ACUTE LEUKEMIA

MODERATOR :- DR.SUDHIR.SINGHPRESENTER :- DR.VIJAY.P.RATURI

ACUTE MYELOID LEUKEMIA :-

• AML is characterized by uncontrolled proliferation myeloid progenitor cells.

• Abnormal proliferation and aberrant differentiation of the malignant cells leads to inhibition of normal hematopoiesis

• Characterization of transforming genetic events is important in diagnosis , defining prognosis , planning t/t in AML.

EPIDEMIOLOGY :-

• Incidence rate of AML in india is 3-5 cases/1 lac .

• AML accounts for about 15% - 20% of acute leukemia in in children and adolescent & 80% in adult.

• Incidence of AML rises rapidly after age of 60 median age at diagnosis is 67 years.

Principle and practice of paediatric oncology 6e-

ETIOLOGY :-

• Pathophysiology mechanism are multiple , & are distinct in different type of AML.

• Inherited genetic predisposition and environmental mutagens such as radiation , drugs , & other toxin play a role.

• Association of AML with variety of congenital disorder eg:- ( down syndrome ).

• Large european population based study found no significant familial aggregation for AML or MDS, it means most pt with AML/MDS causative factor is environmental.

PATHOGENESIS :-

• It’s a complex multistep process that result from the interaction of two different classes of mutation.

MUTATION

Impair cell differentiationResulting in clonal expansion of myeloid progenitor

1st class 2nd class Abnormal cell proliferationBy activation of cellularProto oncogenes :-• FLT3 tyrosine kinase• RAS , c- kit

• Some molecular alteration in AML are distinct chromosomal changes ( Translocation, inversion, deletion).

COMMON CYTOGENETIC AB-N & MUTATION IN AML

MUTATION IMPARING DIFFERENTIATION

• t(8,21) • t(15,17)• Inv 16• 11q23 • Rare – t(6,11) t(9,11) t(6,9) inv 3

MUTATION THAT PROMOTESPROLIFERATION

Proto oncogene mutation• FLT3 activationg mutation• RAS mutation• C- kit muation

Tumour suppressor geneMutation• P53• retinoblastoma

RISK FACTOR FOR DEVELOPMENT OF AML :-

ENVIRONMENTAL EXPOSURE• Benzene• Ionizing radiation• Smoking

GENETIC DISORDERS• Down syndrome• Bloom syndrome• Fanconi anemia• Ataxia telengectesia • Klinefelter syndrome

PRE-EXISTING HEMATOLOGICDISORDER :- • MDS• Myelo proliferative disorders• Aplastic anemia

TREATMENT ASSOCIATED• Alkylating agents (deletion chr 5 or 7)• Topoisomerase 2 inhibitor ( changes in chr long arm 11 )

CLINICAL FEATURES :-

• Patient with AML usually present with bone marrow failure that causes symptoms of anemia , bleeding from thrombocytopenia , neutropenic infection

• DIC is seen in APL ( acute promyelocytic leukemia)

• Leukostasis and hyperviscosity causing organ dysfunction usually occur with blast cell count > 100000 /ul

• Rare but striking manifestation of AML includes Sweet syndrome.

LABORATORY FINDINGS :-

HAEMATOLOGIC • Increased WBC with blast in peripheral smear• Anemia , thrombocytopenia , granulocytopenia, DIC

CHEMISTRY• Hyperuricemia, Increased BUN and S.creatinine , high LDH• Hypokalemia , hypercalcemia • Spurious hypoxemia , hypoglycemia

IMAGING STUDIES • Intracranial hemorrhage• Thickened nerve sheath• Lung infiltrates

CLASSIFICATION :- its mainly morphology based on FAB to be more comprehensive WHO classification

FAB classification of AML :-

DIAGNOSTIC EVALUATION:-

According to WHO ,diagnosis of AML require at least20% myeloid blast in peripheral blood or bone marrow

Evaluation of patient with AML at diagnosis includes:-

• Blood count and inspection of blood smear• BM aspirate & biopsy• Cytogenetics• Molecular analysis• L.P if CNS symptom is present

PROGNOSTIC FACTORS :-

CLINICAL PROGNOSTIC FACTOR• Age • AML arising from pre- existing MDS• T/t related AML• Performance status• Extra medullary disease , co- morbid conditions

LABORATORY BASED PROGNOSTIC FACTOR• WBC > 20000u/l at presentation• Cytogenetics• Molecular genetic changes • Multidrug resistance • CD34 +ve blast

• Best predictor of long term outcome next to age are chromosomal & molecular genetic finding in leukemic cells.

