ALBERT

Description: Abstract 3429 The achievement of a CCyR is a known major surrogate endpoint in the treatment of pts with CML that has shown correlation with survival improvement. Second generation TKIs (2nd TKI) have shown significant activity in pts with CML post imatinib (IM) failure and have recently shown superiority when compared to IM 400 mg standard of care in pts with newly diagnosed CML –CP. We assessed the correlation between the achievement of an early CCyR and event-free survival (EFS as defined by the IRIS trial) and overall survival (OS) in sequential phase II trials run at our institution in pts with newly diagnosed CML in CP treated with IM 400 mg daily (n=73), IM 400 mg BID (n=208), and 2nd TKI (n=154). Patient and disease characteristics at start of treatment were listed in Table 1. The overall rates of CCyR were 87 %, 91%, and 96% for pts receiving IM 400 mg/d, 400 mg BID, and 2nd TKI (p = 0.06). The rates of major molecular response (MMR) were 77%, 87%, and 89%, respectively (p = 0.05). Their 3-year EFS and OS rates were 85%, 92%, and 97% (p=0.01), and 93%, 97%, and 100% (p = 0.18), for pts receiving IM 400 mg daily, IM 400 mg BID, and 2nd TKI, respectively. The rates of 3-, 6-, and 12-month (mo) CCyR of the total group were 65%, 83%, and 89%, respectively. Pts with 3-, 6-, and 12-mo CCyR had statistically a significantly better outcome with 3-year EFS and OS rates of 98%, 97%, and 98% and 99%, 99%, and 99%, respectively compared to 83%, 72%, and 67% and 95%, 90%, and 94%, in pts who did not achieve a CCyR. There was no difference in EFS and OS in pts who achieved a CCyR whether they received IM 400 mg daily, IM 400 mg BID, or 2nd TKI (Table 2.). In conclusion, 2nd TKI induced higher rates of CCyR and MMR than IM. The achievement of an early CCyR remains a major determinant for outcome of pts with early CP-CML regardless of the TKI. Table 1. Patients characteristics Parameter 400mg 800mg 2nd TKI No. patient treated 73 208 154 Age (years) Median (range) 48 (15–78) 48 (17–84) 47 (18–85) Splenomegaly Yes (%) 16 (22) 59 (28) 41 (27) Hemoglobin (g/dl) Median (range) 12.7 (7.9–15.7) 12.4 (6.2–16.7) 12.2 (6.7–15.8) WBC (× 109/L) Median (range) 20.5 (1.6–277) 27.9 (2.2–283) 31.8 (0.8–342.5) Platelets (× 109/L) Median (range) 367 (103–1043) 353 (58–1476) 299 (73–2000) Peripheral blast % Median (range) 0 (0–2) 0 (0–12) 0 (0–7) baso % Median (range) 3 (0–16) 3 (0–19) 3 (0–19) Marrow blast % Median (range) 1 (0–6) 2 (0–14) 2 (0–8) baso % Median (range) 2 (0–9) 3 (0–15) 2 (0–12) Sokal risk, no (%) Low 50 (68) 132 (63) 118 (77) Intermediate 22 (30) 57 (27) 27 (18) High 1 (2) 19 (9) 9 (6) Ph + 〉 90 % yes (%) 67/72 (93) 195 (94) 133 (86) Clonal evolution (%) Yes (%) 2 (3) 7 (3) 11/151 (7) Table 2. Outcome Total group 3mo-CCyR 6mo-CCyR 12mo-CCyR y n p y n P Y n P 3-yr EFS 98 83

