Cancers of the haematopoietic system

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21 Cancers of the haematopoietic system

TV. Ajithkumar, HM. Hatcher

Hodgkin’s disease

Epidemiology

Around 1500 cases of Hodgkin’s disease are diagnosed every year in the UK and approximately 350 people die of this disease every year. Males are predominantly affected (male : female 1.8 : 1). There is bimodal peak of incidence with the first peak in those between 15 and 30 and the second peak between 50 and 60 years.

Aetiology

• EBV increases the risk of HD by two- to threefold. In up to 50–90% of classical HD, RS cells stain for EBV DNA.

• Family members of patients affected by HL are at a three to nine fold increased risk of developing the same disease. Same sex siblings have 10 times higher risk of HD.

The WHO classification of HD is shown in Table 21.1. Nodular sclerosis is the common subtype in young adults (more common in females), which presents with early stage supradiaphragmatic disease whereas mixed cellularity presents with generalized lymphadenopathy or extranodal disease with B symptoms. Lymphocyte depletion type presents with advanced stage disease with extranodal involvement and aggressive clinical course.

Table 21.1 WHO classification of Hodgkin’s lymphoma

Classical Hodgkin’s lymphoma	Frequency
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)	60–70%
Mixed cellularity Hodgkin’s lymphoma	20–30%
Lymphocyte-rich classical Hodgkin’s lymphoma (LRCHL)	3–5%
Lymphocyte-depleted Hodgkin’s lymphoma (LDHL)	0.8–1%
Nodular lymphocyte-predominant Hodgkin’s lymphoma (LPHL)	3–5%

LRCHL usually presents in young males with localized cervical node involvement with no B symptoms.

Histologically HD is characterized by the presence of Hodgkin and Reed–Sternberg (H-RS) cells in a background of non-neoplastic cells such as lymphocytes, histiocytes, neutrophils, eosinophils and monocytes. Classical HD is characterized by CD30 positive H-RS cells and the nodular lymphocyte predominant form of HL (LPHL) with CD20 positive lymphocytic and histiocytic (L and H) cells. In classical HD, RS cells stain positive for CD15 (80%) and CD30 (90%).

Clinical features

The most common presentation is lymphadenopathy in the cervical or supraclavicular region (60–70%). Almost two-thirds of patients with classical HL have mediastinal nodal disease producing symptoms: tight chest, cough, venous congestion, or dyspnoea. About 40% of patients present with ‘B-symptoms’ of fever >38°C, drenching night sweats, or weight loss >10% within the previous 6 months (not from other causes). Bone marrow involvement at presentation occurs in less than 10% of cases. Extranodal involvement commonly occurs in the lung.

Investigations and staging

• Blood – full blood count and ESR, biochemistry including LDH.

• Tissue diagnosis – An excision biopsy of a lymph node is required for accurate diagnosis and subtyping. All patients need bone marrow examination.

Staging

Cotswolds modification of the Ann Arbor Classification is used for staging (Table 21.2).

Table 21.2 The Cotswolds modification of Ann Arbor staging for lymphoma

Stage I	Involvement of a single lymph node region or lymphoid structure or involvement of a single extralymphatic site (IE)
Stage II	Involvement of two or more lymph node regions on the same side of the diaphragm; localized contiguous involvement of only one extranodal organ or site and lymph node region(s) on the same side of the diaphragm (IIE)
Stage III	Involvement of lymph node regions on both sides of the diaphragm (III),which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only one extranodal organ site (IIIE) or both (IIISE)
Stage IV	Diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without associated lymph node involvement
Designations applicable to any disease stage
A:	No B symptoms
B:	Presence of B symptoms
X:	Bulky disease (a widening of the mediastinum by more than one third of the chest or presence of a nodal mass with a maximal dimension greater than 10 cm)

Management

HD is a highly curable disease with long-term disease-free survival (DFS) exceeding 80%. Current efforts are to improve the chances of cure with the least long-term toxicity. Measures to preserve fertility should be discussed with all young patients prior to starting chemotherapy.

Patients with early stage disease (clinical stage I/II) are categorized as favourable and unfavourable group based on risk factors (Table 21.3). Prognosis of patients with advanced-stage (stage III and IV) disease is defined using the International Prognostic Score (IPS) (Box 21.1).

Table 21.3 EORTC risk grouping of early stage HD

Treatment group	Definition
Favourable	CS I–II without risk factors
Unfavourable	CS I–II with ≥ 1 risk factors
Risk factors	A large mediastinal mass (>10 cm/> thorax) B age ≥50 years C B symptoms or elevated ESR * D ≥4 involved regions

* Erythrocyte sedimentation rate (≥50 mm/h without or ≥30 mm/h with B-symptoms).

Box 21.1
International prognostic score of Hasenclever

• Serum albumin <4 g/dl

• Haemoglobin <10.5 g/dl

• Male sex

• Age >45 years

• Stage IV disease

• White cell count >15,000/mm³

• Lymphocyte count <600/mm³ and/or <8% of white-cells

Presence of each prognostic factor reduces the 5-year rates of freedom from progression of disease by 8%. i.e. those without any risk factors have a 5-year rate of 80% which is reduced to 45% by the presence of all 7 factors.

Nodular lymphocyte predominant (NLP)

Patients with localized NLP HD are treated with involved field radiotherapy (30–35 Gy in 15–20 fractions) which results in a 96% response rate and >90% 8-year survival (99% for stage I and 94% for stage II). Advanced stage and relapsed NLP disease is treated similar to classical HD.

Since this subtype usually expresses CD20, the anti-CD20 antibody, rituximab may have a future role in the management of these patients.

Classical HD

Early-stage favourable

The current standard treatment is combined modality treatment, consisting of two to four cycles of ABVD chemotherapy (Boxes 21.2 and 21.3), followed by 30–35 Gy in 15–20 fractions of involved field radiotherapy (IF-RT).

Box 21.2
Radiotherapy techniques in lymphoma

Figure 21.2 Nodal regions: cervical (a-b), mediastinal (c), axillary (d-e), mesenteric (f), paraaortic (g), iliac (h-i) and inguinal (j-k).

Box 21.3
ABVD regime

• Doxorubicin 25 mg/m² IV D1 and D15

• Bleomycin 10 units/m² IV D1 and D15

• Vinblastine 6 mg/m² (max 10 mg) IV D1 and D15

• Dacarbazine 375 mg/m² IV D1 and D15

Cycles repeated every 4 weeks

Survival

With combined modality treatment patients in the early-favourable group achieve a disease free survival (DFS) of more than 90% and an overall survival of about 95% at five years. Patients in the early unfavourable group have a DFS of about 84% and an OS of 91%. In advanced stage combination chemotherapy results in 5-year failure free survival of 78% and overall survival of 90%. High-dose therapy and autologous stem cell transplantation results in DFS of 55% and the overall survival 71% at 5 years.

