Highlights in myeloproliferative neoplasms

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1 CONGRESS HIGHLIGHTS 6 Highlights in myeloproliferative neoplasms T. Devos, MD PhD SUMMARY The presentations on myeloproliferative neoplasms at this year s ASH congress were inspiring and innovative. As expected, the main topic in chronic myeloid leukemia (CML) was treatment-free remission (TFR). About 3 oral or poster abstracts on this topic were presented during ASH 26. An update of the important EURO-SKI trial and new results were presented: TFR-studies after treatment with st and 2nd generation tyrosine kinase inhibitors (TKI), as well as TFR-studies after both first and second attempts of TKI-discontinuation. While stopping TKI-treatment is considered in CML, starting new treatments and when to start was the main topic regarding the BCR-ABL negative MPNs polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). A wide panoply of MPN-related topics has been presented at San Diego: late-breaking results of the second-generation JAK-inhibitor pacritinib in MF, interferon-trials in PV and ET, long-term treatment data of the JAK-TKI momelotinib and ruxolitinib, new molecules and novel molecular data, and finally, a special focus on quality of life (QOL). QOL has been a major topic in CML/MPN since several years. In this paper, some key abstracts on CML and MPN, presented at ASH 26, are selected and commented. I m aware that this selection excludes many other abstracts, not reducing their intrinsic value. The aim is to present a broad and representative spectrum of studies on each topic. At the end of the article, some take-home messages will be given. (BELG J HEMATOL 27;8():6-22) CHRONIC MYELOID LEUKEMIA (CML) FIRST ATTEMPT TO STOP TKI: UPDATE OF THE EURO-SKI TRIAL The results of the EURO-SKI (European Stop TKI study) trial were presented earlier this year at the EHA meeting and an update was given at ASH 26. As a reminder, CML-CP (chronic phase) patients taking a TKI (94% on imatinib) for a minimum of three years (median duration of 7.6 years) and showing a stable MR 4 for at least one year (median duration 4.7 years) stopped their TKI in this study. The proportion of patients without recurrence (loss of MMR) after 6 months was 6% and 55% after 2 months. Treatment duration with imatinib (optimal 5.8 years), MR 4 duration prior to stop and duration of IFN pre-treatment did significantly predict the probability of TFR at 6 months. A cost-saving evaluation (taking into account both CML-CP patients with a successful TFR [N=37] and those restarting imatinib [N=279]) showed a total of 9,84 off treatment-months which means an estimated saving of more than 22 million Euro (before the generic imatinib era). SECOND ATTEMPT TO STOP TKI (IMATINIB) A French study investigated a second attempt of TKI discontinuation for sustained deep molecular response (DMR) after a first failure. Most of the 67 CML-CP patients were taking imatinib and restarted the same drug. The median TKI-free period before re-challenge was 4.8 months. At second TKI cessation, 85% of patients were in undetectable molecular disease (UMD), 3% in MR 4.5, 6% in MR 4, 3% in major molecular response (MMR) and the status of 3% was unknown. In total, 4,6% of patients remained treatment-free after 24 months of follow-up (65% at 6 months and 48% at 2 months). Molecular relapses extended later Department of Hematology, UZ Leuven. Please send all correspondence to: Timothy Devos MD, PhD, Department of Hematology, UZ Leuven, Timothy.Devos@uzleuven.be. Conflict of interest: The author has nothing to disclose and indicates no potential conflict of interest.

