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Recommendations for the management of adult chronic myeloid leukaemia in South Africa.

These recommendations are for the use of Fellows, specialist physicians, clinical haematologists and medical oncologists with an interest in the treatment of haematological disorders.

1. Scope

This guideline was developed to address the diagnosis and management of chronic myeloid leukaemia (CML) in the South African setting, with particular reference to the prescribing of BCRABL tyrosine kinase inhibitors (TKIs), and the management of their side-effects. Special focus is also given to the monitoring of response to treatments, given the constraints and shortage of skills in this area in South Africa. The guideline is endorsed by the South African Society of Haematology.

2. Methods

The development of these recommendations was based on local expert opinion, best clinical practice and available treatment options, together with review of the latest international recommendations and recent clinical data. The 2009 International European LeukemiaNet (ELN) and 2010 National Collaborative Cancer Network (NCCN) guidelines for the diagnosis, monitoring and management of CML, and the major clinical trials for the three TKIs that are registered in South Africa, imatinib, dasatinib and nilotinib, were considered.

3. Limitations of the recommendations

These recommendations do not represent all the possible methods of management applicable to all patients; do not exclude any other reasonable methods; and will not ensure successful treatment in every situation. The unique circumstances of each patient, disease stage, co-morbid conditions and treatments available should be taken into account by the responsible physician when deciding on any specific therapy.

4. Introduction and overview

Chronic myeloid leukaemia is a disease of the haematopoietic stem cell characterised by a chromosomal translocation between the long arms of chromosomes 9 and 22 which leads to formation of the so-called Philadelphia chromosome. This t(9;22) translocation results in the formation of the BCR-ABL fusion gene, which codes for a novel protein tyrosine kinase (TK) that is constitutively activated and therefore leads to increased proliferation of myeloid cells, decreased apoptosis and adhesion, and genetic instability of the leukaemic cells. This genetic instability forms the basis for resistance to treatment and progression of disease.

The incidence of CML is cited at 2/100 000/year with a slight male preponderance; however, local South African incidence or prevalence data are lacking. Since the widespread use of TKIs, the number of patients surviving worldwide has increased greatly, resulting in a progressively increasing prevalence of this disease.

5. Diagnosis of CML

Many patients are asymptomatic and are diagnosed incidentally on the basis of a raised white blood cell (WBC) count. Clinical features include symptoms such as fatigue, malaise, weight loss, abdominal fullness and early satiety (due to splenomegaly), and rarely bleeding due to platelet dysfunction. Clinical findings may include hepatosplenomegaly, gouty arthritis, pallor, bone tenderness or features of hyperviscosity in patients with a high WBC count (e.g. headaches, visual and neurological disturbances, dyspnoea and angina). Patients should be carefully evaluated for extramedullary disease beyond the liver and spleen, which may have prognostic and staging implications (Table I). Clinical findings, especially spleen size, should be carefully documented for follow-up purposes and for calculation of the Sokal score, which is of prognostic value (online calculator available at www.roc.se/sokal.asp).

6. Disease phases

CML occurs in three different phases (chronic phase (CP), accelerated phase (AP), and a blastic phase (BP)). Most patients present in the CP. Classification is either by the European LeukaemiaNet (ELN) or the World Health Organization (WHO) criteria.

7. Laboratory investigations

Table II sets out the required laboratory tests for a newly diagnosed patient with CML. These are key to the correct staging of the patient, form the basis for further follow-up, and have direct bearing on prognosis.

8. Treatment with tyrosine kinase inhibitors

Before the introduction of the TKIs, the treatment of CML included hydroxyurea, interferon alpha (IFN-a), low-dose cytarabine and allogeneic haematopoietic stem cell transplantation. With the advent of imatinib, which specifically targeted the TK activity of the oncogenic proteins encoded by BCR-ABL, the management of CML changed dramatically. The following sections provide an overview of the available data supporting the use of TKIs in CML.

