A Phase I-II Study of Ruxolitinib (INCB18424) for Patients with Chronic Myeloid Leukemia with Minimal Residual Disease While on Therapy with Imatinib

Background: The JAK2/ STAT pathway has been implicated in the survival and proliferation of the leukemic stem-cell in chronic myeloid leukemia (CML). BCR-ABL mediates the activation of STAT3 and STAT5, inhibiting stem-cell differentiation. Activation of JAK1 and JAK2 leads to STAT3 phosphorylation and has been associated with tyrosine kinase inhibitors (TKI) resistance. Thus, the inhibition of JAK2/STAT pathway and nonreceptor tyrosine kinase (TYK2) could increase the sensitivity to TKIs activity and potentially eradicate early progenitors. The JAK1/2 inhibitor ruxolitinib, approved for the treatment of myelofibrosis, has also moderate inhibitory activity against TYK2. This Phase I/II study aims to determine the efficacy of ruxolitinib and TKI activity in CML with residual disease.

Methods: This is a single-arm Phase I/II trial of Ruxolitinib in combination with TKI for CML with minimal residual disease while on TKI therapy. Eligible patients (pts) included adults 18 years and older, on imatinib therapy for a minimum of 18 months with no dose modifications in the last 6 months. Patients with complete hematologic response (CHR) but without a major molecular response (MMR) or complete cytogenetic response (CCyR) or with loss of MMR at any time were included. ECOG performance status 0-2 and adequate organ function was required. Patients on therapy for at least 2 years without MMR or 5 years without a CMR (i.e., undetectable transcripts, ≥100,000 copies ABL) were included. Patients on TKI after alpha-interferon (INF) or prior TKI failure were included. Ruxolitinib was given at a dose of 5 mg BID, 10 mg BID, and 15 mg BID daily in 28 days cycles for up to 2 years. The primary endpoint was to determine the dose-the limiting toxicity and maximal tolerated dose of the combination. Secondary endpoints were to determined safety and clinical activity, and the effect on molecular responses by DNA PCR.

Results: A total of 8 pts with chronic phase-CML and detectable BCR-ABL transcript levels were enrolled between November 2013 and July 2018. The median age was 38.6 years [26-81]. Four pts (50%) were male. 2 pts (25%) had failed INF, and 2 pts (25%) had received one prior TKI (1 pt failed dasatinib, and 1 pt discontinue nilotinib due to adverse effects). The imatinib dose was 300 mg (n=1) and 400 mg (n=7). The median time on TKI therapy was 8.6 years [2.4-14.8]. At baseline 7 pts (87.5%) had a CCyR, and 3 pts (37.5%) had achieved a MMR. Baseline characteristics are listed in Table 1.

The median time on study was 11.4 months. 2 pts achieved CMR after 1 and 12 months on therapy respectively, 5 pts had stable disease (1 pt in MMR and 4 pts in CCyR), and 1 pt had no response, with persistent BCR-ABL PCR above 2%. (Table 2) The median time to best response was 1 month [1-25]. Molecular responses by DNA PCR are illustrated in Figure 1.

The treatment was well tolerated, with mostly grade I-II adverse events (AEs). There were no dose-limiting toxicities. The most common non-hematological adverse events (AEs) were infections (62.5%), pain (50%), fatigue (37.5%), hypertension (25%) and diarrhea (25%) of grade I-II. The most frequent hematological AE's were grade I-II anemia (25%) and grade III-IV neutropenia (12.5%). Adverse events are listed in Table 3.

With a median follow-up of 44.7 months, 1 pt did not respond and died during treatment from an unknown cause, and 2 pts lost CMR after 2 and 7 months respectively. Of the 5 pts with SD, 2 pts lost the CCyR after 5 and 6 months. Overall, 1 patient remains on the study and 7 pts discontinued treatment, including 2 pts that withdrew consent due to adverse effects (grade II fatigue),1 pt due to death, 1 pt due to lost of response and 3 pts for persistence of BCR-ABL transcripts.

Conclusions: The ruxolitinib and imatinib combination was safe and well-tolerated in CP-CML, with an acceptable AE profile; with most toxicities limited to grade I-II AE. Nonetheless, the incidence of a CMR was 25% (2 pts) with a short duration of response. There was no apparent clinical benefit seen with the combination. The study is no longer recruiting patients. (NCT01751425)

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