Follow-up

Two-thirds of relapses occur within 3 years of initial treatment and more than 90% occur within 5 years. Since a significant proportion of patients who relapse can be successfully salvaged, all patients need regular follow-up (Box 21.4). Follow-up is also helpful in identifying and managing long term side effects such as endocrine dysfunction.

Box 21.4
Follow-up and screening after treatment for HD

• History and physical examination, FBC, ESR, LDH, electrolytes, liver function tests and chest X-ray at each visit if chest CT is not done: 3–4-monthly for first 2 years, 6-monthly for years 3–5 and then annually.

• CT scan chest: 6–8 monthly for first 2 years, yearly for years 3–5 and then only if any abnormality on CXR.

• CT abdomen and pelvis: in stage I–II annually for 5 years; in stage III–IV, 6-monthly for first 2 years, annually for years 3–5.

• Others:

• Serum TSH estimation 6-monthly if radiotherapy to neck.

• Mammogram: annually beginning at age 40; if received radiotherapy above the diaphragm start at age ≥30 years.

• MRI breast: consider for those who received radiation above the diaphragm before age 30 years.

Survivorship issues

The major causes of excess death in survivors of HD are second malignancies and ischaemic heart disease (p. 58).

One of the most common second malignancies is lung cancer which is attributed to mediastinal radiotherapy, chemotherapy and smoking. Patients who had thoracic radiotherapy are encouraged not to smoke. There is 20–50% risk of second breast cancer after mediastinal/axillary radiotherapy in young females and these patients should be screened for breast cancer. Common haematological neoplasms include acute myeloid leukaemia, myelodysplastic syndrome (develops within 3–5 years) and non-Hodgkin’s lymphoma (develops after 5–15 years).

Future perspectives

Future studies will address the issues of improving survival whilst minimizing the risk of long-term side effects. Newer imaging modalities such as functional imaging are already being incorporated into risk stratification to determine future treatments.

Non-Hodgkin’s lymphoma

Introduction

Non-Hodgkin’s lymphomas are a group of lymphoid malignancies of varying subtypes with a range of clinical behaviours and treatment strategies. Around 8450 new cases are diagnosed per year in the UK and 65,980 cases in the USA. The median age is 65, although aggressive B-cell lymphomas are the predominant NHL in younger adults. Male : female ratio is 1.5 : 1. Almost of cases are due to two specific subtypes: diffuse large B-cell lymphoma and follicular lymphoma.

Pathology

The cell of origin is different for each subtype of lymphoma. Classification is by the updated WHO modification of the REAL (revised European and American lymphoma) classification system which is broadly divided into B-cell, T-cell/natural killer cell and Hodgkin’s disease (Table 21.4). Table 21.5 shows cytogenetic and molecular characteristics of NHL.

Table 21.4 Abridged WHO/REAL classification of NHL

T-cell and putative NK-cell neoplasms

• Precursor T-cell neoplasm

• Peripheral T-cell and NK-cell neoplasms

1 T-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia

2 T-cell granular lymphocytic leukaemia

3 Mycosis fungoides/Sézary syndrome

4 Peripheral T-cell lymphoma, not otherwise characterized

5 Enteropathy-type intestinal T-cell lymphoma

6 Adult T-cell lymphoma/leukaemia (human T-lymphotrophic virus [HTLV] 1+)

7 Anaplastic large cell lymphoma

Table 21.5 Cytogenetic and molecular characteristics of NHL

Lymphoma	Cytogenetics	Genes
Burkitt’s	t(8;14)(q24q32) Or t(2;8) or t(8;22)	c-MYC (8q24) Immunoglobulins (other chromosome)
Follicular lymphoma	t(14:18)(q32;q21)	BCL-2 (18q) Ig heavy chain (14q)
Diffuse large B-cell lymphoma	t(14:18)(q32;q21)+others such as p53, p16, p15
Mantle cell lymphoma	t(11;14)(q13;q32)	BCL-1 or PRAD1 (11q) Ig heavy chain (14q)
Anaplastic lymphoma	t(2;5)(p23:q35)	TCR-ALK T cell receptor

Clinical features

The most common presenting symptom is painless lymphadenopathy. B symptoms (weight loss >10% within the previous 6 months, fever, night sweats) occur in up to half of the patients, predominantly in those with high-grade disease. Symptoms can be due to involvement of specific organs such as dyspnoea due to mediastinal nodes or effusion, abdominal symptoms and neurological symptoms such as cord compression.

Evaluation and staging

Initial evaluation includes detailed history, full clinical examination and assessment of performance status. Blood tests include FBC with peripheral smear, serum biochemistry, serum LDH and serological tests for HIV and hepatitis.

Biopsy – Excisional biopsy of an enlarged lymph node or generous incision biopsy is required to make an accurate diagnosis. Immunohistochemistry and genetic analyses are important in making an accurate diagnosis. All patients need bone marrow biopsy with aspiration.

Imaging

CT scans of the neck, chest, abdomen and pelvis are carried out to assess lymphadenopathy and organ involvement (Figure 21.3).

Figure 21.3 CT scan in NHL. Figure shows massive para-aortic lymphadenopathy (A) and iliac and inguinal lymphadenopathy (B).

Other investigations

• Lumbar puncture-CSF studies are needed for patients with neurological symptoms or those with paranasal sinus or testicular involvement.

• Endoscopy depends on the clinical situation and type of lymphoma.

Staging

Prognostic factors

Stage, age, LDH and performance status have prognostic value. The Follicular Lymphoma International Prognostic Index (FLIP) score is used for indolent lymphomas (Box 21.5). The international prognostic index (IPI) is used for patients with diffuse large B-cell lymphoma (Box 21.6).

Box 21.5
Follicular Lymphoma International Prognostic Index

1 Age (≤60 years vs. >60 years).

2 Serum LDH (normal vs. elevated).

3 Stage (stage I or stage II vs. stage III or stage IV).

4 Haemoglobin level (≥12 g/dL vs. <12 g/dL).

5 Number of nodal areas (≤4 vs. >4).

Patients with 0 to 1 risk factors have an 85% 10-year survival rate. Those with three or more risk factors have a 40% 10-year survival rate.

Box 21.6
The International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma)

1 Age (≤60 years of age vs. >60 years of age).

2 Serum LDH (normal vs. elevated).

3 Performance status (0 or 1 vs. 2–4).

4 Stage (stage I or stage II vs. stage III or stage IV).

5 Extranodal site involvement (0 or 1 vs. 2–4).

Patients with two or more risk factors have a less than 50% chance of relapse-free survival and overall survival at 5 years.