8.1 Imatinib

Imatinib is a selective inhibitor of the BCR-ABL TK. Imatinib induces a complete haematological response (CHR) in 80-90% of patients with newly diagnosed CP CML (CP-CML), a complete cytogenetic response (CCyR) in 70-80%, and a major molecular response (MMR), i.e. 3-log reduction of BCR-ABL: BCR or other control gene levels compared with a standardised pre-treatment level by real-time quantitative polymerase chain reaction (RQ-PCR), or RQ-PCR <0.05-0.1%, in 40% of patients. (2)

The landmark IRIS (International Randomized Study of Interferon and STI571) trial results led to the recommendation of imatinib as first-line therapy for patients with CML. (3) The IRIS trial was a phase III, multicentre, randomised, open-label, crossover trial in which 1 106 patients with newly diagnosed CML were randomised to receive initial therapy with either 400 mg imatinib or IFN-[alpha] plus low-dose cytarabine. (3) Responses were significantly in favour of imatinib, with a CHR rate at 18 months of 97% versus 69%, a major cytogenetic response (MCyR) rate of 87% versus 34.7%, and a CCyR rate of 72.6% versus 14.5% in the imatinib and low-dose cytarabine plus interferon arms, respectively. (3) These results were obtained despite 90% crossing over from the interferon plus low-dose cytarabine arm to the imatinib arm. (3) After 8 years of follow-up of the IRIS trial, the estimated event-free survival (EFS) and overall survival (OS) rates were 81% and 85%, respectively. (4)

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

About 10% of patients never achieve a CHR on imatinib by 3 months and about 25% do not achieve a CCyR by 18 months, thus fulfilling the ELN 2009 criteria of treatment failure. (5,6) Treatment failure usually results from the development of mutations in the TK domain of the BCR-ABL gene which affects the binding of imatinib to the adenosine triphosphate (ATP) binding site of the BCR-ABL protein. About 20% of patients who initially achieve a CHR or a cytogenetic response lose their responses over time with subsequent disease progression. (3) Intolerance to treatment and poor compliance are also reasons for treatment failure and discontinuation. (7,8) To overcome the problem of resistance, novel TKIs have been studied, two of which are commercially available in South Africa, namely nilotinib and dasatinib. South African regulatory authorities have approved both these TKIs for treatment of patients with resistance or intolerance to imatinib.

8.2 Dasatinib

Dasatinib is an oral Src and Abl kinase inhibitor with a potent BCR-ABL inhibitory effect. (9,10) Approval by the Food and Drug Administration (FDA) for the treatment of all phases of imatinib-resistant CML and Philadelphia (Ph)-positive acute lymphoblastic leukaemia (ALL) was granted in 2006. This was based on the efficacy and safety findings of the open-label phase 2 START studies (Sarcoma (SRC)/ABL Tyrosine Kinase Inhibitions Activity Research Trials of Dasatinib) aimed at patients resistant or intolerant to imatinib. (11-15) In the START-R study, high-dose imatinib (400 mg twice daily) was compared with dasatinib (70 mg twice daily) in 150 imatinib-resistant (to 400-600 mg daily) patients in CP CML. (15) Significantly higher response rates were seen with dasatinib when compared with high-dose imatinib at 24 months, with a CCyR rate of 44% versus 18% in the two groups, respectively. (15) These responses were durable, with MCyR maintained in 90% of dasatinib responders compared with 74% of imatinib responders. (15) Evidence from dose optimisation studies led to a change in the recommendations, with 100 mg as a once-daily dose recommended for CML in CP and 140 mg once daily for CML in advanced-phase CML (AP and BP) and Ph-positive ALL. (16,17) The phase III dasatinib versus imatinib study in treatment-naive CML patients (DASISION) compared the efficacy and safety of dasatinib (100 mg once daily) with imatinib (400 mg once daily) in patients with newly diagnosed CP CML and confirmed a CCyR at 12 months of 77% and 66% (p=0.007) with dasatinib and imatinib, respectively. (18) The impact of these recent findings within the current registered indications, recommendations and current socio-demographic and socio-economic setting in South Africa is still under review. In South Africa, dasatinib remains registered for the treatment of CML, following intolerance or resistance to imatinib or other first-line therapies for CML and Ph-positive ALL.

