chapter6164-177).pdf · *chapter6 aplasticanaemia phillipscheinberg,neals.young...

* CHAPTER 6Aplastic anaemia

Phillip Scheinberg, Neal S. Young

IRON2009_CAP.6(164-177):EBMT2008 4-12-2009 16:11 Pagina 164

1. IntroductionAplastic anaemia (AA) is the paradigmatic member of the bone marrow failuresyndromes (BMFS). BMFS are inherited or acquired disorders characterised byimpaired haematopoiesis and single or multilineage cytopenias. In colony assays,haematopoietic precursor cells are diminished in BMFS. In AA, pancytopenia iscommon and the bone marrow is hypocellular, replaced by fat with residual plasmacells and lymphocytes. Severity of disease is determined by the degree of cytopenias,with severe AA (SAA) cases meeting two of the following three blood count criteria:absolute neutrophil count (ANC) < 0.5x109/L, platelet count < 20x109/L, andabsolute reticulocyte count (ARC) < 60x109/L. Apart from the diminution in CD34+cells, ineffective haematopoiesis is not a characteristic of AA.Inherited BMFS are usually (but not always) diagnosed in childhood, when cytopeniasand/or characteristic physical findings are observed. A short stature, hyperpigmentation(café au lait spots), abnormal thumbs and microcephaly occur in Fanconi anaemia;hyperpigmentation, nail dystrophy and oral leukoplakia in dyskeratosis congenita;exocrine pancreatic insufficiency, malnourishment, malabsorption and short staturein Shwachman-Diamond syndrome; abnormalities in the head, face and palate areassociated with Diamond-Blackfan anaemia; and limb abnormalities characterisethrombocytopenia with absent radii. However, physical abnormalities may notalways be present in patients with an inherited BMFS and the identification of specificmutations in genes of the telomere complex in patients with “acquired” AA has blurredthe distinction between the inherited and acquired forms of AA (1). In this chapter,only the acquired form of AA will be discussed.

2. Aetiology and pathogenesisThe incidence of AA in the West is approximately 2 cases per million, and a higherincidence is observed in Southeast Asian countries such as Thailand (4.4 cases per million)and China (7.4 cases per million). Despite many links of certain exposures to the onsetof marrow failure, the triggering agent in AA remains largely elusive. In one of the largestepidemiologic studies to date in AA, an NHLBI-sponsored study in Thailand from 1989to 2002 confirmed the association of environmental factors with AA, such as benzene,pesticides, and certain medical drugs (sulfonamides and thiazides) and revealed factorsnot previously linked to AA such as animal exposure (ducks, geese), animal fertilisers,and use of unbottled water (2). EBV infections have also been associated with AA, andin a subgroup of patients, the onset of pancytopenia is preceded by an episode of hepatitisthat is seronegative for the common hepatitis viruses. Although a causative agent isnot identified in the majority of cases, suppression of haematopoiesis in AA is believedto involve the destruction of the primitive haematopoietic compartment by activated

DISORDERS OF ERYTHROPOIESIS, ERYTHROCYTES AND IRON METABOLISM165

CHAPTER 6 • Aplastic anaemia


THE HANDBOOK 2009 EDITION166

cytotoxic T cells and their cytokine products (3). The description of non-randomskewing of the VB-chain families of the T cell receptor suggests disease-specificoligoclonal expansion, further supporting an immune pathogenesis in AA.Recently, a defect in the ability of haematopoietic stem cells to repair telomereerosion has been recognised as a contributor to marrow failure. Telomeres arenucleotide tandem repeats at the 5’-end terminus of a chromosome’s DNA that areeroded with each cell division. To counter this erosion in cells with a high replicativecapacity, the telomerase repair complex extends telomeres by adding nucleotiderepeats to the end of the chromosome. Shortened telomeres and mutations in genesof the telomere complex (TERC, TERT, DKC1) are aetiologic in dyskeratosis congenitaand also occur in children and adults with apparently “acquired” SAA, who lack theclassic phenotypic abnormalities attributed to inherited marrow failure syndromes(1). Such abnormalities are found in less than 10% of “acquired” SAA; androgens,which enhance telomerase activity, may be beneficial in these cases.