2 7..8 TFR rate Months No. of patients at risk TFR (MR 4,5 ) rate after year after discontinuation of nilotinib 62.2% (9%CI, ) FIGURE. TFR rate after stopping nilotinib in the NILSt-study. 3 over time in comparison to other TFR studies leading to a drop to 33% at, and beyond 36 months. In a multivariate analysis, gender, age, disease phase, prognostic scores, prior interferon exposure, initial TKI type and duration of UMD were not found to have an impact on the outcome after the second attempt. In contrast, a longer time to obtain the first UMD before the first attempt was associated with a significantly lower molecular disease-free survival rate after the second discontinuation (p=.48). 2 TFR AFTER STOPPING A SECOND GENERATION TKI (2G-TKI) In the Japanese NILSt-trial (Stop Nilotinib), CML-CP patients who obtained MR 4.5 by treatment with imatinib or nilotinib, were further treated with nilotinib for 2 years. The patients who maintained MR 4.5 during those 2 years were eligible for discontinuation of nilotinib. At loss of MR 4.5, nilotinib was resumed. The TFR-rate at 2 months after discontinuation of nilotinib was 62.2% (Figure ). The total duration of imatinib or nilotinib therapy, the time to MR 4.5 and the duration of prior deep MR on treatment, did not significantly predict the probability of TFR. Even some patients with a duration of prior deep MR exceeding years, experienced loss of MR 4.5 after treatment discontinuation. 3 The NILSt-trial differs from the ENESTop-study. In the latter trial, a sustained MR 4.5 for year was required for inclusion and nilotinib was reinitiated at loss of MMR or confirmed loss of MR 4. Hughes et al. presented a sub-analysis of the ENESTop-study. Interestingly, this analysis showed that the prior reason to switch from imatinib to nilotinib (intolerance, resistance, or physician preference) did not influence the TFR success rate. 4 In the Dasatinib-STOP (D-STOP), a Japanese prospective multicenter trial, dasatinib was discontinued in CMLpatients who maintained DMR for over 2 years consolidation therapy (in contrast to the published DADI-trial where maintenance of DMR for over year only was required). 5,6 The treatment-free survival (TFS) was 62.9% at year and all relapsed patients responded again to dasatinib. Interestingly, differences in lymphocyte counts, NK cells and NK-LGL cells were seen at the end of consolidation (just before TKI discontinuation) between the patients (later on) maintaining TFR and patients who did not. If confirmed, this could represent a biomarker for predicting successful discontinuation in the future. 6 THE TWO-STEP STRATEGY: FIRST REDUCE THE DOSE OF TKI, THEN STOP Another strategy to obtain TFR is to halve the dose of TKI during one year and discontinue the TKI in a second step. The advantage of this approach is that also patients with MR 3 can be considered for stopping treatment. The hypothesis is that more patients will be

3 CONGRESS HIGHLIGHTS 8 % 8% Probability 6% 4% 2% MMR MR 4 Numbers at risk Time (months) FIGURE 2. Relapse Free Survival (RFS) in the Destiny-trial. 7 able to reduce therapy safely and that a proportion of these patients will go on to stop therapy. The British De-Escalation and Stopping Therapy with Imatinib, Nilotinib or sprycel (DESTINY) trial explores this strategy and the interim results were presented at ASH 26. The first phase of the study (the 5% dose reduction phase) is now completed. Key entry requirements included CML-CP patients on TKI for at least 3 years and at least in MR 3 (MMR) for the last 2 months. Loss of MR 3 prompted resumption of full dose of their entry TKI. While molecular relapse rates are low in both the MMR and MR 4 group, MMR patients relapsed more frequently and earlier than MR 4 patients (Figure 2). All patients experiencing molecular relapse (loss of MMR) re-achieved this within 4 months of restarting standard full dose TKI. Patients on 5% of the initial TKI dose experienced a reduction in side effects within the first 3 months of de-escalation. 