8.3 Nilotinib

Nilotinib is also a second-generation TKI that inhibits the BCR-ABL TK more potently and selectively than imatinib. (6,19,20) Nilotinib was approved by the FDA and the Medicines Control Council (MCC) for treating imatinib-intolerant and resistant patients with CML in CP and AP (but not for BP or Ph-positive ALL). In a phase II open-label study evaluating 280 CP-CML patients who had imatinib resistance or intolerance, MCyR and CCyR rates of 48% and 31%, respectively, were achieved. (21) Responses were found to be durable with long-term follow-up without the development of additional safety issues. (22) Nilotinib was studied in first-line therapy in a phase III study, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials--Newly Diagnosed Patients (ENESTnd) study, which compared the efficacy and safety of nilotinib (at a dose of either 300 mg or 400 mg twice daily) with that of imatinib (400 mg per day) in patients with newly diagnosed CP-CML. (23) The rates of CCyR by 12 months were significantly higher for nilotinib, namely 80% and 78% in the nilotinib 300 mg twice daily and 400 mg twice daily arms versus 65% in the imatinib 400 mg arm (p<0.001). A significant improvement in the time to progression to AP or blast crisis was seen in the nilotinib arms. (23) In South Africa nilotinib is registered as second-line therapy for CML, following intolerance or resistance to imatinib.

9. Management of CML

This should be done by a trained clinical haematologist or oncologist with experience in the management of patients with CML. Fig. 1 outlines the initial treatment of all three phases of CML.

9.1 Monitoring response in patients on imatinib

Monitoring of response to TKI therapy is very important (Fig. 2). Reaching specific goals within a given time has direct bearing on patient outcome. The aim is to get the patient to CCyR within 18 months. Table III provides definitions of response and Table IV the criteria against which response is monitored. We believe that one of the most important ways of ensuring that a patient reaches CCyR is by monitoring and acting early when action is required. Failure to do so may jeopardise a patient's chance of having a long-term response. On the basis of the degree of haematological response (HR), cytogenetic response (CyR), and molecular response (MR), and the time when these responses are achieved, the overall response to imatinib can be defined as optimal, suboptimal and failure.

9.2 Managing common side-effects of imatinib

Imatinib is generally well tolerated and has a favourable safety profile with an overall low incidence of severe adverse events in newly diagnosed CP-CML patients. The general management of common side-effects are outlined in Table V.

10. Pregnancy and breastfeeding

For the management of patients who are pregnant, want to fall pregnant or are breastfeeding, see Table VI.

11. Human immunodeficiency virus (HIV) infection and CML

The occurrence of CML in association with HIV infection is likely to be coincidental rather than causal. Globally this association is rarely described. (24) However, in South Africa, in the era of the HIV pandemic, it is being observed more frequently (M Patel, et al.--unpublished data).

CML in association with HIV presents with atypical and aggressive disease. (24) Both CML and HIV may cause myelosuppression and immunosuppression. Despite this, both chemotherapy/TKIs and combination antiretrovirals (cARVs) have been used safely and effectively. cARVs should be commenced in all patients with HIV-CML, irrespective of the CD4 count (as the CD4 count is usually elevated, mirroring the high white cell count and therefore not a reliable indicator of the stage of HIV in CML).

Drug interactions between cARVs and TKIs such as imatinib may require adjustment of treatment. Imatinib is mainly metabolised by the cytochrome P450 (CYP3A4) iso-enzyme, and concurrent administration of antiretroviral and antimicrobial drugs that induce or inhibit CYP3A4 may lead to drug-drug interactions.

In individuals who harbour both diseases, concurrent treatment with the TKIs (imatinib) and cARVs can result in appropriate control of the CML and HIV infection and long-term survival.

12. Role of allogeneic haematopoietic stem cell transplantation in CML

Since the introduction of imatinib in CP-CML, allogeneic stem cell transplantation is no longer considered as first-line treatment. Table VII lists indications for allogeneic stem cell transplantation.

