Stem Cell Transplant (SCT) for Patients (pts) with Chronic Myeloid Leukemia (CML) Resistant to Tyrosine Kinase Inhibitors (TKI) with BCR-ABL Kinase Domain (KD) Mutation T315I.

Abstract Background: Resistance to TKI therapy is associated with development of KD mutations in approximately 50–60% of pts. Although many imatinib-resistant mutations respond well to second generation TKI, T315I is insensitive to all currently available TKI (imatinib, dasatinib, nilotinib) in vitro and in the clinic. SCT is frequently recommended for these pts but there is no available data about the efficacy of SCT in such pts. Aims: To investigate the efficacy and safety of SCT for patients with TKI-resistant CML with a T315I mutation. Methods: We reviewed the outcome of all pts with T315I that have received a SCT at MD Anderson Cancer Center. Results: Seven pts received 8 transplants. Their median age was 44 years (yrs) (range, 26 to 64 yrs). The median time from diagnosis to SCT was 42 months (mo) (range, 9–160 mo). All pts had become resistant to with imatinib; 5 received dasatinib and 1 nilotinib after imatinib failure, and 6 pts received other additional therapy prior to SCT. At the time of SCT 2 pts were in chronic phase (CP), both in partial cytogenetic response; 2 in accelerated (AP) with active disease; and 3 in second or greater CP from lymphoid blast phase (BP) (1 in minor cytogenetic response, 2 major molecular response, 1 complete molecular response –CMR-). Six transplants were from matched unrelated donors and 2 from cord blood. Best response after SCT was CCyR in 3 (2 AP, 1 BP), CMR in 4 (2 CP, 2 BP), and 1 unknown (died early). After a median follow-up of 11 months from SCT, 4 pts are alive; the 2 transplanted in CP are alive after 11 and 42 months after SCT and in CMR; 1 pt transplanted in AP has a sustained CCyR 20 mo after SCT with persistent T315I representing 94% of transcripts by pyrosequencing; and 1 in BP has a CMR sustained 6 mo after a second SCT (relapsed 5 months after first SCT) 3 pts have died: 1 AP and 2 BP, all with relapse. Conclusion: SCT appears to be an effective strategy for pts with CML with T315I, although longer follow up is needed. Results are significantly better when pts are transplanted in CP. Thus, SCT should be considered in pts with resistance to TKI once T315I is identified, ideally in CP.

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Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy.

Blood ◽

10.1182/blood.v110.11.1943.1943 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1943-1943

Author(s):

Elias Jabbour ◽

Hagop Kantarjian ◽

Dan Jones ◽

Srdan Verstovsek ◽

Alessandra Ferrajoli ◽

...

Keyword(s):

Kinase Inhibitors ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Cell Transplant ◽

2Nd Generation ◽

Hematologic Response ◽

T315i Mutation

Abstract Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome. Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure. Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64). Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.

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Clinical Characteristics and Outcome of Patients (pts) with F317L BCR-ABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽

10.1182/blood.v110.11.1949.1949 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1949-1949

Author(s):

Elias Jabbour ◽

Hagop Kantarjian ◽

Dan Jones ◽

Susan O’Brien ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Treatment Failure ◽

