Myelofibrosis could take a one-two punch from iron chelation therapy and Janus kinase (JAK) inhibitors, giving some patients a potential survival advantage, haematologists suggest.
An Italian retrospective study of 69 myelofibrosis patients on JAK inhibitor ruxolitinib and iron chelator deferasirox found those who responded to iron chelation survived 20%–30% longer than non-responders at three years’ follow-up.
Iron chelation responses (ICR) were seen in half the cohort, and 46% had erythroid responses (ER), shown as a reduced need for transfusion. Thirteen patients even achieved transfusion independence, the study found.
Decreased transfusion dependence “should contribute to improved chelation response” and appeared to do so, as those who had an ER were more likely to obtain ICR, Associate Professor David Ross wrote in an accompanying editorial.
“These two responses were closely related, and both were associated with improved overall survival, although in multivariable analysis only iron chelation response remained statistically significant (hazard ratio 0.33, 95% confidence interval 0.13–0.83)”, noted Associate Professor Ross, of the Department of Haematology and Bone Marrow Transplantation, Royal Adelaide Hospital.
ICR was achieved when serum ferritin was < 1,000 µg/L or reduced by ≥ 50% from baseline for three months. Meanwhile, ERs were defined as a ≥ 50% transfusion requirement reduction and/or ≥ 15 g/L increase in Hb values.
While deferasirox, rather than ruxolitinib, drove ER, the study authors suggested the combination may offer greater overall benefit than either drug alone.
The JAK inhibitor is effective in decreasing myelofibrosis-related splenomegaly and improving patients’ symptoms, while deferasirox helps tackle the anaemia, which may be exacerbated by ruxolitinib, they wrote.
Additionally, the observed survival increase “could correspond to the biological observation of a possible correlation between an efficient chelation and a reduction in oxidative stress and genetic instability in haematopoietic stem cells (HSC) and myeloid progenitors,” they suggested.
“Indeed, both [ruxolitinib] and [deferasirox] reduce the bone-marrow oxidative damage, with interaction with NF-KB and JAK–STAT signalling, and could operate a potential therapeutic synergy.”
The treatment did come with some adverse effects, although no unexpected toxicities were reported.
Drugs were administered for median 12.4 months at median starting doses of 30 mg ruxolitinib and 1000 mg deferasirox per day. Around 50% of patients needed dose reductions and some discontinued due to side-effects such as infection, anaemia or thrombocytopenia, skin rash, renal impairment and epigastric pain.
The study authors concluded that deferasirox and ruxolitinib may be “effective and well tolerated in [myelofibrosis] patients, with a safety profile that is clinically manageable with regular patient monitoring”.
The investigators suggested clinicians ought “not to procrastinate the start of [iron chelation therapy] in patients with [myelofibrosis] during [ruxolitinib] treatment”, despite the need for study in larger cohorts, and ideally, randomised trials.
The latter might not be feasible, Associate Professor Ross wrote in his editorial. He noted that deferasirox was widely available to myelofibrosis patients in much of the developed world and therefore patients and their physicians “might be reluctant to participate in a study in which an available therapy is withheld.”
“In the absence of higher quality data, the [study] is consistent with prior retrospective studies suggesting a benefit of iron chelation for [myelofibrosis], and extends those observations to contemporary practice with the use of ruxolitinib,” he said.
The study and editorial are available in the British Journal of Haematology.