7 GENERIC IMATINIB As generic imatinib molecules will become available, it is relevant to mention 3 abstracts on this topic. First, the prospective data of the Polish Imatinib Generics Registry led to the conclusion that the different generics of imatinib that were tested are not inferior to branded imatinib in terms of clinical efficacy and tolerability in patients with CML CP. The investigators did not observe a higher switching rate between imatinib generics and second generation TKI. 8 A second Indian study, retrospectively comparing first-line treatment with branded versus generic imatinib (,93 CML patients; single center), came to the same conclusions. There was no difference in EFS, TFS or OS between the two groups. The frequency of reported grade -2 non-hematological adverse events (musculoskeletal pain, muscle cramps, peripheral edema) and hematological adverse events was comparable. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the branded imatinib group (.2%). Adherence was poor in a comparable amount of patients in both groups (6.% vs. 7.2%). 9 Finally, reassuring results with a generic imatinib were also reported from an Algerian group. A NOVEL MOLECULE IN CML: ABL ABL is a potent, specific BCR-ABL inhibitor, which binds a pocket on the BCR-ABL kinase domain that is normally occupied by the autoregulatory myristoylated N-terminus of ABL. The latter is lost upon fusion with BCR. ABL, a molecule with a distinct allosteric mechanism of action, is designed to inhibit BCR-ABL in a non-atp-competitive manner. It maintains activity against BCR-ABL mutations that confer resistance to TKIs. ABL can thus be combined with ATP-competitive TKIs. Patients with CML (CP, AP or BP) with failure of 2 prior TKIs and Ph+ ALL patients with

4 9 PROUD-PV CONTINUATION-PV Naïve patients in need of cytoreduction HU pre-treated (<3yrs and not full responders) Stratified Randomisation by age, prev. HU, prev. TE Ropeginterferon Hydroxyurea Ropeginterferon BAT Efficacy analysis* Efficacy analysis** Eligible PV patient population per WHO 28 criteria 2 months treatment Up to 3-5 years treatment FIGURE 3. Study design PROUD-PV trial. 3 Courtesy of H. Gisslinger failure of prior TKI were enrolled in a phase doseescalation study. Only the data of the CML patients were presented at ASH 26. Overall, 65% of the patients received at least 3 different TKIs before entering the study, 6% of the patients were resistant to their last prior TKI and 4% had a T35I mutation. Escalating doses of ABL were administered orally on continuous twice-daily or oncedaily schedules or in combination with imatinib, nilotinib or dasatinib. In total, 44% of patients achieved and maintained MMR by 2 months. In addition to this, 8% of patients in cytogenetic relapse achieved a complete cytogenetic response (CCyR) by 6 months. Only in 8 patients with relapsed or progressive disease had detectable myristoyl binding pocket mutations (V468H, I52L). Lipase increase (8%), thrombocytopenia (7%), anemia (5%) and neutropenia (4%) were reported as the most common grade 3-4 adverse events. ABL was generally well tolerated in heavily treated patients with CML resistant to or intolerant of prior TKIs. ABL 4 mg BID has been recommended for CML-CP patients without T35I mutations. BCR/ABL NEGATIVE MYELOPROLIFERATIVE NEOPLASMS (MPN) LATE BREAKING DATA WITH PACRITINIB IN MYELOFIBROSIS The PERSIST-2 study is a randomized, open-label phase 3 trial with the 2 nd generation JAK-inhibitor pacritinib (PAC) versus best available treatment (BAT) in myelofibrosis patients with thrombocytes./µl. Prior JAK2 inhibitor use was allowed. The most common BATs were ruxolitinib (45%) and hydroxurea (9%). Different schedules of PAC were prescribed (2 mg BID and 4 mg QD). The results were presented during the late breaking abstract session. A significantly higher percentage of patients in the pooled PAC arm achieved the primary endpoint of a spleen volume reduction (SVR) 35% (8% versus 3% in the BAT arm). 25% of PAC patients had a 5% reduction in total symptom scores (TSS) as compared to 4% of BAT patients (p=.79). The PAC BID-group showed the best results: for both efficacy points (SVR 35% and 5% reduction TSS) the improvement was significant over BAT. As known, concerns have risen about the cardiac and