Mutation Detection ◽

Point Mutations ◽

Cytogenetic Response ◽

In Vitro Mutagenesis ◽

Molecular Response ◽

Cell Transplant ◽

Best Response

Abstract Background. Point mutations of the Bcr-Abl KD are the most frequently identified mechanism of resistance in pts with CML who failed TKI. The setting for outgrowth of different mutations and their subsequent response to different TKIs varies significantly. For example, mutations in codon 317, which would be predicted to impair dasatinib binding, have been generated during in vitro mutagenesis with dasatinib but not nilotinib, and the F317L, in particular, has been reported following treatment with dasatinib. Aims. We assessed the incidence and pattern of development F317L mutations in pts with TKI-resistant CML at our institution and responses following change in therapy. Results. F317L mutation was detected in 20 patients: 12 occurred among 99 pts (12%) after imatinib failure who had KD mutation assessment, and 8 among 16 pts (50%) who developed new mutations on dasatinib therapy (among 77 treated) (p=0.001). Median age for all pts with F317L was 49 years (range, 34–66 years). Pts had received imatinib for a median of 23 months (mo) (range, 2–69). Best response to imatinib was complete hematologic response in 11 and cytogenetic response in 8 (5 complete, 2 partial, 1 minor). One pt did not respond. At the time the mutation was detected, 8 pts were in chronic (CP), 6 in accelerated (AP) and 6 in blast phase (BP). Patients with F317L-mutated tumors developing on imatinib or dasatinib had similar characteristics as those who had KD mutations at other sites or no mutation detected. Among pts with F317L at start of 2nd TKI, 3 received dasatinib and all 3 had transient hematologic responses (best response) (1 partial -PHR-, 2 complete -CHR-) lasting 4, 12 and 19 mo;.4 were treated with nilotinib and 3 responded (1 CHR, 1 major molecular response-MMR-,1 complete molecular response -CMR-); 2 had imatinib dose escalation after appearance of F317L and both had a sustained complete cytogenetic response (CCyR) for 24+ and 26+ months; one pt received stem cell transplant and is in CMR 20 months after transplant; one pt did not respond to a combination of imatinib and farnesyl transferase inhibitor; and one pt was lost of follow-up with no further therapy. Among pts who developed F317L while on dasatinib (n=8), 4 never responded and 4 had an initial response to dasatinib (1 CHR, 3 CCyR) lost after a median of 15 months (range, 3 to 26); one pf these was then treated with nilotinib and achieved an ongoing CCyR for 3+ months and 2 received bosutinib after failing both nilotinib and dasatinib, achieving a transient CHR lasting 6 and 9 months, respectively. After a median follow-up of 29 months from treatment failure and 25 months from the detection of F317L, 10 pts (50%) are alive (7 CP, 2 AP, 1 BP at F317L). Median survival of pts with F317L from mutation detection was 19 mo. Survival of pts with F317L was similar to those with other mutations or without mutation when survival was dated from the time of treatment failure (p=0.51) or from mutation detection (p=0.92). Conclusion. F317L occurs more frequently after dasatinib therapy paralleling the findings of in vitro studies. TKIs showing differential in vitro activity against this mutation (e.g. nilotinib or INNO-406) may represent good candidates for treatment failure associated with F317L-mutated tumors.

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Nilotinib Efficacy According to Baseline BCR-ABL Mutations in Patients with Imatinib-Resistant Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v112.11.3216.3216 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3216-3216 ◽

Cited By ~ 8

Author(s):

Andreas Hochhaus ◽

Dong-Wook Kim ◽

Giovanni Martinelli ◽

Timothy P. Hughes ◽

Simona Soverini ◽

...

Keyword(s):