13. Summary and conclusions

CML is a chronic myeloproliferative disorder characterised by a chromosomal translocation between the long arms of chromosomes 9 and 12 resulting in the formation of the BCR-ABL fusion gene. This gene codes for a novel 210 kD TK leading to myeloid cell overproliferation, as well as genetic instability that forms the basis of resistance to treatment and progression to accelerated and blastic phases. The management of CML was revolutionised with the advent of imatinib, a small-molecule BCR-ABL TKI, approved in South Africa in 2002, which results in a MCyR in nearly 90% of patients and a CCyR in over 70%. (3) After 7 years of follow-up of the landmark IRIS trial, CCyR has been maintained in 75% of patients with estimated EFS, OS and CML OS (the survival rate looking only at patients who died of CML) rates of 81%, 86% and 93%, respectively.

Unfortunately, up to 25% of patients fail to achieve a MMR by 18 months, and a further 20% lose their responses, primarily owing to resistance to imatinib. Nilotinib, an imatinib analogue, and dasatinib, an Src and Abl TKI, overcome imatinib resistance in most patients, except those with T315I mutations. Dasatinib has also been approved for patients in blast crisis. Nilotinib and dasatinib also show better molecular responses than imatinib in newly diagnosed patients, but this indication has not been approved in South Africa. Allogeneic stem cell transplantation plays a role in patients in subsequent CP after a blast crisis and with T315I mutations, although novel agents such as ponatinib may overcome resistance in these otherwise TKI-resistant patients.

Acknowledgement. The authors thank Dr Daleen Struwig for editorial assistance with the preparation and submission of this manuscript

Conflict of interest. The authors are all members of the Novartis Oncology Advisory Board, which received funding from Novartis Pharmaceuticals. Individual members also received honoraria and grants from the company. Other relevant conflicts of interest are tabulated below.
Disclosure of financial interest           Prof. L M  Prof. N    Dr A
                                            Dreosti   Novitsky  Schmidt

Novartis   Research grants/donations          Yes       Yes       No
           Honoraria                          Yes       Yes       Yes
           Consulting fees                    Yes       Yes       No
           Congress attendance/assistance     Yes       Yes       Yes

Bristol    Research grants/donations          Yes       Yes       No
Myers      Honoraria                          Yes       Yes       No
Squibb     Consulting fees                    Yes       Yes       No
           Congress attendance/assistance     No        Yes       Yes

Pfizer     Research grants/donations          Yes       Yes       No
           Honoraria                          Yes        No       No
           Consulting fees                    Yes        No       No
           Congress attendance/assistance     Yes        No       No

Disclosure of financial interest           Prof. V  Prof. M
                                            Louw     Patel

Novartis   Research grants/donations         Yes      Yes
           Honoraria                         Yes      Yes
           Consulting fees                   Yes      No
           Congress attendance/assistance    Yes      Yes

Bristol    Research grants/donations         Yes      Yes
Myers      Honoraria                         Yes      Yes
Squibb     Consulting fees                   Yes      No
           Congress attendance/assistance    Yes      Yes

Pfizer     Research grants/donations         Yes      Yes
           Honoraria                         No       No
           Consulting fees                   No       No
           Congress attendance/assistance    No       Yes

Disclosure of financial interest           Prof. P   Dr P
                                            Ruff    Willem

Novartis   Research grants/donations         Yes      Yes
           Honoraria                         Yes      Yes
           Consulting fees                   Yes      No
           Congress attendance/assistance    Yes      Yes

Bristol    Research grants/donations         Yes      No
Myers      Honoraria                         No       Yes
Squibb     Consulting fees                   No       No
           Congress attendance/assistance    No       No

Pfizer     Research grants/donations         Yes      No
           Honoraria                         Yes      No
           Consulting fees                   No       No
           Congress attendance/assistance    Yes      No


Accepted 17 August 2011.

References

(1.) Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809-1820.

(2.) Kantarjian HM, Talpaz M, O'Brien S, et al. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 2006;108:1835-1840.

(3.) O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.

(4.) Deininger M, O'Brien SG, Guilhot F, et al. International Randomized Study of Interferon Vs STI571 (IRIS) 8-year follow up: Sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. American Society of Hematology Annual Meeting 2009. http://abstracts.hematologylibrary.org/cgi/content/abstract/114/22/ 1126?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=deininger&searchid=1&FIR STINDEX=0&volume=114&issue=22&resourcetype=HWCIT (accessed 13 September 2011).

(5.) Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-2417.

(6.) Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-6051.