3. Clinical featuresSymptoms derive from low blood counts. Anaemia leads to fatigue, weakness,lassitude, and headaches, and in older patients, dyspnea and chest pain.Thrombocytopenia produces mucosal bleeding, petechiae of the skin, epistaxis, andgingival bleeding, which are frequent and early complaints. Bleeding can be briskin the presence of accompanying physical lesions, as in gastritis and fungal infectionof the lungs. The most feared complication of thrombocytopenia is intracranialhaemorrhage. Bacterial and fungal infections in the setting of neutropenia are a majorcause of morbidity and mortality. Constitutional symptoms, lymphadenopathy ororganomegaly are not characteristic of AA and suggest another diagnosis.

4. Differential diagnosisPancytopenia and a hypocellular bone marrow indicate AA. Occasionally, isolatedcytopenia may precede pancytopenia, and mimic an alternate diagnosis such asidiopathic thrombocytopenic purpura. Anaemia with reticulocytopenia and decreasederythroid precursors in the marrow is diagnostic of red cell aplasia; severe neutropeniaand absent granulocytic precursors in the marrow suggests agranulocytosis, especiallywhen a relevant drug exposure is present; and thrombocytopenia and absentmarrow megakaryocytes characterise amegakaryocytic thrombocytopenic purpura.Secondary causes of pancytopenia are often suspected from the history or physicalexamination (cirrhosis, infections, autoimmune disease) and usually do not posea diagnostic challenge.Because AA is a diagnosis of exclusion, the main distinction to be made is from otherprimary marrow diseases (Table 1). In myelofibrosis, hepatosplenomegaly is common,


Disease Characteristics Diagnosis

Constitutional

Fanconi anaemia Short statureCafé au lait spotsAnomalies of upper limb or thumb

Chromosome breakage test

Dyskeratosis congenita HyperpigmentationNail dystrophyOral leukoplakia

Short telomeresMutations in TERC, TERT, DKC1,NOP10, TINF2

Shwachman-Diamond Exocrine pancreatic insufficiencyMalabsorption, short statureNeutropenia

SBDS gene mutations

Diamond-Blackfan anaemia Short stature, abnormal thumbsReticulocytopenia

RPS17, RPS19, RPS24 genemutations

Acquired

Single lineage cytopenia

Pure red cell aplasia

Agranulocytosis

Amegakaryocyticthrombocytopenicpurpura

Anaemia, reticulocytopenia

Severe neutropeniaRelevant drug exposure

Thrombocytopenia

Absent marrow erythroidprecursors

Absent marrow granulocyticprecursors

Absent marrow megakaryocytes

Pancytopenia

Myelodysplasia

Aleukaemic leukaemia

Paroxysmal nocturnalhaemoglobinuria

Myelofibrosis

Large granularlymphocytic leukaemia

Older patients, insidious onsetMarrow usually normo- orhypercellular

Very young or very old patients

Haemolysis (high LDH, lowhaptoglobin, haemoglobinuria)Thrombosis

HepatosplenomegalyLeukoerythroblastic blood smear

Older age, insidious, neutropeniaAssociation with other commonautoimmune diseases

Marrow morphology andcytogenetics

Blasts in spicules

Deficient GPI-anchored proteinson flow cytometry

Fibrosis on marrow biopsy

Large granular lymphocytes inperipheral smearFlow cytometryT-cell receptor gene rearrangement



