2018 CML Updates and

Case Presentations
Camille N Abboud, MD
Washington University in St Louis Medical School
 Disclosures
Employee Washington University
Research support Novartis, Pfizer, Astrazeneca, Merck, Cellerant, Actinium
Consultant Gerson Lehman Group, Cardinal Health, Seattle Genetics, Incyte, Bayer
Equity ownership: BMS, Abbvie, Merck, Gilead, Abbott labs
Immediate family member
Speakers Bureau Jazz (Vyxeos)
Scientific Advisory Board Seattle Genetics, Jazz, Agios
Honoraria Cardinal Health, Jazz, Pfizer, Agios, Bayer
Chronic Myeloid Leukemia Updates 2018
How to treat? When can we stop?

Monitor or not?
Can we predict
response?

Mutational analysis?
Overcoming TKI Resistance:
(PI3Kinase inhibitors, NFkB or
BET inhibition, IL-1b pathway

Targeting CML BCR-ABL1-positive leukemic initiating cells or The Holy

Grail? Hedghog inhibition, PML targeting agents, AlloSCT +/- CAR-T
 Normal and Leukemic Hemopoiesis
Normal
CD123 (IL-3Ra)

Leukemic IL-8 (CXCL8)

KL C-Kit
NFkB activation
CXCR4
VEGFRs
CX3CR1 Fibronectin

N-cadherin
KL
IL-1 VEGF Leptin
CXCL12/SDF-1
BMPs, HGF
Fractalkine (CXCL1) B-FGF
Osteoblast
 General features and critical pathways that contribute to CP CML
LSCs being quiescent, refractory to apoptosis, and prone to DNA
damage.

Tessa L. Holyoake, and David Vetrie Blood 2017;129:1595-

1606

©2017 by American Society of Hematology

LSC survival signaling in the CP CML BMM.
CML-specific surface markers
AIC-47. Schematic diagram showing the
mechanism of AIC-47 in CML cells.
• Cancer cells achieve the Warburg effect by dominant expression of
PKM2, which is regulated by the c-Myc/BCR-ABL/PTBP1 signaling
• AIC-47 decreases c-Myc and BCR/ABL and as a consequence, AIC-47
perturbs the Warburg effect
• AIC-47 also blocks the compensatory activation of fatty-acid oxidation
through the inhibition of LCAD activity
Inoue A, Kobayashi C, Shinohara H et al: CML stem cells and molecular target therapies for overcoming
resistance And disease persistence. Int J Hematol 2018: 108:365-370
 Figure 1 Schematic representation of the ABL1 and BCR genes and the BCR-ABL1 kinase

Quintas-Cardama, A. et al. Blood 2009;113:1619-1630

Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.

Figure 2 Molecular signaling in BCR-ABL1-positive myeloid progenitors

Quintas-Cardama, A. et al. Blood 2009;113:1619-1630

Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.

A, Metaphase karyogram of a newly diagnosed man with CML. The yellow
arrows indicate the derivative chromosome 9 and the Philadelphia
chromosome (Ph). B, Schematic of chromosomes 9, 22 and the derivatives
resulting from t(9;22)(q34;q11).
Talpaz M, Saglio G, Atallah E, and Rousselot P: Cancer 2018;124:1660-72
Jabbour and Kantarjian: Chronic myeloid leukemia:2018 update on diagnosis,therapy and monitoring.
Am J Hematol 2018:93:442-459
Mechanisms of TKI resistance in CML
Deciding when to lower the dose based on leukemic burden and BCR-ABL1 transcript levels. BCR-ABL1 transcript levels
are monitored by real-time quantitative polymerase chain reaction. The relationship to transcript levels and possible
outcomes is indicated. CCyR indicates complete cytogenetic response; IS, International Scale; MMR, major molecular
response; MR4.5, molecular response with 4.5-log reduction of BCR-ABL1 transcripts

