1. Providing Optimal Care for Patients With Chronic Myeloid Leukemia
Thank you for joining us for the Clinical Care Options’ “Providing Optimal Care for Patients With Chronic Myeloid Leukemia.” My name is Douglas Smith. I am Associate Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, and I will be your host for today’s webcast.
This program is supported by educational grants from Bristol-Myers Squibb and Novartis Oncology.

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3. Faculty
B. Douglas Smith, MD Associate Professor Hematological Malignancies Kimmel Cancer Center Johns Hopkins University Baltimore, Maryland
B. Douglas Smith, MD, has disclosed that he has received consulting fees from Ariad, Celgene, and Novartis.

4. Agenda
Overview of CML
Pathophysiology and Epidemiology
Diagnosis and Workup
Choice of Frontline Therapy for Chronic-Phase CML
Monitoring Response to Frontline TKI Therapy
Choice of Second and Subsequent Lines of Therapy
Patient Compliance to TKI Therapy
Managing Treatment-Related Toxicity
CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
Before we begin, I’d like to review what we hope to accomplish with today’s lecture. First off, we’d like to provide an overview of chronic myeloid leukemia, talk a little bit about the pathophysiology and epidemiology of this myeloid malignancy, and talk about how one diagnoses it and patients are worked up to ensure all the important clinical information is obtained at the time of diagnosis. We will review the current choices of frontline therapy, how one can best monitor patients for their response to tyrosine kinase inhibitor therapies. We’ll review second and subsequent lines of treatment, the importance of patient compliance, and how one manages treatment-related toxicity.

5. Philadelphia Chromosome Translocation in CML Results in BCR-ABL Oncogene9
9q+
Stem cell disorder
Characterized by myeloproliferation
Well-described clinical course
Ph 22q- 22
Translocation
BCR
BCR ABL
ABL
Transcription and translation
BCR-ABL fusion protein
Inhibition by TKI
CML, chronic myeloid leukemia; Ph, Philadelphia chromosome; TKI, tyrosine kinase inhibitor.
Chronic myeloid leukemia is one of the most important oncologic disorders and in part because it was the first oncologic disorder where a chromosome abnormality was identified. The Philadelphia chromosome is that specific chromosome abnormality. And as you can see from this cartoon, the Philadelphia chromosome is actually comprised of a balanced translocation between chromosome 9 and chromosome 22. This translocation brings the Abelson kinase together with the break cluster region and creates a fusion called the BCR-ABL. Importantly the presence of the Philadelphia chromosome gives this cell its proliferative advantage over normal cells and results in this chronic myeloid proliferative disease called chronic myeloid leukemia.
It’s important to understand that this is a stem cell disorder so the translocation is located in early progenitor cells within the bone marrow compartment. It’s characterized by a proliferation, such that cells accumulate and patients with CML tend to have high blood counts at the time of their presentation.
Constitutive tyrosine kinase
Phosphorylation of multiple substrates
Mitogenic signaling and genomic instability increased
Apoptosis and stromal regulation decreased
CML

6. Accumulation of immature myeloid cells New cytogenetic changes
Natural History of CML
Accumulation of immature myeloid cells
New cytogenetic changes
Chronic Phase
Accelerated Phase
Blast Phase
Duration
If untreated, 3-5 yrs
Varies
Median survival of several mos
Prognosis
Responsive to treatment
Decreased responsiveness
Resistant to treatment
Symptoms
Asymptomatic OR Fatigue Weight loss Abdominal pain or discomfort Night sweats
Progressive splenomegaly Myelofibrosis
Bleeding complications Infection complications
CML, chronic myeloid leukemia.
There’s a natural history that’s well described for patients with chronic myeloid leukemia. We tend to think of it in 3 distinct phases: a chronic phase, accelerated phase, and blast crisis phase. Each of these has a specific duration, a prognosis associated with them and typically with certain symptoms. For example, chronic phase traditionally has been felt to last 3-5 years when untreated. Where patients are treated with chronic-phase CML, they tend to be fairly responsive to early treatments, and interestingly, many patients with chronic-phase CML are asymptomatic at the time of their presentation. If they do have symptoms, they tend to be related to an enlarged spleen, some mild fatigue, weight loss, and sometimes night sweats. As patients progress towards accelerated phase, the duration of accelerated phase tends to be quite variable. It is associated with decreased responsiveness to therapy and signs and symptoms tend to involve progressive splenomegaly and instability of the patient’s blood counts.
The third and most dangerous phase of CML is the blast crisis phase. We tend to think of this as being akin to having acute myeloid leukemia. Median survival untreated is weeks to months. It’s very resistant to therapy and patients often have significant instability of their blood counts, which can lead to being at risk from bleeding and infectious complications during this phase.
Radich JP, et al. Proc Natl Acad Sci U S A. 2006;103: Sawyers CL. N Engl J Med. 1999;340: Druker B, et al. Chronic leukemias. In: Cancer, principles, and practice of oncology. 17th ed

7. Diagnosis of CML Sensitivity Hematologic Cytogenetic Molecular
Karyotype (Ph chromosome)
FISH
PCR
(BCR-ABL fusion)
CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization; PCR, polymerase chain reaction; Ph, Philadelphia chromosome.
The diagnosis of CML is traditionally made by reviewing the blood smear, the bone marrow, and looking specifically for evidence of the Philadelphia chromosome. This slide really tries to depict the fact that there are numerous ways that one can make the diagnosis of CML. There is a very distinct peripheral blood smear that’s filled with myeloid cells of all different types. The bone marrow tends to be very hypercellular with significant myeloid hyperplasia. Traditional cytogenetics can detect the Philadelphia chromosome—again the balanced translocation between chromosome 9 and 22. You can also detect cytogenetic abnormalities using FISH markers that actually can find the abnormal 9 and 22 using fluorescent in situ hybridization staining of the blood cells. Finally, one can detect the BCR-ABL fusion by molecular techniques such as PCR, giving us multiple ways that one can find and define the diagnosis of CML.
Peripheral blood (with myeloid cells)
Bone marrow (with myeloid hyperplasia)
Chromosomal translocation
t(9;22)(q34;q11)
Abnormal BCR-ABL
Red: BCR Green: ABL
Yellow: fusion
Abnormal BCR-ABL
Lane 1: BCR-ABL+ Lane 2: BCR-ABL-
Courtesy of Neil Shah, MD, PhD.

8. Workup and Primary Treatment for Patients With CP CML
History and physical exam, determine spleen size by palpation
CBC with differential, platelets
Blood chemistry profile
HLA testing
BM aspirate and biopsy
FISH
QPCR with IS
Determine risk score
Primary treatment, if Ph or BCR-ABL positive
Discuss treatment options
TKI
HSCT
Clinical trial
Initiate treatment with 1 of the following
Imatinib 400 mg
Nilotinib 300 mg BID
Dasatinib 100 mg QD
BID, twice daily; BM, bone marrow; CBC, complete blood count; CP CML, chronic-phase chronic myeloid leukemia; FISH, fluorescence in situ hybridization; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; IS, International Scale; Ph, Philadelphia chromosome; QD, once daily; QPCR, quantitative real-time polymerase chain reaction; TKI, tyrosine kinase inhibitor.
When one approaches a patient that has a new diagnosis of chronic-phase CML, there’s several things that I think are very important in making sure that we’re collecting the right information and working up the patient properly. As noted, a history and physical is very important. One can often determine spleen size by palpation, obtaining a CBC with a differential in platelets, blood chemistry profile. Bone marrow testing is quite critical to the initial diagnosis of CML. One can look for the Philadelphia chromosome by FISH testing, and we often recommend that early on in diagnosis patients receive a PCR-based test, in part, to ensure that the patient’s BCR-ABL transcript is recognized by the PCR primers.
Using this clinical information, one can determine a risk score and that is very important in determining the patient’s prognosis moving forward.
Once the diagnosis of CML is confirmed via the patient’s testing for the Philadelphia chromosome, discussing the treatment options is really the next step. Frontline therapy with tyrosine kinase inhibitors is the standard of care in the year I think it’s also important to begin discussions with patients regarding hematopoietic stem cell transplant and clinical trials. However, these tend to be therapies that we reserve for patients who are not showing initially good responses to TKI therapy. Again, there are 3 drugs approved for frontline therapy for patients with chronic myeloid leukemia, and we’ve listed them on the slide.
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

