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Guidelines for Acute leukaemia and myelodysplastic/myeloproliferative disorders of 54

Title: Clinical management guidelines for Acute Leukaemia and Myelodysplastic/Myeloproliferative disorders

Author(s)

Professor MF McMullin

Ownership:

Approval by: Haematology CRG & NICaN Drugs & therapeutics Committee

Approval date:

May 2016

Operational Date:

May 2016 Next Review:

May 2017

Version No. 1.1 Supercedes 1.0

Links to other policies

Version control for drafts:

Date Version Author Comments

February 2016

1.0 Prof MF Mullan

Amended to reflect comments from D&T Committee

May 2016 1.1 Prof MF Mullan


Good medical practice and the Manual of Cancer Services Chemotherapy Measures mandate the use of agreed guidelines on use of SACT within each disease site. For each disease site these guidelines should specify the acceptable ranges of regimen options for named steps on the patient pathway to include adjuvant/neo-adjuvant, first/second etc. line palliative regimens and ideally should include decision trees. References must be included for each regimen. They should be updated every 2 years. The guideline should specify if a treatment is not recurrently funded. Only those regimens listed in the guideline will be available for use in the particular disease site. The SACT regimen protocols will be produced using the guidelines for every regimen listed in the disease site SACT guideline and will contain additional detail on route of administration, tests required prior to starting a course, dose modifications etc. The minimum acceptable dataset is completion of

Page 1

For each step on the patient pathway (neo-adjuvant/adjuvant/etc each line of palliative treatment) – as a minimum an algorithm containing the detail below is sufficient for now with the understanding that the full guideline will be completed in the near future

o Drug name and dose o If there is more than one choice the guideline should specify why one

regimen would be chosen as opposed to another o References

Completed signature page

Each guideline should be in the Regional format and be signed up to by each consultant working within the disease. The hard copy with signatures and electronic version should be sent to Bridget Tourish. It will then be uploaded onto RISOH.


Authorisation of Systemic Anti-Cancer Therapy (SACT) Guidelines for acute

leukaemia and Myelodysplastic/Myeloproliferative disorders These SACT guidelines are accepted for the treatment of acute leukaemia and myelodysplastic/myeloproliferative disorders

Consultant Haematologist Signature Print Name/Title

Dr Consultant Haematologist











Dr

Signature Print name/Title Date

Written by Systemic Guidelines Author

Professor McMullin, Consultant Haematologist

Approved by Site Clinical Lead


Approved by SACT Clinical Lead/Clinical Director

Dr Clinical Director/SACT CL

Review Date


Consultant Haematologist












1.0 INTRODUCTION / PURPOSE OF POLICY

1.1 Background

Systemic anti-cancer therapy (SACT) is a key treatment in acute leukaemia. These

guidelines describe the agreed management for patients with acute leukaemia, and

myelodysplastic/myeloproliferative disorders. These guidelines should be read in

conjunction with the latest and applicable national /international guidance.

1.2 Purpose

To ensure consistent use of SACT for patients with acute leukaemia, and

myelodysplastic/myeloproliferative disorders.

2.0 SCOPE OF THE POLICY

This document is aimed at all clinical staff involved in the management of patients

with acute leukaemia, and myelodysplastic/myeloproliferative disorders . They are

designed to supplement current national and international guidelines and NICE/

SMC advice relating to these disorders. It should be noted that these CMG

guidelines are written to reflect current advice and practices but regular updating will

be required as new evidence emerges.

3.0 ROLES/RESPONSIBILITIES

It is the responsibility of all clinical staff involved in the management of patients with

acute leukaemia, myelodysplastic/myeloproliferative disorders to familiarise

themselves with these guidelines.


4.0 Key policy principles 4.1 Acute Myeloid Leukaemia 4.1.1 Diagnostic criteria 4.1.2 Primary treatment 4.1.3 Acute promyelocytic leukaemia (APL) 4.1.4 Poor risk, refractory or relapsed patients 4.1.5 Relapsed APL 4.2 Indications for allogeneic transplant in AML 4.3 Precursor Cell Lymphoblastic leukaemia in

adults

4.3.1 Diagnostic criteria 4.3.2 Risk factors, Remission status and

investigations

4.3.3 Primary treatment 4.3.4 Adults not suitable for UKALL 14 entry 4.3.5 Treatment of primary refractory disease 4.3.6 Treatment of ALL relapsing after CR 4.3.7 CNS Leukaemia at diagnosis 4.4 Myelodysplastic Syndromes 4.5 Myelodysplastic/Myeloproliferative Neoplasms 4.5.1 CML 4.5.2 Primary therapy in CML 4.5.3 Management of CML patients who are resistant

or intolerant to imatinib

4.5.4 Management of CML in Pregancy 4.5.5 Bone marrow transplantation 4.6 Chronic Myeloproliferative disorders


4.1 Acute myeloid leukaemia 4.1.1 Diagnostic Criteria Core Criteria • More than 20% blast cells by flow cytometry, or morphology when the quality of the EDTA sample is sub-optimal (use higher figure), or more than 5% blasts in the presence of a balanced translocation Peripheral blood (PB) with high white count in older patients is acceptable. However, cytogenetics not valid on PB samples. • Myeloid lineage demonstrated by immunophenotype • The immunophenotype can be one of two patterns: Type A: CD34+, CD117+, CD13+, CD33+, HLA-DR+, cCD3-, cCD79- Type B: CD34-, CD117+, CD13+, CD33+, CD15var+, cCD3-, cCD79-, MPO+ (by flow) Intermediate phenotypes occur and are acceptable to define myeloid lineage. • Cytogenetics allows risk stratification. Cytogenetic analysis should be mandatory in the initial/diagnostic evaluation of all patients and at suspected or confirmed relapse. • Molecular analysis

FLT3 ITD: 40% CN (cytogenetically normal) AML

NPM1 mutation: ~50% CN AML, CEBPmutation: ~15% CN AML All cases of acute promyelocytic leukaemia (APML) must have: • CD34+/-, CD13-hetero+, CD33-homo+++, CD117+, CD15-, HLA-DR-, MPO+++ (by flow)

• Microparticulate pattern with anti-PML

• Confirmation of t(15;17) by cytogenetics and PML/RARA pcr

Essential Investigations

• Coagulation screen

• Renal and liver function tests

• CXR

• ECG +/- echocardiogram


Definitions;

Induction chemotherapy is given to induce a complete remission – in NCRI (MRC) trials

this is defined as a normocellular marrow with less than 5% blasts.

Consolidation or post-remission chemotherapy is necessary to prevent early relapse

and increase the chance of cure, and may include stem cell transplantation.

Risk stratification is used to determine consolidation therapy. From the results of AML 10

and 11 the MRC have defined the following risk groups:

Good risk: Any patient with favourable genetic abnormalities – t(8;21), inv(16),

t(16;16), irrespective of other genetic abnormalities or marrow status after Course 1.

Standard: Any patient not in either good or poor risk groups.

Poor risk: Any patient with more than 15% blasts in the bone marrow after Course

1, or with adverse genetic abnormalities: -5, -7, del(5q), abnormal (3q) or complex

(5 or more abnormalities) – and without favourable genetic abnormalities or with

Flt3 ITD

(Grimwade, et al 2001, Kottaridis, et al 2001, Wheatley, et al 1999)

AML17 uses a new risk index derived from outcome data from previous AML trials.


4.1.2 Primary Treatment in Acute leukaemia

All cases of acute myeloid leukaemia, except acute promyelocytic leukaemia

• All eligible patients up to age 60, or above this and suitable for intensive therapy, with de

novo or secondary AML should be considered for entry to NCRI AML AML17 trial and

subsequent trials.

• Non-trial standard and favourable risk patients (except APML) fit for intensive

chemotherapy should receive standard DA induction chemotherapy .

Da 60 3+10

Daunorubicin 60mg/m2 Days 1,3,5 Ref: AML17 trial protocol

Cytarabine 100mg/m2 twice daily

Days 1-10

followed by:

Da 3+8

Daunorubicin 50mg/m2 Days 1,3,5 Ref: AML17 trial protocol

Cytarabine 100mg/m2

twice daily Days 1-8

Options for non-trial consolidation chemotherapy includes HD AraC or MIDAC and/or stem

cell transplantation. Consider MiDAC in adverse-risk cytogenetics (Burnett et al. 2013; J Clin

Oncol).

Midac

Mitoxantrone 8mg/m2 Days 1 to 3 Ref: AML 14 trial


Days 1 to 3

High dose Cytarabine


Days 1,3,5 Ref: AML 15 trial


Stem cell transplantation for non-trial standard risk patients is not routinely recommended

but should be considered and discussed on a case by case basis. Stem cell

transplantation in CR1 should be considered as course 3 or 4 for non-trial patients with

adverse risk.

• All patients over the age of 60 with acute myeloid leukaemia (except Acute Promyelocytic

Leukaemia) de novo or secondary AML who are fit for intensive treatment should be

entered into AML 18 trial when available. They should normally be over the age of 60, but

patients under this age are eligible if they are not considered fit for the MRC AML17 trial.

Conversely fit patients in their early 60s may be considered for AML17. If a clinician is not

willing to randomise between the chemotherapy options, then DA should be given.

• Patients >60 unable to tolerate induction should be entered into the non-intensive arm of

AMLL1 or the TAP Trial RaVVa as available. Non-trial patients lacking an adverse risk

karyotype are candidates for low-dose Ara-C. AML with 20-30% blasts should be

considered for 5-azacitidine therapy.