Treatment

Follicular lymphoma

Follicular lymphoma accounts for approximately 20% of all lymphomas and has a variable clinical course. The median age at presentation is 50 years. Most patients present with advanced disease and median survival is 10–15 years from diagnosis. Spontaneous regression can occur and 40% of patients transform to an aggressive histologic type. Over 90% have rearrangement of the bcl-2 gene which inhibits apoptosis.

Early stage

Only about one-third of patients with follicular lymphoma present with stages I and II or limited stage III (with up to five involved lymph nodes areas) disease. Treatment options include watchful waiting, or radiotherapy (Box 21.2).

Advanced stage

The optimal treatment for patients with bulky stage II, III and stage IV disease is yet to be defined. There is no proven role for early chemotherapy in asymptomatic patients. A watch and wait policy is appropriate for these patients. Alternatives include the anti CD20 antibody (rituximab), alkylating agents or experimental therapies. Indications for systemic treatment are:

• Symptomatic bulky disease

• Massive hepato-splenomegaly

• Bone marrow suppression

• B symptoms

• Transformed lymphoma

The commonly used regime is either single agent chlorambucil or fludarabine. Chlorambucil results in 50–75% response rate with no complete response, whereas fludarabine can result in a complete response (15%). Combination chemotherapy (e.g. CVP and CHOP) (Table 21.6) have no overall survival benefit. The role of chemotherapy with rituximab is being investigated. Elderly patients may be treated with rituximab or single agent chemotherapy.

Table 21.6 Chemotherapy regimes in NHL

• CHOP – cyclophosphamide, adriamycin, vincristine and prednisolone

• CVP – cyclophosphamide, vincristine and prednisolone

• ESHAP – etoposide, methylprednisolone, cytarabine and cisplatin

• BEAM – BCNU, etoposide, cytarabine, melphalan

• CODOX-M – cyclophosphamide, vincristine, doxorubicin, araC, methotrexate

Relapse

Two trials report prolonged event-free survival and overall survival with a combination of rituximab with chemotherapy (CHOP).

High-grade lymphoma

High-grade lymphomas include a number of lymphoma subtypes including:

• Diffuse large B cell (DLBCL)

• Burkitt’s

• Mantle cell

• Lymphoblastic lymphoma/leukaemia (precursor T/B lymphoma/leukaemia) (p. 310, leukaemias).

• HIV associated (p. 296).

DLBCL

Diffuse-large cell lymphoma (DLBCL) comprises 30% of NHL and is characterized by an aggressive clinical behaviour with rapidly enlarging lymphadenopathy frequently associated with extra-nodal disease.

In early-stage disease without adverse factors (see Box 21.6), treatment is with 3–4 cycles of CHOP in combination with rituximab (R-CHOP) followed by involved-field radiation therapy (30–35 Gy in 1.75–3 Gy per fraction) or 6–8 cycles of R-CHOP.

Patients with early stage disease with adverse factors and advanced disease are treated similarly. CHOP chemotherapy with rituximab shows a significant improvement in response rate, event-free and overall survival in younger and older patients. Patients with bulky disease seemed to benefit the most from rituximab. The role of additional locoregional radiotherapy in patients with bulky sites or extra-nodal disease is of no proven benefit. With this approach, the 5-year survival of early stage disease is 80–90% and that of advanced disease is around 50%.

In diffuse-large cell lymphoma, risk factors for CNS relapse are involvement of the skull, more than one extra-nodal manifestation (especially testis), IPI >1 and bone marrow infiltration and hence need to be considered for CNS prophylaxis.

Burkitt’s lymphoma

Burkitt’s lymphoma is a rare (2–3%) aggressive B cell NHL There are two main forms: the endemic form observed in Africa and associated with EBV and the sporadic form which accounts for up to 30% childhood lymphomas (p. 323, children’s cancers). The endemic form classically presents with enlargement of the jaw. The sporadic form presents rapidly increasing disease with intra-abdominal masses often involving the gastrointestinal tract (especially ileocaecal), ovaries or kidneys. Bone marrow and CNS involvement is frequent. These patients are at a high risk of developing tumour lysis syndrome due to an almost 100% cell turnover (p. 342). Survival rates vary from 30% to 70% and have improved with intensive regimes and risk group. Low-risk patients include those with a low LDH and those with a completely resected abdominal/single lesion. All others should be considered high risk.

Treatment with intensive multiagent chemotherapy (e.g. CODOX-M) is started rapidly with tumour lysis prophylaxis. There is no evidence to support high-dose treatment with transplantation as first line treatment. CNS involvement is extremely common and hence CNS prophylaxis is essential for all cases.

Relapse should be treated with further intensive chemotherapy and young fit patients should then be considered for autologous or allogeneic stem cell transplantation.

Mantle cell lymphoma

Mantle cell lymphoma (MCL) comprises less than 4% of NHL. The median age at presentation is 62 years. It usually presents with advanced disease involving the bone marrow and/or spleen. Overall long term survival is poor at less than 20% but with recent improvement in median survival from 2.7 to 4.8 years.

Optimal initial treatment in MCL is yet to be established. The commonly used first line chemotherapy regime is CHOP. Other first line options include fludarabine-containing regimens, single agent cladribine and a combination of high-dose methotrexate with cytarabine. Consolidating autologous stem cell transplantation in first remission improves progression free survival in eligible younger patients. Rituximab maintenance therapy seems to be a therapeutic alternative particularly in elderly patients. In relapsed patients, fludarabin-containing regimens, bendamustine and bortezomib seem to be effective. In the absence of allogenic stem cell transplantation, a potentially curative but investigative treatment option, the median survival is 4–6 years.

Primary extra-nodal NHL

Primary extra-nodal NHLs are defined as lymphomas which present with a predominantly extra-nodal tumour mass which represent approximately 25 to 30% of NHL.

Histologically, nearly 50% of all extra-nodal lymphomas are diffuse, large B-cell lymphomas. It is the most common histological subtype in the testis, brain, bone, thyroid and sinus.

The vast majority of the remaining group arise from the mucosa-associated lymphoid tissue (MALT) and represents 5–10% of all NHL. The most common involved sites are the stomach, small intestine, orbit, salivary glands and the lung.

Primary CNS lymphoma

Primary CNS lymphoma occurs are a median age of 60 years in immunocompetent patients and 30 years in HIV patients. Primary CNS lymphoma often has a rapidly progressive course. Systemic dissemination is rare. The finding of characteristic features on CT (Figure 21.4) and MRI imaging should prompt a stereotactic biopsy. Management of primary CNS lymphoma is discussed on p. 276.

