Connecting Spleen Volume Reduction to Survival Outcomes in MF

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue. Her spleen was palpable 6-7 cm below the left costal margin​, but she had no known comorbidities. Next-generation sequencing revealed a JAK2 V617F mutation​, and her karyotype was46XX.​ A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​, and a blood smear was positive for leukoerythroblastosis​.

Her laboratory values also led to a diagnosis of primary myelofibrosis (MF). Risk stratification based on the dynamic international prognostic scoring system gave her a score of intermediate-1, and based on the mutation-enhanced international prognostic score system for transplantation-age she was also determined to be at intermediate risk​.

DISCUSSION QUESTIONS

• Did the overall survival data from the COMFORT-I trial (NCT00952289) and COMFORT-II trial (NCT00934544) impact the way you manage patients with MF?​
• How do you monitor and manage anemia in patients with primary MF prior to starting Janus kinase (JAK) inhibitor therapy?​

RAAJIT K. RAMPAL, MD, PHD: If you look at several pieces of data, there is a correlation between [the patient] achieving a spleen volume reduction [SVR] and overall survival [OS] results. This a key finding [when looking] at pooled data from COMFORT-I and COMFORT-II and the RUXOREL-MF study [NCT03959371], which used the response to ruxolitinib after 6 months [RR6] model that looked at factors associated with survival and patients treated [with ruxolitinib (Jakafi)] in the real world.^1,2 Both of those analyses demonstrated that achieving at least a 35% spleen volume response correlated to better survival.

Raajit K. Rampal, MD, PhD​Director, Center for Hematologic Malignancies

Director, Myeloproliferative Neoplasms Program

Memorial Sloan Kettering Cancer Center​

New York, NY

Now, does it have to be at least a 35% reduction? No, in fact, if you look at the pooled COMFORT-I and COMFORT-II data, as much as a 10% SVR does increase odds of survival.¹ There is a trend towards increasing survival benefit as the amount of SVR increases, but it's not statistically significant.¹ However, I think that does argue that achieving a SVR is an important thing.

SUBHASH C. PROOTHI, MD: If we are making patients more anemic with this therapy, are we not affecting their quality of life?

RAMPAL: In somebody who has a preserved hemoglobin, in the first 3 months you may expect there is going to be a decrease in hemoglobin and you're going to potentially have to transfuse them or give an [erythropoiesis stimulating agent], but it will recover to a reasonable number after 3 months.

Longer term it becomes more problematic; in other words, there is this RR6-model that demonstrated if the patient continues to be transfusion dependent by about 6 months, there is a detrimental effect on survival.² But to your point, of course that's going to also have a detrimental effect on the patient's quality of life if you're committing them to transfusions.

ALEXANDER BARSOUK, MD: We see this OS difference [with these data]. But my question is, for those patients who were randomly assigned, when did their treatment start? [Did it start] when they were diagnosed or when they developed symptoms?

RAMPAL: In order to qualify for the COMFORT trials, the patient had to have a certain symptom burden measured by the total symptom score. Some of these patients were recently diagnosed patients, however, they had to have a certain threshold of spleen and symptoms to qualify for the study. So, does that apply to the patients that we see in the real world? Not entirely.

^References:

^{1. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al; COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015 Sep;100(9):1139-45. doi:10.3324/haematol.2014.119545}

^{2. Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855-1864. doi:10.1182/bloodadvances.2021006889}