 〈 2 OS at 2 yr was 92.7% and 79.1%, depending on the achievement of a spleen response (SR) or not (NR), respectively (p=0.034). Analogously, in pts with CCI≥2 the achievement of a spleen response significantly increased survival (79.2% vs 55.3% in pts without spleen response, p=0.011). Notably, OS was comparable in pts with lower CCI /no spleen response and in pts with higher CCI/spleen response (79.1% vs 79.2%) (Figure 1). BMI was evaluable in 269 pts: 169 pts (62.8%) were classified as under-weight/normal for a BMI 〈 25, whereas 100 pts were overweight/obese (BMI ≥25). Pts with BMI≥25 were more frequently male (71% vs 47.3%, p 〈 0.001) and with a lower incidence of anemia (30% vs 42%, p=0.049). BMI stratification did not correlate with differences in spleen response (p=0.83) and TSS (p=0.18) or onset of anemia/infections during treatment (p=0.49 and p=0.28). Starting and median doses, as well as percentage of pts reducing RUX dose over time, were similar in the two groups. Summary: In MF pts treated with RUX, BMI and comorbidities did not influence the achievement of spleen/symptom responses, maintenance of RUX dose or onset of drug-related anemia. Although CCI stratification correlated with survival, as in Ph+ leukemias treated with TKIs, the achievement of a spleen response was able to counterbalance the negative prognostic effect of a higher CCI. Consequently, higher BMI and CCI should not be regarded as contraindication to RUX therapy. Figure Figure. Disclosures Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding. Cimino:Bristol-Mayer: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.5464.5464

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Hematological Oncology, Wiley, Vol. 40, No. 5 ( 2022-12), p. 846-856

Abstract: The impact of secondary infections (SI) on COVID‐19 outcome in patients with hematological malignancies (HM) is scarcely documented. To evaluate incidence, clinical characteristics, and outcome of SI, we analyzed the microbiologically documented SI in a large multicenter cohort of adult HM patients with COVID‐19. Among 1741 HM patients with COVID‐19, 134 (7.7%) had 185 SI, with a 1‐month cumulative incidence of 5%. Median time between COVID‐19 diagnosis and SI was 16 days (IQR: 5–36). Acute myeloid leukemia (AML) and lymphoma/plasma cell neoplasms (PCN) were more frequent diagnoses in SI patients compared to patients without SI (AML: 14.9% vs. 7.1%; lymphoma/PCN 71.7% vs. 65.3%). Patients with SI were older (median age 70 vs. 66 years, p  = 0.002), with more comorbidities (median Charlson Comorbidity Index 5 vs. 4, p   〈  0.001), higher frequency of critical COVID‐19 (19.5% vs. 11.5%, p  = 0.046), and more frequently not in complete remission (75% vs. 64.7% p  = 0.024). Blood and bronchoalveolar lavage were the main sites of isolation for SI. Etiology of infections was bacterial in 80% ( n  = 148) of cases, mycotic in 9.7% ( n  = 18) and viral in 10.3% ( n  = 19); polymicrobial infections were observed in 24 patients (18%). Escherichia coli represented most of Gram‐negative isolates (18.9%), while coagulase‐negative Staphylococci were the most frequent among Gram‐positive (14.2%). The 30‐day mortality of patients with SI was higher when compared to patients without SI (69% vs. 15%, p   〈  0.001). The occurrence of SI worsened COVID‐19 outcome in HM patients. Timely diagnosis and adequate management should be considered to improve their prognosis.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v40.5

DOI: 10.1002/hon.3048

Language: English

Publisher: Wiley

Publication Date: 2022

detail.hit.zdb_id: 2001443-0

In: Hematological Oncology, Wiley, Vol. 37, No. 4 ( 2019-10), p. 418-423

Abstract: The 2016 WHO criteria identified early primary myelofibrosis (PMF) as an individual entity with milder clinical features and better outcome compared with overt PMF. Here, we compared early and overt PMF patients treated with ruxolitinib in terms of baseline clinical/laboratory characteristics, response, and toxicity to treatment. We observed that early‐PMF patients achieve better and more stable spleen and symptoms responses, with significantly lower rates of hematological toxicities. No differences in overall and leukemia‐free survival were detected between the two cohorts. The application of 2016 WHO criteria is crucial to identify those PMF patients who deserve a stricter monitoring during treatment.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v37.4