Figure 21.4 CT scan in primary CNS lymphoma. Non-contrast enhancing CT scan shows a periventricular hyperdense lesion (A) which uniformly enhances on contrast administration (B).

The prognosis of HIV-associated primary CNS lymphoma is generally worse and depends on the CD4+ cell count. Whereas patients with a CD4+ cell count >200/µl can achieve a long-term remission, those with a CD4+ cell count less than 200/µl do not respond to chemotherapy. These patients may respond to highly active antiretroviral therapy.

Bone lymphoma

In most cases, involvement of the bone is secondary in patients with advanced-stage lymphoma whereas primary bone lymphoma is rare. The presenting symptom is mainly localized bone pain. DLBCL is the most common histological diagnosis.

The median age is 63 years. 10-year overall survival is approximately 41%. Three different prognostic groups (patients <60 years with IPI 1–3, patients ≥60 years with IPI 0–3, and patients ≥60 with IPI 4–5) with significantly different overall survival at 5 years of 90%, 61% and 25%, respectively, have been identified. The treatment involves combination of rituximab and CHOP with or without radiotherapy. Radical surgery does not improve outcome.

Testicular lymphoma

Primary testicular lymphoma represents 1–2% of all NHL. It is the most common malignancy of the testis in men older than 60 years and the most common presentation is unilateral painless scrotal swelling. DLBCL is the most common histology and diagnosis is usually established by initial orchidectomy. Approximately 80% of cases are stage I or II at presentation. A low IPI, no B-symptoms, the use of anthracyclines, and prophylactic contralateral scrotal radiotherapy are significantly associated with longer survival. Systemic chemotherapy alone seems not to be effective in preventing relapses in the contralateral testis because the testis is a sanctuary site (p. 35). Treatment consists of 6–8 courses of R-CHOP followed by prophylactic irradiation of the contralateral testis. Although data are not convincing, prophylactic intrathecal therapy should be considered. This approach results in a 3-year overall survival of 86% and 3-year progression-free survival 77%.

Cutaneous NHL

Primary cutaneous lymphomas differ considerably in their clinical course and outcome from systemic lymphomas. Primary cutaneous lymphomas are generally divided into lymphomas with an indolent or an aggressive clinical course. Approximately 75% of primary cutaneous lymphomas are T-cell lymphomas which include mycosis fungoides (MF) and Sezary syndrome (SS) and 25% are primary cutaneous B-cell lymphomas.

Clinical features

Mycosis fungoides typically presents with erythematous patches, plaques and tumours usually in areas not often exposed to sunlight (Figure 21.5). Most patients have multiple lesions and ulcerations can occur. The course of the disease is indolent.

Figure 21.5 Cutaneous lymphoma.

From Darell Rigel: Cancer of the Skin (Saunders), with permission.

The lesions of mycosis fungoides can be classified into four groups: Patches, papules and/or plaques affecting less (T1) or more (T2) than 10% of body surface, T3 with tumours >1 cm and T4 with erythroderma affecting more than 80% of body surface. In T1 disease outcome is excellent and also patients with T2 disease have a median overall survival of more than 10 years.

Patients with erythrodermic mycosis fungoides have a median survival of 5 years and those with visceral involvement have an even worse survival with only one or two years.

Sezary syndrome is defined as an erythrodermic cutaneous T-cell lymphoma with haematologic evidence of leukaemic involvement and can be preceded by mycosis fungoides. The clinical behaviour of the disease is aggressive.

Primary cutaneous marginal zone B-cell lymphoma and primary cutaneous follicle centre B-cell lymphoma usually show an indolent clinical behaviour.

Spontaneous resolution may occur. Primary cutaneous follicle centre B-cell lymphoma preferentially involves the head and trunk with solitary or grouped plaques and tumours. The 5-year survival is excellent with more than 95% in both entities.

In contrast, primary cutaneous diffuse-large B-cell lymphoma, leg-type, behaves aggressively and affects predominantly elderly patients. This entity typically presents as red solitary or multiple nodule on the leg but can also rarely be found at other sites. Both cutaneous relapses and extracutaneous dissemination are frequent. With a 5-year survival of only 50%, prognosis is significantly worse than in the other two entities.

Management of cutaneous T-cell lymphoma

In patients with early stages of MF topical therapy with mechlorethamine or bexarotene, superficial radiotherapy and phototherapy (PUVA) are appropriate treatment options.

Patients with more advanced disease will require systemic treatment. Total skin electron beam therapy (TSEBT) is appropriate in patients with generalized thickened plaques due to its depth of penetration. The rate of complete responses is greater than 80% but the long-term outcome is not affected. TSEBT should be followed by an adjuvant therapy such as mechlorethamine or PUVA.

Systemic therapy with the orally administered retinoid bexarotene can achieve response rates of 50%. MF and SS are relatively chemoresistant diseases. The most frequently used combination chemotherapy regimens include cyclophosphamide, vincristine and prednisone (CVP) with or without doxorubicin. High-dose chemotherapy followed by autologous stem cell transplantation in patients with advanced disease has been shown to induce high response rates in most patients but the responses were predominantly of short duration. In contrast, allogeneic transplantation seems to induce long-term durable remissions of more than 3 years.

Management of cutaneous B-cell lymphoma

Due to their indolent course and excellent outcome in primary cutaneous marginal zone and follicle centre B-cell lymphoma a watch-and-wait strategy is the adequate management in most cases. In patients with limited symptomatic skin lesions, local excision or radiotherapy (20–36 Gy) are the first treatments of choice. Cutaneous relapses can be treated in the same way as the initial lesion and do not worsen prognosis.

In patients with extensive skin lesions rituximab is the treatment of choice. Oral chlorambucil is a treatment option often used in Europe. A multiagent chemotherapy is rarely indicated in these types of cutaneous lymphomas with the exception of patients developing extracutaneous disease.

The role of stem cell transplantation in aggressive lymphoma

Autologous stem cell transplantation has become the standard treatment in younger patients with a first chemosensitive relapse of aggressive lymphoma. The role of autologous stem cell transplantation in relapse after rituximab-containing front-line treatment has not been determined.

The role of allogeneic transplantation in the management of patients with aggressive lymphoma remains controversial.

Recent advances

The use of FDG-PET imaging in lymphomas is evolving. It is useful to define the extent of disease as well as allow cessation of treatment when a previously metabolically active area becomes inactive after treatment.

Several new monoclonal antibodies are under investigation including atumumab (a human monoclonal IgG1 antibody against a small loop epitope on the CD20 molecule) and epratuzumab (anti-CD22). Radioimmunotherapy (RIT) is an innovative treatment modality that combines the tumour cell targeting ability of monoclonal antibodies with the cytotoxic effect of radiation by linking a radioisotope to the antibody. This is under investigation for NHL with ⁹⁰Y-ibritumomab tiuxetan and ¹³¹I-tositumumab. Other agents under investigation include bortezomib (30–40% response) and lenalidomide.

