Prediction of outcomes in patients with Ph+ chronic myeloid leukemia in chronic phase treated with nilotinib after imatinib resistance/intolerance

Abstract

The purpose was to assess predictive factors for outcome in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) treated with nilotinib after imatinib failure. Imatinib-resistant and -intolerant patients with CML-CP (n = 321) were treated with nilotinib 400 mg twice daily. Of 19 baseline patient and disease characteristics and two response end points analyzed, 10 independent prognostic factors were associated with progression-free survival (PFS). In the multivariate analysis, major cytogenetic response (MCyR) within 12 months, baseline hemoglobin ≥120 g/l, baseline basophils <4%, and absence of baseline mutations with low sensitivity to nilotinib were associated with PFS. A prognostic score was created to stratify patients into five groups (best group: 0 of 3 unfavorable risk factors and MCyR by 12 months; worst group: 3 of 3 unfavorable risk factors and no MCyR by 12 months). Estimated 24-month PFS rates were 90%, 79%, 67% and 37% for patients with prognostic scores of 0, 1, 2 and 3, respectively (no patients with score of 4). Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients.

Introduction

The successful introduction of the selective BCR-ABL tyrosine kinase inhibitors (TKIs), which suppress the molecular processes driving Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP), has revolutionized the management and outcome in CML.¹ In patients with newly diagnosed Ph+ CML-CP, imatinib mesylate therapy induced high rates of complete cytogenetic response (CCyR) and major molecular response, and improved survival in Ph+ CML.^2–5 Following imatinib treatment, more than 90% of patients obtained complete hematologic response (CHR), and more than 80% achieved CCyR. With 8 years of follow-up, the results were favorable, resulting in a major change in the natural history of the disease.⁶

Despite the benefit of imatinib over prior treatments, some patients may develop resistance,⁷ with a reported annual resistance rate of 2 to 4% in patients with newly diagnosed CML-CP during the first 3 years, with the incidence decreasing over time thereafter.⁸ Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of patients with Ph+ CML-CP or accelerated phase (AP) and resistance or intolerance to imatinib therapy.^9,10 After 24 months of follow-up of imatinib-resistant and -intolerant patients treated with nilotinib in the pivotal phase II study, achievement of major cytogenetic response (MCyR) was demonstrated in 59% of patients and CCyR in 44% of patients.¹¹

Despite the success of nilotinib therapy in patients resistant to or intolerant of prior imatinib treatment, some patients did not achieve optimal responses to therapy.¹² Early identification of these patients would permit earlier interventions to maximize treatment benefits and improve outcomes for this patient population. The purpose of the analysis was to identify the baseline patient and disease factors and the time-dependent response end points that potentially may predict for differences in long-term outcomes.

Materials and methods

Patients

Three hundred and fifteen patients with Ph+ CML-CP who were resistant to or intolerant of imatinib and not known to have the BCR-ABL T315I mutation at study entry were treated with nilotinib 400 mg orally twice daily in an ongoing open-label, single-treatment arm phase II study (N = 321) that has been previously described (study AMN-2101).^10,11 CML-CP was defined as <15% blasts in peripheral blood, <20% basophils, <30% blasts and promyelocytes and >100 × 10⁹/l platelets.¹³ Patients were treated on an Institutional Review Board (IRB)-approved protocol. Informed consent was obtained in accordance with the Declaration of Helsinki. Response criteria were as previously described.² CHR was defined as a white blood cell count <10 × 10⁹/l, a platelet count <450 × 10⁹/l, no immature cells (blasts, promyelocytes, myelocytes) in the peripheral blood and disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly). Response was further categorized by the best cytogenetic remission as complete (0% Ph+), partial (PCyR; 1–35% Ph+), minor (mCyR; 36–65% Ph+), and minimal (66–95% Ph+). MCyR included CCyR and PCyR (that is, ≤35% Ph+). Response rates were calculated based on the intent-to-treat population.

Progression-free survival (PFS) was measured from the start of study drug to the earliest date of the following: progression to AP or blast phase (BP), discontinuation due to progression (as assessed by investigator), or death from any cause on nilotinib therapy. Event-free survival (EFS) was measured from the start of study drug to the earliest date of the following: progression to AP or BP, discontinuation due to adverse events or laboratory abnormalities, discontinuation due to progression (as assessed by investigator), or death from any cause on nilotinib therapy. Patients for whom none of these events were reported were censored at the cut-off date or at the discontinuation date if they discontinued for other reasons not included in the composite end point. This trial was registered at http://www.clinicaltrials.gov as NCT00109707.

