ALBERT

Description: Key Points Nilotinib induced deeper molecular responses than continued imatinib in patients with minimal residual disease on long-term imatinib. These deeper responses may enable more patients to benefit from treatment-free remission trials.

Description: Key Points IL-3 receptor α (CD123) expression is elevated in CML progenitor and stem cells compared with healthy donors. CD123 monoclonal antibody targeting represents a novel, potentially clinically relevant approach to deplete CML progenitor and stem cells.

Description: Introduction A correlation exists between innate immune responses and outcomes in cancer treatment, and immunological features may be prognostic biomarkers of TKI response in chronic phase CML patients (CML-CP pts). Marin et al (Leuk 2012) found KIR2DS1 to be associated with CCyR, OS and PFS, while Kreutzman et al (Exp Hem 2012) showed KIR2DL5A/B to be associated with MMR. We examined the prognostic significance of KIR (Killer Immunoglobulin-like Receptor) genotypes in CML-CP pts in the TIDEL-II study who received upfront treatment with imatinib and early switching to nilotinib for suboptimal responses. Method TIDEL-II is a multicentre, single arm prospective ALLG trial for de novo CP-CML pts in 2 equal sequential cohorts of 105 pts in each. All pts started on imatinib (IM) 600mg OD. Pts were monitored for achievement of time dependent molecular targets (BCR-ABL 10%, 1% and 0.1% IS at 3, 6 and 12 months respectively). Pts in cohort I (C1) who failed these targets were dose escalated to IM800. Pts failing to achieve these targets subsequently, or who were already on IM800, switched to nilotinib 400mg BID (NIL). Pts in cohort II (C2) who failed their time dependent targets switched to NIL regardless of their IM dose. Switching to NIL was also permitted for Grade III/IV or persistent Grade II non-hematological toxicity or loss of response. Baseline samples were available for 148 pts, on which KIR genotyping was done retrospectively using the KIR Genotyping SSP Kit (Invitrogen, Carlsbad, CA). Molecular response and survival outcomes were analysed as stratified by early molecular response (EMR, BCR-ABL ≤10% at 3 months), gender, Sokal Index, age and KIR genotype. Results The 24 month MMR rate was 73% and EMR failure was 12%. Overall and progression-free survival (PFS; events = transformation to AP/BC + any death) was 94% and 93% at 4 years respectively. Failure free survival (FFS; events in PFS in addition to loss of MMR / CCyR and failure according to 2013 ELN criteria) was 76% at 4 years. In a competing risk univariate analysis, EMR correlated with MMR achievement as expected, but not Sokal, age or sex. This analysis also showed inferior MMR achievement for pts with KIR2DL5B (HR 0.423, p=0.00041), KIR2DL2 (HR 0.607, p=0.0048) and KIR2DS3 (HR 0.547, p=0.0027) genotypes. The number of pts with these alleles were 31 (21%), 83 (56%) and 44 (30%) respectively. As predicted from the population distribution of KIR genotypes, these 3 alleles were in strong linkage disequilibrium. Only KIR2DL5B (2DL5B) and EMR remained independent predictors of MMR in a multivariate model (2DL5B positive HR 0.52, p=0.034). KIR2DL5B positivity was also independently associated with inferior rates of MR4.5 (HR 0.42, p=0.031) (Fig. top panels). Four year PFS was inferior for pts positive for 2DL5B (86% vs 97%, p=0.04), as was FFS (67% vs 80%, p=0.05) (Fig. lower panels). There was no correlation between 2DL5B status and EMR achievement. However pts negative for 2DL5B who had EMR failure were more likely to achieve MMR, 7/13 pts (54%), compared with 0/5 2DL5B positive pts (all 18 pts switched to NIL). This was not statistically significant (p=0.09), due to the small numbers. In patients who achieved EMR, 94% of 100 2DL5B negative pts achieved MMR, vs 76% of the 25 2DL5B positive pts. Among pts with EMR failure, 2DL5B positivity was associated with a trend for inferior survival at 4 years. PFS was 91% vs 98% and FFS was 80 vs 84% for 2DL5B pos vs neg pts respectively. Conclusion KIR genotypes had previously been correlated with achievement of CCyR, PFS and OS. Here, we have demonstrated that the KIR2DL5B allele correlated with lower rates of MMR and MR4.5 in a multivariate analysis, even in a treatment schema allowing patients failing early molecular targets to be treated with nilotinib, independent of EMR. Additionally, KIR2DL5B positivity was associated with inferior PFS and FFS. Multiple studies have shown the prognostic significance of EMR, as has our data. KIR genotyping information may further refine the prognosis of patients failing to achieve EMR. Prognostic markers available at CML-CP diagnosis, such as KIR genotypes, may have clinical