Morotti A, Fava C, Saglio G. Milestones and monitoring. Curr Hematol Malig Rep. 2015;10:167-172.
Case 1: (GT) CML-CP, in TFR
• CML-CP on imatinib since 1/20/2008, WBC CT 152,000, HB 12.1, PLT
CT 202,000, no splenomegaly, ANC 87.8, Eos abs 1.0, Baso abs 2.0.
CCyR 8/10/2009, MMR with undetectable BCR/ABL1 since 4/06/15
• Cataracts surgery, T2DM, hypothyroidism, myalgias, orbital edema,
fatigue, switched to nilotinib on 3/31/18 to attain a deeper remission
but developed acute inflammatory pancreatitis and TKI stopped on
4/12/18.
• BCR/ABL1 undetected at Wash U 7/23/18, GenPath undetected on
8/20/18, up to 0.014% on 9/20/18, 0.098% in a later test and 0.49%
at Wash U on 12/17/18. (now lost MMR).
Treatment Discontinuation
• Quiescent stem cells determine that most CML patients will harbor residual
leukemic cells and will remain QRPCR positive. However, QRPCR levels tend to
decrease over time and some patients will achieve either a CMR or a very deep
response (MR4.0 or higher). Once CMR is obtained, there is no indicator to
ascertain whether CML was eradicated or if the level of residual CML cells is below
the limit of detection. The only way to find this out is through TKI discontinuation.
• In 2010, the pivotal STIM trial was published: In this study, CML patients in
continuous CMR since at least 2 years were enrolled. The final results of this and
several other studies conducted subsequently show that approximately 50% of
patients will relapse and need to resume treatment; most relapses develop within
the initial 7 to 8 months, although late relapses were documented up to 48 months
after discontinuation; and among the nonrelapsed patients, more than half will
show some positive QRPCR results postdiscontinuation which do not increase over
the MMR (0.1%) threshold generally accepted to define relapse.
Treatment Discontinuation Ctnd

• Why these Ph-positive cells do not grow in absence of TKI is not clear and
represents an important and still unsolved biologic question.
• Factors that appear to predict maintenance of remission include treatment
duration >5 years, CMR duration >2 years, negativity of digital PCR before
discontinuation, and, in some studies, an older age of the patient.
• The use of second-generation TKIs causes a faster drop in QRPCR values
initially; however, most controlled studies report a gradual decrease in the
differences between the imatinib and the second-generation TKIs over
time; patients who started a second-generation TKI and then discontinued
it have the same risk (50%) of CML relapse than patients who discontinued
imatinib.
Laneuville P: When to Stop Tyrosine Kinase Inhibitors for the Treatment of CML.
Curr Treat Options in Oncol (2018) 19:15
Imatinib Cessation Therapy
• Safety
• Side effects after discontinuation of TKI
• Correlation with depth and length of response to initial treatment
• Most patients who loose MR4.5 and relapse MMR or > can restart TKI
and attain MR4.5 or MMR.
• Obvious advantages less TKI toxicity to patients and cost saving to
Health systems.
Strategy for Treatment Discontinuation
• Patients who failed discontinuation, and after achieving a new CMR