Statistical considerations

Twenty-one factors and covariates were prospectively defined for the modeling exercise, including 19 baseline factors (including the occurrence of grade 3/4 myelosuppression in the first 3 months) and two cytogenetic response factors based on previously published data.^14,15 Cox proportional hazards regression models were used to investigate associations of PFS with 19 baseline patient and disease characteristics and two response end points. The two response factors included no mCyR (Ph+ metaphases >65%) by 6 months of nilotinib therapy and no MCyR (Ph+ metaphases >35%) by 12 months. The 19 baseline factors included presence of additional chromosomal abnormalities at baseline; age at study entry (years); duration of prior imatinib treatment (months); baseline CHR status (no baseline CHR [0] vs baseline CHR [1]); time from diagnosis of CML (months); prior highest imatinib dosage (mg); grade 3/4 myelosuppression (anemia, neutropenia, and thrombocytopenia) event during the first 3 months from first dose; highest prior imatinib dose (<600 mg [0] vs others [1]); baseline mutation status (no mutation [0] vs any mutation [1] for patients with available mutation data); resistance to (0) vs intolerance of (1) imatinib therapy; hemoglobin at start of nilotinib therapy (g/l); best response to prior CML therapy; percent Ph+ metaphases at start of nilotinib; achievement of prior cytogenetic response; baseline alkaline phosphatase level; baseline percent of blasts in peripheral blood; baseline percent of basophils in peripheral blood; prior interferon-alfa therapy and sex. The effects of these factors on PFS, EFS and overall survival (OS) and the achievement of MCyR by 12 months of therapy were evaluated.

Cox proportional hazard regression modeling was used to identify significant factors associated with PFS. Landmark analyses, also using Cox proportional hazard regression models, were used to check that associations between PFS and achievement of cytogenetic response accounted for the possibility of guarantee-time bias.^16–18 Dichotomized versions of two of the baseline continuous covariates (hemoglobin and basophils) were also considered as candidate factors. The cut points for dichotomizing these covariates were determined by examining the P values associated with log-rank tests of PFS conducted over a range of cut points and selecting a rounded value of the cut point in the vicinity of the value that produced the minimum P value.

The regression modeling was used as a guide to develop a simple scoring system based on a small number of factors. Survival probabilities were estimated by the Kaplan-Meier method and compared by the log-rank test.

Results

Univariate analyses

With a median follow-up of 28 months (range, 1–36 months), the incidence of MCyR was 60% and CCyR was 44%. The estimated 24-month PFS rate was 64% and survival rate was 87%. Univariate analyses on the continuous baseline covariates and the dichotomous factors are shown in Tables 1 and 2, respectively. Of the continuous factors considered, low baseline hemoglobin level (hazard ratio [HR] = 0.979; P < 0.001), high baseline percent of basophils (HR = 1.078; P < 0.001) and high baseline percent of Ph+ metaphases (HR = 1.013; P < 0.0009) were significantly associated with the highest risk for progression.

Table 1.

Univariate analyses of the continuous baseline covariates on progression-free survival

Covariate	n	Median	Range	HR	P value
Age (years)	315	58	21–85	1.004	0.619
Baseline hemoglobin (g/l)	313	121	77–172	0.979	<0.001
Baseline basophils (%)	313	2	0–29	1.078	<0.001
Baseline blasts (%)	304	0	0–12	1.074	0.209
Time since diagnosis (months)	315	58	5–275	1.002	0.409
Highest prior imatinib dose (mg)	314	600	300–1200	1.000	0.506
Baseline Ph+ metaphases (%)	302	100	0–100	1.013	0.009
Duration of prior treatment (months)	265	26.87	0.03–71	1.008	0.184

Abbreviation: HR, hazard ratio for a unit increase in the covariate.

Table 2.

