Chronic Myeloid Leukaemia

East Midlands Network Guidelines for the Investigation
and management of Patients

with Chronic Myeloid Leukaemia (CML)
Written by Dr. JL Byrne, Dr A Hunter, Dr M Lyttlelton
1. Definition of Chronic Myeloid Leukaemia (CML)

CML is a clonal haemopoietic stem cell disorder characterised by the presence of
the Philadelphia chromosome (t 9:21) or bcr-abl fusion gene within the affected cells.
Patients present with raised white cell counts and immature cells, such as
myelocytes, in the peripheral blood. Platelet counts are often high, basophilia may
be present and splenomegaly is common.
2. Investigations at Presentation
The following should be performed at diagnosis before treatment is initiated
History and examination to include the size of the liver and spleen in cm
below the costal margin
Venepuncture for the following investigations:

o FBC with differential
o Coagulation screen
o U+Es
o LFTs
o Urate
o PCR sample to ascertain bcr-abl status in EDTA sample
BMA and trephine with:-

- morphology to assess blast count
- karyotype to include FISH for bcr-abl, 9q deletion analysis
- immunophenotype to assess blast cell count
Sokal and Hasford score for Risk Assessment (see Appendix 1 and
www.ihnet.org )
o Sokal score risk group
<0.8 low
0.8-1.2 intermediate
>1.2 high
Document Code: EMCN-DC-0008-09 Date of Issue: May 2009 Review Date: May 2011
Written By: Professor Martin JS Dyer, Dr Cathy Authorised by: EMCDAG Page Number: 1/14
Williams
Issue No: 1 Website: Check www.lnrcancernetwork.nhs.uk for latest version
East Midlands CML Guidelines
3. Pre-treatment Management
Referral to Haematology Specialist Nurse if available
Referral to the appropriate Leukaemia MDT
Written material to be provided according to local protocol
eg
Leukaemia Research CML booklet
Leukaemia CARE Booklet
Leukaemia CARE contact card
Cancerbacup contact card
Macmillan Cancerline contact number
Haematology Ward contact details
Appropriate drug specific patient information leaflet
Consider Fertility options

Male patients Consider sperm storage
Female patients Consider referral to Assisted Conception Unit
The Assisted Conception Unit will not cryopreserve sperm or ova from
patients on chemotherapy, including Hydroxycarbamide and imatinib.
Patients must be referred before starting treatment or in the event this is not
possible treatment will need to be interrupted once disease control has been
established to allow collection of gametocytes.
4. Assessment of disease status at diagnosis
WHO criteria:
Chronic Phase
Blasts less than 10% in bone marrow and peripheral blood

Peripheral blood basophils < 20%
Absence of other criteria suggestive of accelerated or blastic phase
Accelerated Phase
Blasts 10-19% in bone marrow or peripheral blood

Peripheral blood basophils > 20%
Persistent thrombocytopenia (<100x109/L) unrelated to therapy, or persistent
thrombocytosis (>1000x109/L) unresponsive to therapy
Increasing WBC count unresponsive to therapy
Cytogenetic evidence of clonal evolution
Written By: JL Byrne A Hunter M Lyttelton Authorised by: EMCDAG Page Number: 2/14
Blastic Phase
Blasts in peripheral blood or bone marrow > 20%

Presence of extramedullary blastic disease
Large foci or clusters of blasts in the bone marrow biopsy
Patients with very high white cell counts who appear to have accelerated disease
should be reclassified when the white cell count has been controlled on
Hydroxycarbamide
5.0 Treatment of Chronic Phase

Consider eligibility for NCRI SPIRIT 2 or other trials for newly diagnosed
patients
If evidence of leukostasis discuss white cell depletion with local BMT

