Kuykendall Evaluates Ruxolitinib for a Patient With Myelofibrosis

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Case-Based Roundtable Meetings SpotlightCase-Based Roundtable Meetings Spotlight July 2 2021
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During a Targeted Oncology Case-Based Roundtable event, Andrew Kuykendall, MD, discussed the case of 68-year-old patients with myelofibrosis.

Andrew Kuykendall, MD

Andrew Kuykendall, MD

During a Targeted Oncology Case-Based Roundtable event, Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discussed the case of 68-year-old patients with myelofibrosis.

Targeted OncologyTM: What prognostic models are used in patients with myelofibrosis?

KUYKENDALL: The prognostic models in myelofibrosis [MF] are the original IPSS [International Prognostic Scoring system] followed by DIPPS [Dynamic IPSS] and DIPPS-Plus from 2009, 2010, and 2011, respectively. The IPSS and DIPPS are similar and include the same clinical features of age, hemoglobin, white blood cell count, peripheral blood blasts, and constitutional symptoms. The DIPPS is a bit different because it gives increased weight to the hemoglobin of less than 10 g/dL. It is dynamic, meaning it can be used at any time point during the disease.1,2

The DIPPS-Plus was built upon the DIPPS and was the first prognostic model to start incorporating genetic data because they looked at unfavorable karyotypes and the role they play in disease progression. They also looked at platelet count and red blood cell transfusion dependence. The DIPPS-Plus uses red blood cell transfusion dependence and gives an increased weight to a hemoglobin of less than 10 g/dL. The prognostic significance of anemia in MF is significant.2,3

The median survival based on these [3 risk assessment tools] can be divided into 4 groups: low, intermediate-1, intermediate-2, and high risk. The intermediate-2 and high-risk groups have a median survival of less than 5 years [using all the 3 risk assessment tools]. These are the groups we would consider for an allogeneic stem-cell transplant [ASCT] because the benefits outweigh the risks when the median survival is less than 5 years.2

There’s much debate on the relevance of these prognostic models and whether they should be employed from a treatment decision-making standpoint outside the realm of deciding if a patient is a transplant candidate.

The MIPSS70 [Mutation-Enhanced International Prognostic Scoring System] score also has low, intermediate, and high-risk groups plus other variables are incorporated too including clinical ones like anemia, and leukocytosis, thrombocytopenia. Peripheral blood blasts must be 2% or greater and presence of constitutional symptoms is also included. So, these are classic IPSS or DIPPS variables.4

Another variable is bone marrow fibrosis that is grade 2 and above, which is found in almost everyone with MF. The recent World Health Organization entity of prefibrotic MF would not fall under this category because it is grade 1 fibrosis or lower. There is also the absence of Type 1 CALR mutation, which is a driver mutation found in about 25% to 30% of patients with MF. Most of these patients have type 1 CALR mutation that has a more favorable prognosis compared with those patients who have either JAK2 or MPL mutated disease as their driver mutation. Mutations in the high molecular risk [HMR] category involve the genes ASXL1, EZH2, SRSF2, or IDH1 and IDH2. These genes when mutated lead to a more aggressive course and worse overall outcomes. Presence of an HMR mutation is scored as one point and if it is 2 or more HMR mutations, then it is scored as 2 points. This shows the relative weight of these adverse mutations. With a JAK2 mutation as well as a couple of HMR mutations, you get 4 points and are at intermediate risk bordering on high risk if you just have some symptoms or anemia.4,5

The MIPSS70-Plus version 2.0 risk model identifies a very high-risk karyotype. The cytogenetic abnormalities that are almost acute myeloid leukemia [AML]-defining are Inversion 3, isochrone 17q, chromosome 7 abnormalities such as monosomy 7, 11(q), which are MLL [mixed-lineage leukemia] rearrangements, as well as some autosomal trisomies that are often seen in AML. It also incorporates the U2AF1 Q157 mutations, which we now know are prognostically detrimental and adjusts for age and gender in anemia. The MIPSS70-Plus v2.0 is certainly much more complicated, but does a better job of risk-stratifying patients into 5 different categories as opposed to 3. This ranges from very high-risk to very low risk and certainly each of these has different survival rates.6