DOI: 10.1002/hon.2619

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 2001443-0

In: Hematological Oncology, Wiley, Vol. 38, No. 3 ( 2020-08), p. 372-380

Abstract: The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow‐up from ruxolitinib start of 3 years (range 0.1‐7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient‐years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate‐1 risk patients (2.3 vs 5.6 per 100 patient‐years in intermediate‐2/high‐risk patients, P   〈  .001). In PMF and SMF cohorts, previous interferon therapy seemed to correlate with a lower probability of BP (HR 0.13, P = .001 and HR 0.22, P = .02, respectively). In SMF, also platelet count 〈 150 × 10 9 /l (HR 2.4, P = .03) and peripheral blasts ≥3% (HR 3.3, P = .004) were significantly associated with higher risk of BP. High‐risk category according to dynamic International Prognostic Score System (DIPSS) and myelofibrosis secondary to PV and ET Collaboration Prognostic Model (MYSEC‐PM predicted BP in patients with PMF and SMF, respectively. Median survival after BP was 0.2 (95% CI: 0.1‐0.3) years. Therapy for BP included hypomethylating agents (12.3%), induction chemotherapy (9.2%), allogeneic transplant (6.2%) or supportive care (72.3%). Patients treated with supportive therapy had a median survival of 6 weeks, while 73% of the few transplanted patients were alive at a median follow‐up of 2 years. Progression to BP occurs in a significant fraction of ruxolitinib‐treated patients and is associated with DIPSS and MYSEC‐PM risk in PMF and SMF, respectively.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v38.3

DOI: 10.1002/hon.2737

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 2001443-0

In: Hematological Oncology, Wiley, Vol. 39, No. 3 ( 2021-08), p. 409-418

Abstract: In 816 patients with 2016 World Health Organization‐defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post‐PV myelofibrosis (PPV‐MF) and survival. Patients were subgrouped according to CCI = 0 (58.1%, no comorbidities) or CCI ≥ 1 (41.9%) and according to normal/underweight (BMI  〈  25, 54.5%) or overweight/obesity (BMI ≥ 25, 45.5%) at PV diagnosis. BMI was available for 529 patients. Patients with CCI ≥ 1 were older and more frequently presented cardiovascular risk factors compared to patients with CCI = 0 ( p   〈  0.001), while overweight/obese patients were more frequently males ( p   〈  0.001). Cumulative incidence of thromboses with death as competing risk was 13.3% at 10 years. Multivariable analysis with death as competing risk showed that previous thromboses (subdistribution hazard ratio [SHR]: 2.1, p  = 0.01) and hypertension (SHR: 1.77, p  = 0.04) were significantly associated with a higher thrombotic risk, while BMI ≥ 25 lost statistical significance (SHR: 1.69, p  = 0.05) and CCI ≥ 1 was excluded after evaluation of goodness of fit. After a median follow‐up of 6.1 years, progression to PPV‐MF occurred in 44 patients, and 75 patients died. BMI ≥ 25 was associated with a lower probability of progression to PPV‐MF (SHR: 0.38, CI95%: 0.15–0.94, p  = 0.04) and better survival (hazard ratio [HR] : 0.42, CI95%: 0.18–0.97, p  = 0.04). CCI ≥ 1 did not affect progression to PPV‐MF ( p  = 0.44) or survival ( p  = 0.71).  The evaluation of CCI and BMI may improve the prognostic definition of PV. In patients with hypertension an accurate evaluation of thrombotic risk is warranted.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v39.3

DOI: 10.1002/hon.2843

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 2001443-0

In: Blood Advances, American Society of Hematology, Vol. 6, No. 1 ( 2022-01-11), p. 327-338

Abstract: Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin’s lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2021005691

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 2876449-3

In: Cancer, Wiley, Vol. 126, No. 6 ( 2020-03-15), p. 1243-1252

Abstract: In real‐world data from 524 patients who received ruxolitinib for myelofibrosis, the incidence of and risk factors associated with drug discontinuation were investigated along with how reasons for discontinuation, disease phase at discontinuation, and salvage therapies may influence outcomes. At 3 years, higher risk category, lower platelet count, unfavorable karyotype, and transfusion dependency at the start of ruxolitinib were associated with a greater probability of drug discontinuation; and outcomes were significantly better in patients who discontinued in chronic phase versus blast phase and in those who received investigational agents and/or ruxolitinib rechallenge.