5 CONGRESS HIGHLIGHTS 2 hemorrhagic events in the PERSIST- trial and PAC has been temporarily on full clinical hold by the FDA since February 26 (which has led to a study truncation of the PERSIST-2 study). In the PERSIST-2 trial, the most common adverse events (AEs) associated with PAC were gastrointestinal (diarrhea, nausea) and hematologic (anemia and thrombocytopenia) and were less frequent for BID vs. QD administration. Grade 3-4 cardiac AEs occurred in 7%, 3% and 9% of PAC BID, PAC QD and BAT patients respectively. In conclusion, PAC 2 mg BID appeared to have a better benefit/risk profile than BAT. 2 PHASE 3 INTERFERON TRIALS IN MPN: PROUD-PV AND MPD-RC 2 Interferon alfa has been used for more than 3 years in PV patients. High rates of hematologic response, independence from phlebotomy, improvement of pruritus and sustained JAK2-allele burden reduction have been consistently reported in phase 2 trials. However, a headto-head assessment with other treatment options in confirmatory trials has been lacking so far. The results (2 month data) of the PROUD-PV trial (Figure 3), a randomized phase 3 study comparing the monopegylated ropeginterferon alfa-2b (AOP24) with hydroxyurea (HU) in PV patients, were shown. The primary endpoint was non-inferiority of ropeginterferon versus HU at 2 months of therapy in terms of complete hematological response rate (CHR defined as normal hematocrit, leukocyte and platelet counts, spleen size and absence of phlebotomy in the preceding 3 months). In the study, 62% of patients were naïve to cytoreduction and 38% were HU-pretreated (no prior interferon therapy was allowed). After progressive dose escalation, a median plateau dose of 45 µg ropeginterferon (every two weeks sc) was reached from week 28, compared to a median plateau dose of,25 mg HU from week 8 onwards. Non-inferiority of ropeginterferon has been demonstrated as the CHR rate at 2 months was 43% for AOP24 and 45% for HU (p=.28). Safety and tolerability of ropeginterferon showed benefits over HU. Particularly thyroid and psychiatric disorders were not significantly increased in the APO24-arm compared to the HUarm. 3 The MPD-RC 2 phase 3 trial compares first-line treatment of pegylated interferon-α (PEG) with HU in high-risk, treatment naïve ET and PV patients (diagnosis <5 years). The primary endpoint was the CHR rate between the arms after 2 months of therapy. A first interim analysis was planned when 75 patients completed the one year treatment and these results were presented. No differences in CHR, molecular response rates (decrease of V67F JAK2 allele burden) and phlebotomy need (for PV patients) were seen between the PEG- and the HU-group. Toxicity was not a major reason for discontinuation in either arm at 2 months. Longer follow up of both treatments is needed as interferon is a slow-acting drug: at least 3 years are needed for it to reach its full hematological effect. That was the general comment in the room after this oral abstract presentation. 4 LONG-TERM FOLLOW UP DATA AFTER TREATMENT WITH JAK-INHIBITORS (MOMELOTINIB AND RUXOLITINIB) The data of the phase 3 studies with the JAK-inhibitor momelotinib in myelofibrosis patients (the SIMPLIFY studies) are analyzed at the moment. Meanwhile, interesting 6-year follow data of the phase /2 trial with momelotinib were presented at ASH. Clinical improvement was documented in 57% of patients, anemia response in 44%, and a spleen response was seen in 43%. In total, 5% of the patients became transfusion independent. The majority of patients had marked improvements in their symptoms. Grade or 2 peripheral neuropathy (PN) occurred in 47% of patients, no grade 3 peripheral neuropathy (PN) was reported. 8% of the responding MF patients discontinued treatment after a median treatment duration of 2.3 years. 5 The effect of ruxolitinib on bone marrow fibrosis in MF patients after one year of treatment was not convincing. Now, bone marrow was evaluated after 5 years of treatment with ruxolitinib in COMFORT-I study patients. Improvement or stabilization in BM fibrosis at final grading was observed in 73% of patients. The median time to a confirmed improvement in BM fibrosis grade was 26 weeks. 6 NEW MOLECULE: NS-8 The results of a phase trial with NS-8, a novel selective small molecule inhibitor of JAK2, in MF patients have been recently published. 7 In phase 2, reductions in MF-SAF symptom score were observed for all symptoms after 3 cycles, including patients with prior JAK2 inhibitor treatment. 56% showed >5% reduction in spleen size, including 47% patients with prior JAK2 treatment. The dose of NS-8 is 3 mg QD. A randomized phase 3 will be indispensable to confirm these encouraging data. 8