All these prognostic models are defined and developed in patients with primary MF [PMF] and not patients who had MF evolving from polycythemia vera [PV] or essential thrombocythemia [ET]. There’s much debate on whether the latter group are representative of the patient population with PMF. The MYSEC-PM model is a prognostic model specifically developed for patients with post-PV or post-ET MF. Some of the variables are slightly modified such as hemoglobin is less than 11 g/dL, not 10 g/dL; platelets are less than 150 × 109/L, not 100 × 109/L; circulating blasts have to be 3% or greater, not 1% or 2%. The CALR-unmutated genotype (JAK2 or MPL mutations) and presence of constitutional symptoms variables are similar to the other models. Instead of creating an arbitrary threshold for age there is a bit more nuance and patients get 0.15 points per year. They then get divided up into low, intermediate-1, intermediate-2, and high-risk categories. The high-risk group and the intermediate-2 risk group have median survival rates of around 5 years or less.7

Based on the NCCN [National Comprehensive Cancer Network] guidelines, any of these models can be used, but those that incorporate both genetic and clinical features are preferred in order to get a good assessment of patients who are then stratified into lower-risk and higher-risk categories.8

What would be the next appropriate step for the management of this patient?

Initiating ruxolitinib [Jakafi] and referring for transplant, or just referring for transplant are reasonable options. Initiating fedratinib [Inrebic] is also a reasonable option, but it’s not often done.9,10 [Enrolling the patient] in a clinical trial certainly could be considered, but it depends on whether a site is offering a trial and if the patient is interested and motivated to get into one.

The NCCN has guidelines for treatment of higher risk MF and this patient meets the criteria for higher risk MF. Symptom burden is assessed using the symptom assessment form, which has been validated in MF trials. Platelet count is important because it dictates whether patients can go on to standard JAK inhibitors, which weren’t really studied in this group of patients.8

If patients have a platelet count of less than 50 × 109/L, they are transplant candidates. If they’re not a transplant candidate, consider clinical trials. There are a good number of clinical trials that are enrolling patients with severe thrombocytopenia, so that is something that may indicate an early trial referral.

Assess transplant candidacy of patients with platelet counts greater than 50 × 109/L, who are probably 85% to 90% of patients. Transplants take time, so you’re probably looking at treatment as well. Both ruxolitinib and fedratinib are approved in the frontline setting. Ruxolitinib is more frequently used in the frontline setting, but fedratinib’s indication allows it to be used as well.9-11 Clinical trials are also included as a reasonable frontline option for these patients.

If the patient is not a transplant candidate and has symptomatic anemia only, then a different algorithm applies. JAK inhibitor therapy for patients who don’t have big spleens or disease-related symptoms results in a lot of toxicity without much of the benefit.

Which data support the use of ruxolitinib in the frontline setting? Ruxolitinib is approved based on 2 phase 3 randomized clinical trials. The COMFORT-I study [NCT00952289] is a double-blind placebo-controlled trial that was done largely in the United States. The COMFORT-II study [NCT00934544] was done largely in Europe. In the COMFORT-I study, patients were randomized to ruxolitinib vs placebo and in the COMFORT-II study patients were randomized 2:1 to ruxolitinib vs best available therapy [BAT].11-13

Spleen volume reduction of 35% or greater was seen in 41.9% and 28% of patients [treated with ruxolitinib in the COMFORT-I and COMFORT-II trials, respectively]. This was compared with 0.7% treated with placebo in the COMFORT-I and 0% treated with BAT in the COMFORT-II trials. Certainly, there was great activity in terms of spleen volume reduction.13

Majority of patients [in the ruxolitinib arms] achieved improvement in their spleen volume even if it was not a spleen reduction response of 35% or greater. In the placebo group, majority of patients had an increase in their spleen volume while enrolled in the study because the natural history of the disease shows spleen growth and ruxolitinib reversed that and caused spleen volume reduction.

