chronic leukemia
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By Mohammed Adem, Jigjiga University

By Mohammed Adem, Jigjiga University

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  • CML: Chronic myelogenous leukemia/chronic myeloid leukemia/chronic myelocytic leukemia/chronic granulocytic leukemia,It is clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22philadelphia is the chromosome which result from the t(9;22)(q34;q11)part of the Abelson proto-oncogene ABL is moved to the BCR gene on chromosome 22 & partof chromosome 22 moves to chromosome 9.The abnormal chromosome 22is the Ph.Ph occur in as many as 20% of adults and 5% of children with ALL, and in rare cases of AML.1,7
  • Prognostic Factors: Age at diagnosis Splenomegaly Blasts > 5% in blood or marrow at diagnosis Basophilia > 7% Platelets > 700,000
  • Blast cells can be classified as myeloid, lymphoid, erythroid, or undifferentiated. Based on morphologic, cytochemical, and immunologic features CML evolve to½-AML,1/3 ALL Occurrence of de novo blast crisis or following imatinib therapy is rare.
  • The incidence increases slowly with age until the middle forties, when it starts to rise rapidly.. About 75% of all lymphoid leukemias and 90% of all lymphomas are of B cell origin. A cell becomes committed to B cell development when it begins to rearrange its immunoglobulin genes. B cells are even more susceptible to acquiring mutations during their maturation in germinal centers.A cell becomes committed to Tcell differentiation upon migration to the thymus and rearrangement of T cell antigen receptor genes clinically most aggressive lymphoid leukemia is Burkitt's leukemia, which has the phenotype of a mature follicle center IgM-bearing B cellLeukemias bearing the immunologic cell-surface phenotype of more primitive cells (e.g., pre-B ALL, CD10+) are less aggressive and more amenable to curative therapy than the "more mature" appearing Burkitt's leukemia cells.The major value of cell-surface phenotyping is to aid in the differential diagnosis of lymphoid tumors that appear similar by light microscopy.
  • Phis the t(9;22) which fuses the BCR(breakpoint cluster region) gene on chromosome 22 to the ABL(ABELSON) gene on chromosome 9.
  • The Ph can be found in both myeloid and lymphoid cells, which suggests that the transformed cell of CML is a pluripotent stem cell.attachment of the BCR sequences to ABL results in three critical functional changes: (1) the Abl protein becomes constitutively active as a tyrosine kinase (TK) enzyme, activating downstream kinases that prevent apoptosis; (2) the DNA-protein-binding activity of Abl is attenuated; and (3) the binding of Abl to cytoskeletal actin microfilaments is enhanced.
  • Hematologic findingsElevated WBC at DxPlatelet counts are almost alwayselevated at diagnosisMild degree of normocyticnormochromicanemia is presentLeukocyte alkaline phosphatase is low in CML cellsPhagocytic functions are usually normal at diagnosis and remainnormal during the chronic phaseHistamine production secondary to basophilia
  • Lab features in disease acceleration Increasing degrees of anemiaunaccounted by bleeding or therapy. Cytogenetic clonal evolution or blood or marrow blasts between 10 and 20% Blood or marrow basophils 20% or more, Platelet count <100,000/UL .
  • The Hasford systemwas developed on interferon (IFN) –treated patients. It identified percentage of circulating blasts, spleen size, platelet count, age, and percentage of eosinophils and basophils as the most important prognostic indicators and is better in predicting survival time. It include more low risk groups but left only a small number of cases in the high risk group.
  • Presence of bcr-abl by reverse-transcription polymerase chain reaction.
  • Intensive leukapheresis may control the blood counts in chronic-phase CML; however, it is expensive and cumbersome. It may also have a role in the treatment of pregnant women in whom it is important to avoid potentially teratogenic drugs.Splenectomy was used in CML in the past because of the suggestion that evolution to the acute phase might occur in the spleen. However, this does not appear to be the case, and splenectomy is now reserved for symptomatic relief of painful splenomegaly unresponsive to imatinib or chemotherapy, or for significant anemia or thrombocytopenia associated with hypersplenism. Splenic radiation is used rarely to reduce the size of the spleen.