utility. Furthermore, the KIR genotype may provide useful information in combination with other biomarkers and could be incorporated into future prognostic scoring systems for CML-CP. Figure 1 Figure 1. Disclosures Yeung: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Branford:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Clinical scoring systems, such as Sokal risk, continue to have prognostic relevance for patients (pts) treated with tyrosine kinase inhibitors (TKI) and may have utility in combination with emerging biomarkers. The BCR-ABL value at 3 and 6 months (mo) of TKI are the strongest predictors of response. However, recent data demonstrate that the rate of BCR-ABL decline from the pre imatinib level adds significant predictive information (Hanfstein, Leukemia 2014; Branford, Blood 2014). Among poor risk pts with 〉10% at 3 mo in our cohort of first line imatinib, those with a slow rate of decline from their pre imatinib value, assessed by calculating the number of days over which BCR-ABL halved (halving time), predicted significantly poorer outcomes. Notwithstanding the importance of the 3 and 6 mo values, a prognostic biomarker obtained at an earlier timepoint may allow opportunities for therapy optimization. We therefore examined the prognostic significance of the rate of BCR-ABL decline at 1 mo in the context of other predictors of response. Aim: To determine whether baseline factors (age, gender, Sokal risk and imatinib starting dose: 400, 600 or 800 mg) and the BCR-ABL halving time at 1 mo of imatinib have predictive significance. Method: 528 first line imatinib treated pts were evaluated (median 45 mo of imatinib). Molecular assessment was performed pre imatinib and at 1 mo for 470/528. 453 of these 470 pts had a Sokal score available and were included in the analysis of outcome. Results: The median BCR-ABL halving time at 1 mo of imatinib was 17 days, quartiles 11, 29. An initial rapid BCR-ABL decline, indicated by halving times in the lowest quartile of ≤11 days (n=115), was associated with significantly superior rates of MMR by 12 mo, MR4.5 and failure-free survival (FFS) by 4 years compared with longer halving times of 〉11 days (n=338), Table. MMR by 12 mo was assessed since it represents an optimal response and is associated with subsequent deep molecular response. By univariate and multivariate regression analysis only the 1 mo halving time and Sokal risk significantly predicted MMR, MR4.5 and FFS. These factors were independent and there was no difference between the median 1 mo halving times among the Sokal risk groups, P = .36. The high Sokal risk pts had significantly poorer outcomes. To improve response prediction, these pts were divided into 2 groups according to their 1 mo halving time; ≤11 days (n = 28) and 〉11 days (n=90). A 1 mo halving time of ≤11 days was associated with significantly improved outcomes for these pts, Table and Figure. The responses equated to those of pts with low Sokal risk: high risk ≤11 days vs low risk: MMR by 12 mo 57% vs 59%, P = .95; MR4.5 by 4 years 36% vs 40%, P = .82; FFS by 4 years 79% vs 84%, P = .39. The high Sokal risk pts with the rapid initial BCR-ABL decline also had a lower probability of BCR-ABL 〉10% at 3 mo (early molecular response [EMR] failure), which is considered a warning or treatment failure; ≤11 days vs 〉11 days: 14% vs 33%, Table. Table 1 Outcome* by Sokal risk and BCR-ABL halving time at 1 mo of imatinib Factor No. of pts EMR % 3 mo MMR % 12 mo MR4.5 % 48 mo FFS % 48 mo Sokal Low 195 90 59 40 84 Intermediate 140 79 50 35 71 High 118 71 43 26 59 P value 29 days) was associated with a significantly lower cumulative incidence of MMR by 12 mo: low Sokal risk ≤29 days (n = 151) vs 〉29 days (n = 44) 65% vs 39%, P = .002; intermediate Sokal risk ≤29 days (n = 103) vs 〉29 days (n=37) 57% vs 31%, P = .004, Figure. Conclusion: Imatinib treated high Sokal risk pts have a higher rate of treatment failure and poorer molecular response. However, our data suggest their prognosis can be refined by taking into account the kinetics of BCR-ABL decline after only 1 mo of treatment. A rapid initial decline defined a subgroup of high Sokal risk pts with outcomes equivalent to those of low Sokal risk pts. Frequent molecular monitoring in the critical first months of treatment could enhance outcome prediction and limit the indication for a change of treatment. Figure 1 Figure 1. Disclosures Branford: Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Yeung:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ross:Novartis: Honoraria, Research Funding; BMS: Honoraria. Seymour:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Hughes:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding.