Table 1: Differential diagnosis in primary bone marrow failure


the peripheral blood is leukoerythroblastic in appearance, and fibrosis is present inthe marrow. Leukaemias can rarely present with bone marrow hypocellularity withabsence of blasts in the peripheral blood; the spicules should be carefully examinedfor the presence of blasts. In older patients, chronic cytopenia(s) can be a manifestationof T-cell large granular leukaemia, often associated with other autoimmune diseasessuch as rheumatoid arthritis, and is characterised by large granular lymphocytes inthe peripheral smear, an expanded CD8+CD57+ population in the peripheral blood, andclonal T-cell receptor gene rearrangement by polymerase chain reaction.The more difficult distinction is between AA and myelodysplasia (MDS), which canpresent with a hypocellular marrow in about 20% of cases. Dysmorphic findings inthe marrow are modest in AA and much more striking in MDS; chromosomes in themarrow are almost always normal in AA but are frequently abnormal in MDS. Aparoxysmal nocturnal haemoglobinuria (PNH) clone, characterised by red blood cellsand neutrophils deficient in glycosylphosphatidylinositol anchored proteins (e.g.CD55 and CD59) can be detected at presentation by flow cytometry in about40–50% of AA and in about 20% of MDS patients. In these cases, clone size is oftensmall and haemolysis may be undetectable (especially in transfused cases) andthrombosis is unusual. The clone size can expand over time and lead to moresignificant clinical haemolysis. Primary PNH occurs when the degree of cytopeniais not severe and the clinical symptoms are dominated by severe haemolysis(manifested by anaemia, elevated lactate dehydrogenase level and dark urine),esophageal spasm, abdominal pain and/or complications of thrombosis (Budd-Chiari,deep vein thrombosis, strokes).

5. TreatmentThe definitive treatment in SAA is either haematopoietic stem cell transplantation(HSCT) or immunosuppressive therapy (IST). Long-term survival with either treatmentmodality has been comparable at about 75% (3). HSCT from a histocompatible siblingis the treatment of choice in children (4). Because an HLA-identical sibling is availablein only a minority of cases, IST is the most commonly employed treatment in SAAworldwide. Transplant-related mortality and graft-versus-host disease (GVHD) limitthe success of HSCT with graft rejection, a common problem in the early days oftransplantation for SAA, now an unusual occurrence probably due to the use of lessimmunogenic blood products.

5.1 Immunosuppressive therapy (IST)IST is usually delivered as antithymocyte globulin (ATG) + cyclosporine (CsA) (3).Antithymocyte globulin (ATG) is prepared by collecting gamma immunoglobulins




after immunising horse or rabbit with human thymocytes. Major toxicities of ATGinclude infusion related allergic reactions (anaphylaxis is a rare occurrence), serumsickness and transient blood count depression and with CsA, common sideeffects include nephrotoxicity, hypertension, gingival hypertrophy, andtremulousness. The long-term outcome of horse ATG + CsA has been reported inlarge studies in the US, Europe, and Japan (3): haematologic response isobserved in about 2/3 of patients; relapse subsequently occurs in 1/3 ofresponders; and clonal evolution occurs in 10–15% of cases (Table 2). Theresponse rate in children to IST is higher than in adults at about 75% and thelong-term survival among responders is excellent, about 90% (5). Efforts toimprove further the results of h-ATG/CsA by adding male hormones, G-CSF, otherimmunosuppressive agents such as mycophenolate mofetil and sirolimus have beendisappointing with no improvement in the response rate or reduction in the relapseor evolution observed to date (3). More potent lymphocytotoxic agents such ascyclophosphamide (Cy) are active in SAA but in a randomised study were foundto be associated with significant morbidity and mortality (3). Experimentalprotocols using the rabbit formulation of ATG and alemtuzumab are currently beinginvestigated and will help determine if more intensive lymphocytotoxic therapyis beneficial in SAA. In patients who are unresponsive to initial h-ATG/CsA thesuccess of a repeat course of IST with rabbit ATG + CsA has varied between 30and 70% (3). Relapse is often responsive to reinstitution of CsA but retreatment


Table 2: Studies with horse ATG plus cyclosporine in SAA

Clonal evolution is to dysplastic bone marrow changes and/or cytogenetic abnormalities.* With androgens and ± G-CSF** With mycophenolate mofetil*** With sirolimus in 35 patients

Study Study years N Medianage (yrs)