  • Patients should have acceptable end-organ function, be <30 years of age results in 5-year disease-free survival similar to matched-sibling donor transplantation.For all other groups, patients receiving BMT from unrelated donors have higher rates of graft failurePatients with more advanced stages are offered peripheral blood SCT
  • Nearly all patients with CML are treated initially As expected in more aggressive disease, lower response rates are reported in the accelerated phase and blast crisis with imatinib.Imatinib is metabolized by cytochrome CYP3A4, and possible drug interactions Presence of bcr-abl by reverse-transcription polymerase chain reaction.physician experience and patient preference must be factored into the treatment selection process.
  • Busulfan is rarely used because randomized trials show that hydroxyurea treatment provides a significant survival advantage over busulfan.Hydroxyurea rapidly lowers high circulating WBCs in chronic phase CML. Hydroxyurea inhibits the enzyme ribonucleotide reductase. which inhibits DNA. synthesis.Before imatinib, when allogeneic SCT was not feasible, IFN- therapy was the treatment of choice. Only longer follow-up of patients treated with imatinib will prove whether IFN- will still have a role in the treatment of CML. Its mode(s) of action in CML is still unknown.
  • Progression to accelerated/blastic phases of the disease was noted in 3% of patients treated with imatinib as compared to 8.5% of patients treated with IFN- and cytarabine during the first year. Over time, the annual incidence of disease progression on imatinib decreased gradually to <1% during the fourth and fifth years, and If no any CR following six months of imatinib are unlikely to achieve major MR and other t/t approaches should be offered .dasatinib or SCT. But IFN-alfa if no other optionsno patient who achieved CCR during the first year of imatinib treatment progressed to the accelerated/blastic phases of the disease.
  • Criteria of accelerated phaseBlasts in blood or bone marrow-10-19%Basophilia ≥ 20%Thrombocytopenia 1000G/lAdditional chromosomal aberrationsrefractory splenomegaly or refractory leucocytosisCriteria of blast phaseBlasts ≥20%extramedullary tumorsPhenotype of blastsMieloblasts - 50%Limphoblasts - 30%Megakarioblasts – 10%Acute myelofibrosis
  • No definite leukemogenic role of chemicals, including benzene, exposure to Ionizing radiation and viruses has been established for CLL.
  • cell aplasia dec cell growthA positive direct antiglobulin test has been seen in 35% or more of CLL cases.
  • complaints that might lead to the diagnosis include fatigue, frequent infections, and new lymphadenopathychemistry tests to measure major organ functionimaging studies of the chest and abdomen looking for pathologic lymphadenopathyThe peripheral WBC count is high due to increased numbers of small, well-differentiated, normal-appearing lymphocytes.The leukemia lymphocytes are fragile, and substantial numbers of broken, smudged cells are usually also present on the blood smear.Immunophenotyping will eliminate the T cell disorders and can often help sort out other B cell malignancies. For example, only mantle cell lymphoma and typical B cell CLL are usually CD5 positive
  • Patients whose presentation is typical B cell CLL with no manifestations of the disease other than bone marrow involvement and lymphocytosis (i.e., Rai stage O and Binet stage A) can be followed without specific therapy for their malignancy. some will never require therapy for this disorder.If the patient has an adequate number of circulating normal blood cells and is asymptomatic, many physicians would not initiate therapy for patients in the intermediate stage of the disease manifested by lymphadenopathy and/or hepatosplenomegaly. However, the median survival for these patients is ~7 years, and most will require treatment in the first few years of follow-up. Patients who present with bone marrow failure (i.e., Rai stage III or IV or Binet stage C) will require initial therapy in almost all cases.
  • immune manifestations of typical B cell CLL should be managed independently of specific antileukemia therapy.glucocorticoid therapy for autoimmune cytopeniasand globulin replacement for patients with hypogammaglobulinemiashould be used whether or not antileukemia therapy is given.The most common treatments for patients with typical B cell CLL/smalllymphocytic lymphoma have been chlorambucil or fludarabine, alone or in combination.Chlorambucil can be administered orally with few immediate side effects. And Often chosen in elderly pts requiring therapy.fludarabine is administered IV and is associated with significant immune suppression and by far the more active agent and is the only drug associated with a significant incidence of complete remission.The combination of fludarabine withrituximaband cyclophosphamide achieves complete responses in 69% of patients.For young patients presenting with leukemia requiring therapy, regimens containing fludarabine are the treatment of choicecombination chemotherapy regimen used in other lymphomas(NH, FL,MALTL....) can also be used CVP (cyclophosphamide, vincristine, and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), although fludarabine-containing regimens may be preferable.Rituximab chimeric monoclonal antibody directed against the CD20 molecule on B lymphocytes.