Low Dose Cytarabine (Ara-C)

Cytarabine 20mg twice daily

Days 1-10 Ref: AML 14 trial

Azacitidine

Azacitidine 75mg/m2 Days 1-7 Ref: Itzykson et al. Blood 2011

• All induction remission chemotherapy should be delivered in level II/III trusts. Non-

intensive arm can be delivered in level 1 after discussion in MDT.

• Patients not able to tolerate induction chemotherapy should be treated palliatively or

offered experimental therapy where available.


4.1.3 Treatment Acute promyelocytic leukaemia (APL)

• All eligible patients up to age 60 with APL should be asked to participate in the NCRI

AML 18 trial when available.

• APL patients in complete remission (CR) should have molecular monitoring by bone

marrow and blood examination every 3 months for 2-3 years to look for signs of early

relapse.

• Non-trial patients should be treated per AML15 Spanish arm protocol with molecular

monitoring

AML15 Spanish Arm

Spanish Arm Course 1

Idarubicin 12 mg/m2 Days 2, 4, 6 and 8 Ref: AML15

ATRA 45mg/m2/day On day 1 of induction therapy until first CR is achieved or until completion of 2 courses of chemotherapy


Idarubicin 7 mg/m2 Days 1, 2, 3, 4 Ref: AML15

ATRA 45 mg/m2 /day On days 1-15 (15 doses) if patient is in CR after Course 1, otherwise ATRA until morphological CR.


Mitoxantrone 10 mg/m2 Days 1-5 Ref: AML15

ATRA 45 mg/m2 /day Days 1-15


Idarubicin 12 mg/m2 Day 1 Ref: AML15

ATRA 45 mg/m2 /day Days 1-15

Spanish Arm maintenance x 2 years

6-Mercaptopurine 50mg/m2 PO Daily Ref: AML15

Methotrexate 15/mgm2 PO Once weekly

ATRA 45 mg/m2 /day Days 1-15 every 3 months

Note hold 6-mercaptopurine and Mtx when taking ATRA


• Consider ATO+ATRA as 1st line treatment - Induction and consolidation of patients not

eligible for the AML17 trial, specifically those > 60 years for whom anthracyclines are

contraindicated or where myelosuppression is to be avoided (Slack, JL et al 2002, Estey E

et al Blood 2006, Sanz MA et al 2009).

Arsenic Trioxide + ATRA induction for patients not suitable for anthracycline/standard therapy

Arsenic Trioxide 0.3mg/kg D1-5 (wk 1) Ref: AML 17

Arsenic Trioxide 0.25mg/kg Twice weekly (wk 2-8)

ATRA 45mg/m2 D-1 – continued until remission is achieved

Arsenic Trioxide + ATRA consolidation for patients not suitable for anthracycline/standard therapy

Arsenic Trioxide 0.3 mg/kg D1-5 Wk 1 Ref: AML 17

Arsenic Trioxide 0.25 mg/kg Twice weekly Wk 2-4 Then 4 weeks off then repeat for total of 4 cycles

ATRA 45mg/m2 Wk 1-2, wk 5-6, 9-10 13-14, 17-18, 21-22, 25-26

4.1.4 Poor risk, refractory or relapsed patients

(Craddock, et al 2005, Kantarjian, et al 2003).

• For patients aged <60 yrs, consider use of prognostic index, (Breems et al 2005) which

considers duration of first complete remission, cytogenetics at diagnosis, age at relapse,

and whether previous stem-cell transplantation was performed. The index divides patients

into 3 groups: group A (overall survival [OS] of 70% at 1 year and 46% at 5 years), an

intermediate risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk

group C (OS of 16% at 1 year and 4% at 5 years).

Options are DA, Flag-Ida or MEC depending on what treatment the patient has

previously received for treating poor-risk, relapsed or refractory AML outside a clinical trial.

Mylotarg 3mg/m2 may be added if patient has an allogeneic transplant option. (Mylotarg is

not recommended if patient has previously received the same). NOTE currently Mylotarg is

not available for use in routine management of AML.


Flag-IDA

Filgrastim 30MIU Days 1-7 Ref: AML17 – MRC protocol. Idarubicin 8mg/m² Days 4, 5, 6

Fludarabine 30mg/m² Days 2-6

Cytarabine 2000mg/m² Days 2-6

MEC

Mitoxantrone 8mg/m2 Days 1-5 Ref: Kohrt, H.E. et al Am. J. Hematol 2010; 85:877-881 Waddell J.A. et al Hospital Pharmacy 2003. 218-221

Etoposide 100mg/m2 Days 1-5

Cytarabine 1000mg/m2 Days 1-5

Gemtuzumab Ozagamicin (Mylotarg) in conjunction with AML chemotherapy regimens

Gemtuzumab 3mg/m2 Days 1 Ref: AML15 – MRC protocol. Sievers EL et al JCO, 2001

• All suitable patients should be discussed with a transplant specialist to consider stem cell

transplantation in CR2. (Level 4). Patients refractory to second line therapy or with short

CR1 and refractory to re-induction should be discussed with the transplant team for

consideration of combined chemotherapy-reduced intensity transplants.

4.1.5 Relapsed Acute Promyelocytic Leukaemia

Follow AML15 algorithm namely ATO (Arsenic Trioxide) followed by stem cell transplantation (auto if PCR negative, allo if positive).

Induction Treatment

One of two treatment schedules can be followed for induction:

A) ATO 0.15mg/kg daily by a slow (1-2 hour) infusion for a maximum of 50 days.

B) ATO 0.30mg/kg daily for 5 days followed by 0.25mg/kg twice weekly for up to 7 weeks

Patients should have a marrow re-assessment at 28 days which should include

molecular assessment. If the patient is in morphological and molecular remission


they should enter consolidation treatment. If the patient is not in haematological

remission or is in haematological but not molecular remission two doses of

Idarubicin (10mg/m2) should be added on 2 consecutive days and the

morphological and molecular status re-checked 2 weeks later. The ATO treatment

should be continued at the induction dose. When the patient is confirmed to be in

haematological remission they should enter the consolidation phase.

Aresnic Trioxide – induction therapy in relapsed setting

Arsenic Trioxide 0.30mg/kg Days D1-5 (wk 1) Ref: MRC AML15

Arsenic Trioxide 0.30mg/kg Twicwe weekly (wk 2-7)

• Older patients, if initially fit for induction chemotherapy and CR duration > 1 year,

consider offering re-induction. If not fit for re-induction or short CR, experimental therapy or

supportive care.

4.2 Current indications for referral for consideration for allogeneic stem

cell transplant in AML

All patients must be considered fit for allogeneic stem cell transplant

Clear indications

Adverse risk by karyotypic risk group or AML17 index high-risk

Relapsed AML in CR2 (relapsed APL only if not in molecular CR after re-

induction).

Should be considered

FLT3 ITD mutated (+/- NPM1 mutation): although poorer prognosis, the evidence

for a benefit from allo SCT remains inconsistent.

Minimal residual disease detected after course 1 or 2 induction therapy: again

almost certainly poorer prognosis but no benefit for allo SCT yet demonstrated (lack

of randomised controlled trials or large cohort studies to date).

Standard risk patients lacking a molecular abnormality: inconsistent trial data


Core-binding factor with either persistent high-level minimal residual disease

and/or c-kit mutation

Not currently recommended

Favourable risk AML, traditionally defined as APL or core-binding factor leukaemia

Normal karyotype with either NPM1 mutation or biallellic CEBPmutation as a sole

molecular abnormality: these AML subtypes have a good prognosis with

chemotherapy alone and should not receive an allograft in CR1.

Please consider all patients with limited co-morbidity for suitability for allogeneic stem cell

transplantation and discuss with the BCH transplant team. Novel approaches to allo SCT

are also emerging including combined chemotherapy – RIC SCT for previously ineligible

patients.

Transplant protocols –

Cyclophosphamide ATG – aplastic anaemia -sibling allograft

Cyclophosphamide IV 50mg/kg D-5 to D-1 Storb R et al. Biol Blood Marrow Transplant. 2001; 7(1): 39-44. Storb R et al

Blood 1994; 84(3): 941-49

Rb-ATG test dose 2.75mg only D-6

Rb-ATG 3.75/kg D-4 to D-2

Cyclophosphamide TBI – AML/ALL- sibling allograft

TBI D-7 to -4

Cyclophopshamide IV 60mg/kg D-3 to D-2 Deeg H J et al. Bone Marrow Transplantation 1986 Dec; 151-7 Clift R A et al Blood 1990 Nov 1;76 (9): 1867-71

Rest D-1

Stem cell return D 0

Busulphan cyclophosphamide –AML/ALL- sibling allograft

Busulphan IV 3.2mg/kg D-8 to D-5 Kashyap A et al. Biology of Blood and Marrow Tranplantation 2002; 8: 493-500

Cyclophosphamide IV 60mg/kg D-3 to D-2


Flu Mel Campath AML – RIC

Fludarabine 30 mg/m2/day D–7 to D–3 AML 15

Melphalan 140 mg/m2 D-2

Campath 1H IV 20mg/day D-8 to D-4

FBC- (FLU BU Campath)* RIC

Fludarabine 30mg/m2 D-9 to D-5 AML 15

Busulphan 4mg/kg/day D-3 to d-2

Campath 1H 20mg/day IV D-5 to D-1

* use of phenytoin and low molecular weight heparin for VOD

prophylaxis is optional)

Flamsa-BU for patients up to 60 years old with high risk disease

Fludarabine 30mg/m2 D-12 to D-9 AML 17 trial protocol

Cytarabine 2000mg/m2 D-12 to D-9

Amsacrine 100mg/m2/d D-12 to D-9

REST day D-8to D-6

Busulphan IV 3.2mg/kg x 3 hrs D-5 to D-3

Busulphan IV 1.6mg/kg x 3 hrs D-2

FludarabineIV 30mg/m2 x 1hr D-3 to D-2

ATG 10mg/kg – sibling donors 20mg/kg for unrelated donors

Initiation GVHD propylaxis Ciclosporin D-1

Initiation GVHD propylaxis MMF D0

Infusion of HPC-A/ HPC-BM D0

GVHD prophylaxis- this will be regimen specific and will include ciclosporin and

Methotrexate.