Univariate analyses of the effect of dichotomous factors on progression-free survival

Dichotomous factor	Level	n	%	HR	P value
Sex	Male	157	50
	Female	158	50	0.928	0.722
Imatinib resistant/intolerant	Resistant	222	70
	Intolerant	93	30	0.530	0.015
BL CHR	No	202	64
	Yes	113	36	0.488	0.003
BL hemoglobin (g/l)	< 120	143	46
	≥120	170	54	0.506	0.001
BL basophils (%)	≥4	97	31
	< 4	216	69	0.487	<0.001
Other chromosomal abnormalities	No	233	74
	Yes	82	26	1.296	0.251
BL mutation	No	143	54
	Yes	123	46	2.594	<0.001
BL mutation with low sensitivity to nilotinib	No	288	91
	Yes	27	9	10.153	<0.001
BL mutation with IC50 ≥150 nM	No	286	91
	Yes	29	9	8.197	<0.001
Prior cytogenetic response	No	130	42
	Yes	182	58	0.667	0.055
Highest prior dose of imatinib (mg)	< 600	86	27
	≥600	228	73	1.717	0.042
Prior interferon-alfa	No	124	39
	Yes	191	61	1.356	0.166
Grade ≥3 myelosuppression in first 3 months	No	201	64
	Yes	114	36	1.183	0.434

Abbreviations: BL, baseline; CHR, complete hematologic response; HR, hazard ratio for the second level of the factor relative to the first level.

Among the dichotomous factors, imatinib resistance, no CHR at baseline, low baseline hemoglobin level, high baseline percent of basophils, high baseline percent of Ph+ metaphases, presence of a baseline mutation, presence of a baseline mutation with low sensitivity to nilotinib (E255K/V, Y253H, F359C/V), presence of a baseline mutation with IC₅₀ ≥150 nM, and highest prior dose of imatinib ≥600 mg were significantly associated with an unfavorable PFS.

High baseline percent of Ph+ metaphases (when considered as a categorical variable with more than two categories) was significantly associated with an unfavorable PFS (HR = 1.342; P = 0.012) (Table 3). Both the 6-month mCyR (HR = 1.342; P = 0.012) and the 12-month MCyR (HR = 0.219; P < 0.001) were significantly associated with a better PFS (Table 3).

Table 3.

Univariate analyses of the effects of ordinal multilevel factors and response outcomes on progression-free survival

Ordinal factor	Level	N	%	HRa	P value
Baseline Ph+ metaphases (%)	0	9	3	1.342	0.012
	>0 and ≤35	25	8
	>35 and ≤65	18	6
	>65 and ≤95	75	25
	>95 and ≤100	175	58
Prior best response to therapy	No CHR	27	9	0.902	0.074
	CHR but no CyR	103	33
	Minimal CyR	19	6
	Minor CyR	28	9
	PCyR	57	18
	CCyR	77	26
Response outcome	Level	N	%	HRb	P-value
Minor cytogenetic response by 6 months	No	123	39	0.255	<0.001
	Yes	192	61
Major cytogenetic response by 12 months	No	138	44	0.219	<0.001
	Yes	177	56

Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; CyR, cytogenetic response; PCyR, partial cytogenetic response; Ph+, Philadelphia chromosome positive.

^aHR, hazard ratio for a unit increase in the category number (according to ordering given in table).

^bHR, hazard ratio for the second level of the factor relative to the first level.

Multivariate analyses

Multivariate analyses were conducted on the nine significant (P < 0.05) baseline covariates, incorporating only the dichotomous versions of baseline hemoglobin level and baseline percent of basophils. Backward selection produced a model for PFS with two factors, baseline percent of basophils and baseline mutations with low sensitivity to nilotinib. When baseline hemoglobin level was included in the model, the hazard ratios and P values were (Table 4):

Table 4.

Multivariate analysis for progression-free survival

Variable	P value	Hazard ratio
Baseline hemoglobin, (g/l)	0.0458	0.637
Baseline basophils in peripheral blood (%)	0.0136	0.580
Baseline BCR-ABL mutations with low sensitivity to nilotinib (0 = none or unknown, 1 = present)	<0.0001	7.125

• Baseline hemoglobin in g/l (<120 is 0, ≥120 is 1); HR = 0.637; P = 0.0458

• Baseline basophils percent (≥4 is 0, <4 is 1); HR = 0.580; P = 0.0136

• Baseline mutations with low sensitivity to nilotinib (0 = none or not known, 1 = present); HR = 7.125; P < 0.0001

Landmark analyses

Exploratory multivariate analyses that also incorporated the time-dependent response outcomes (mCyR by 6 months and MCyR by 12 months) confirmed their association with PFS. Subset selection procedures identified MCyR by 12 months as more strongly associated with PFS than MCyR by 6 months.

