Page 13 - Essential Haematology

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Features contained within your textbook
CHAPTER 5
Megaloblastic
anaemias and ▲ Every chapter has its own chapter - opening page that offers a list
REVISED
other macrocytic of key topics contained within the chapter
anaemias CHAPTER 1
Haemopoiesis
Key topics Throughout your textbook you will fi nd a series of icons outlining
■ Megaloblastic anaemias 59 Key topics
■ Vitamin B 12 59 ■ Site of haemopoiesis 2
■ Folate 62 the learning features in the book:
■ Vitamin B 12 deficiency 63 ■ Haemopoietic stem and progenitor cells 2
■ Folate deficiency 64 ■ Bone marrow stroma 3 5
■ Tissue-specific stem cells
■ Clinical features of megaloblastic anaemia 65 ■ The regulation of haemopoiesis 6
■ Diagnosis of vitamin B 12 or folate deficiency 67 ■ Haemopoietic growth factors 6 ▼
■ Other megaloblastic anaemias 71
■ Systemic diseases associated with folate or ■ Growth factor receptors and signal transduction 8
vitamin B 12 deficiency 71 ■ The cell cycle 10
■ Other macrocytic anaemias 71 ■ Apoptosis REVISED 11 13 13 The coloured line in the margin indicates
■ Transcription factors
■ Adhesion molecules
is needed for undergraduate medical
Essential Haematology, 6th Edition. © A. V. Hoffbrand and P. A. H. Moss. Published 2011 by Blackwell text that we consider more advanced than
Publishing Ltd.
students and more appropriate for
postgraduates
Essential Haematology, 6th Edition. © A. V. Hoffbrand and P. A. H. Moss. Published 2011 by Blackwell
Publishing Ltd.
Self - assessment multiple choice questions
and answers are available on the
companion website: www.wiley.com/go/
essentialhaematology . You can also
access these questions by clicking on this
icon in your Desktop Edition
▲ Your textbook is full of useful photographs,
230 / Chapter 17 Acute lymphoblastic leukaemia Chapter 17 Acute lymphoblastic leukaemia / 231
illustrations and tables. The Desktop Edition
Induction 100 100
e.g. vincristine, asparginase, 96±3
dexamethasone (or prednisolone) ± daunorubicin 80 84±2 81±2 80 72%
Consolidation 74±2 MRD+ (≥1%) n = 9 version of your textbook will allow you to copy
e.g. daunorubicin, cytosine arabinoside, vincristine, 60 60
REVISED REVISED
etoposide, thioguanine or mercaptopurine, Probability of overall survival (%) 43%
cyclophosphamide in one to four courses 40 48±2 Cumulative incidence of relapse MRD+ (≥0.1% – <1%) n = 14
Possible stem cell 40 23% and paste any photograph or illustration into
transplantation 20 MRD+ (<0.1%) n = 19
Cranial prophylaxis 20 10%
e.g. high dose systemic methotrexate 21±4 MRD– n = 123
or multiple intrathecal methotrexate 0
or cranial irradiation (1800–2400 rad) 0 10 20 30 40 0 assignments, presentations and your own notes.
+ intrathecal methotrexate Studies 1 to 4, 1962–1966 0 1 2 3 Years 4 5 6 7 8
Years after diagnosis
Maintenance therapy Studies 5 to 9, 1967–1979
e.g. mercaptopurine, methotrexate, vincristine, Study 10, 1979–1983 Figure 17.8 Cumulative incidence of relapse according to minimal residual disease (MRD) levels at the end of
dexamethasone (or prednisolone) Studies 11 and 12, 1984–1991 remission induction in children with acute lymphoblastic leukaemia (ALL) treated at St Jude Children’s Research The photographs and illustrations are also available
Studies 13A, 13B and 14, 1991–1999
Late intensification (as consolidation) (b) Study 15, 2000–2010 Hospital. (Courtesy of Dr D. Campana.)
