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mature platelet apoptosis.90 A phase II clinical trial of the BCL-2 inhibitor navitoclax in combination with ruxoli- tinib in MF patients is ongoing and results are awaited with interest. Other emerging agents indirectly targeting the marrow niche are the telomerase inhibitor, imetelstat (GRN163L, Geron, USA), which has been investigated in both ET and MF patients and initial clinical results are encouraging.91,92 Unfortunately, subsequent studies in MF revealed limited overall spleen responses, significant myelosuppression, and in some patients, hepatic toxicity; therefore, recruitment for the study was suspended (Geron Corporation, June 7 2017, press release). However, the data presented in ASH-2018 showed complete and partial responses in 21% cases, with bone marrow fibrosis reversal in four cases with complete response (CR); OS after 27.4 months of treatment was 19.9 months in the low-dose therapy arm and 29.9 months in the higher-dose therapy arm.93 Unfortunately, 93% of patients discontin- ued the study, and of these, 25% were due to adverse events. Recent data presented at the EHA congress 2019 demonstrated that when survival data from the 9.4 mg/kg imetelstat-cohort, from the phase-II trial in ruxolitinib relapsed/refractory higher-risk MF, was compared to 'real world' data for this group of patients treated with best alternative therapy (BAT), there was a potential OS advan- tage (30.69 months in the imetelstat group, HR 0.35 months, P<0019); although this was an unweighted analy- sis and had inherent comparative limitations.94 Geron plans to conduct an up-dated phase II trial meeting with the FDA to determine if there is a regulatory path forward for imetelstat in MF in 2020.
MDM2 inhibitors alter the MDM2/p53 interaction, in order to restore p53 functionality/activity. Preliminary data from early phase studies in PV and ET demonstrated favorable clinical responses. Mascarenhas et al. recently presented the results of a phase I study in which 13 JAK2- mutated PV/ET patients were treated with idasanutlin and combined with pegylated interferon if a partial response was not achieved following cycle 6. Responses were robust: 58% for the monotherapy cohort and 50% for the combination therapy cohort after 6 cycles, with a median treatment duration of 16.8 months.95 Two multinational clinical trials are currently open investigating the efficacy and safety of the MDM2 inhibitor KRT-232 for ruxoli- tinib-failure/intolerant MF patients and poorly controlled PV patients. Recently, Lu et al. presented early data from a combinatorial study of an MDM2 antagonist and BET inhibitor in MF patients.96 This combination reduced hematopoietic colony formation by MF-CD34+ cells and targets the microenvironment by reducing the pro-inflam- matory cytokine milieu. Results of this particular combi- natorial approach are eagerly awaited, as is the combina- tion of a BET inhibitor with JAKi. Lastly, as introduced above, another potential niche pathway target is the estro- gen-signaling axis. Inhibition of estrogen-signaling has recently been explored in the TAMARIN trial, investigat- ing clinical benefits and molecular responses induced by the concomitant administration of tamoxifen to patients with MPN established on treatment (excluding interfer- on).
Historically, the exact relationship between BM fibrosis and clinical outcome/prognosis in MF has been somewhat unclear. An important question is: does improvement in BM fibrosis correlate with improved overall symptom/ spleen burden and OS? This has not been comprehensive-
ly studied in the clinical trial setting, particularly in the longer term. Kvasnicka et al. recently examined the effects of long-term ruxolitinib therapy on BM cytomorphology and fibrosis in 68 patients compared to 192 matching patients with BAT.97 Compared to baseline reticulin fibro- sis grade, ruxolitinib, in contrast to BAT, was associated with augmented odds of fibrosis grade stabilization or improvement and decreased odds of a worsening of retic- ulin fibrosis. Furthermore, this was often associated with higher degrees of reduction in spleen size. Similar effects have also been noted in a much smaller cohort of patients treated with fedratinib.98,99 Collectively, these data suggest a possible disease-modifying effect, at least in a subset of those patients undergoing JAKi therapy, which evidently requires a longer duration of drug exposure. Novel thera- pies such as PRM151, a recombinant human pentraxin-2 analog, have also demonstrated promising findings fol- lowing reductions in BM fibrosis in some patients with MF. In the first stage of the clinical trial, 27 patients with either primary or secondary MF and ≥ grade 2 reticulin fibrosis were due to receive PRM-151 ± ruxolitinib for 24 weeks; 20 completed therapy.100 In general, the agent was well tolerated, both alone and with JAKi, with no evi- dence of myelosuppression. Improvements in symptoms and modest reductions in splenomegaly in some were observed and 11 out of 25 patients evaluated had a reduc- tion in BM fibrosis by ≥ 1 grade. A total of 18 patients were in the open label extension, all of whom received a monthly infusion of PRM-151 at 10 mg/kg, treated for up to 35 cycles (140 weeks).101 A total of 50% were also receiving ruxolitinib. A similar percentage of patients experiencing reductions in spleen size and improvements in total symptom score (TSS) were seen in both the com- bination and monotherapy arms. Improvements in retic- ulin grade was observed in 71% and 44% of those with Grade 2 and 3 marrow fibrosis at baseline, respectively. Recent results presented at the EHA 2019 by Verstovsek et al. showed that BM fibrosis decreased at any time point in 28% of patients, and 16-29% patients had a ≥50% reduc- tion in transfusion requirement or hemoglobin improved >10 g/L for 12 consecutive weeks.102
Other therapeutic agents have been developed during recent years to specifically target the BM fibrosis and/or relevant pathways in MPN, but with limited success. Inhibitors of hedgehog signaling, important in both prim- itive and definitive hematopoiesis, cellular proliferation and survival, have been studied both as monotherapies and in combination with ruxolitinib in MF.103 IPI926, an oral hedgehog-inhibitor, was studied as a monotherapy in MF; however, no significant improvements in fibrosis were reported and the study was discontinued.104 The SMO-inhibitor sonidegib (LDE225, Novartis, Switzerland) has been investigated in combination with ruxolitinib in a phase-Ib/II study and demonstrated spleen and symptom responses in a minority of patients, and, in some patients, reductions or stability in BM fibrosis.105 Schneider et al. have showed that Gli1+ mesenchymal cells are involved in the fibrosis pathogenesis of MF. The investigators have used GANT61, an inhibitor of Gli1 transcription factor that regulates the hedgehog signaling pathway, in MF murine models and demonstrated reductions in both the fibrosis and the malignant clone. These results suggest a possible new target in reducing marrow fibrosis in MF.58
Pirfenidone, an established antifibrotic agent, showed promising results in vitro by reducing both fibroblast activ-
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haematologica | 2020; 105(5)