4.3 PRECURSOR CELL LYMPHOBLASTIC LEUKAEMIA IN ADULTS

4.3.1 Diagnostic Criteria

Precursor B-cell Lymphoblastic Leukaemia

Typical Cases

• Bone marrow or solid tissue infiltration with blast cells

• Immunophenotype: CD19+, CD22+, TdT+, CD117-, CD34var, CD45 wk

Variants

• BCR-ABL associated phenotype: CD34-homo+++, CD10-homo+, CD13+ and/or CD33+,

CD38wk/-.

• t(12;21) associated: common ALL phenotype with CD10-hetero+, CD13+ and/or CD33+.

Precursor T-lymphoblastic Leukaemia

Typical Cases

• Bone marrow or solid tissue infiltration with blast cells

• Immunophenotype: CD19-, TdT+, cCD3+, CD2+, CD7+, CD22-, MPO- (by flow)

Immunologic classification of ALL (Ludwig, et al 1994)

B –lineage

Pro B-ALL HLA-DR+, TdT+, and /or CD79+ and /or CD22+, CD10 -, cy IgM-/surface Ig-

Cytogenetics t(4;11), Molecular genetics:ALL1(MLL)-AF4

Common-ALL HLA-DR+,TdT+, and /or CD79+ and /or CD22+, CD10+, cy IgM-/surface Ig-

Cytogenetics: t(9;22), Molecular genetics: BCR-ABL

Pre B-ALL HLA-DR+,TdT+, and /or CD79+ and /or CD22+, CD10+/-, cytoplasmic

immunoglobulin (cyIgM) + Cytogenetics: t(9;22), t(1;19), Molecular genetics: BCR-ABL;

E2A-PBX1 B-ALL HLA-DR+,TdT+, and /or CD79+ and /or CD22+, CD10+/-, surface

immunoglobulin (sIgM+)

Cytogenetics: t(8;14), Molecular genetics: CMYC-IgH


T-lineage

Early T-ALL TdT+, cytoplasmic CD3(cyCD3)+,CD7+,CD5+/-,CD2+/-

Cytogenetics: t(11;14), Molecular genetics: LMO1/–TCRa/d

Cortical T-ALL TdT+, cyCD3+, CD7+, CD1a+, Surface CD3(sCD3)+/–

(ThyALL) Cytogenetics: t(10;14), Molecular genetics: HOX-11-TCRa/d

Mature T-ALL TdT+, sCD3+,CD1a***

4.3.2 Risk factors, remission, essential investigations

Risk factors: any of the following

Age >35 years

WBC at Diagnosis: B ALL >30 x109/L, T ALL>100 x109/L

Cytogenetics: (Moorman, et al 2007) Ph chromosome, t(4;11)(q21;q23),

t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low

hypodiploidy/near triploidy (Ho-Tr)

Definition of Remission Status

When a blast cell population with a leukaemia-associated phenotype is detected

unequivocally by flow cytometry or PCR and not by morphological assessment it will be

reported as morphological remission but not in remission by flow or PCR with the extent of

infiltration stated.


• Coagulation screen and fibrinogen

• Renal and liver function tests

• CXR

• ECG +/- echocardiogram

• Consideration of options for transplantation

• Lumbar puncture as part of treatment protocol


4.3.3 Primary Treatment

(Annino, et al 2002, Manera, et al 2000, Pui, et al 2003, Vilmer, et al 2000)

Patients aged 25 years or over with Philadelphia negative ALL:

UKALLXIV trial is open and patients should enter trial if consent or follow protocol (N.B.

patients should still be registered with CTSU at diagnosis for MRD study) All new patients

should be discussed with the transplant service, as there are a number of issues that will

be helped by prior warning/ consideration.

Patients aged 25 years or older with Philadelphia positive ALL (up to age 60):

UKALLXIV Ph positive arm is open and should be encouraged to enter into trial.

Patients aged 15-24 (up to 25th birthday) with Ph neg ALL:

Patients aged 15-24 (up to 25th birthday) with Ph pos ALL:

Should follow UKALL2003 and if found to be Ph positive, such patients should transfer

back to UKALLXIV Ph pos arm . NOTE it is anticipated that UKALL 2011 will be opened in

2016 . However if found to be Ph positive, such patients should transfer back to UKALLXIV

Ph positive arm.

Adults (Ph+ve) eligible but not in trial

Should be treated with the current NCRI UKALL XIV trial protocol. Early notification to the

transplant team is essential for these patients.

ALL Phase 1 Induction

Daunorubicin 30mg/m2 Days 1,8,15,22 Ref: UKALL 14 trial

Vincristine 1.4mg/m2 (max dose 2mg)

Days 1,8,15,22

Dexamethasone 10mg/m2 Days 1-4, 8-11, 15-18

PEG Asparaginase** 1000iu/m2 IV Day4, 18

Imatinib 400mg (escalating to 600mg after 2 weeks depending on tolerance)

Day 1-28

Methotrexate 12.5mg Intrathecal Day 14

**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol – patients >40 years should omit Day 4. PH+ve patients should not receive PEG asparaginase**


ALL Phase 2 Induction

Cyclophosphamide 1000mg/m2 IV Days 1,15 Ref: UKALL 14 trial

Cytarabine 75mg/m2 IV Days 2-5, 9-12, 16-19,23-26

Mercaptopurine 60mg/m2 PO Days 1-28

Imatinib 600mg as tolerated and continued until transplant if possible.

Methotrexate 12.5mg Intrathecal Days 1,8,15,22

ALL Intensification therapy

Methotrexate 300mg/m2 Day 1,15 Ref: UKALL 14 trial

Methotrexate* 2700mg/m2 Day 1,15

PEG Asparaginase** 1000iu/m2 IV Day 2, 16


*NOTE folinic acid resuce must be given – consult with protocol for details. **PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol**

ALL Consolidation Cycle 1

Cytarabine 75mg/m2 Days 1,2,3,4,5 Ref: UKALL 14 trial

Etoposide 100mg/m2 Days 1,2,3,4,5

PEG Asparaginase** 1000iu/m2 IV Day 5



**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol**






**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol


ALL Consolidation Cycle 3 days (1-28)

Daunorubicin 25mg/m2 Days 1,8,15,22 Ref: UKALL 14 trial

Vincristine 1.4mg/m2 Days 1,8,15,22

PEG Asparaginase** 1000iu/m2 IV Day4

Dexamethasone 10mg/m2 (cap at 20mg)

Day 1-4, D8-11,D15-18, D22-25

Methotrexate 12.5mg Intrathecal Day 2, 17


Day 1-28

**PH +ve patients should receive imatinib as per UKALL14 trial protocol, PH-ve patients should receive peg-asparaginase as per UKALL 14 trial protocol**

ALL Consolidation Cycle 3 (days 29-42)

Cyclophosphamide 1000mg/m2 Day 29 Ref: UKALL 14 trial

Cytarabine 75mg/m2 Days 30-33, 37-40

Mercaptopurine 60mg/m2 Day29-42

Dexamethasone 10mg/m2 (Cap at 20mg)

Day 1-4, D8-11, D15-18, D22-25


Day 29-42






ALL Maintenance therapy (Non transplant ) continue for 2 years

Vincristine 1.4mg/m2 IV Every 3 months Ref: UKALL 14 trial Prednisolone 60mg/m2 PO 5/7 every 3 months

Mercaptopurine 75mg/m2 PO Daily

Methotrexate 20mg/m2 PO or IV Once per week – avoid same day as cotrimoxazole

Imatinib dose depending on tolerance To continue with this throughout maintenance

Methotrexate 12.5mg Intrathecal Once every 3 months


4.3.4 Adults too old for UKALL 14 trial entry

When open should be offered UKALL 60+. Fit patients who are only a few years older than

the cut-off could be discussed with the trial coordinators.

It should be remembered that the prognosis for patients 50-60 years and older is poor,

particularly if there are other poor prognostic features (e.g. Ph+ve/ t(4;11))

1. Fit and informed and willing : consider a UKALLXIV like schedule but may need

reduced dosage or early termination depending on response and tolerance.

2. Less fit, older or uncertain: a less intensive schedule is appropriate.

Outlined below is

Pathway for ALL Philadelphia positive patients

Intensive pathway for ALL Philadelphia negative patients

Intensive + pathway for ALL Philadelphia negative patients

Nonintensive pathway in ALL Philadelphia –ve patient

Pathway for ALL Philadelphia positive patients

Regimen Phase 1 induction elderly ALL (Ph +ve)* 28days

Dexamethasone 3mg/m2 PO Days 1-3 Ref: UKALL60+ Idarubicin 10mg/m2 PO Day 1

Vincristine 1mg/m2 ( cap at 2mg) IV Day 1

Imatinib 400mg/day PO– escalate to 600mg within 2 weeks as tolerated

Days 1-28

Intrathecal Methotrexate 12.5mg IT Days 8,15,22 *Bone marrow aspirate should be performed after day 28 as asoon as maximum counts are

reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to phase

2 when neuts >0.75x 109/L and plts >75x10

9/L. See protocol for further details.