tried a second discontinuation, have a lower (approximately 30%) but
present possibility of remaining in remission. Similarly, patients who
achieve and maintain a response of MR4.0 or higher seem to have the
same chances of maintaining their response after discontinuation
than patients who discontinue in CMR.
• Patients who discontinue should be monitored monthly or bimonthly
for the initial 8 months and then every 3 to 4 months for 4 years. If no
relapse develops, it is advisable to continue to monitor the patient
once or twice per year indefinitely.
Strategy for Treatment Discontinuation Ctnd
• It is important not to overemphasize the issue of discontinuation: This
is relevant only for some patients such as those who experience
important AEs with all TKIs used, or for young patients who suffer
psychologically from the need of continuous drug treatment; in both
cases, an optimal disease management can effectively contain these
issues in many cases.
• Patients (and treating physicians) should remember that CML is a
rapidly lethal disease if not adequately treated, and that this remains
the first priority in CML management. The vast majority of patients
reach a normal life expectancy and close to normal quality-of-life
indexes, if optimally managed.
Case 2: CML-AP, ASXL1 mutation and focal fibrosis
• 35 year old woman presented with splenomegaly, leukocytosis, 18% circulating
blasts and marrow 90% cellular, megakaryocytic dysplasia and hypolobate forms.
WBC CT 53.8, HB 8.0, PLT CT 134,000, Trisomy 8 (in 10/20 metaphases) and ASXL1
mutation.
• Received 7+3 induction plus dasatanib (8/04/2017). Leukostasis, retinal
hemorrhages and blurred vision, sepsis and GI bleeding.
• Now normal CBC, MR 4.5 undetectable BCR/ABL1 and normal cytogenetics.
Balsat M, Alcazer V, Etienne G, et al. First-line second generation tyrosine kinase inhibitors
in newly diagnosed accelerated phase chronic myeloid leukemia patients. Oral presentation
at: American Society of Hematology 60th Annual Meeting & Exposition;
December 1-4, 2018; San Diego, CA. Abstract 48.cc
Approved indications for TKIs and omacetaxine
in CML
Molecular response rates at 3, 6, 9, and 12 months
(modified intent-to-treat population) BFORE Trial
Adverse Events of Second-Line and Subsequent TKI Therapy in CP-CML
Case 3: CML-CP > CML-AP
• At age 54, presented 7/12/2013 with left sided weakness and blurred vision
(TIA), WBC CT 67.6, ANC 51.2, Eos abs 2.2, Baso abs 0.6, Mono abs 0.6.
Dasatanib 100 mg QD started
• Patient active smoker, ETOH abuse, non compliant with visits, never achieved a
CCyR or CMR. Developed CML-AP, with acquired E255K and V299L mutations
(while on dasatanib monotherapy). WBC CT 196,000 and Eos abs 8.6, Baso abs
1.6 both very high heralding disease transformation, Hydroxyurea started and
decitabine Cycle 1 + imatinib added
• Decitabine 5 days plus imatinib mesylate 600 mg QD continued after he was
hospitalized acutely for hyperleukocytosis and multiple arterial thrombi requiring
stents and vegetations of his mitral and aortic valves, requiring clopidogrel and
warfarin anticoagulation.
Case 3: 7/10/13 CHRONIC PHASE CML
Case 3: 7/10/13 CHRONIC PHASE CML

