Next-Generation JAK Inhibition for Patients With Myelofibrosis

When to Stop or Switch JAK Inhibitor Therapy in Myelofibrosis

CASE SUMMARY

Six months ago, a 72-year-old woman with a history of hyperlipidemia (controlled on rosuvastatin [Crestor]) and hypertension (controlled on amlodipine [Norvasc]), developed itching, bloating, loss of appetite, a notable 20 lb weight loss, drenching night sweats, and significant fatigue.

Abdominal examination revealed splenomegaly, spleen palpable 8 cm below the left costal margin without hepatomegaly. CT scans of the chest, abdomen, and pelvis revealed moderate mediastinal lymphadenopathy and splenomegaly.

A peripheral blood smear produced a leucoerythroblastic picture with nucleated threads and immature cells in the periphery. Next-generation sequencing showed a CALR mutation (allele frequency, 22%). Bone marrow biopsy showed megakaryocyte proliferation with atypia, 3+ reticulin fibrosis. Cytogenics were normal.

White blood cells

33 x 109/L​

Absolute neutrophil count

1.4 x 103 cells/mm3​

Hemoglobin

9.8 g/dL​

Hematocrit

38%

Platelets

126,000/​μL

Peripheral blood blasts​

3%

A decision to initiate ruxolitinib (Jakafi) was made. ​There was initial symptom improvement in appetite, night sweats, and weight at a dose of 10 mg twice daily, and the dose was increased to 15 mg twice daily. One month later, platelet count decreased to 100,000/μL, and the dose was reduced to 10 mg twice daily. One month later, platelet count dropped to 32,000/μL, and the patient received a red blood cell transfusion. After another month, platelet count remained at 85,000/μL.

What are you most likely to recommend for this patient now?

JEANNE M. PALMER, MD: There is not a right or a wrong answer. [The majority of participants chose] pacritinib [Vonjo]. If you stop ruxolitinib and go directly to pacritinib, which you can do, then you should be OK, but if you stop the ruxolitinib and their platelets go back up, always remember that sometimes, you can convince [insurance providers] to give you pacritinib, even if the platelets are higher off the ruxolitinib.

If this patient’s platelet count nadired at 66,000/μL (instead of 32,000/μL), what would you be most likely to recommend for this patient?

DISCUSSION QUESTIONS

  • How do you define ruxolitinib failure? ​
  • What are triggers for you intervene earlier versus later?​
  • What are triggers for you to change therapy?​

PALMER: Alright, so one of the big questions that comes up, or I think that's going to be very important for the myeloproliferative neoplasms community to answer, is the definition of ruxolitinib failure, so what are the various things that may happen to a patient that would make you say the ruxolitinib is not working?

VEENA CHARU, MD: I think if the patient has constitutional symptoms and is not improving, the spleen is not getting smaller, and then they are continue to require blood transfusions.

PALMER: Any other comments on what defines ruxolitinib failure for patients? And what triggers you to change therapy?

MANOJ AGARWAL, MD: The return of blood transfusion requirements, which will indicate progression of disease, and therefore, repeat bone marrow [biopsy].

RONALD GOLDBERG, MD: Three things: laboratory results, spleen [volume], and quality of life.

PALMER: That is the name of the game, isn't it? We have a very recurrent theme in those 3 things.

When they actually looked at what drove ruxolitinib discontinuation, based on the European database, lack of response is one, loss of response was another one of the big ones.1 Blast phase was actually almost a quarter of the patients. Allogeneic stem cell transplant and a favorable response. Ruxolitinib-related adverse events [AEs] was also slightly over a quarter of the patients, and then ruxolitinib-unrelated AEs, which was an interesting distribution.

DISCUSSION QUESTIONS

  • Would you taper ruxolitinib dosing for:
    • Interruption/hold
    • Discontinuation
    • Switching to another Janus kinase (JAK) inhibitor or other therapy?
  • How can switching from one JAK inhibitor to another be done safely?
  • What has been your experience with ruxolitinib interruption/discontinuation? With fedratinib?

PALMER: Would you taper the ruxolitinib dosing for interruption or hold or discontinuation or switching to another JAK inhibitor? Do you usually taper ruxolitinib if you're going to switch to another JAK inhibitor, or do you just directly switch to another JAK inhibitor, and [what is] the setting where you've done that? For what it's worth, I generally try to taper down the ruxolitinib a little bit before I will switch them to another JAK inhibitor.

What has been your experience with discontinuation or interruption of ruxolitinib? [Have you had] patients who just decided they were just going to stop it, or start to go down on the doses a lot without discussing?

CHUNHUI FANG, MD: My patient on pacritinib developed liver toxicity, so we held the medication, she improved, we'd rechallenge her, she again got liver function [tests with] ALT [alanine transaminase] being very high, so we had no choice but to stop completely without tapering, but she went onto pacritinib, and she seemed to be OK.

Reference:

1. Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer. 2020;126(6):1243-1252. doi:10.1002/cncr.32664