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Ruxolitinib Rechallenge Can Improve Constitutional Symptoms and Splenomegaly in Patients With Myelofibrosis: A Case Series

Clin Lymphoma Myeloma Leuk. 2018;18(11):e463-e468

Micro-Abstract

There are no approved treatment options for patients with myelofibrosis in whom ruxolitinib fails or ceases to control symptoms and splenomegaly. We conducted a retrospective, multi-institutional case series of 13 patients with myelofibrosis who were retreated with ruxolitinib after treatment had been held owing to loss of or inadequate response. Retreatment resulted in significant spleen size reduction in 69% of patients and symptom improvement in 92% of patients. Four patients received a second re-challenge with ruxolitinib after losing their response, and all 4 experienced improvement. Our findings suggest that patients with myelofibrosis who lose their responses or have inadequate responses to ruxolitinib treatment can achieve reduction in spleen size and constitutional symptoms on re-exposure to ruxolitinib.

Abstract

Introduction

Myelofibrosis (MF) is one of the classic myeloproliferative neoplasms and can occur de novo or following transformation from polycythemia vera (PPV MF) or essential thrombocythemia (PET MF). It can be associated with constitutional symptoms and splenomegaly, both of which can negatively impact quality of life. The only curative option for MF is allogeneic stem cell transplantation. Studies have shown that JAK2 inhibitors such as ruxolitinib are effective in reducing both splenomegaly and symptom burden. Although there is no approved treatment for patients who progress on ruxolitinib, anecdotal evidence suggests patients may respond to a re-challenge of ruxolitinib after drug cessation.

Patients and Methods

We conducted a multi-institutional, retrospective case series to study patients who were re-challenged with ruxolitinib after inadequate response to or loss of response with an initial treatment course. Thirteen patients were identified. Six patients had primary MF, 3 patients had PPV MF, and 4 patients had PET MF. Ten patients were JAK2-positive, 2 were CALR-positive, and 1 patient had neither mutation. Nine patients received 1 ruxolitinib re-challenge, and 4 received 2 re-challenges. Response was defined as improvement in constitutional symptoms and/or reduction in spleen size.

Results

During the primary treatment course with ruxolitinib, there was improvement in constitutional symptoms and reduction in spleen size in 92% and 85% of patients, respectively. Following cessation of ruxolitinib, all patients received a first re-challenge course with improvement in symptoms and splenomegaly in 92% and 69%, respectively. Of the 4 patients who received a second re-challenge course of ruxolitinib, all had improvements in spleen size and constitutional symptoms. Six patients have continued on a first or second ruxolitinib re-challenge course with good response.

Conclusion

Our study demonstrates that re-exposure to ruxolitinib following a period of treatment cessation in patients with MF can lead to durable responses with regards to both splenomegaly and symptom burden.

Keywords: Refractory myelofibrosis, Relapsed myelofibrosis, Resensitize, Retreatment, Treatment cessation.

Introduction

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by splenomegaly, progressive anemia, and constitutional symptoms, and can arise de novo (primary MF) or after polycythemia vera (PPV MF) or essential thrombocythemia (PET MF). 1 Splenomegaly from MF can be severe and negatively impact quality of life owing to symptoms such as pain, early satiety, bloating, and, in extreme cases, ischemia and splenic infarct. 2 The presence of constitutional symptoms, such as weight loss, unexplained fever, and night sweats, is associated with shortened survival in MF. 3 Although erythropoietin stimulating agents, corticosteroids, androgens, immune modulators, and hydroxyurea are all options in the management of MF, 4 the only curative option remains allogeneic hematopoietic stem cell transplantation. 5

The discovery of the Janus kinase 2 (JAK2) V617F mutation in MPNs led to further understanding of the pathogenesis of MF and to the discovery of additional mutations disrupting JAK-STAT and other pathways. 6 7 8 Ruxolitinib is an oral, selective inhibitor of JAK 1 and 2. 9 In the landmark COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I and COMFORT-II) trials, ruxolitinib showed significant clinical benefits in reducing spleen size and improving MF-related constitutional symptoms over placebo and best available therapy. 10 11 12 13 14 However, these studies did not specify what subsequent therapy was offered to patients who discontinued ruxolitinib owing to progression – defined as ≥ 25% increase in spleen volume from on-study nadir, splenic irradiation or splenectomy, leukemic transformation, or death – or toxicities. To date, there remains no approved treatment option for patients who progress on ruxolitinib. Preclinical models and limited case reports demonstrated response to ruxolitinib re-challenge. 15 16 17 18 Based on these findings, we performed a retrospective study examining a series of patients with primary, PPV, and PET MF who were retreated with ruxolitinib.