CD34 IHC—rare blasts

Micromegakaryocytes, meyloid left-shift
Case 3: 10/30/13. Hypocellular marrow
• CHR, but no CCyR or MMR
• Dasatanib monotherapy
• Skipped several visits
• By 7/29/15 double mutations
noted V299L and E255K
TKI Options for BCR/ABL1 TKD
Mutations
Recommended Treatment BCR-ABL1 Mutation
Dasatinib Y253H
  E255K/V
  F359V/C/I
Nilotinib F317L/V/I/C
  T315A
  V299L
Bosutinib Y253H
  E255K/V
  F317L/V/I/C
  F359V/C/I
  T315A
Ponatinib T315I
Fig 1. IC50 values for bosutinib, imatinib, dasatinib, and nilotinib against 18 mutated forms of BCR/ABL
expressed in Ba/F3 transfected cells

Redaelli, S. et al. J Clin Oncol; 27:469-471 2009

Copyright © American Society of Clinical Oncology

Responses Based on BCR-ABL1 Mutations Status
Key features of ponatinib
Case 3: 9/24/15 Accelerated phase CML
Case 3: 4/20/16 CML-AP, post Decitabine and
Imatinib (7 cycles) prominent eosinophilia
Valent P, Horny H-P, Arock M: The underestimated role of basophils in Ph+ CML. Eur J Clin Invest 2018:48:cl 3000, 1-9
Valent P, Horny H-P, Arock M: The underestimated role of basophils in Ph+ CML. Eur J Clin Invest
2018: 48:cl 3000, 1-9
Case 3: 5/31/16 hypocellular marrow
• Omecataxine + imatinib
mesylate on 5/05/16
• Skin rash, elevated histamine
levels, basophilia followed by
severe pancytopenia leading to
acute GI bleeding
• Bridged to a sibling alloSCT
FLUBU4 Day 0 on 6/20/16
• On Day + 25 complete
engraftment no GVHD.
EBMT risk score is 5 (AP, >40 years, > 1 year from Dx, female donor), transplant related mortality 70%.
Conlusions Case 3
• CML-CP high risk, failed to attain CCyR or MMR, acquired double
mutations
• Progressed to CML-AP, hyperleukocytosis, basophilia and eosinophilia
• Decitabine + TKI able to normalize counts but not PCR
• Aplasia after omecataxine
• Required alloSCT to normalize counts and attain BCR/ABL1 negativity.
CML: Role of Decitabine plus TKIs
• Inhibits DNMT3a and reverses gene silencing in cancer cells
• Activates the TRAIL apoptotic pathway in leukemic cells
• Active in CML-AP and BP + imatinib 600 mg (Oki Y, et al. Cancer 2007;
109:899-906)
• Inhibition of NFKb in LSCs ? (may potentiate depth of response)
• Potentiation of Check point inhibition (Neoantigens?)
• Reduction of cellularity allowing for remodeling of the HSC niches and
normal hematopoiesis
Treatment of Advanced Disease: Plan BMT
• The progression of CML to AP or BC markedly decreases survival probabilities, especially
in BC, because tumor heterogeneity increases, and with it the likelihood for the leukemia
to harbor enough mutant clones able to survive any targeting strategy.
• When AP develops, chances for durable responses still exist, especially when AP
definition is met because of thrombocytopenia or basophilia, and are only slightly lower
than patients in CP; for example a phase II study using bosutinib showed a 4-year
progression-free survival and OS of 49% and 59%, respectively. Patients who evolved to
BC face instead a grim prognosis; in this stage, TKI treatment has to be considered a
nontoxic bridge to transplant if the patient can undergo this procedure, with median OS
in the range of 6 to 12 months.
• A different situation exists instead when patients are diagnosed directly in AP or BC and
do not evolve to advanced disease after months or years of TKI treatment. In such a
situation, it is logical to expect better results from TKI treatment; however, the number
of patients in this condition is so small that no study is ongoing and data are not
available. This represents an area where more collaborative research is needed.
CML Role of BMT
• This procedure represented in the past the only curative option for CML patients, before the so-
called imatinib era. The relatively high rates of transplant-related mortality and morbidity versus
the unprecedented response and OS rates with TKI therapy changed the indication for allogeneic
stem cell transplantation in CP CML, preferentially performed with a human leukocyte antigen
identical sibling or unrelated donor, from being a first-line option in most patients to a late-line
therapy used only in few patients.