6 2 KEY TAKE HOME MESSAGES FROM ASH 26 An increasing amount of data emerge on safely discontinuing TKI-treatment (both first and second generation TKI) in CML-CP patients with a long-lasting and uninterrupted deep molecular response. 2 Both treatment duration (> 5.8 years) and length of MR 4 (> 3. years) are predictive parameters for TFR after discontinuing TKI in CML-CP patients treated with imatinib only. However, prognostic factors for successful TFR are not consistently identified across the different TFR-studies. Specific biomarkers for TFR-prediction in CML are needed. 3 The TFR-strategy in CML is cost-saving. However, a continuous molecular monitoring of CML patients after stopping the TKI is required as late relapses have been described. 4 For the first time, data of large prospective controlled trials of interferon therapy in MPN (PV/ET) were presented. Ropeginterferon alpha-2b is non-inferior compared to hydroxurea in inducing CHR at year of treatment and shows benefits over hydroxurea in safety and tolerability. As interferons are known to be slow-acting in MPN, results of long-term treatment might be even more promising. 5 Pacritinib, an oral kinase inhibitor with specificity for JAK2 and FLT3, does effectively reduce spleen volume and symptom burden in myelofibrosis patients treated with prior JAK-inhibition. The well-known concerns on the safety of the drug are now under investigation. IMPACT OF MPN ON QUALITY OF LIFE AND EMPLOYMENT The MPNs (MF, PV, ET) are associated with a pronounced symptom burden, such as fatigue, night sweats, itching and concentration problems. This may compromise patient activities of daily living and quality of life (QoL). Two abstracts focused on QoL in MPN. After the US MPN Landmark survey, the results of a global MPN Landmark survey were presented at ASH. 9,2 The most commonly reported symptom among all MPN subtypes was fatigue (54% MF, 45% PV, and 64% ET). When asked which symptom patients would most like to have resolved, most patients referred to improvement in fatigue across all disease subtypes (44% MF, 35% PV, and 45% ET) as well as blood clot dissolution (5% MF, 75% PV, and 75% ET). Other symptoms most patients wanted to resolve included bone pain in patients with MF (59%), strokes and pruritus in patients with PV (67% and 63% respectively) and strokes and headaches in patients with ET (67% and 58% respectively). Overall, patients experienced an average of 5. symptoms at diagnosis. 2 A survey amongst 595 MPN patients focused on the impact of MPN on employment status and work productivity. The most commonly reported changes in employment since diagnosis were leaving a job (3%), followed by taking medical disability leave (26%), reducing work hours for 3 months (24%) and taking early retirement (9%). Leaving a job was the most commonly reported first change in employment after MF and PV diagnosis (5% and 44%, respectively), whereas reducing work hours for 3 months was the most commonly reported first change in employment in ET (37%). Among patients who were employed fullor part-time at the time of survey participation, 28% reported missing work in the past 7 days because of their MPN. As such, MPNs have a substantial negative impact on patients employment status and work productivity and special attention should be given to this. 2 REFERENCES. Mahon F, Richter J, Guilhot J, et al. Cessation of tyrosine kinase inhibitors treatment in CML patients with deep molecular response: results of the Euro-SKI trial. Presented at ASH 26; abstract Legros L, Pagliardini T, Nicolini F, et al. Second TKI discontinuation in CML patients that failed first discontinuation and subsequently regained deep molecular response after TKI re-challenge. Presented at ASH 26; abstract Kadowaki N, Kawagushi T, Kuroda J, et al. Discontinuation of nilotinib in patients with CML who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 stop nilotinib (Nilst) trial. Presented at ASH 26; abstract Hughes T, Boquimpani CM, Takahashi M, e al. Treatment-free remission in patients with CML-CP according to reasons for switching from imatinib to nilotinib: subgroup analysis from ENESTop. Presented at ASH 26; abstract 792.