(7.) Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007;8:1018-1029.

(8.) Apperley JF. Part II: management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007;8:1116-1128.

(9.) Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399-401.

(10.) O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005;65:4500-4505.

(11.) Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007;109:3207-3213.

(12.) Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007;109:4143-4150.

(13.) Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109:2303-2309.

(14.) Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007;110:2309-2315.

(15.) Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer 2009;115:4136-4147.

(16.) Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008;26:3204-3212.

(17.) Kantarjian H, Cortes J, Kim DW, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood 2009;113:6322-6329.

(18.) Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010;362:2260-2270.

(19.) Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.

(20.) Jabbour E, Cortes J, Kantarjian H. Novel tyrosine kinase inhibitors in chronic myelogenous leukemia. Curr Opin Oncol 2006;18:578-583.

(21.) Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007;110:3540-3546.

(22.) Jabbour E, Cortes J, Kantarjian H. Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors. Cancer 2011;117:897-906.

(23.) Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010;362:2251-2259.

(24.) Tsimberidou A-M, Medina J, Cortes J, et al. Chronic myeloid leukemia in a patient with acquired immune deficiency syndrome: complete cytogenetic response with imatinib mesylate: report of a case and review of the literature. Leuk Res 2004;28:657-660.

V J Louw, Division of Clinical Haematology, Department of Internal Medicine, University of the Free State, Bloemfontein; L Dreosti, Department of Medical Oncology, University of Pretoria; P Ruff, Division of Medical Oncology, University of the Witwatersrand, Johannesburg; V Jogessar, Department of Haematology, University of KwaZulu-Natal, Durban; D Moodley, Parklands Medical Centre, Berea, Durban; N Novitzky, Division of Haematology, Departments of Medicine and Pathology, University of Cape Town; M Patel, Clinical Haematology Unit, Department of Medicine, Chris Hani Baragwanath Hospital and University of the Witwatersrand; A Schmidt, Oncology Department, Panorama Medical Centre, W Cape; P Willem, Department of Molecular Medicine and Haematology, University of the Witwatersrand

Corresponding author: V J Louw (louwvj@ufs.ac.za)
Table I. Phases of chronic myeloid leukaemia

European Leukaemia
Net (ELN) criteria
(1)                    WHO criteria

Chronic phase (CP)

None of the criteria
for AP or BP met

Acceleration phase
(AP)

Blast cells in PB or   Blasts 10/19% of WBCs in PB and/or nucleated BM
BM 15-29%              cells

Blast cells +          Peripheral blood basophils [greater than or
promyelocytes in PB    equal to] 20%
or BM >30%; with
blast cells <30%

Basophils in PB        Persistent thrombocytopenia (<100x[10.sup.9/]l)
[greater than or       unrelated to therapy or
equal to] 20%          persistent thrombocytosis (>1 000x[10.sup.9/]/l)
                       unresponsive to therapy

Persistent             Increase in spleen size and increase in WBC
thrombocytopenia       unresponsive to therapy
(platelets
<100x[10.sup.9]/l)     Cytogenetic evidence of clonal evolution
unrelated to therapy

Blastic phase (BP)

Blast cells in PB or   Blasts [greater than or equal to] 20% of
BM [greater than or    peripheral blood white cells or nucleated
equal to] 30%          bone marrow cells

Extramedullary         Extramedullary blast proliferation
involvement
(excluding liver and   Large foci or clusters of blasts in the bone
spleen)                marrow biopsy specimen

Note: Clinical trials often use the ELN criteria while
most diagnostic laboratories report the WHO criteria.

PB = peripheral blood; BM = bone marrow.

