Dear Editor,
RRuxolitinib (RUX) is the first JAK1/JAK2 inhibitor (JAKi) approved for the treatment
of splenomegaly and symptoms related to myelofibrosis (MF)
1,2
. By JAK1 inhibition, RUX reduces the production of several inflammatory cytokine
(IL-6, IL-1rα, MIP-1β, TNF-β, and CRP), whereas myelosuppression is mainly exerted
through JAK2 inhibition. Despite considerable clinical efficacy, some patients fail
to obtain and/or maintain a stable response or are intolerant to RUX
3,4
. Thus, ~40% of patients discontinue RUX within 3 years of therapy
5
.
In the early phase I/II study of RUX in MF, most patients experienced relapse of their
symptoms and worsening splenomegaly after RUX discontinuation
1
, and life-threatening adverse events (AEs) occurred in 5 out of 47 patients, including
respiratory distress, septic-like shock and disseminated intravascular coagulation-like
syndrome. These events, attributed to an acute rebound of cytokine storm, were defined
as RUX discontinuation syndrome (RDS), and careful tapering under close physician
supervision was suggested as a preventive strategy
6
. Further cases of severe AEs attributed to RUX discontinuation have been subsequently
described, despite a careful stepwise reduction of RUX
7–9
, also in the setting of patients that received RUX as a bridge to transplantation
10,11
(Supplemental Table 1). RDS typically presents within 3 weeks from RUX discontinuation,
apparently without relation with RUX dose, and seems to improve after RUX reintroduction.
However, these findings were based on case reports or limited series of patients,
and available data are insufficient to estimate the impact of RDS in routine clinical
practice.
The current study aims to investigate in a real-world context: (1) modalities of RUX
discontinuation; (2) incidence, timing, and severity of RDS; (3) outcome and risk
factors associated with RDS.
In 2016, a clinical network was established to collect information about RUX therapy
in MF
12
. This network now includes 22 academic hematology centers where MF patients are followed
by hematologists with specific MPN-driven practice.
A specific survey was conducted in all participating Centers with the scope to obtain
comprehensive information regarding timing/modalities of RUX discontinuation, and
subsequent outcome. RDS included all new symptoms that occurred within 21 days from
RUX discontinuation and were interpreted by the treating Hematologist as caused by
RUX discontinuation. Based on the previous definition, RDS was graded as mild if no
intervention was required, moderate if symptoms required medical interventions including
RUX restarting, steroids, oral analgesics, and severe if intravenous medications,
hospital admissions, splenectomy, or delaying of hematopoietic allogeneic transplantation
(HCT) were needed
11
.
At data cutoff date (1 May 2020), 700 RUX-treated MF patients were included in the
database. After a median follow-up from RUX start of 36.1 months, 251 (35.9%) patients
discontinued RUX and were evaluable for RDS.
At the time of decision to stop RUX, 53% of these 251 patients were older than 70,
68.5% presented anemia and 45.8% had large splenomegaly (>10 cm below costal margin,
BCM); 27.5% of patients had a MPN-10 Total Symptom Score > 20. Failure (lack/loss
of response, or leukemic transformation) was the main cause of RUX stop (60.6%), whereas
AEs (mainly hematological) and other reasons caused RUX discontinuation in 28.6% and
10.8% of patients, respectively. In most cases, AEs were concomitant to failure/suboptimal
responses. Indeed, at the time of RUX stop, 36.7% of patients presented a platelet
count below 100 × 109/l and 31.5% had transfusion-dependent anemia. Also, in 7.6%
of the patients, a grade 2–3 infectious event was recorded before RUX discontinuation.
RUX daily dose (mg BID) was: 5, 10, 15, or 20 in 46.2, 23.1, 15.6, and 15.1% of patients.
Notably, at the time of RUX start, the dose of RUX was 5, 10, 15, or 20 mg BID in
27.9, 17.2, 18.4, and 36.5% of patients. The concomitance of AEs with a poor response
to RUX most likely led to a progressive RUX dose reduction in many patients; hence,
at the time of the final decision to discontinue the drug, many patients were already
taking low doses.
In 162 patients, RUX was abruptly discontinued. In the remaining 89 patients (35.5%),
RUX dose was gradually decreased before discontinuation. Tapering was associated with
hydroxyurea and/or corticosteroids in 34 (38.2%) patients. RUX tapering pattern was
very variable among Centers and consisted of dose reductions of 5 or 10 mg per day
at variable intervals, ranging from a dose reduction every 30 days to one every 3
days. The median duration of tapering was 14 days (range 3–60). No association was
found between tapering use and clinical/laboratory parameters or RUX dose at the time
of RUX discontinuation. However, tapering use was consistent within the single Centers,
and was regularly performed in only 4 Hematology Centers (Supplemental Fig. 1).
RDS occurred in 34 (13.5%) patients after a median time of 7 days (range, 2–21) from
RUX stop. The incidence rate of RDS was 0.7 per 100 patient-days.
RDS was mild in 21 (61.8%) patients. Mild RDS consisted in symptomatic spleen increase
in 62% of the cases, whereas 9.4% of patients experienced a flare in constitutional
symptoms (fever, weight loss, night sweats); in six patients (28.6%), other MF-related
symptoms (fatigue, itching, bone pain, abdominal discomfort) occurred. The median
time from RUX stop to mild RDS was 10 days (3–21). After RUX discontinuation, ten
patients (47.7%) did not receive further therapy because of progression to blast phase
and/or unfitness; eight patients (38%) were treated with different therapies (including
demethylating agents, splenectomy, and HCT), whereas three patients (14.3%) received
a JAKi, after a median time of 9 months.
