Haematology — Long Cases

8 Haematology—Long Cases Fric Tse, Yok-Lam Kwong, and Luen-Bik To 8.1 A man with fever (acute leukaemia) History A 45-year-old man presented with a 2-week history of fever, easy bruising, and gum bleeding. His full blood count showed severe anaemia, a high white cell count, and marked thrombocytope- nia. A bone marrow biopsy was performed and acute myeloid leukaemia was diagnosed. He was treated with combination chem- otherapy resulting in a complete remission. He was continued on consolidation chemotherapy but had a relapse of his leukaemia 6 months later. He was readmitted for further chemotherapy. Physical examination He had pallor and petechiae but no lymphadenopathy. There was 4 splenomegaly of 4 cm below the costal margin. Fundoscopic €Xamination showed the presence of retinal haemorrhages. Questions ‘1‘ What other information in the past history may be Important? * He may have had prior exposure to radiation, chemotherapy, and toxic chemicals. He may also have a past history of

110 Problem-Based Medical Case Management Case 8.1 myelodysplastic syndrome, myeloproliferative disease or chronic myeloid leukaemia. 2. Which type of acute leukaemia commonly affects gum and skin? e Acute monocytic leukaemia has a predilection to infiltrate the gums and skin. 3. What is the percentage of blast cells in the marrow that is required for the diagnosis of acute leukaemia? o 20%. 4. What examinations are usually performed on the bone marrow biopsy for a precise classification of the leukaemia? e These include morphological examination, cytochemistry, immunophenotyping, cytogenetics, and molecular genetic analysis. 5. Why is it important to differentiate acute promyelo- cytic leukaemia (APL) from the other types of acute myeloid leukaemia? e APL is associated with a higher risk of life-threatening bleed- ing, especially intracranial bleeding, and therefore requires intensive transfusion of platelets and fresh frozen plasma. APL responds well to initial treatment with all-trans retinoic acid and chemotherapy. Arsenate therapy is also very effective against this leukaemia. APL is associated with a good prognosis. 6. What are the important general side effects of the chemo- therapy given for acute leukaemia? ° These include nausea and vomiting, mucositis, diarrhoea, and neutropenic infections. 7. What are the common causes of neutropenic infections? * They are usually Gram negative bacterial infections. Gram positive bacterial infection is increasingly common and is often associated with the use of indwelling central venous catheter. Prolonged neutropenia is commonly associated with fungal infections. . 8. Why is haematopoietic stem cell transplantation effective in treating acute leukaemia? * High-dose chemotherapy/total body irradiation is used to eradi- cate the leukaemia. Also, the T-cells in the donor haematopoietic

Case 8.2 Haematology 111 stem cells induce a graft versus leukaemia effect against resid- ual disease that has survived the high-dose chemotherapy. Pitfalls and tips « Acute myeloid leukaemia has to be distinguished from acute lymphoblastic leukaemia as the treatment is different. + The diagnosis of acute promyelocytic leukaemia has to be considered if there is severe clinical bleeding. There is usually laboratory evidence of disseminated intravascular coagulation. + Cytogenetics and certain somatic genetic mutations provide very important prognostic information and are useful for decid- ing the treatment strategy. * Elderly patients with acute leukaemia usually have a very poor prognosis. The leukaemia tends to be resistant to chemotherapy. Also, old patients do not tolerate chemotherapy very well. 8.2 A woman with easy bruising (idiopathic thrombocytopenic purpura) History A 40-year-old woman with good past health has presented with a bleeding tendency including easy bruising, gum bleeding, and menorrhagia for 1 week. She was subsequently found to have a low platelet count. Immune thrombocytopenic purpura (ITP) was diag- nosed and steroid therapy was commenced. However, the response to steroid was unsatisfactory. She was admitted for splenectomy. Physical examination There were Cushingoid features: moon face, buffalo hump, and truncal obesity. There were generalized petechiae. No lymphad- enopathy and no hepatosplenomegaly were detected. The blood pressure was normal. Fundoscopic examination was normal. Urine glucose was negative.