Consultant
Start allopurinol
If no immediate need to treat, await karyotype and start imatinib as first line
treatment
If need to initiate immediate treatment, hydroxycarbamide (hydroxyurea) until

karyotype confirmed, then change to imatinib once Philadelphia positive
status is confirmed
Obtain consent for chemotherapy and ensure patient has information sheet
5.1. Dose of Hydroxycarbamide
If WCC < 100, hydroxycarbabmide is not indicated
If WCC> 100 and <200 prescribe Hydroxycarbamide 1 to 2g/day dependent

upon age and end organ damage.
If WCC>200 prescribe 2g/day
5.2. Dose of Imatinib in Chronic Phase
The starting dose of imatinib is 400mg a day orally.
Dose interruptions or reductions may be necessary if Grade 3 haematolgoical

toxiicy occurs.
Re-escalation of doses to 400 mg daily should be attempted when counts

have recovered.
Doses below 300mg a day are not effective and should be avoided.
In patients who develop recurrent neutropenia on imatinib the use of G-CSF

should be considered.
5.3. Monitoring of Patients on Imatinib
Liver function and FBC weekly for 4-6 weeks or at any dose change
until stable, then 2 weekly for 6 weeks, thereafter up to every 3 months
BMA with karyotype: at diagnosis

at 3 months (optional)
at 6 months
at 1 year
then yearly if tolerated and patient has achieved
complete cytogenetic remission, otherwise
continue 3-6 monthly
or at disease progression
or if prolonged pancytopenia on imatinib
Q-pcr: for bcr-abl 3 monthly from achievement of major

cytogenetic remission (EDTA sample to
Hammersmith)
repeat in 1 month if > 1 log rise
Mutational analysis: primary treatment failure

loss of haematological / cytogenetic response
sub-optimal response
transcript level increase > 1 log on 2 occasions
Imatinib levels: Consider if sub-optimal response /

treatment failure (Contact Novartis rep to
arrange)
5.4 Assessment of Response to Treatment
Response criteria are taken from the European Leukaemianet Guidelines combining
the failure and sub-optimal response categories as recommended by Marin et al
2008.
Good response is defined as a complete cytogenetic response by 12 months and a

major molecular response of bcr-abl/abl ratio (i.e. bcr/abl/abl ratio < 0.1) by 18
months of treatment.
Patients will be considered as non-responders if:
After 3 months of imatinib therapy:

o Have failed to achieve complete haematological response.
o Have failed to achieve at least 35% Ph-negativity
o Have failed to achieve complete cytogenetic response
Although achievement of a major molecular response (bcr-abl/abl ratio of < 0.1 by 18

months is considered optimal there is little evidence to warrant a change of treatment
on this basis alone. Recommend discuss individual case at MDT for options
5.5 Management of non-responders
Assess patient for non-compliance (consider Imatinib level)
Assess patient for allogeneic transplantation and tissue type siblings
Increase dose of Imatinib to 600mg
Send sample for bcr-abl mutation status
Consider switch to 2nd line tyrosine kinase inhibitor if no response to higher

dose of Imatinib after 3m of high dose Imatinib therapy
Choice of 2nd line agent (Dasatinib / Nilotinib) at treating physicians discretion

depending on patient factors / type of mutation if detected (see Section 8)
5.6. Management of patient intolerance
Grade 1-2 non-haematological toxicity is common and may resolve following

dose interruption and reinstatement at lower dose. (Doses below 300 mg not
recommended)
Simple analgesics my be used to treat muscle aches and pains, quinine may
be useful for cramps and diuretics may be required to treat weight gain and
fluid retention
Dasatinib or nilotinib / alternative TKI if persistent Grade 2 or greater non-

haematological toxicity (NB Haematological toxicity unlikely to improve with
2nd line TKI)
Consider SCT if toxicity persists after trial of both 2nd line agents
Interferon or Peg Interferon
Hydroxycarbamide long term
5.7. Loss of Response or Disease progression:
A patient may be regarded as having lost his/her response to imatinib if:
They lose a complete haematological response, or