Response Relapse Clonalevolution

Survival

German 1986-1989 84 32 65% 19% 8% 58% at 11 yrs

NIH 1991-1998 122 35 61% 35% 11% 55% at 7 yrs

EGBMT 1991-1998 100 16 77% 12% 11% 87% at 5 yrs

Japan* 1992-1997 119 9 68% 22% 6% 88% at 3 yrs

German/Austrian 1993-1997 114 9 77% 12% 6% 87% at 4 yrs

Japan 1996-2000 101 54 74% 42% 8% 88% at 4 yrs

NIH** 1999-2003 104 30 62% 37% 9% 80% at 4 yrs

NIH*** 2003-2005 77 26 57% 26% 10% 93% at 3 yrs


with ATG may be necessary, with response rates of 50–60% reported (3). Clonalevolution to monosomy 7 is problematic and has been associated with progressionto leukaemia and poor survival (3). However, other cytogenetic abnormalities suchas trisomy 8 do not portend to a worse outcome and may be associated withresponsiveness to IST.Survival is strongly correlated with haematologic response after IST, especially therobustness of blood count recovery defined by an ARC or platelet count > 50x109/L3–6 months after ATG (6). Despite the need for further therapy in relapsed patients,relapse has not been associated with a worst outcome, but sometimes the recurrenceof pancytopenia is irreversible and fatal. Methods to predict response to IST havebeen proposed but to date none has gained wide acceptance, due to impracticalityin the clinic or subjectivity of the laboratory parameters. The pre-treatment ARC andabsolute lymphocyte count (ALC) have recently been shown to correlate withresponse after h-ATG/CsA: patients with an initial ARC ≥ 25x109/L had approximatelyan 80% response rate compared to those with an ARC < 25 and ALC < 1x109/L,in whom the response rate was about 40% (7). In addition, a pre-treatment ANC< 0.2x109/L was associated with a greater likelihood of death in the first 6 monthsafter IST.

5.2 HSCTIn HLA-matched sibling HSCT, a non-myeloablative and radiation-free conditioningregimen with Cy + ATG is most often employed, although the added benefit of ATGwas not confirmed in a randomised study comparing Cy/ATG to Cy alone asconditioning (8). Acute II–IV GVHD occurs in 20–30% and chronic GVHD isobserved in about 40% of cases: continued immunosuppressive therapy is oftenrequired in chronic GVHD resulting in decreased survival (9). The incidence ofchronic GVHD may be higher in younger patients (less than 20) when G-CSFmobilised CD34+ cells from the peripheral blood (as compared to bone marrow)is used as the stem cell source (10). A heavy transfusion history andallosensitisation have been major risk factors for rejection in SAA, which can nowbe overcome by potent reduced intensity immunosuppressive conditioningregimens containing fludarabine (11).With the development of large donor registries and an effective network, alternativesources of stem cells have been available to some who lack a histocompatiblesibling. Overall, the experience with matched unrelated donor (MUD) HSCT is inferiorto that of sibling donor HSCT, with long-term survival reported at about 50% withbetter outcomes observed in children (12) (Table 3). The outcome for MUD HSCThas improved overtime due to better donor selection (through high resolution




typing), better supportive care and improved conditioning regimens. In somereports the outcome for children after a MUD HSCT rivals that of transplant froma histocompatible sibling donor (3). However, rejection remains a problem in adultsafter radiation-free conditioning regimens, suggesting that radiation is stillrequired to allow for successful engraftment after MUD HSCT (13, 14). Despite thebetter outcome with MUD HSCT in recent years, there is no consensus regardingthe optimal conditioning regimen, the number of patients treated in each protocolis usually small and follow-up has been relatively short, with the long-termconsequences from this procedure still unknown. The experience with umbilicalcord and haploidentical transplants in SAA is limited, and early results suggestthat the outcome is less favourable compared to a matched sibling and MUD HSCT.Cord transplants should be performed in clinical research protocols only when themore favourable stem cell sources are not available.