Description: Background: Ponatinib is an approved potent, oral, pan-BCR-ABL inhibitor active against native and mutant BCR-ABL. Ponatinib had substantial clinical activity in the phase 2 PACE trial in patients (pts) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation. In the frontline setting, positive associations between achieving response at an early time point (landmark) and long-term outcomes have been shown for tyrosine kinase inhibitors (TKIs) in CML pts. Since landmark analyses have not been reported for a heavily pretreated population, in particular 3rd line and beyond, this retrospective analysis investigated the impact of achieving early landmark responses with ponatinib on long-term outcomes in PACE pts. Methods: Ponatinib treated CP-CML pts in PACE with valid cytogenetic and molecular assessments were included. Pts who met response criteria at entry, were missing assessments or not evaluable (10%) and cytogenetic status (MCyR, 10%). Furthermore, pts who achieved MCyR or CCyR at 3 months were significantly more likely to have improved PFS after 2 years compared with those who did not. This trend was similar for OS: achievement of MCyR or CCyR at 3 months was associated with an increased likelihood of OS after 2 years (Table). Similar trends were observed for 6-month molecular and cytogenetic landmark analyses (Table). Conclusions: In these refractory CML pts, the rapid and deep reduction in BCR-ABL levels achieved with ponatinib translated into improved long-term outcomes. These data validate the usefulness of assessing BCR-ABL levels at early time points as a goal of therapy with ponatinib since achieving early landmark response appears to be a strong predictor of better long-term outcomes. Table Impact on 2-Year Outcomes* 3-month Molecular n ≤10% BCR-ABL IS n 〉10% BCR-ABL IS P-valuea 82 PFS = 76% 79 PFS = 57% 0.0366 86 OS = 85% 89 OS = 86% 0.6182 ≤1% BCR-ABLIS 〉1% BCR-ABLIS 75 PFS = 84% 133 PFS = 59% 0.0001 77 OS = 90% 148 OS = 84% 0.0507 MMR No MMR 32 PFS = 96% 180 PFS = 64% 0.0035 33 OS = 96% 197 OS = 84% 0.0402 3-month Cytogenetic n MCyR n No MCyR P-valuea 97 PFS = 85% 97 PFS = 52% 10% BCR-ABL IS P-valuea 84 PFS = 83% 55 PFS = 51% 0.0012 88 OS = 94% 73 OS = 84% 0.0274 ≤1% BCR-ABLIS 〉1% BCR-ABLIS 95 PFS = 84% 86 PFS = 55% 0.0001 101 OS = 93% 106 OS = 87% 0.1415 MMR No MMR 57 PFS = n/a 128 PFS = 60% 0.0002 61 OS = 95% 150 OS = 87% 0.0580 6-month Cytogenetic n MCyR n No MCyR P-valuea 116 PFS = 72% 57 PFS = 51%