• Cytogenetic analysis is basis of stratification on pt in three Risk groups with different responses to chemotherapy.

• Approx 40-50% pt have normal karyotype at time of diagnosis and most of them fall into intermediate risk.

• Best studied mutation , internal tandem duplication of FLT3 gene are found in approx 20-30% of AML pt.

• Outcome of younger AML pt has improved markedly over last 3 decades due to advances in chemotherapy & supportive care.

TREATMENT OF AML :-

• T/t plan in AML pt depends on age , performance factor , prognostic factors detected by cytogenetics, FISH, and PCR.

• T/t for AML is divided into 2 phases :- - remission induction - post remission therapy

• Goal of remission induction is to achieve a CR defined by criteria :- - < 5% blast in BM - absent extramedullary leukemia - neutrophil count > 1000/ul - platelet count > 1lac/ul

• It’s not surprising that clinical trials confirm an almost 100% risk of relapse when pt receive only induction chemotherapy.

• Long term survival requires post remission t/t .

• Intensive chemotherapy given after achievement of CR is termed as consolidation therapy

INITIAL MANAGEMENT :- Initial evaluation should include following

• History and physical examination• CBC with differential count• Coagulation studies• Serum chemistries with uric acid, calcium • Evaluation of renal and liver function• Hep B and C , HSV ,CMV , varicella , HIV serologies.• BM aspirate for morphology, cytochemistry , cytogenetics , molecular genetic studies• BM biopsy• HLA typing of pt • L.P in high risk pt with CNS symptoms• chest radiograph and ECG• Central venous catheter placement

• Workup should be followed by discussion with the patient about the diagnosis , prognosis , side effect of therapy , impact on life style , anticipated requirement for support by family and friends.

• In elderly pt , decision to give only supportive t/t without chemotherapy may be reached jointly by pt and attending physician.

• Final outcome depends not only on choice of chemotherapy but also on close monitoring ,prevention,

and management of complication.

• Pt should be monitored for side effect such as cardiotoxicity due to anthracyclines or neurotoxicity from

high dose of cytosine arabinoside.

INDUCTION THERAPY :-

• The m.c used chemotherapy regimen consist of 1 or 2 cycles of combination of cytarabine 100-200 mg /m2 given by continous i.v infusion over 7 days and 3 days of an anthracycline ( eg :- duanorubicin 60-90 mg /m2 , idarubicin 10-13 mg/m2 or mitoxantrone 10-12 mg/m2 by iv bolus)

• This “ 3 + 7 “ regime result in CR rates of approx 70-80% in patients younger than 55 – 60 years.

• If leukemia persist in BM at day 14 or 21, a 2nd identical or modified course of CT is given.

• High dose duanorubicin is now considered a new std care in the initial t/t of patient < 65 years of age with good performance status and adequate cardiac function.

• In a recent phase 3 trial ,pt were randomized to receive a traditional induction 3+7 regimen or to receive same regimen in combination with fractionated small dose of gemtuzumab.

• Trial demonstrated significant advantage in event free survival and DFS at 2 years for pt who were treated on gemtuzumab arm.

POST REMISSION TREATMENT :-

• Nearly all patients in CR after induction therapy have residual disease that without further management leads to relapse.

• Main strategies to prevent relapse is HDAC and allogenic or autologous HSCT.

• Consolidation t/t improves survival in younger pt with AML

• Consolidation with HDAC using daily dose of 1-6 gm/m2 is the std for patient younger than 60 years.

• Pt over the age 0f 60 years do not benefit from HDAC consolidation.

• Evidence has suggest 1-4 courses of HDAC are reasonable.

• For younger pt choice between HDAC and HSCT based on risk of relapse

HAEMATOPOIETIC STEM CELL TRANSPLANTATION:-

• High dose Marrow ablative c.t and total body irradiation followed by autologous or allogenic stem cell rescue have been widely used in AML.

• Autologous HSCT requires stem cell collection from pt while in CR.

• Allogeneic HSCT are obtained from HLA matched siblings, unrelated donors, and cord blood or haploidentical donors

• Multiple trials comparing std consolidation c.t with HSCT have demonstrated that allo HSCT provides best anti- leukemic therapy with the lowest risk of recurrence followed by auto HSCT .

RISK BASED APPROACH TO AML :-

<A> BETTER RISK AML :- pt with better risk karyotype t(8,21) or inv 16 ,NPM1 mutation do well with either intensive consolidation chemotherapy or auto HSCT . long term DFS of 60-70% can be achieved.