Description: Background: Submicroscopic deletions of the derivative chromosome 9 [Del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Del der(9) is a powerful prognostic indicator associated with unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by Del der(9). Methods: We investigated the prognostic impact of Del der(9) in 353 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=161) or dasatinib (n=192). The presence of Del der(9) prior to 2nd generation TKIs was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 245 patients. The median age was 53 years (range, 15–83) and the median follow-up was 24 months (range, 1–53). The primary endpoints evaluated were complete hematologic response (CHR), cytogenetic response, and survival. Results: Twenty-eight (11%) patients carried Del der(9) and 217 an intact der(9). Among patients with deletions, 22 were in chronic phase (CP), 4 in accelerated phase (AP), and 2 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 122 were in CP, 55 in AP and 40 in BP. Overall, 229 (93%) patients were assessable for response after a median of 25 months (range, 1–53) of therapy. The outcome by CML phase is shown in Table 1. CML phase Deletion der(9) No. CCyR (%) p EFS (12 mo) p OS (12 mo) p No 122 79 0.77 86 0.05 97 0.04 CP Yes 22 75 60 78 Not done 46 No 55 36 1.0 37 0.47 60 0.95 AP Yes 4 25 67 75 Not done 27 No 40 19 1.0 0 0.85 35 0.39 BP Yes 2 0 0 0 Not done 35 There was no difference in response rates among patients in CP, but those without Del der(9) had an improved EFS and OS at 24 months compared with those carrying Del der(9) (EFS: 86% vs 60%, p=0.05; OS: 97% vs 78%; p=0.04). Notably, whereas a trend towards worse EFS (p=0.05) and OS (p=0.12) was observed in patients in CP with Del der(9) treated with nilotinib, these outcomes were not significantly affected by Del der(9) in patients receiving dasatinib (EFS: p=0.47; OS: p=0.76). Conclusion: Our results suggest that, in contrast to what has been reported with imatinib therapy, patients with CML-CP carrying Del der(9) who failed imatinib may have a worse survival than their counterparts without deletions after treatment with 2nd generation TKI. This deleterious effect is more apparent among patients treated with nilotinib than among those receiving dasatinib.

Description: Background: Submicroscopic deletions of the derivative chromosome 9 [del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Deletion of der(9) is powerful prognostic indicator associated with an unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by deletions of der(9). Methods: We tested the prognostic impact of the deletions of der(9) in 323 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=144) or dasatinib (n=179). The presence of deletions of der(9) was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 244 patients. The median age was 55 years (range, 15–83) and the median follow-up was 18 months (range, 1–44). The primary endpoints evaluated were survival, complete hematologic response (CHR) and cytogenetic responses. Results: Twenty-eight (12%) patients were found to have del der(9) and 216 an intact der(9). Among patients with deletions, 16 were in chronic phase (CP), 8 in accelerated phase (AP), and 4 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 112 were in CP, 54 in AP and 50 in blastic phase (BP). Overall, 222 (91%) of 244 patients were assessable for response. There was no significant difference between patients with or without deletions regarding the rate of CHR, major (MCyR) or complete (CCyR) cytogenetic responses, and event-free (EFS), and overall (OS) survival at 12 months for the total population. CML Phase deletion der(9) [No. Patients] CCyR (%) p EFS (12 months) p OS (12 months) p No (112) 72 1 84 0.2 97 0.01 Chronic Yes (16) 73 78 92 Not Done (30) No (54) 31 0.7 54 0.22 69 0.62 Accelerated Yes (8) 38 75 88 Not Done (27) No (50) 24 1 9 0.56 30 0.56 Blastic Yes (4) 25 25 25 Not Done (22) Among pts in CP there was no difference in response rate or EFS, but pts without del der(9) had an improved OS at 12 months compared with those carrying der(9) (97% vs 92%; p=0.01). There appears to be no significant difference between pts treated with nilotinib and those treated with dasatinib. Conclusion: Our results suggest that although the outcome of patients with CML treated in AP or BP with either nilotinib or dasatinib does not differ regardless of their deletion status, those in CP carrying del der(9) deletions may have a worse overall survival than their counterparts without deletions. This is in contrast to what has been reported with imatinib therapy. The reason for this difference is unclear.

