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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2826_Библиотеки_им_академика_М_И_Перельмана.pdf
Myeloablative Therapy and HSCT 253
• Chemicals, e.g. benzene compounds used in industry.
• Drugs, e.g. AML occurs after treatment with alkylating agents (e.g.
melphalan),
• Radiation exposure can induce genetic damage to haemopoietic
precursors and increased incidences of leukaemia have been seen in
survivors of Hiroshima and Nagasaki and in patients treated with ionizing
radiation.
• Viruses, e.g. human T-cell lymphotropic retrovirus type 1 (HTLV-1) is
associated with some types of leukaemia.
• Genetic factors are suggested by the increased incidence in patients
with chromosomal disorders (e.g. Down’s syndrome is linked to
a 30-fold increased risk of developing leukaemia). Chromosomal
abnormalities have been described in patients with leukaemia. The
Philadelphia (Ph) chromosome is found in 97% of cases with CML
and some patients with ALL. In the Ph chromosome the long arm of
chromosome 22 is shortened by reciprocal translocation to the long
arm of chromosome 9 (t(9;22)). The protein product of the resulting
‘fusion’ gene, BCR-ABL, has tyrosine kinase activity, and enhanced
phosphorylating activity compared with the normal protein, resulting
in altered cell growth, stromal attachment and apoptosis. The
leukaemic cells of most patients with acute promyelocytic leukaemia
(APML) have the translocation t(15;17) involving the retinoic acid
receptor alpha (RARa) on chromosome 17 and the promyelocytic
leukaemia gene (PML) on chromosome 15. The resulting PML-RARa
fusion protein shows reduced sensitivity to retinoic acid and prevents
differentiation of myeloid cells.
Acute leukaemia
The acute leukaemias are characterized by a clonal proliferation of myeloid or
lymphoid precursors with reduced capacity to differentiate into more mature
cellular elements. There is accumulation of leukaemic cells in the bone marrow, peripheral blood and other tissues, with a reduction in red cells, platelets
and neutrophils.
Epidemiology
Both types of acute leukaemia can occur in all age groups, but ALL is predominantly a disease of childhood, whereas AML is seen most frequently in
older adults (middle-aged and elderly).
Clinical features
These are the result of marrow failure: anaemia, bleeding and infection, e.g.
sore throat and pneumonia. Sometimes there is peripheral lymphadenopathy
and hepatosplenomegaly.
254 Malignant disease
Investigations
• Blood count. Haemoglobin and platelets are low. White blood cell count
is usually raised, reflecting the proliferating population, but may be low if
the leukaemic cells are confined to the bone marrow.
• A definitive diagnosis is made on the peripheral blood film and a bone
marrow aspirate. The various subtypes (Table 6.2) are classified on the
basis of morphology and immunophenotyping, and cytogenetic studies
of blast cells. Auer rods (a rod-like conglomeration of granules in the
cytoplasm) within blast cells are pathognomonic of AML. If the patient
has a fever, blood cultures and chest X-ray are essential. Blood count
shows anaemia and thrombocytopenia. The white cell count is usually
raised, but may be normal or low.
• Blood film shows characteristic leukaemic blast cells.
• Bone marrow aspirate usually shows increased cellularity, with a high
percentage of abnormal lymphoid or myeloid blast cells. Lineage is
confirmed by immunophenotyping.
• Lumbar puncture and cerebrospinal fluid examination are performed
after blasts have been cleared from peripheral blood in all patients with
ALL with monoblast/monocytic component as the risk of central nervous
system (CNS) involvement is high. It is less critical in AML.
• Minimal residual disease (MRD) testing via flow cytometry and molecular
technologies is increasingly being used to detect very low levels of
malignant cells. An MRD-positive result can predict relapse before it is
visible by morphology, and may prompt an early change in treatment.
Conversely, an MRD-negative result can provide confidence for
de-escalating treatment.
Table 6.2 World Health Organization classification of acute
leukaemia
A. AML (acute myeloid leukaemia)
1. AML with recurrent cytogenetic abnormalities (including acute
promyelocytic leukaemia with t(15;17) or variants)
2. AML with multilineage dysplasia (often secondary to a pre-existing MDS)
3. AML and MDS, therapy-related, occurring after chemotherapy or
radiotherapy
4. AML – not otherwise categorized
B. ALL (acute lymphoblastic leukaemia)
1. Precursor B-cell acute lymphoblastic leukaemia
2. Burkitt cell leukaemia
3. Precursor T-cell acute lymphoblastic leukaemia
MDS, myelodysplastic syndrome.