112 Problem-Based Medical Case Management Case 8.2 Questions 1. 4. What is the normal platelet lifespan? The lifespan of platelet is normally about 7-10 days and is reduced to 1-2 days in immune thrombocytopenic purpura. . What are the differential diagnoses? The differential diagnoses include causes of marrow failure (acute leukaemia, aplastic anaemia, myelodysplastic syndrome, and marrow infiltration by neoplastic diseases) and other causes of increased platelet consumption (hypersplenism, dissemi- nated intravascular coagulation, thrombotic thrombocytopenic purpura). . What are the expected bone marrow biopsy findings in ITP? The bone marrow in ITP shows increased megakaryocytes, sug- gesting a consumptive cause of thrombocytopenia. What are the useful investigations for the purpose of exclu- sion of disseminated intravascular coagulation (DIC)? In DIC, there will be fragmented red cells in the peripheral blood film, prolongation of prothrombin time and activated partial thromboplastin time, depressed fibrinogen level, and increased D-dimer. . If the patient is anaemic, what is the most likely cause? Bleeding and iron deficiency anaemia are most likely. However, if there is evidence of haemolytic anaemia, one has to con- sider the diagnosis of Evans syndrome (autoimmune haemo- lytic anaemia and immune thrombocytopenia) or thrombotic microangiopathy (microangiopathic haemolytic anaemia and thrombocytopenia). . What is the initial treatment strategy for ITP? Primary causes such as drugs should be removed. Treatment may not be necessary if the thrombocytopenia is mild (when platelet count is more than 30 x 10°/L) and is not associated with clinical bleeding. Otherwise, first line therapy is corticosteroid. . What are the side effects of corticosteroid therapy? Important side effects of corticosteroid therapy include Cushingnoid features, hypertension, fluid retention, hypoka- laemia, gastritis, diabetes mellitus, osteoporosis, cataract,

Case 8.2 Haematology 113 increased risk of infections especially tuberculosis, psychosis, myopathy, and easy bruising. . What are the indications for splenectomy in ITP? Splenectomy is considered if the disease is refractory to steroid, requires a high dose of steroid for the maintenance of a safe platelet count, or relapses after responding to steroid. . What are the risks of splenectomy? Splenectomy is associated with surgical risks of the operation. Also, splenectomy results in an increased risk of infection, especially by encapsulated bacteria such as pneumococcus and haemophilus. 10. What are the necessary precautions before and after splenectomy? Appropriate vaccinations are given before splenectomy. Patients must be warned of the increased risks of infection after the operation. Prophylactic antibiotics are often recommended, but their precise usefulness is undefined. Pitfalls and tips ITP may be associated with other autoimmune diseases, such as systemic lupus erythematosus and autoimmune haemolytic anaemia. Always remember drugs as causes of ITP. Splenomegaly is usually absent in ITP. Anti-platelet antibody test is usually not useful in confirming the diagnosis of ITP. Intravenous immunoglobulin therapy may cause a rapid but transient rise in platelet count in ITP and is useful in life-threat- ening bleeding. Most patients with [TP respbnd to steroid therapy but relapse is common, especially when steroid treatment is stopped. Azathioprine may be used as a steroid sparing agent in patients having a response to steroid. Neutropenia is a possible side effect, and azathioprine should not be used together with allopurinol. About 75% of the ITP may respond to splenectomy.