Description: Background: Novel Tyrosine Kinase Inhibitors (TKIs) are used in the treatment of CML pts who fail imatinib. However, more than half of chronic phase (CP) pts will not achieve complete cytogenetic response (CCyR), and the criteria for when to consider alternate therapy among such pts are not well defined. Methods: We analyzed the pattern of cytogenetic response in 113 pts with CML in CP receiving nilotinib (n=43, 38%) or dasatinib (n=70, 62%) after imatinib failure in order to determine which milestones are important for long-term survival, and to develop a predictive model for the early identification of poor-risk pts. Pts (n=26, 23%) with clonal evolution with no other criteria for accelerated phase were included in the analysis. The previous best response to imatinib was CCyR in 24%, major cytogenetic response (MCyR, 1–35% Ph+) in 20%, minor cytogenetic response (mCyR, 36–95% Ph+) in 15%, complete hematological response (CHR) in 39%, and no response (NR) in 3%. Results: Median follow-up was 27 months. The cumulative probability of CCyR was 35%, 42% and 48% after 3, 6 and 12 months of 2nd TKI therapy. The achievement of MCyR or better by 12 months (12MMCyR) was an important milestone in determining future survival: 1-year survival from the 12 month landmark was 97% for the pts who achieved 12MMCyR, compared with 84% for those who did not (p=0.01). In contrast, no protection was conferred by lesser responses, with comparable survival for pts in mCyR, CHR and NR (86%, 83% and 88% respectively, p=0.78). The one year risk of progression to accelerated or blast phase, loss of hematologic response or death was 3% for pts in 12MMCyR, and 17% for those in mCyR or CHR (p=0.003). Early cytogenetic response was predictive of eventual 12MMCyR, with pts not achieving any degree of cytogenetic response by 3 to 6 months being unlikely to reach MCyR or better by 12 months (Table). Significant (p

Description: Backgound. Imatinib mesylate therapy has significantly improved the prognosis of CML. A minority of pts in CP-CML are primary resistant to imatinib or develop resistance during treatment. Second generation TKIs such as dasatinib and nilotinib demonstrated efficacy in overcoming imatinib resistance, with high rates of hematologic and cytogenetic responses in CML post imatinib failure. Study Aims and Study Group. We assessed the impact of prior best response to imatinib on outcome of 120 pts in CP treated with new TKIs at our institution after imatinib failure: 75 (62%) received dasatinib and 45 (38%) recived nilotinib. Median age was 57 years (range, 21–83). The median duration of the disease was 67 months (range, 4–241). Pts have been followed for a median of 22 months (range, 1–44) from the start of 2nd generation TKIs. Results. Best response to imatinib was hematologic in 47 pts (40%) and cytogenetic in 60 (50%) (complete in 28, partial in 16, minor in 16). Five pts (4%) were primary refractory and 8 (6%) were intolerant. At the start of 2nd generation TKIs, 87 pts (73%) were in active CP with no complete hematologic response (CHR). Eighty-five (71%) harbored more than 90% Philadelphia-positive metaphases, and clonal evolution was noted in 28 pts (23%). Patients that had achieved a cytogenetic response at any time during their imatinib therapy had a better outcome than those who had only a hematologic response: CHR rates 98% vs 68%, p

Description: Background. Different types of BCR-ABL fusion mRNAs can be found in pts with CML due to different genomic breakpoints and alternative splicing. The two major forms join ABL exon 2 with exons 13 or 14 of BCR, resulting in two main transcripts, b2a2 and b3a2, respectively, that codify for a p210 protein present in the majority of CML patients. b3a2 is more frequent in newly diagnosed patients than the b2a2 transcript, and occasionally both transcripts may be present. The clinical significance of the specific transcript among CML pts treated with imatinib has not been clearly established, and some have suggested that b2a2 may be associated with better outcome. (Blood2006108: Abstract 4780) Genet.Mol. Res.4(4): 803–811 (2005)Journal of Clinical Oncology, 2007 Vol 25, No 18S (June 20 Supplement), 2007: 7043. Purpose: To determine if there is a difference in outcome after imatinib therapy in CML pts according to their BCR-ABL transcript. Methods: We analyzed 480 pts with CP CML treated with imatinib, 251 receiving imatinib as frontline therapy and 229 after interferon (IFN) failure. Molecular response was evaluated using RT PCR every 3 months (mo). Results: The median follow-up was 62 mo (range 1–92 mo) Median age was 51 years (range 15–84). Overall, 187 of 480 (39%) pts expressed b2a2, 234 (49%) b3a2, 55 (11%) expressed both, and 4 (1%) expressed e1a2. The rates of major and complete cytogenetic response were similar for pts with b3a2 and b2a2, both in the newly diagnosed and the post-IFN failure: CCyR 91% for b3a2 and 89% for b2a2 in frontline, and 72% and 78%, respectively in the post-IFN failure group. However, among 433 pts evaluable for molecular response, transcript levels were significantly lower at 3, 6 and 12 months from start of therapy for pts with b3a2 compared to those with b2a2 (Table 1). Table 1. Median BCR-ABL transcript levels over time by transcript type 3 months 6 months 9 months overall b2a2 1.8284 0.318 0.186 0.0464 b3a2 0.5175 0.0553 0.0352 0.0033 p-value 0.001