Clonal Selection ◽

Blast Crisis ◽

Chronic Phase ◽

Response Rates ◽

Cytogenetic Response ◽

Kinase Domain ◽

Molecular Response ◽

Abl Kinase ◽

Imatinib Resistant

Abstract Resistance or intolerance to imatinib in CML-CP occurs in ~20–30% of cases. The most frequent cause of resistance is clonal selection of cells harboring BCR-ABL kinase domain mutations. Nilotinib is a rationally designed, selective and potent BCR-ABL inhibitor with activity against most BCR-ABL mutants (not T315I) indicated for the treatment of Ph+ CML patients (pts) in chronic (CP) or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. This subanalysis of a phase II study of nilotinib in imatinib-resistant CML-CP pts assessed the occurrence of BCR-ABL mutations at baseline and during nilotinib treatment and their impact on treatment outcome after 12 months of nilotinib therapy. Of 321 CML-CP pts, 281 (88%) had baseline mutation data available, 114/281 (41%) had detectable BCR-ABL mutations prior to nilotinib therapy. The frequency of mutations at baseline was 55% among imatinib-resistant pts (n=192) and 10% among imatinib-intolerant pts (n=89). 23% of imatinib-resistant pts had mutations that were sensitive to nilotinib in vitro (IC50 ≤150 nM). These 12 different mutations (n=44) spread across the entire BCR-ABL kinase domain including P-loop, A-loop, and other regions. 14% of imatinib-resistant pts had 3 mutations that were less sensitive to nilotinib in vitro (IC50 >150 nM; Y253H, E255K/V, and F359C/V) and another 15% had a total of 16 mutations with unknown sensitivity to nilotinib. In imatinib-resistant pts lacking baseline mutations, after 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 28% of pts. In pts with detectable mutations, 51% achieved MCyR, 32% CCyR, and 20% MMR. Cytogenetic response rates in pts harboring mutations sensitive to nilotinib (MCyR 59%; CCyR 41%) or mutations with unknown sensitivity to nilotinib (MCyR 63%; CCyR 50%;) were comparable to those for pts without baseline mutations (MCyR 60%; CCyR 40%). Pts with mutations less sensitive to nilotinib in vitro had less favorable response after 12 months of therapy (23% MCyR). Pts with baseline mutations had a higher rate of disease progression during nilotinib treatment compared to pts without baseline mutations (46% vs. 26%). Different rates of progression were also observed with different mutations: 34% (15/44) of pts with mutations sensitive to nilotinib vs. 69% (18/26) with mutations less sensitive to nilotinib progressed. Mutations most frequently associated with progression were E255K/V (6/7) and F359C/V (9/11). Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. During nilotinib therapy, 48/281 (17%) pts had newly detectable mutations, which were more frequent in pts with baseline mutations than in pts without baseline mutations (29% vs. 9%, respectively). The majority of pts without baseline mutations also did not have newly detectable mutation at the time of progression (n=14/18) suggesting that pts without baseline mutations are less likely to progress due to newly detectable mutations. In the 63 pts who progressed, 29% had no detectable mutation at progression, suggesting the involvement of alternative mechanisms of resistance in these pts. Overall, nilotinib treatment results in significant cytogenetic responses in pts with imatinib-resistant CML-CP with or without BCR-ABL mutations. The majority of imatinib-resistant pts with detectable BCR-ABL mutations at baseline also responded to nilotinib. Pts with BCR-ABL mutations sensitive and with unknown sensitivity to nilotinib in vitro achieved significant response rates with nilotinib therapy, comparable to those for pts without baseline mutations.

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Characteristics and Outcome of Patients (pts) with V299L BCR-ABL Kinase Domain (KD) Mutation After Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽

10.1182/blood.v116.21.3428.3428 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3428-3428

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Dan Jones ◽

Yin Cameron ◽

Elizabeth Burton ◽

...

Keyword(s):

Research Funding ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Cytogenetic Response ◽

Experimental Models ◽

Molecular Response ◽

Primary Resistance ◽

Secondary Resistance ◽

Abl Kinase

Abstract Abstract 3428 Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML at our institution, and the response following change of therapy. V299L mutation was detected in 15 pts with CML: 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 69 of the 170 evaluable (i.e., had abl sequencing) pts (13%) who developed mutations on dasatinib, and 5 among 19 of the 72 evaluable pts (26%) who developed mutations on bosutinib (p<0.001); none of the 51 pts who developed mutations on nilotinib (among 125 tested) acquired V299L. Median age for pts with V299L was 56 years (range, 26–82 years). Eight pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). The median time to development of V299L was 14 mos (range, 1–30 mos) for those treated with dasatinib (7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib), and 13 mos (range, 2–48 mos) for those treated with bosutinib (after imatinib failure in 1, and as 3rd TKI after imatinib and dasatinib failure). The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 5 bosutinib) was complete hematologic response only in 6 (40%, 4 dasatinib, 2 bosutinib), minor cytogenetic response in 2 (13%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (27%; 3 dasatinib, 1 bosutinib); no response in 3 pts (20%; 1 dasatinib, 2 bosutinib). The median duration of response was 17 mos. V299L was associated with primary resistance in 4 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 5 pts were in chronic (CP), 7 in accelerated (AP), and 3 in blast phase (BP). 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 in CPresponded (major molecular response sustained for 40+ mos). One pt received INNO406 and did not respond. One pt in BP was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 23 mos (range, 3–48 mos), from the time V299L was detected, 8 died (4 CP and 4 BP). In conclusion, V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation if treated in chronic phase, but more data is need to evaluate the long-term benefit of this approach. Disclosures: Jabbour: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

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Chronic Myeloid Leukemia in Chronic Phase: Survival in the Era of Tyrosine Kinase Inhibitors Is Similar to That of the General Population in All Age Groups

Blood ◽

10.1182/blood.v124.21.1801.1801 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1801-1801

Author(s):

Koji Sasaki ◽

Sara S. Strom ◽

Susan O'Brien ◽

Elias Jabbour ◽

Farhad Ravandi ◽

...

Keyword(s):

General Population ◽

Kinase Inhibitors ◽

Age Groups ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Age Group ◽

Newly Diagnosed ◽

Free Survival ◽

Best Response

Abstract Introduction Tyrosine kinase inhibitors (TKIs) are effective treatments for chronic myeloid leukemia in chronic phase (CML-CP) in terms of response rates and clinical outcomes including overall survival (OS). The purpose of this study was to compare OS in each age group with newly diagnosed CML-CP compared to that of general population in the same age group in the era of multiple TKIs. Methods Response and survival data for 483 patients (pts) with newly diagnosed CML-CP who enrolled in five consecutive or parallel prospective clinical trials of imatinib at a dose of 400 mg or 800 mg daily, imatinib at a dose of 800 mg with pegylated interferon, dasatinib, or nilotinib were analyzed. The pts were divided into groups by age at diagnosis, as follows: 15-45 years; 45-65 years; 65-85 years; over 65 years. All pts, regardless of age, were divided into the following response groups within 1 year of treatment: complete cytogenetic response (CCyR); major molecular response (MMR); MR4.5 defined as more than or equal to 4.5 log reduction of BCR-ABL on the international scale; or complete molecular response (CMR). Pts also were assessed for OS, event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). OS was dated from the start of therapy until death from any cause at any time. EFS was calculated from the start of therapy to loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated (AP) or blast phase (BP), or death from any cause during study therapy. TFS was calculated from the start of therapy to transformation to AP or BP, or death during study therapy. FFS was calculated from the start of imatinib, dasatinib or nilotinib to an event (as defined above), discontinuation for any reason, or death. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test was used for univariate comparisons. Pvalues of less than 0.05 were considered statistically significant. Five-year relative survival rates were calculated from the five-year absolute OS divided by the estimated five-year OS in the general population. Estimated OS rates in the U.S. general population were obtained from national vital statistics reports for the year 2009. Results Of the 483 pts analyzed in the study, 271 were treated with imatinib, 101 with nilotinib, and 111 with dasatinib. The age breakdown was as follows: 15-45 years, 197 pts; 45-65 years, 222 pts; 65-85 years, 64 pts; over 65 years, 64 pts. No pts older than 85 years were enrolled in this study. Sokal risk score at diagnosis, and type of TKI treatment were analyzed by age group, cumulative best response, and five-year OS, EFS, TFS, and FFS, and the results are summarized in Table 1. Five-year OS in the general population, relative five-year OS in all age groups, and relative five-year OS by response group are also described in Table 1. As expected, 5-year OS decreased with increasing age groups, but for all age groups OS was similar to 5-year OS in the corresponding age group in the general population. 5-year OS in pts of ages 15-85 who achieved CCyR or better was similar to that in the general population. Conclusion In the era of TKIs, the OS rates in pts with newly diagnosed CML-CP in all age groups are only slightly lower to that of general population. However, the OS rates in pts who achieved CCyR or better within 1 year of treatment is similar to that of general population. Table 1. Patient Characteristics and Outcomes by Age Group Age 15-45 [n= 197] No. (%) Age 45-65 [n= 222] No. (%) Age 65-85 [n= 64] No. (%) P Sokal Risk Score .419 Low 129 (65) 158 (71) 48 (75) Intermediate 56 (28) 48 (22) 12 (19) High 12 (6) 16 (7) 4 (6) Type of TKIs .364 Imatinib 113 (57) 116 (52) 42 (66) Nilotinib 42 (21) 50 (23) 9 (14) Dasatinib 42 (21) 56 (25) 13 (20) Cumulative Best Response CMR 91 (46) 124 (56) 33 (52) .142 MR4.5 127 (64) 158 (71) 47 (73) .230 MMR 162 (82) 197 (89) 54 (84) .162 CCyR 171 (87) 208 (94) 59 (92) .048 5-y Outcome (%) FFS 77.9 74.5 60.6 .043 TFS 93.8 93.4 87.4 .224 EFS 81.0 89.2 78.9 .094 OS 96.2 93.5 80.1 < .001 5-y Absolute OS 5-y Relative OS 5-y OS in General Population Age Group (%) Ages 15-45 96.2 96.9 99.3 Ages 45-65 93.5 97.1 96.3 Ages 65-85 80.1 97.1 82.5 Ages 15-85 92.7 98.2 94.4 Ages 15-85 by Response (%) CCyR within 1 year 97.3 103.1 94.4 MMR within 1 year 97.9 103.7 94.4 MR4.5 within 1 year 97.1 102.9 94.4 CMR within 1 year 96.7 102.4 94.4 Disclosures Jabbour: Ariad, Novartis, BMS, Pfizer, and Teva : Consultancy. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.

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Outcome of Patients (pts) with Chronic Myeloid Leukemia (CML) After Failure to 2nd and 3rd Tyrosine Kinase Inhibitors (TKIs)

Blood ◽

10.1182/blood.v116.21.1238.1238 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1238-1238

Author(s):

Liunan Li ◽

Hagop Kantarjian ◽

Meng Zhao ◽

Susan O'Brien, MD ◽

Elias Jabbour ◽

...

Keyword(s):

Tyrosine Kinase ◽

Patient Population ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Cytogenetic Response ◽

Kinase Domain ◽

Abl Kinase ◽

Kinase Domain Mutations ◽

Lost To Follow Up

Abstract Abstract 1238 Background: First and second generation tyrosine kinase inhibitors are effective for most pts with CML in chronic phase. Approximately 80% of pts achieve complete cytogenetic response (CCyR) with imatinib, but nearly 15% of them eventually lose response. With dasatinib, nilotinib or bosutinib, approximately 50% of those who failed imatinib achieve CCyR, and about 15% of them eventually lose response. Using one of these agents after failure to 2 prior TKIs results in CCyR in only about 20%, usually of short duration. Thus, some pts receive and fail therapy with 3rd TKI. No standard therapy is available for these pts. Although their outcome is presumed to be poor, this has not been systematically analyzed. Understanding their outcome is important since new investigational options are being developed to treat this patient population, and understanding their expected outcome is needed to better comprehend the results obtained. Aim: To analyze the outcome of patients who have received and failed 2nd and 3rd TKI. Methods: We reviewed the records of 64 CML pts treated at MD Anderson Cancer Center from 2005–2009 who received treatment with 3 sequential TKIs. The second TKI was bafetinib (INNO-406, 1pt), bosutinib (12 pts), dasatinib (13 pts), and nilotinib (38 pts). Upon failure to 2nd TKI, 27 pts were in chronic (CP), 20 pts in accelerated (AP), 14 pts in blast phase (BP), and 3 pts in 2nd chronic phase, and were started on a 3rd TKI: bafetinib (6 pts), bosutinib (12 pts), dasatinib (35 pts), and nilotinib (11 pts). Results: After a median follow-up of 36 months (mo) (range, 3 – 71), 14 (22%) pts were still on 3rd TKI, including nilotinib (4 pts), dasatinib (7 pts), bafetinib (1 pt), and bosutinib (2 pts). Fifty (78%) pts failed therapy, including 16 pts (1 in 2nd CP, 2 in CP, 4 in AP, and 9 in BP) died during therapy with 3rd TKI. Among the 34 pts alive after 3rd TKI failure, their median age was 59 years (range, 19 to 92), and 17 were female. Their median time from diagnosis of CML was 76 mo (22 to 241). They failed the 3rd TKI after a median of 5.8 mo (range, 0.3 to 45) on therapy, with 27 pts being resistant (1 had minor cytogenetic response, all others 100% Ph+) and 7 pts were intolerant to 3rd TKI. The best response to a 3rd TKI was 1 partial cytogenetic (PCyR), 1 minor and 1 minimal cytogenetic response, 7 complete hematologic responses (CHR), and 24 with no response (NR). Upon failure to 3rd TKI, 16 pts were in CP (4 with BCR-ABL kinase domain mutations including two F359V, and one Y253H and one F317L), 11 in AP (6 with BCR-ABL kinase domain mutations including two G250E, and one each for F317L, F359C, T315I, and F317L), and 7 in BP (3 pts with BCR-ABL kinase domain mutations, two T315I and one V299L). These stages at the end of 3rd TKI represented no stage change in 26 patients, a progression in 5 pts (3 from CP to AP, 1 from CP to BP, 1 from AP to BP), and an improvement in 3 (from AP to CP in 2, from BP to AP in 1). Of those in CP, 16 pts were in complete hematologic responses (CHR). The median Ph+ metaphase after failure to 3rd TKI was 94% (8 to 100). After failure to 3rd TKI, 4 pts received dasatinib, 5 nilotinib, 4 bafetinib, 2 AP24534, 3 omacetaxine + imatinib, 6 single-agent omacetaxine, 4 stem cell transplantation, and 1 each for MK-0457, hydroxyurea, vincristine + deaxmethasone, idarubicin + imatinib + Ara-C, and DCC-2036. One pt was lost to follow-up. Response to subsequent therapy is described in the table 1 . After a median follow-up of 4 mo since failure to 3rd TKI, 15 of 34 pts have died, including 4 of 16 in CP, 5 of 11 in AP, and 6 of 7 in BP. The median survival from failure to 3rd TKI was 25 mo (12 mo for pts in CP, 6 in AP, and 1 in BP). Among patients who are still alive, 12 pts are still receiving the 4th therapy which were 3 pts received nilotinib, 2 dasatinib, 2 homoharringtonine, 2 AP245341, 1 bafetinib, 1 DCC-2036, and 1 hydroxyurea since failure to 3rd TKI, and 6 pts have changed to subsequent therapies after 4th therapy, including 5 pts on AP24534, 1 pt on XL228, and one lost to follow-up. Conclusions: Patients who have failed therapy with 2nd and 3rd TKI have a very poor prognosis with rare responses and a very short expected survival. New therapies that may improve their outcome and prolong their survival are urgently needed for this patient population. Disclosures: No relevant conflicts of interest to declare.

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Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) Surviving More Than 5 Years (yrs) after Initial Therapy with TKIs

Blood ◽

10.1182/blood-2018-99-119995 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5442-5442

Author(s):

Eran Tallis ◽

Hagop M. Kantarjian ◽

Catherine Kendall Major ◽

Maria Vazquez ◽

Gautam Borthakur ◽

...

Keyword(s):

Research Funding ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Cytogenetic Response ◽

Initial Therapy ◽

Treatment Discontinuation ◽

Molecular Response ◽

Equal Distribution ◽

Genetics Research

Abstract Background: The introduction of tyrosine kinase inhibitors (TKIs) as the first line of treatment for CP-CML changed the natural history of the disease. The life expectancy of CML pts is now approaching that of the general population, with more pts having the option to discontinue treatments after achieving deep molecular response (DMR). In this study we sought to explore long-term outcomes of CML survivors including late relapses, durability of response, comorbidities, and feasibility of treatment discontinuation. Methods: We performed a chart review of pts with CP CML treated at our institution with frontline TKIs who have survived at least 5 yrs from initiation of their treatment. Results: We analyzed 388 pts treated with frontline TKIs between the years 2000-2011: 57% started treatment with imatinib, 22% with nilotinib and 21% with dasatinib. We grouped pts into two cohorts: those who received only one TKI throughout the entire follow up period (n= 299; 77%) and those who changed TKIs due to relapse or toxicity (n=89; 23%). The median follow up duration was 12 yrs [5-19] for both groups. Median overall Survival (OS) for pts surviving at least 5 yrs was not reached for those remaining on one TKI whereas OS for those who changed TKIs was 151 mo (p=0.27). For those who changed therapy, there was an equal distribution of initial TKI (p=0.67). Seventy patients (18%) required a change in TKI more than 5 years after starting treatment. After 5 years of treatment best response was MR4.5 in 66%, major molecular response (MMR) in 20%, complete cytogenetic response (CCyR) in 8%, partial cytogenetic response (PCyR) in 1%, and complete hematologic response (CHR) in 3%. Nine patients had lost CHR (2%) and 4 had progressed to blast phase before the 5 yr mark. At last follow up, 77% of patients had achieved MR4.5, 12% MMR, 3% CCyR, 1% PCyR, and 4% CHR. Eleven patients lost CHR (3%) with 6 patients progressing into blastic phase. Ninety two percent of patients with MR4.5 at 5 years of treatment maintained their response, and 8% lost MR4.5: 6% to MMR, 1% to CCyR, and 1% to CHR. Sixty six percent of patients with MMR at 5 years of treatment improved their response to MR4.5, 21% maintained MMR and 13% lost response - 5% to CCyR, 5% to CHR, and 3% lost CHR. Fifty five percent of patients in CCyR at 5 years improved their response to MMR (35%) or MR4.5 (19%) while 26% of patients lost cytogenetic response. Out of the patients who improved their response, 29% did so after starting a new TKI. More patients who never changed TKI achieved MR4.5 compared to those who who changed TKIs at some point (70%) (p=0.0021). Treatment discontinuation was considered for pts who sustained MR4.5. Forty nine pts (13%) discontinued TKIs after a median time of 9 yrs [5-17]. Withdrawal symptoms were observed in 24% of pts and primarily included joint or muscle pain. After a median follow up of 2 yrs [0-7] after discontinuation, 90% of pts remained in MR4.5. Five pts (10%) lost MR4.5 after discontinuation: 4 (8%) remained in MMR and 1 (2%) lost MMR to CHR. All these patients resumed therapy except for one who has sustained MMR still with no treatment. Patient's comorbidities were evaluated at initiation of treatment, at 5 yrs of follow up and at last follow up. An increase in patients' comorbidities was more pronounced for HTN and cardiovascular disease reaching up to 47% and 37% of patients at last follow up vs 26% and 13% at baseline respectively. Depression and/or anxiety were seen in 7% of patients at baseline and increased to 20% of patients at last F/U. Secondary malignancies developed in 48 pts (12%), mainly prostate cancer in 11 pts, non-melanoma skin cancer in 10 pts and melanoma in 5 pts. GU and colon cancers were seen in 1% of pts. Conclusion: Survivors of CML have a generally favorable outcome. However late relapses may occur (14% in our series) often requiring a change in treatment. This underscores the need to continued monitoring beyond 5 years. Co-morbidities and second malignancies may also occur in many patients, underscoring the need for a holistic follow-up of these patients. Disclosures Bose: Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding. Ravandi:Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Jazz: Honoraria. Kadia:BMS: Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Pemmaraju:Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; samus: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; daiichi sankyo: Research Funding; plexxikon: Research Funding; novartis: Research Funding; SagerStrong Foundation: Research Funding. Daver:Kiromic: Research Funding; Novartis: Research Funding; Sunesis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Novartis: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy; ImmunoGen: Consultancy; Karyopharm: Research Funding; Otsuka: Consultancy; ARIAD: Research Funding; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Pfizer: Consultancy. DiNardo:Medimmune: Honoraria; Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Agios: Consultancy. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; cellectis: Research Funding; abbvie: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.

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Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

Clinical Management Issues ◽

10.7175/cmi.v4i2s.1072 ◽

2015 ◽

Vol 4 (2S) ◽

pp. 17-20

Author(s):

Mario Annunziata

Keyword(s):

Side Effects ◽

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Chronic Myeloid Leukemia Patient ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

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Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Cancers ◽

10.3390/cancers12092521 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2521

Author(s):

Gabriel Etienne ◽

Stéphanie Dulucq ◽

Fréderic Bauduer ◽

Didier Adiko ◽

François Lifermann ◽

...

Keyword(s):

Kinase Inhibitors ◽

De Novo ◽

Chronic Phase ◽

Risk Scores ◽

Prolonged Treatment ◽

Molecular Response ◽

First Line ◽

Treatment Free Remission ◽

Tki Discontinuation

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

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Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

Blood Advances ◽

10.1182/bloodadvances.2019000268 ◽

2020 ◽

Vol 4 (3) ◽

pp. 530-538 ◽

Cited By ~ 9

Author(s):

Onyee Chan ◽

Chetasi Talati ◽

Leidy Isenalumhe ◽

Samantha Shams ◽

Lisa Nodzon ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Inverse Correlation ◽

Cancer Center ◽

Molecular Response ◽

Starting Dose ◽

Dose Dependent Fashion ◽

Dose Dependent

Abstract Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

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