Description: Background: Ponatinib is an approved potent oral tyrosine kinase inhibitor active against native and mutated forms of BCR-ABL, including T315I. The phase 2 PACE study demonstrated that ponatinib is highly active in heavily pretreated Philadelphia chromosome‒positive leukemia patients. Ponatinib efficacy and safety were evaluated in newly diagnosed CP-CML patients in the EPIC trial. Methods: EPIC was a multicenter, international, phase 3, randomized, 2-arm, open-label trial of ponatinib (45 mg once daily) compared with imatinib (400 mg once daily) in newly diagnosed CP-CML; patients were stratified by Sokal risk score (low [1.2]). On 18 October 2013,EPIC was terminated due to the observation of arterial thrombotic events in the ponatinib development program. Consequently, none of the prospectively defined endpoints could be analyzed. Data as of 1 April 2014 are presented for endpoints that could be analyzed: BCR-ABLIS

Description: Introduction: Early molecular response (EMR, BCR-ABL (IS) ≤ 10% at 3 months) is a strong predictor of outcome in imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients, but for patients who transform early 3 months may be too late for effective therapeutic intervention. Thus, alternative approaches are required to identify poor responders at the time of diagnosis. The aim of this study was to identify plasma biomarkers at diagnosis that will predict for subsequent EMR failure, early transformation or the development of BCR-ABL1 kinase domain mutations. Cytokine profiling has proven valuable in identifying prognostic factors in myelofibrosis and myelodysplastic syndromes; however, similar comprehensive studies are lacking to date in CML. Methods: Plasma samples from CP-CML patients enrolled to the TIDEL II trial were collected prior to starting imatinib treatment (n=186) and after 6 months on TKI (n=17); and compared to those of healthy donors (n=19). The levels of 39 cytokines, chemokines and growth factors (CC&GF) were measured using a Luminex multiplex assay. To identify potential biomarkers to predict EMR failure, random forest analysis and recursive partitioning techniques in R were applied as statistical methods. Results: Plasma concentrations of 13/39 CC&GF were significantly elevated at CP-CML diagnosis compared to healthy donor samples. Most (EGF, bFGF, VEGF, TGF-α, CXCL1, CCL4, sCD40L and IL-4) werenormalized after 6 months of TKI treatment while others (TNF-α, sIL-2Ra, IL-8, IL-10, IL-1a) remained at higher levels, possibly reflecting persistent disease-induced alterations within the microenvironment. A third subset of CC&GF, such as CCL2, CCL3 and CCL22, showed higher circulation levels only in TKI-treated patients but not at diagnosis, suggesting that changes in these CC&GF could be treatment-related. 183/186 patients had BCR-ABL1 assessments available at 3 months, and 23/183 (13%) did not achieve EMR. Random forest analysis identified TGF-α, IL-6 and IFN-α as the most important CC&GF associated with EMR failure. Recursive partitioning incorporating these three variables produced a classification tree based only on TGF-α and IL-6, and demonstrated that 12/20 (60%) of patients who were TGF-αhi/IL-6hi failed to achieve EMR (Table 1). Importantly, this group contained 3/3 (100%) patients who transformed within the first 12 months of TKI treatment. Both TGF-α (7.99 vs. 60.57 pg/ml, p

Description: Key Points More patients with chronic myeloid leukemia in chronic phase achieve EMR on frontline nilotinib than imatinib. EMR failure on frontline nilotinib or imatinib predicts poor outcomes in patients with chronic myeloid leukemia in chronic phase.

Description: Key PointsSIFD is a syndromic form of congenital sideroblastic anemia associated with immunodeficiency, periodic fevers, and developmental delay. SIFD is due to partial loss-of-function mutations in the CCA-adding enzyme TRNT1.