Regimen Phase 2 induction elderly ALL (Ph +ve)* 28 days


Vincristine 1mg/m2 ( cap at 2mg) PO Day 1

Imatinib PO-continue with previously tolerated dose

Days 1-28

Intrathecal Methotrexate 12.5mg IT Days 8,15,22

*Bone marrow aspirate should be performed after day 28 as asoon as maximum counts are

reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to

consolidation when neuts >0.75x 109/L and plts >75x10


Regimen Consolidation elderly ALL (Ph +ve)* 28 days


Vincristine 1mg/m2 ( cap at 2mg) IV Day 1

Imatinib PO-continue with previously tolerated dose

Days 1-28

Intrathecal Methotrexate 12.5mg IT Day 2 only *Bone marrow aspirate should be performed after day 28 as soon as maximum counts are


consolidation when neuts >0.75x 109/L and plts >75x10


Regimen: Maintenance elderly ALL (Ph +ve)* 24 months

6-Mercaptopurine* PO 25mg/m2 – 75mg/m2 starting dose – titrate for counts as per protocol

Daily Ref: UKALL60+

Imatinib PO continue with previously tolerated dose Daily

Prednisolone PO 60mg/m2 5 days every 3 months

Vincristine 1.4mg/m2 IV (max dose 2mg) Days 1-28

Intrathecal Methotrexate 12.5mg IT Every 3 months

*6-mercaptopurine should be started at 25mg/m2/day and then should be increased upwards in 25% increments to tolerance.- see protocol for details

Intensive pathway for ALL Philadelphia negative patients

Regimen Intensive pathway Phase 1 induction elderly ALL (Ph -ve)* 28days

Dexamethasone 6mg/m2 PO Days 1-3, 7-9 Ref: UKALL60+ Idarubicin 14mg/m2 PO Day 1

Vincristine 1mg/m2 (cap at 2mg) IV Day 1,15,22

Intrathecal Methotrexate 12.5mg IT Days 7,14,21 *Bone marrow aspirate should be performed after day 28 as asoon as maximum counts are

reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to Phase

2 when neuts >0.75x 109/L and plts >75x10



.

Regimen Intensive pathway Phase 2 induction elderly ALL (Ph -ve)* 17days

Vincristine 1mg/m2 (cap at 2mg) IV Day 1,15 Ref: UKALL60+ Cytarabine 75mg/m2 IV Day 1-3, 15-17

Cyclophosphamide 300mg/m2 Day 1,15

Intrathecal Methotrexate 12.5mg IT Days 7,14 *Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are


intensification when neuts >0.75x 109/L and plts >75x10

9/L. See protocol for further

details.

Regimen Intensive pathway Intensification elderly ALL (Ph -ve)* 28days

Methotrexate** 1g/m2 IV (infusion as local policy)

Days 1,15

** Local policies may be followed for folinic acid resuce after IV methotrexate

admisnistraion during induction2. REVIEW PROTOCOL FOR SPECIFIC DETAILS.

*Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are


consolidation1 when neuts >0.75x 109/L and plts >75x10

9/L. See protocol for further

details.

Regimen ConsolidationCycle 1,2,3 (28 day cycle to be repeated 3 times) Elderly ALL (Ph -ve)* 28days


Vincristine 1mg/m2 (cap at 2mg) IV Day 1

Methotrexate 5mg/m2 PO Days 1,8,15,22

6-mercaptopurine 50mg/m2 PO Day 1-28

Regimen: Maintenance elderly ALL (Ph -ve)* 24 months

6-Mercaptopurine* PO 25mg/m2 – 75mg/m2

starting dose – titrate for counts as per protocol Daily Ref:

UKALL60+

Methotrexate 5mg/m2 PO weekly Daily

Prednisolone PO 60mg/m2 5 days every 3 months

Vincristine 1.4mg/m2 IV (max dose 2mg) Days 1-28

Intrathecal Methotrexate 12.5mg IT Every 3 months *6-mercaptopurine should be started at 25mg/m

2/day and then should be increased upwards in 25%

increments to tolerance.- see protocol for details


Intensive + pathway for ALL Philadelphia negative patients

Regimen: Intensive + Phase 1 in elderly ALL (Ph -ve)* 28 days cycle

Methotrexate 12.5 mg+Dexamethasone** 4mg IT 2,9,16 Ref: UKALL60+ Vincristine 1mg/m2 IV (max dose 2mg) Day 1,8,15

Doxorubicin 40mg/m2 IV Day 1,8,15

Prednisolone 40mg/m2 divided in 2 daily doses Days 1-21 and taper dose to 0mg D22-28

Intrathecal Methotrexate 12.5mg IT Every 3 months *Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are reached . if counts are not recovered after day 28 – consider bone marrow. Proceed to intensification when neuts >1.0x 10

9/L and plts >100x10


**Dexamthasone 4mg IT may be substituted with hydrocoertisone suspended in 3- 6ml sterile saline.

Regimen: Intensvie + Phase 2 in elderly ALL (Ph -ve)* 22 days cycle

Cytarabine 200mg/m2 IV over 1 hour Day 1,8 Ref: UKALL60+ Etoposide 120mg/m2 IV over 1 hour Day 1,8

Methotrexate** 500mg/m2 IV over 2 hours Day 4,11

Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day 1 *Bone marrow aspirate should be performed after day 22 as asoon as maximum counts are reached . if counts are not recovered after day 35 – consider bone marrow. Proceed to consolidation when neuts >1.0x 10



**Local policies may be followed for folinic acid resuce-

Regimen: Intensive + Consolidation in elderly ALL (Ph -ve)* 21 days cycle

Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day14 Ref: UKALL60+ Vincristine 1mg/m2 IV (max dose 2mg) Day 1,8,15

Doxorubicin 40mg/m2 IV Day 1,8,15

Prednisolone 40mg/m2 divided in 2 daily doses Days 1-21 *Bone marrow aspirate should be performed after day 17 as asoon as maximum counts are reached . if counts are not recovered after day 28 – consider bone marrow. Proceed to consolidation 2 when neuts >1.0x 10


9/L but no sooner than “day 22” of consolidation1. See protocol

for further details. **Dexamthasone 4mg IT may be substituted with hydrocoertisone suspended in 3- 6ml sterile saline.

Regimen: Intensive + Consolidation 2 in elderly ALL (Ph -ve)* 22 days cycle

Cytarabine 1000mg/m2 IV Day1,2 Ref: UKALL60+ Pegylated-asparaginase 1000iu/m2 Day 3,18

OR

E.coli Asparaginase 6000iu/m2 Day3-12

Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day 1

*Proceed to maintenance year 1 when neuts >1.0x 109/L and plts >100x109/L.


Regimen: Intensive + Maintenance year 1 in elderly ALL (Ph -ve)* 13x28 day cycles

Prednisolone 1mg/kg/d PO Day1-7 Ref: UKALL60+ Vincristine 1.4mg/m2 IV (max dose 2mg) Day 1


Methotrexate 15mg/m2 PO Days 8,15,22

Methotrexate 12.5 mg+Dexamethasone** 4mg IT Day 2 **NOTE Methotrexate 12.5 mg+Dexamethasone 4mg IT is to given at day 2 ONLY during the first 4 cycles of maintenance treatment Patients may only proceed to maintenance year 2 after year 1 when neuts >0.75x 10

9/L and plts >75x10

9/L.

Regimen: Intensive + Maintenance year 2 in elderly ALL (Ph -ve)* 13x28 day cycles


Methotrexate 15mg/m2 PO Days Day1,8,15

Nonintensive pathway in ALL Philadelphia –ve patients

Regimen Induction Phase 1 Elderly ALL (Ph -ve)* 28days





Methotrexate 12.5mg IT Once during cycle

Patients may only proceed to phase 2 when neuts >0.75x 109/L and plts >75x109/L.

Regimen Induction Phase 2 Elderly ALL (Ph -ve)* 28days





Methotrexate 12.5mg IT Once during cycle

Patients may only proceed to consolidation 1 when neuts >0.75x 109/L and plts >75x109/L.


Regimen Induction Consolidation Elderly ALL (Ph -ve)* 28days

6-mercaptopurine 25mg/m2 -75mg/m2 PO Daily Ref: UKALL60+ Methotrexate 5mg/m2 PO weekly

Prednisolone 60mg/m2 5 days every 3 months

Methotrexate 12.5mg IT Every 3 months but may be omitted at discretion of treating clinician

Vincristine 1.4mg/m2 (max 2mg/dose) IV Every 3 months

Patients may only proceed to maintenance after consolidation 1 when neuts >0.75x 109/L and plts >75x109/L.

3. Elderly or frail: Vincristine x4 (1mg) and prednisolone followed by standard maintenance

is simple. CNS prophylaxis may be considered on a case-by-case basis, and would be

with serial lumbar punctures following the completion of the vincristine phase.

ALL non intensive

Vincristine 1mg IV Days 1,8,15,22 Ref:

Prednisilone PO 40 mg/m2 Days 1-28 followed by taper

4.3.5 Treatment of primary refractory disease

This will be defined post 2nd phase induction in UKALL XIV regime or equivalent time

point in other treatments.

• See below for a discussion of the use of Imatinib in Ph+ve cases.

Refractory disease has a dismal outlook with no schedule being clearly optimal.

• We suggest HyperCVAD (Kantarjian, et al 2000) for B cell ALL and hyper-CVAD with a

Nelarabine containing regimen for T cell ALL. Other alternatives including FLAG-Ida or

High dose Ara-C schedules or clofarabine alone can be considered as 3nd line treatment.

Nice has not reviewed Nelarabine but SMC has “accepted nelarabine for the treatment of

patients with T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic

lymphoma (T-LBL) whose disease has not been improved or has returned following


treatment with at least two chemotherapy regimens. It should only be used by specialists

as a treatment to bridge to stem cell transplant”. Therefore Nelarabine would be subject to

a CPC until routinely commissioned.

