WhatsApp in CML ?

From Cutting Edge to

Future Horizons…

Pia Raanani, MD

Institute of Hematology, Davidoff Cancer Center

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WhatsApp in CML - Topics• Introduction and general aspects

• Age Adjusted Treatment• AYA

• Pregnancy

• Pediatrics

• Elderly• CVS complications

• Treatment Free Remission• Clinical trials• Real – life (out of clinical trials)• Predictors for TFR

• Treatment Failure• Adherence• Mutations (NGS)• Management

• PROs and QOL

• State of the Art and the Future

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Philadelphia Chromosome

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6 7 8 10 119 12

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19 20 21 22 x Y

The Philadelphia (Ph) Chromosome Leads to CML

The Philadelphia (Ph) Chromosome Leads to CML

Clinical Course: Phases of CML

Chronic phase

Median duration 5–6 years

Accelerated phase

Median duration6–9 months

Blast crisis

Median survival3–6 months

Advanced phases

Blast Phase

CP CML: scoring systems

Eutos

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Age Adjusted Treatment

Pediatrics, AYA, Elderly

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CML in Adolescents and Young

Adults [AYA] & Pediatrics

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Challenges & Special Issues in AYA with CML

• No specific current standards or recommendations

• Only 13–27% of the total CML population: lack of clinical trials

• Fast achievement of sustained DMR of utmost importance

• Young women – pregnancy

• TFR and cure - especially important for the younger population

• Adherence to treatment is a major issue in AYA with CML

• Fast achievement of DMR is important in this group

• A challenge and Achilles heel in AYA

• QOL & PROMS - main issue for AYA: limited by side effects of TKIs

• Allogeneic SCT - a more readily available option for AYA

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Analysis of Outcomes in AYA with

CML Treated Upfront with TKIs :The MD Anderson Experience

• 468 pts. treated in MD

Anderson – 61 AYA

• AYA defined as 15 – 29 yrs.

• Difference between AYA

and older patients:

• Incidence of splenomegaly

• Distribution in Sokal risk groups

18Pemmaraju et al. Haematologica 2012

Response to Therapy According to Age Group

• Rates of CCyR, MMR and CMR significantly higher in

older patients compared to AYA

• A favorable trend for EFS for older

patients

• Transformation free and OS similar for

both groups

19Pemmaraju et al. Haematologica 2012

Kalmanti et al. Ann Hematol 2014 20

• AYA presented with

more aggressive

disease parameters (spleen, WBC, blasts, Hb)

• AYA –higher rate of

> 10% ratio @ 3 mos.

21Kalmanti et al. Ann Hematol 2014

• No significant difference in

cumulative incidences of CCR,

MMR and MR4 between AYA & others

• No inferior survival in AYA compared

to others

• No difference in progression to AP / BP

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young patients do well in spite of poorer

prognostic indicators

Kalmanti et al. Ann Hematol 2014

Two Most Relevant Studies in AYA CML

Patients with Contradicting Results

23Pemmaraju & Cortes Acta Haematologica 2014

24Hijiya & Suttorp Blood 2019

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Pregnancy in CML Patients Treated with TKIs

• CML accounts for 10% of all leukemias diagnosed during pregnancy

• Incidence of CML in pregnancy : 1/100,000 per year

Courtesy of Dr. Adi Shacham-Abulafia

Pregnancy in CML Patients Treated with TKIs

• What kind of response is needed before stopping TKI?

• Should IVF be considered to minimize the time

between stopping therapy and getting pregnant?

• How to manage rising PCR during pregnancy?

• Which treatment should be used?

• What is the likelihood to respond after delivery?

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Suggested algorithm for management of CML diagnosed during pregnancy

Evaluate- WBC, Plt & gestational age

WBC <100-150X109/L

& Plt<500-1000X109/L

AP CML

no action, except

aspirin +/- LMWHFailure to control

hematologic parameters

CP CML

Start TKI

+/-

Pregnancy

termination

Elisabetta Abruzzese, Expert Review of Hematology 2016

R. Palani, et al., Ann Hematol 2015

WBC >100-150X109/L

& Plt>500-1000X109/L

Leukapheresis/INF

HU/TKIs*

after organogenesis & placenta formation

Courtesy of Dr. Adi Shacham-Abulafia

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*Basically, TKIs not

recommended &should be avoided during pregnancy

Options for Planned Pregnancy in CML

STABLE MMR OR DEEPER FOR 24 MOS.

Stop TKI @ CMR

If CMR sustained for several months stop

contraceptives

On/off approach

Stop TKI at ovulation and

monitor b-HCG

Restart TKI if menstrual cycle

occurs

Stop TKI @ 1st

positive pregnancy test

(7-10 days after ovulation)

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Pregnancy Management in CML Patients: Report of 224 Outcomes of ELN Database (Abruzzese et al.)