Landmark analyses from 12 months confirmed the association of PFS with MCyR by 12 months (P < 0.001) and baseline mutations with low sensitivity to nilotinib (P < 0.001). These results supported including MCyR by 12 months and nilotinib sensitivity mutations as part of the prognostic scoring system.

In these landmark analyses, the dichotomized factors for baseline hemoglobin level and baseline percent of basophils appeared to be less strongly associated with PFS (P = 0.277 and P = 0.055, respectively). Nevertheless, these two baseline factors were included in the scoring system because their importance as predictors of PFS prior to the availability of 12-month cytogenetic response assessments was previously established in published studies.^13,19 These factors were also shown to be significant in the multivariate analyses presented here.

The univariate and multivariate analyses in this study confirmed the effects of three baseline variables that significantly and consistently correlated with PFS among patients treated with nilotinib after imatinib failure. These results supported the inclusion of baseline hemoglobin, percent basophils, and nilotinib sensitivity mutations into the prognostic scoring model that was developed and retrospectively evaluated as part of this study. The landmark analyses supported inclusion of MCyR by 12 months.

Prognostic model

Various factors have been previously described as independent prognostic factors of CML patient outcomes.^{13–15,19,20} Four of these factors were confirmed in this study as significant dichotomized prognostic markers and were used to create a scoring system that could serve as a model to further evaluate their effects on patient outcomes. These four factors were baseline BCR-ABL mutations associated with low pharmacological sensitivity to nilotinib, baseline hemoglobin <120 g/l, baseline basophils ≥4% and drug resistance as defined by lack of MCyR by 12 months. Patients were assigned a score of 4 and then 1 was subtracted for the presence of each of the favorable factors. Scores potentially ranged from 0 to 4, with 0 being the best (ie, no unfavorable factors present) and 4 being the worst (ie, four unfavorable factors present) In the rare cases (3 of 315) in which patients had missing values for a factor, their scores were not reduced. In the analysis of all four factors, the majority of patients scored 0 (n = 77), 1 (n = 116) or 2 (n = 82). A restricted score, or “baseline score,” was also calculated in the same way using only the three baseline factors (that is, excluding MCyR status by 12 months). The majority of patients in the analysis of only baseline factors scored 0 (n = 109) or 1 (n = 153).

The Kaplan-Meier estimates of PFS and OS in the four-factor score groups are shown in Table 5 and Figures 1A and 1B. As hypothesized, the 2-year PFS rates strongly correlated with the score groups, in which PFS was best for patients with the lowest scores (score = 0, no unfavorable factors present) and decreased as the scores increased (Figure 1A). The nine patients in the “worst” group (score = 4) did not reach the 12-month landmark: eight patients experienced a PFS event and one was censored before 12 months. The 2-year PFS rates were 89%, 67%, 50%, 19% and 0% for patients with scores of 0, 1, 2, 3 and 4, respectively. The 2-year OS rates were also significantly better among patients with a score of 0 (99%; P < 0.001) when compared with the rates of patients with scores of 1, 2, 3 or 4 (88, 76, 82 and 87%, respectively).

Table 5.

Kaplan-Meier estimates of 24-month PFS and OS and 12-month MCyR in the overall and baseline score groups

PFS and OS according to score groupsa
Score	N (%)	% at 24 months (95% CI)b
		PFS	OS
0	77 (24)	89 (78–94)	99 (91–100)
1	116 (37)	67 (56–76)	88 (80–93)
2	82 (26)	50 (35–63)	76 (65–84)
3	31 (10)	19 (5–41)	82 (61–92)
4	9 (3)	0 (NA)	87 (39–98)

PFS, OS, and MCyR according to baseline score groupsb
Score	N (%)	% at 24 months (95% CI)		% at 12 Months
		PFS	OS	MCyR
0	109 (35)	79 (68–86)	93 (86–97)	71
1	153 (49)	65 (55– 73)	84 (77–89)	55
2	41 (13)	39 (21–57)	81 (64–91)	32
3	12 (4)	0 (NA)	90 (47–99)	25

Abbreviations: CI, confidence intervals; MCyR, major cytogenetic response; NA, not applicable; OS, overall survival; PFS, progression-free survival.

^aAdverse features were hemoglobin <120 g/l, percent of basophils ≥4%, baseline mutations with low sensitivity to nilotinib and no MCyR by 12 months of therapy.

^bAdverse features were hemoglobin <120 g/l, percent of basophils ≥4% and baseline mutations with low sensitivity to nilotinib.

