The goal for treatment in people with myelofibrosis should shift towards a greater emphasis on reduction in spleen volume, since this is likely to impact overall survival, according to medical oncologist Professor Srdan Verstovsek from the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas. To this end, he says it’s important to optimise the dose of ruxolitinib (Jakavi) – the only approved therapy for this condition.

 Professor Verstovsek was an investigator in the pivotal clinical trials for ruxolitinib in myelofibrosis. The trials showed that ruxolitinib improved quality of life, reduced spleen volume and prolonged survival.¹ Professor Verstovsek is also lead author of a number of post hoc analyses of the trial data, including one investigating the impact of dose adjustments on cytopenias, spleen volume and symptom improvement.²

Efficacy outcomes are associated with the final titrated dose

An analysis of the COMFORT-1 trial data² investigated the impact of the dose of ruxolitinib in the final four weeks of the treatment period (the final titrated dose) on efficacy measures, such as spleen volume and improvement in myelofibrosis symptoms.  It also looked at the relationship between ruxolitinib doses and changes in platelet count and haemoglobin.

Dose adjustments were predominantly made in the first 8 – 12 weeks of treatment, coinciding with low platelet count and haemoglobin levels. These dose adjustments were effective in managing the treatment-related cytopenias, the authors say.

With regard to efficacy outcomes, final titrated doses of 10 mg twice daily and above were associated with clinically meaningful reductions in spleen volume and symptom improvement. While there was no further benefit to symptom improvement beyond the 10 mg twice daily dose, further reductions in spleen volume occurred with higher doses.²

“During the clinical studies, we invested time and effort looking at the most appropriate dosing regimens,” Professor Verstovsek says. “We found that a starting dose around 10mg twice daily without dose escalations results in symptomatic improvement, but optimal spleen volume reductions occur at higher doses, which is why dose titration is important,” he explains.

“To change outcomes from ‘some reduction’ in spleen volume to ‘an optimal reduction’ in spleen volume, a dose higher than 10 mg twice daily is needed,” says Professor Verstovsek. “This needs to occur in the first 6 months of treatment,” he adds.

Doses in Australia are predominantly 10 mg twice daily: PBS data

The recommended starting dose for ruxolitinib is based on platelet count, and the dose should be reduced if platelet count decreases below 100 x 10⁹/L, with treatment to be interrupted if the platelet count decreases below 50 x 10⁹/L (or the absolute neutrophil count decreases below 0.5 x 10⁹/L).¹ Once platelets and neutrophils recover, the dose can be gradually increased with careful monitoring.

PBS data shows the majority of first scripts for ruxolitinb are for 15 mg or 20 mg twice daily, in line with the approved starting dose for all patients except those with very low platelets. However, there is a trend in favour of the 10 mg twice daily dose over time, with the majority of scripts being for this dose at 12 months. This suggests that the starting dose is reduced in many patients without up-titration at a later date.

Professor Verstovsek has a potential explanation for the low rate of up-titration: “Clinicians are obviously happy when a patient says they feel better, and they may question the need for higher doses, since higher doses will increase the chance that the patient experiences neutropenia or anaemia,” he suggests.

“If you stay with doses around 10 mg twice daily, there is less of a risk of needing to manage neutropenia or anaemia, but the trade-off is that you are not getting the spleen volume reductions,” says Professor Verstovsek.

Options for managing anaemia beyond dose modifications

Ruxolitinib is an inhibitor of Janus Associated Kinases (JAKs), which have a role in the signaling of cytokines and growth factors that are important for haematopoiesis, and anaemia is an expected effect of treatment.¹ Options for managing anaemia include blood transfusions or dose reductions, although dose reductions are not mandated in the approved product information.¹ The clinical trial data indicates that haemoglobin levels eventually recover to near baseline values, rather than continually decline over time.²

Professor Verstovsek explains that anaemia was found to have little impact on patient quality of life or overall survival in the clinical trials.^3,4 “Our data suggests that improvement in quality of life occurs to the same extent in patients with anaemia compared to patients without anaemia. Survival benefit was equally seen in those with or without anaemia,” he says.