  • Rituximab is effective in autoimmune cytopenia refractory to glucocorticoids.
  • immune manifestations of typical B cell CLL should be managed independently of specific antileukemia therapy.glucocorticoid therapy for autoimmune cytopeniasand globulin replacement for patients with hypogammaglobulinemiashould be used whether or not antileukemia therapy is given.The most common treatments for patients with typical B cell CLL/smalllymphocytic lymphoma have been chlorambucil or fludarabine, alone or in combination.Chlorambucil can be administered orally with few immediate side effects. And Often chosen in elderly pts requiring therapy.fludarabine is administered IV and is associated with significant immune suppression and by far the more active agent and is the only drug associated with a significant incidence of complete remission.The combination of fludarabine withrituximaband cyclophosphamide achieves complete responses in 69% of patients.For young patients presenting with leukemia requiring therapy, regimens containing fludarabine are the treatment of choicecombination chemotherapy regimen used in other lymphomas(NH, FL,MALTL....) can also be usedCVP (cyclophosphamide, vincristine, and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), although fludarabine-containing regimens may be preferableBecause of expense, γ globulin is often withheld until the patient experiences a significant infection

chronic leukemia chronic leukemia Presentation Transcript

  • Chronic leukemias Mohammed Adem Jimma university Clinical pharmacy PGYI mohzum@hotmail.com 31,Augest 2011 Mohammed A 1
  • Outline• Definition• Introduction• Epidemiology• Etiology & path physiology• Clinical feature and diagnosis• patient management• Outcome Evaluation CML then CLL 31,Augest 2011 Mohammed A 2
  • Chronic leukemias• when the malignant clone is able to differentiate accumulation of more mature cells of the affected cell type.• Differs from acute in that its clinical course is indolent. Most are asymptomatic at presentation• survive for several yrs after their initial Dx, even without Rx.• In certain CL evolution in to acute d/se may occur, which may need d/t mgt approach. Mohammed A 3 31,Augest 2011 3
  • Chronic leukemias…Include:hairy cell leukemia, andprolymphocytic leukemia.CML,CLL,. Mohammed A 4 31,Augest 2011
  • CML Is a hematologic cancer that results from an abnormalproliferation of an early myeloid progenitor cell. Results in abnormal proliferation and accumulation of progenic cell ,mature myeloid cells, erythroid compartment and platelets in the bone marrow& peripheral blood• The cytogenic hall mark Ph chromosome (9:22) in up to 95% BCR gene on chrom 22q11-ABL gene on chrom9q34. Mohammed A 5 31,Augest 2011
  • Mohammed A 6 31,Augest 2011 6
  • CML…• The clinical course has 3 phases: chronic phase, accelerated phase, and blast phase/crisis.• The disease begins in the chronic phase in which s/s can be controlled with chemotherapy.• Then progresses to a transition phase, known as accelerated phase, in w/c blast counts in the bone marrow and peripheral blood increase despite ongoing therapy. Mohammed A 7 31,Augest 2011 7
  • CML…• Finally, there is blast crisis, a terminal phase that is similar to acute leukemia that can lead to rapid clinical deterioration and death.• Why transition? poorly understood.• 85 to 90% present in the chronic phase.• Today this evolution into the accelerated& blastic phases can be delayed if not prevented/cured Mohammed A 8 31,Augest 2011 8
  • Epidemiology• The incidence of CML is 1.5 per 100,000 people/yr.• 1/5th of all cases of leukemia in the US.• The commonest leukemia in Africa& Ethiopia.• uncommon in children and adolescents• Median age at presentation is 70-80.• Common male Mohammed A 9