Myeloablative Therapy and HSCT 255
Management
The initial requirement of therapy is to return the peripheral blood and bone
marrow to normal (complete remission) with ‘induction chemotherapy’
tailored to the particular leukaemia and the individual patient’s risk factors.
This treatment also impairs normal bone marrow function and leads to a
major risk of life-threatening infection. The risk of failure of treatment is
based on the cytogenetic pattern. Successful remission induction is always
followed by further treatment (consolidation), the details being determined
by the type of leukaemia and the patient’s risk factors (and the patient’s
tolerance of treatment). Recurrence is almost invariable if ‘consolidation’
therapy is not given.
Supportive care. Before starting treatment the following need to be
performed:
• Correction of anaemia, thrombocytopenia and coagulation abnormalities
by administration of blood, platelets and blood products
• Treatment of infection with intravenous (i.v.) antibiotics
• Prevention of the acute tumour lysis syndrome (p. 252).
Treatment
Acute myeloid leukaemia
Complete remission is usually achieved in about 80% of patients under the
age of 60 years with no significant comorbidity, in whom treatment is offered
with curative intent. Older patients tolerate cytotoxic therapy less well than
younger patients due to additional comorbidities, and their disease is often
more aggressive in its biology. As a result, treatment-related morbidity and
mortality are both higher and outcome is less successful.
Low risk of treatment failure (based on the cytogenetic pattern)
• A moderately intensive combination of i.v. chemotherapy, e.g. cytosine
arabinoside (cytarabine) and daunorubicin, is given at intervals to allow
marrow recovery in between. This is followed by consolidation therapy
with a minimum of four cycles of treatment given at 3–4-week intervals.
The confirmation of deep remission by MRD negativity may allow
some patients to move into a good-risk group and remove the need for
transplant.
Intermediate risk
• Consolidating chemotherapy to induce remission followed by siblingmatched allogeneic bone marrow transplantation, despite its attendant
risks.
High risk of treatment failure
• This is only curable with allogeneic transplantation but unfortunately
‘high risk’ is more common with advancing age when the toxicity of this
treatment increases greatly.
256 Malignant disease
Acute promyelocytic leukaemia
APML is a variant of AML that is specifically associated with disseminated
intravascular coagulation (DIC; p. 233), which may worsen when treatment
is started. It is conventional to combine chemotherapy for APML with alltrans-retinoic acid (ATRA), which causes differentiation of promyelocytes and
rapid reversal of the bleeding tendency caused by DIC. Successful remission
induction is followed with maintenance ATRA.
Complete remission occurs in at least 90% of younger adults with APML
and at least 70% will expect to be cured. Long-term survival following
recurrence is rarely achieved without allogeneic transplantation.
Acute lymphoblastic leukaemia
As with AML, the aim is to achieve remission with induction chemotherapy and
consolidate the response with further chemotherapy or an allogeneic transplant. MRD stratification is increasingly employed to select patients who are at
high risk (for treatment intensification) or low risk (for treatment de- escalation).
The drugs used differ from AML. Remission induction is undertaken with combination chemotherapy including vincristine, dexamethasone, asparaginase
and daunorubicin. Details of consolidation will be determined by the risk of failure but is usually with intensive chemotherapy and then maintenance therapy
for 2 years to reduce the risk of disease recurrence. The presence of the t(9;22)
Philadelphia translocation has traditionally been associated with increased
risk, but the use of tyrosine kinase inhibitors (e.g. imatinib) in combination with
chemotherapy has improved outcomes considerably.
Unlike AML, ALL tends to involve the CNS, so treatment also includes
prophylactic intrathecal drugs, e.g. methotrexate or cytosine arabinoside
(cytarabine). Cranial irradiation is used in those at very high risk or in those
with symptoms.
The prognosis in children with ALL is excellent. Almost all achieve
complete remission and 80% are disease free at 5 years. Prognosis worsens
with advancing years. Overall, 70%–80% adults achieve complete remission
with only about 30% being cured.