Maintenance therapy as above (2–3 years) from the complications of bone marrow failure involve the use of vincristine, cyclophosphamide, to download from the companion website
(a) and leukaemic infiltration (Fig. 17.1). The aim of cytosine arabinoside, daunorubicin, etoposide or
remission induction is to rapidly kill most of the
mercaptopurine given as blocks in different combi-
Figure 17.6 Acute lymphoblastic leukaemia (ALL). (a) Flow chart illustrating typical treatment regimen. tumour cells and get the patient into remission. This nations. Three blocks of intensification are generally
(b) Kaplan–Meier analyses of overall survival in 2628 children with newly diagnosed ALL. (Updated from is defined as less than 5% blasts in the bone marrow, given for children, with more sometimes used in ▼
Pui C.H. and Evans W.E. (2006) N Engl J Med 354, 169.) normal peripheral blood count and no other symp- adults.
toms or signs of the disease. Dexamethasone, vinc-
Normal BM ALL diagnosis ALL remission ristine and asparaginase are the drugs usually used Central nervous system directed therapy
Few of the drugs given systemically are able to reach
and they are very effective – achieving remission in
over 90% of children and in 80–90% of adults
the CSF and specific treatment is required to
(in whom daunorubicin is also usually added).
prevent or treat central nervous system (CNS)
is not the same as cure. In remission a patient may
intravenously, intrathecal methotrexate or cytosine
CD10 PE CD38 FITC CD34 PerCP CD10 PE CD38 FITC CD34 PerCP CD10 PE CD38 FITC CD34 PerCP However, it should be remembered that remission disease. Options are high-dose methotrexate given 186 / Chapter 13 Acute myeloid leukaemia Chapter 13 Acute myeloid leukaemia / 187
still be harbouring large numbers of tumour cells
arabinoside, or cranial irradiation. Cranial irradia-
ranial irradia-
le in children
tion is now avoided as far as possible in children
and without further chemotherapy virtually all
patients will relapse (see Fig. 13.8). Nevertheless,
because of substantial side-effects. CNS relapses still
NS relapses still
occur and present with headache, vomiting, papil-
achievement of remission is a valuable first step in
miting, papil-
the treatment course. Patients who fail to achieve
loedema and blast cells in the CSF. Treatment is is
Treatment
with intrathecal methotrexate, cytosine arabinoside
ne arabinoside
remission need to change to a more intensive
CD19 APC
cranial irradia-
and hydrocortisone, with or without cranial irradia-
protocol.
tion and systemic reinduction because bone marrow 1000 10 4 10 4 Remission
e bone marrow
induction
Figure 17.7 Detection of minimal residual disease (MRD) by four-colour flow cytometry in: normal bone marrow Intensification (consolidation) disease is usually also present. 800 10 3 10 3 Consolidation Relapse
mononuclear cells (BM), BM from a patient with B lineage ALL at diagnosis and in remission 6 weeks after Complete
diagnosis. The cells were detected with four different antibodies (anti-CD10, anti-CD19, anti-CD34, anti-CD38) These courses use high doses of multidrug chemo- Maintenance 600 remission Severe 100
therapy in order to eliminate the disease or reduce
attached to fluorescent labels abbreviated as PE, APC, PerCP and FITC, respectively. The tridimensional plot SSC-H: Side Scatter FL4-H: CD19 APC 10 2 FL4-H: CD33 APC 10 2 10 12 Bone
adults and for
shows the immunophenotype of CD19 + lymphoid cells in the three samples. MRD of 0.03% of cells expressing the tumour burden to very low levels. The doses of This is given for 2 years in girls and adults and for 400 marrow
ptopurine and
failure Mild
the leukaemia-associated phenotype (CD10 + , CD34 + , CD38 − ) were detected at 6 weeks, confirmed by polymer- chemotherapy are near the limit of patient tolerabil- 3 years in boys, with daily oral mercaptopurine and 10 1 10 1 Conventional detection level 10
venous vincris-
ase chain reaction (PCR) analysis. (From Campana D. and Coustan-Smith E. (1999) Commun Clin Cytometry ity and during intensification blocks patients may once-weekly oral methotrexate. Intravenous vincris- 200 92.4 10 10 Detection level by molecular or 5
al dexametha-
38, 139–52, with permission.) need a great deal of support. Typical protocols tine with a short course (5 days) of oral dexametha- immunological techniques
0 10 0 10 0
0 200 400 600 800 1000 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 1
FSC-H: Forward Scatter FL3-H: CD3 PerCP FL3-H: CD34 PerCP 10 8
10 4 10 4 Maintenance Resistant disease 0.1
chemotherapy
(biochemical,
(ALL)
biological
10 3 10 3 Figure 13.6 FACS analysis of Number of leukaemic cells 10 6 (chemo±TBI) SCT anatomical, % leukaemic cells in bone marrow
resistance)
FL4-H: CD33 APC 10 2 FL2-H: CD117 PE 10 2 AML – tumour cells are initially 10 4 0.01
gated on forward scatter (FSC)
analysis reveals (i) lack of
10 1 10 1 versus side scatter (SSC). Further 10 2 0.001
expression of lymphocyte markers
10 0 10 0 (CD3 and CD19), (ii) expression
10 1
10 0
of CD33 and (iii) CD117 as well
10 3
10 2
10 3
10 0 10 1 10 2 REVISED 10 4 REVISED
10 4
FL2-H: CD117 PE FL1-H: Anti-HLA-DR FITC as HLA-DR on a subset of cells. 10 0 Time 0.0001
Haemolytic anaemia is caused by transfusion), there is haemoglobinaemia, Figure 13.8 Acute leukaemia: principles of therapy. ALL, acute lymphoblastic leukaemia; SCT, stem cell
shortening of the red cell life. The red cells methaemalbuminaemia, haemoglobinuria 1 2 15q22 3 4 5 6 3 4 5 17q12 6 7 8 9 transplantation; TBI, total body irradiation.