Figure 1.

Survival of patients by overall scores according to the prognostic model. Kaplan-Meier estimates of progression-free survival by score groups (A); overall survival by score groups (B); progression-free survival by baseline component of scores (C), which excludes major cytogenetic response by 12 months as a factor because it is not known at baseline, and overall survival by baseline component of scores (D), which excludes major cytogenetic response by 12 months as a factor because it is not known at baseline.

Because one of the factors, MCyR status by 12 months, was not known at baseline, an analysis was conducted considering only the baseline factors: hemoglobin level, percent basophils, and mutation status (Table 5 and Figures 1C and 1D). Again, the 2-year PFS rates were best for patients with the lowest baseline scores (score = 0, no unfavorable baseline factors present) and worst for patients with the highest baseline score (score = 3, all three unfavorable baseline factors present) (Figure 1C). The 2-year PFS rates were 79, 65, 39 and 0% for patients with scores of 0, 1, 2 and 3, respectively. The 2-year OS rates also appeared to be higher among patients with a score of 0 (93%) vs patients with scores of 1, 2 or 3 (84, 81, and 90% respectively), but this difference was not statistically significant (P = 0.06; Fig 1D).

This baseline model also predicted for the 12-month probability of achieving MCyR. Similar to the analyses of PFS, the 12-month probability of achieving MCyR significantly correlated with prognostic score. MCyR by 12 months was achieved by 71, 55, 32 and 25% of patients with scores of 0, 1, 2 and 3, respectively (P < 0.001; Table 5).

PFS and OS rates from the 12-month landmark analyses in the score groups are shown in Table 6 and Figures 2A and 2B. The nine patients in the worst prognostic group (score = 4) did not reach the 12-month landmark: eight patients experienced a PFS event and one was censored before 12 months. Thus, this category was not included in the landmark analysis for PFS but was included in the landmark analysis for OS (because all patients were followed for survival).

Table 6.

Associations of PFS and OS with MCyR status by the 12-month landmark analysis in the baseline score groups^a

MCyR at 12 months	N (for PFS)	% at 24 months (95% CI)	N (for OS)	% at 24 months (95% CI)
		PFS		OS
Score = 0
No	11	48 (16–75)	27	84 (62–94)
Yes	69	91 (81–96)	74	100
Score = 1
No	27	66 (44–82)	55	87 (74–93)
Yes	68	79 (67–87)	83	93 (84–97)
Score = 2
No	11	31 (8–59)	27	83 (60–93)
Yes	9	78 (37–94)	13	85 (51–96)

Abbreviations: CI, confidence intervals; MCyR, major cytogenetic response; OS, overall survival; PFS, progression-free survival.

Baseline adverse features were hemoglobin <120 g/l, percent of basophils ≥4% and baseline mutations with low sensitivity to nilotinib.

^aNo analysis is presented for baseline score = 3 because the sample size was too small (n = 2).

Figure 2.

Survival of patients according to the 12-month landmark analysis. Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) by score groups.

Overall, the 2-year PFS and OS rates were highest for patients with the lowest scores and lowest for patients with the highest score (Figures 2A and 2B). Patients with a score of 3 (n = 13) had lower PFS rates than the other score groups at all time points, particularly compared with patients with a score of 0 (Figure 2A). Although 2-year OS rates were relatively similar in the 1, 2, 3 and 4 score groups, OS was 100% among patients with a score of 0 (Figure 2B).

Achievement of MCyR by 12 months was a critical prognostic factor (Table 6). The 2-year PFS rates among patients with scores of 0, 1 or 2 who had MCyR by 12 months vs those who did not were 91 vs 48%, 79 vs 66% and 78 vs 31%, respectively. Score group 3 was not included in this analysis because of its small sample size (n = 2).

We repeated the analysis assessing the validity of this score on EFS. This model also predicted for EFS. The 2-year EFS rates were 81, 50, 29, 8 and 0% for patients with scores of 0, 1, 2, 3 and 4, respectively (P < 0.001).

Discussion

The availability of second-generation TKIs has provided new therapeutic options for patients with CML after imatinib failure. This is the largest study that has evaluated prognostic factors predicting response to nilotinib in patients with CML-CP resistant to or intolerant of imatinib therapy. We described two prognostic scores that can be used to predict PFS in this patient population. Both can be used to predict PFS, but at different times (one at baseline and one after 12 months). The first is based on three baseline factors that were identified through univariate and multivariate analyses. The second prognostic score includes achievement of MCyR by 12 months in addition to those three factors. This four part score can be used when 12-month response results are known.