Table II. Initial work-up

Baseline laboratory investigations

FBC + differential

Urea and electrolytes, liver enzymes, serum LDH, serum urate

Pregnancy test

BM aspirate and trephine biopsy for:

Morphology, including differential count to determine phase of
disease

Assessment of fibrosis

Cytogenetic assessment on BM to determine:

* % Philadelphia-positive cells (preferably 20 metaphases)

* Presence of variant Philadelphia chromosome translocation

* Presence of additional abnormalities, e.g. double Ph,
isochromosome 17q, trisomy 8

FISH analysis optional:

* Only done where conventional cytogenetics not available or fails

* Or, to document a BCR-ABL positivity for variant
translocation and masked Ph

Note: If BM material unavailable (e.g. due to marrow fibrosis),
analysable metaphases may also be obtained from blood leukocytes

Real-time RQ-PCR on PB to establish:

* A baseline level

* The transcript type (1-2% have atypical BCR-ABL fusion
products that are undetectable by standard RQ-PCR)

FBC = full blood count; LDH = lactate dehydrogenase;
BM = bone marrow; FISH = fluorescence in situ hybridisation
RQ-PCR = real-time quantitative polymerase chain
reaction; PB = peripheral blood.

Table III. Definitions of response

Haematological                Complete (CHR)     WBC <10x[10.sup.9]/l

(check every 2 weeks until                       Basophils <5%
CHR, then 3-monthly)
                                                 No myelocytes,
                                                 promyelocytes,
                                                 myeloblasts in the
                                                 differential count

                                                 Platelet count
                                                 <450x[10.sup.9]/l

                                                 Spleen non-palpable

Cytogenetic                   Complete (CCyR)    No Ph+ metaphases

(check every 6 months until   Partial (PCyR)     1-35% Ph+ metaphases
CCyR, then every 1-2 years)   Minor (mCyR)       36-65% Ph+ metaphases
                              Minimal (minCyR)   66-95% Ph+ metaphases
                              None (noCyR)       >95% Ph+ metaphases

Molecular                     Major (MMR)        Ratio of BCR-ABL to
                                                 ABL (or BCR or GUS)
(every 3 months once CCyR                        [less than or equal
until MMR, then every 3-6                        to] 0.1% on the
months)                                          international scale

                              Complete (CMR)     Undetectable BCR/ABL
                                                 mRNA transcripts by
                                                 real/time
                                                 quantitative and/or
                                                 nested PCR in two
                                                 consecutive blood
                                                 samples of adequate
                                                 quality (sensitivity
                                                 >[10.sup.4])

Note: CHR, CCyR and MMR should be confirmed on 2 subsequent
occasions. CCyr is evaluated by morphologic cytogenetics of at least
20 bone marrow metaphases. FISH of peripheral blood cells should be
used only if marrow cells cannot be obtained. Molecular response by
PCR is assessed on peripheral blood cells.

Table IV. South African modified ELN recommendations
for goals of first-line therapy (imatinib) for CML

            Optimal response    Failure             Warnings

Baseline    N/A                 N/A                 Clonal
                                                    chromosomal
                                                    abnormalities
                                                    (CCA)/Ph+

3 months    CHR                 Less than CHR       N/A

6 months    At least PCyR       No CyR (Ph+ >95%)   N/A
            (Ph+ [less  than
            or equal to]35%)

12 months   CCyR                Less than PCyR      Less than MMR
                                (Ph+ >35%)

18 months   MMR                 Less than CCyR      Less than MMR

Any time    Stable or           Loss of CHR         CCA/Ph-
            improving MMR       Loss of CCyR        confirmed loss of
                                Mutations *         MMR
                                CCA/Ph+

* BCR-ABL mutations known to be poorly sensitive to imatinib.

Table V. Managing common imatinib side-effects

Side-effect           Mechanism                 Management

Non-haematological

Superficial oedema    Inhibition of PDGFR in    Dose interruption
(peri-orbital)        dermal dendrocytes        seldom required

                      Occurs in >50% of pts     Limit salt intake

                      Related to dose, older    Topical phenylephrine
                      age and females           0.25%

                                                Diuretics in severe
                                                cases, especially with
                                                severe peripheral
                                                oedema

Nausea and vomiting   Local irritation          Take imatinib with
                      gastric mucosa            largest meal of day (2
                                                hours before bedtime in
                      Dose-related              pts with history of
                                                oesophagitis or hiatus
                                                hernia)

                                                Anti-emetics if
                                                symptoms persist

                                                If on higher dose (600
                                                or 800 mg)-split dose
                                                in two

Muscle cramps                                   Calcium and magnesium
                                                supplements

                                                High fluid intake

Diarrhoea             Inhibition of c-KIT in    Anti-diarrhoeals, e.g.
                      interstitial Cajal        loperamide
                      cells