In the COMFORT-II study, 97% of patients on ruxolitinib had a decrease in their spleen volume vs 56% of patients on BAT. Ruxolitinib is certainly life-changing for patients.13

Why is the 35% reduction in spleen volume threshold used?

In the development of ruxolitinib, when they were looking at different doses, they decided in a subgroup of people to do MRI measurement in addition to spleen measurement by palpation. They found an MRI spleen volume reduction of about 32% correlated with a 50% spleen reduction by palpation, so the 35% threshold was used because it best correlates with a 50% reduction in physical exam spleen volume. It certainly is more reliable as a measurement than different people doing an exam on a patient in the clinic.13

There is a correlation between symptoms and spleen reduction. Some symptom responses looked at [in the COMFORT-I trial] were largely associated with the spleen including abdominal discomfort, pain under the left ribs, and early satiety as opposed to true constitutional symptoms including night sweats, itching, bone pains, and inactivity to a lesser degree.

A good proportion of patients treated with ruxolitinib were able to get a symptom response defined as a 50% reduction in symptoms compared with very few in patients treated with placebo. Spleen-related symptoms as well as night sweats, itching, and inactivity improved greatly in patients too. Patients get improvement in their symptoms in sometimes days, if not weeks. About 40% of patients got a 50% reduction of symptoms within the first month on therapy, which is really remarkable.

Which symptom scales were used for the COMFORT-II trial?

The COMFORT-II trial used a few different symptom scales. One was a very functional scale called the EORTC QLQ-C30 [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30], which looks at different ways of functioning such as role functioning, global health, quality of life, mental functioning, and emotional functioning. This is important for patients who want to go back to being able to live their life and feel like MF has caused a problem with that. Many patients are able to have better role functioning and overall global quality of life after treatment with ruxolitinib compared with BAT. There are remarkable improvements in specific symptoms like fatigue, dyspnea, insomnia, and appetite loss.13

Is there a survival benefit for patients on ruxolitinib?

The survival data was controversial to some degree. But patients who are initially randomized to ruxolitinib even after factoring in patients that crossed over have a survival benefit compared with control. There is a small, but significant survival advantage for patients treated with ruxolitinib compared with the control arm [HR, 0.70; 95% CI, 0.540.91; P = .0065].13

A statistical challenge is that patients who were on the control arm were allowed to cross over to the ruxolitinib arm after 6 months. These trials had intermediate-2 or high-risk patients, with large spleens, so in the right patient starting early seems to be associated with a survival benefit.

An older [retrospective analysis] from 2009 that was used to develop some of these prognostic guidelines and the early prognostic models looked at causes of death in patients with PMF. About 50% of the patients looked at had died and in those whose final cause of death was determined, the transformation to acute leukemia dominated as a reason. Other causes included PMF progression without acute transformation, thrombosis, cardiovascular reasons, infection, bleeding, and portal hypertension.1

I would hesitate to say that the reason most patients die of MF is due to acute leukemia. A hematologic center is more likely to note the patient who died of acute leukemia than the one who traveled out of town and got hit by a car. But there is progression of disease, whether it’s to acute leukemia or just more progressive disease that leads to death.

Does spleen response affect outcomes of ruxolitinib-treated patients with MF? What dose of ruxolitinib is used?

Patients who had a spleen response with ruxolitinib seemed to do better than those that didn’t. Even patients who had a transient spleen response also considered as “unstable responders” still derived a survival benefit from being on ruxolitinib. Baseline factors associated with less likelihood of a spleen response are higher risk disease, larger spleens—although other studies have shown that’s not a factor—higher white blood cell counts, a delay in starting ruxolitinib after diagnosis, and lower doses of ruxolitinib.12

The spleen responses in particular are dose-dependent. That’s why we’re really aggressive about trying to get to the higher doses of ruxolitinib. The approved dose ranges from 5 mg to 25 mg twice a day. At week 24, patients on a dose of less than 10 mg twice a day do not show significant spleen volume responses. But patients on the higher doses have spleen responses that are remarkable and quite frequent in patients that are on 25 mg twice a day.