The four independent factors identified by our study as predictive of outcomes were the achievement of MCyR by 12 months of therapy (HR = 0.359; P < 0.0001), baseline hemoglobin level ≥120 g/l (HR = 0.985; P = 0.0291), baseline percent of basophils <4% (HR = 1.070, P = 0.0128), and the absence of baseline mutations with low sensitivity to nilotinib (E255K/V, Y253H and F359C/V) (HR = 6.097; P ≤ 0.0001). These findings are consistent with previous experience with imatinib therapy after interferon failure, in which more aggressive forms of disease (eg, high basophil levels, lack of CHR and high percent of Ph+ metaphases) were associated with poor response to imatinib therapy, suggesting the presence of aggressive clones with intrinsic resistance to therapy.¹³ Our findings are in line with a previous report from the M. D. Anderson Cancer Center where patients with high IC₅₀ kinase domain mutations treated with nilotinib had a low likelihood of achieving MCyR, with a negative impact on EFS and OS.²⁰

Recently, a multivariate analysis investigating baseline factors predictive of cytogenetic response was reported for patients receiving dasatinib after imatinib failure.²¹ In this analysis, age, lower percent of Ph+ metaphases, shorter duration of CML, longer duration of prior imatinib therapy, prior response or intolerance to imatinib, absence of splenomegaly and no prior allogeneic stem cell transplantation (SCT) predicted for the achievement of MCyR and CCyR. Because of the inclusion of different baseline factors and statistical end points, comparisons between the multivariate analyses of dasatinib and nilotinib cannot be made.

In patients with 12-month cytogenetic results available, the four factors were combined to create a single prognostic score that stratified patients into five prognostic subsets. The best groups were patients having none of the three unfavorable disease risk factors and achieving MCyR by 12 months. Patients in the worst group had all three of the unfavorable disease risk factors and did not achieve MCyR by 12 months. This is a simple scoring system that is easily applicable in the clinic, provided that patients were adequately monitored during imatinib therapy, allowing assessment of their response to imatinib. This scoring system could serve to advise patients of their prognosis and treatment options.

An important question is whether these factors can predict for significant differences in PFS (for example, subsets with expected 24-month PFS >75% vs <50%). If such is the case, then patients in the favorable group (no adverse factors at baseline) might rely on second-generation TKIs indefinitely, whereas those in the unfavorable group (three adverse factors) would be well advised to pursue an SCT at the time of imatinib failure. A trial of nilotinib could be initiated while the patient is preparing for transplant; however, in view of the poor long-term prognosis, SCT would be recommended when available. In contrast, in patients with one or two baseline adverse features, close monitoring is needed, and alternative options could be considered, particularly if response is suboptimal after 12 months of therapy with nilotinib. In addition, these factors are not applicable for patients with imatinib intolerance and those in advanced-stage disease.

Achieving 12-month MCyR is a known major determinant of outcome in previous generations of therapy including interferon-alfa and imatinib,⁵ and in patients treated with second generation TKIs.¹⁴ The 12-month landmark analysis showed that achieving MCyR by 12 months was the most dominant independent predictive factor for PFS after the start of therapy (Table 6) and may compensate for the presence of unfavorable baseline factors, such as kinase domain mutations with low sensitivity to nilotinib therapy that remain uncommon. This is in line with the results of the pivotal trial in which the 2-year PFS rates were 94 and 79% in patients with and without 12-month MCyR, respectively, and is consistent with a smaller retrospective analysis from the M. D. Anderson Cancer Center, where the achievement of 12-month MCyR constituted the sole independent predictive factor for EFS.¹⁹

In summary, the outcome of patients after imatinib failure treated with nilotinib could be predicted. Patients with anemia, high proportion of basophils in peripheral blood or a kinase domain mutation with low sensitivity to nilotinib have a poor PFS and OS when treated with nilotinib and could be offered additional treatment options. The achievement of 12-month MCyR could compensate for the presence of these unfavorable adverse features. Patients achieving MCyR after 12 months of therapy can continue on nilotinib; those not achieving it would consider alternative options. This decision will also depend on other variables, such as the age of the patient, and donor matching. The scoring system described here needs to be prospectively evaluated and validated in future clinical trials.