Novel cytotoxic drugs, including clofarabine and nelarabine, are increasingly
used for relapsed/refractory cases, as are a range of monoclonal antibodies
in B-ALL, including rituximab (anti-CD20), inotuzumab (calicheamicin-labelled
anti-CD22) and blinatumomab (CD19/CD3 bispecific T-cell engager antibody).
Chimeric antigen receptor T-cell (CAR-T) immunotherapy has shown significant
promise in ALL and is likely to see increased use in coming years.
Chronic myeloid leukaemia
Clinical features
CML occurs most commonly in middle age and is characterized by the
presence of the Ph chromosome. There is an insidious onset, with fever,
Myeloablative Therapy and HSCT 257
weight loss, sweating and symptoms of anaemia. Massive splenomegaly is
characteristic.
Untreated, this chronic phase lasts 3–4 years. This is usually followed by
blast transformation, with the development of acute leukaemia (usually acute
myeloid) and, commonly, rapid death. Less frequently, CML transforms into
myelofibrosis, death ensuing from bone marrow failure.
Investigations
• Blood count usually shows anaemia and a raised white cell count (often
>100×109/L). The platelet count may be low, normal or raised.
• Bone marrow aspirate shows a hypercellular marrow with an increase in
myeloid progenitors.
• The Ph chromosome and the BCR-ABL oncogene are shown by
cytogenetics and reverse transcriptase polymerase chain reaction
(RT-PCR).
Management
Imatinib, a tyrosine kinase inhibitor that specifically blocks the enzymatic
action of the BCR-ABL fusion protein, is first-line treatment for the chronic
phase. Imatinib produces a complete haematological response in over 95%
of patients, and 70%–80% of these have no detectable BCR-ABL transcripts
in the blood. Event-free and overall survival appear to be better than for other
treatments. Imatinib can be continued indefinitely.
In the acute phase (blast transformation) most patients have only a shortlived response to imatinib, and other chemotherapy as for acute leukaemia is
used in the hope of achieving a second chronic phase.
Chronic lymphocytic leukaemia
CLL, the most common form of leukaemia, is an incurable disease of older
people, characterized by an uncontrolled proliferation and accumulation of
mature B lymphocytes.
Clinical features
CLL usually follows an indolent course. Early CLL is generally asymptomatic
and isolated peripheral blood lymphocytosis is frequent. Symptoms are a
consequence of bone marrow failure: anaemia, infections and bleeding. An
autoimmune haemolysis contributes to the anaemia. Some patients may be
asymptomatic, the diagnosis being a chance finding on the basis of a blood
count performed for a different reason. There may be lymphadenopathy and,
in advanced disease, hepatosplenomegaly.
Investigations
• Blood count shows a raised white cell count with lymphocytosis
(>5 × 109/L). There may be anaemia and thrombocytopenia.
258 Malignant disease
• Blood film shows small lymphocytes of mature appearance with ‘smear
or smudge cells’, an artefactual finding due to cell rupture while the film
is being made.
• Bone marrow reflects peripheral blood, usually heavily infiltrated with
lymphocytes.
• Immunophenotyping is essential to exclude reactive lymphocytosis and
other lymphoid neoplasms.
• Cytogenetics to characterize the specific mutation can be helpful in
assessing prognosis.
Management
The decision to treat depends on the stage of the disease and more recently
on cytogenetic markers. Early-stage disease is treated expectantly whereas
advanced-stage disease is always treated immediately. Other indications
for treatment include anaemia, recurrent infections, splenic discomfort and
progressive disease.
Combination therapy with fludarabine, cyclophosphamide and
rituximab (p. 250) has become standard first-line therapy and can
induce complete remission. Obinutuzumab or ofatumumab, both novel
anti-CD20 monoclonal antibodies, are preferred in the elderly or less fit
to rituximab in combination with chlorambucil. Alemtuzumab (p. 250) is
used in patients in whom there is disease progression after treatment
with fludarabine.
Prognosis
The median survival from diagnosis (10 years) is very variable and correlates
closely with disease stage at diagnosis and cytogenetic findings, e.g. patients
with either 11q or 17p deletions (the sites of two tumour suppressor genes)
are at high risk of not responding to initial treatment and rapid progression.
In other patients there is near-normal life expectancy.