  • Etiology• The cause is unclear• No familial association of CML has been noted..• Benzene exposure does not inc. the risk of CML but AML.• Is not associated with any known oncogenic viruses• smoking can accelerate the progression to blast crisis in pre-imatinib era.• CML is not a frequent 2dry leukemia after Rx of other cancers with radiation or anti-CA agents or both.• Ionizing radiation in high doses is the only known risk factor for CML. Mohammed A 10
  • PathogenesisGenetic abnormalityThe product of the fusion gene plays a central role in thedev’t of CML.The oncogene BCR-ABL encodes an enzyme tyrosinephosphokinase (usually p210).Through this chromosomal translocation, the ABLprotooncogene is able to escape the normal genetic controlson its expression and is activated into a functionaloncogene p210BCR-ABL Mohammed A 11
  • Pathogenesis…• The attachment of the BCR sequences to ABL results in:• p210BCR-ABL is constantly active, and this unregulated activity results in cell proliferation, inhibition of apoptosis, and accumulation of the malignant clone. Mohammed A 12
  • Pathogenesis… Hematopoietic abnormality Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation increased white cell count Megakaryocytopoiesis /plt is often expanded Erythropoiesis is usually deficient Function of the neutrophils and platelet is nearly normal Mohammed A 13
  • Clinical Presentationsapproximately 70% of patients are asymptomatic at the time of Dx.• Sx related to hyper metabolism:weight loss, lassitude, anorexia or night sweats• platelet dysfunction.Bruising ,epistaxis, menorrhagia or hemorrhage from any site.• Anemia.• Organ infiltration:Splenomegally early satiety , LUQ pain/massOther SxUrticaria,visual disturbance, Unexplained fever , bone and joint pain ,thrombosis such as vasoocclusive disease, CVA,MI . Mohammed A 14
  • Physical Findings• Splenomegaly :the most common physical finding (> 90%)• Mild hepatomegaly ( occasionally).• Persistent splenomegaly despite continued therapy is a sign of disease acceleration.• Lymphadenopathy and myeloid sarcomas are unusual except late in the course of the disease; when present the prognosis is poor.• Bruising , Fever, Bleeding (gingivae most common) Mohammed A 15
  • Laboratory and Radiographic Work-up:• CBC with manual differential• Leukocyte alkaline phosphatase• Uric acid level• Cytogenetic study: Ph chromosome• Bone marrow biopsy• organ functions Mohammed A 16
  • Lab feature…Lab feature in Stable/chronic phase CML1. CBC RBC a mild degree of NCNC anemia Leukocytosis (WBC >100 103 /µL, or 100 109/L). Usually <5% circulating blasts +/- Basophilia, eosiophilia Thrombocytosis ( ~50% of patients in chronic phase)2. Phagocytic functions of neutrophil are usually normal Mohammed A 17
  • Lab feature…3. Bone marrow or chromosomal findings Hypercellularity with presence of blasts Presence of Ph/ shortened chromsome increased myeloid to erythroid ratio4. Other basic studies;organ function, uric acid… Mohammed A 18
  • Prognostic Factors• The clinical outcome of patients with CML is variable• Before imatinib era, expect death 10% of pts within 2 years and in about 20% yrly thereafter, and the median survival time was ~4 years Sokal system• percentage of circulating blasts,• spleen size,• platelet count,• age, and• cytogenetic clonal evolution Mohammed A 19
  • Treatment of CMLDesired Outcomecomplete hematologic remission. early goal.complete Cytogenetic remission. Elimination of ph.complete molecular remission. ????RT-PCR -tive Mohammed A 20
  • Treatment…Nonpharmacologic Therapy Allogeneic Stem Cell Transplantation• Is the only curative treatment option for CML.• It is an option for younger pts (younger than 50 yrs)• Cure rates are superior when pts are transplanted in chronic phase within the 1st yr of dx and may be as high as 70%.• significant risks10% to 20% early mortality (100 days). Splenectomy Leukapheresis Mohammed A 21
  • Nonpharmacologic...Leukapheresis Useful in emergencies where leukostasis-related complications such as pulmonary failure or cerebrovascular accidents are likely. Possible role in the treatment of pregnant women in whom it is important to avoid potentially teratogenic drugsSplenectomy painful splenomegaly unresponsive to chemotherapy or hypersplenism Does not influence survival but improves certain aspects of management Mohammed A 22