9. Criteria for Hematologic, Cytogenetic, and Molecular Response
Complete hematologic response
Complete normalization of PB counts, leukocyte count < 10 x 109/L
Platelet count < 450 x 109/L
No myelocytes, promyelocytes, or blasts in PB
No palpable splenomegaly
No disease symptoms
Cytogenetic response
Complete
No Ph+ metaphases
Partial
1% to 35% Ph+ metaphases
Major
0% to 35% Ph+ metaphases (complete + partial)
Minor
> 35% Ph+ metaphases
Molecular Response
≥ 3 log reduction in BCR-ABL mRNA or BCR-ABL/ABL ≤ 0.1% by QPCR (International Scale)
Complete (CMR or MR4.5)
No detectable BCR-ABL mRNA using assay with sensitivity at least 4.5 logs below standardized baseline
CMR, complete molecular response; MR4.5, molecular response of 4.5 log reduction; PB, peripheral blood; Ph, Philadelphia chromosome; QPCR, quantitative real-time polymerase chain reaction.
Once patients are initiated on therapy for their CML, it’s important to monitor them hematologically, cytogenetically, and molecularly to determine how they are responding to treatments. As you can see from this slide, ultimately the goal is to stabilize their blood counts and their bone marrow function and to eliminate the Philadelphia chromosome. A complete hematologic response is noted by normalization of the blood counts. Ideally, patients will have shrinkage of an enlarged spleen and have no disease symptoms once they’ve achieved a complete hematologic response.
Cytogenetically, there are different levels of cytogenetic response, but importantly, we like to think of patients achieving a major cytogenetic response showing less than 35% Philadelphia chromosome positivity. Ideally, the majority of patients started on frontline TKI therapy will actually achieve a complete cytogenetic response where you’ll no longer be able to detect the Philadelphia chromosome by cytogenetics or by FISH.
Molecular responses are determined by the change in the PCR. Importantly, a lot of effort has been put in to try and standardize PCR-based testing, and there’s something referred to as the international standard which tries to normalize PCR values across various laboratories. According to the international standard, a major molecular response is considered in patients who have greater than a 3 log reduction in the BCR-ABL messenger RNA transcripts. This can be noted as less than or equal to 0.1% on the international scale. It turns out that even PCR-based testing has its limits and sensitivities, and somewhere around a log reduction of 4-5 logs, most PCR testing reveals no evidence of the Philadelphia chromosome. That is not to say the patients don’t have any disease in their body—simply the limits of detection of this assay is about 4.5 logs, below which patients are no longer detectable.
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

10. Imatinib Changed the Therapeutic Landscape for Patients With Ph+ CML
Best available therapy 5-Yr OS, %
Imatinib* 93
IFN- or SCT + second-line imatinib† 71
IFN- or SCT‡ 63
IFN- 53
Hydroxyurea 46
Busulfan 38
1.0
2010
0.9
, imatinib*
0.8
2000
0.7
0.6
, IFN- or SCT plus second-line imatinib†
Survival Probability (All Ph+ CML Disease Phases)
1990
0.5
, IFN- or SCT‡
0.4
CML, chronic myeloid leukemia; IFN-, interferon-alpha; OS, overall survival; Ph, Philadelphia chromosome; SCT, stem cell transplantation.
When one looks at the history of treatment for patients with chronic myeloid leukemia, it turns out that there’s been a really dramatic improvement in survival with the introduction of tyrosine kinase inhibitors in the early 2000s. For example, in the thick purple line, one can see that looking at survival in patients when interferon, stem cell transplants were used, plus second-line therapies with a TKI imatinib, one can see we’re making gradual but steady improvement in the outcomes for patients with CML. If we look at the top line, the blue line, looking at an estimated overall 5-year survival in patients treated up front with imatinib, we’re looking at an incredible number of 93%. The stepwise improvement has really been a dramatic change for patients with CML.
1980
0.3
, IFN-
0.2
, hydroxyurea
0.1
1970
, busulfan 2 4 6 8 10 12 14 16 18 20 22
Yrs After Diagnosis
1960
*CML IV. †CML IIIA. ‡CML III.
Leitner AA, et al. Internist (Berl). 2011;52: 10

11. IRIS 8-Yr Update: OS (ITT) With Imatinib Treatment in CML
100 80 60
Estimated OS at 8 yrs: 85%
(93% considering only CML-related deaths)
OS (%) 40
CML, chronic myeloid leukemia; ITT, intent to treat; OS, overall survival.
The study that really led to the use of imatinib in the upfront setting is referred to as the IRIS study. Here, I show a curve of the 8-year follow-up looking at overall survival using an intent-to-treat analysis for patients who were initiated on imatinib in that randomized study which compared upfront imatinib to interferon-based therapy. The estimated overall survival at 8 years is about 85%. This number jumps to 93% when one only considers CML-related deaths. 20 12 24 36 48 60 72 84 96
108
Mos Since Randomization
Deininger M, et al. ASH Abstract 1126.

12. IRIS 8-Yr Update: Most Events in First 3 Yrs
Event Loss of CHR Loss of MCyR AP/BC Death during treatment
7.5 7 6 5
4.8
AP/BC
Probability of Event 4
3.3 3
2.8 2
1.8
1.7
1.5
1.4
1.3
AP/BC, accelerated phase/blast crisis; CHR, complete hematologic response; CML, chronic myeloid leukemia; EFS, event-free survival; MCyR, major cytogenetic response.
In further looking at the IRIS study, one can see that most adverse events tend to occur early on in the patient’s treatment course. Here we have the probability of events and specifically noted events like loss of hematologic response, loss of the major cytogenetic response, a transition towards accelerated or blast crisis or death during treatment in the blue bars, and the transition to accelerated or blast crisis phase in the orange bars. Again, early on, the first 3 years, the majority of events appeared to occur. Most patients appear to be fairly stable beyond the first several years of treatment with TKI. 1
0.9
0.8
0.5
0.3
0.4 1 2 3 4 5 6 7 8 Yr
Estimated EFS at 8 yrs: 81%
Estimated rate of freedom from progression to AP/BC at 8 yrs: 92%
Deininger M, et al. ASH Abstract 1126. 12 12

