Deferasirox in the management of iron overload in patients with myelofibrosis treated with ruxolitinib: The multicentre retrospective RUX-IOL study.

Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.

COVID-19 infection in chronic myeloid leukaemia after one year of the pandemic in Italy. A Campus CML report.

Limited information is available on the impact of the COVID-19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on 8 665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS-CoV-2-positive patients (2·5%). Most patients (57%) were diagnosed as having SARS-CoV-2 infection during the second peak of the pandemic (September 2020 to January 2021). The majority (35%) was aged between 50 and 65 years with a male prevalence (73%). Fifty-six percent of patients presented concomitant comorbidities. The median time from CML diagnosis to SARS-CoV-2 infection was six years (three months to 18 years). Twenty-one patients (9·6%) required hospitalization without the need of respiratory assistance, 18 (8·2%) were hospitalized for respiratory assistance, 8 (3·6%) were admitted to an intensive care unit, while 170 (78%) were only quarantined. Twenty-three percent of patients discontinued tyrosine kinase inhibitor (TKI) therapy during the infection. Twelve patients died due to COVID-19 with a mortality rate of 5·5% in the positive cohort and of 0·13% in the whole cohort. We could also document sequelae caused by the SARS-CoV-2 infection and an impact of the pandemic on the overall management of CML patients.

Second primary malignancy in myelofibrosis patients treated with ruxolitinib.

Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22-4·60, P = 0·01] and thrombocytosis> 400 × 109 /l at RUX start (HR:1·98, 95%CI: 1·10-4·60, P = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24-7·92, P = 0·02) and duration of hydroxycarbamide and RUX therapy > 5 years (HR: 3·20, 95%CI: 1·17-8·75, P = 0·02 and HR: 2·93, 95%CI: 1·39-6·17, P = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11-5·25, P = 0·03), platelet > 400 × 109 /l (HR: 3·30, 95%CI: 1·67-6·50, P = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48-8·14, P = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.

Chronic lymphocytic leukemia cells impair osteoblastogenesis and promote osteoclastogenesis: role of TNFα, IL-6 and IL-11 cytokines.

Bone skeletal alterations are no longer considered a rare event in chronic lymphocytic leukemia (CLL), especially at more advanced stages of the disease. This study is aimed at elucidating the mechanisms underlying this phenomenon. Bone marrow stromal cells, induced to differentiate toward osteoblasts in osteogenic medium, appeared unable to complete their maturation upon co-culture with CLL cells, CLL-cell-derived conditioned media (CLL-cm) or CLL-sera (CLL-sr). Inhibition of osteoblast differentiation was documented by decreased levels of RUNX2 and osteocalcin mRNA expression, by increased osteopontin and DKK-1 mRNA levels, and by a marked reduction of mineralized matrix deposition. The addition of neutralizing TNFα, IL-11 or anti-IL-6R monoclonal antibodies to these cocultures resulted in restoration of bone mineralization, indicating the involvement of these cytokines. These findings were further supported by silencing TNFα, IL-11 and IL-6 in leukemic cells. We also demonstrated that the addition of CLL-cm to monocytes, previously stimulated with MCSF and RANKL, significantly amplified the formation of large, mature osteoclasts as well as their bone resorption activity. Moreover, enhanced osteoclastogenesis, induced by CLL-cm, was significantly reduced by treating cultures with the anti-TNFα monoclonal antibody infliximab. An analogous effect was observed with the use of the BTK inhibitor, ibrutinib. Interestingly, CLL cells co-cultured with mature osteoclasts were protected from apoptosis and upregulated Ki-67. These experimental results parallel the direct correlation between amounts of TNFα in CLL-sr and the degree of compact bone erosion that we previously described, further strengthening the indication of a reciprocal influence between leukemic cell expansion and bone structure derangement.

Impact of comorbidities and body mass index on the outcome of polycythemia vera patients.

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.

Bosutinib in the real-life treatment of chronic myeloid leukemia patients aged >65 years resistant/intolerant to previous tyrosine-kinase inhibitors.

To evaluate the role of bosutinib in elderly patients aged >65 years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500 mg/day in 25 patients (24.8%), 400 mg/day in 7 patients (6.9%), 300 mg/day in 33 patients (32.7%), 200 mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis.

BACKGROUND: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome. METHODS: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis. RESULTS: At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate-2-risk/high-risk category (Dynamic International Prognostic Score System), a platelet count <100 ×109 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib-related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome. CONCLUSIONS: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies.

The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs.

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia.

Risk factors for progression to blast phase and outcome in 589 patients with myelofibrosis treated with ruxolitinib: Real-world data.

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 × 109 /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.

Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia.

BACKGROUND: Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined. METHODS: Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated. RESULTS: Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed. CONCLUSIONS: Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.