They lose a complete cytogenetic response, or
There is an increase of 30 or more percentage points in the number of Ph-
positive bone marrow metaphases examined at an interval of 3 months or
longer, or
They develop new cytogenetic abnormalities in the Ph-positive clone, or
There is an increase in the Bcr-Abl/Abl ratio of one log or more on serial
testing or the Bcr-Abl/Abl ratio rises into the range associated with Ph-
positivity, or
Progression towards accelerated/blastic phase
5.8 Role of Stem Cell Transplant (SCT)
All patients should be treated with Imatinib as first line therapy.
Chronic phase disease patients who are non-responders or have sub-optimal

response may be considered for SCT if aged < 65 yrs with a fully matched
sibling donor.
Such patients should be referred to local Transplant Consultant and

counselled regarding the risks / benefits of SCT.
Patients may choose SCT as 2nd line treatment or prefer a trial of a 2nd line
TKI first.
Patients failing 2nd line TKI should be considered for SCT from either sibling
donor or alternative donor
5.9. Conditioning Protocol
<55 years Consider fully myeloablative conditioning transplant or mini-allo

trial
> 55 yrs Reduced intensity conditioning transplant (local protocol)
6.0. Treatment of Accelerated Phase Disease

Starting dose of Imatinib 600 mg to control disease
Monitor as per section 5.3.
If the patients disease responds they should be considered for SCT (sib allo
or UD) after approx 6 months of Imatinib as response to Imatinib unlikely to be
durable
If patient does not respond after 3m change to dasatinib or nilotinib/other

licensed tyrosine kinase inhibitor, consider admission to trial. Consider for
SCT if response
Consider Interferon alpha, busulphan or long term hydroxycarbamide
6.1. Assessment of response (Accelerated Phase Disease at Diagnosis)

o Have failed to achieve haematological remission
After 6 months of therapy
o Have failed to achieve at least 35% Ph-negativity

o Have failed to achieve complete cytogenetic response
7.0. Treatment of Blast Crisis

Starting dose of Imatinib 800mg to control disease
Monitor as per section 5.3
If no response (i.e.still > 20% blasts) after 4 weeks switch to Dasatinib

(Nilotinib not licensed for blast crisis)
If no response to 2nd line TKI consider combination chemotherapy (eg FLAG /

ADE)
If the patients disease responds and transplant candidate consider SCT (sib
or UD donor) as response to TKIs unlikely to be durable.
7.1. Assessment of response (Blast Crisis at presentation)
- Have failed to achieve complete haematological response (return to CP

disease).
- Have failed to achieve at least a partial cytogenetic response
7.2. Progression to blast cell crisis on Imatinib
Change to dasatinib or nilotinib/alternative TKI
If the patient is fit consider AML type induction chemotherapy (eg FLAG /
ADE)
If control obtained, consider SCT (allo or MUD)
o if patient is unsuitable for intensive treatment consider busulfan or

hydroxycarbamide
8.0 Use of Second Line Tyrosine Kinase Inhibitors
Dasatinib and Nilotinib are licensed for use in CP patients who have failed
Imatinib therapy (see section 5.4)
Consider switching to 2nd line agent for non-responders to Imatinib as outlined

in Section 5.5 after checking Imatinib level, mutation status and after trial of
higher dose Imatinib 600 mg for 3 months (see Algorithm for use of 2nd line
TKIs (Appendix 2)
These drugs may also be used for CP patients (see Section 4 for definition)
who are intolerant of Imatinib (see section 5.6)
Such patients should be discussed at the appropriate MDT

Analysis for possible bcr-abl mutations should be undertaken for all such
patients (EDTA sample to Hammersmith)
The presence of a mutation may aid the decision of which agent to choose
since some mutations are known to respond better to one agent or another
If no mutation is detected then choice of agent is at the discretion of the

treating physician
Detection of the T315I mutation will exclude patients from 2nd line TKIs which
are unlikely to be effective and such patients should be urgently considered
for SCT
The starting dose of dasatinib is 100 mg od and for nilotinib is 400 mg bd
Monitoring should be as in section 5.3
If patients are on dasatinib therapy monitor for possible pleural effusions and
consider a routine CXR after 4 weeks or if symptomatic
Patients with advanced phase CML (AP/BC see section 4 for definition) who
fail or are intolerant of Imatinib should be switched to dasatinib since the
evidence for efficacy of nilotinib in this situation is not proven and it is
unlicensed for BC disease
Treatment should be discontinued if there is failure to respond after 6 months

of therapy
It may be necessary to switch to another 2nd line agent if there is intolerance

to the first one or if there is a failure to respond and there is no viable
transplant option (ref 13-16)
9.0 Management of CML and Pregnancy

