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Persistence of myelofibrosis treated with ruxolitinib
Lessons from the clinic
Ruxolitinib discontinuation syndrome
Interruption of ruxolitinib treatment typically leads to recrudescence of cytokine-mediated symptoms within a week,38 often accompanied by increasing spleen size, highlighting the persistence of the underlying disease. The accumulation of p-JAK2 likely accounts for the prompt onset of withdrawal symptoms when ruxolitinib is stopped, since the increased p-JAK2 will rapidly lead to downstream signaling in the absence of the drug. Ruxolitinib has a short half-life of approximately 3 h,58 so the drug is washed out rapidly if dosing is interrupted. Although the accumulation of p-JAK2 is likely to be a class effect of type 1 JAK inhibitors, we are not aware of any reports of discontinuation syndrome with fedratinib, momelotinib, or pacritinib. Both fedratinib and pacritinib have very long half-lives of more than 24 h.59,60 Delayed clearance of these drugs may reduce the risk of withdraw- al phenomena. Momelotinib has a half-life of 4-6 h,61 sim- ilar to that of ruxolitinib, so withdrawal phenomena might be predicted to occur with abrupt discontinuation of momelotinib.
In most patients who discontinue ruxolitinib there is a return to near baseline severity of symptoms, but in rare cases there are life-threatening manifestations thought to be due to an exaggerated inflammatory response. Ruxolitinib discontinuation syndrome is a diagnosis of exclusion based on a temporal relationship between drug withdrawal and onset of clinical manifestations, which can appear from less than 24 h to up to 3 weeks after dis- continuation. In the original phase I/II trial, three of 47 patients who discontinued ruxolitinib developed acute respiratory distress syndrome.62 In the phase III COM- FORT-I study, one patient developed acute respiratory dis- tress, pyrexia and splenic infarction following ruxolitinib discontinuation.38 Coltro and co-workers described a case of JAK2 V617F essential thrombocythemia evolving to acute myeloid leukemia with acute respiratory distress syndrome developing after ruxolitinib was discontinued, and improving within 48 h of re-introduction of the drug.63 Other reports include a patient who developed tumor lysis-like syndrome,64 a case of acute respiratory failure,65 and a case of acute respiratory distress syndrome that twice resolved after ruxolitinib re-introduction.66
Of note, of the nine published cases of life-threatening ruxolitinib discontinuation syndrome reported in the liter- ature, all were reported to have a JAK2 mutation. This is a disproportionate enrichment compared to the prevalence of the CALR mutation (~35% of cases of myelofibrosis). Further research into mutation-specific side effects of kinase inhibitors is warranted.
Some experts recommend tapering the ruxolitinib dose rather than abrupt discontinuation, especially when the reason for the therapy interruption is an adverse event other than cytopenia.67,68 One of the commonest causes of ruxolitinib discontinuation is infection.69 By stabilizing the active conformation of JAK2 in a manner that prevents dephosphorylation and degradation, type I inhibitors may rarely induce a signaling state that heuristically resembles a cytokine storm (Figure 2C).51 Experimental co-culture of JAK2 V617F cells with increased levels of cytokines in the medium promoted the accumulation of p-JAK2, since sig- naling through cytokine receptors is still capable of induc- ing p-JAK2 in the presence of ruxolitinib. Intriguingly, acti-
vation of JAK1 by interleukin-3 also led to phosphoryla- tion of JAK2, suggesting that both JAK1 and JAK2 may be involved in withdrawal signaling.51 These findings provide a biological rationale for why inflammation and discontin- uation of ruxolitinib could interact to cause more severe withdrawal phenomena.
Ruxolitinib wash-out and rechallenge
A number of cases have been reported in which a ‘drug holiday’ led to restoration of ruxolitinib response upon re- challenge,70,71 as predicted by the experimental models of ruxolitinib persistence and wash-out. When ruxolitinib is withdrawn the accumulated p-JAK2 becomes susceptible again to ubiquitination and degradation, so that after a wash-out period the untreated cell biology is restored for a variable period of time. Understanding this phenome- non has important implications for the design of clinical trials of second-line agents after ruxolitinib. It is often in the patient’s interest to minimize the interval between stopping ruxolitinib and starting a second-line agent, because of the increase in symptom burden that common- ly occurs. However, if baseline response assessments for the second-line agent are undertaken too early there may be further deterioration after the ‘baseline’ assessment. In the randomized FREEDOM-2 study, wash-out and resumption of ruxolitinib will be compared to wash-out of ruxolitinib followed by institution of fedratinib (NCT03952039). This study will provide important new data on the effects of ruxolitinib rechallenge.
Inhibition of JAK1 versus JAK2 versus both
Many of the symptoms of myelofibrosis are related to increased levels of pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α. Symptomatic improvement in response to ruxolitinib is correlated with a reduction in cytokine levels.72 Importantly, many cytokines signal through JAK1 and suppression of JAK1 signaling by dual inhibitors, such as ruxolitinib and momelotinib, may contribute to the symptomatic benefit observed with these treatments. A selective JAK1 inhibitor, itacitinib (INCB039110), has been tested in a phase II clinical trial involving 87 patients with myelofi- brosis.73 Symptomatic improvement was comparable to that seen with ruxolitinib (total symptom score reduced by 50% at 24 weeks in 49% of patients versus 46% in the COMFORT-I study) whereas the splenic responses were less (≥35% reduction in spleen volume in 17% of patients at 24 weeks versus 32-42% in the COMFORT studies). Conversely, a 50% reduction in total symptom score was seen in 36% of patients treated with the JAK2-selective
inhibitor, fedratinib.74
It may be an oversimplification that JAK1 inhibition
mediates improvement in inflammatory symptoms and JAK2 inhibition mediates cytoreductive effects. There may be some crosstalk between JAK1 and JAK2, or splenic responses could perhaps be due to inhibition of cytokine- mediated recruitment of cells to sites of extramedullary hematopoiesis.
Secondary resistance to ruxolitinib: comparison with chronic myeloid leukemia
Secondary resistance to TKI therapy is perhaps best understood in chronic myeloid leukemia. Resistance often
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