• CML patients can pursue a normal life including planning a family, with several caveats

• TKIs should not be used during pregnancy

• Selected TKIs, specifically IM and NIL which have little placental transfer, can be started after organogenesis

• Tx. can be delayed w/o jeopardizing outcome

• If therapy during pregnancy is deemed necessary, IFN can induce and maintain hematologic remission

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Men Desiring to Conceive a Pregnancy

• Available data do not indicate increased risk for

infants conceived under TKI (most data - imatinib)

• A shared physician - patient decision whether to:

• Continue TKI therapy during efforts to conceive

• Delay initiation of TKI therapy

• Interrupt TKI therapy to facilitate conception with TKI-

unexposed sperm

• Consult on sperm preservation prior to TKIs Rx.

• Termination of pregnancy conceived while a man

is on TKI therapy - not recommended

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• CML constitutes 2% of all leukemias in children <15

years with an annual incidence of 1 : 106

• There are clear differences between CML in

children and adults in terms of:

• Disease presentation and progression

• The underlying CML biology and host factors

• Treatment considerations

• The validity of the existing scores

• Treatment complicated by growth retardation

31Hijiya et al. Blood 2016

Discontinuation of TKIs in Pediatric CML

Results from a Japanese trial

• 21 pts. < 15 years of age at diagnosis

• TKI may be safely discontinued also in children if:

• treated for ≥ 3 years

• had sustained MR4.0 for ≥ 2 years

• Included patients who relapsed after HSCT

• Indications for allogeneic HSCT in children:

• Failure of TKI therapy

• Progression while on a TKI

• CML-BP

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• Growth abnormalities are associated with imatinib

• Less experience with 2nd & 3rd generation TKIs

• A few case reports describe a decrease in markers of

fertility in children treated with TKIs

• An important goal :avoidance of life long treatment

with TKIs

• Treatment must take into account minimizing

toxicities for 6 or 7decades*

33*Only imatinib is indicated for pediatric CML patients, namely for children >3 years

Hijiya et al. Blood 2016

CML in the (Very) Elderly

A Change in the Paradigm..

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• According to the SEER program registries’ data -

28.6% of CML patients are 75 years or older

• Only 3.8% of them are represented in clinical trials

(compared to 79% of patients < 65 years old)

• All TKIs have shown efficacy in elderly CML patients

• Their use is accompanied by toxicity in the elderly

35Kanapuru B, ASH 2017, #861; Steegmann JL Leukemia 2016

Several Trials That Demonstrate Activity of TKIs in Elderly CML Patients…

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Age did not have a

relevant impact on DMR

associated with nilotinib in

newly diagnosed patients

Older patients on IM 800 mg,

in contrast to IM 400 mg,

achieved MMR & DMR as fast

as younger patients

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Low-dose (< 20 mg)

dasatinib generates an

adequate MR in most elderly

patients without severe AEs

A “real-life” cohort of 65

CML patients > 65 years

treated frontline with

dasatinib

• (30% ≥ 3 comorbidities)

• MMR in 77% of patients

• Dasatinib has important

role in the frontline

treatment of elderly with

comorbidities

Several Trials That Demonstrate Activity of TKIs in Elderly CML Patients…

How to Treat CML in Older Adults

38Luskin & DeAngelo Journal of Geriatric Oncology 2018

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Treatment Free Remission

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Cure In CML In The 3rd Millennium:A Target Or A Dream?

>3000 pts.

Pierre Laneuville, 2018 43

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TKI Discontinuation In CML

TKI treatment:Deep and sustainedmolecular response

TKI discontinuation:Treatment-free remission (TFR)

TKI-discontinuation:Molecular relapse

Hematological relapsein the absence of

TKI reintroductionSTOP

Normal HSC

Normal progenitor

LSC

Leukemic progenitor

Leukemic mature cell

Predominantly normalhematopoiesis

Predominantly normalhematopoiesis

Predominantly leukemic hematopoiesisIncreasingly leukemic hematopoiesis

Courtesy of Dr. Delphine Rea

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Can We Predict If And When TKI Treatment May Be Stopped?

• The probability to obtain a deep molecular response during 1st line TKI treatment depends on:

– CP-CML prognostic score at diagnosis.

– Treatment:

• Potency of TKI (Standard dose imatinib < 2nd generation TKIs)

• Single agent TKI versus combination therapy (IFN)

– Time on treatment.

– Early molecular response:

• BCR-ABL1 ratio at 3 months: 10% IS < 1% IS < 0.1% ISLarson RA, et al. Leukemia. 2012.;26: 2197-2203.Hochhaus A, et al. Leukemia. 2016;30: 1044-1054.Cortes JE, et al. J Clin Oncol . 2016; 34: 2333-2340.

Preudhomme C, et al. New Engl J Med. 2010. 363: 2511-2521.Hochhaus A, et al. Leukemia. 2016;30: 1044-1054.

Courtesy of Dr. Delphine Rea

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Can We Predict for a Successful TFR?

• The British Group introduced a predictive score for

successful TFR in CML based on a Hammersmith Cohort

and validated by other British centers

• Variables strongly associated with prolonged TFR :

• Age above or below 40 yrs.