may break down in the reticuloendothelial and haemosiderinuria. PML BCR-1 RAR α Induction
e.g. daunorubicin, cytosine arabinoside,
system (extravascular) or in the circulation Genetic defects include those of the red BCR-1/L PML RAR α thioguanine or etoposide therapy is that of basing the treatment schedule of
An important concept developing in AML
(intravascular). cell membrane (e.g. hereditary SUMMARY Consolidation individual patients on their risk group. Favourable
cytogenetics and remission after one course of
e.g. daunorubicin, cytosine arabinoside,
Haemolytic anaemia may be caused by spherocytosis), enzyme deficiencies (e.g. Figure 13.7 Generation of the t(15; 17) translocation. The PML gene at 15q22 may break at one of three thioguanine or etoposide chemotherapy both predict for a better prognosis.
different breakpoint cluster regions (BCR-1, -2 and -3) and joins with exons 3–9 of the RARα gene at 17q12.
In contrast, monosomy 5 or 7 abnormalities, blast
inherited red cell defects, which are usually glucose-6-phosphate dehydrogenase or Three different fusion mRNAs are generated (termed long (L), variable (V) or short (S)) and these give rise to Consolidation cells with the FLT3 internal tandem duplication
fusion proteins of different size. In this diagram only the long version resulting from a break at BCR-1 is shown.
mutation or poorly responsive disease places patients
e.g. m-AMSA, etoposide,
cytosine arabinoside
intrinsic to the red cell, or to acquired pyruvate kinase deficiency) or into poor risk groups which need more intensive
treatments (Table 13.3).
Promyelocytic leukaemia with the t(15; 17)
Monitoring of minimal residual disease during
causes, which are usually caused by an haemoglobin defects (e.g. sickle cell translocation responds to treatment with high doses Prognosis and treatment stratification Possible stem cell Further consolidation and after chemotherapy is being investigated as a
e.g. mitoxantrone, idarubicin,
transplantation,
high dose cytosine

allogeneic or autologous
abnormality of the red cell environment. anaemia). of ATRA which causes differentiation of the abnor- The outcome for an individual patient with AML arabinoside, anti-CD33 means to guide appropriate treatment. It may be
will depend on a number of factors including age
performed by polymerase chain reaction (PCR) or
antibody
mal promyelocytes and results in improved progno-
Features of extravascular haemolysis Acquired causes of haemolytic anaemia sis. Interestingly, in rare variants of RARα is fused and white cell count at presentation. However, the Figure 13.9 Acute myeloid leukaemia: flow chart flow cytometric analysis of the abnormal ‘leukaemia-
to other genes and in these cases ATRA treatment
associated immunophenotype’ that is seen in over
genetic abnormalities in the tumour are the most
is not successful. important determinant. illustrating typical treatment regimen. 90% of cases.
include jaundice, gallstones and include warm or cold, auto- or allo-
splenomegaly with raised reticulocytes, antibodies to red cells, red cell
unconjugated bilirubin and absent fragmentation syndromes, infections, toxins
haptoglobins. In intravascular haemolysis and paroxysmal nocturnal
(e.g. caused by ABO mismatched blood haemoglobinuria.
▲
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