Follow-up in NHL

The purpose of follow-up is to detect early relapse and to educate about possible long-term complications. A typical schedule is 3-monthly follow up for 1 year, 4-monthly during the 2nd year, 6 monthly for the 3rd year, annually up to 10 years and then on alternate years. At each visit detailed history is taken and clinical examination is done with routine bloods including LDH and ESR. Chest X-ray is done in patients with chest disease at presentation. Further investigations are needed depending on any new symptoms or signs or other abnormal tests.

Acute leukaemias

Introduction

Acute lymphoblastic leukaemia (ALL) occurs most frequently either between the ages of 15–25 (p. 321) or over the age of 75. In the UK there are 200 new adult cases per year and the male : female ratio is roughly equal. Acute myeloid leukaemia (AML) occurs more frequently and the median age at presentation is 65. In the UK, around 2000 new cases are diagnosed per annum.

Pathology

AML and ALL are characterized by circulating blasts cells which may be seen in the peripheral blood. Bone marrow examination with immunophenotypic analysis is needed for establishing a diagnosis. Both myeloblasts and lymphoblasts are characterized by a high nuclear : cytoplasmic ratio and prominent nuclei. Azurophilic Auer rods are pathognomonic of AML (Figure 21.6).

Figure 21.6 AML M3 shows promyelocytes with multiple/stacked Auer rods (A) and AML with a blast in the centre showing an Auer rod (B).

Courtesy of Dr. Priyanka Mehta, Bristol Oncology Centre.

The French–American–British (FAB) classification recognizes three subtypes of ALL: L1 (30%), L2 (60%) and L3 (10%), whereas the current WHO classification incorporates immunophenotyping and cytogenetics. By immunophenotyping, 75% ALL arise from B-cell progenitors and 25% from T-cells.

The FAB classification recognizes eight subtypes of AML: M0 minimal myeloid differentiation (3%), M1 poorly differentiated myeloblasts (15–20%), M2 myeloblastic with differentiation (25–30%), M3 promyelocytic (5–10%), M4 myelo-monoblastic (20%), M5 monoblastic (2–9%), M6 erythroblastic (3–5%), and M7 megakaryoblastic (3–12%). The recent WHO classification incorporates cytogenetics and classifies AML as:

• AML with recurrent cytogenetic abnormalities.

• AML with multilineage dysplasia.

• AML and MDS, therapy related.

• AML not otherwise categorized.

Clinical features

The majority of patients present with features of bone marrow failure, which include anaemia, neutropenia and thrombocytopenia, clinically manifesting as fatigue, and pallor, fever and patechiae, easy bruising or bleeding. ALL can produce weight loss, bone pain, symptoms of CNS disease and features of extramedullary infiltration (in 50%) such as lymphadenopathy, splenomegaly or a mediastinal mass. AML can present with gum infiltrates (M4/M5) and disseminated intravascular coagulation (M3). A small proportion of acute leukaemia can present with features of hyperleucocytosis (WBC >100 × 10⁹/L) such as dyspnoea and CNS symptoms.

Clinical examination may show lymphadenopathy, bruising, patechiae, gum hypertrophy, hepato-splenomegaly, chest signs of effusion, and mediastinal mass.

Diagnosis

Blood tests include FBC and peripheral smear with cytogenetics and immunohistochemistry and biochemistry, including uric acid. Bone marrow examination is essential for definitive diagnosis of acute leukaemia and subtyping.

Prognostic factors and risk classification

The most important predictor of outcome in both AML and ALL are presentation, karyotype, age and response to initial treatment.

ALL

Clinical features (age >50 years, WBC count), immunophenotyping (pro-B, early-T, mature-T), cytogenetics and molecular biology [t (9;22), t (4;11)], and response to treatment (late achievement of response, minimal residual disease [MRD] positivity) have prognostic importance and are used to define standard risk (those without any risk factors) and high risk (those with one or more risk factors) ALL. Philadelphia chromosome positive (Ph+) ALL (t (9; 22)/BCR-ABL) predicts a high relapse rate and <10% chance of overall survival with chemotherapy alone. This group of patients is eligible for treatment with tyrosine kinase inhibitors such as imatinib.

AML

Based on cytogenetics there are three prognostic groups in AML:

• Favourable group with core binding factor (CBF) leukaemias [inv (16), t (16; 16), or t (8;21)], and t (15;17). This group represents 10% of patients and involves mainly patients <60 years of age. With intensive treatment survival rates are around 60%.

• Unfavourable group with monosomies or partial deletions of chromosome 5 and/or 7, or with abnormalities involving chromosome 3. This group constitutes about 30–40% of all patients, on average older (>50–60 years) often with an antecedent haematological disorder or AML related to therapy. The survival rates are around 20%.

• Intermediate group – the remaining 50–60% of patients with normal cytogenetics falls into this group whose outcome is intermediate.

Treatment

The principle of management of acute leukaemia is to achieve a morphological complete remission (<5% blast cells in bone marrow) with induction chemotherapy followed by further chemotherapy as consolidation chemotherapy. CNS directed treatment and maintenance treatment (up to 2 years) are part of the ALL treatment. It is being increasingly recognized that an early allogeneic transplantation is beneficial in high-risk ALL patients.

ALL

Current treatment of adult ALL leads to long-term survival of 30–40%. Initial chemotherapy utilizes vincristine, corticosteroids and daunorubicin (induction). Such intensive combination chemotherapy results in a complete remission (CR defined as <5% blast cells with return of marrow cellularity and function and disappearance of extramedullary manifestations) in 80–90% cases. Once CR is achieved consolidation therapy is started with a combination of chemotherapy. In patients with Ph+ disease, concurrent tyrosine inhibitor imatinib (a tyrosine kinase inhibitor [p. 312]) may improve survival. CNS directed treatment with intrathecal methotrexate and high-dose methotrexate and/or cranial radiation to treat the central nervous system is required for patients who are not planned to have undergo bone marrow transplantation.

After consolidation, maintenance therapy given over 1.5 to 2 years is still standard in ALL. Omission of maintenance therapy has been associated with shorter DFS rates. Daily doses of mercaptopurine and weekly doses of methotrexate are the backbone of maintenance, and are combined with monthly pulses of vincristine and corticosteroids. Intrathecal treatment is also continued but the frequency decreases in the maintenance phase. Patients with mature B-ALL do not require maintenance. In T-ALL, the benefit of maintenance chemotherapy has been questioned.