THE LYMPHOMAS
The lymphomas are B- and T-cell malignancies of the lymphoid system. They
are the fifth most common malignancy in the Western world (more common than leukaemia) and are increasing in incidence for reasons that are
unclear. The disease is classified on the basis of histological appearance into
Hodgkin’s and non-Hodgkin’s lymphomas.
Hodgkin’s lymphoma
Hodgkin’s lymphoma is primarily a disease of young adults. Previous infection with Epstein–Barr virus (EBV) is thought to play a role in pathogenesis
in some patients.
The Lymphomas 259
Clinical features
Painless lymph node enlargement (often cervical nodes) is the most common
presentation. These lymph nodes have a rubbery consistency on examination. There may be hepatosplenomegaly. Systemic ‘B’ symptoms are fever,
drenching night sweats and weight loss (>10% in previous 6 months). Other
constitutional symptoms, such as pruritus, fatigue, anorexia and alcoholinduced pain at the site of the enlarged lymph nodes, also occur.
Investigations
• Blood count may be normal or show a normochromic, normocytic anaemia.
• The erythrocyte sedimentation rate (ESR) is usually raised and is an
indicator of disease activity.
• Liver biochemistry may be abnormal, with or without liver involvement.
• Serum lactate dehydrogenase (LDH) if raised is an adverse prognostic
marker.
• Chest X-ray may show mediastinal widening from enlarged nodes.
• Diagnosis is by lymph node biopsy and histological examination showing
Reed–Sternberg cells (binucleate or multinucleate malignant B lymphocytes)
in a background rich in benign small lymphocytes and histiocytes.
• Disease staging is by positron emission tomography and computed
tomography (PET/CT) to establish extent and distribution of metabolically
active sites of disease.
Differential diagnosis
This includes any other cause of lymphadenopathy (Table 6.3). Persistently
enlarged lymph nodes must always be excised for histological and microbiological examination for diagnostic purposes.
Management
Treatment is given with curative intent. The choice of treatment depends on:
• Stage (Table 6.4).
• Involved sites.
• ‘Bulk’ of lymph nodes involved.
• Presence of ‘B’ symptoms.
• Early-stage disease (stage IA, IIA with no bulk) is treated with brief
chemotherapy (ABVD, doxorubicin (Adriamycin), bleomycin, vinblastine,
dacarbazine) followed by involved field irradiation (20–30 Gy).
• Advanced disease (all other stages) is treated with cyclical combination
chemotherapy (eight cycles of ABVD) with irradiation at sites of bulk
disease. PET/CT is used to detect disease activity after treatment and
to distinguish between active tumour (PET-positive) and necrosis or
fibrosis (PET-negative) in residual masses. Irradiation, with its attendant
complications, can be omitted in PET-negative masses after chemotherapy.
260 Malignant disease
Table 6.3 Differential diagnosis of lymphadenopathy
Localized Generalized
Local infection
Pyogenic infection, e.g.
tonsillitis
Tuberculosis
Infection
Epstein–Barr virus
Cytomegalovirus
Toxoplasma sp.
Tuberculosis
HIV infection
Lymphoma Lymphoma
Secondary carcinoma Leukaemia
Systemic disease
Systemic lupus erythematosus
Sarcoidosis
Rheumatoid arthritis
Drug reaction, e.g. phenytoin
HIV, human immunodeficiency virus.
Table 6.4 Staging classification of Hodgkin’s lymphoma
Stage Definition
I Involvement of a single lymph node region or a single extralymphatic
organ or site
II Involvement of two or more lymph node regions on the same side
of the diaphragm, or localized involvement of an extralymphatic
organ or site and of one or more lymph node regions on the same
side of the diaphragm
III1 Involvement of lymph node regions on both sides of the diaphragm,
which may also be accompanied by involvement of the spleen (IIIS)
or by localized involvement of an extralymphatic organ (IIIE) or site
or both (IIISE)
IV Diffuse or disseminated involvement of one or more extralymphatic
organs or tissues, with or without associated lymph node
involvement
Each stage can also be graded A (no ‘B’ symptoms) or B (with ‘B’ symptoms), X (bulky
disease) or E (involvement of a single extranodal site that is contiguous or proximal to the
known nodal site).
The Lymphomas 261
Prognosis is related to the stage of disease at presentation, with a 5-year
survival rate of over 90% in stage I declining to 60% in stage IV. The presence
of ‘B’ symptoms indicates more severe disease with a worse prognosis.