• Previous TKI resistance

• Duration of MR4

• Type of transcript

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Time To Relapse After TKI Discontinuation

STIM trial

1: High risk of relapse soon after TKI discontinuation(usually between 3 and 12 months)

2: Few late relapses (usually during the 2nd year): decrease in the relapse risk as time passes

Very late relapses not reported yet

1 2 3

Etienne G, et al. J Clin Oncol. 2017;35(3):298-305. Courtesy of Dr. Delphine Rea48

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TKI Withdrawal Syndrome During TFRthere ain't no such thing as a free lunch

• Timing:– Occurs within 1 to 2 months after TKI discontinuation.

• Frequency:– About 30% of patients.

• Symptoms:– New onset or worsening of “inflammatory-like” musculoskeletal pain,

arthralgia, usually mild to moderate.– No systemic marker of inflammation.– Unrelated to molecular response status.– Exact mechanism unknown.

• Duration:– Resolution during the 1st year after TKI cessation or upon TKI resumption

in relapsing patients.

• Treatment:– None or analgesics (very rarely requires TKI reintroduction).

Richter J, et al. J Clin Oncol. 2014 ;32(25):2821-2823. Courtesy of Dr. Delphine Rea 51

Treatment Failure:

Non-Adherence & BCR-ABL1

Mutations

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Genotypic

changes

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BCR-ABL1 Point mutations

Next Generation Sequencing (NGS)

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Recently, a French trial showed:

• NGS can detect low level mutations in patients treated

with first line 2GTKI±Peg-IFN after only 3 to 6 months on

therapy

• Before these become detectable by SS

• Despite achieving an optimal response according to ELN

2013

• This might be a trigger for earlier intervention although

more studies are needed 55

1st line 2nd line 3rd line 4th line

Dasatinib

Nilotinib

Bosutinib (I, R?)Nilotinib (I, R?)Imatinib (I)Ponatinib (R)

Ponatinib (R,I)Other 2G TKI (I,R?)SCT (R)

SCT (R)Other TKI (I)Novel agents in

clinical trials (ABL-001)(R,I)

Bosutinib (I,R?)Dasatinib (I,R?)Imatinib (I)Ponatinib (R)

Ponatinib (R,I)Other 2G TKI (I,R?)SCT (R)

SCT (R)Other TKI (I)

Novel agents inclinical trials (ABL-001) (R,I)

Dasatinib (R,I)Nilotinib (R,I)Bosutinib (I, R)

Bosutinib (R,I)Ponatinib (R,I)Other 2G TKI (I,R?)

SCT (R)

SCT (R)Other TKI (I)Novel agents in

clinical trials (ABL-001) (R,I)

Imatinib

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Bosutinib

Nilotinib (I,R?)Dasatinib (I,R?)Imatinib (I)Ponatinib (R)

Ponatinib (R,I)Other 2G TKI (I,R?)SCT (R)

SCT (R)Other TKI (I)Novel agents inclinical trials (ABL-001) (R,I)

Patient Reported Outcomes (PROs)

& Qulaity of Life (QOL)

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Patients’ Perspectives About Discontinuation

• Breccia et al. collected the results of a questionnaire

administered to 1133 pts during regional meetings in Italy:

“If in the future there is a perfect and long-lasting response to the

treatment, would you accept the opportunity to interrupt the

treatment for your illness?”

• 49% answered that they would prefer not to interrupt

treatment being afraid of losing the results achieved

• 16% would like to discontinue

• 20% did not have a firm opinion 58

Breccia M. & Foa R. Curr Oncol Rep. 2018 20(3):23

PROs Show Superior QOL of Patients Treated With 1st

Compared to Newer Generations TKIs

• 195 patients on Imatinib,

Nilotinib or Dasatinib

completed a QOL

questionnaires

• Overall, the symptomatic

profile was more severe in

patients who received either

dasatinib or nilotinib

compared to imatinib

• Since patients on 2nd

generation TKIs were almost

2 decades younger, these

differences might reflect the

significance that

"Generation Y" gives to QOL

• Questionnaires were provided by the EORTC

• Questionnaires were composed of functional, symptom and global health/QOL scales/items

• Questionnaires included 34 items related to symptoms experienced by patients within the week before

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Shacham-Abulafia, Rosenman, Leader, Sharf, Raanani, Rozovski, EHA24, Amsterdam 2019

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IdeallyIdeally

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On a personal note…

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• Galit Granot, Ph.D

• Ayala Gover-Proaktor , Ph.D

• Alona Telerman, Ph.D

• Adi Shacham-Abulafia, M.D

• Avi Leader, M.D

• Ofir Wolach, M.D

• Oren Pasvolsky, M.D

• Alon Rozental, M.D

• Uri Rozovski, M.D

• Giora Sharf

• All the medical and lab team

• Our Collaborators from other hospitals

• CML patients’ group

• Our patients….

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