Transplantation

Salvage therapy

The outcome of salvage therapy remains unsatisfactory. CR rates range from 10–50% and long-term DFS is poor. Various combinations of chemotherapy are used. Although stem cell transplantation (SCT) is superior to chemotherapy with long-term DFS rates of 20–40% in salvage therapy, only 30–40% of patients who achieved a second complete remission are eligible for SCT and fewer than 50% have enough time before disease recurrence to undergo SCT.

AML

Induction

70–90% patients achieve a CR with two courses of induction chemotherapy with cytarabine and an anthracycline (usually idarubicin). Complete remission is defined as <5% blasts cells in the bone narrow, absence of cells with Auer rods and resolution of peripheral blood cytopenia.

Post-induction

Patients with favourable cytogenetics receive two further courses of consolidation chemotherapy with cytarabine, an anthracycline and etoposide. Patients with intermediate and unfavourable cytogenetics, those under 40 years with a HLA identical sibling are considered for allogeneic transplantation. The role of post-consolidation maintenance therapy is not clearly defined and hence not recommended.

There is some suggestion that in younger patients with primary refractory AML, allogeneic transplant may improve survival and hence may be considered for those who fail to achieve CR after two courses of induction chemotherapy.

Allogeneic stem cell transplantation is also indicated after a second CR with salvage chemotherapy in relapsed patients.

Acute promyelocytic leukaemia (APML)

APML has a high risk of disseminated intravascular coagulation (DIC). Patients with DIC should be treated with supportive measures (frozen plasma, fibrinogen and platelet support) and all-trans retinoic acid (ATRA) to reverse the coagulopathy. ATRA acts by stimulating differentiation of the leukaemic blasts. In addition to treating DIC, when administered with idarubicin it reduces the risk of disease relapse (DFS >80%). In patients achieving a CR, two further courses of anthracycline based chemotherapy are given as consolidation. ATRA syndrome is the major toxicity of this treatment characterized by fever and leakage of fluid into the extravascular space producing fluid retention, dyspnoea, effusions, and hypotension. It is treated with high doses of methylprednisolone or dexamethasone.

In patients relapsing after initial CR, arsenic trioxide achieves a CR of 80%. Some studies show that in patients with APML and t (8;21) and inversion (10), a second CR autologous transplantation can result in high rates of DFS.

New agents

Monoclonal antibodies are an attractive treatment option in ALL, especially in the setting of MRD. The agents studied include rituximab (anti-CD20 antibody) and alemtuzumab (anti-CD52).

New drugs being studied for AML include drugs that specifically bind to the surface of the AML blasts such as Mylotarg (gemtuzumab ozogamicin), agents that inhibit the multidrug-resistant (MDR) protein (PSC-833, Zosuquidar) etc.

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) accounts for 20% of leukaemia. The median age at diagnosis is 55 years. Males are affected more frequently than females (male : female ratio of 1.3 : 1). There are 750 new cases per year in the UK. Only recognized risk factor is prior radiation.

Cytogenetics

About 90–95% patients with CML exhibit a chromosomal translocation that results in one shortened chromosome 22 (22q– called the Philadelphia [Ph] chromosome) and one elongated chromosome 9 (9q+). The resulting fusion oncoprotein from the BCR-ABL1 fusion gene has deregulated tyrosine kinase activity which probably is thought to be the initiating event in the chronic phase of CML.

Patients with CML but without Ph chromosome may still have BCR-ABL rearrangement which will behave similar to Ph+ disease. Patients without Ph chromosome and BCR-ABL molecular abnormalities are classed as atypical CML and they often need a different approach to treatment approach.

Natural history

The three phases of disease are:

• Chronic phase (CP) – 90% of patients present at this stage. Without treatment median survival is 3–4 years.

• Accelerated phase (AP) – characterized by increasing blast count and organomegaly. Median survival is 1–2 years and most progress to blastic phase in 4–6 months.

• Blast phase (BP) – resembles acute leukaemia with >20% blasts in peripheral blood or marrow. 20–30% of BP is lymphoid, 50% myeloid and 25% undifferentiated. Median survival is 3–6 months.

AP and BP are combined as advanced phase disease.

Clinical features

50% patients are asymptomatic and are diagnosed following an abnormal blood count. The remainder presents with non-specific symptoms of weight loss, excessive sweating, spontaneous bleeding and pain due to splenic enlargement and hyperviscosity. Some patients with hyperuricaemia present with a gout-like arthritis. Symptoms of advanced stage include general cachexia, fever, bone marrow failure and bone pain.

Investigations

Full blood count and peripheral smear

• Chronic phase – WBC count is usually around 20–30 × 10⁹/L. Peripheral smear shows myelocytes and myeloblasts.

• Accelerated phase – raised WBC count, anaemia, thrombocytosis or thrombocytopenia.

• Blastic phase – shows blasts or blasts and promyelocytes in the blood.

Bone marrow

Bone marrow shows hypercellular marrow with complete loss of fat spaces. Metaphase cytogenetics or FISH is useful to identify Ph chromosome. The presence of the BCR-ABL1 fusion gene may be identified by real time quantitative polymerase chain reaction (RQ-PCR).

Management

Chronic phase

Initial treatment is with the tyrosine kinase inhibitor (TKI), imatinib (400 mg daily). This results in 5-year event free survival of 83%, overall survival of 89% and a cumulative complete cytogenetic response (CCyR) of 87%. Indefinite treatment is recommended. RQ–PCR for the BCR-ABL transcript is the cornerstone for monitoring patients for response to treatment. Patients with a suboptimal response or failure to respond to an initial dose are treated either with an increased dose of imatinib (600–800 mg daily) or a second generation TKI such as dasatinib (70 mg twice daily).

Patients who fail treatment with a TKI may be considered for allogenic stem cell transplant. The suitable candidates are aged <60 years and have an HLA-identical sibling or an HLA-matched unrelated donor.

Advanced phase

Newly diagnosed patients with advanced phase disease are treated with imatinib 660–800 mg daily. The median survival of these patients is 7.5 months and hence fit patients who respond to treatment should proceed to allogenic SCT if there is an appropriate donor. Those who have had previous imatinib are treated with dasatinib or allogenic SCT.

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most frequent (30%) leukaemia in the Western world. The median age at diagnosis is 70 years. There is a 2 : 1 male : female ratio. The aetiology is unknown. No specific risk factors have been identified.

Clinical features

About 50–70% patients are asymptomatic. The most frequent presentation is painless symmetrical lymphadenopathy. Other presenting features include systemic symptoms of weight loss, night sweats, tiredness and features of bone marrow failure. Autoimmune complications especially haemolytic anaemia and immune thrombocytopenia can occur. Infections are common due to hypogammaglobulinaemia.