Hyper CVAD Course A

Cyclophosphamide 300mg/m2 Days 1,2,3 Ref: J Clin Oncol. Feb; 18(3) Doxorubicin 50mg/m2 Day 4

Vincristine 2mg Days 4, 11

Dexamethasone 40mg Days 1-4, 11-14

Hyper CVAD Course B

Methotrexate 200mg/m2 Days 1 Ref: J Clin Oncol. Feb; 18(3) Methotrexate 800mg/m2 Days 1

Cytarabine 3000mg/m2 Days 2,3

Nelarabine

Nelarabine 1500mg/m2 Days 1,3,5 Ref: Blood 2007; 109

Nelarabine/Cyclophosphamide/Etoposide

Nelarabine 650mg/m2 Days 1,2,3,4,5 Ref: Br J Haem 2010, 150

Cyclophosphamide 440mg/m2 Days 1,2,3,4,5


Clofarabine

Clofarabine 40mg/m² Days 1,2,3,4,5 Ref: Blood (2005) 105 NO3. P940-947 AML 16

It may be worth discussing these patients with the trial co-ordinators and they should all be

reviewed at the MDT.

4.3.6 Treatment of ALL relapsing after CR (Fielding, et al 2007)

• There is no current trial within the network. UKALL XIV patients should be discussed with

the trial co-ordinators.

• If there is still curative intent then transplant options will be considered if possible and the

patient should be discussed with the transplant centre prior to a decision to give further

treatment as this may influence the choice of therapy.


• Outcome after relapse (Fielding, et al 2007). Survival at 1 year was 22% and 7% at 5

years.

• Factors predicting a good outcome after salvage therapy were:

1. Young age (OS of 12% in patients younger than 20 years vs. OS of 3% in

patients older than 50 years; P < .001)

2. Duration of first remission (CR1) (OS of 11% in those with a CR1 of more than 2

years versus OS of 5% in those with a CR1 of less than 2 years; P < .001)

• HyperCVAD (Koller, et al 1997) for B cell ALL and hyper-CVAD/CLAEG for T cell ALL

followed by transplant is the recommended option. Nelarabine may be used as 2nd line

agent (licensed for 3rd line use). CNS prophylaxis in the form of intrathaecal therapy with

12 mg MTX on day 2 and 8 with each course of Hyper CVAD.

• See below for a discussion of the use of Imatinib in this setting for Ph+ve cases.

• These cases need discussion at an MDT incorporating transplant advice (see above).

Relapse has a very poor prognosis, particularly if it occurs less than a year from treatment

end. If there is no transplant option then further chemotherapy can be considered as for

refractory cases (see above).

Monotherapy in relapsed/refractory cases can achieve CRs in up to a third of patients

although these are not durable. Imatinib can be a useful agent in re-establishing short term

remission prior to transplant. Post transplant relapses can also be managed in this way.

The place of Imatinib in these circumstances should be discussed at an appropriate MDT

(see above). Dasatinib or Nilotinib can be used for refractory relapse on Imatinib. CNS

prophylaxis must be considered in the context of the treatment schedule agreed at the

MDT. (Level 1). NOTE : Dasatinib and Nilotinib are not routinely commissioned for use in

Ph+ve ALL and would be subject to approval through an IFR.

Imatinib

Imatinib 400mg (up to 600mg as tolerated)

Days 1-28 Ref: MRC UKALL 12

Dasatinib

Dasatinib 140mg once daily

Days 1-28 Ref: Blood 2008; 112


Nilotinib

Nilotinib 400mg twice daily Days 1-28 Ref: Blood 2007; 110 (10)

4.3.7 CNS leukaemia at diagnosis

• The UKALLXIV protocol can be followed for all patients. This consists of weekly IT MTX

until clear then radiotherapy, depending on whether they are proceeding to transplant.

• As an alternative to IT MTX, IT Depocyte should be considered. (note Depocyte is not

routinely commissioned and would be subject to approval through an IFR).

• For CNS and BM relapse consider* IT + Salvage therapy (hyper-CVAD)

• For Solitary CNS relapse consider* IT + Salvage therapy (as above)

All above salvage treatments should be consolidated with a transplant modality

(*Consider radiotherapy for CNS disease if no transplant option)

Special issues in prophylaxis

Fungal infection – continues to be a particular hazard. Prophylaxis must be with a

minimum of oral fluconazole (itraconazole may be better but is not proven). Serious

consideration should be given to prophylactic amphotericin B i.v. at a dose of 0.25-

0.5mg/kg on alternate days (no standard dose has been established).

Please note that there is a drug-drug interaction between itraconazole and

vincristine which lead to increased vincristine neurotoxicity. Posaconazole could be

considered as antifungal prophylaxis for first induction when vincristine is used.

PCP – Prophylaxis is required and is standard (example: septrin 960mg bd orally 3x a

week or atorvacone or dapsone.).


4.3.8 Transplant

MRC UKALL XII/ECOG E2993, sibling donor versus no-donor analysis, showed that

Philadelphia chromosome–negative patients with a donor had a 5-year improved overall

survival (OS), 53% versus 45% (P= .01), and the relapse rate was significantly lower (P

.001).

The survival difference was significant in standard-risk patients, but not in high-risk

patients with a high non relapse mortality rate in the high risk donor group.

Patients randomized to chemotherapy had a higher 5-year OS (46%) than those

randomized to autologous transplantation (37%; P =.03).There is no evidence that a single

autologous transplantation can replace consolidation/maintenance in any risk group

(Goldstone, et al 2008)

4.4 MYELODYSPLASTIC SYNDROMES

Diagnostic Criteria

Typical Cases

• Hypercellular marrow in the presence of cytopenia

• Erythroid series shows nuclear budding or bridging, vacuolation of late erythroblasts,

multinuclear cells, asynchronous haemoglobinisation.

• Myeloid series shows abnormal granulation, pseudo-Pelger change, maturation

asynchrony, increased numbers of CD34+ myeloblasts, usually >3.5% by flow cytometry.

The blasts should have the phenotype CD34+, CD45+, CD117+, CD15-.

• Megakaryocytes are cytologically abnormal with micro forms and nuclear lobe

separation.

• Single lineage dysplasia in the appropriate clinical context is sufficient for a diagnosis of

MDS (WHO classification)

Variants

• Any of the above features in a hypocellular marrow. Increased bone marrow fibrosis and

an excess of blasts are most useful to differentiate from aplastic anaemia.


• 5q- as sole cytogenetic abnormality often with increased abnormal megakaryocytes +/-

increased platelets and anaemia.

Prognostic Factors

The International Prognostic Scoring System (IPSS) is superior to earlier systems and will

increasingly inform therapeutic decision making (viz. 5q- and Lenalidomide) (Greenberg, et

al 1997).The IPSS requires cytogenetic analysis in all patients, and cytogenetic analysis is

therefore recommended for all patients at diagnosis. If cytogenetics is not available, the

Sanz score can be used (Sanz, et al 1989).

Management

The following recommendations are based on a very limited evidence base with little

standardisation between studies. Supportive treatment with blood and platelet

transfusions, and antibiotics is the mainstay of treatment, but selected groups may benefit

from chemotherapy and other specific treatment. (Bowen, et al 2003)

Anaemia

• RBC transfusion should be considered in any patient with symptomatic anaemia.

• Iron chelation with s/c desferrioxamine should be considered principally in stable

transfusion dependent patients with low/INT-1 IPSS score (predicted survival > 4 yrs)

(especially pure sideroblastic anaemia [WHO RARS], pure refractory anaemia [WHO RA]

and 5q- syndrome).

Initiate iron chelation at serum ferritin >1000 mcg/l, with annual eye and ear assessment.

There is no evidence for benefit from IV desferal given at the same time as blood

transfusion. Desferrioxamine remains chelator of choice if tolerant and effective.

Alternatives are Deferiprone (This is not licensed for these indications, requires a weekly

full blood count and should be initiated only if the baseline neutrophils > 1.5 x 109/l),

Deferasirox (not supported by SMC for use in MDS but licensed for this indication) and a

combination of Deferiprone daily plus Desferrioxamine 3 x /week.

Erythropoietin (EPO) +/- G-CSF can reduce transfusion requirements in selected patients.

This will become increasingly important as blood supplies fall. This should be restricted to

patients with Serum EPO < 500 IU/l and Low transfusion requirement (≤ 2 units / month).


Immunosuppression with ALG or cyclosporin can be beneficial in hypoplastic MDS. ALG

should only be used in patients <65 years and only in centres with experience of its use in

aplastic anaemia. (Level 2). Prednisolone is started on the day after ATG is completed at

dose of 1 mg/kg/day for two weeks, followed by rapid tapering over the following two

weeks. CSA should be commenced as the prednisolone dose is tapered, at a dose of 5

mg/kg/day to achieve trough blood levels of 100 to 200 μg/l. CSA should be continued

whilst the blood count continues to rise.

A slow tapering of the drug (25 mg every 2‒3 months) can be started after a minimum of a

further 6 months of therapy, to reduce the risk of later relapse. (Guidelines for the

Diagnosis and Management of Adult Aplastic Anaemia- BCSHguidelines 2015)

ATG Rabbit

Methylprednisilone 2mg/kg Days 1-5 Ref: B. J. Haem 2009; 147

ATG Rabbit 2.5mg/kg Days 1-5

ATG Horse*

Methylprednisilone 2mg/kg Days 1-4 Ref: N Eng J Med 2011; 365 ATG Horse 40mg/kg Days 1-4

*ATG Horse – is available through request via CPC

Lenalidomide (Revlimid) is an effective agent in MDS with del 5q and has been approved

by NICE for use in this condition TA 322.