A moderate RDS occurred in 10 out of 34 (29.4%) patients, after a median time from
RUX stop of 8.5 days (range, 3–20) and comparable to mild RDS. Moderate RDS was represented
by symptomatic spleen enlargement (seven patients), or constitutional symptoms appearance/increase
(three patients). RDS therapy consisted in corticosteroids (eight patients) or enrollment
in a clinical trial with a non-JAKi. Three patients received RUX rechallenge after
an average time of 2.6 years from first discontinuation.
A total of three cases of severe RDS were observed and consisted of: spleen rupture
causing splenectomy (case 1); fever, dyspnea, confusion, and dizziness requiring hospitalization
(case 2); severe ARDS treated in intensive care unit (case 3) (Supplemental Figure
2). Severe RDS occurred within 48 h after RUX discontinuation and the patient’s condition
rapidly improved after RUX rechallenge.
No fatal cases of RDS were observed.
In multivariable Cox regression analysis, only platelet count <100 × 109/l (HR 2.98,
95%CI 1.29–6.90) and spleen ≥10 cm BCM (HR 2.03, 95%CI 1.01–4.17) at RUX stop were
significantly associated with higher probability of RDS (Fig. 1a). Overall, 19 out
of 251 patients (7.6%) re-started RUX after drug discontinuation. RDS was significantly
associated with the need of RUX rechallenge, with 8/34 (23.5%) RDS patients eventually
resuming RUX (p < 0.001) (Fig. 1b). Notably, the occurrence of RDS did not significantly
influence overall survival.
Fig. 1
Risk factors at ruxolitinib discontinuation associated with subsequent discontinuation
syndrome (a) and probability of RUX rechallenge according to RDS (b).
a Risk factors were identified with a Cox regression model. In order to use a parsimonious
model owing to the small number of events, only variables with p value < 0.05 in univariate
analysis were considered for multivariable analysis. Moreover, collinearity amongst
variables was detected by means of Pearson correlation test. Ultimately only platelet
count and spleen size were considered in multivariable analysis and both remained
statistically significant. b Given that RDS is a time-dependent covariate, the curves
were obtained with the Simon-Makuch technique to take the change in an individual’s
covariate status over time into account. One week from ruxolitinib stop, which is
the median time from RUX stop to RDS occurrence, was chosen as the landmark time point.
Overall, this study shows that symptoms and/or splenomegaly significantly increase
in ~15% of patients soon after RUX stop, with sometimes considerable clinical deterioration
in already frail patients. This frequency is consistent with the report by Shanavas
et al.
11
, who found that 10 out of 66 (15%) patients treated with RUX before HCT developed
RDS. RDS was mild to moderate in eight cases, and severe in two cases, eventually
leading to HCT delay. In our cohort, the incidence of severe RDS appeared to be lower
(1%) than initially reported (11%)
6
. Whether this difference is related to the smaller number or to a more advanced disease
of patients enrolled in phase I–II study, compared with those treated with RUX in
subsequent years, remains to be defined. Indeed, compared with patients included in
the phase I/II trial, that were all at intermediate-2/high risk and mostly (92%) affected
by severe splenomegaly, this study included many patients that started RUX while at
intermediate-1 risk (47.2%), with a lower incidence of baseline large splenomegaly
(63.3%) or thrombocytopenia (15.4%). Also, owing to its retrospective nature, an underestimation
of RDS cannot be fully ruled out in the present study. However, both experiences highlight
that re-expansion of MF after RUX can be sudden and potentially life-threatening,
and that a rapid diagnosis of RDS is critical, as the reintroduction of RUX can quickly
improve clinical status in most cases.
Since RDS is an early event, any other therapy should be started as close as possible
to RUX discontinuation, as already observed and indicated in the context of RUX as
bridge to HCT
13
. Importantly, the possible occurrence of RDS may be anticipated in a substantial
fraction of patients that discontinue RUX during the screening phase of clinical trials
enrolling patients with failure or suboptimal response to RUX. In these cases, careful
monitoring, and disclosure of potential risk of RDS to the patients are recommended.
This real-world experience also highlights that, despite specific indications
14
, prevention strategies of RDS were infrequent and inconsistent across different Centers,
with only a minority of patients gradually reducing the dose or introducing prophylactic
corticosteroids. This has probably prevented the detection of a correlation between
tapering and RDS reduction. Despite these limitations, implementation and standardization
of discontinuation strategies should be pursued for a better RDS prevention in the
future.
Finally, we observed that the risk of RDS was significantly higher in patients with
a greater burden of the disease at the time of discontinuation. Particularly, the
increased incidence of RDS in patients with large splenomegaly may indicate that unexpectedly,
in at least some patients deemed refractory to RUX, the maintenance of JAK2 inhibition
has a non-negligible activity. In this context, the re-use of a JAKi may be particularly
reasonable. The reintroduction of RUX has already shown to achieve some clinical responses
15
. Possibly, second-generation JAKi may have an even greater clinical relevance in
this setting.
In conclusion, these results confirm the need for a careful surveillance of MF patients
at the time of RUX discontinuation. A quick switch to alternative treatments, if clinically
indicated, should be planned particularly for patients who stop RUX with large splenomegaly.
In the absence of available alternatives, the occurrence of RDS may indicate a residual
disease control activity and identify a population that can still benefit from JAK2i.
Supplementary information
Supplemental Table 1
Supplemental Figure 1
Supplemental Figure 2