• Since 1999, the number of BMTs for CML declined dramatically, and today, <5% of CML patients
need to resort to BMT.
• In CP, patients carrying the highly resistant T315I mutation have BMT as the only alternative in
case ponatinib would not work or be tolerated due to its considerable cardiovascular toxicity.
Thus, the option of an allogeneic transplantation should be addressed and discussed. Likewise, in CP
patients with first-line failure in whom a second-line TKI is initiated, human leukocyte antigen typing
and identification of a family donor and/or search for an unrelated donor should be initiated.
However, in this scenario, it is prudent to await response to the secondary TKI.
• In any subsequent line of treatment, the decision for or against transplantation has to carefully
balance the already obtained response, alternative therapeutic options such as clinical trials, and
the potential outcome of transplantation.
Bone Marrow Transplantation
• In patients with AP, there is an indication to consider allogeneic stem cell
transplantation. However, in some patients with AP bordering CP, long-term TKI
therapy is an option.
• Patients in BC CML have a dismal prognosis with an expected survival of <1 year.
In these patients, only allogeneic BMT carries the potential of long-term
survival. In this setting, restoration of hematologic response either with a TKI or
intensive chemotherapy is advised before rapidly proceeding to transplantation.
• After BMT, TKI treatment can be started at sign of disease persistance (e.g., if
QRPCR remains positive at day 100 post BMT), provided that no resistance to that
particular TKI was present before the BMT.
• The management of a patient relapsing after BMT is extremely complex: TKI can
be used, provided that there is no clinical or biochemical (i.e., resistant
mutations) sign of resistance. Donor lymphocyte infusion is another therapeutic
option that can be combined with TKIs.
New Molecules
• ABL001 is an imatinib-unrelated compound able to bind ABL kinase in an
allosteric fashion; it binds to the myristoyl pocket of ABL1 and induces
the formation of an inactive kinase conformation. ABL001 has shown
clinical activity as monotherapy or in combination with nilotinib in phase
I and II studies.
• PF114 is a new compound that in a single phase II study obtained
cytogenetic responses in 4 orf 11 heavily pretreated patients
• K0706 is another ponatinib-derived compound which, similarly to PF114
is devoid of activity against VEGFR and thus should present better
cardiovascular safety profile. Currently it is in phase I development.
• These molecules produced responses also in patients with the T315I
mutation.
Asciminib (ABL0001)
Phase I Data on Ascitinib (ABL0001), ASH 2018
• Asciminib, a Specific Allosteric BCR-ABL1 Inhibitor, in Patients with
Chronic Myeloid Leukemia Carrying the T315I Mutation in a Phase 1
Trial. Delphine Rea, Fabian Lang, Dong-Wook Kim, Jorge E. Cortes,
Timothy P. Hughes, Hironobu Minami, Massimo Breccia, Daniel J.
Deangelo, Andreas Hochhaus, Moshe Talpaz, Yeow Tee Goh, Philipp le
Coutre, Michael W. Deininger, Gabriel Etienne, Manu Sondhi, Kaushal
Mishra, Paola Aimone, Janet Ng-Sikorski and Michael J. Mauro .
Blood 2018 132:792; doi: https://doi.org/10.1182/blood-2018-99-
113609
Delphine Rea et al Blood 2018:132:792
BCR/ABL1 Transcript Levels Over Time in Asciminib-Treated Ponatinib-Naïve or Ponatinib R/I
Patients
George G, Atallah EL, Mauro MJ, et al: Patients' Perspectives on the
Definition of Cure in Chronic Myeloid Leukemia: A US Based Survey.
Blood 2018 132:5843
• The H. Jean Khoury Cure CML consortium (HJKC3) is a collaborative
effort of physicians and researchers at 17 academic centers.
• The HJKC3-001 2017 Patient Survey sought to define pts' expectations
for treatment in CML to serve as a guidepost for future research in
this area.
• This survey demonstrates that pts do not consider disease control
with life-long oral medication as cure; rather, cure requires the
absence of treatment.
• Overwhelmingly, pts indicated the importance of continuing CML
research with an ultimate goal of treatment-free cure.
Chronic Myeloid Leukemia Updates 2018
How to treat? When can we stop?