Consider trial of EPO plus low/ absent transfusion * G-CSF for 6-12 weeks

Marrow not hypo-cellular, or RA/RAEB plus EPO<200U/l Consider trial of EPO for 6

Hypo-cellular but pt unfit for low/ absent transfusion * weeks, then add G-CSF for

immunosuppression 6 weeks +/- EPO escalation

Other: high EPO +/- Supportive care


ANAEMIA

(symptomatic) *<2units/month Hypocellular marrow Consider ALG if suitable

Neutropenia

• Neutropenic sepsis should be managed as for patients undergoing chemotherapy

according to the hospital antibiotic policy.

There is no indication for routine antibiotic or antifungal prophylaxis, or for prophylactic

growth factor support. Anecdotally regular granulocyte colony-stimulating factor by sc.

route can be helpful in patients with severe neutropenia and recurrent life threatening

infections.

Thrombocytopenia

• Both the degree of thrombocytopenia and platelet dysfunction can contribute to bleeding

problems. In the absence of bleeding or fever, the threshold for platelet transfusion is 10 x

109/l.

• Antifibrinolytics and danazol may be useful in some patients.

Consider if any trials open for eligibility

Chemotherapy and Stem Cell transplantation

• All MDS patients, with the possible exception of IPSS Low plus limited symptomatic

cytopenias should be considered at diagnosis for suitability for allogeneic stem cell

transplant and should be discussed with the transplant team as appropriate.

• Non-intensive: patients aged >60 years with >10% blasts should be offered therapy

within the AMLL1 non-intensive trial if appropriate.

5-azacytidine (Vidaza) improves overall survival in MDS patients with IPSS/INT-2 and

CMML-2 (non-proliferative with WCC< 15 x 109/L by 9 months) (24 months) compared with

conventional care regimens (15 months)(supportive care, low dose cytarabine, or intensive

chemotherapy) achieving haematological responses in up to 45% of patients with MDS,

and complete remissions in up to 20%.


Azacitidine

Azacitidine 75mg/m2 Days 1-7 Ref: Itzykson et al. Blood 2011

Responses are similar with 5-aza-2- deoxycytidine(Decitabine/Dacogen) but a survival

advantage has yet to be demonstrated.

5- azacitidine is licensed in Europe and is the worldwide standard of care for the above

MDS categories.

Intensive: patients aged >60 years with >10% blasts should be offered therapy within the

AML18 intensive trial. Patients <60 years with >10% blasts and/or INT-2/ High risk disease

should be considered for the NCRI AML17 study.

All patients < 70 years should be considered for fitness for stem cell transplantation. In

patients <55 years, if a donor (sibling or unrelated) is available, allogeneic stem cell

transplantation should be discussed. In fit patients >55 years reduced intensity allogeneic

stem cell transplantation should be considered.

• Selected patients with INT-1 or even Low risk MDS should be considered for allogeneic

SCT on individual grounds. (Level 4) Examples include young patients with platelet

refractory thrombocytopenia, or heavy red cell transfusion requirement in the absence of

an alternative cause for anaemia. Chemotherapy prior to transplant will be necessary in

this group only in the rare patient with blasts 5-10%.

• Reduced intensity SCT (Level 4) should be offered in the context of clinical trials, where

available. Data for RIC SCT outcome are encouraging, particularly in the INT-1 / INT-2

patients.

• Note that a raised serum ferritin >2500 mcg/l is an adverse prognostic factor for

transplant related mortality and overall survival in MDS patients treated with allografts. As

yet there is no evidence that this adverse outcome can be modified by pre-transplant iron

chelation therapy.


4.5 Myelodysplastic / Myeloproliferative Neoplasms

Typical Cases

• Bone marrow examination with cytogenetics is required for diagnosis. FBC should be

supplied to HMDS on request.

• Persistent peripheral blood (1 x 109/l) monocytosis (>3 months)

• <20% bone marrow blasts.

• Normal or MDS type cytogenetics.

Variant

CMML with eosinophilia and translocations involving the PDGFRgene is rare but

important, as this variant is sensitive to imatinib therapy.

Refractory Anaemia with Ring Sideroblasts and thrombocytosis (RARS-t) is JAK2

mutated in 50% cases.

A very rare variant is described without monocytosis but with increased neutrophil and

immature myeloid cells in peripheral blood. This is termed atypical CML. Absence of BCR-

ABL is essential and the report must describe this as an MDS variant to avoid confusion

with CML.

Management

• CMML patients should be managed with supportive care for cytopenias and

cytoreductive therapy with hydroxycarbamide for symptomatic myeloproliferation.

Although chemotherapy alone is rarely effective for CMML, younger and / or fitter

patients should be discussed with the transplant team for consideration of allograft

4.5.1 CHRONIC MYELOID LEUKAEMIA

Diagnostic Criteria

Chronic phase CML

• t(9;22) as part of a single or complex translocation, or BCR-ABL transcripts must be

present in every case

• Maximally cellular marrow with left shifted, myeloid series, monolobated megakaryocytes

and suppressed erythroid series

• <5% blasts in bone marrow


Prognostic Groups

• 5-10% blasts. The marrow should be repeated in 1 month to establish rate of change of

blast cell population.

• Accelerated phase (AP): 10-19% blasts or >20% basophils in marrow or blood,

associated with clinical progression or refractoriness to treatment (WHO criteria). Other

features may include persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or

persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy; increasing WBC

unresponsive to therapy; cytogenetic evidence of clonal evolution and excessive marrow

fibrosis or dysplastic features.

• Blast crisis (BC): >20% myeloid blasts or >5% lymphoid blasts or solid extramedullary

tumour deposit consisting mainly of blasts.


• Full blood count with manual differential.

• Full examination with documentation of liver and spleen size. Ultrasound scanning of the

abdomen to more accurately document spleen size may be considered.

• Routine biochemistry to include U&Es, LFTs, calcium, LDH and urate.

• Bone marrow aspirate and trephine with sample sent for cytogenetics

• Bone marrow and peripheral blood sample for RT-PCR

• All newly diagnosed patients should have either a Sokal or Hasford (Euro) score

calculated.

This can be done using simple web based programmes found at www.roc.se/sokal.asp

and www.pharmacoepi.de. respectively

• A full family history, in particular paying attention to potential sibling donor details, should

be taken. Tissue typing may need to be considered.

4.5.2 Primary Therapy

Patients in Chronic Phase (CP)

• All new patients should be offered entry into the SPIRIT 3 study when open which will

start all patients on imatinib and then change therapy in those who do not have an

adequate response at 3 months.


• In the absence of published data to support the role of autologous stem cell

transplantation in the treatment of CML, routine collection of autologous stem cells at

diagnosis is not indicated.

In patients with symptoms of leucostasis consideration may be given to therapeutic

leucopheresis.

• All patients should be well hydrated and receive allopurinol 300mg daily.

• In non-trial patients, initial cytoreductive therapy should be with Imatinib 400 mg daily or

Nilotinib 300mg bd.(depending on patient age and comorbidities). NICE TA 251.

Imatinib CML

Imatinib 400mg Days 1-28 Ref:

Nilotinib CML

Nilotinib 300mg bd (may be escalated up to 400mg-600mg bd depending on clinical situation

Days 1-28 Ref: Blood 2007; 110 (10) Nilotinib SPC

• Initial therapy with hydroxycarbamide 0.5g – 2g daily can be considered for patients

contemplating entry into SPIRIT 3 or other drug trials.

Hydroxycarbamide

20mg/kg Days 1-28 Ref: Hydroxycarbamide SPC

Monitoring of therapy

• FBC, U&Es and LFTS weekly for 1st 4 weeks, then reduced frequency depending on

response.

• All patients should have a baseline bone marrow examination with cytogenetic analysis

and peripheral blood sample for quantitative RT-PCR.

• Peripheral blood PCR should be carried out every 3 months. 10ml of EDTA blood is

required.

• Bone marrow (BM) examination with cytogenetics should be carried out in patients with

an inadequate response according to the following criteria:


At 3 months:

If 1 log reduction in BCR-ABL not achieved (5.5% according to local reference range)

(BM should be performed at 6 months).

At 12 months:

If <3 log reduction (>0.055%)

Bone marrow cytogenetics should also be performed on patients who have > 2-5 fold rise

in BCR-ABL, confirmed on repeat sample taken at a six week interval. Mutation screening

will also be performed

Response Criteria

• Optimal response according to the revised European leukaemia Net Guidelines

(Baccarani, et al 2013) are:

At 3 months, at least a partial cytogenetic response (PCyR - Ph +ve < 35%) or BCR-

ABL1<10%

After 6 months of therapy: A complete cytogenetic response or BCR-ABL1<1%

After 12 months of therapy BCR-ABL1<0.1%

Patients in Accelerated Phase (AP)

• Patients presenting in the accelerated phase of CML should receive Imatinib 600mg

daily, which is associated with a reported progression-free survival rate of 67% at 12

months, and overall survival of 66% at 36 months.

Patients in Blast Crisis (BC)

• Patients presenting in blast crisis present a difficult management problem. The best

responses have been reported to Imatinib 600-800mg daily, with reported 12 month

survival rates of 32%.Major cytogenetic responses have been reported in 16% of patients,

and complete cytogenetic responses in 7%. Dasatinib is also licensed for this indication, at

a dose of 70mg bd and nilotinib at 400mg bd.