13. Intolerance/Resistance Occurs in Some Patients With Ph+ CP CML on Imatinib
Disposition of Patients After 8 Yrs of Follow-up (IRIS Trial)
Discontinuation of Frontline Imatinib
6.6%
6.7%
55%
37.8%
55%
45%
35.6%
13.3%
CML, chronic myeloid leukemia; CP, chronic phase; Ph, Philadelphia chromosome; SCT, stem cell transplantation.
That’s not to say that all patients do well with upfront therapy with imatinib. And in fact, as this slide shows, patients from the IRIS study, about 45% of them ended up discontinuing their frontline therapy with imatinib for numerous reasons: adverse events, some went on to stem cell transplant, unfortunately some died. And again, up to about 35% of patients had what was considered an unsatisfactory therapeutic effect from upfront imatinib.
Discontinued frontline imatinib
Continued frontline imatinib
Adverse effects Unsatisfactory therapeutic effect Death
SCT
Other reason cited
Deininger M, et al. ASH Abstract 1126. 13

14. Patients diagnosed with Ph+ CP CML within 6 mos (N = 846)
ENESTnd: Comparison of Nilotinib and Imatinib in Newly Diagnosed CP CML
Primary endpoint: MMR at 12 mos
Secondary endpoint: durable MMR at 24 mos
Stratified by Sokal risk
Nilotinib 300 mg BID
(n = 282)
Patients diagnosed with Ph+ CP CML within 6 mos (N = 846)
Nilotinib 400 mg BID
(n = 281)
5-yr follow-up
BID, twice daily; CML, chronic myeloid leukemia; CP, chronic phase; MMR, major molecular response; Ph, Philadelphia chromosome; QD, once daily.
Efforts to build upon the success of imatinib have led to the development of other TKIs. Nilotinib is one such TKI, and here we present the data that randomized patients between upfront nilotinib vs imatinib. As you can see there were 2 distinct doses of the nilotinib chosen: 300 mg twice a day or 400 mg twice a day in this large phase III randomized study. We refer to this study as the ENESTnd study. The primary endpoint selected to assess the response in the over 840 patients who were treated on this study, was a major molecular response at 12 months. The goal was to determine how well these therapies would lower the patients’ tumor burden as measured by PCR.
Imatinib 400 mg QD
(n = 283)
Saglio G, et al. N Engl J Med. 2010;362: Larson RA, et al. Leukemia. 2012;26: Kantarjian HM, et al. ASH Abstract 1676.

15. ENESTnd 4-Yr Update: Cumulative Incidence of MMR in CP CML
100 80 60 40 20 12 6 24 18 30 42 36 48 54
Mos Since Randomization
Patients With MMR (%)
Nilotinib 300 mg BID Nilotinib 400 mg BID
Imatinib 400 mg QD
By 1 yr: 55% (P < .0001)
By 4 yrs: 76% (P < .0001)
51% (P < .0001) ∆24% to 28%
73% (P < .0001) ∆17% to 20%
56%
27%
BID, twice daily; CML, chronic myeloid leukemia; CP, chronic phase; MMR, major molecular response; QD, once daily.
Looking at the 4-year update for the ENESTnd study, the cumulative incidence of major molecular response—again the study’s primary endpoint—for patients was noted. You can see that the 2 treatment arms using nilotinib upfront were clinically significantly different than the patients who received imatinib upfront. At 4 years, 56% of patients had achieved a major molecular response on imatinib compared to 73% and 76% for the 2 arms of nilotinib.
MMR = BCR-ABL ≤ 0.1%.
Kantarjian HM, et al. ASH Abstract 1676.

16. ENESTnd 4-Yr Update: Cumulative Incidence of MR4.5
Nilotinib 300 mg BID Nilotinib 400 mg BID
Imatinib 400 mg QD
100 80 60
By 4 yrs:
40% (P < .0001)
Patients With MR4.5 (%) 40
37% (P = .0002) ∆14% to 17%
BID, twice daily; MR4.5, molecular response of 4.5 log reduction; QD, once daily.
The ENESTnd trial also looked at the cumulative incidence of achieving molecular undetectability. This would be a molecular response at 4.5 logs and again there was a statistically significant difference between the 2 nilotinib arms compared to the imatinib arm.
By 1 yr: 20
11% (P < .0001)
23%
∆6% to 10%
7% (P < .0001) 1% 6 12 18 24 30 36 42 48 54 60
Mos Since Randomization
MR4.5 = BCR-ABL ≤ %.
Kantarjian HM, et al. ASH Abstract 1676.

17. Including Clonal Evolution
Progression to AP/BC on Study (Including After Treatment Discontinuation)
P = .0497
Nilotinib 300 mg BID 20 15 10 5
P = .0074
HR: 0.5 ( ) 19
Nilotinib 400 mg BID
HR: 0.3 ( )
Imatinib 400 mg QD
Patients (n) 9 6
3.2%
2.1%
6.7%
AP, accelerated phase; BC, blast crisis; BID, twice daily; QD, once daily.
A final incredibly important point made from this study was the fact that patients who were initiated on one of the 2 nilotinib arms had a lower risk of progressing to advanced phase—accelerated or blast crisis—as compared to patients who were treated on imatinib. This was clearly an important factor in helping to move the drug nilotinib into the frontline setting for patients with chronic-phase CML.
Including Clonal Evolution
Rates of progression to AP/BC were also lower with nilotinib vs imatinib when including all progressions occurring on study
ENESTnd is the only phase III pivotal trial to prospectively collect progression events occurring after treatment discontinuation
No new cases of progression to AP/BC after discontinuation of core treatment were observed since the 3-yr analysis
Kantarjian HM, et al. ASH Abstract 1676.

18. DASISION: Comparison of Dasatinib and Imatinib in Newly Diagnosed CP CML
Stratified by Hasford risk score
Dasatinib 100 mg QD
(n = 259)
Patients newly diagnosed with CP CML (N = 519)
5-yr follow-up
Imatinib 400 mg QD
(n = 260)
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CP, chronic phase; MMR, major molecular response; OS, overall survival; PFS, progression-free survival; QD, once daily.
A second large phase III study was undertaken following the same pattern as the ENESTnd. This trial, called the DASISION trial, randomized patients between frontline imatinib 400 mg daily compared to dasatinib 100 mg daily—again, a large study, looking at 519 patients randomized with a primary endpoint here of complete cytogenetic response at 12 months.
Primary endpoint: confirmed CCyR at 12 mos
Key secondary endpoints: MMR, time in confirmed CCyR, time to confirmed CCyR and MMR, PFS, OS
Kantarjian HM, et al. Blood. 2012;119: Jabbour E, et al. Blood. 2014;123:

19. DASISION 3-Yr Update: Cumulative Incidence of MMR
100
Dasatinib 100 mg QD
Imatinib 400 mg QD
1.6-fold higher likelihood of achieving MMR with dasatinib; HR: 1.62 (95% CI: ; P < .0001)
By 3 yrs:
69% 80
By 2 yrs:
64%
By 1 yr:
46% 60
Subjects With MMR (%)
55% 40
46% 20
23%
MMR, major molecular response; QD, once daily.
Looking at the cumulative incidence of a major molecular response, again, treatment with dasatinib was more likely to achieve a major molecular response compared to treatment with imatinib upfront. By one year, 46% of the patients with dasatinib had achieved a major molecular response compared to 23% of patients on imatinib. Although over time these curves begin to get a little closer, by 3 years there’s still a difference between the dasatinib-treated patients and the imatinib-treated patients. 12 24 36
Mos
MMR 3-Yr Cumulative Rates, %
Hasford Risk Score
Low
Intermediate
High
Dasatinib 83 65 61
Imatinib 57 43
Kantarjian HM, et al. Blood. 2012;119: Jabbour E, et al. Blood. 2014;123:

20. DASISION 3-Yr Update: Cumulative Incidence of MR4 and MR4.5 in CP CML
Dasatinib 100 mg QD
Imatinib 400 mg QD 40
P = 30
22%
12%
17% 9% 3% 2%
Patients With MR4.5 (%) 20
CML, chronic myeloid leukemia; CP, chronic phase; MR4.5, molecular response of 4.5 log reduction; QD, once daily.
When one looks at the achievement of undetectability, again, somewhere around a log reduction of , dasatinib again appears to achieve this much more readily than imatinib. This held true at 3 years with a 22% of patients on dasatinib achieving a molecular response of either 4.0 or 4.5 compared to 12% of patients with imatinib. 10 12 24 36
Mos
MR4.5 = BCR-ABL ≤ %.
Kantarjian HM, et al. Blood. 2012;119: Jabbour E, et al. Blood. 2014;123:

21. DASISION 3-Yr Update: Transformation to AP/BC CML20
Dasatinib 100 mg QD
Imatinib 400 mg QD 16 15 13 11
Patients (n) 10 8 5
AP, accelerated phase; BC blast crisis; CML, chronic myeloid leukemia; ITT, intent to treat; QD, once daily.
Looking at the ability of dasatinib to prevent patients from transitioning to accelerated or blast crisis CML, again, fewer patients on dasatinib transitioned or transformed to acute phase disease compared to those patients treated with imatinib.
n =
259
260
259
260
On Study
Including Follow-up Beyond Discontinuation (ITT)*
*Yrly evaluations after discontinuation currently stipulated per protocol; additional patient status provided by investigators at other times.
Kantarjian HM, et al. Blood. 2012;119: Jabbour E, et al. Blood. 2014;123:

22. Approach to First-line Therapy Based on Comorbidities and Managing Treatment-Related Events
Noting that there are 3 drugs to choose from in the frontline setting, and having some understanding that the second generation drugs nilotinib and dasatinib have showed favorably going head-to-head with imatinib in the frontline setting, what other factors do we need to take into account in helping to select the frontline therapies?
Well, one needs to understand that each of these drugs is associated with numerous side effects. The side effect profiles of each of these agents can often help a physician begin to determine the best treatment for their individual patients.

23. Frontline Treatment Options Based on Adverse Effect Spectrum of TKIs in CML
Imatinib
Edema/fluid retention myalgia
hypophosphatemia 
GI effects (diarrhea, nausea)
Common Effects Myelosuppression transaminase  electrolyte Δ
CML, chronic myeloid leukemia; GI, gastrointestinal; TKIs, tyrosine kinase inhibitors.
One of the important things to keep in mind when one chooses a frontline therapy is that each of the available TKIs has both common side effects, as well as unique side effects. And depending on your patient’s comorbidities and other medical issues, this might also help guide its selection of frontline therapy with TKIs.
The cartoon presented shows some common side effects associated with each of the 3 frontline TKIs. In the middle, one can see the common effects of myelosuppression, elevated transaminases, and electrolyte changes.
When one thinks of imatinib, fluid retention, myalgias, GI effects such as diarrhea and nausea are very common. Dasatinib is associated with the development of pleural and pericardial effusions in some patients. It also has a later side effect of the development of pulmonary arterial hypertension. And nilotinib is associated with elevated pancreatic enzymes, poor glucose control and hyperglycemia, as well as prolongation of the QTC and dysrhythmias. So when one looks at these profiles, this might in fact help us select the TKI for our patient.
Nilotinib
Pancreatic enzyme 
indirect hyperbilirubinemia hyperglycemia
QT prolongation cardiovascular events
Dasatinib
Pleural/pericardial effusions
bleeding risk pulmonary arterial hypertension

24. Myelosuppression AEs With TKIs Imatinib, Dasatinib, and Nilotinib30
ENESTnd[1]
IRIS[2]
DASISION [3]
Neutropenia
Thrombocytopenia
Anemia 25 24 21 20 19 17
Grade 3/4 Adverse Effects, % 15 12 12 11 10 9 10 9 9
AEs, adverse events; TKIs, tyrosine kinase inhibitors.
Now, looking at myelosuppression, which is very common with the initiation of therapy with TKIs, we’ve put together a slide to really look at the incidence of neutropenia, thrombocytopenia, and anemia in each of the 3 major studies. The IRIS study’s in the middle. ENESTnd, looking at nilotinib vs imatinib upfront, is on the left. And the DASISION trial, looking at dasatinib vs imatinib upfront, is on the right.
One can take away a couple of important facts; and that is that neutropenia and thrombocytopenia are typically associated with second-generation drugs compared to the use of imatinib. While they're certainly common with imatinib, the incidence and likelihood of seeing neutropenia and thrombocytopenia is higher when one uses a second-generation drug. And this is important to note because, while the responses may be higher in the use of second-generation drugs upfront, the side effects profiles also come into play on whether that really is the best agent for your patient. 6 6 5 4 4
Nilotinib
Imatinib
Imatinib
Dasatinib
Imatinib
1. Kantarjian HM, et al. ASH Abstract Druker BJ, et al. New Engl J Med. 2006;355: Jabbour E, et al. Blood. 2014;123:

25. Treatment Options Based on Adverse Effect Spectrum of TKIs in CML
Imatinib
Edema/fluid retention myalgia
hypophosphatemia 
GI effects (diarrhea, nausea)
Ponatinib
Pancreatic enzyme 
hypertension
skin toxicity
thrombotic events
Common Effects Myelosuppression transaminase  electrolyte Δ
Bosutinib
Diarrhea
nausea/emesis
rash
CML, chronic myeloid leukemia; GI, gastrointestinal; TKIs, tyrosine kinase inhibitors.
When one looks across the board at all of the TKIs and the common side effect profile, here looking at bosutinib, notable diarrhea, GI upset; and ponatinib, again, pancreatic enzyme elevation, hypertension, as well as arterial and venous thrombotic events, one can again get a better understanding that each of these drugs may have a particular role in an individual patient.
Now there's been a great deal of focus on vascular events over the past few years, and this is in part due to the fact that patients have now been on TKIs into the second decade of time. And we're now understanding later effects that, in fact, the TKIs, while they really changed the face of CML from a response and a survival standpoint, they’re also associated with some problems.
Nilotinib
Pancreatic enzyme 
indirect hyperbilirubinemia hyperglycemia
QT prolongation cardiovascular events
Dasatinib
Pleural/pericardial effusions
bleeding risk pulmonary arterial hypertension

26. ENESTnd: Cardiac and Vascular Events by 4 Yrs (All Grades)
Patients With an Event, n (%)
Nilotinib 300 mg BID
(n = 279)
Nilotinib 400 mg BID
(n = 277)
Imatinib 400 mg QD
(n = 280)
IHD
11 (3.9)
14 (5.1)
3 (1.1)
PAOD
4 (1.4)
5 (1.8)
0 (0)
Between Yrs 3 and 4, a total of 5 new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event
1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related serious AE (arterial stenosis limb) leading to treatment discontinuation
AE, adverse effect; BID, twice daily; IHD, ischemic heart disease; PAOD, peripheral arterial occlusive disease; QD, once daily.
Here looking at the ENESTnd trial, with—looking specifically at cardiac and vascular events, one can see a similar pattern emerging compared to cytopenias. For example, the incidence of ischemic heart disease or arterial occlusive disease in patients looking at second-generation nilotinib appear to be higher than with using the first-generation drug imatinib. And specifically, when looking at the nilotinib 2 dosing, there appears to be a dose response, noting that there’s more events in patients on higher doses of nilotinib. There are lots of laboratory investigations ongoing to understand why the second-generation drugs and why the advanced drugs appear to be associated with more cardiovascular events, but certainly we're starting to see that trend.
Kantarjian HM, et al. ASH Abstract 1676.