5.3 Other aspects of treamtentDespite the significant lack of progress in augmenting the response rate since theintroduction of h-ATG/CsA in the late 1980s, survival in SAA has dramaticallyimproved in recent years. Once strongly linked to response to IST, survival among


Table 3: Comparison between treatment modalities for SAA

Immunosuppression Sibling HSCT Unrelated HSCT

Availability All patients HLA-matched sibling Matched unrelated donor,preferably 10/10 on high resolutionmolecular typing

Cost Moderate High High

Suitability All ages Best in children andadults < 40

Best in children and young adults

Conditioning Cy; Cy + ATG Various

Acutetoxicity

Infusion related to ATG;related to oral CsA

TRM; acute GVHD;infection; graft failure

Same as sibling HSCT but ata higher incidence

Longer termcomplications

Relapse (in responders);clonal evolution

Chronic GVHD; modestincrease in risk of solidtumours

Chronic GVHD; modest increasein risk of solid tumours

Outcome Haematologic response in70% with often partialrecovery of blood counts

Haematologic cure withsuccessful engraftment

Haematologic cure withsuccessful engraftment

Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TBI, total body irradiation; CsA, cyclosporine; TRM,transplant related mortality; GVHD, graft-versus-host-disease; HSCT, haematopoietic stem celltransplantation.


non-responders (which was dire in the 1990s) has now improved such that mostpatients are expected to be alive 2-3 years after IST regardless of their responsestatus (15). The reasons for this improvement probably include better and safertransfusional support (leucodepleted products from single donor apheresis;decreased risk of transmissibility of infections) and less toxic and more potentantifungal therapies, some of which can be administered orally. These improvementshave allowed non-responders to be alive to undergo salvage therapies (repeat ISTor HSCT) and/or receive supportive care for several years. In addition, ironoverload in chronically transfused patients can now be managed with moreconvenient oral agents (deferasirox, Exjade®) which have been shown to be asefficacious in reducing iron burden similar to more traditional iron chelating agents(deferoxamine, Desferal®).

6. SummaryIn summary, SAA has evolved from a disease that was nearly universally fatal to onethat can be successfully managed with IST or HSCT, with the majority of patientsexpected to be alive years after the diagnosis. In recent years, evidence thatcorroborates an autoimmune pathogenesis in AA has accumulated. In some casesmarrow failure may occur as result of a deficient stem cell compartment, asmutations classically associated with inherited forms of AA are now being identifiedin patients with idiopathic acquired AA. Horse ATG + CsA is the standardimmunosuppressive regimen and the treatment of choice in patients who are notsuitable for HSCT. In general, patients less than 20 years of age should receive anHLA-matched sibling transplant as initial therapy and those over the age of 40 shouldprobably receive a course of IST first. Patients between 20–40 years of age couldreceive either treatment modality but our practice has been to administer IST firstif the ANC is not too low and serious infections have not occurred. For alternativedonor transplants, our practice has been to consider a MUD HSCT in children afterunresponsiveness to a course of IST and in adults who failed at least two courses.

AcknowledgementsThis work was supported by the Intramural Research Program of the National Institutes of Health,National Heart, Lung and Blood Institute.

References1. Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood 2008;

111: 4446-4455.



2. Issaragrisil S, Kaufman DW, Anderson T, et al. The epidemiology of aplastic anemia inThailand. Blood 2006; 107: 1299-1307.

3. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology andtreatment of aplastic anemia. Blood 2006; 108: 2509-2519.

4. Bacigalupo A, Brand R, Oneto R, et al. Treatment of acquired severe aplastic anemia:Bone marrow transplantation compared with immunosuppressive therapy—The EuropeanGroup for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37: 69-80.

5. Scheinberg P, Wu CO, Nunez O, Young NS. Long-term outcome of pediatric patients withsevere aplastic anemia treated with antithymocyte globulin and cyclosporine. J Pediatr2008; 153: 814–819.

6. Rosenfeld S, Follmann D, Nunez O, et al. Antithymocyte globulin and cyclosporine forsevere aplastic anemia: Association between hematologic response and long-termoutcome. JAMA 2003; 289: 1130-1135.

7. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressivetherapy and survival in severe aplastic anaemia. Br J Haematol 2008; 144: 206-216.

8. Champlin RE, Perez WS, Passweg JR, et al. Bone marrow transplantation for severe aplasticanemia: A randomized controlled study of conditioning regimens. Blood 2007; 109: 4582-4585.

9. Deeg HJ, Leisenring W, Storb R, et al. Long-term outcome after marrow transplantationfor severe aplastic anemia. Blood 1998; 91: 3637-3645.

10. Schrezenmeier H, Passweg JR, Marsh JC, et al. Worse outcome and more chronic GVHDwith peripheral blood progenitor cells than bone marrow in HLA-matched sibling donortransplants for young patients with severe acquired aplastic anemia. Blood 2007; 110:1397-1400.

11. Srinivasan R, Takahashi Y, McCoy JP, et al. Overcoming graft rejection in heavilytransfused and allo-immunised patients with bone marrow failure syndromes usingfludarabine-based haematopoietic cell transplantation. Br J Haematol 2006; 133: 305-314.

12. Passweg JR, Perez WS, Eapen M, et al. Bone marrow transplants from mismatchedrelated and unrelated donors for severe aplastic anemia. Bone Marrow Transplant 2006;37: 641-649.

13. Bacigalupo A, Locatelli F, Lanino E, et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplasticanemia: A report from the EBMT-SAA Working Party. Bone Marrow Transplant 2005; 36:947-950.

14. Deeg HJ, O’Donnell M, Tolar J, et al. Optimization of conditioning for marrowtransplantation from unrelated donors for patients with aplastic anemia after failure ofimmunosuppressive therapy. Blood 2006; 108: 1485-1491.

15. Scheinberg P, Wu CO, Nunez O, Young NS. Marked improvement in short- and long-termsurvival in severe aplastic anemia patients treated with immunosuppression in the past18 years. ASH Annual Meeting Abstracts 2007; 110: 506a.




Multiple Choice Questionnaire

To find the correct answer, go to http://www.esh.org/iron-handbook2009answers.htm

1. A 7-year old girl presents to the outpatient clinic complaining of shortnessof breath and bruises on her arms. The bruises appeared 6 months previouslyand were attributed to minor trauma, and the shortness of breath began3 months earlier but worsened recently. In the last several days gumbleeding was noted on brushing her teeth. There have been no otheraccompanying symptoms. On physical examination the BP was 100/70mmHg, heart rate 102, respiratory rate 24 and temperature 36.8°C. The heartand lung examination were normal. There was no hepatosplenomegaly orlymphadenopathy. A faint tan-to-gray hyperpigmented macular eruption wasnoted over the upper trunk and the nails appeared dystrophic. Bruises onboth upper extremities were noted along with some mild gum bleeding.Family history was significant for a brother with asthma and a maternalaunt who had died of pulmonary fibrosis. Full blood count showed WBC1.2x109/L, absolute neutrophil count 0.320x109/L, haemoglobin 7.4 g/dL,platelet count 8x109/L, absolute reticulocyte count 15x109/L. Electrolyte,kidney and liver function tests were within normal limits. A bone marrowbiopsy was hypocellular for age and the aspirate showed milddyserythropoiesis. Cytogenetics were normal and flow cytometry forparoxysmal nocturnal haemoglobinuria revealed a small clone of 3.5%. Whichis the most likely diagnosis?a) Idiopathic acquired severe aplastic anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

b) Fanconi anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) Shwachman-Diamond. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d) Dyskeratosis congenita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. A 24-year old male presents with a 1-year history of progressive fatigue andintermittent nose bleeding. He took over the counter medications andherbs with no improvement. There is no history of constitutional symptoms.On physical examination the BP was 105/85, heart rate 98, respiratory rate22, temperature 37.2°C. He has a short stature and according to the fatherhis two younger siblings were also short. His 15-year old brother has a historyof anaemia. Café-au-lait spots were noted over the back along with somemild bruises. The remainder of the examination was unremarkable. A fullblood count showed WBC 1.9x109/L, absolute neutrophil count 0.4x109/L,



haemoglobin 9 g/dL, platelet count 20x109/L, and absolute reticulocyte count9x109/L. A bone marrow biopsy was hypocellular for age and no significantdysmorphic findings were present on the aspirate. Cytogenetics were normal.Which of the following tests is more likely to be diagnostic:a) Flow cytometry for paroxysmal nocturnal haemoglobinuria . . . . . . . . . . . . . . .