114 Problem-Based Medical Case Management Case 8.3 » Thrombopoietin receptor agonists such as eltrombopag (orally every day) and romiplostim (subcutaneously every week) have been shown to be very effective in steroid refractory ITP and cases not responding to splenectomy. ¢ Other treatment strategies, such as with danazol, cyclophos- phamide, cyclosporine, anti-CD20, and anti-CD52 monoclonal antibodies, have been shown to be useful in some refractory cases of ITP. 8.3 Bone pain with anaemia (multiple myeloma) History A 70-year-old woman presenting with back pain was diagnosed to have multiple myeloma. While receiving chemotherapy, she com- plained of progressive bilateral lower limb weakness. There was also urinary and bowel incontinence. Physical examination showed that there was mild pallor. There was paraplegia with increased tone and brisk reflexes in the lower limbs. The plantar responses were extensor bilaterally. Questions 1. What are the complications of multiple myeloma? « These include bone destruction, renal failure, bone marrow failure, bacterial infection, hypercalcaemia, and occasionally hyperviscosity syndrome. . What complication has developed in this patient? Spinal cord compression from vertebral collapse fracture. . What should be the immediate management for this patient? Urgent decompression spinal surgery or radiotherapy should be considered. . Why is renal failure common in multiple myeloma? e Contributing factors may include obstruction of distal renal tubules by protein casts, toxic effect of light chain on renal LRSI -

Case 8.3 Haematology 115 tubules, deposition of light chain in renal glomeruli, amyloidosis, infection, hypercalcaemia, dehydration, and hyperuricaemia. 5. Why are multiple myeloma patients more prone to infection? + Contributing factors may include impaired B-cell function and neutropenia. 6. What types of infection are common in multiple myeloma? + Encapsulated bacterial infection such as pneumococcus and haemophilus. 7. What are the common symptoms of hypercalcaemia? * Polyuria, polydipsia, anorexia, vomiting, lethargy, stupor or coma. 8. What are the common symptoms of the hyperviscosity syndrome? » Heart failure, bleeding tendency, dizziness, somnolence, and coma. 9. What are the typical haematological findings in multiple myeloma? * Normochromic and normocytic anaemia (sometimes macro- cytic due to formation of red cell rouleaux), marked rouleaux formation on blood film, with neutropenia and thrombocyto- penia. There may be a leucoerythroblastic blood picture. The erythrocyte sedimentation rate can be very high (commonly > 80 mm in the first hour). 10. What are the important diagnostic features of multiple myeloma? * These include monoclonal paraprotein in serum and/or mono- clonal free light chains in urine, the presence of discrete lytic bone lesions, and monoclonal plasma cell proliferation in the bone marrow. 11. What are the different treatment options for multiple myeloma? * Asymptomatic patients with smouldering disease may require no treatment until there is disease progression. * The standard treatment comprises a combination of a protea- some inhibitor (bortezomib), an immunomodulatory drug (thalidomide or lenalidomide), and dexamethasone. Other drug

116 Problem-Based Medical Case Management Case 8.3 combinations are also used depending on the age and physical fitness of the patients. Radiotherapy is very effective for treat- ing local disease and for pain control. Supportive treatment includes transfusion, antibiotics and pain control, plasmapher- esis for hyperviscosity syndrome, and management of hyper- calcaemia. Bisphosphonate is commonly given to reduce bone pain and retard the progression of bone lesions. Autologous haematopoietic stem cell transplantation is not curative but may provide a more prolonged control of the disease and is the standard of care for transplant-eligible patients. Most patients will still eventually relapse. Allogeneic haematopoietic stem cell transplantation may provide a cure for multiple myeloma, but the procedure-related mortality is high, and is thus reserved only for young patients with adverse cytogenetic features and poor response to autologous transplant, and with HLA compat- ible donors. Pitfalls and tips * Spinal cord compression may complicate multiple myeloma. ‘It is an emergency and must be recognized and diagnosed early to minimize irreversible neurological damage. Patients may present with an acute onset of paraplegia. Urinary and bowel incontinence may also be present. * Multiple myeloma has to be distinguished from monoclo- nal gammopathy of undetermined significance. In the latter, a serum paraprotein is present. However, patients are usually asymptomatic, and typical features of multiple myeloma, such as anaemia, lytic bone lesions, renal function impairment, and hypercalcaemia are absent. Monoclonal gammopathy of undetermined significance does not require any specific treat- ment. Furthermore, patients with lymphoproliferative disease or lymphomas may also have paraproteinaemia.