Monitor or not?
Can we predict
response?

Mutational analysis?
Overcoming TKI Resistance:
(PI3Kinase inhibitors, NFkB or
BET inhibition, IL-1b pathway,
Bcl-2 inhibitors

Targeting CML BCR-ABL1-positive leukemic initiating cells or The Holy

Grail? Hedghog inhibition, PML targeting agents, CAR-T cell CLL1 /
CD33 followed by alloSCT non myeloablative regimen
Happy Holiday Celebration: Finally! Snoopy
Dreams of a Ton of Presents!
References
• Shanmuganathan N, Hughes TP: Molecular monitoring in CML: how deep? How often? How should
it influence therapy? Blood 2018: 132: 2125-2133.
• Talpaz M Saglio G, Atallah E, Rousselot P: Dasatanib Dose Management for the Tre atment of CML.
Cancer 2018:124:1660-1672.
• Radich JP, Deininger MI, Abboud CN et al: Chronic Myeloid Leukemia Version 1.2019. JNCCN
2018;16:1108-1135.
• Konopleva M, Quintas Cardama A, Kantarjian H, Cortes J: Molecular Biology and Cytogenetics of
Chronic Myeloid Leukemia. Chapter 4, in PH Wiernick et al (eds) Neoplastic Diseases of the Blood,
pp 29-47, Springer International Publishing AG, 2018.
• Holyoake TL, Vetrie D: The chronic myeloid leukemia stem cells: stemming the tide of persistence.
Blood 2017:129:1595-1606.
• George G, Atallah EL, Mauro MJ, et al: Patients' Perspectives on the Definition of Cure in Chronic
Myeloid Leukemia: A US Based Survey. Blood 2018 132:5843;
• Cortes JE, Gambacorti-Passerini C, Deininger MW et al: Bosutinib Versus Imatinib for Newly
Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol.
2018 ; 36:231-237.
Case 4: MPN with eosinophilia
72 year old man presented with claudication and fatigue,
blood counts showed elevated WBC CT with eosinophilia,
blasts at 1% or less of the differential. BCR/ABL 1, JAK2
V617F, FIP1L1-PDGFRA negative and ETV6-PDGFRB fusion
gene positive with t(5;12)(q33;p13),-21.
Case 4: Clinical Course
• WBC CT 196,500, HB 7.7, HCT 24.6, PLT CT 140,000. Neutrophil abs
164.2, Eosinophil abs 13.4, Basophil abs 1.6. Spleen 12.7 cm by
sonogram.
• Patient lacked insurance coverage so he received a total of 5 cycles of
ten day decitabine inpatient + 100mg daily of imatinib mesylate.
• Eosinophils cleared in one cycle and FISH for ETV6/PDGFRB became
negative after cycle 1, and his marrow normalized. Imatinib
maintenance 100 mg daily given until July 2016.
• Now off TKI, in CR, and CCyR. WBC CT 8.1, HB 11.4, PLT CT 349,000
on 06/08/18.
CML: Role of Decitabine plus TKIs
• Inhibits DNMT3a and reverses gene silencing in cancer cells
• Activates the TRAIL apoptotic pathway in leukemic cells
• Active in CML-AP and BP + imatinib 600 mg (Oki Y, et al. Cancer 2007;
109:899-906)
• Inhibition of NFKb in LSCs ? (may potentiate depth of response)
• Potentiation of Check point inhibition (Neoantigens?)
• Reduction of cellularity allowing for remodeling of the HSC niches and
normal hematopoiesis
QUESTIONS?
• Is this response related to sensitivity of that fusion kinase to low dose
imatinib?
• Daily TKI administration may not be necessary when combining it with
decitabine and can improve on poor compliance (e.g. Case 1)
• Mechanisms of action: enhanced apoptosis (TRAIL), gene
reprogramming, remodeling of hematopoietic niches, decreased
inflammatory signals?
• Could a similar strategy be used in CML patients with high Eutos or
Sokal scores?
 H&E

Initial Marrow Biopsy on 12/17/12

40X
H&E
Reticulin
Case 2: 1/23/17 Normocellular marrow
Case 4: Clinical Course
• WBC CT 196,500, HB 7.7, HCT 24.6, PLT CT 140,000. Neutrophil abs
164.2, Eosinophil abs 13.4, Basophil abs 1.6. Spleen 12.7 cm by
sonogram.
• Patient lacked insurance coverage so he received a total of 5 cycles of
ten day decitabine inpatient + 100mg daily of imatinib mesylate.
• Eosinophils cleared in one cycle and FISH for ETV6/PDGFRB became
negative after cycle 1, and his marrow normalized. Imatinib
maintenance 100 mg daily given until July 2016.
• Now off TKI, in CR, and CCyR. WBC CT 8.1, HB 11.4, PLT CT 349,000
on 06/08/18.
CML: Role of Decitabine plus TKIs
• Inhibits DNMT3a and reverses gene silencing in cancer cells
• Activates the TRAIL apoptotic pathway in leukemic cells
• Active in CML-AP and BP + imatinib 600 mg (Oki Y, et al. Cancer 2007;
109:899-906)
• Inhibition of NFKb in LSCs ? (may potentiate depth of response)
• Potentiation of Check point inhibition (Neoantigens?)
• Reduction of cellularity allowing for remodeling of the HSC niches and
normal hematopoiesis
QUESTIONS?
• Is this response related to sensitivity of that fusion kinase to low dose
imatinib?
• Daily TKI administration may not be necessary when combining it with
decitabine and can improve on poor compliance (e.g. Case 1)
• Mechanisms of action: enhanced apoptosis (TRAIL), gene
reprogramming, remodeling of hematopoietic niches, decreased
inflammatory signals?
• Could a similar strategy be used in CML patients with high Eutos or
Sokal scores?