Description: The criteria to define chronic (CP), accelerated (AP) and blast phase (BP) CML vary in the literature. The WHO recently proposed, based on the literature and collective experience of the clinical advisory committee, new criteria for myeloid malignancies including CML in an attempt to provide more uniform criteria (Blood2002; 100:2292). Imatinib is the current standard therapy for CML, and the criteria used in most studies using imatinib are shown below in contrast to the WHO proposal: Phase Criteria Imatinib WHO *Unrelated to therapy (Rx), **Unresponsive to Rx, Plts=platelets, BM=bone marrow AP Blasts 15–29% 10–19% Blasts + promyelocytes ≥ 30% NA Basophils ≥ 20% ≥ 20% Plts 1000 x 109/L** No Yes Increasing spleen size and WBC** No Yes CE At any time Not at diagnosis (Dx) BP Blasts ≥ 30% ≥ 20% Extramedullary disease Yes Yes Large clusters of blasts in BM NA Yes We investigated the clinical validity of the WHO proposal among 809 patients (pts) with CML in all stages treated with imatinib at MDACC since 1999. According to the imatinib classification, 537 (66%) pts were in CP, 196 (24%) in AP, and 76 (9%) in BP. When analyzing the specific subsets of pts where the classifications differ, major findings are: 1) Pts with CE at Dx (n=14) have similar cytogenetic (CG) complete remission (CR) rate (86%) than pts (n=477) with imatinib CP (75%, p=.53), but it is lower when CE develops after Dx (34/64, 53%; p=.0005). Similar results are found for overall survival (OS) and progression-free survival (PFS). 2) CG CR rate among pts with 20%–29% blasts (4/19, 21%) is more similar to that of AP (37/99, 37%)(p=0.19) than to pts with ≥30% blasts (5/76, p=0.07). This trend is more significant for OS and PFS. 3) Pts with increasing WBC and spleen, or plts 〉1000 x109/L unresponsive to Rx have a CG CR rate (9/42, 21%; p=.07) lower than others with AP, but there is no difference in OS or PFS. 4) Pts with plts 〉1000 x109/L without prior Rx have similar outcome as those with CE developing on therapy. In conclusion, based on results imatinib therapy, AP can be defined as blasts ≥10%, basophils ≥20%, plt 1000 x109/L (unresponsive to Rx), increasing WBC and spleen (unresponsive to Rx), and CE not at diagnosis; BP is defined by blasts ≥30% or extramedullary disease; pts who develop CE during the course of Rx of with plts 〉1000 x109/L not related to Rx constitute an intermediate group between CP and AP; all others are CP.

Description: Sokal and Hasford scores have been used to estimate the survival of CML patients following alkylator-based or interferon-based therapy, and may also predict the outcome of patients receiving first-line imatinib. These scores were designed for patient characteristics at the time of diagnosis and they have been assumed to have no clinical value at other times during the course of the disease (eg. second-line or subsequent therapy). We seek to determine the applicability of the Sokal and Hasford scores in predicting outcomes in patients receiving second or subsequent-line therapy with imatinib and other novel tyrosine kinase inhibitors (TKI). This analysis is based on 379 CML patients in chronic phase (90%) or accelerated phase as defined by cytogenetic clonal evolution (10%), who were enrolled on clinical trials of imatinib following interferon failure (n=294), or nilotinib or dasatinib following imatinib failure (n=85). Significance of relationship between Sokal and Hasford risk categories and response were tested using the Chi-Square test, and differences in survival assessed using the log-rank method. P-values are summarised below: Imatinib following Interferon Failure Nilotinib/Dasatinib Following Imatinib Failure Sokal Hasford Sokal Hasford *comparison between low and intermediate risk groups only Low Risk 219 (74%) 176 (60%) 39 (46%) 45 (53%) Intermediate Risk 65 (22%) 111 (38%) 34 (40%) 38 (45%) High Risk 10 (3%) 6 (2%) 12 (14%) 2 (2%) Any Cytogenetic Response p

Description: Abstract 341 Background: Nilotinib, an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl and approximately 30-fold more potent than imatinib, is effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims: To investigate the efficacy and safety of nilotinib as first-line therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Sixty-five pts (61 CP, 4 AP) have been treated for a median of 17 mo (range 1 to 43). The median age was 46 years (range 19 to 86). Among 48 pts who were not in CHR at the start, 47 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 51 pts followed for at least 3 mo, 50 (98%) achieved a complete cytogenetic response (CCyR). MMR has been achieved in 32 (63%) pts, including 12 (24%) with a complete molecular response. The rate of CCyR at different time points (intention-to-treat) for pts in CP compares favorably to that observed in historical controls treated with imatinib 400 mg or 800 mg daily: MMR was achieved by 55% at 12 mo and 53% at 24 mo (corresponding rates with imatinib 400 mg 34 and 55%, and with imatinib 800 mg 58% and 66%, respectively). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 11%, neutropenia 12%, and anemia 5%. Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%, and non-neutropenic fever in 6%. 24 (37%) pts had transient treatment interruptions and 11 (17%) had dose reductions. The actual median dose is 800 mg daily. Ten pts have discontinued therapy: 4 pts for toxicity, 2 because of transformation to accelerated or blast phase, and 4 for other reasons. 24 mo EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 90%. All patients are alive. Among pts in AP, 3 achieved CCyR (all of them sustained); one patient progressed to blast phase and died. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 mo after the start of therapy and MMR in more than 50% at 12 months with a favorable toxicity profile. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of nilotinib as initial therapy for CML, and indication for which nilotinib is not approved.. O'Brien:Novartis: Research Funding. Jones:Novartis: Research Funding, Speakers Bureau. Jabbour:Novartis: Speakers Bureau; BMS: Speakers Bureau. Borthakur:Novartis: Speakers Bureau. Kantarjian:Novartis: Research Funding; MGI Pharma (Eisai): Research Funding; Genzyme: Research Funding; BMS: Research Funding.

Description: We analyzed the association between achievement of early complete cytogenetic response (CCyR) and event-free survival (EFS) and overall survival (OS) in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib 400 mg (n = 73), or imatinib 800 mg daily (n = 208), or second- generation tyrosine kinase inhibitors (n = 154). The overall CCyR rates were 87%, 91%, and 96%, respectively (P = .06); and major molecular response (MMR) rates were 77%, 87%, and 89%, respectively (P = .05). Their 3-year EFS rates were 85%, 92%, and 97% (P = .01), and OS rates were 93%, 97%, and 100% (P = .18), respectively. By landmark analysis, patients with 3-, 6-, and 12-month CCyR had significantly better outcome: 3-year EFS rates of 98%, 97%, and 98% and OS rates of 99%, 99%, and 99%, respectively, compared with 83%, 72%, and 67% and 95%, 90%, and 94%, in patients who did not achieve a CCyR. Among patients achieving CCyR at 12 months, the depth of molecular response was not associated with differences in OS or EFS. In conclusion, second tyrosine kinase inhibitors induced higher rates of CCyR and MMR than imatinib. The achievement of early CCyR remains a major determinant of chronic myeloid leukemia outcome regardless of whether MMR is achieved or not.