If CML is diagnosed during pregnancy then leucapheresis may be used to
control the wcc initially
Interferon may be considered if beyond the first trimester and Imatinib should
be started after delivery
Due to the risk of teratogenicity of imatinib female patients must be counselled
to use adequate contraceptives whilst taking Imatinib
Female patients wishing to attempt a pregnancy should be counselled and
advised to stop Imatinib treatment for at least 1 month before conception (or
immediately pregnancy is confirmed if accidental pregnancy discovered
Such patients can either be managed with IFN or leucaphereses during

pregnancy and Imatinib restarted on delivery
10.0 Indications for referral to leukaemia MDT
All patients should be referred to the leukaemia MDT at diagnosis.
Any patient who fails Imatinib therapy or has not achieved a complete
cytogenetic response at 12 months must be referred to the MDT
Any patient who is not able to tolerate Imatinib must be referred to the MDT
Any patient who develops disease progression must be referred to the MDT
11.0. Audit
The leukaemia MDT will perform regular audits to ensure that this policy is adhered
to and in particular to assess the following
% of newly diagnosed patients treated according to NICE guidance.(bi-

annual)
% of patients experiencing dose modifications of Imatinib due to toxicity
% of patients undergoing cytogenetic / molecular monitoring according
to this policy
% of patients failing Imatinib therapy
% of patients failing Imatinib therapy who are re-discussed at MDT
% of patients requiring a 2nd line TKI
% of patients responding to 2nd line TKI
% of patients undergoing SCT
Consultation Group
Dr JL Byrne, Dr A Hunter, Dr M Lyttleton, Prof NH Russell, D S Mittal, Dr A Bowen,
Dr K Saravanamuttu, Dr R Faulkner, Dr M Kwan, Dr A Haines, Dr A Smith
References
1. Validation and extension of the EBMT Risk Score for patients with chronic
myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell
transplants.
Passweg JR, Walker I, Sobocinski KA, Klein JP, Horowitz MM, Giralt SA;
Chronic Leukemia Study Writing Committee of the International Bone Marrow
Transplant Registry. Br J Haematol 2004; 125(5):613-20
2. Prognosis and prognostic factors for patients with chronic myeloid leukemia:
nontransplant therapy.
Hasford J, Pfirrmann M, Hehlmann R, Baccarani M, Guilhot F, Mahon FX,
Kluin-Nelemans HC, Ohnishi K, Thaler J, Steegmann JL; Collaborative CML
Prognostic Factors Project Group. Semin Hematol. 2003;40(1):4-12
3. Prognostic Discrimination in Good-Risk Chronic Granulocytic Leukaemia.

Sokal J, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY,
Braun TJ, Clarkson BD, Cervantes F, Rozman and the Italian Cooperative
CML study group. Blood 1984; 63: 789-799
4. Prognostic Discrimination among younger patients with chronic granulocytic

leukaemia: relevance to bone marrow transplantation.
Sokal J, Baccarani M, Tura S, Fiacchini M, Cervantes F, Rozman C, Gomez

GA, Galton DA, Canellos GP, Braun TJ Blood 1985; 66:1352-1357
5. Risk assessment for patients with chronic myeloid leukaemia before

allogeneic blood or marrow transplantation. Chronic Leukemia Working Party
of the European Group for Blood and Marrow Transplantation.
Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A,
Frassoni F, Gahrton G, Kolb HJ, Niederwieser D, Ruutu T, Vernant JP, de
Witte T, Apperley J. Lancet. 1998 Oct 3;352(9134):1087-92.
6. NICE appraisal no 70 Full guidance on the use of imatinib for chronic myeloid
leukaemia. October 2003
7. Evolving concepts in the management of chronic myeloid leukaemia:

recommendations from an expert panel on behalf of the European
LeukaemiaNet. Blood. 2006; 108:1809-1820
8. New tyrosine kinase inhibitors in chronic myeloid leukaemia. Martinelli et al,