  • Outcome of SCT depends on:• the patient (e.g., age and phase of disease);• the type of donor [e.g., syngeneic (monozygotic twins) or HLA-compatible allogeneic, related or unrelated];• the preparative regimen (myeloblative or reduced intensity);• posttransplantation treatment. Mohammed A 23
  • Treatment…Pharmacologic Therapy The success of therapy depends in part on the clinical phase of the disease. I. tyrosine kinase inhibitors:Imatinib mesylate (Gleevec). 1st line 400mg/d, 600-800mg/d induces CHR in more than 97%. 6wks CCR in about 76% of pts in chronic phase. 9-12months Most pts have traces of the d/se when measured by RT- PCR &are not cured of their d/se. CMR 7% Progression to other phases is 3%. Then <1% Mohammed A 24
  • Treatment…II. an alternative therapyfor patients who do not respond to imatinib andare not candidates for stem cell transplantation. Nilotinib (400mg bid) , Dasatinib (100mg/d). Interferon-α & Cytarabine. Conventional chemotherapy {hydroxyurea* or busulphan} Mohammed A 25
  • Clinical data Allogeneic SCT can be considered for pts with accelerated/blastic phases or who fails to respond to imatinib. imatinib (400 mg/d) is more effective than IFN- and cytarabine. CHR and CCR rate, at 18 months with imatinib was 97% and 76% compared to IFN and Cytarabine.(69% and 40% respectively). Cyclophosphamide +total-body irradiation had more complications(hospital admision and stay) compared to Cyclophosphamide+ Busulfan. If no any CR following six months of imatinib are unlikely to achieve major MR and other t/t approaches should be offered . Mohammed A 26
  • Clinical data...IFN-α1–3 mu SC 3 xwk, increasing to daily as tolerated Before imatinib, when allogeneic SCT was not feasible. Only longer follow-up of patients treated with imatinib will prove whether IFN- consideration. With availability of TKIs, it is now offered only if all other options have failedHydroxyurea induces rapid disease control 1–4 g/d to be halved with each 50% reduction of the WBC. cytogenetic remissions are uncommon Mohammed A 27
  • Clinical data...Busulphan• acts on early progenitor cells, has a more prolonged effect.• not recommended due to its serious A/Es:  Unexpected &occasionally fatal myelosuppression in 5–10%  Endocardial; Marrow and Pulmonary fibrosis  Addison-like wasting syndrome;  Obstructive bronchiolitis ,Alopecia Mohammed A 28
  • Rx of accelerated phaseIs similar to stable/chronic phase of CML Rx of Blast Crisis• Rx is generally ineffective and depends on the phenotype blast cells.• AML/ALL treatment protocol.imatinib poor response.(HR 21%). In 52% of patients Mohammed A 29
  • STG of EthiopiaGeneral Rx Symptomatic anaemia, dehydration and electrolyte if present Allopurinol, 100 mg P.O. TID should be started before the initiation of specific treatmentChemotherapy• Hydroxyurea p.o 2 to 4 g/day initially .depending on the cell count. withheld if the WBC count < 10,000/ L• Busulphan, 4 to 8mg/day .stopped when the WBC count below 20,000/ L. Mohammed A 31,Augest 2011 30 30
  • Outcome EvaluationMonitor for complications of disease and treatment & for relapse.• HR at 3 months.• CR at 9 to 12 months.• MR/ bcr-abl transcripts is currently the best available test to monitor d/se response. Q 3month• ADR and manage accordingly• ddI imatinibe (cyp3A4,fluid retention) Mohammed A 31 31,Augest 2011 31
  • Take a Break !… orChronic lymphocytic leukemia Mohammed A 31,Augest 2011 32 32
  • Chronic lymphocytic leukemia A cancer of lymphoid cells with primary involvement of bone marrow and blood. lymph nodes, and spleen. In most cases, the cells are monoclonal B lymphocytes (95% ) that are CD5+ T cell CLL can occur rarely. The main feature is a progressive accumulation of functionally incompetent, long-lived lymphocytes considered to be due to decreased apoptosis rather than increased proliferation. Mohammed A 31,Augest 2011 33 33
  • Epidemiology• is the most prevalent form of leukemia in western countries.• 1/3rd of all cases and is 2x as CML.• most frequently in older adults and is exceedingly rare in children. Age of presentation 70 years.• More common in white persons than in African Americans. M:F 2:1 Mohammed A 34 31,Augest 2011 34
  • Etiology• The specific aetiology of CLL is unknown.• Genetic factors play a role in high incidence of CLL in some families. Chromosomal abnormalities deletion at 13q14 (50%).• No established viral etiology.• No definite leukemogenic role of environmental factors chemicals, including benzene, exposure to Ionizing radiation and virus.• There is inc. incidence in farmers (???role of herbicides or pesticides) rubber manufacturing workers, asbestos workers, and tire repair workers Mohammed A 35
  • Pathogenesis Cell of OriginThe exact cell of origin is controversial but has been described as an antigen-activated B lymphocyte.• The normal T cell to B cell ratio is reversed in CLL where nearly 90% of all lymphocytes are B cells.• Monoclonal lymphocytes accumulate in theperipheral blood, bone marrow, lymphoid tissues, and sometimes other organs.• Infiltration of the bone marrow may eventually result in pancytopenia( too few cells) Mohammed A 36
  • PathologyimmunodeficiencyI. Deficiency of normal B cells often leads to bacterial infection.II. The absolute number of T cells may vary But the function is invariably abnormal.III. Defective regulation of T-cell immunity leads to chronic inflammation.IV. Regulatory mechanisms normally control and terminate T cell activation.V. however, these mechanisms fail leading to chronic T cell activation and subsequently to inflammationHypogammagloblenimia.• Dysfunctional antibody generation by the incompetent malignant and normal B cells under the dysregulation of aberrant T cells. Mohammed A 37
  • Autoimmunity .. PathologyAutoimmunity• Frequent autoimmune complications in CLL and due to antibodies restricted to hematopoietic/ blood cell• Autoimmune hemolytic anemia occurs in 10% to 25% of cases at some time during the course.• Autoimmune thrombocytopenia (2%)• Pure red cell aplasia (dec cell growth). <1%• Autoimmune neutropenia (< 1%) Mohammed A 38
  • Clinical presentations• Approximately 40% are asymptomatic at dx. Often found incidentally when a CBC is done for another reason.• In symptomatic cases complaint is  features of anemia,  Easy bruising/Gingival bleeding, Thrombocytopenia.  Organomegaly, bone pain ;Flank pain; generalized itching  Lymphadenopathy when present as lymphoma.  Frequent infections. CLL weakens B cell immunity• B symptoms are not common at dx. Mohammed A 39
  • Diagnosis Careful Hx and PE Diagnostic testings• CBC• Peripheral blood smear• Bone marrow biopsy• Cytogenetic studies/Immunophenotyping.• Molecular testing/Cytometry• Imaging studies of the chest and abdomen,pelvis• major organ function test RFT,HFT, electrolytes Mohammed A 40
  • The diagnostic criteria for CLLA. A peripheral blood lymphocyte count of greater than >5 × 109/L; usually >10 × 109/L.B. presence of B cell-specific antigens CD5(+) .C. A bone marrow aspirates showing greater >30% lymphocytesD. A patient presenting with an autoimmune hemolytic anemia or autoimmune thrombocytopenia. B-cells CLLE. Findings may include hypogammaglobulinemia, hypergammaglobulinemia, or monoclonal gammopathy.F. Mohammed A 41
  • Mohammed A 42
  • Staging of Typical B Cell Lymphoid LeukaemiaStage Clinical Features Median Survival, YearsRAI System0. Low risk Lymphocytosis only in blood and marrow >10I: Intermediate risk Lymphocytosis + lymphadenopathy 7II Intermediate risk Lymphocytosis + splenomegaly /hepatomegalyIII: High risk Lymphocytosis + anemia 1.5IV High risk Lymphocytosis + thrombocytopeniaBinet SystemA  Fewer than 3 areas of clinical >10 lymphadenopathy.  no anemia or thrombocytopeniaB Three or more involved node areas; 7  no anemia or thrombocytopeniaC Hemoglobin 10 g/dL and/or 2  platelets <100,000/L Mohammed A 43
  • Poor prognostic factors• Advanced Rai or Binet stage• Lymphocytosis• Splenomegaly/Hepatomegaly; Lymphadenopathy• Anemia; Thrombocytopenia• Diffuse marrow histology• Poor response to chemotherapy Mohammed A 44
  • TreatmentDesired Outcome provide palliation of symptoms and improve overall survival. Reduction in tumor burden and improvement in d/se Sx Resolution of lymphadenopathy and organomegaly Normalization of peripheral blood counts, Elimination of lymphoblasts in the bone marrow. Mohammed A 45
  • Treatment...Nonpharmacologic TherapyStem cell transplantation.  Offers longer d/s free remissions  Early mortality after transplant is as high as 40% in CLL.  Mortality can be dec by reducing its intensity but unclear whether it will produce long-term disease-free survival. Mohammed A 46
  • Treatment... Treatment...Pharmacologic TherapySingle-Agent Chemotherapy1. purine analog: fludarabine2. an alkylating agent: chlorambucil (Leukeran®)3. Monoclonal Antibodies: Rituximab Mohammed A 47
  • Treatment... Treatment...Fludarabine fludarabine based chemotherapy is used as first-line therapy for younger patients. is superior to chlorambucil in achieving higherresponse rates and producing a longer duration of response. is effective in previously untreated pts, as well as in pts who have chlorambucil-resistant d/se. The most commonly used dose is 20 mg/m2 iv daily for 5 consecutive days. every 4 weeks . Mohammed A 48
  • Treatment... Treatment...Chlorambucil• can be taken daily po tabs 4 -10 mg/day. to a single dose of 40–80 mg every 3–4 weeks• The ease of administration and limited S/Es make it practical option for symptomatic elderly pts who require palliative therapy. Mohammed A 49
  • Treatment... Treatment...Rituximab• directed against the CD20 molecule on B lymphocytes.• Alone can induce partial responses in untreated and previously treated CLL patients.• 3 times weekly for 4 weeks rather than once weekly• higher doses are required than those used in non-Hodgkin’s lymphoma.• however, the typical 375 mg/m2 dose is still used commonly Mohammed A 50
  • Treatment... Treatment...Combination Therapy. The combination of fludarabine, cyclophosphamide, and rituximab is supperior compared with fludarabine alone. Cyclophosphamide 250 mg/m2 + fludarabine) complete responses in 69% of patients molecular remissions in 50% of the cases Regimen used in other lymphomas CVP ;CHOP but at the expense of increased infections. Mohammed A 51
  • Treatment... Treatment...• Associated conditions should be managed independently of specific antileukemia therapy.• Steroids therapy for autoimmune cytopenias and• Immunoglobulin replacement for patients with hypogammaglobulinemia. in the setting of serious infection• Antibiotics• Blood products• Radiotherapy, Splenectomy Mohammed A 52
  • STG of EthiopiaGeneral• Early stage and asymptomatic d/se should be observed w/o t Rx.• Infections, if present, should be treated aggressively• symptomatic anemia should be transfused packed RBC.• Allopurinol, 100mg P.O.TID is given before the initiation of specific Rx. First line• Chlorambucil, 0.1 to 0.2mg/kg P.O. QD for 3 to 6 weeks. 15 -30mg/m2 P.O. may be given over 3 - 4 days every 14 -21 days. PLUS• Prednisolone, 0.5-1mg/kg may be added. OR• Cyclophosphamide, 2 -4 mg/kg P.O daily PLUS Prednisolone Mohammed A 53
  • Outcome Evaluation• Reduction of malignant lymphocytes.• Stage of the disease• Response to treatment and possible relapse• Regular follow-up throughout treatment ;Since CLL is not a curable d/se, palliation of Sx is a reasonable goal in older pts, and• Aggressive therapies are reserved for younger pts with high-risk CLL.• ADRs Mohammed A 54
  • REFERENCESJoseph T. Dipiro et.al; Pharmacotherapy, pathophysiologic approach, 7th edition.Pharmacotherapy principle and practice, 2007Harrison’s Principle of Internal Medicine,17th ed.2008. Mohammed A 55
  • Thank youQuestions???? Mohammed A 56 31,Augest 2011 56