7 22 CONGRESS HIGHLIGHTS 5. Imagawa J, Tanaka H, Okada M, et al. Discontinuation of dasatinib in patients droxyurea in polycythemia vera patients. Presented at ASH 26; abstract 475. with CML who have maintained deep molecular response for longer than year 4. Mascarenhas J, Prchal JT, Rambaldi A, et al. Interim analysis of the Mye- (DADI trial): a multicentre phase 2 trial. Lancet Haematology 25; 2: loproliferative Disorders Research Consortium (MPD-RC) 2 global phase III 6. Kumagai T, Nakaseko C, Nishiwaki K, et al. Discontinuation of dasatinib after trial of front line pegylated interferon alpha-2a versus hydroxyurea in high risk PV deep molecular response for over 2 years in patients with CML and the unique and ET. Presented at ASH 26; abstract 479. profiles of lymphocyte subsets for successful discontinuation: a prospective, 5. Tefferi A, Barraco D, Lasho TL, et al. Momelotinib therapy in myelofibrosis: multicenter Japanese Trial (D-STOP) trial. Presented at ASH 26; abstract years follow-up data on safety, efficacy and the impact of mutations on overall 7. Copland M, Clark RE, Polydoros F, et al. Chronic Myeloid Leukaemia patients and relapse-free survival. Presented at ASH 26; abstract 23. with stable molecular responses (at least MR3) may safely decrease the dose of 6. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Effects of long-term ruxoli- their TKI: data from the British Destiny Study. Presented at ASH 26; abstract 938. tinib on bone marrow morphology in patients with myelofibrosis enrolled in the 8. Sacha T, Gora-Tybor J, Szarejko M, et al. Imatinib generics in treatment COMFORT-I study. Presented at ASH 26; abstract 949. of CML: a prospective observation in large cohort of patients from the Polish 7. Verstovsek S, Talpaz M, Ritchie E, et al. A phase I, open-label, dose-escalation, Imatinib Generics Registry. Presented at ASH 26; abstract 629. multicenter study of the JAK2 inhibitor NS-8 in patients with myelofibrosis. 9. Madhav D. Generic imatinib in Chronic Myeloid Leukemia: survival of the Leukemia 26 Sep (Epub ahead of print). cheapest. Presented at ASH 26; abstract Verstovsek S, Talpaz M, Ritchie E, et al. A phase /2 study of NS-8, an oral.entasoltan B, Bekadja MA, Bouhass RA, et al. Outcome of frontline treatment JAK2 inhibitor, in patients with primary myelofibrosis, post-polycythemia vera with generic imatinib in adult patients with CML in the Algerian population: a first myelofibrosis or post-essential thrombocythemia myelofibrosis. Presented at multicenter study. Presented at ASH 26; abstract 899. ASH 26; abstract Hughes T, Ottman OG, Minami H, et al. Expanded Phase study of ABL, 9. Mesa RA, Miller CB, Thyne M, et al. Myeloproliferative neoplasms have a a potent, allosteric inhibitor of BCR-ABL, reveals significant and durable responses significant impact on patients overall health and productivity: the MPN Landmark in patients with CML-Chronic Phase with failure of prior TKI therapy. Presented survey. BMC Cancer 26; 6: at ASH 26; abstract Harrison CN, Koschmieder S, Foltz L, et al. The impact of myeloproliferative 2. Mascarenhas J, Hoffman R, Talpaz M, et al. Results of the PERSIST-2 phase neoplasms on patients Quality of Life and productivity: results from the Inter- 3 study of Pacritinib versus Best Available Therapy, including ruxolitinib, in patients national MPN Landmark Survey. Presented at ASH 26; abstract with myelofibrosis and platelet counts,/µl. Presented at ASH 26; 2. Yu J, Parasuraman S, Paranagama D, et al. Impact of myeloproliferative LBA-5. neoplasms on patients employment status and work productivity in the United 3. Gisslinger H, Klade C, Georgiev P, et al. Final results from PROUD-PV, a States: results from the Living with MPN Patient Survey. Presented at ASH 26; randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hy- abstract VO LU M E8 F E B R U A R Y 2 7