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v126.6

DOI: 10.1002/cncr.32664

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1128-1128

Abstract: Background: Response to ruxolitinib (RUX), the only JAK1/2 inhibitor commercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Therefore, pts' selection is based only on clinical needs. Aims: To evaluate the impact of pre-treatment clinical/laboratory factors, as well as RUX dose, on response to RUX in a cohort of "real-life" MF pts. Methods: A multicenter observational study on WHO-defined MF was conducted in 18 Italian Hematology Centers. Data were extracted from a database that included retrospective data on pts treated before January 2015. Subsequently, data were prospectively collected and updated at a 6-month interval.Response to RUX was evaluated according to IWG-MRT criteria. Results: Between June 2011 and Apr 2016, 408 pts with PMF (54.4%), or postET (27.7%) / post-PV (17.9%) were treated with RUX. At RUX start, baseline characteristics were (median): age, 68.5 y (range, 26.5-89); ≥65 y, 63.5%; male, 56.4%; hemoglobin (Hb), 10.7 g/dL (7-16.7); transfusion-dependence 27.9%; PLT, 256×109/L (50-1887); PLT 〈 100×109/L, 9.6%; spleen enlargement, 96.6% (spleen length ≥10cm: 64.2%); total symptoms score (TSS), 20 (12-70).International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.7%), intm-2 (47.3%), high (37%). Molecular data were available for 332 pts (81.4%) and was positive in 81% (JAK2V617F), 6.3% (CALR), 1% (MPLW515K/L); 2.7% (triple negative). 30 pts (9%) were JAK2V617Fnegative but did not receive further molecular evaluation. Karyotype was abnormal in 55 (26%) out of 210 evaluable pts (unfavorable: 8.1%). Median follow-up from MF diagnosis was 3.8 yr (0.3-29.6) and median RUX exposure was 20 mos (3-56.2). Overall, 152 out of 365 (42%) pts with spleen ≥5cm achieved a spleen response at any time during RUX therapy. At 3 and 6 mos, the response was achieved by 26.6% and 34.4% of evaluable pts, respectively. In univariate analysis, pre-treatment factors negatively correlating with spleen response were: transfusion dependence, platelet count ≤200x109/l, spleen palpable ≥10 cm below costal margin, grade 3 marrow fibrosis, intm-2/high IPSS risk and interval between MF diagnosis and RUX start ≥2y. Three variables remained significant in multivariate regression logistic analysis: large splenomegaly (HR: 2.05, 95%CI: 1.1-3.7; p=0.02), time-interval ≥2y (HR: 1.78, 95%CI:1.0-3.1; p=0.04) and transfusion dependency (HR: 1.95, 95%CI:1.0-3.7; p=0.04). Spleen response significantly correlated with the average RUX dose in the first 12 wks, with pts treated with doses ≥10 mg BID having better response rates (47.3% vs 26.6% if dose 〈 10 mg BID, HR:2.36, 95%CI:1.3-4.3, p=0.005). 360 pts had a TSS 〉 10 at RUX start and 319 (88.6%) achieved a symptom response. In multivariate analysis, factors associated with worse responses were: transfusion dependency (HR: 3.15, 95%CI 1.5-6.4, p=0.001) and a baseline TSS 〉 20 (HR: 6.7, 95%CI 3.2-13.8, p 〈 0.001). RUX titrated dose 〈 10 mg BID during the first 12-wks of therapy negatively correlated with symptoms response (HR: 2.6, 95%CI 1.05-6.7, p=0.037). Drug-related anemia (acquisition of transfusion dependency or Hb 〈 10g/dl in pts with a previous Hb≥10) was observed in 127/291 (43.6%) evaluable pts. The probability to develop anemia was significantly higher in females (HR: 1.63, 95%CI 1.03-2.57, p=0.036). Notably, anemia was not influenced by RUX 12-wks titrated dose (41.8% in pts with RUX titrated dose 〈 10 mg BID vs41.5% with higher doses). 80 (19.6%) pts discontinued RUX because of: lack/loss of response (28.8%); drug-related toxicity (27.5%, specifically: thrombocytopenia, 16.2%; infection, 6.3%; anemia, 5%); disease progression with/without acute evolution (8.8%); death (13.8%); allogeneic transplant (8.8%); 2ndneoplasia (3.8%); other unrelated causes (8.5%). Summary/Conclusion: In a real-life setting, IWG-MRT-defined spleen and symptoms response rates were observed in 42% and 88.6% of evaluable pts, respectively. Disease severity (in terms of transfusion dependency and large splenomegaly) and a delay in RUX start ≥2yr from diagnosis identified pts with lower spleen response rates. Titrated doses 〈 10mg BID significantly correlated with poorer spleen and symptoms responses. Overall, these data point out the importance of an early treatment and of an effective (≥ 10 mg BID) titrated dose in order to achieve better therapeutic results. Disclosures Palumbo: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Bonifacio:Novartis: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy. Tiribelli:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Fanin:Novartis: Speakers Bureau. Merli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Breccia:Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1128.1128