27. Dasatinib and Pulmonary Arterial Hypertension
After-market incidence in the French Pulmonary Hypertension registry
9 cases identified from Nov 2006 (approval) – Sept 2010
Moderate/severe with functional and hemodynamic impairment
No exposure to other TKIs at time of diagnosis
Improved in 8/9 patients within 4 mos of dasatinib discontinuation
Lowest estimated incidence of pulmonary hypertension: %
TKI, tyrosine kinase inhibitor.
Looking at dasatinib and the incidence of pulmonary arterial hypertension which it's been associated with, the incidence is low but it is real. Nine cases were identified from a French pulmonary hypertension registry. And what's important to understand is that these patients were symptomatic. They had moderate to severe dysfunction at the time of their diagnosis. And importantly, 8 of the 9 patients identified improved with the discontinuation of dasatinib. So, in fact, it’s important to recognize that there are vascular pulmonary events associated with the use of TKIs and that, when they’re discovered, discontinuation of the drug is the standard approach and many patients will get better. There are not clear guidelines as to what is the best next-line drug if you’re no longer able to take nilotinib or dasatinib or imatinib for these reasons. But it’s certainly important to understand that discontinuation results in improvement of patient symptoms.
Montani D, et al. Circulation. 2012;125:

28. TKIs: General Strategies to Manage Myelosuppression in CP CML
Grade 4 neutropenia: ANC < 1000/mm3 (I,N); < 500/mm3 (D) or
Grade 3/4 thrombocytopenia: PLT < 50,000/mm3 (I,N); ≤ 50,000/mm3 (D)
Hold treatment until ANC ≥ 1500/mm3 or PLT ≥ 75,000/mm3 (I)
ANC > 1000/mm3 or PLT > 50,000/mm3 (N)
ANC ≥ 1000/mm3 or PLT ≥ 50,000/mm3 (D)
Resume at original starting dose when levels reached (I); if reached ≤ 2 wks (N); or ≤ 7 d (D)
Resume at reduced dose if recurrence (I); if low count >2 wks (N); if low count > 7 d (D)
ANC, absolute neutrophil count; CML, chronic myeloid leukemia; CMS, Centers for Medicaid and Medicare Services; CP, chronic phase; D, dasatinib; EPO, erythropoietin; FDA, US Food and Drug Administration; I, imatinib; N, nilotinib; PLT, platelet; TKI, tyrosine kinase inhibitor.
I will show you a chart that has been worked out, really taking into account the NCCN guidelines for strategies to manage myelosuppression. When one experiences grade 4 neutropenia or grade 3/4 thrombocytopenia, I think it's important to consider holding treatment. The idea is to let the bone marrow begin to recover away from the TKI. And when counts improve, then depending on how robust the response is, one can resume the TKI at the noted starting dose. Or if you see recurrent myelosuppression, then one should consider a dose reduction in the therapy. I think the chart provided gives some guidelines as to how one would consider doing that.
Grade 3/4 anemia: EPO effective, but CMS and FDA do not support use in myeloid malignancies
Growth factors can be used with TKIs for patients with resistant neutropenia
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

29. Strategies to Manage Nonhematologic AEs
Grade 2/3 Adverse Effect
Management Recommendation
Diarrhea
Supportive care
Edema
Diuretics; supportive care
Fluid retention
Diuretics; supportive care; dose reduction, interruption, or discontinuation; consider ECG to check LVEF
Gastrointestinal
Take imatinib with meals and water
Myalgia
Calcium supplement; tonic water
Rash
Topical or systemic steroids; dose reduction, interruption, or discontinuation
Pleural/pericardial effusion
Diuretics; dose interruption: consider prednisone 20 mg QD for 3 days for significant symptoms, reduce dose
AE, adverse effect; ECG, echocardiogram; LVEF, left ventricle ejection fraction; QD, once daily; TKI, tyrosine kinase inhibitor.
Strategies to manage the other nonhematologic AEs are largely supportive care. I think it’s important that we really work hard to recognize that there could be a TKI-related event going on in patients and, again, the diarrhea, the nausea, the vomiting, and the fluid retention seem pretty easy to observe. Pericardial and pleural effusions, some myalgias, may be a little bit less easy to observe and so taking a good history and evaluating patients, knowing in the back of your mind that individual TKIs may be associated with such side effects, I think is really critical to long-term outcomes for your patient.
Grade 2/3 AEs (except hepatotoxicity): if not responsive to supportive care, treat as grade 4
Grade 4 AEs or ≥ 2 hepatotoxicity
Hold until ≤ grade 1; resume at reduced dose level; consider change to another TKI
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

30. Monitoring Response to First-line Therapy
Once patients have been initiated on their primary therapy for CML, and once one has gotten through the first few weeks of acutely managing the expected toxicity profile, the question comes, how does one best monitor their response to their TKI?

31. Recommendations for Response Monitoring in CML
Cytogenetic Analysis BM
Molecular Analysis QPCR
BCR-ABL1 Analysis
At diagnosis
At diagnosis
If inadequate initial response (failure to achieve PCyR or BCR-ABL1 ≤ 10% at 3 and 6 mos or CCyR at 12 and 18 mos)
If QPCR is not available
Every 3 mos
until CCyR
Again at 3 and 6 mos OR
CCyR confirmed
If not in CCyR or MMR
Every 3 mos for 3 yrs
Any sign of loss of response (cytogenetic or hematologic relapse)
Again at 12 mos
Every 3-6 mos thereafter
BM, bone marrow; CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; MMR, major molecular response; NCCN, National Comprehensive Cancer Network; PCyR, partial cytogenetic response; QPCR, quantitative real-time polymerase chain reaction.
When one looks at the recommendations for response monitoring provided by the NCCN guidelines group, one can see that to make the diagnosis, it’s important to have a cytogenetic analysis of bone marrow early on. This is very important if PCR testing is not available. We would suggest that cytogenetics from the bone marrow be tested again at either 3 and 6 months, once again at 12 months, again, if one does not have PCR-based testing.
When talking about molecular analysis of response, the recommendations suggest that this should be done at the time of diagnosis, then every 3 months until a complete cytogenetic response is obtained, and again, once patients have a complete cytogenetic response—every 3 months for the first 3 years, then every 3-6 months thereafter. Ultimately, one is hoping to achieve evidence for a major molecular response, which suggests that patients have at least a 3 log reduction in their PCR from the time of diagnosis. Major molecular responses have been associated with long-term disease stability in many studies.
If not in MMR and lack of CCyR at previous analysis OR
1-log increase in BCR-ABL1 transcript levels with MMR
Again at 18 mos
1-log increase in BCR-ABL1 transcript levels and loss of MMR
Repeat in 1-3 mos
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