b) T-cell receptor gene rearrangement study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) Chromosomes breakage test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d) Testing for DKC1 gene mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. A 62-year old male has a 1-month history of pancytopenia and a hypocellularbone marrow. The biopsy cellularity is 10% with no significant dysplasticchanges. Cytogenetics are normal and flow cytometry for paroxysmalnocturnal haemoglobinuria shows a clone of 5%. He is receiving platelettransfusions every 4 days and red blood cell transfusion every 10 days. TheWBC is 1.6x109/L, absolute neutrophil count 0.8x109/L, haemoglobin 8 g/dL,platelet count 9x109/L, and absolute reticulocyte count 15x109/L.Electrolyte, kidney and liver function tests were within normal limits. Hewas diagnosed with diabetes mellitus 2 years previously, which is controlledwith oral sulfonylureas. He has no other significant medical history and hisfamily history is unremarkable for haematologic disorders. He has oneyounger sister who is histocompatible. Which of the following is thepreferred treatment option:a) Anti-thymocyte globulin plus cyclosporine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

b) Cyclosporine monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) Haematopoietic stem cell transplantation from the sister . . . . . . . . . . . . . . . . .

d) Androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. A 3-year old girl presented to the emergency room with sepsis. She wasdoing well until 12 hours prior to her admission when she began developingfevers and chills. The BP was 60/40 mmHg, heart rate 130, respiratory rate32, temperature 40.5°C. Chest x-ray was normal. The physical examinationwas otherwise unremarkable and there was no significant past medical orfamily history. The WBC was 0.6x109/L, absolute neutrophil count 0.4x109/L,haemoglobin 9 g/dL, platelet count 10x109/L, and absolute reticulocytecount 5x109/L. Blood cultures were drawn and broad spectrum antibioticswere initiated. Blood cultures grew Escherichia coli and the fever andhypotension resolved over the subsequent days on antibiotics. Evaluation




in the hospital revealed a bone marrow that was hypocellular for age(5%) with no dysplastic changes seen in the aspirate. Cytogenetics werenormal, testing for Fanconi anaemia was negative, and flow cytometry forparoxysmal nocturnal haemoglobinuria did not reveal a clone. Her olderbrother who is 8 years of age is histocompatible. Which is the treatmentmodality of choice once she recovers from the septicemia:a) Anti-thymocyte globulin plus cyclosporine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

b) G-CSF plus erythropoietin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) Haematopoietic stem cell transplantation from the brother . . . . . . . . . . . . . . .

d) Male hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5. A 32-year old male was treated for severe aplastic anaemia 4 years priorwith anti-thymocyte globulin plus cyclosporine with partial recovery of theblood counts achieving transfusion independence. The WBC was 4.2x109/L,absolute neutrophil count 1.6x109/L, haemoglobin 10.5 g/dL, platelet count55x109/L, and absolute reticulocyte count 125x109/L. He began complainingof episodes of dark urine in recent months that lasted 3-4 days that wasaccompanied by fatigue. The haemoglobin level during these episodesdecreased to 8 g/dL and he improved with red cell transfusions. He has theseepisodes every 3 months. Electrolytes, kidney and liver function tests arewithin normal limits except for an elevated lactate dehydrogenase. Whichof the following surface molecules are likely to be deficient in his red bloodcells and neutrophils in this patient:a) CD45 and CD52. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

b) CD25 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) CD55 and CD59. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d) CD3 and CD57 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



NOTES



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