                      Dose-related              Take imatinib with
                                                large meal and water

Rash                  Inhibition of c-KIT in    Topical steroids
                      the skin                  effective in majority
                                                of cases In severe
                                                cases, oral
                                                corticosteroids, dose
                                                interruptions or
                                                occasionally
                                                discontinuation may be
                                                required

Hepatic toxicity                                With grade 2-3
                                                toxicities, dose
                                                interruption until
                                                toxicity is grade 1,
                                                followed by resumption
                                                of therapy at a reduced
                                                dose

                                                Alternative
                                                therapies should be
                                                considered for grade 4
                                                toxicity

Hypophosphataemia     Multiple effects on       Phosphate replacement
                      bone turnover by          if severe
                      inhibition of PDGFR

Haematological
toxicity

Neutropenia           Inhibition of c-KIT,      Dose interruption is
                      which is essential for    not recommended for
                      the development of        grade 1 -2 toxicity
                      normal blood cells

                      Suppression of the        Grade 3 /4 toxicity is
                      malignant clone until     defined as ANC
                      normal haematopoiesis     <1x[10.sup.9]/l: dose
                      replaces the marrow       interruption until ANC
                                                1-1.5x[10.sup.9]/l,
                                                then resume at 400 mg/d
                                                if recovery within 2
                                                weeks

                                                In the event of
                                                recurrent grade 3-4
                                                toxicity or delayed
                                                recovery, dose
                                                reduction to 300 mg

                                                Consider growth factors
                                                for patients with
                                                recurrent or persistent
                                                grade 3-4 toxicity

Thrombocytopenia      Inhibition of c-KIT,      Dose interruption is
                      which is essential for    not recommended for
                      the development of        grade 1-2 toxicity
                      normal blood cells
                                                Grade 3-4 toxicity is
                      Suppression of the        defined as a platelet
                      malignant clone until     count <50x[10.sup.9]/l:
                      normal haematopoiesis     dose interruption until
                      replaces the marrow       platelet count is
                                                50x[10.sup.9]/l, then
                                                resume at 400 mg/d if
                                                recovery within 2 weeks

                                                In the event of
                                                recurrent grade 3-4
                                                toxicity or delayed
                                                recovery, dose
                                                reduction to 300 mg

Anaemia               Inhibition of c-KIT,      Dose interruption is
                      which is essential for    not indicated for
                      the development of        toxicity of any grade
                      normal blood cells
                                                Dose reductions may
                      Suppression of the        help in patients with
                      malignant clone until     chronic anaemia
                      normal haematopoiesis
                      replaces the marrow

Note: Toxicity grades according to CTCAE (Common Terminology
Criteria for Adverse Events) criteria.

PDGFR = platelet-derived growth factor receptor.

Table VI. Pregnancy and breastfeeding

Pregnancy       Refer to specialised centres

                Discuss with patient in detail

                Multidisciplinary approach is required

                Interferon-[alpha] has been used, although there are
                risks

                Although the risk of fetal abnormalities is low
                with imatinib, avoidance of imatinib during
                conception and gestation is recommended

                Effective contraception is recommended for men
                and women using TKIs

Breastfeeding   Imatinib is secreted in the breastmilk

                Owing to the potential for serious adverse events
                in the infant, breastfeeding is not recommended

Table VII. Indications for stem cell transplantation in
advanced disease

1. At diagnosis in AP or BP as first- or second-line therapy,
preferably after imatinib

2. 2nd or subsequent CP

3. T315I mutation

4. Imatinib failure in patient with good transplant risk score
(EBMT risk score 0-2) and who is not a good candidate for a
2nd-generation TKI

5. All patients failing a 2nd-generation TKI

EBMT = European Group for Blood and Marrow Transplantation.
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Title Annotation:Guideline
Author:Louw, V.J.; Dreosti, L.; Ruff, P.; Jogessar, V.; Moodley, D.; Novitzky, N.; Patel, M.; Schmidt, A.;
Publication:South African Medical Journal
Article Type:Disease/Disorder overview
Geographic Code:6SOUT
Date:Nov 1, 2011
Words:4783
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