Description: Background: Discontinuation of tyrosine kinase inhibitor (TKI) treatment for patients (pts) with CML is desirable for both clinical and economical reasons. Two studies, STIM and TWISTER, demonstrated that treatment free remission (TFR) is achievable in a proportion of pts. A qualifying period of 3 years of imatinib and sustained undetectable BCR-ABL with a sensitivity of MR5 or MR4.5 for at least 2 years was required before discontinuation. Due to the very slow clearance of BCR-ABL after an initial rapid reduction in the first year of imatinib, the number of pts meeting discontinuation criteria potentially requires many years of imatinib. New discontinuation studies may require at least 3 years of TKI treatment but are exploring less stringent molecular criteria for discontinuation. The first requirement is the achievement of MR4.5 (≤0.0032%) or even MR4 (≤0.01%), and these responses must be maintained. More potent TKIs when administered as first line or after switch from imatinib are associated with higher rates of deep molecular response, which potentially leads to a greater number of pts who qualify for a discontinuation trial. It is unknown what proportion of imatinib treated pts who have not achieved a deep molecular response at 3 years will subsequently do so, and in which subgroup of patients a switch to a more potent TKI is warranted if TFR is the goal. Aim: Since BCR-ABL levels at milestone response timepoints strongly predict long term molecular response, we determined whether the BCR-ABL level at the first qualifying timepoint for a discontinuation trial (3 years) predicts the achievement of deep molecular response. Method: 528 consecutive chronic phase pts treated with first line imatinib were examined (400, 600 or 800 mg). Those who met the following criteria at 3 years were included: CCyR or 1% BCR-ABL, no MR4.5 and at least 6 months of further imatinib therapy. Only 4 pts did not have CCyR at 3 years and were not included since they also had treatment failure. The cohort is historical so was not confounded by switching to another TKI after 3 years of imatinib. Landmark analyses according to the BCR-ABL response level at 3 years were performed for MR4 and MR4.5. These responses required confirmation at consecutive measurements. Results: 147 pts met the analysis criteria. The median follow up on imatinib after the 3 year landmark was 1.5 years, range 0.75 – 9.8. At 3 years of imatinib the median BCR-ABL was 0.03%, range 0.004% - 1.4%. The cumulative incidence of MR4 for the 116 pts without MR4 at 3 years was 52% by 5 years after the landmark. The cumulative incidence of MR4.5 for the 147 pts was 62% by 5 years after the landmark. Pts were divided into 3 BCR-ABL response levels at the landmark: MR2 (〉0.1%) n=45; MMR (〉0.01 – 0.1%) n=71; and MR4 (〉0.0032 – 0.01%), n=31. Landmark analyses demonstrated that pts with MR2 at 3 years of imatinib had a negligible probability of achieving MR4 and MR4.5 with up to 5 additional years of imatinib, Figure. Only 2 and 1 of these 45 pts reached MR4 and MR4.5, respectively. Furthermore, pts with MMR at 3 years had a significantly lower cumulative incidence of MR4.5 compared to pts with MR4: MMR vs MR4, 61% vs 100% by 5 years after the landmark, P 〈 .0001, Figure. Intuitively, pts with BCR-ABL close to MR4.5 could be predicted to achieve that response. However, the median time to reach MR4.5 for the pts with MR4 at 3 years was at 1.5 years of additional imatinib, demonstrating the very slow kinetics of BCR-ABL clearance. The starting dose of imatinib had no effect on the achievement of MR4 or MR4.5. Only 1 of the 147 pts lost CCyR (pt with MMR at 3 years). Conclusion: This study has further demonstrated that the BCR-ABL value is a powerful predictor of response, not only in the first months of treatment but also at later timepoints when long term management decisions are made. If the aim of therapy is to qualify for TFR studies, our data suggest that pts without an MMR at 3 years of imatinib have minimal chance of reaching the deep molecular responses required, even with up to 5 additional years of imatinib. Pts who switched to nilotinib without MMR in the ENESTcmr trial were indeed more likely to achieve MR4.5 compared to continuing on imatinib (Hughes Blood 2014). In our study, most pts with MR4 at 3 years of imatinib achieved the deep molecular response criteria with 2 additional years of imatinib. These findings may help clinical decisions when considering a switch of treatment to optimize discontinuation options. Figure 1 Figure 1. Disclosures Branford: Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Ross:Novartis: Honoraria, Research Funding; BMS: Honoraria. Yeung:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding.