1. Chronic Myeloid Leukemia: Managing Patients After Failure of TKI Therapy
Elias Jabbour, MD
Associate Professor
Department of Leukemia University of Texas
M. D. Anderson Cancer Center
Houston, Texas
TKI, tyrosine kinase inhibitor.
This program is supported by an educational grant from Teva Pharmaceuticals.

2. Faculty Disclosure
Elias Jabbour, MD, has disclosed that he has received consulting fees from Ariad, Bristol-Myers Squibb, and Pfizer and funds for research support from Ariad, Novartis, Pfizer, and Teva.

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4. CML Survival by Era 1.0 92% 83% 0.8 68% 0.6 Survival Probability 43%
Treatment Era
TKI 2001-today
(CML-related deaths)
(all deaths)
≤ 1982
1.0
92%
83%
0.8
68%
0.6
Survival Probability
43%
0.4
35%
CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
During the past several years, great progress in the treatment of CML has been observed. Today, the expected survival of patients with chronic-phase CML is 25 years or longer after diagnosis, with 90% of patients being alive 10 years after diagnosis.[1] As seen in this slide, survival in these patients has greatly increased with the advent of the TKIs. The focus of this program is the optimal treatment options for CML after progression on 2 previous TKIs, including sequencing of TKIs in second-line and third-line treatment, as well as the non-TKI option of omacetaxine, a first-in-class cetaxine, and SCT.
Reference:
1. Kantarjian H, Cortes J. Chronic myeloid leukemia. In: Kasper D, Fauci AS, Hauser S, et al, editors. Harrison’s principles of internal medicine, 19th edition. New York, NY: The McGraw-Hill Companies; p. 135.
0.2 8% 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Yrs
Slide credit: clinicaloptions.com
Kantarjian H, et al. Harrison’s Principles of Internal Medicine 2014.

5. Current CML Monitoring Recommendations
Establish confirmed CCyR in the first yr (bone marrow biopsy at 6 and 12 mos)
Once CCyR is established (0% Ph+ marrow metaphases)
Monitor BCR-ABL level by FISH and QPCR assays every 6 mos
If MMR observed (BCR-ABL < 0.1%), may continue to monitor with QPCR only (watch for false results)
If QPCR ↑ by log10 and/or MMR lost (BCR-ABL > 0.1%) → monitor more frequently
Perform mutation studies if resistance occurs or there is a need to change TKIs
Change therapy only for loss of CCyR, not based on MMR
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; MMR, major molecular response; Ph+, Philadelphia chromosome positive; QPCR, quantitative polymerase chain reaction; TKI, tyrosine kinase inhibitor.
Monitoring is a key component of CML treatment. In addition to providing the appropriate therapy, we must be sure that the patient is responding to that therapy in a timely manner.[1] Complete hematologic response (CHR)—no palpable splenomegaly, white blood cells < 10 x 109/L, platelets < 450 x 109/L, no circulating immature myeloid cells, < 5% basophils on differential—should be achieved by 3 months. The gold standard in CML treatment is establishing a CCyR in the first year, ideally by 6 months. Patients who achieve CCyR (0% Philadelphia chromosome–positive marrow metaphases measured by quantitative PCR) during the first year have the best potential for long-term OS.
At the start of treatment, we monitor patient BCR-ABL levels every 3 months using both quantitative PCR and FISH. The aim is to have concordance between these results to minimize false positives or false negatives. Once the patient achieves a major molecular response (MMR) with PCR BCR-ABL < 0.1% on an international scale, one might monitor with PCR only.
One issue we face in our practice is that PCR results might fluctuate. Provided the fluctuation is within log10, we do not need to consider further action at that time. It is important to emphasize therapy adherence with the patient and make sure that he/she is taking the medications. Nevertheless, it is recommended to repeat the PCR and monitor the patient closely. Whenever there is an increase of more than 1 log10 and a loss of CCyR, then treatment failure has occurred, and mutational analysis should be performed to determine whether resistant mutations are present. A change of therapy is needed only when there is a loss of CCyR and PCR is > 1%.
Reference:
1. Deininger MW. Diagnosing and managing advanced chronic myeloid leukemia. Am Soc Clin Oncol Educ Book. 2015:e381-e388.
Slide credit: clinicaloptions.com
Deininger M. Hematology Am Soc Hematol Educ Program. 2015:

6. Surveillance for Mutations
Prevalence of BCR-ABL mutations in 1301 pts receiving imatinib or second-generation TKI in GIMEMA trials
TKI Failure
Mutations, %
Overall
No CHR at 3 mos
No CHR at 6 mos
No PCyR at 12 mos
No CCyR at 18 mos
Loss of CCyR
Loss of CHR 27 19 11 17 31 50
Suboptimal Response
Mutations, %
Overall
No CyR at 3 mos
No PCyR at 6 mos
No CCyR at 12 mos
No MMR at 18 mos
Loss of MMR 5 7 8 4
CCyR, complete cytogenetic response; CHR, complete hematologic response; CyR, cytogenetic response; MMR, major molecular response; PCyR, partial cytogenetic response; TKI, tyrosine kinase inhibitor.
Mutations drive resistance in 50% of treatment failures, changing the amino acid sequence of tyrosine kinase in a way that the drug can no longer bind to the protein. That presents the question: When should mutational analysis be performed? The data shown here from the GIMEMA group indicate that mutations occur at a higher rate in patients who have lost CHR or CCyR, defining treatment failure.[1]
In patients with suboptimal response, that is, loss of MMR or failure to achieve MMR, mutations occur at a very low rate. Therefore, mutation testing in this setting is not indicated.
Reference:
1. Soverini S, Gnani A, De Benedittis C, et al. Validation of the new European LeukemiaNet (ELN) recommendations for BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia: an analysis of the GIMEMA CML Working Party studies. Blood. 2011;118. Abstract 112.
Slide credit: clinicaloptions.com
Soverini S, et al. Blood. 2011;118. Abstract 112.

7. Response, PFS With Second-Generation TKIs in Imatinib-Resistant CP-CML
Dasatinib[1,2]
Nilotinib
Bosutinib
Follow-up, yrs
2*[1,2]
6†[3]
2*[4]
4*[5]
2*[6]
Pts, N
167‡
226
321‡
200
Discontinued, n (%) NR
114 (69)
197/321‡ (61)
224 (70)
108 (51)
MCyR, %
63‡ 56
59‡ 58
CCyR, %
50‡ 41
45‡ 46
PFS, %
80‡
49‡
64‡
57‡
81‡
CCyR, complete cytogenetic response; CP-CML, chronic-phase chronic myeloid leukemia; MCyR, major cytogenetic response; NR, not reported; TKI, tyrosine kinase inhibitor.
What are the choices for second-line TKI therapy after frontline imatinib has failed? Today, there are 3 TKIs for second-line therapy in CML approved by the FDA and European regulatory agencies: dasatinib, nilotinib, and bosutinib, with dasatinib and nilotinib also approved for frontline therapy.
As shown in this slide, these 3 TKIs induce responses in up to 50% of cases in this setting, with slightly fewer patients responding to nilotinib[1,2] and bosutinib[3] than dasatinib.[4,5] Once failure of frontline therapy has occurred, responses may not be as durable in second-line therapy as shown here, that is, rates of PFS decrease. Therefore, once a patient progresses on imatinib therapy and starts second-line treatment, monitoring is crucial because up to 50% of patients do not respond or maintain a response.
References:
1. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117:
2. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27:
3. Gambacorti-Passerini C, Brümmendorf TH, Kim DW, et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014;89:
4. Dasatinib [package insert]. Princeton, NJ: Bristol-Myers Squibb; October 2015.
5. Shah NP, Cortes JE, Schiffer CA, et al. Four-year follow-up of patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving 100 mg of dasatinib once daily. J Clin Oncol. 2010;28:15s. Abstract 6512.
*Minimum follow-up.
†Data lock.
‡Includes imatinib-intolerant pts.
1. Dasatinib. [package insert]. October Shah NP, et al. J Clin Oncol. 2010;28:15s. Abstract Shah NP, et al. Blood. 2014;123: Kantarjian HM, et al. Blood. 2011;117: Giles FJ, et al. Leukemia. 2013;27: Gambacorti-Passerini C, et al. Am J Hematol. 2014;89:
Slide credit: clinicaloptions.com

8. Long-term Survival With Dasatinib in Pts With Progression on Imatinib
100 80 60 40 20
OS by Dasatinib Dose After Imatinib Failure 65 73 68 70
OS (%)
100 mg QD
140 mg QD
50 mg BID
70 mg BID 6 12 18 24 30 36 42 48 54 60 66 72 78 84
As seen in this study by Shah and colleagues,[1] OS with dasatinib after imatinib was approximately 70% at 7 years, with 40% maintaining a PFS. This indicates that there are other effective options for a patient who progresses after frontline and/or second-line therapy, with OS with many of these agents superior to what has been shown at this stage with SCT. Therefore, transplantation should be considered but later in the therapy sequence.
Reference:
1. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA Am J Hematol. 2016;91:
Mos
OS, PFS Over 7 Yrs
Imatinib Resistant
Imatinib Intolerant
Overall
OS, % (95% CI)
63 (53-71)
70 (52-82)
65 (56-72)
PFS, % (95% CI)
39 (29-49)
51 (32-67)
42 (33-51)
Slide credit: clinicaloptions.com
Shah NP, et al. Am J Hematol. 2016;91:

9. Predictors of Long-term Outcome to Second-line TKIs in Pts With CML
3-Mo CCyR N
Event, n
3-Mo CCyR N
Deaths, n
Yes No 40 80 12 46
P = .002
Yes No 40 80 3 26
P = .005
1.0
1.0
0.8
0.8
0.6
0.6
Probability EFS
Probability OS
0.4
0.4
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
When considering second-line therapy for CML after frontline TKI failure, one must consider the options: SCT, second-line TKIs, or a drug with a different mode of action, omacetaxine. How do we decide? Our group studied patients on second-line TKI therapy with dasatinib (n = 78) or nilotinib (n = 45) after imatinib failure, and we performed landmark analyses at different time points.[1] We learned that the 3-month response to these agents is crucial. Patients who achieved CCyR by the third month (one third of the patients in our cohort) had the best outcomes: OS at 5 years of approximately 90%, and event-free survival of approximately 80%. However, patients who did not achieve CCyR at 3 months had worse outcomes: OS of 70% and event-free survival of less than 40% at 5 years. This tells us that these patients need additional therapy or transplantation to improve their outcome. The take-away message from this analysis is that we need to closely monitor 3-month progress on second-line therapy and, in those who do not achieve CCyR, at 3 months, with follow-up again at 6 and 12 months. In our study, CCyR was the only factor independently associated with OS and event-free survival. If CCyR is achieved at one of these time points, then there is no need to change treatment. If not, we should consider a third line of therapy.
Reference:
1. Jabbour E, Kantarjian H, Ghanem H, et al. The achievement of a 3-month complete cytogenetic response to second-generation tyrosine kinase inhibitors predicts survival in patients with chronic phase chronic myeloid leukemia after imatinib failure. Clin Lymphoma Myeloma Leuk. 2013;13:
0.2
0.2 12 24 36 48 60 12 24 36 48 60
Mos
Mos
Slide credit: clinicaloptions.com
Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2013;13:

10. Outcomes in Pts Who Progress With Mutation T315I or After ≥ 2 TKIs
OS in Pts With T315I[1]
FFS in Pts With ≥ 2 Prior TKIs[2]
1.0
Log-rank P < .001
1.0
CP CML
AP CML
BP CML
Ph+ ALL CP AP BP
0.8
0.8
0.6
0.6
Probability of OS
Probability of FFS
0.4
0.4
0.2
0.2
ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CP, chronic phase; CML, chronic myeloid leukemia; FFS, failure-free survival; Ph+, Philadelphia chromosome positive; TKI, tyrosine kinase inhibitor.
What outcomes should be expected in patients who have progressed after 2 lines of therapy or acquired a T315I mutation?
As shown in this slide, prognosis for patients who progress after 2 TKIs is driven by stage of CML. For those with chronic-phase CML, event-free survival at 2 years is only 50%. Prognosis is poorer in patients with accelerated or blast phase CML.[1] If disease has progressed to blast phase, patients do poorly regardless of whether T315I is present.[2] In these patients, therapy should be changed when necessary without delay. The next question is: What are the options for third-line therapy? That is the topic for the next area of discussion.
References:
1. Garg RJ, Kantarjian H, O’Brien S, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114:
2. Nicolini FE, Mauro MJ, Martinelli G, et al. Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation. Blood. 2009;114: 12 24 36 48 60 72 6 12 18 24 30 36
Mos
Mos
Pts at Risk, n
CP CML
AP CML
BP CML
Ph+ ALL
1. Nicolini FE, et al. Blood. 2009;114: Garg RJ, et al. Blood. 2009;114:
Slide credit: clinicaloptions.com

11. Omacetaxine for the Treatment of CML After ≥ 2 TKIs or With T315I Mutation
Omacetaxine, first-in-class inhibitor of protein elongation[1]
FDA approved for pts with chronic-phase or accelerated- phase CML who are intolerant or resistant to ≥ 2 TKIs
Potent inhibitory activity against leukemic cells, including T315I+ cells[1]
Activity independent of BCR-ABL binding
Induces apoptosis by inhibiting the antiapoptotic oncoprotein Mcl-1[2]
Inhibits cell growth and induces apoptosis in CD34+ cells[3]
Clinical activity in CML after imatinib failure[4]
CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
If a patient progresses after 2 TKIs, with or without the T315I mutation, there are 3 primary options: ponatinib, omacetaxine, or SCT.
Omacetaxine is a first-in-class cetaxine, an inhibitor of protein elongation,[1] approved for patients with chronic or accelerated CML who progress after treatment with 2 or more TKIs, and it is indicated in NCCN guidelines as an option for patients with CML resistant or intolerant to 2 or more TKIs.[2] Omacetaxine has a different mode of action than TKIs, with activity against leukemic cells, including cells with the T315I mutation[1] and independent of BCR-ABL. The drug is able to induce apoptosis and inhibits cell growth apoptosis in CD34+ cells.[3,4] This means that omacetaxine might be combined with different TKIs to treat and potentially cure these patients.
References:
1. Chen Y, Hu Y, Michaels S, et al. Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia. 2009;23:
2. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: chronic myelogenous leukemia. Available at: Accessed October 19, 2016.
3. Tang R, Faussat AM, Majdak P, et al. Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells. Mol Cancer Ther. 2006;5:
4. Allan EK, Holyoake TL, Craig AR, Jørgensen HG. Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukemia. 2011;25:
1. Chen Y, et al. Leukemia. 2009;23: Tang R, et al. Mol Cancer Ther. 2006;5: Allan EK, et al. Leukemia. 2011;25: Quintas-Cardama A, et al. Cancer. 2007;109:
Slide credit: clinicaloptions.com

12. Response to Omacetaxine in CML Pts With T315I Mutation
Response to Omacetaxine in Pts With CML
Response, % CP
(n = 62) AP
(n = 17) BP
(n = 15)
Hematologic
CHR HI
RCP 77 NA 35 29 18 6 47 20 7 27
Cytogenetic
MCyR
CCyR
Minor 44 23 16 21 --
Median survival, mos NR 19 2
AP, accelerated phase; BP, blast phase; CCyR, complete cytogenetic response; CHP, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; HI, hematologic improvement; MCyR, major cytogenetic response; RCP, return to chronic phase.
Based on in vitro studies, clinical phase I and II studies were launched in patients who had progressed on multiple TKIs and those who acquired the T315I mutation.
At the time of this phase II study,[1] there were no TKIs that were active in the presence of T315I mutation. Therefore, omacetaxine alone was assessed in 94 patients with CML and the T315I mutation. Patients were treated with omacetaxine 1.25 mg/m2 SC BID for 14 days, as induction. Those who responded received the maintenance dose, 1.25 mg/m2 BID, for 7 days in the 28-day cycle. In the treated population, approximately 25% had progressed after 1 TKI and acquired T315I mutation, almost 50% progressed after 2 TKIs, and an additional 25% progressed after 3 or more TKIs.
Among patients with chronic-phase CML, 77% had a CHR, and 44% achieved a cytogenetic response (CCyR in 16%). This is a good response in those with progression after multiple TKIs. Good activity was seen as well in patients with advanced-stage disease, although at lower rates. In accelerated-phase disease, only 6% (1/17 patients) achieved CCyR. Most patients were in the chronic phase, and omacetaxine may be a good option to consider in this scenario. The median survival for patient with chronic-phase disease was not reached: At 2 years, 68% of patients in the chronic phase were still alive vs second-line TKI therapy where survival is 70% at 2 years in patients without CCyR at 3 months.
Reference:
1. Cortes J, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012;120:
Cortes J, et al. Blood. 2012;120:
Slide credit: clinicaloptions.com

13. Omacetaxine for CML After Failure of ≥ 2 TKIs
Response to Omacetaxine Treatment in Pts With CML CP
(n = 76) AP
(n = 35)
Median DoR, mos
Median cycles, n (range)
Median duration of exposure, mos
12.5
6 (1-58) 8 5
2 (1-29) 2
Primary endpoint responses, %
MCyR: 18
CCyR: 8
MaHR: 14
CHR: 11
Median PFS, mos
9.6
3.6
Median OS, mos
40.3
14.3
Ongoing response, n 6 1
AP, accelerated phase; CP, chronic phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; DoR, duration of response; MaHR, major hematologic response; MCyR, major cytogenetic response; TKIs, tyrosine kinase inhibitors.
This slide shows the data from the regulatory trial of omacetaxine of all patients who progressed after 2 or more TKIs.[1] This study was the final 24-month analysis of 111 evaluable patients—76 with chronic-phase disease and 35 in the accelerated phase. As a reminder, the dose was omacetaxine 1.25 mg/m2 SC BID for 14 days as induction and then 1.25 mg/m2 BID for 7 days in each 28-day cycle. The median number of cycles was 6 in patients with chronic-phase disease and 2 in those with accelerated-phase disease. Median exposure duration for those in chronic phase was 8 months.
The primary endpoint for patients in chronic phase was major cytogenetic response (MCyR), achieved by 18% with a CCyR achieved by 8%. In patients with accelerated-phase disease, 14% achieved the primary endpoint of major hematologic response and 11% achieved a CHR. The rate of response among those who had progressed after 2 or more TKIs was 12.5%. Median OS for those in the chronic phase was 40 months and 14 months for those in the accelerated phase. At the time of this report, 7 patients had an ongoing response, including 1 with accelerated phase disease.
Reference:
1. Cortes JE, Kantarjian HM, Rea D, et al. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015;121:
Slide credit: clinicaloptions.com
Cortes J, et al. Cancer. 2015;121:

14. Hematologic AEs With Omacetaxine Treatment
AEs, % (> 5% pts)
CP (n = 81)
AP (n = 41)
Any Grade
Grade ≥ 3
Thrombocytopenia 77 67 61 51
Anemia 64 40 54 39
Neutropenia 52 48 24 22
Leukopenia 26 12 7
Lymphopenia 17 16 2
Febrile neutropenia 14 15 10
Bone marrow failure 11
Pancytopenia 9 5
Leukocytosis 6 1
AE, adverse event; AP, accelerated phase; CP, chronic phase.
The safety profile of omacetaxine observed in this trial is consistent with that observed in earlier studies.[1.2] As seen in this slide, hematologic events were the most common events grade ≥ 3, particularly thrombocytopenia, anemia, and neutropenia, usually in the first 3 cycles. Complete blood counts should be performed weekly during induction and early maintenance cycles, and next cycle should be delayed as needed.[3]
Diarrhea, nausea, fatigue, and infections were the most common nonhematologic adverse events, with infections the most common grade ≥ 3 adverse event (chronic phase: 12%; accelerated phase: 27%).[4]
References:
1. Cortes JE, Nicolini FE, Wetzler M, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk. 2013;13:
2. Nicolini FE, Khoury HJ, Akard L, et al. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013;98:e78-79.
3. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: chronic myelogenous leukemia. Available at: Accessed October 19, 2016.
4. Cortes JE, Kantarjian HM, Rea D, et al. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015;121:
Slide credit: clinicaloptions.com
Cortes J, et al. Cancer. 2015;121:

15. DoR and Overall OS With Omacetaxine in Pts With CML
DoR in CP CML Pts (n = 81)
OS in CP and AP CML Pts
1.0
CP (n = 81)
AP (n = 41)
CHR
MCyR
0.8 25 22
CCyR 20
0.6 15
Probability of Survival
Pts (n) 11 10
0.4 10 8 5 5 5 4 4 3 2
0.2 2
AP, accelerated phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; DoR, duration of response; MCyR, major cytogenetic response.
This slide demonstrates the duration of response in patients with chronic-phase CML and OS in the full study population.[1] Patients had a durable response with CHR, with duration extending beyond 18 months in some cases. Median OS for patients is approximately 34 months but only 16 months for those with accelerated-stage disease. Five patients—all in chronic phase—discontinued omacetaxine therapy after being scheduled for SCT. For these, omacetaxine was a bridge to get them to transplantation.
Reference:
1. Cortes J. Subcutaneous omacetaxine mepesuccinate in chronic or accelerated chronic myeloid leukemia resistant to two or more tyrosine kinase inhibitors including imatinib. Program and abstracts from the ESH-iCMLf International Conference Chronic Myeloid Leukemia: Biology and Therapy; September 20-23, 2012; Baltimore, Maryland. 2 1 1
< 3
3-5
6-11
12-17
≥ 18
Mos 4 8 12 16 20 24 28 32 36 40
Mos
Slide credit: clinicaloptions.com
Cortes J, et al. ESH-iCMLf

16. OS in CP CML Pts With/Without Major Cytogenetic Response With Omacetaxine
1.0
0.8
0.6
Probability of OS
0.4
Responder
Nonresponder n 16 65
Events, n 2 28
Median OS, Mos NR
27.8
0.2
CML, chronic myeloid leukemia; CP, chronic phase; NR, not reached.
This slide depicts data on OS among patients with chronic-phase disease who had achieved an MCyR.[1] An MCyR included a CR or PR, which is either confirmed or unconfirmed. An event was defined as death from any cause. Approximately 80% of those who responded were alive at 40 months; median survival had not yet been reached. Among those without an MCyR, median survival is approximately 28 months.
Reference:
1. Cortes J. Subcutaneous omacetaxine mepesuccinate in chronic or accelerated chronic myeloid leukemia resistant to two or more tyrosine kinase inhibitors including imatinib. Program and abstracts from the ESH-iCMLf International Conference Chronic Myeloid Leukemia: Biology and Therapy; September 20-23, 2012; Baltimore, Maryland. 4 8 12 16 20 24 28 32 36 40
Mos 16 65 56 51 14 38 13 30 10 24 8 17 6 12 3 7 1 4 2
Responder
Nonresponder
Slide credit: clinicaloptions.com
Cortes J, et al. ESH-iCMLf

17. OS in CP CML Pts With/Without Major Hematologic Response With Omacetaxine
1.0
0.8
0.6
Probability of OS
0.4
Responder
Nonresponder n 56 25
Events, n 16 14
Median OS, Mos NR
20.3
0.2
CML, chronic myeloid leukemia; CP, chronic phase; NR, not reached.
This slide depicts OS for patients with chronic-phase disease by hematologic response.[1] Among those with major hematologic response, median survival has not yet been reached. Among those who did not have a major hematologic response, median survival is approximately 20 months.
How do we translate these results to practice? In my practice, if I have a patient who has progressed after 2 TKIs, do I suggest a SCT? Based on these data, if the patient in the chronic phase has an MCyR on omacetaxine, I may defer SCT. Among those who do not respond, I suggest going directly to SCT.
Reference:
1. Cortes J. Subcutaneous omacetaxine mepesuccinate in chronic or accelerated chronic myeloid leukemia resistant to two or more tyrosine kinase inhibitors including imatinib. Program and abstracts from the ESH-iCMLf International Conference Chronic Myeloid Leukemia: Biology and Therapy; September 20-23, 2012; Baltimore, Maryland. 4 8 12 16 20 24 28 32 36 40
Mos 56 25 55 17 54 13 42 10 35 8 27 7 20 5 16 2 8 2 4 1 3
Responder
Nonresponder
Slide credit: clinicaloptions.com
Cortes J, et al. ESH-iCMLf

18. Bosutinib: Response in Third-line Therapy
Response to Third-line Bosutinib in Pts With CML
Response, %
IM + D Resistant
(n = 38)
IM + D Intolerant
(n = 50)
IM + N Resistant
(n = 26)
CHR 68 76
MCyR
CCyR
PCyR 39 22 17 42 40 2 38 31 1
Probability of 4-yr sustained MCyR* 43 87 78
D/c due to AEs 21 44 12
PD/death at 4 yrs 24 16 35
AE, adverse events; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; D, dasatinib; D/c, discontinuation; IM, imatinib; MCyR, major cytogenetic response; N, nilotinib; PCyR, partial cytogenetic response; PD, progressive disease.
Bosutinib is a Src BCR-ABL inhibitor that does not inhibit c-KIT or PDGFR and, therefore, does not cause severe myelosuppression or pleural effusion. These data are from a 48-month update of an open-label phase I/II study of 119 patients with CML and progression after imatinib plus either dasatinib or nilotinib.[1] Progression was defined by either resistance or intolerance.
Among patients with resistance to 2 TKIs, the likelihood of achieving a CCyR is approximately 22% with previous dasatinib failure and 31% with previous nilotinib failure. MCyR responses were similar, at 39% with dasatinib and 38% with nilotinib; 43% and 78% of patients, respectively, maintained MCyR responses at 4 years. Among patients with intolerance to TKI therapy, rather than resistance, the level of response is higher. Bosutinib is today approved for second line and third line and is being tested as frontline TKI therapy.
Reference:
1. Gambacorti-Passerini C, Khoury HJ, Kantarjian HM, et al. Bosutinib as third-line therapy in patients (Pts) with chronic phase chronic myeloid leukemia (CP CML) following failure with imatinib plus dasatinib and/or nilotinib: 48-month update of a phase 1/2 study. Blood. 2014;124. Abstract 4559.
*Based on Kaplan-Meier estimates.
Gambacorti-Passerini C, et al. Blood. 2014;124. Abstract 4559.
Slide credit: clinicaloptions.com

19. Response to Ponatinib in Pts With CML Median Time to Response, Mos
PACE: Response to Ponatinib in Phase II Study of Pts With CML Resistant to ≥ 1 TKI
Response to Ponatinib in Pts With CML
Response
Resistant/
Intolerant
T315I
Total
Median Time to Response, Mos
CP CML, n
MCyR, %
CCyR, %
MMR, %
MR, %
203 56 48 31 19 64 72 70 58 34
267 60 54 38 22
2.8
5.5 NR
AP CML, n
MaHR, % 65 62 18 61 83
0.7
BP CML, n 32 24 29
1.0
Ph+ ALL, n 10 50 36 41
ALL acute lymphocytic leukemia; AP, accelerated phase; BP, blast phase; CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CP, chronic phase; MaHR, major hematologic response; MCyR, major cytogenetic response; MMR, major molecular response; MR, molecular response; Ph+, Philadelphia chromosome positive; TKI, tyrosine kinase inhibitor.
Ponatinib is a BCR-ABL inhibitor shown in in vitro studies to be very potent, inhibiting CML cell growth, and it is active in patients with the T315I mutation. The phase II PACE trial included chronic-phase and advanced-stage disease patients who had progressed after multiple TKIs.[1] These were highly experienced patients; 58% had received 3 or more TKIs.
Among those with chronic-phase disease with or without T315I mutation, the likelihood of achieving CCyR was 54%. In patients who had this mutation, the likelihood of having CCyR was higher—70%—and this was due to the shorter exposure to other TKIs. Response occurred rapidly—median time to CCyR was 2.8 months. A similar response occurred in advanced-stage disease as well, although at a lower rate and with less durable response.
Reference:
1. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood. 2014;124. Abstract 3135.
Cortes J, et al. Blood. 2014;124. Abstract Kantarjian HM, et al. J Clin Oncol. 2014;32(5suppl). Abstract 7081.
Slide credit: clinicaloptions.com

20. PACE: Efficacy of Ponatinib in CP CML
Responses at Any Time
Duration of Response
Probability of Continued Response (%)
Total (N = 267)
R/I (n = 203)
100
T315I (n = 64)
100 80 80 72 70 60
Total
R/I
T315I n
148
103 45
Lost MCyR, n 20 16 4
Pts (%) 59 58 60 55 53 48 40 39 41 40 33 34 27 20 23 22 19 20
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CP, chronic phase; MCyR, major cytogenetic response; MMR, major molecular response; MR, molecular response; R/I, resistant/intolerant.
This slide demonstrates the sustainability of the responses observed with ponatinib.[1] Among the total population, MCyR occurred in 59% of patients and CCyR in 50%. In this setting, highly experienced patients obtained deeper molecular responses: 39% with a MMR, and MR4 and MR4.5 were seen with 27% and 22% of patients, respectively. These were durable responses; at 4 years, large majorities have maintained their responses, including those with the T315I mutation.
Why are these data relevant? These data show that in patients with chronic-phase CML who respond to ponatinib, there is a high likelihood that they will maintain their response. Therefore, in these patients, transplantation should be reserved for a later line of progression.
Reference:
1. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood. 2014;124. Abstract 3135. 12 24 36 48 60
MCyR
CCyR
MMR
MR4
MR4.5
Mos After First MCyR
33% achieved MMR or better
83% estimated to maintain MCyR at 36 mos
Slide credit: clinicaloptions.com
Cortes J, et al. Blood. 2014;124. Abstract 3135.

21. Outcomes With Ponatinib in Pts With CP CML Without T315I
Impact of low-level mutations present after imatinib resistance on treatment response to ponatinib investigated in 363 TKI-resistant pts
n = 231 pts with CP CML
PFS
FFS
No mutations, n = 112
1 mutation, n = 39
≥ 1 mutations, n = 17
1.0
P = .58
1.0
P = .71
0.8
0.8
0.6
0.6
Probability PFS
Probability FFS
CML, chronic myeloid leukemia; CP, chronic phase; FFS, failure-free survival.
Ponatinib has been shown to be effective against all known mutations and is effective in patients with multiple mutations who generally have poor outcomes and progress rapidly. This slide shows the data based on mutations other than T315I in 363 patients with imatinib resistance.[1] These data show that even in those with a compound mutational pattern (compound mutations without T315I mutation), both PFS and failure-free survival are similar to those with no mutations.
Reference:
1. Parker WT, Yeung DT, Yeoman AL, et al. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood. 2016;127:
0.4
0.4
0.2
0.2 6 12 18 24 30 36 6 12 18 24 30 36
Mos After Commencing Ponatinib
Mos After Commencing Ponatinib
Slide credit: clinicaloptions.com
Parker WT, et al. Blood. 2016;127:

22. Comparative Efficacy of Third-line TKI Therapy for Achieving CCyR
Comparison of third-line TKIs after failure of imatinib and dasatinib or nilotinib (treatment-specific probabilities with 95% CI range)
Post Imatinib and Dasatinib
Post Imatinib and Nilotinib
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Ponatinib
Ponatinib
0.67
0.54
Bosutinib
Dasatinib
Probabilities for CCyR by Treatment
Nilotinib
Bosutinib
0.27
0.26
0.25
0.2
CCyR, complete cytogenetic response; TKI, tyrosine kinase inhibitor.
Lipton and colleagues[1] performed a meta-analysis of efficacy trials of TKIs in third-line therapy, comparing ponatinib, nilotinib, bosutinib, and dasatinib, either after first-line and second-line therapy with imatinib and dasatinib or imatinib and nilotinib. Ponatinib was superior in this setting compared with other TKIs. Therefore, among TKIs, ponatinib should be the choice of therapy in third line, particularly in those with low risk of vascular events.
Reference:
1. Lipton JH, Chuah C, Guerci-Bresler A, et al. EPIC: a phase 3 trial of ponatinib compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2014;124. Abstract 519.
Bosutinib
Khoury 2012, n = 87
Nilotinib
Giles 2010, n = 37
Nicolini 2009,
n = 218
Garg 2009, n = 9
Ponatinib
Cortes 2012,
n = 16
Cortes 2013,
n = 52
Bosutinib
Khoury 2012, n = 27
Dasatinib
Quintas-Cardama
2007, n = 4
Garg 2009, n = 16
Ponatinib
Cortes 2012, n = 3
Cortes 2013, n = 33
Lipton JH, et al. Leuk Res. 2015;39: Lipton JH, et al. Blood. 2014;124. Abstract 4551.
Slide credit: clinicaloptions.com

23. Arteriothrombotic Events in Trials of TKIs
Rate of Arteriothrombotic Events
Trial, % of Pts
Imatinib
Other TKI
ENESTnd[1] 3
10-16
DASISION[2] 2 5
EPIC[3] 7
PACE[4] -- 27
TKI, tyrosine kinase inhibitor.
Thrombotic events are the most serious adverse event seen with TKIs and have been documented in all TKI clinical trials. The risk is higher with ponatinib and nilotinib than with the other TKIs. In the PACE trial of ponatinib, for example, 27% of patients had grade 3 or 4 vascular events.[1] In the ENESTnd trial, 10.0% of patients receiving nilotinib 300 mg BID and 16.0% receiving nilotinib 400 mg BID had vascular events vs 2.5% on the imatinib arm.[2] When considering the use of TKIs, one must include risk factors such as diabetes and hypertension, and patients should be monitored very carefully.
References:
1. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood. 2014;124. Abstract 3135.
2. Larson RA, Kim D-W, Issaragrilsil S, et al. Efficacy and safety of nilotinib (NIL) vs imatinib (IM) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): long-term follow-up (f/u) of ENESTnd. Blood. 2014;124. Abstract 4541.
1. Larson RA, et al. Blood. 2014;124. Abstract Cortes JE, et al. Blood. 2014;124. Abstract Lipton J, et al. Blood. 2014;124. Abstract Cortes JE, et al. Blood. 2014;124:Abstract 3135.
Slide credit: clinicaloptions.com

24. Risk Factors for Arteriovascular Events With Ponatinib
Risk Factors for Arteriovascular Events From Full Multivariate Analysis
Covariate
Odds Ratio
P Value
Dose intensity
1.71
< .001
History of ischemic disease
2.64
Age at study entry
1.63
Time from diagnosis to first dose
1.58
< .05
Dorer and colleagues[1] investigated the risk factors for arteriovascular events in patients receiving ponatinib in phase I, II, and III trials. In a multifactorial analysis, they determined that dose intensity, history of ischemic disease, age, and time from first diagnosis were significantly associated with risk of a vascular event. For these patients, one should consider an alternative treatment, such as omacetaxine. Another possibility is to reduce the dose of ponatinib. Each 15-mg reduction lessens the risk of vascular event; I would recommend using 30 mg or even 15 mg in patients at risk.
Reference:
1. Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84-91.
Slide credit: clinicaloptions.com
Dorer J, et al. Leuk Res. 2016;48:84-91.

25. Impact of Prospective Dose Reductions of Ponatinib on Outcomes and ATEs
44% of pts underwent dose reductions
The majority who underwent dose reductions maintained their response after 1 yr
95% of pts in MCyR
94% of pts in MMR
Similar maintenance of response was seen in pts without dose reductions
Of 70 pts without earlier ATEs, 7% had a new ATE following dose reduction vs 10% of pts without a dose reduction
ATE, arteriothrombotic event; MCyR, major cytogenetic response; MMR, major molecular response.
In the PACE study, investigators assessed the effect of dose reduction of ponatinib on its efficacy.[1] Among the 44% of patients who had their dose reduced, the majority maintained response to the drug at 1 year.
All TKIs have a risk of vascular adverse events, requiring caution when considering treatment in patients, particularly those with previous cardiovascular risk factors. Of 70 patients without earlier arterial thromboembolic events (ATEs), 7% had a new ATE following dose reduction vs 10% of patients without a dose reduction. Therefore, if I have a patient with a previous vascular event who progressed after multiple TKIs, and the choices are omacetaxine or ponatinib, omacetaxine may be the safer option.
Reference:
1. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood. 2014;124. Abstract 3135.
Slide credit: clinicaloptions.com
Cortes J, et al. Blood. 2014;124. Abstract 3135.

26. OS With TKI After Imatinib Failure or With SCT
Dasatinib[2]
100
SCT[1] 80 60
100
100 mg QD
140 mg QD
50 mg BID
70 mg BID
70% to 77%
OS (%)
FFS 40 20
Score 0 or 1 (n = 634) 75
Score 2 (n = 881) 12 24 36 48 60 72
OS (%)
Score 3 (n = 867)
Mos 50
Score 4 (n = 485)
Nilotinib[3]
100 25
Score 5-7 (n = 275) 80
FFS, failure-free survival; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor.
With alternative options for later lines of therapy in patients with CML who have progressed on multiple TKIs, when is SCT appropriate? At 2 years with nilotinib or dasatinib, survival is approximately 90%, and at 5 or 6 years, it is still at least 75%.[1,2] Therefore, in my practice, I will not recommend transplantation in second line or even third line. I would try other options discussed earlier—either ponatinib or omacetaxine—before I would recommend transplantation.
References:
1. Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014;123:
2. Kantarjian H, Giles F, Bhalla K, et al. Update on imatinib-resistant chronic myeloid leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24 months: clinical response, safety, and long-term outcomes. Blood. 2009;114. Abstract 1129.
87% at 24 mos 60
OS (%) 40 12 24 36 48 60 72 84
Mos 20 3 6 9 12 15 18 21 24 27 30 33 36
1. Gratwohl A, et al. Lancet. 1998;352:
2. Shah NP, et al. Blood. 2014;123:
3. Kantarjian H, et al. Blood. 2009;114. Abstract 1129.
Mos
Slide credit: clinicaloptions.com

27. M. D. Anderson Cancer Center: Outcomes With Allogeneic SCT After TKI Failure
EFS OS CP
Adv P
Total, n
Events, n 16 31 7 18 CP
Adv P
Total, n
Events, n 16 31 4 12
1.0
1.0
P = .027
P = .030
0.8
0.8
0.6
0.6
Probability of EFS
Probability of OS
0.4
0.4
Adv P, advanced phase (accelerated phase or blast phase); CP, chronic phase; EFS, event-free survival; SCT, stem cell transplant; TKI, tyrosine kinase inhibitor.
These are data from the University of Texas M. D. Anderson Cancer Center depicting outcomes after allogeneic SCT in patients with CML after progression with multiple TKIs.[1] In our center, SCT can lead to 4-year survival in approximately 70% of patients with chronic-phase disease and nearly 60% of patients with advanced-stage disease. As noted earlier, in patients who have progressed after multiple TKIs, I will initiate therapy with ponatinib or omacetaxine. If response is achieved quickly, I would continue with my treatment. If not, I would recommend SCT.
Reference:
1. Jabbour E, Cortes J, Santos FP, et al. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations. Blood. 2011;117:
0.2
0.2 12 24 36 48 60 12 24 36 48 60
Mos
Mos
Slide credit: clinicaloptions.com
Jabbour E, et al. Blood. 2011;117:

28. Ponatinib vs SCT for CML With T315I Mutation
100 80
OS (%) 60
Mos CP
Ponatinib vs SCT
Median OS, Mos
Disease Group
Ponatinib
SCT
P Value CP NR
103
.013 AP 56
.889 BP 7 11
.026
Ph+ ALL 32
.136 40 20 12 24 36 48
100
Ponatinib
SCT 80
OS (%) 60
Mos AP 40 20 12 24 36 48
ALL acute lymphocytic leukemia; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; NR, not reached; Ph+, Philadelphia chromosome positive; SCT, stem cell transplantation.
Nicolini and colleagues[1] performed a retrospective analysis in which they matched patients treated in the PACE trial who had theT315I mutation with similar patients from the European Bone Marrow Transplant Registry who had received SCT.
The analysis showed that in patients with chronic-phase CML, ponatinib was superior to SCT, with median OS not reached for ponatinib vs 103 months for SCT. Although patients treated with ponatinib should be monitored carefully for vascular events, there is otherwise a low risk of toxicity compared with risks with SCT. In patients with accelerated disease, results were similar for both groups. However, among patients with blast-phase disease, SCT remains superior.
Based on this analysis, I would recommend that patients in the chronic phase and who are not at risk of vascular events should receive ponatinib or omacetaxine as an alternative to ponatinib. For those in advanced-stage disease, SCT is the better option.
Reference:
1. Nicolini FE, Basak GW, Kim DW, et al. The impact of ponatinib versus allogeneic stem cell transplant (SCT) on outcomes in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with the T315I mutation. Blood. 2015;126. Abstract 480.
100
Ponatinib
SCT 80
OS (%) 60
Mos BP 40 20 12 24 36 48
Slide credit: clinicaloptions.com
Nicolini FE, et al. Blood. 2015;126. Abstract 480.

29. Role of TKIs and Omacetaxine in Progressive CML and Timing of SCT
Status
Role of TKIs or Omacetaxine
Timing for AlloSCT
AP/BP CML
Interim treatment to MRD
ASAP
CP CML: imatinib failure with T315I
Ponatinib or omacetaxine
If no response to ponatinib or omacetaxine
CP CML: imatinib failure, no CE, no mutations, good initial response
Long-term second-line TKIs
Third-line after failure of second-line TKI
CP CML: imatinib failure, CE, bad mutations, no CG response
Second-line treatment
Imatinib failure in pts ≥ 65 yrs of age
May forgo alloSCT for many yrs of better QoL
Allo, allogeneic; AP, accelerated phase; ASAP, as soon as possible; BP, blast phase; CE, chromosomal evolution; CG, cytogenetic; CML, chronic myeloid leukemia; CP, chronic phase; MRD, minimal residual disease; QoL, quality of life; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor.
This slide depicts my algorithm for SCT in the treatment of CML. I consider SCT today as an option in advanced-stage disease. I use TKIs, omacetaxine, and other chemotherapy–TKI combinations as a bridge to SCT to reduce disease burden.
In patients with chronic-phase CML today who acquire T315I mutation, I consider ponatinib first or omacetaxine if ponatinib is not an option due to risk for cardiovascular disease. If there is no response to these agents in these patients, I recommend SCT.
For the patient with chronic-phase CML who has had received imatinib but has no clonal evolution or resistance associated compound mutations and who had good initial response, I see a role for second-line and even third-line therapy with TKIs, and I would defer SCT as long as possible.
Conversely, if a patient has progressed after imatinib therapy with compound mutations and did not have any cytogenetic response, one could try a second-line TKI with close monitoring at 3 and 6 months. If an optimal response is not attained, SCT or omacetaxine would be an option for this patient.
Finally, there are many patients for whom SCT would not be a good option—older patients in particular. For these patients, one could opt for TKIs or omacetaxine before considering SCT. Older patients should be monitored carefully for possible cardiovascular risk factors.
Slide credit: clinicaloptions.com

30. Phase I Study of ABL001 in CML
ABL001: allosteric inhibitor of BCR-ABL
Multicenter, open-label phase I dose escalation study of CML pts in CP or AP with failure of ≥ 2 prior TKIs due to resistance or intolerance
59 pts treated with 2 (41%) or ≥ 3 (59%) prior TKI
ABL mg BID (n = 43) or mg QD (n = 11)
5 pts nilotinib (300 BID) + ABL001 (40 BID)
Tmax 2-3 hrs; t1/2 5-6 hrs
5 DLTs: Grade 3 ↑ lipase (n = 2; 40 BID, 200 QD), acute coronary event (150 BID), bronchospasm (200 BID); Grade 2 myalgia/ arthralgia (80 BID)
Responses (29 evaluable):
CHR 2/12 (within 2 mos)
CCyR 8/12 (within 6 mos)
MMR 10/29 (within 6 mos)
AP, accelerated phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; DLT, drug-limiting toxicity; MMR, major molecular response.
One of the exciting drugs being investigated in CML is ABL001, an allosteric inhibitor of the kinase protein that is active in the presence of the T315I mutation. The drug is in early-stage development, having just entered clinical phase I trials.
Early data on ABL001 show good efficacy at very early stages in 59 patients who had progressed after multiple TKIs.[1] Among 29 evaluable patients, 10 patients achieved MMR and 8 achieved CCyR. However, there is still a concern about vascular events with this drug, particularly at higher doses. ABL001 may also require combination with nilotinib or other drugs, which may exacerbate vascular event risk. Trials of this drug are ongoing, and I look forward to the results.
Reference:
1. Ottmann OG, Alimena G, DeAngelo DJ, et al. ABL001, a potent, allosteric inhibitor of BCR-ABL, exhibits safety and promising single- agent activity in a phase I study of patients with cml with failure of prior TKI therapy. Blood. 2015;126. Abstract 138.
Slide credit: clinicaloptions.com
Ottmann OG, et al. Blood. 2015;126. Abstract 138.

31. Moving Forward
Better prognostic models needed taking into consideration patient and CML risk factors
May indicate second-line TKI as frontline treatment for high- risk pts
Deep sequencing techniques detect higher rates of compound mutations
These pts would be more sensitive to third-line TKI or omacetaxine
In cases of failure of second-line TKI either frontline (rare) or second line, should consider third-line TKI or omacetaxine
Pts’ comorbidities should be considered in TKI choice
CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
Reviewing CML treatment in 2016, generic imatinib is now available, changing the dynamic with dasatinib and nilotinib in first-line therapy. We look forward to developing smarter models to predict outcomes and select patients in whom second‑generation TKIs would be advantageous. Deep sequencing techniques can help to identify patients at risk of progression in whom a third‑generation TKI or combination with omacetaxine or other approaches are needed. Finally, among patients who have progressed after second‑generation TKIs, we should consider third‑generation TKIs or omacetaxine, with SCT as a possible choice if these options are not indicated. Comorbidities, particularly vascular risk factors, should be monitored carefully because they will play a role in treatment choice.
Slide credit: clinicaloptions.com

32. Summary: State-of-the Art Treatment of CML in 2016
There are many effective options for CML treatment: the TKIs imatinib, dasatinib, nilotinib, bosutinib, and ponatinib; the protein elongation inhibitor omacetaxine; and SCT
CCyR is an endpoint of treatment and correlates with improved survival
Early response (3-6 mos) predictive—do not change therapy at 3 mos; monitor and decide at 6 mos
Aim for pt PCR of BCR-ABL < 10% by 6 mos, and for CCyR (or BCR-ABL < 1%) by 12+ mos—if not achieved, change therapy
Deeper MMR improves event-free survival; no impact on transformation or OS
No clear benefit for CMR
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CMR, complete molecular response; MMR, major molecular response; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor.
In summary, we now have a range of effective choices for treating CML: the TKIs imatinib, dasatinib, nilotinib, bosutinib, and ponatinib; the non-TKI omacetaxine; and SCT. CCyR should be the endpoint of treatment because it correlates with survival. Monitoring is key; early responses are important. If an optimal response is not attained by 3 months, continue to monitor with current therapy until 6 months. Results at 6 months will predict long-term outcome. If a patient does not have a PCR at ≤ 10% at 6 months or ≤ 1% (or CCyR) at 12 months, a change in therapy is recommended. These are the only indications for modification of therapy at those milestones. Deeper molecular responses have no impact on OS. Sustained complete molecular response in chronic-phase CML is required in order to stop therapy. However, that option should be considered in an optimal setting.
Slide credit: clinicaloptions.com

33. Go Online for More CCO Coverage of Chronic Myeloid Leukemia!
Capsule Summaries of all the key data Additional CME-certified slidesets on CML with expert faculty commentary on key studies
clinicaloptions.com/oncology