10% patients can undergo transformation to a more aggressive tumour, most commonly diffuse large B-cell lymphoma, called Richter’s syndrome.

Diagnosis

CLL is a proliferative disorder of monoclonal CD5+ B lymphocytes. The diagnostic criteria for CLL are:

• Lymphocytosis >5 × 10⁹/l.

• Typical morphology – small to medium sized lymphocytes with clumped chromatin, absent nucleoli and scanty cytoplasm.

• Typical immunophenotype – SmIg (weak), CD5+, CD19+, CD20 (weak) and CD23+.

A direct Coombs test and serum immunoglobulin estimation is needed. Bone marrow examination helps to establish the extent and pattern of marrow involvement and to evaluate response to treatment.

Staging

Two staging systems exist based on the extent of disease and bone marrow failure and correlate with median survival (Table 21.7).

Table 21.7 Staging systems and survival in CLL

Treatment

Most patients need only active monitoring. Treatment is indicated only when one of the following features is present:

• Progressive marrow failure.

• Massive (>10 cm) or progressive lymphadenopathy.

• Massive (>6 cm) or progressive splenomegaly.

• Rapidly rising lymphocyte count in peripheral blood (doubling time <6 months or >50% rise in lymphocyte count within 2 months).

• Systemic symptoms:

• weight loss >10% in six months

• fever >38°C for >2 weeks

• extreme fatigue or night sweats

• Autoimmune cytopenias (this may only require treatment of the autoimmune component not necessarily the leukaemia).

The treatment options are chlorambucil, fludarabine with cyclophosphamide and alemtuzumab (if no response or relapse following fludarabine). Most patients are actively monitored after initial treatment. Recently the role of consolidation treatment with monoclonal antibodies and stem cell transplantation are being evaluated.

The choice of salvage treatment depends on the first line treatment and clinical situation at relapse. Patients with previous prolonged remission (>12 months) will respond to the same treatment but with a shorter duration of remission. Patients who are refractory to chlorambucil can be treated with fludarabine or its combination. Treatment options after fludarabine treatment are alemtuzumab, CHOP chemotherapy, and allogeneic transplantation.

Richter’s transformation is treated with CHOP chemotherapy which yields 40% response and a poor survival of <6 months.

Supportive treatment

Patients with hypogammaglobulinaemia with recurrent infection need regular intravenous immunoglobulin (400 mg/kg 3–4 weekly). Patients on intensive treatment with purine analogues and alemtuxumab (Campath) need Pneumocystis jiroveci prophylaxis. All patients need influenza vaccine annually.

Splenectomy may be useful for patients with features of hypersplenism and symptomatic splenic enlargement.

New agents

Oblimersen sodium, an antisense molecule to Bcl-2 (Bcl-2 is an anti-apoptotic protein, is highly expressed in CLL cells), in combination with fludarabine and cyclophosphamide has shown to improve CR. Lenolidomide, an anti-angiogeneic agent, and flavopiridol, a cyclin dependent kinases inhibitor, are shown to have activity in CLL.

Hairy cell leukaemia

Hairy cell leukaemia (HCL) constitutes 2% of lymphoid leukaemias. The median age at presentation is 55 years and males are commonly affected. There is no known aetiological factor.

One-quarter of patients are asymptomatic and diagnosis is made after an incidental finding of splenomegaly or cytopenia. One-quarter of patients present with abdominal symptoms due to splenomegaly; one quarter of patients with non-specific symptoms of fatigue, weight loss and fever and the remainder present with features of bleeding or recurrent infections.

Peripheral smear shows cytopenia and the presence of hairy cells, cells twice the size of a normal lymphocyte with cytoplasmic projections and an oval nucleus (Figure 21.7). Bone marrow biopsy is important in definitive diagnosis, which shows an interstitial or focal pattern of infiltration. Immunophenotyping is necessary to distinguish HCL from other B-cell lymphomas.

Figure 21.7 Peripheral-blood smear showing characteristic hairy-cell features.

From Mey U, Strehl J et al. Advances in the treatment of hairy cell leukaemia, Lancet Oncology 2003;4:86–94.

Asymptomatic patients can be observed until the development of cytopenia or systemic symptoms, when treatment is indicated. The mainstay of treatment is nucleoside analogues, Pentostatin and cladribine, which give a complete remission of >80% with a 10-year overall survival of 95–100%. Since both drugs can cause lymphopenia, patients presenting with cytopenia are treated either with G-CSF support during nucleoside analogue treatment or initial interferon alfa for two months followed by nucleoside analogue treatment.

Patients with a large spleen and with little or moderate bone marrow can be treated with splenectomy with delayed purine analogues until progression.

The majority (70%) of relapsed patients respond to retreatment with pentostatin or cladribine. In patients who fail to respond to nucleoside analogues, rituximab is useful.

Myelodysplastic syndromes

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal stem cell disease characterized by dysplasia and ineffective haematopoiesis in one or major cell lineages. Although the marrow is producing an excess of cells, these are immature and destroyed before reaching the circulation such that the peripheral blood appears hypocellular. The median age of occurrence is 70 years with over 90% patients over the age of 50 at the time of diagnosis.

There are a number of types including:

• Refractory anaemia

• Refractory anaemia with ring sideroblasts

• Refractory anaemia with excess blasts

• Refractory anaemia with excess blasts in transformation

• Chronic myelomonocytic leukaemia

In the majority of cases, MDS occurs as a de novo disorder; recently secondary MDS/AML as a result of chemotherapy/radiotherapy is increasing. Radiotherapy and alkylating agent related MDS occurs 5–6 years after treatment whereas topoisomerase II inhibitor (e.g. etoposide and teniposide) related MDS develops at a median interval of 33–34 months after exposure.

Presentation depends on the associated cytopenia. Evaluation includes bone marrow biopsy with iron stain and cytogenetic studies, erythropoietin levels and iron studies. The International Prognostic Scoring System (IPSS) defines four risk groups for overall survival and AML evolution, based on the percentage of marrow blasts, specific cytogenetic abnormalities and number of cytopenias. Treatment is complex which depends on the subtype of MDS, IPSS, performance status and co-morbidities which is not dealt with in this text-book. In general the initial treatment is supportive but can later involve chemotherapy or even stem cell transplantation. Median survival is related to IPSS score and ranges from a few months to many years.

Solitary plasmacytoma

The incidence of solitary plasmacytoma is one-tenth of myeloma. Solitary plasmacytomas can occur in bone (solitary bone plasmacytoma – SBP) or in extramedullary sites (extramedullary plasmacytoma – SEP). SBP commonly involves the spine, ribs, femur, humerus, and skull and SEP commonly occurs (80%) in the upper respiratory tract. In >50% cases solitary plasmacytoma is a precursor of myeloma. It is more common in men and the median age at diagnosis is 10 years younger than patients with multiple myeloma.

