TRANSFORM-1: Key safety and efficacy results

Ruxolitinib (RUX) monotherapy is currently the standard of care for patients diagnosed with myelofibrosis, with spleen volume reduction ≥35% (SVR35) at Week 24 consistently in the range of 29%–49%.¹ While patients experience symptom improvement and spleen volume reduction ≥35%, limited benefit remains in key clinical outcomes.¹ Navitoclax (NAV), a novel oral B-cell lymphoma-extra-large and B-cell lymphoma-2 inhibitor in combination with RUX has shown antitumor activity and clinical benefit in the recent phase II REFINE trial (NCT03222609).

At the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, Pemmaraju presented key efficacy and safety data from the phase III TRANSFORM-1 study (NCT04472598), the first randomized clinical trial investigating NAV + RUX combination compared with RUX + placebo (PBO) in patients with Janus kinase inhibitor-naïve myelofibrosis. We summarize the key points below.

Study design¹

• A total of 252 patients were enrolled in the study and randomized 1:1
  • NAV 100/200 mg once daily + RUX 15/20 mg twice daily (n = 125)
  • RUX 15/20 mg twice daily + PBO (n = 127)
• The primary endpoint was SVR35 at Week 24
• Secondary endpoints included SVR35 at any time, duration of SVR35, and change in Total Symptom Score (TSS) from baseline to Week 24
• Patient eligibility criteria are shown in Table 1

Table 1. Eligibility criteria*

ECOG, European Co-operative Oncology Group; JAK, Janus kinase; MF, myelofibrosis. *Adapted from Pemmaraju,.1
Eligibility criteria
Age ≥18 years
ECOG performance score ≤ 2
Intermediate-2 or high-risk MF
Measurable splenomegaly
Evidence of symptoms
No prior JAK inhibitor therapy

Results¹

• Baseline patient characteristics were similar between the two treatment arms (Table 2)

• The median follow-up was 14.9 months

Table 2. Baseline patient characteristics*

CALR, calreticulin; DIPSS+, Dynamic International Prognostic Scoring System plus; HMR, high molecular risk; JAK, Janus kinase; MPL, ; myeloproliferative leukemia virus oncogene; NAV, navitoclax; PBO, placebo; RUX, ruxolitinib; TSS, Total Symptom Score. *Adapted from Pemmaraju.1
Characteristic, % (unless otherwise stated)	NAV + RUX (n = 125)	RUX + PBO (n = 127)
Age, years	70	69
Sex, male	50	64
Number of prior lines of therapy, median (range)	1	1
Median spleen volume, cm3	1,441	1,639
Median TSS	21	24
DIPSS+ risk
Intermediate-1	6	4
Intermediate-2	83	87
High-risk	10	9
Driver mutation
JAK2V617F	65	62
CALR	18	20
MPLW515	11	8
HMR mutations	48	43

Efficacy

• The median time to first SVR35 response was similar in both treatment groups

• 12.3 months in the combination group vs 12.4 months in the placebo group

• SVR35 at Week 24 was twice as high in the combination group vs the placebo group (Figure 1)

NAV, navitoclax; PBO, placebo; RUX, ruxolitinib; SVR35, spleen volume reduction ≥35%.
*Adapted from Pemmaraju.¹

• The mean change in TSS from baseline at Week 24 in the combination group was 9.7 vs 11.1 in the placebo group (p = 0.2852).
• Reduction in TSS ≥50% at Week 24 was experienced by 39.2% of patients in the combination group vs 41.7% of patients in the placebo group.
• NAV + RUX doses were higher in responders vs non-responders

Safety

• 33% of patients discontinued treatment
  • The most common cause of discontinuation was adverse events (AEs), 14% in the NAV + RUX group and 11% in the RUX + PBO group
• The most common AEs of any grade experienced by >30% of patients receiving NAV are shown in Figure 2

AE, adverse event; NAV, navitoclax; PBO, placebo; RUX, ruxolitinib.
*Adapted from Pemmaraju.¹

• Grade ≥3 AEs were experienced by 85% of patients in the combination group and 70% of patients in the placebo group
• Serious AEs were experienced by 26% of patients in the combination group and 32% of patients in the placebo group
• Dose interruptions or reductions were mainly due to thrombocytopenia
  • None were due to bleeding events

Conclusion

This was the first randomized clinical trial investigating NAV + RUX in this setting. SVR35 at Week 24 was doubled for patients treated with combination therapy compared with RUX + PBO. AEs were manageable, mainly through dose modification. Further evaluations are ongoing to investigate overall survival and clinical responses in patient subgroups.