Is symptom response equivalent with the dose of ruxolitinib used? What are some expected hematologic effects?

Symptom responses are equivalent across the different doses. If we’re targeting spleen responses, we want to be aggressive about getting that dose up to at least 20 mg to 25 mg twice a day. But if patients have relatively well-controlled spleens and maybe cytopenia, symptom response can be accomplished with lower doses. The guidelines from this data recommend against starting with a low dose. If necessary, reduce dose, but try starting at a higher dose first to give the patient the best chance of succeeding. If you start low in patients, try to escalate as quickly as can be tolerated. Doses less than 10 mg twice a day are not effective in the long term.

For adverse events [AEs], ruxolitinib is associated with some anemia and thrombocytopenia. The COMFORT-I study had grade 3 or 4 anemia or thrombocytopenia. Anemia was much more common at 45% followed by thrombocytopenia at 13% and neutropenia at 7%. The COMFORT-II study was similar with anemia being seen in 42% of patients, compared with 31% on BAT. So, this gives us a caveat that anemia is also a part of this disease process and is just exacerbated by ruxolitinib. Thrombocytopenia was equivalent with that seen on BAT.11

What are the guideline recommendations for ruxolitinib use in patients with MF who have low platelet counts (50-100 × 109/L)?

In the COMFORT-I and COMFORT-II studies, patients with platelets between 50 to 100 × 109/L weren’t included. But the label extends recommendations for dosing to these patients at a starting dose of 5 mg twice a day, which is not effective. There was a subsequent study called the EXPAND study [NCT01317875] that looked at patients with low platelets and stratified them to stratum 1, 75-99 × 109/L, and stratum 2, 50-74 × 109/L.14

From the study, they deemed that the appropriate safe starting dose in patients with thrombocytopenia is probably 10 mg twice a day, which is the lowest effective dose in achieving spleen and symptom responses. The new recommendation based on the results of the EXPAND study is to start thrombocytopenic patients at 10 mg twice a day and closely monitor them because dose reductions may be needed. But at least they get a chance of an initial good response. Patients in stratum 1 had 40% occurrence of thrombocytopenia compared with patients in stratum 2 who had 78% occurrence of thrombocytopenia that frequently required dose reduction.14

With the more aggressive dosing strategy they achieved spleen responses in a solid proportion of patients with 50% reduction from the baseline spleen volume in about half the patients. There were better improvements in stratum 1 than stratum 2 in symptom scores. So, patients in stratum 1 were able to receive a longer duration of the higher dose, required less dose reductions, and were able to achieve better symptom improvement than those in stratum 2. There were improvements in a variety of symptoms in both strata.14

REFERENCES:

1. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901. doi:10.1182/blood-2008-07-170449

2. Bose P, Verstovsek S. The evolution and clinical relevance of prognostic classification systems in myelofibrosis. Cancer. 2016;122(5):681-692. doi:10.1002/cncr.29842

3. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703-1708. doi:10.1182/blood-2009-09-245837

4. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36(4):310-318. doi:10.1200/JCO.2017.76.4886

5. Tefferi A, Nicolosi M, Mudireddy M, et al. Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia. 2018;32(5):1189-1199. doi:10.1038/s41375-018-0018-z

6. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for primary myelofibrosis. J Clin Oncol. 2018;36(17):1769-1770. doi:10.1200/JCO.2018.78.9867

7. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017;31(12):2726-2731. doi:10.1038/ leu.2017.169

8. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2021. Accessed July 5, 2021. https://bit.ly/3hh9d60

9. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed July 5, 2021. https://bit.ly/3dErcBr

10. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. doi:10.1001/jamaoncol.2015.1590

11. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/ NEJMoa1110557

12. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

13. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

14. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dosef inding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947-954. doi:10.3324/ haematol.2018.204602

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