Non-Hodgkin’s lymphoma
These are malignant tumours of the lymphoid system classified separately
from Hodgkin’s lymphoma. There is a malignant clonal expansion of lymphocytes, which occurs at different stages of lymphocyte development.
Most (80%) are of B-cell origin. In general, neoplasms of non-dividing
mature lymphocytes are indolent, whereas those of proliferating cells (e.g.
lymphoblasts, immunoblasts) are much more aggressive. The B- and T-/
natural killer (NK) cell lymphomas are each further divided on this basis,
e.g. precursor B-cell lymphoma, and then again subdivided based on cytogenetics and immunophenotyping. The aetiology is unknown in most cases
but some are associated with a specific infection, e.g. Helicobacter pylori,
and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Immune
suppression, immunosuppressant drugs (particularly as used for solid
organ transplantation) and human immunodeficiency virus (HIV) infection
are all associated with an increased incidence of lymphoma.
Clinical features
Presentation is rare before the age of 40 years. Most patients present with
painless peripheral lymph node enlargement. Systemic symptoms as in
Hodgkin’s lymphoma may occur. Extranodal involvement is more common
than in Hodgkin’s lymphoma and almost any organ in the body can be
involved. Bone marrow infiltration leads to anaemia, recurrent infections
and bleeding. Skin involvement with T-cell lymphoma presents as mycosis
fungoides and Sézary syndrome.
Investigations
• Blood count may show anaemia. An elevated white cell count or
thrombocytopenia suggests bone marrow involvement. The ESR may be
raised.
• Liver biochemistry may be abnormal if the liver is involved.
• Serum LDH and β2-microglobulin are prognostic indicators.
• Chest X-ray, CT, PET and gallium scans are of help in staging.
• Bone marrow aspiration and trephine biopsy will confirm marrow
involvement.
• Lymph node biopsy is required for definitive diagnosis and subtype
classification.
Management
Treatment depends on the lymphoma type and stage (similar to Hodgkin’s
lymphoma). Diffuse large B-cell lymphoma is the most common lymphoma
262 Malignant disease
and first-line treatment is with cyclical combination chemo-immunotherapy
(R-CHOP; rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine) and prednisolone) with field irradiation for those with bulky disease.
Between 60% and 70% of those with early-stage disease will achieve a cure
with this regimen.
• Primary gastric lymphoma in many cases is associated with H. pylori
infection. Treatment to eradicate the infection (p. 89) is usually all that is
required provided there is no evidence of disease outside the stomach.
This is followed by close endoscopic surveillance.
• Burkitt’s lymphoma occurs mainly in African children and is associated
with EBV infection. Jaw tumours are common, usually with gastrointestinal
involvement. Treatment is with cyclical combination chemotherapy.
THE PARAPROTEINAEMIAS
Multiple myeloma
Multiple myeloma is a malignant disease of the plasma cells of bone marrow, accounting for 1% of all malignant disease. There is clonal proliferation
of bone marrow plasma cells usually capable of producing monoclonal
immunoglobulins (paraproteins), which in most cases are immunoglobulin
(Ig) G or IgA. The paraproteinaemia may be associated with excretion of light
chains in the urine (Bence Jones protein) which are either kappa or lambda;
sometimes there are light chains without a paraproteinaemia.
Clinical features
The median age of presentation is 60 years. There is:
• Bone destruction: increased osteoclastic activity causes bone pain (back
ache is the most common presenting symptom), osteolytic lesions,
pathological fractures, spinal cord compression and hypercalcaemia.
• Bone marrow infiltration with plasma cells resulting in anaemia,
infections and bleeding.
• Acute kidney injury has multiple causes: deposition of light chains in the
tubules, hypercalcaemia, hyperuricaemia and amyloid deposition in the
kidneys.
Paraproteins may form aggregates in the blood, which greatly increase
the viscosity, leading to blurred vision, gangrene and bleeding. Infections
are also due to a reduction in the normal polyclonal immunoglobulin levels
(immune paresis).
Investigations
Two out of three diagnostic features should be present:
• Paraproteinaemia on serum protein immunofixation or Bence Jones
protein in the urine
• Radiological evidence (CT, magnetic resonance imaging [MRI]) of lytic
bone lesions