32. New Criteria for Failure of TKI Therapy
RT-PCR > 10% by IS or no PCyR response at 3 mos (Ph+ > 35%)
if imatinib was initiated as first TKI, switch is indicated
if nilotinib or dasatinib were initiated, consider switching to alternate TKI (except imatinib) or continue TKI
Less than CCyR at 12 or 18 mos
Cytogenetic or hematologic relapse at any time
Lack of MMR is not failure according to NCCN guidelines; the presence of MMR can, in the absence of cytogenetic data, imply the presence of CCyR
For guidance from 5 experts on monitoring response to first-line therapy and switching therapy, an online Interactive Decision Support Tool is available at
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; IS, International Scale; MMR, major molecular response; NCCN, National Comprehensive Cancer Network; PCyR, partial cytogenetic response; Ph, Philadelphia chromosome; RT-PCR, real-time polymerase chain reaction; TKI, tyrosine kinase inhibitor.
When one asks the question of whether or not the patient is actually failing their tyrosine kinase inhibitor therapy, there are some criteria that we can use to help us determine this. As noted by our case, the RT-PCR was greater than 10% at 3 months of therapy with the TKI. This is concerning for primary resistance to TKI, and it puts the patient at somewhat greater risk of failing treatment long term by continuing them on their imatinib therapy in this setting. If patients are on imatinib as frontline therapy and do not achieve a greater than 10% reduction in their PCR by 3 months, the NCCN guidelines suggested a switch to a different TKI is indicated. For those patients who are initiated on frontline therapy on a second-generation drug, either nilotinib or dasatinib, the data are less clear whether a switch is indicated at 3 months or not, and the NCCN guidelines suggest that one should consider this on a case-by-case basis.
Other criteria for failure of TKI is patients who have less than a complete cytogenetic response by 12 or 18 months; patients who end up losing a cytogenetic or hematologic response at any time are also considered failure of TKI therapy. Interestingly, patients who have a very nice response but fail to achieve a major molecular response is actually not considered a treatment failure, according to the NCCN guidelines. However, patients who do not achieve a major molecular response are certainly a group of folks that we need to monitor very carefully. I’ll direct you to the fact that, looking at some guidance on some of these tough cases from 5 experts in monitoring patients with CML, one can go to an online interactive support tool noted in the yellow here at the clinicaloptions.com CML tool.
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

33. BCR-ABL/ABL Cutoff ~ 10% IS at 3 Mos Predicts Survival
1.0
BCR-ABL/ABL ≤ 9.84%
8-yr OS: 93.3%
0.8
BCR-ABL/ABL > 9.84%
8-yr OS: 56.9%
0.6
Probability of Survival
0.4
P < .001
IS, International Scale; OS, overall survival.
Again, looking at the 3-month data, I think it’s pretty clear from this graph, looking at the probability of survival for patients who’d achieve a 10% reduction at 3 months compared to those who don’t. This was a report by Marin and colleagues in the Journal of Clinical Oncology suggesting that the overall survival was significantly different between groups of patients who achieved an early response measured by PCR compared to those who did not. This paper is really one of the key data points for the NCCN’s decision that if you’re on imatinib for 3 months and don’t achieve a 10% reduction, one should consider switching to a second drug.
0.2 1 2 3 4 5 6 7 8
Yrs From Onset of Imatinib Therapy
Marin D, et al. J Clin Oncol. 2012;30:

34. Clinical Evaluation of TKI-Resistant Patients With CML
Evaluate compliance and attempt to identify interacting medications, supplements, or foods
Evaluate peripheral blood to identify evidence of a hematologic relapse or signs of PD
Perform bone marrow biopsy to evaluate for morphologic relapse, signs of PD
Assess the karyotype from bone marrow biopsy for evidence of a cytogenetic relapse, clonal evolution, or the development of additional karyotypic changes in non-Ph+ clones
Assess for mutations in the BCR-ABL sequence that may inform therapeutic options
CML, chronic myeloid leukemia; PD, progressive disease; Ph, Philadelphia chromosome; TKI, tyrosine kinase inhibitor.
Again, it is important to understand that, when patients are not achieving the responses you want or in patients that are losing their responses to their present TKI, it’s vital to understand whether the patient has a resistance to the TKI being used or there are other things involved, such as compliance. It’s very important to understand whether patients are actually taking their drug and whether they’re taking their drug properly. Any time we’re concerned for a clinical TKI resistance, it’s recommended the patients undergo bone marrow testing to make sure they’re not missing progression of the disease and to reassess their Philadelphia chromosome status and to look for resistance patterns emerging to the TKI.

35. Why Perform Abl Kinase Mutation Analysis?
Some patients with CML can be either initially refractory to TKIs or eventually develop resistance to TKI therapy[1]
BCR-ABL1 kinase domain mutations are the most frequently identified mechanism of acquired TKI resistance[1]
Impair TKI binding by disrupting drug contact sites or causing conformational changes[1]
Clinical data indicate that the available TKIs have unique resistance profiles[2]
BCR-ABL1 kinase domain mutation analysis should be considered when selecting therapy for patients previously treated with TKI therapy[2]
CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
The test that’s often performed is an ABL kinase mutation analysis because in fact there are now emerging data that suggest that certain TKIs have differential responses and differential sensitivities to the various mutations that may emerge over time. While we don’t have lots of data in this realm, it is important to understand that finding a mutation may help guide your choice for second and subsequent therapies. There are reports available—when one finds a specific TKI mutation—that will help determine response. It is important to understand that there are publications that specifically look at individual ABL kinase mutations and the in vitro and some in vivo sensitivities of different TKIs and that these may help guide our decisions for therapy in patients who have these mutations.
1. Ernst T, et al. Semin Oncol. 2012;39: NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

36. When to Perform Abl Kinase Mutation Analysis?
After TKI failure, as defined by NCCN guidelines
After confirmed 10-fold increase in BCR-ABL transcripts or MMR loss
Evidence of disease progression
MMR, major molecular response; NCCN, National Comprehensive Cancer Network; TKI, tyrosine kinase inhibitor.
The NCCN guidelines recommend performing ABL kinase mutations when you have primary failure of the TKI or when you have secondary failure, meaning the patient’s had a very nice response, but then has lost that response. Such criteria include a 10-fold increase in your BCR-ABL transcripts or loss of a major molecular response. ABL kinase mutation testing should also be done at any time that the disease has gone from chronic phase to accelerated or blast crisis.
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v

37. Treatment Options Based on BCR-ABL Kinase Domain Mutation Status
Ponatinib, omacetaxine, HSCT, or clinical trial
V299L
Consider nilotinib or omacetaxine*
T315A
Consider nilotinib, imatinib,† bosutinib, or omacetaxine*
F317L/V/I/C
Consider nilotinib, bosutinib, or omacetaxine*
Y253H, E255K/V, F359V/C/I
Consider dasatinib, bosutinib, or omacetaxine*
Any other mutation
Consider high-dose imatinib,‡ dasatinib, nilotinib, bosutinib, or omacetaxine*
HSCT, hematopoietic stem cell transplantation; TKI, tyrosine kinase inhibitor.
This table presents some of the basic, well-described mutations seen and what treatment options are recommended. Again, this was part of the NCCN guidelines. The one that I think is important to understand is the T315I mutation, where the only TKI that appears to be effective is ponatinib. Also, treatments for this mutation include omacetaxine, a stem cell transplant, and clinical trials. Again, depending on the individual mutation, there is some guidance from this chart and from other publications that might steer you towards TKIs that may offer some potential efficacy.
Ponatinib is an option for mutations other than T315I but only when no other TKI therapy is indicated.
*Option for patients with resistance/intolerance to ≥ 2 TKIs.
†If mutation detected following dasatinib treatment.
‡No sufficient dose-escalation data indicating if mutations with low IC50 are sensitive to high-dose imatinib.
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v 37

38. Patient Compliance to TKI Therapy
TKI, tyrosine kinase inhibitor.
I mentioned in the previous few slides that it’s important to really determine TKI compliance. The reason I say this is because now we’re developing and understanding that long-term adherence is really critical to maintaining responses.