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4303-4303

Abstract: Background Myelofibrosis (MF) is featured by an inflammatory condition that can also drive the progression of disease. Ruxolitinib (RUX) is the-first-in-class Jak1/2 inhibitor approved for treatment for MF. Clinical benefits of RUX are presumably derived from reduction of inflammatory cytokines even if the exact mechanism remains unclear. Recent reports have identified the ratio between absolute neutrophils count (ANC) and absolute lymphocyte count (ALC), called NLR, as a simple parameter that mirrors the inflammatory status and the myeloid associated immune suppression. In various malignancies NLR has been indicated as predictor of progression free survival (PFS) and overall survival (OS). Our preliminary work in a single-center experience showed that patients with NLR 〉 6 before RUX start had a lower chance to obtain 〉 50% spleen reduction in the first 12 weeks or a complete resolution of splenomegaly at 24 weeks. Objective : We proposed to test NLR=6 as bio-marker in MF to apply into clinical practice as a possible predictor of response to RUX. Methods We used two separate cohorts to validate NLR (as a continuous variable and as a cut off 6) as predictor of response to RUX bases on our preliminary data from healthy volunteers (data not shown). Cohort (#1) including 111 MF patients from MD Anderson Cancer Center treated with RUX on phase 1/2 clinical trial from 2007 to 2010; and cohort (#2) including 367 patients treated at 18 Italian centers between years 2012 - 2018. Spleen responses to RUX treatment, PFS and OS were independently validated in cohorts #1 and 2. As cohort 1 included patients treated on clinical trial, spleen was assessed by MRI before and after 24 weeks of RUX therapy, and by physical examination at week 12. In cohort #2, spleen size was assessed by physical examination before, after 12 and 24 weeks of RUX continuous treatment in a real-life setting. NLR was calculated using data obtained from the complete blood count before RUX start and correlated with driver mutations, early spleen reduction, progression free survival (PFS), defined as time from RUX start to last follow-up or progressive disease (including progression to acute myeloid leukemia, ≥20% blasts in peripheral blood or bone marrow, AML) or death for any reason; and overall survival (OS). Results : Clinical and demographics characteristics of patients in each cohort are summarized in Table 1. In cohort #1 we found that NLR was lower in patients with lower bone marrow fibrosis (grade 0-1: 6.2±0.8 versus grade 2-3: 7.3±0.8, p=0.03). Similarly, in cohort #2, patients with grade 0-1 bone marrow fibrosis had lower NLR than those carrying grade 2-3 bone marrow fibrosis (7.7±0.7 versus 10.6±1.3, p=0.04). NLR was higher in patients carrying JAK2 (V617F) mutation (mean +/- SD, 6.4±0.6 vs 5.3±0.5, p=0.02 in cohort 1 and 9.1±0.6 vs 5.0±0.5, p=0.002 in cohort 2). While in cohort 1 NLR appeared lower in CALR (exon 9 indel) mutated patients, the difference was statistically significant in cohort 2 (5.4±0.8 vs 8.9±0.6, p=0.03). In both cohorts, there were no differences in NLR in either triple negative or MPL (exon 10) patients. In cohort 1, the mean percentage change from baseline in palpable spleen length was −47.7% at week 12 and −53.4% at week 24. NLR=6 was able to identify at baseline early response to RUX with 66.9% sensitivity and 72.3% specificity (HR 1.68, p=0.01). Patients with NLR 〉 6 before RUX start had a lower chance to obtain a complete resolution of splenomegaly at 24 weeks (p=0.001). These observations were confirmed in cohort 2 where NLR 〉 6 was able to identify at baseline early response to RUX with 50.3% sensitivity and 67.7% specificity (HR 1.56, p=0.01). The mean percentage change from baseline in palpable spleen length was −60.3% at week 12 and −66.7% at week 24. Patients with NLR 〉 6 before RUX start had a lower chance to obtain a complete resolution of splenomegaly at 24 weeks (p 〈 0.002). At the time of this analysis, 84/111 (75.6%) patients in cohort 1 and 122/367 (33.2%) in cohort 2 had died (p 〈 0.001). Progression to AML occurred in 6/111 (5.4 %) patients of cohort 1 and in 35/367 (9.5%) patients of cohort 2 (p=0.03). With median follow-ups of 47.8 months and 35.2 months for cohorts 1 and 2, respectively, NLR as a continuous variable or NLR 〉 6 was not a predictor of PFS or OS. Conclusions : NLR before RUX start could serve as a useful, simple and early predictor of spleen response in MF patients; and it positively correlates with JAK2 mutation and higher fibrosis grade. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitolo:Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Cuneo:Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Verstovsek:Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116418

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7