Patients and Methods

This study was a multi-institutional, retrospective case series conducted at the University of Southern California and Cleveland Clinic. Patients with a diagnosis of primary, PPV, or PET MF, based on the World Health Organization 2016 criteria for PMF and the International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria for PPV MF and PET MF, 19 20 who were retreated with ruxolitinib at least once between 2012 and 2017 were included in this series. Patient information was submitted de-identified to a central Research Electronic Data Capture (REDCap) database for centralized analysis. Institutional review board approval was obtained at each respective site for retrospective chart review, and a data use agreement was executed between the 2 sites.

Electronic medical records and clinician office visit notes for individual patients were searched for demographic information (including age, gender, ethnicity), past medical history, subjective history, type of MF, mutational analysis data (JAK2, CALR, c-MPL, or other), laboratory values, bone marrow biopsy results, physical examination including spleen size, length of ruxolitinib treatment courses, and preceding and interim treatment when patients were not receiving ruxolitinib. Subjective history included MF-related constitutional symptoms which were defined as presence of any: unexplained fever, night sweats, fatigue, and weight loss. Presence of and return of any of these symptoms was recorded. An objective symptom assessment tool was not used. MF risk scores were calculated using the Dynamic International Prognostic Scoring System (DIPSS) after extracting appropriate variables documented at the time of initiation of ruxolitinib treatment. 21 Spleen size was defined as the length of the spleen in centimeters below the left costal margin as palpated by the clinician.

Subjects who received a primary treatment course with ruxolitinib of at least 2 weeks were included. Treatment was administered per the United States Food and Drug Administration prescribing information by the treating physician; the maximum tolerated dose was given to achieve spleen size reduction and symptom improvement, with a minimum dose of 5 mg twice daily used for patients with or developing severe cytopenias. A re-challenge course was defined as any re-exposure to ruxolitinib for at least 2 weeks, with at least 1 week between courses. The duration of therapy for each course was calculated. Ruxolitinib dose at the time of initiation and cessation of any course was recorded. Spleen size at the time of initiation and cessation of ruxolitinib for each course was recorded. Patients were continued on therapy if there appeared to be clinical benefit, which was captured as spleen length reduction and/or symptom improvement. Discontinuation of ruxolitinib occurred at the treating physician's discretion. Reasons for discontinuation could be grouped into 3 categories: (1) loss of response or inadequate response; (2) change to alternate therapy; or (3) intolerable toxicity. Loss of response (disease progression) was defined by the treating physician as either recurrence of symptoms that could not be controlled with other medications or any growth of spleen volume by ≥ 25% from the nadir. Inadequate response was defined as lack of reduction in spleen size and/or persistence of constitutional symptoms despite the therapy. Information regarding complete blood count, including blast percentage, was extracted from the electronic medical records at the start of each ruxolitinib course, 1 month after starting each ruxolitinib course, at the time of the smallest spleen size while on ruxolitinib, and at the time of ruxolitinib cessation.

Results

Thirteen eligible patients were identified; their characteristics are shown in Table 1 . There were 6 males and 7 females, with a median age of 71 years (range, 43-87 years). Six patients had primary MF, 3 patients had PPV MF, and 4 patients had PET MF. Five patients were high risk, 6 patients were intermediate-2 risk, and 2 patients were low risk according to the DIPSS. Ten patients were JAK2-positive, 2 were CALR-positive, and 1 patient had neither mutation. Four of 13 patients were tested for c-MPL mutation, and all were negative.

Characteristic N
Median age, y (range) 71 (43-87)
>60 11
<60 2
Gender  
Male 6
Female 7
Ethnicity  
White 11
Black 1
Hispanic 1
MF type  
Primary MF 6
Post-PV 3
Post-ET 4
DIPSS score  
High 5
Intermediate-2 6
Intermediate-1 0
Low 2
Mutation status  
Jak2 V617F 10
Calreticulin (CALR) 2
Non-Jak2 or CALR 1
Constitutional Sx 13/13
Abbreviations: DIPSS = Dynamic International Prognostic Scoring System; ET = essential thrombocythemia; MF = myelofibrosis; PV = polycythemia vera.

Table 1Patient Demographics at Baseline

 

Of the 13 patients, 9 patients received 1 ruxolitinib re-challenge course, and 4 patients received 2 re-challenge courses. The median starting dose for both the primary treatment course and first re-challenge course was 10 mg orally twice per day (range, 5-25 mg twice daily). During the primary treatment course, all patients experienced improvement in at least 1 of the response endpoints: 12 (92%) of 13 patients had improvement in constitutional symptoms, and 11 (85%) of 13 patients had mean reduction in spleen size of 10.9 cm and a median reduction in spleen size of 6 cm (range, 4-28 cm). The median duration of therapy for the primary treatment course was 62 weeks (range, 6-194 weeks).