39. Long-term Adherence to Imatinib Is Critical for Achieving Molecular Response
Adherence to imatinib tracked for 3 mos in 87 consecutive CML patients with CCyR using microelectronic monitoring devices
MMR
CMR
Adherence > 90% (n = 64)
Adherence > 90% (n = 64)
1.0
Adherence ≤ 90% (n = 23)
1.0
Adherence ≤ 90% (n = 23)
0.8
0.8
P < .001
P = .002
0.6
0.6
Probability of MMR
Probability of CMR
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CMR, complete molecular response; MMR, major molecular response.
When one goes back and looks at the Marin publication from JCO 2010, looking at adherence, he looked at patients being tracked for about 3 years, and one saw that those patients who were adhering to a drug had a better likelihood of achieving a major molecular response and a complete molecular response to those patients who were not adherent. This shouldn’t surprise anybody and yet it’s quite distinctive. Our efforts really need to focus on being sure that our patients are able to maintain the treatment of their drug consistently on a day-to-day basis.
0.4
0.4
0.2
0.2 6 12 18 24 30 36 42 48 54 60 66 72 6 12 18 24 30 36 42 48 54 60 66 72
Mos Since Start of Imatinib Therapy
Mos Since Start of Imatinib Therapy
Marin D, et al. J Clin Oncol. 2010;28:

40. Practical Strategies to Improve Adherence to TKI Therapy
Intentional nonadherence (will not adhere)
Help patient manage adverse events
Offer personalized advice
Unintentional nonadherence (cannot adhere)
Use adherence-supporting technologies
TKI, tyrosine kinase inhibitor.
You know, there are lots of reasons that patients are not adherent to their therapy. There are some ones where patients sort of say, “I don’t feel well. I don’t like taking this drug. My CML’s not bothering me; I’m not going to take it.” And then there are some more unintentional problems. There are financial issues and different stresses in people’s lives to maintain these drugs, so it’s really important that one recognize it and one directly ask our patients about it.
Clifford S, et al. Pharm World Sci. 2006;28: Eliasson L, et al. Leuk Res. 2011;35:

41. Missing the odd dose is OK
Practical Strategies to Improve Adherence to TKI Therapy: Communication!
Be frank about consequences of missing doses and be specific
Missing the odd dose is OK
If you miss > 2 doses in 1 mo, it is likely to affect your response to therapy
TKI, tyrosine kinase inhibitor.
I think it is also very important to be very frank and explicit about the consequences of missing doses of therapy. As we can see, the likelihood of success is markedly impacted by being adherent to your drug. So I believe that in talking with our patients, we need to be very clear that missing doses, even as few as 2 or 3 doses in a given month, are likely to impact the success of the therapy.
Eliasson L, et al. Leuk Res. 2011;35:

42. Choice of Second- and Subsequent Lines of Therapy
When we talk about second and subsequent lines of therapy, one begins to have additional drugs in the mix, specifically bosutinib and ponatinib. These drugs are very effective second- and third-line therapy; however, they are not approved for frontline treatment.

43. Options for Second- or Later Line of Therapy for CP CML
Why are you considering a change?
Adverse effects/intolerance?
Primary resistance (ie, suboptimal response)?
Secondary resistance (ie, loss of response)?
What are your treatment options?
Increase imatinib dose (not favored)
Start nilotinib
Start dasatinib
Start ponatinib
Start bosutinib
Start omacetaxine (patients with resistance/ intolerance to ≥ 2 TKIs; generally not preferred to TKI)
Allogeneic bone marrow transplantation
Clinical trial
CML, chronic myeloid leukemia; CP, chronic phase; TKIs, tyrosine kinase inhibitor.
So what are the options for second or later lines of therapy for CML? Well I think it’s important to understand why you’re considering a change: Is the patient intolerant of a drug? Is the patient showing evidence of primary or secondary drug resistance? And again, we’ve listed numerous treatment options, and the only one I’ll make note of is that when folks are not doing well on a given drug, the likelihood of long-term benefit from simply a dose increase of that same drug does not appear to be as favorable as moving to a different drug. Now, there haven’t been every iteration of clinical trial developed for this, but in general, we don’t typically favor increasing doses when there are other agents that one can move to that may provide more benefit.

44. PACE: Primary Endpoint Responses With Ponatinib
Outcome, n/N (%)
CP CML
AP CML
BP CML
Ph+ ALL
Primary endpoint
MCyR
MaHR*
MaHR
R/I to dasatinib or nilotinib
104/203 (51)
37/65 (57)
17/48 (35)
T315I mutation
45/64 (70)
9/18 (50)
15/46 (33)
Total†
149/267 (56)
46/83 (55)
29/94 (31)
ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; MaHR; major hematologic response; MCyR, major cytogenetic response; Ph, Philadelphia chromosome; R/I, resistant/intolerant.
This PACE study looked at ponatinib as a salvage therapy for patients who had chronic-phase, accelerated-phase, or even blast-crisis CML who had failed 1, 2, or 3 TKIs previously. And importantly, ponatinib is the main drug for patients who have T315I mutations, and one can see that in that group of patients, there was a 70% response rate in patients with chronic phase, there was a 50% response rate with single-agent ponatinib in the accelerated phase, and for patients with the T315I mutation and blast crisis, about a third of patients responded to single-agent ponatinib. Responses included major hematologic responses, as well as cytogenetic responses.
*15 patients with MaHR at baseline (n = 14) or no baseline assessment (n = 1) counted as nonresponders.
†N comprises all eligible patients treated with ponatinib. It excludes 5 unassigned non-T315I patients (3 CP, 2 AP) who were post-imatinib, but treated; all 5 achieved MCyR.
Cortes JE, et al. N Engl J Med. 2013;369:

45. PACE: Response to Ponatinib by Previous CP CML Therapy
Previous Approved TKIs*
CP CML, n/N (%)
MCyR
CCyR
MMR
R/I cohort
Imatinib only
2/4 (50)
Imatinib + dasatinib or nilotinib
43/68 (63)
33/68 (49)
19/68 (28)
Imatinib + dasatinib + nilotinib
52/119 (44)
44/119 (37)
35/119 (29)
T315I cohort
10/12 (83)
9/12 (75)
8/12 (67)
23/30 (77)
22/30 (73)
16/30 (53)
12/22 (55)
11/22 (50)
CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CP, chronic phase; MCyR, major cytogenetic response; MMR, major molecular response; R/I, resistant/intolerant; TKI, tyrosine kinase inhibitor.
Again, looking at the data a little bit further, when patients were moved to ponatinib therapy, based on their prior success of their previous TKI, one can see that based on the responses to whether they were on imatinib only, or imatinib and combinations of other second generation drugs—dasatinib or nilotinib—one can see that the chance of achieving a major cytogenetic response was nearly 50% in all these groups. A complete cytogenetic response, again nearly 50% for many patients, and in fact patients went on to achieve major molecular responses despite not having great responses to 1, 2, and even 3 TKIs in the past. When one sorts out the T315I-mutated patients, again response to ponatinib was really dramatic in these patients who were not able to achieve good responses to previous treatments with imatinib or imatinib plus other second-generation drugs.
*Patients may have received other anticancer agents or investigational TKIs.
Of 19 patients with CP CML previously treated with any single approved TKI, 15 (79%) had MCyR
Cortes JE, et al. N Engl J Med. 2013;369:

46. Bosutinib Third-line: Best Cumulative Response
IM + DAS Resistant (n = 37)
IM + DAS Intolerant (n = 50)
IM + NI Resistant (n = 27)
IM + NI ± DAS (n = 4)*
Total (N = 118)
Median follow-up, mos (range)
20.0 ( )
34.5 ( )
23.0 ( )
34.5 ( )
28.5 ( )
Hematologic response,† n (%)
Evaluable patients
Complete 37
23 (62) 49
39 (80) 26
20 (77) 4
3 (75)
116
85 (73)
Cytogenetic response,ठn (%)
Major
Partial
Minor 35
11 (31)
5 (14)
6 (17) 43
13 (30)
12 (28)
1 (2)
4 (9)
9 (35)
7 (27)
2 (8)
2 (50)
108
35 (32)
26 (24)
9 (8)
6 (6)
AP, accelerated phase; BP, blast phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; DAS, dasatinib; IM, imatinib; NI, nilotinib.
Bosutinib, also a third-line agent that’s very effective for many patients who are either resistant or intolerant to imatinib plus dasatinib, or imatinib plus nilotinib. Again, when one looks at cytogenetic response, for example, to patients who were resistant to imatinib and dasatinib, there are major complete and even partial cytogenetic responses to third-line bosutinib. These responses appear to be even more favorable in patients who were intolerant to the previous TKIs. The same story holds true for patients who were resistant to both imatinib and nilotinib, as well, as there are responses, including major and complete cytogenetic responses, seen in patients who are resistant to all 3 of those TKIs. Please note, though, there is a very small number of patients in this category, but it does give us pause to realize that there are responses seen even in third- and fourth-line TKI therapies. They’re not as robust as we’d like, but certainly having numerous drugs to use suggests that we can still salvage some patients even as far out as third-line therapy.
*Includes 3 fourth-line patients and 1 third-line patient with nilotinib intolerance.
†Patients with CHR at baseline were evaluable for hematologic response.
‡Patients with CCyR at baseline were considered nonresponders for assessment of cytogenetic response.
§At median follow-up of 28.5 mos.
Confirmed transformation to AP CML while on treatment occurred in 5 (4%) patients; no patient transformed to BP CML
Khoury HJ, et al. Blood. 2012;119:

47. Omacetaxine for CP CML Following Failure of ≥ 2 TKIs
122 patients with CP (n = 81) or AP (n = 41) CML with intolerance/resistance to ≥ 2 previous TKIs
Omacetaxine 1.25 mg/m2 BID x 14 days of 28-day cycle (induction), then x 7 days of 28-day cycles (maintenance)
Outcome
CP (n = 81)
AP (n = 41)
2 TKIs (n = 45)
3 TKIs (n = 36)
2 TKIs (n = 17)
3 TKIs (n = 24)
Primary endpoints
MCyR, %
Median duration, mos
CCyR, %
MHR, %
CHR, %
27.0
17.7
13.0 --
11.0 NR
6.0
35.0
13.4
21.0
6.4
17.0
Median PFS, mos
10.5
6.5
3.6
4.8
Median OS, mos
30.1
12.0
24.6
AP, accelerated phase; BID, twice daily; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; MCyR, major cytogenetic response; MHR, major hematologic response; NR, not reported; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
I’ll mention that one of the more recently approved drugs for the use in CML is omacetaxine. Now this is a different class of drugs, and I tend to think of this in my mind as more like a low-dose chemotherapy drug. Omacetaxine is given intravenously, it’s not orally used, and this is for patients who have accelerated or chronic-phase CML who are resistant or intolerant to at least 2 prior TKIs. And this is more given in the style of acute leukemia therapy, where patients are treated with the drug twice a day for 14 days, and then it’s given cyclically 7 days or so every 28 day cycle in order to try to stabilize the patient’s bone marrow, improve their blood counts and try to maintain them with a response. It’s important to note that there have been responses to omacetaxine in patients with the T315I mutation, again the best TKI in that setting is ponatinib. When ponatinib is not able to be tolerated, one also might consider omacetaxine for these patients. My specific advice in looking at the response table noted is the responses are not particularly robust, although certainly it is a drug that has activity for these patients.
Nicolini FE, et al. ASCO Abstract 6513.

48. When to Consider Allo HSCT for CML
No longer recommended as first-line treatment option for CP CML
TKI failure in AP/BP CML: use new TKI as bridge to MRD, then HSCT as soon as possible
T315I mutation in any CML phase: use ponatinib as bridge to MRD, then HSCT for AP/BP CML; consider HSCT for CP CML
TKI failure in CP CML
Use alternative TKI, evaluate HSCT based on response to therapy
If 70 yrs of age or older or if poor HLA match, may decide to forgo curative allo HSCT option for several yrs of CML control
Allo HSCT, allogeneic hematopoietic stem cell transplantation; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; HLA, human leukocyte antigen; MRD, minimal residual disease; TKI, tyrosine kinase inhibitor.
This all brings us to the point of when you’re through several different TKIs, maybe have tried omacetaxine, and trying to really maintain your patient with CML as stable as you can. When does one consider an allo-stem cell transplant? Well, allo-transplant is still an important therapy for patients with CML. It is, however, no longer recommended as a first-line therapy for patients who present with chronic-phase CML. The use of an allo- stem cell transplant should be very individualized. However, most of the groups within the NCCN guideline panel believe that, when there is evidence that patients are failing 1 or 2 lines of TKI therapy, that it appears to make sense to begin to think about allogeneic stem cell transplant in these patients with the hopes that if they respond to, say, their third-line therapy, that may be the optimal time to try to move them towards a stem cell transplant.
Patients who have a T315I mutation are also folks that many patients will move to a stem cell transplant. It’s unclear the durability of responses seen to drugs like ponatinib and omacetaxine, and if patients are stable, one might consider a stem cell transplant at that time.
Finally, patients who have blast crisis who are then treated back into a chronic-phase, so-called second chronic phase, tend to be folks that we focus on for a stem cell transplant. We realize that patients who progress to blast-crisis CML are typically very drug resistant, very hard to control their disease, and they have a likelihood of relapsing within months on early studies, and so if one gets an opportunity in second chronic phase to move the right patients to stem cell transplant, those are certainly other indications that are important to consider.

49. Summary Multiple first-line options
Early monitoring and response matters
Multiple second-line options
Comorbid conditions and mutation analysis can help guide treatment choice
Adherence to therapy is critical for optimal response
Treatment-related adverse effects can be managed in most cases
When we look at today’s program, there are several important messages. The first is that there are multiple first-line options. There are 3 drugs approved for first-line treatment for patients with CML. One needs to take into account the individual patient characteristics, the side effects of each of the drugs in helping to make that selection. It's important to monitor patients very early, both for toxicities as well as early response. There are now some data that suggest that response as early as 3 months might help guide patients’ therapies and give some information on whether it’s appropriate to continue the current therapy on that patient or switch them to another TKI.
There are multiple second-line options that, again, thinking about the side effect profile of each drug is very important. Patients’ comorbid conditions as well as mutational analysis can help guide which drug one moves to in the second- and third-line settings. We must always remember that adherence is not a given for many patients, and it’s a real challenge for many of our patients, and it’s very important to recognize this and do what we can to encourage patients to remain on their medications. There are certainly some studies that suggest that adherence is the major reason for first-line drug failure.
And finally, with a good strategy, one can usually help manage most treatment-related adverse events and really the proper management of these effects really will help patients maintain adherence and help keep them safe on the drugs.
CDE

50. Go Online for More CCO Coverage of CML!
A text module with in-page polling summarizing a discussion of 3 experts on the care of patients with CML A downloadable slideset on CML management An interactive decision support tool on monitoring first-line response and switching therapy in CML
clinicaloptions.com/oncology