Clinical features

Pain is the most common clinical symptom of solitary bone plasmacytoma. Spinal plasmacytoma can present with spinal cord compression. Presentation of extramedullary plasmacytoma depends on the site of origin.

Diagnosis

The diagnostic approach is the same as that for myeloma and solitary plasmacytoma is diagnosed when there is no evidence of myeloma. MRI of the spine and pelvis should be performed in all patients as up to one-third of patients may have additional occult lesions that will be missed on skeletal survey (Figure 21.8). There may be a monoclonal gammopathy, which has prognostic significance, in 24–72% of patients.

Figure 21.8 MRI scan of the lumbo-sacral spine of a 69-year-old man who presented with cauda equina syndrome due to L4 compression (arrow). Biopsy of L4 vertebra showed plasmacytoma and MRI showed another lesion in L1 and changes in L2 (arrow heads), suggesting myeloma.

Treatment

Radical radiotherapy is the treatment for choice of SPB and SEP (Box 21.7). There is no role for surgery in SPB in the absence of structural instability or neurological compromise. Patients who need surgery receive postoperative radiotherapy. There is no data to recommend adjuvant chemotherapy. Some consider chemotherapy for patients at high risk of failure (e.g. tumour >5 cm).

Box 21.7
Treatment of solitary plasmacytoma

Dose

• Lesion <5 cm – 40 Gy in 20 fractions.

• Lesion >5 cm – 50 Gy in 25 fractions.

Monitoring and further treatment

• 6-weekly for 6 months and then at long interval.

• Patients not responding to radiotherapy should be treated as multiple myeloma.

Patients with apparent SBP with extensive disease on MRI

• Consider as having multiple myeloma.

• Treatment is either with radiotherapy for symptomatic plasmacytoma followed by observation until progression or as multiple myeloma.

Surgery is avoided in head and neck SEP. Surgery may be considered for SEP at other sites. After a complete excision, radiotherapy may not be necessary and patients with incomplete excision require radiotherapy. Adjuvant chemotherapy may be considered for tumours of >5 cm and high-grade tumours.

Prognostic factors

Increased serum M protein level and an abnormal free light chain ratio are risk factors for progression to myeloma. The 10-year myeloma free survival is 29% in patients with a persistent serum or urinary M protein compared with 91% in those in whom the M protein was not detectable following radiation therapy. Other factors associated with progression to myeloma include axial disease, lesion >5 cm and old age.

Survival

The 10-year overall survival is >50% and DFS is 25–50% for SBP. The 10-year DFS for SEP is 70–80% and has a less risk of distant relapse compared with SBP. Median time to progression of SBP to myeloma is 2–4 years and the overall survival of SBP varies from 7.5–12 years.

Myeloma

Introduction

Myeloma accounts for 1–2% of all malignancies and 10% of all haematological cancers. About 4000 cases are diagnosed in the UK annually. The median age at presentation is 70 years and men are more commonly affected. The aetiology of myeloma is not known.

Myeloma is the result of clonal proliferation of plasma cells. 98% cases have production of paraprotein with IgG being most frequent (60%), followed by IgA (20%), light chain (20%), IgD (9%) and rarely IgE or IgM. 2% of tumours are non-secretory.

Clinical features

The most common presenting symptoms of myeloma are fatigue and bone pain. Pain may be due to bone disease, pathological fracture or nerve compression. Other presenting features include symptoms due to anaemia, renal failure (20–30%), hypercalcaemia and infections.

Investigations and diagnosis

Initial investigations for suspected myeloma include full blood count with ESR, biochemistry including albumin, calcium and uric acid, and electrophoresis of serum and concentrated urine.

Further investigations include serum and urine immunofixation to confirm and type monoclonal protein. Patients with heavy chain myeloma, serum electrophoresis (82%) or serum immunofixation (93%) can detect immunoglobulins. Up to 20% of patients have light chain myeloma which requires detection by urine electrophoresis, immunofixation or serum free light chain test. 1–2% patients have non-secretory myeloma. Serum beta2 microglobulin estimation is important in staging.

Stage (% of patients)	Criteria	Median survival (months)
I (29)	Serum beta2-microglobulin <3.5 mg/L Serum albumin ≥3.5 g/dL

62 II (38) Not stage I or III* 44 III (34) Serum beta2-microglobulin ≥5.5 mg/L 29 Categories of stage II:

• Serum beta2-microglobulin <3.5 mg/L but serum albumin <3.5 g/dL

• Serum beta2-microglobulin 3.5 – <5.5 mg/L irrespective of serum albumin level

Prognostic factors

Performance status is one of the important predictors of outcome and is a key determinant of transplant eligibility. Other prognostic factors include age, ISS stage, creatinine, calcium, albumin, immunoglobulin subtype, extent of bone marrow involvement, plasmablastic morphology and lactate dehydrogenase and cytogenetic changes.

Treatment

Myeloma is rarely curable and a minority of patients achieve long-term remission following allogenic stem cell transplantation. Chemotherapy is indicated for symptomatic myeloma and asymptomatic myeloma with myeloma-related organ damage. The median time to progression from asymptomatic to symptomatic myeloma is 12–32 months. Monitoring of asymptomatic myeloma includes 3-monthly clinical assessment and measurement of paraprotein.

Treatment of newly diagnosed multiple myeloma is rapidly evolving. The North American approach involves risk categorization of patients based on molecular cytogenetics and upfront use of novel agents such as bortezomib (a proteasome inhibitor) and lenalidomide (an analogue of thalidomide) whereas such an approach is yet to be adopted in the UK (Figure 21.10). Table 21.9 shows regimes in newly diagnosed myeloma. Treatment response is assessed by the International Myeloma Working Group definitions of response criteria.

Figure 21.10 Management of myeloma.

Table 21.9 Regimes in newly diagnosed myeloma

Regimen	Response rate
Regime for patients not eligible for ASCT
Melphalan–prednisolone–thalidomide (MPT)	75%
Bortezomib–melphalan-prednisone (VMP)	70%
Cyclophosphamide–dexamethasone–thalidomide (CDT)	72%
Regime for patients eligible for ASCT
Vincristine–Adriamycin–dexamethasone (VAD)	52%
Thalidomide–dexamethasone (Thal/Dex)	65%
Lenalidomide–low dose dexamethasone (Rev/Dex)	70%
Bortezomib–dexamethasone (Vel/Dex)	80%
Bortezomib–thalidomide–dexamethasone (VTD)	90%