The primary course of ruxolitinib was discontinued in 9 of 13 patients owing to loss of or inadequate response: all 9 experienced new growth of the spleen, 3 of whom also had return of constitutional symptoms; 1 had lack of symptom improvement despite spleen size reduction. Four of 13 patients discontinued due to intolerance to ruxolitinib ( Figure 1 ). Details regarding spleen size, treatment duration and period of treatment cessation(s) are provided in Table 2 .

gr1
 

Figure 1
Swimmers Plot of Treatment Details in 13 Patients With Myelofibrosis

N Initial Ruxolitinib Treatment Course Weeks Between Second Ruxolitinib Treatment Course Weeks Between Third Ruxolitinib Treatment Course
Spleen Sz at Start, cm Smallest Spleen Sz Achieved, cm Improvement in Sx Duration, wk Reason for DC Spleen Size upon DC Spleen Sz at Start, cm Smallest Spleen Sz Achieved, cm Improvement in Sx Duration of Response, wk Spleen Sz at Start, cm Smallest Spleen Sz Achieved, cm Improvement in Sx Duration of Response, wk
1 12 8 Yes 29 T 12 4 15 10 Yes 85>
2 15 10 Yes 193 LR 18 6 14.5 8 Yes 63>
3 11 5 No 28 IR 10 176 12 14 Yes 35
4 15 10 Yes 21 T 12 3 12 9 Yes 106>
5 28 0 Yes 194 LR/C 7 18 21 7 Yes 84
6 17 11 Yes 27 LR 18 113 10 14 No 103
7 2 4 Yes 80 LR/C 10 21 13 9 Yes 16
8 10 0 Yes 117 LR/C 4 8 18 10 Yes 41
9 21 0 Yes 166 LR 19 23 22 12 Yes 63
10 6 0 Yes 106 LR 7.5 5 7.5 3 Yes 83 4 7 4 Yes 40>
11 6 6 Yes 6 T 6 4 6 10 Yes 97 10 18 10 Yes 18
12 11 0 Yes 42 T 0 31 0 0 Yes 80 30 8 7 Yes 77>
13 34 16 Yes 153 LR/C 23 4 33 24 Yes 7 9 30 24 Yes 84>
Abbreviations: C = clinical trial; DC = discontinuation; I = inadequate response; LR = loss of response; N = patient number; Spleen Sz = spleen size below left costal margin in cm measured by manual palpation; Sx = constitutional symptoms; T = intolerable toxicity.

Table 2Disease Characteristics and Treatment Details of Patients Undergoing Ruxolitinib Retreatment

 

During the first re-challenge course, 9 (69%) of 13 patients had a mean reduction in spleen size of 7.1 cm and a median reduction in spleen size of 6.5 cm (range, 3-14 cm), 3 (23%) had an increase in spleen size (median, 4 cm; range, 2-4 cm), and 1 patient had no palpable spleen before or after treatment ( Figure 2 ). All but 1 patient (92%) had improvement in constitutional symptoms. Patient 6 had both increase in spleen size and lack of improvement in constitutional symptoms, but was kept on ruxolitinib treatment owing to lack of alternative therapies. Three patients (23%) continue with stable spleen size and improvement in constitutional symptoms on their first re-challenge course of ruxolitinib ( Figure 1 ). Ruxolitinib was ultimately discontinued in 7 (54%) of 13 patients owing to loss of response or intolerance to ruxolitinib, whereas 1 patient went on to clinical trial.

gr2
 

Figure 2
Spleen Size Change in cm During Ruxolitinib Courses
Abbreviations: P11 = no change in size during initial treatment; P12 = no palpable spleen during second treatment.

 

Four patients (31%) received a second re-challenge course of ruxolitinib, and all had improvements in spleen size and constitutional symptoms. Three patients (23%) continue to have ongoing responses and remain on their second re-challenge course of ruxolitinib ( Figure 1 ).

Four patients expired during ruxolitinib treatment. The median duration of therapy for both the first and second re-challenge course has not yet been reached as patients from both groups have continued on treatment.

Discussion

In this study, we found that patients who lose their response or have inadequate response to ruxolitinib treatment can be successfully re-challenged with ruxolitinib. The majority of the patients in our series had a reduction in spleen size with the primary ruxolitinib treatment course, and all but 1 experienced symptom improvement. During the first retreatment course, 69% of the patients experienced a mean reduction in spleen size (7.1 cm) that was significant but less robust than the original response (mean, 10.9 cm). In select cases, even a second re-challenge can be successful, as 31% of patients in our series went on to receive a third ruxolitinib course, all with decreases in spleen size and improvement in constitutional symptoms. In some cases, responses on re-challenge have been durable and occur despite interim treatment with standard therapies or treatment on clinical trial.

Our findings are consistent with other limited case reports in the literature. One letter to the editor described 2 patient cases of primary and secondary MF that experienced response to retreatment with ruxolitinib after initially having progression of disease on the drug. 14 These responses also included reduction in splenomegaly, improvement in constitutional symptoms, and increased hemoglobin levels. Another recent case report described a successful response to ruxolitinib retreatment in combination with hydroxyurea, with improvements in symptomatic splenomegaly, cachexia, and reduced transfusion requirements after initial partial relief in symptoms with single-agent ruxolitinib. 18 Separately, in the large phase IIIb expanded-access JAK Inhibitor RUxolitinib in Myelofibrosis Patients (JUMP) trial, it was noted that 207 of the 1144 total patients had therapy interruption with ruxolitinib for 7 days or more before treatment restart. It was noted that this retreatment group had a 68% rate of ≥ 50% reduction in palpable spleen size, with a trend towards improved symptoms as measured by the Functional Assessment of Cancer Therapy-Lymphoma total score. It is important to note, however, that these patients mostly had ruxolitinib held owing to intolerable toxicities to the drug, rather than progression on the drug. 22

Recently, Newberry et al showed that clonal evolution and thrombocytopenia during ruxolitinib therapy correlated with poor outcomes. 23 In our cohort, 3 patients had platelets < 100 × 10 9 /mcL before starting ruxolitinib and 3 additional patients developed platelets < 100 × 10 9 /mcL during treatment. Among the latter 3 patients, 2 died during the treatment period. However, among the 9 patients with platelets < 260 × 10 9 /mcL at the start of therapy, only the 2 with < 100 × 10 9 /mcL died during the median follow-up of 57 months. Among the 9 patients who were DIPSS INT-2 and high risk, the median overall survival was 55 months, which is better than that reported for the MD Anderson Cancer Center (MDACC) cohort. Whether our treatment approach, the lower number of patients who had or developed thrombocytopenia, or other factors account for the difference cannot be ascertained from this small sample size.

The mechanism behind resensitization to ruxolitinib is unclear. Although JAK2 inhibition clearly has a benefit in improving constitutional symptoms and splenomegaly, drugs targeting this pathway do not decrease or eliminate the MPN clone. 15 The mechanism behind drug tolerance in chronic exposure of JAK2-mutant cells to JAK2 inhibitors has been described. Ross Levine and colleagues found no evidence of second site kinase mutations in vitro. Rather, the group found a reactivation of JAK-STAT signaling with hetero-dimerization between activated JAK2 and JAK1 or TYK2. In other words, there was an activation of JAK2 in trans by other JAK kinases. This phenomenon was also shown to be reversible, whereupon JAK2 inhibitor withdrawal was associated with a re-sensitization to JAK2 inhibitors. 15 This re-sensitization phenomenon forms the basis for an intermittent treatment strategy. 16

Our study is limited as it is a retrospective case series with a selection bias. Given the retrospective nature, there were no standardized protocols for ruxolitinib dosage, schedule, or duration of ruxolitinib cessation, and individual treatment was subject to the treating physicians' clinical judgement. Unlike other major prospective clinical trials, like the COMFORT-I study, that used the Myelofibrosis Symptom Assessment Form version 2.0 to standardize presence and severity of MF-related symptoms, the symptoms recorded and followed in our study were not submitted in a standardized questionnaire, but rather, reported by patients during clinic visits and subject to physician interpretation. 24 Measurement of spleen size in our study, although generally done consistently by the same practitioner during serial follow-up clinic visits, is also subject to human error and inter-examiner differences. Again, this differed from other major clinical trials, such as COMFORT-I and COMFORT-II, which used imaging with magnetic resonance imaging or other modalities to objectively measure spleen size changes throughout the course of treatment. 12 24

In summary, this multi-center retrospective case series demonstrates the feasibility and effectiveness of ruxolitinib retreatment to sustain second or even third responses in terms of symptoms and splenomegaly. These responses are often durable and sustained, and are seen even after failure of initial ruxolitinib treatment, as well as failure of other standard or experimental therapies. These results suggest that ruxolitinib retreatment is a safe and potentially effective therapeutic option for patients who have exhausted other standard therapies.

Clinical Practice Points

 

  • There are no approved therapies for patients with myelofibrosis in whom ruxolitinib fails or loses its efficacy against splenomegaly and constitutional symptoms.

  • In this retrospective case series, 13 patients with myelofibrosis in whom ruxolitinib therapy was ineffective, poorly tolerated, or had lost its efficacy underwent a period of treatment cessation lasting at least 2 weeks.

  • A majority of patients sustained improvements in spleen size and symptom control on rechallenge with ruxolitinib.

  • Four patients experienced improvement with a second retreatment course of ruxolitinib.

  • Patients with myelofibrosis with loss of or inadequate response may benefit from retreatment with ruxolitinib after a brief treatment hold.

 

Disclosure

The authors have stated that they have no conflicts of interest.

Supplemental Data

Data Profile

References

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