Professor Verstovsek recommends blood transfusions to manage the anaemia while optimising the dose for maximum spleen volume reduction. He says alternatives to this approach are to either reduce the dose and escalate after levels have recovered, or commence with a lower dose and escalate while monitoring haemoglobin and platelet levels.

A poster at the European Haematology Association Congress in June⁵ presented the results of a study investigating the safety and efficacy of a reduced starting dose of ruxolitinib of 10 mg twice daily with delayed up-titration in patients with myelofibrosis and anaemia.

The authors found that this dosing regimen allowed for up-titration in the majority of patients with no real increase in the number of transfusions required. The regimen also resulted in 56% (95% CI 41.3–70.0; n/N=28/50) of patients with a 50% or greater reduction in spleen length at Week 24. The authors concluded, “These results reinforce the evidence that, in myelofibrosis patients with splenomegaly and/or constitutional symptoms, it is not necessary to delay or withhold treatment of ruxolitinb because of coexistent or treatment-emergent anaemia.”

Authors of a small published open-label study investigating a dose escalation regimen also concluded that this approach may limit worsening anaemia during early ruxolitinib therapy.⁶ A total of 45 patients with myelofibrosis commenced on a 10 mg twice daily dose of ruxolitinib, with 5 mg twice a day increases at week 12 and week 18 (if required for increased efficacy) to a maximum dose of 20 mg twice daily.

This dosing regimen resulted in a low rate of anaemia (26.7%) and a low proportion of patients needing dose reductions due to anaemia and thrombocytopenia (11.1% and 6.7%, respectively). The authors also report a dose response in the effect on spleen volume.⁶

Spleen size reduction and impact on survival

Professor Verstovsek and colleagues published an analysis of data from long-term follow-up of patients enrolled in an open-label phase 2 study of ruxolitinib.⁷ The analysis compared outcomes in the study population to matched historical controls and showed significantly longer survival in the ruxolitinib-treated patients compared to the controls. The analysis also found that the factor most closely correlated with survival in ruxolitinib-treated patients was the degree of spleen size reduction.

Some authors have questioned whether there is sufficient evidence supporting a benefit in overall survival with ruxolitinib, since analyses are against historical controls and overall survival was not a primary outcome in the pivotal clinical trials.⁸ While Professor Verstovsek acknowledges these limitations, he says his clinical experience reinforces his views on the value of ruxolitinib. “I have seen patients completely transformed with this treatment and still alive ten years later,” he says.

Professor Verstovsek’s maintains that dose optimisation is the best approach to treatment. He says, “It needs to be a dose that the prescriber is comfortable using in their patient. We must remember that treatment needs to extend beyond considerations of quality of life and symptom management to take into account reductions in spleen volume.”

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References

1. Jakavi Australian Approved Product Information www.novartis.com.au/products_healthcare.html
2. Verstovsek S. et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets and Therapy 2014;7:13–21 https://www.ncbi.nlm.nih.gov/pubmed/24368888
3. Verstovsek S. Changing myelofibrosis’s natural course. Blood 2014;123:1776–1777. http://www.bloodjournal.org/content/123/12/1776?sso-checked=true
4. Gupta V. et al. The impact of anemia on overall survival in patients with myelofibronsis treated with ruxolitinib in the COMFORT studies. Haematol 2016:101(12):e482–e484 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479619/
5. Cervantes F, et al. Safety and efficacy of ruxolitinib (RUX) in patients with myelofibrosis (MF) and anaemia (Hb ,10 g/dL): Results from the REALISE trial. In: 24^th EHA Congress; June 13 – 16, 2019; Amsterdam https://library.ehaweb.org/eha/2019/24th/267082/francisco.cervantes.safety.and.efficacy.of.ruxolitinib.28rux29.in.patients.with.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1550%2Aot_id%3D20980
6. Talpaz M et al. Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study. Journal of Hematology and Oncology 2018; 11:101 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081850/
7. Verstovsek S. et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012; 120(6):1202–1209 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081158/
8. Cervantes F & Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood 2017; 129: 832–837. http://www.bloodjournal.org/content/129/7/832?sso-checked=true

AU-10006. September 2019.