The phase 3 REACH 3 trial[1] investigates ruxolitinib compared with investigator's choice of therapy for glucocorticoid
refractory or dependent moderate to severe chronic graft versus host disease (GVHD).
This REACH 3 study was done in patients who were 12 years or older with moderate to
severe glucocorticoid refractory or dependent chronic GVHD. The drugs administered
in investigator's choice of therapy arm include everolimus, extracorporeal phototherapy,
ibrutinib, imatinib, infliximab, low-dose methotrexate, mycophenolate mofetil, sirolimus,
and rituximab. REACH 3 study shows improvement in overall response at 24 weeks in
the patients' arm administered with ruxolitinib compared with the control cohort (49.7%
vs 25.6%, odds ratio 2.99, p < 0.001). Ruxolitinib also led to greater median failure-free survival (>18.6 vs. 5.7 months, hazard ratio
0.37, p < 0.001) and higher symptom response (24.2% vs 11%, odds ratio 2.62, p = 0.001). The dose of ruxolitinib used was 10 mg twice daily (bd). In REACH 1,[2] a phase 2 study investigating the role of ruxolitinib in patients 12 years or older
with grades 2 to 4 steroid refractory acute GVHD, the starting dose of ruxolitinib
was 5 mg bd for first 3 days. It also included an option to increase the dosage to
10 mg bd in absence of cytopenia. In REACH 2 study,[3] a phase 3 study evaluating ruxolitinib in patients 12 years or older with grades
2 to 4 steroid refractory acute GVHD, the planned dose of ruxolitinib was 10 mg bd.
The median dose administered was 16.8 mg in two divided doses. In REACH 1 study, ruxolitinib
could be tapered after day 180 in patients who achieved complete response or very
good partial response in acute GVHD and had discontinued corticosteroids for at least
8 weeks. In REACH 2 study, tapering of ruxolitinib was allowed after day 56 in the
responsive patients. In REACH 1 study, corticosteroids were tapered as per institutional
guidelines, with physician discretion allowed. In REACH 2 study, continuation of glucocorticoids
was allowed alongside ruxolitinib or control therapy. Wu et al[4] have reported a weight-based dosing of ruxolitinib in chronic GVHD patients wherein
patients having a weight more than 60 kg received 10 mg bd while patients ≤60 kg received
5 mg bd.
In REACH 3 study, 16.4% patients discontinued ruxolitinib due to adverse events. In REACH 3 study, grade ≥3 thrombocytopenia and anemia was
noted in 15.2% and 12.7% of patients respectively in ruxolitinib arm and 10.1% and
7.6% of patients respectively in the arm receiving control therapy. The incidence
of cytomegalovirus infections was 5.5% and 8.2% in ruxolitinib and control arm respectively.
The incidence of grade ≥3 pneumonia in the patients of ruxolitinib arm and control
arm was 8.5% and 9.5% respectively.
The authors in REACH 3 study have not reported the median dose of ruxolitinib administered.
It is recommended that dose of ruxolitinib be reduced when coadministered with fluconazole.[5]
[6] It would be worthwhile to have the author's opinions regarding the use of lower-dose
ruxolitinib coadministered with fluconazole, especially in resource constrained settings.
The primary end point of REACH 3 study was the overall response at week 24. No reasoning
has been given as to why week 24 was chosen as the end time point. In REACH 3 study,
a higher overall response was seen in ruxolitinib arm than in control arm regardless
of the organs involved. However, the response rates in lung and liver were unsatisfactory
in both the patient arms. The response rate in lungs was 8.6 and 6.1% respectively
in ruxolitinib and control arms. The response rate in liver was 24.4 and 21.7% respectively
in ruxolitinib and control arm. This demonstrates that treatment of chronic GVHD in
case of the recovery of these organs can be very difficult. Over 50% of patients enrolled
in this trial had acute GVHD. The authors have included patients who were treated
with ruxolitinib for steroid refractory acute GVHD. The number of such patients and
the response rates of ruxolitinib in this subset in chronic GVHD would be interesting
to know. In REACH 3, patients treated previously with two or more systemic therapies
for chronic GVHD in addition to glucocorticoids with or without calcineurin inhibitors
were ineligible. Wu et al[4] included patients who had received 1–6 lines of second-line therapies for chronic
GVHD. The median time taken to respond to ruxolitinib and the data regarding nonresponders
or patients who had early deteriorating effects from ruxolitinib arm in REACH 3 study
would further aid in our understanding. The overall survival in the ruxolitinib responders
versus nonresponders would also be interesting. The limitations of REACH 3 study include
the absence of a strong end point such as glucocorticoid-free remission, and the presence
of confounders including concomitant treatments. This makes the determination of the
effect on glucocorticoid dose over time with ruxolitinib as compared with commonly
used therapies difficult.
REACH 3 study leads to important practice-changing conclusions, especially regarding
the use of ruxolitinib in steroid refractory chronic GVHD. In resource-limited settings
as in our country, the administration of ruxolitinib with azole antifungals may help
in reducing the dose and hence the financial burden. The use of ruxolitinib should
be started earlier rather than later in the case of steroid refractory chronic GVHD.