Haematologica (2005) 90: 534-541
9. Nilotinib (formerly AMN 107), a highly selective BCR-ABL tyrosine kinase

inhibitor, is effective in patients with Philadelphia-chromosome positive
chronic myeloid leukaemia in chronic phase following imatinib resistance and
intolerance. Kantarjan et al, Blood 2007, 110: 3540-3546
10. Dasatinib induces notable haematologic and cytogenetic responses in chronic

phase chronic myeloid leukaemia after failure of imatinib therapy. Hochhaus
et al, Blood first edition paper prepulished on-line Nov 30 2006
Dasatinib induces complete haematologic and cytogenetic respnses in

patients with imatinib resistant or intolerant chronic myeloid leukaemia in blast
crisis. Cortes et al, Blood first edition paper pre-published on line Dec 21,
2006
12. European LeukemiaNet criteria for failure or suboptimal response reliably

identify patients with CML in early chronic phase treated with imatinib whose
eventual outcome is poor. Marin D et al. Blood 2008
13. Giles F, Le Coutre PD, Bhalla KN et al Efficacy and tolerability of Nilotinib in

chronic myeloid leukaemia patients in chronic phase (CML-CP) who failed
prior imatinib and dasatinib therapy: updated results of a Phase II study.
Blood 2008;12(11) Abstract #3234
14. Quintas-Cardama A, Kantarjian H, Jones D, Nicaise C, O'Brien S, Giles F,

Talpaz M, Cortes J. Dasatinib (BMS-354825) is active in Philadelphia
chromosome-positive chronic myelogenous leukemia after imatinib and
nilotinib (AMN107) therapy failure. Blood. 2007 Jan 15;109(2):497-9
15. Breccia M, Cannella L, Nanni M, Stefanizzi C, Alimena G.

Nilotinib can override dasatinib resistance in chronic myeloid leukemia
patients with secondary resistance to imatinib first-line therapy. Acta
Haematol. 2007;118(3):162-4. Epub 2007 Sep 20.
16. Baraska M, Lewandowski K, Gniot M, Iwoa M, Lewandowska M, Komarnicki

M. Dasatinib treatment can overcome imatinib and nilotinib resistance in CML
patient carrying F359I mutation of BCR-ABL oncogene.
J Appl Genet. 2008;49(2):201-3.
APPENDIX ONE
Calculation of Sokal Score
To calculate the Sokal score the following information is required:
Age in years
Spleen size below the costal margin in cm
Platelet count on FBC
Blast cell percentage in the peripheral blood
The calculation can be done via the Hammersmith website www.ihnet.org by clicking
on the word Sokal in the diagnosis screen
Calculation of the Hasford Score
To calculate the Hasford score the following information is required:
Age in years
Spleen size below the costal margin in cm
Platelet count on FBC
Blast cell percentage in the peripheral blood
Basophil count
Eosinophil count
The calculation can be done via the Hammersmith website www.ihnet.org and
clicking on the word Hasford in the diagnosis screen.
Appendix 2 Switching to 2nd Line Tyrosine Kinase Inhibitors
Failure to achieve complete Failure to achieve partial Failure to achieve major

haematological response cytogenetic response cytogenetic response
after 3m Imatinib after 6m Imatinib after 12m Imatinib
Failure to achieve Loss of cytogenetic

complete cytogenetic response or 1 log increase
response after 18m in bcr-abl transcripts
Imatinib
Send blood for bcr-abl

mutation analysis and
Grade 3-4 toxicity imatinib level. Increase
on Imatinib dose Imatinib to 600 mg
No bcr-abl mutation Bcr-abl mutation T315I bcr-abl

identified present (not T315I) mutation identified
Is the patient responding Start 2nd line tyrosine Stop Imatinib or 2nd
to and tolerating high kinase inhibitor (eg line TKI. Consider
No dasatinib or nilotinib) allograft or other
dose Imatinib?
Monitor response at 3m experimental Rx
Yes
Has the patient had a No Stop Imatinib or 2nd