• NICE do not recommend continued use of Imatinib in patients presenting in CP who progress to AP or BC after exposure to the drug. Management of such cases should be discussed with the MDT lead for Leukaemia, but a second generation tyrosine kinase inhibitor (2G – TKIs, Nilotinib should be given while assessing BMT options. For patients in


BC, options include acute leukaemia type therapy (as for AML or ALL depending on phenotype) and rarely, autologous stem cell transplantation. NOTE NICE (TA 251) does not recommend Dasatinib for people with chronic myeloid leukaemia in the chronic phase who have not had treatment for chronic myeloid leukaemia before. Therefore its use would be subject to approval through an IFR

Side effects of imatinib and their management

Imatinib is well tolerated by the majority of patients.

• Nausea if it occurs often improved if the drug is taken with food, or split doses. Normal

antiemetics

and in the few patients who experience diarrhoea, anti-diarrhoeal agents can be given

• Side effects include mild allergic type rashes, which may respond to simple anti-

histamines.

• Severe dermatological reactions have been documented which may require steroid

therapy or in some cases the discontinuation of Imatinib.

• Arthralgia is seen in 60% of patients and usually responds to simple treatment with

nonsteroidals, and usually settles after the first few months of treatment

• Fluid retention may be troublesome and occurs in the majority of cases often just as

simple peri-orbital oedema. More severe oedema is often quite refractory to diuretic

therapy and may require dose reduction or discontinuation. Reducing salt intake should be

tried.

• Cytopenias may occur in up to 14% of patients. If thrombocytopenia (plts < 50 x 109/l) or

neutropenia (neuts < 1 x 109/l) develop, imatinib should be stopped. If counts recover in

two weeks, restart at 400mg/day. If not consider introducing at 300mg/day with G-CSF or

platelet support as necessary. Symptomatic anaemia should be managed with blood

transfusions as clinically indicated, but erythropoietin therapy may be effective.


4.5.3 Management of Chronic Myeloid Leukaemia Patients who are resistant or intolerant to imatinib Intolerance

• Patients who are intolerant of imatinib should be treated with a second generation TKI, ie nilotinib. NOTE NICE does not recommend Dasatinib for people with chronic myeloid leukaemia in the chronic phase who have not had treatment for chronic myeloid leukaemia before and its use would be subject to approval through an IFR. The choice would be influenced by the nature of the intolerance to imatinib, and also other pre-morbid conditions as per resistant patients. Sub-optimal response

The following describes a reasoned approach to the patient with a sub-optimal response:

• Consider compliance (which may require use of plasma level monitoring)

• If the patient has achieved a complete cytogenetic response but not a major molecular

response, consider merely continuing at present dose and monitoring closely. CCyR is the

most important prognostic factor for progression free survival and as long as the patient

achieves a CCyR, OS and PFS are not affected by how long it takes to get there.

• However if CCyR has not been achieved by 18 months of therapy, consider dose

escalation.

Failure

• Patients failing imatinib should receive a 2nd generation tyrosine kinase inhibitor.

Published efficacy data show little difference between the two licensed drugs, Nilotinib

400mg bd and Dasatnib 100mg od in this setting.

NOTE NICE does not recommend Dasatinib for people with chronic myeloid leukaemia in

the chronic phase who have not had treatment for chronic myeloid leukaemia before and

its use would be subject to approval through an IFR.

Factors that may influence choice are:

Presence of a kinase domain mutation:

This information will only be informative in a minority of patients, where the presence of a

so called ‘breakthrough’ mutation will predict the response to one or other of the available

TKIs. These are Y253H, E255K/V and F359C/V which will be resistant to Nilotinib, and


F317L and V299L which will be resistant to Dasatinib. T315I is associated with resistance

to both 2G – TKIs as well as imatinib and such patients should not be treated with these

agents, and be assessed for allogeneic SCT.

Pre-morbid conditions

The following table summarises the factors that may influence choice of one or other 2nd

generation TKI (after Laneuville, 2009):

Co-morbidity Dasatinib Nilotinib

Pancreatitis Y N

Cardiovascular disease N Y

Autoimmune disease N Y

Dietary restriction Y N

Post SCT N Y

GI bleeding N Y

Cardiac disease ?Y ?N

(arrhythmia, prolonged QTc)

4.5.4 Management of CML in Pregnancy

• There is little in the way of large published series about the management of chronic

myeloid leukaemia in pregnancy. However, a number of the concerns that are associated

with myeloproliferative disorders (MPD) in pregnancy will also apply to CML.

• There are two scenarios:

1. A patient presenting with CML in pregnancy

2. A patient on Imatinib who becomes pregnant

• As regards the first scenario, there is little evidence that pregnancy itself adversely

affects the natural course and prognosis of CML but any haematological disorder that may

lead to hyperleucocytosis and possibly thrombocytosis is likely to affect fertility, and may

lead to an adverse outcome of the pregnancy itself because of thrombotic or bleeding

complications.


This is certainly true in primary thrombocythaemia (PT) where first trimester abortion is the

most frequent complication but increased perinatal mortality and premature delivery are

also observed. Placental infarction due to thrombosis is the most consistent event.

As regards management, it is desirable that some attempt to control the white cell count

(and perhaps platelet count) in pregnancy should be attempted. However, Imatinib is

teratogenic with a 25 % incidence of fetal abnormality in the only series collected (Pye, et

al 2008)

Hydroxyurea is teratogenic in animals and one stillbirth and one malformed infant have

been reported after exposure in pregnancy. It should generally be avoided, but there are

several well documented cases of successful outcomes in PT with hydroxyurea given

throughout pregnancy.

• Alternative treatments include -interferon, which has been well documented as being

safe in the management of PT in pregnancy, and leucopheresis. This is the most common

therapeutic manoeuvre cited in the literature with good control of the white cell count and a

successful outcome for mother and baby in all reported cases.

Based on the published evidence, a reasonable recommendation for the management of

CML in first chronic phase diagnosed in pregnancy would be as follows:

• Initial leucopheresis to control the white cell count, together with allopurinol and aspirin

therapy, especially if there is associated thrombocytosis.

• Instigation of -interferon therapy to maximum tolerated dose to control the white cell

count with intermittent leucopheresis to keep the white cell count below 20 x109/l and

platelets below 400 x109/l until delivery.

• No particular precautions need to be taken at delivery, assuming stable peripheral blood

parameters, and normal vaginal delivery should be possible.

• The management of accelerated phase or blast crisis occurring in pregnancy is much

more difficult. Either of these situations should warrant consideration of early termination of

pregnancy and the introduction of Imatinib therapy, but it is possible that hydroxyurea may

control the situation at least until the baby is of a great enough gestational age to deliver

safely. This policy would be associated with a relatively low risk of foetal abnormality. More

specific therapy, including bone marrow transplantation could then be considered following

parturition.

• In the second scenario, management will be influenced by to the patient’s response thus

far to imatinib, and its duration. Recently published data suggests that stopping imatinib in

patients who have achieved a stable complete molecular response (greater than 2 years)


can be done with only a small risk of disease progression, with re-establishment of control

if progression occurs (Mahon, et al 2008). Consideration in such a patient could be given

to discontinuing therapy and monitoring closely until delivery. In all other cases, interferon

therapy as described above would be preferable.

4.5.5 Bone Marrow Transplantation

• Bone marrow transplantation remains the only proven curable treatment for patient with

chronic myeloid leukaemia. However, the emergence of Imatinib has led to a reappraisal

of the appropriate timing of BMT. The current consensus is that all patients should have a

trial of imatinib therapy with close monitoring of their haematological, cytogenetic and

molecular responses. BMT remains an option for patients failing IM therapy, but treatment

with a 2G - TKI may be more appropriate in some patients. This should be discussed with

the MDT lead.

4.6 CHRONIC MYELOPROLIFERATIVE DISORDERS

Guidelines

The British Society for haematology has published and updated extensive guidelines

which cover all aspects of management of the myeloproliferative neoplasms.

Polycythaemia Vera

McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D, Polkey

MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B.Guidelines for the

diagnosis, investigation and management of polycythaemia/erythrocytosis. Br. J.

Haematol. (2005) 130(2), 174-195.

McMullin MF, Reilly JT, Campbell P, Bareford D, Green AR, Harrison CN, Conneally E,

Ryan K. Amendment to the guideline for the diagnosis and investigation of

polycythaemia/erythrocytosis.British Journal for Haematology (2007) 138 (6) 821-2.


Essential Thrombocythaemia

Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M, Erber W,

Everington T, Green AR, Hall GW, Hunt BJ, Ludlam CA, Murrin R, Nelson-Piercy C,

Radia DH, Reilly JT, Van der Walt J, Wilkins B, McMullin MF.

Guideline for investigation and management of adults and children

presenting with a thrombocytosis.

British Journal for Haematology (2010) (149) 352-375.

Harrison CN, Butt N, Campbell P, Conneally E, Drummond M, Green AR, Murrin R, Radia

DH, Reilly JT, McMullin MF. Diagnostic pathway for the investigation of

thrombocytosis. British Journal of Haematology ( 2013) May 161(4) 604-6.

Harrison CN, Butt N, Campbell P, Conneally E, Drummond M, Green AR, Murrin R, Radia

DH, Mead A, Reilly JT, Cross NC, McMullin MF. Modification of British Committee for

Standards in Haematology diagnostic criteria for essential thrombocythaemia.

British Journal of Haematology. (2014) Nov;167(3): 421-3.

Myelofibrosis

Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR, Michaeel

NG, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M, Wilkins B, Harrison

CN; Writing group: British Committee for Standards in Haematology. Guideline for the

diagnosis and management of myelofibrosis. British Journal of Haematology (2012)

158(4):453-71.

Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe AS, Green AS, Mikhaeel

G, Gilleece MH, Knapper S, Mead AJ, Mesa RA, Sekhar M, Harrison CN. Use of JAK

inhibitors in the management of myelofibrosis: a revision of the British Committee for

Standards in Haematology guidelines for investigation and management of

Myelofibrosis 2012. British Journal of Haematology. (2014) Nov; 167(3): 418-20.


Diagnostic Guidelines

Diagnostic criteria

Polycythaemia

JAK2-positive polycythaemia vera

A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised

red cell mass (>25% above predicted)*

A2 Mutation in JAK2

Diagnosis requires both criteria to be present

JAK2-negative polycythaemia vera

A1 Raised red cell mass (>25% above predicted) OR

haematocrit >0.60 in men, >0.56 in women.

A2 Absence of mutation in JAK2

A3 No cause of secondary erythrocytosis

A4 Palpable splenomegaly

A5 Presence of an acquired genetic abnormality (excluding

BCR-ABL) in the haematopoietic cells

B1 Thrombocytosis (platelet count >450 × 109/l)

B2 Neutrophil leucocytosis (neutrophil count > 10 × 109/l in non-

smokers; >12.5 × 109/l in smokers)

B3 Radiological evidence of splenomegaly

B4 Endogenous erythroid colonies or low serum erythropoietin


Diagnosis requires A1 + A2 + A3 + either another A or two B criteria

Essential thrombocythaemia

Diagnosis requires A1–A3 or A1 + A3–A5

A1 Sustained platelet count ≥450 × 109/l

A2

Presence of an acquired pathogenetic mutation (e.g. in the JAK2, CALR or MPL

genes)

A3 No other myeloid malignancy, especially PV, PMF, CML or MDS

A4 No reactive cause for thrombocytosis and normal iron stores

A5 Bone marrow aspirate and trephine biopsy showing increased megakaryocyte

numbers displaying a spectrum of morphology with predominant large

megakaryocytes with hyperlobated nuclei and abundant cytoplasm. Reticulin is

generally not increased (grades 0–2/4 or grade 0/3)


Myelofibrosis

Diagnostic criteria for primary myelofibrosis: diagnosis requires A1 + A2 and any two B

criteria

A1 Bone marrow fibrosis ≥3 (on 0–4 scale).

A2 Pathogenetic mutation (e.g. in JAK2 or MPL), or absence of both

BCR-ABL1 and reactive causes of bone marrow fibrosis

B1 Palpable splenomegaly

B2 Unexplained anaemia

B3 Leuco-erthroblastosis

B4 Tear-drop red cells

B5 Constitutional symptomsa

B6 Histological evidence of extramedullary haematopoiesis

Investigation of Suspected Chronic Myeloproliferative Disorder

Raised EPO level – stop investigating for CMPD

JAK 2 /MPL and CALR mutations

Negative

Raised platelets*

No Fe def, no cause

Positive

Suspected

Myelofibrosis

Bone Marrow

http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1365-2141.2012.09179.x/#bjh9179-note-0003


Diagnosis of CMPD

RCM?? Monitor?

JAK 2 testing outside these indications is not interpretable

Diagnostic Criteria

With the exceptions listed below all cases will be reported using the generic term 'chronic

myeloproliferative disorder'.

The diagnosis can only be made on a trephine biopsy and will not be made where only

aspirate smears are available.

Typical Cases

• Marrow shows normal or increased cellularity

• Trilineage expansion with hyperlobated or clustered megakaryocytes

• If any suspicion of CML this should be excluded by PCR

• Blasts <5%. Blasts >5% require repeat marrow within one month to assess progression

to acute leukaemia

Chronic Idiopathic Myelofibrosis: increased reticulin/ fibrosis, sometimes with new bone

formation with appropriate clinical and peripheral blood features


• FBC – Hb is more sensitive than HCT

• Red cell mass (if Hct is normal/ high normal)

• Bone marrow aspirate & trephine biopsy (see diagnostic guidelines)

• Ultrasound abdomen

• CRP, ESR or PV

• U&E, LFT

• EPO

• Ferritin

Mutation analysis for JAK2/MPL/CALR/ASXL1


Primary Therapy of Essential Thrombocythaemia

Recommendation: Risk stratification

Patients should be stratified according to their risk of thrombotic complications. The most

widely accepted risk stratification is as follows:

All patients: asses for ET-related thrombotic risk age, prior history, platelet count

Assess and optimize other vascular risk factors,

such as smoking and diabetes

Start aspirin unless contraindicated

High risk patients

ONE of age >60 yrs, platelet count >1500*109/l, disease related thombosis/haemorrhage

The treatment target should be platelet count <400*109/l

MPD-RC 112 Trial: Pegulated Interferon v Hydroxycarbamide

Hydroxycarbamide plus aspirin should be first line therapy

Interferon alpha is a reasonable treatment option for young patients

For patients who become refractory or intolerant of primary therapy – options include:

i) relaxing the platelet target to 600*109/l

ii) switching either partially (combination therapy) or completely to second line

therapy that is non-leukaemogenic where possible

Low and intermediate risk patients

Intermediate risk: age 40-60 yrs and no high risk factors

Low risk: age <40 yrs and no high risk factors

Treat with aspirin and reverse/aggressively manage vascular risk factors

Enter patient into a clinical trial where open

Only give cytoreductive therapy:

i) in the context of a clinical trial

ii) or if symptomatic (e.g. progressive

splenomegaly, erythromelalgia)

iii) or other severe microvascular symptoms not improved with aspirin

iv) or uncontrolled bleeding associated with high platelet counts


Therapy of Polycythaemia

Polycythaemia vera

• Venesection to maintain the Hct to <0.45.

• Aspirin 75 mg/d unless contraindicated.

• Cytoreduction should be considered if: poor tolerance of venesection; symptomatic or

progressive splenomegaly; other evidence of disease progression, e.g. weight loss, night

sweats; thrombocytosis.

• Choice of cytoreductive therapy, if indicated:

<40 years old: first line interferon, second line hydroxycarbamide

40–75 years old: first line hydroxycarbamide, second line interferon

>75 years old: first line hydroxycarbamide, second line 32P or intermittent low dose

Busulphan

Idiopathic erythrocytosis

• Venesection to reduce the Hct to <0.45 if Hct >0.54.

• Venesection to reduce the Hct to <0.45 if <0.54 and there is increased risk of thrombosis,

i.e. evidence of ischaemia, previous history of thrombosis, peripheral vascular disease,

diabetes or hypertension.

• Cytoreductive therapy is contraindicated

Refer to BCSH Guidelines for details

Therapy of Idiopathic Myelofibrosis

Risk assess using IPSS or current scoring system

Ruxulitinib is licensed for myelofibrosis and is recommended as first line therapy with

symptomatic splenomegaly and/or myelofibrosis related constitutional symptoms which are

impinging upon the quality of life and hepatomegaly and portal hypertension due to

myelofibrosis. NICE has recommended Ruxulitinib (TA 368) in adults with disease-related

splenomegaly or symptoms caused by primary myelofibrosis (also known as chronic

idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential

thrombocythaemia myelofibrosis, only if they have intermediate-2 or high-risk disease. It

will require CPC.


Open trials should be considered in all patients.

A trial of EPO may be given to patients who are symptomatically anaemic and have serum

EPO <120 U/l

Other options which may be considered:

• α-interferon or thalidomide may be efficacious in some cases

• Hydroxycarbamide for: platelets, WBCs or hypermetabolic symptoms

• Splenic irradiation for: hypermetabolic symptoms, leucopenia, symptomatic

splenomegaly or unfit for splenectomy

• Splenectomy should only rarely be considered due to the high complication rate but

indications may include symptomatic splenomegaly, hypersplenism, trauma or rupture

• Patients with a low or intermediate Dupriez score (Dupriez, et al 1996) receiving regular

red cell transfusion should be considered for iron chelation therapy after 25 transfused red

cell units.

• Allopurinol prophylaxis

• Encouraging data for RIC allogeneic stem cell transplantation are emerging. All patients

with IMF <65 years should be discussed with a transplant physician.

5.0 Dissemination

Ruxulitinib

Ruxulitinib 15mg bd Days 1-28 Ref: SPC Ruxulitinib BCSH guidelines – myelofibrosis 2012


This policy will be agreed by all consultant haematologists and clinical oncologists

managing patients with acute leukaemia . The guideline will form the basis for

development of the SACT regimen specific protocols. It will be available on the intranet for

use by all doctors, nurses and pharmacists involved in all stages of SACT assessment and

delivery in patients with

6.0 MONITORING

Use of these guidelines will be monitored using audit.

7.0 EVIDENCE BASE / REFERENCES

Bibliography & references

NOTE these guidelines and protocols have been developed in conjunction with current

guidance from BSCH guidelines, protocols derived from current clinical trials along with

current recommendations from NICE, SMC and Northern Ireland Health Board. Clinicians

are reminded to refer to national guidelines and recommendations and specific trial

protocols for a more complete overview and reference.

8.0 CONSULTATION PROCESS

Consultant Haematologists and consultant Clinical Haematologists who manage acute

leukaemia, myelodysplastic/myeloproliferative disorders.

9.0 APPENDICES / ATTACHMENTS

10.0 EQUALITY STATEMENT


In line with duties under the equality legislation (Section 75 of the Northern Ireland Act 1998), Targeting Social Need Initiative, Disability discrimination and the Human Rights Act 1998, an initial screening exercise to ascertain if this policy should be subject to a full impact assessment has been carried out. The outcome of the Equality screening for this policy is:

Major impact Minor impact No impact.

SIGNATORIES (Policy – Guidance should be signed off by the author of the policy and the identified responsible director). Professor McMullin Date: Author Date: Director

title: clinical management guidelines for acute leukaemia ... · guidelines for acute leukaemia and...

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