Continue high dose
Imatinib response after 3-6m? line TKI. Consider 3rd
line agent, allograft or
other experimental Rx
Yes
Continue 2nd line TKI

and monitor 3 monthly

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East Midlands Network Guidelines for the Investigation

and management of Patients

Written by Dr. JL Byrne, Dr A Hunter, Dr M Lyttlelton

1. Definition of Chronic Myeloid Leukaemia (CML)

The following should be performed at diagnosis before treatment is initiated

Venepuncture for the following investigations:

BMA and trephine with:-

Consider Fertility options

4. Assessment of disease status at diagnosis

Blasts less than 10% in bone marrow and peripheral blood

Blasts 10-19% in bone marrow or peripheral blood

Blasts in peripheral blood or bone marrow > 20%

5.0 Treatment of Chronic Phase

If evidence of leukostasis discuss white cell depletion with local BMT

If need to initiate immediate treatment, hydroxycarbamide (hydroxyurea) until

5.1. Dose of Hydroxycarbamide

If WCC < 100, hydroxycarbabmide is not indicated

If WCC> 100 and <200 prescribe Hydroxycarbamide 1 to 2g/day dependent

If WCC>200 prescribe 2g/day

5.2. Dose of Imatinib in Chronic Phase

The starting dose of imatinib is 400mg a day orally.

Dose interruptions or reductions may be necessary if Grade 3 haematolgoical

Re-escalation of doses to 400 mg daily should be attempted when counts

In patients who develop recurrent neutropenia on imatinib the use of G-CSF

5.3. Monitoring of Patients on Imatinib

BMA with karyotype: at diagnosis

Q-pcr: for bcr-abl 3 monthly from achievement of major

repeat in 1 month if > 1 log rise

Mutational analysis: primary treatment failure

Imatinib levels: Consider if sub-optimal response /

5.4 Assessment of Response to Treatment

Good response is defined as a complete cytogenetic response by 12 months and a

Patients will be considered as non-responders if:

After 3 months of imatinib therapy:

After 6 months of imatinib therapy:

o Have failed to achieve at least 35% Ph-negativity

After 12 months of imatinib therapy:

o Have failed to achieve complete cytogenetic response

Although achievement of a major molecular response (bcr-abl/abl ratio of < 0.1 by 18

5.5 Management of non-responders

Assess patient for non-compliance (consider Imatinib level)

Assess patient for allogeneic transplantation and tissue type siblings

Increase dose of Imatinib to 600mg

Send sample for bcr-abl mutation status

Consider switch to 2nd line tyrosine kinase inhibitor if no response to higher

Choice of 2nd line agent (Dasatinib / Nilotinib) at treating physicians discretion

5.6. Management of patient intolerance

Grade 1-2 non-haematological toxicity is common and may resolve following

Dasatinib or nilotinib / alternative TKI if persistent Grade 2 or greater non-

Interferon or Peg Interferon

Hydroxycarbamide long term

5.7. Loss of Response or Disease progression:

A patient may be regarded as having lost his/her response to imatinib if:

They lose a complete haematological response, or

5.8 Role of Stem Cell Transplant (SCT)

All patients should be treated with Imatinib as first line therapy.

Chronic phase disease patients who are non-responders or have sub-optimal

Such patients should be referred to local Transplant Consultant and

5.9. Conditioning Protocol

<55 years Consider fully myeloablative conditioning transplant or mini-allo

> 55 yrs Reduced intensity conditioning transplant (local protocol)

6.0. Treatment of Accelerated Phase Disease

Monitor as per section 5.3.

If patient does not respond after 3m change to dasatinib or nilotinib/other