<B> POOR RISK AML :- pt with poor risk or FLT3- ITD as well as patients with secondary AML have very poor prognosis .if HLA matched donor is available , these patient should be evaluated for HSCT as soon as possible. - pt with FLT3- ITD should be considered for clinical trials with FLT3 tyrosine kinase inhibitor such as midostaurin, lestaurtinib , sorafenib, quizartinib.

<C> INTERMEDIATE RISK AML :- t/t is complex in the largest & most heterogeneous prognostic group of patient with normal cytogenetics , no molecular marker or marker of unknown impact on therapy. - Allo – HSCT , consolidation chemotherapy , & auto HSCT are considered of equivalent benefit.

- recent meta analysis revealed allogenic HSCT has significant relapse free survival and OS benefit for intermediate risk AML as compared to non allogenic HSCT therapies.

TREATMENT OF ACUTE PREMYELOCYTIC LEUKEMIA :-

• APL is well defined disease entity with overall better prognosis than other AML subgroups.

• It’s a first example of leukemia in which therapy directed against the leukemogenic event , the t(15,17) resulting in PML-RAR fusion transcript, leads to improved outcome.

• With better management of associated coagulopathy and the introduction of ATRA & ATO ,APL now represent the most curable subtype of AML with cure rate of > 90% quoted in large clinical trials.

• The most widely tested t/t for APL consisted of a combination of ATRA & anthracycline based c.t for induction ,followed by at least 2 courses of anthracycline

based c.t and ATRA for consolidation , and maintenance therapy with intermittent ATRA alone.

• Its is now established that ATO is more effective agent in APL than ATRA ( north american intergroup trial).

• Despite the introduction of ATRA and improvement in t/t of coagulopathy ,bleeding remain imp cause of death .

• Coagulopathy is t/td with FFP, fibrinogen , platelets with goals fibrinogen > 150mg/dl and platelets > 30000/ul.

• APL differentiation syndrome is associated with both ATRA & ATO. It is characterised by pleural & pericardial effusion ,weight gain , edema , dyspnoea, fever.

• Its t/td with i.v administration of dexamethasone at a dose of 10mg twice daily.

• Goal of induction and consolidation therapy should be the attainment of PCR negativity for PML – RAR rearrangement as a persistence of such minimal residua disease (MRD) predicts relapse.

TREATMENT OF RELAPSED AND REFRACTORY AML:-

• Unfortunately , AML relapses in majority of patients.

• Approx 25% of younger pt are refractory to std induction c.t .pt with recurrence AML experience lower CR rates with

reinduction chemotherapy compared to initial t/t.

• Therefore, pt with relapsed and refractory Aml are candidates for clinical trials

• Pt with CR > 12 months, reinduction with HDAC containing regimen,since it can achieve a CR rate of 50-60% .

• Pt with short CR ,priority is t/t on a clinical trials.

ACUTE LYMPHOBLASTIC LEUKEMIA :-

• Approx 3-4 cases/lac of ALL are diagnosed each year In INDIA ,more than half of them in children.

• Currently children & adults with ALL have DFS rates of 50-80% respectively.

EPIDEMIOLOGY :- • ALL is most common paediatric malignancy approx 25% of childhood cancer.• ALL occurs between ages of 2-5 years & after 50yr• Slight male predominance • Highest in hispanic children , caucasians have 2 fold

increased risk as compared to african- american

Division of paediatric oncology , Deptt of paediatric, AIIMS , delhi .

ETIOLOGY & RISK FACTOR :-

• Some conditions predispose to ALL most notably trisomy 21(down syndrome) risk increased by 15fold

• EBV infection is implicated in minority of cases of mature b cell ALL.

• Acquired chromosomal ab-N confined to lymphoblast are found in > 90% cases , including

aneuploidy ( M.c hyperdiploidy) and /or translocation in some cases are prenatal in origin.

CLINICAL FEATURES:- Presenting sign and symptoms are always caused by lympho-Blastic infiltration of b.m with blood count abN

COMMON SIGN & SYMPTOMS

• 70% hepatomegaly• 60% fever• 50% fatigue• 50% lymphadenopathy• 40% bleeding• 40% bone or joint pain• 20% anorexia• 10% abnormal pain

SITES OF INVOLVEMENT

• 100% Bone marrow• 10% Ant Mediastinal mass• 5% CNS • 2% Testicular• < 5% others eg:- eye, skin, pericardium, pleura, kidney , brain, ovary, intussusception

EMERGENCY PRESENTATION INTERVENTION• leukostasis

• Neutropenia with fever/infection

• Thrombocytopenia

• DIC

• Tumour lysis syndrome

• Airway obstruction , SVC syndrome

• CNS manifestation

• Ocular involvement

• Spinal cord compression

• O2 , leukapheresis

• Broad spectrum i/v A/B

• Platelet transfusion

• FFP, cryoprecipitate

• Iv hydration , allopurinol or rasburicase , supportive mx• Corticosteroids & radiation

• Corticosteroids & radiation

• Radiation

• Corticosteroids & radiation

LABORATORY FEATURES :-

• The diagnosis is confirmed by demonstration of lymphoblasts in the blood or BM.

• Blast morphology can be classified in three category (L1,L2,L3) according to FAB.

• L3 is of clinical & prognostic significance because L3 is indicative of mature b cell or burkitt type ALL.

• Majority of ALL is of precursor B cell (pre B cell), 10-20% is T-cell,< 5% is mature B-cell or burkitt type.

• L.P is required to evaluate the possibilities of meningeal leukemia.

CLASSIFICATION :-

FAB MORPHOLOGY- L1 : homogenous blast , minimal cytoplasm- L2 : increased nuclear heterogeneity , prominent nucleoli- L3 : basophilic cytoplasm with prominent vacuolization

BONE MARROW - M1 : <5% blast- M2 : 5% - 25% blast- M3 : > 25% blast

CEREBROSPINAL FLUID CYTOLOGY- CNS-1 : no blasts- CNS-2 : wbc < 5/ul with blasts- CNS-3 : wbc >5/ul with blasts , or symptomatic CNS involvement (eg

cranial nerve palsy)

PROGNOSTIC FACTORS :-

• Age is a strong prognostic determinant .

• Outcome is inferior in infants and adults in comparison to children.

• T-cell and mature B-cell disease have historically had lower DFS rates than pre B-cell ALL.

RISK GROUP ASSIGNMENT IN B-cell precursor ALL:-

STANDARD RISK HIGH RISK

age 1-9 10-35 WBC <30,000- <50,000 >30,000 - > 50000

CNS Negative Positive

chromosomes t(12,21) 11q23,t(1:19) double or triple trisomy t(9,22) 4/10/17

DNA index hyperdiploidy hypodiploidy

T/t response RER SER

Post induction MRD <0.01 0.01- 0.1

TREATMENT :-

• Therapy is based on clinicopathologic features, & t/t should be directed by physician familiar with subtype.

• Therapy should be started as soon as possible after the diagnosis.

• T/t is based on phenotype and prognostic factors and include the following phases :- - induction - consolidation - CNS sterilization - maintenance for a total of 2-3 years

COMMON T/T REGIMENS FOR PRE B-CELL ALL & T-CELL ALL

INDUCTION REGIMEN (WEEK 1-4) 3 DRUGS :- <a> prednisolone 40-60mg/m2 or dexa 6mg /m2 PO * 21-28 days ( day 0 , 28) <b> vincristine 1.5mg/m2/dose iv weekly * 4 doses ( day 0,7 , 14,21O) <c> e-coli asparaginase 6000- 10,000 iu/m2/dose im * 6-9 dose 3d /week * 2-3 week <d> IT methotrexate(or triple t/t with hydrocort & cytarabine)

4 DRUG :- add the following to above <a> doxorubicin 25-30mg/m2/dose or duanorubicin 25-45mg /m2/dose iv weekly * 4 doses

5- DRUG : add the following to above <a> cyclophosphamide 800-1200 mg/m2/dose iv * 1 dose

RESPONSE EVALUATION DAY 14 B.M - M1 : rapid early responder - M2 or M3 : slow early reponder

DAY 28 B.M - M1 : remission ,continue with post induction regimen. if MRD is present ,may be allocated to higher risk group - M2 or M3:- induction failure ,salvage re induction required

POST INDUCTION REGIME :-

PRETREATMENT CRITERIA:- - ANC > 750/ul , platelets > 75000/ul - ALT < 2times the upper limit , direct bilirubin normal for age - serum creatinine normal for age - no active infection or life threatening organ dysfunction

CONSOLIDATION ( WEEK 5)

STANDARD BERLIN- FRANKFURT- MUBSTER STUDY GROUP ( BFM)

- cyclophosphamide 1000mg/m2/dose iv * 2 dose - mercaptopurine 60mg/m2 /dose PO once daily * 28 day - cincristine 1.5mg/m2/dose iv * 4 doses - cytarabine 75mg/m2/dose iv - IT methotrexate weekly * 4dose

AUGMENTED BFM :- - above STD BFM + ecoli asparaginase 6000 iu/m2/dose i.m * 12 doses , 3 dose /week

CAPIZZI :-- Cytarabine 3000mg/m2/dose iv * 4 doses weekly - l – asparaginase 6000 iu/m2/dose im at hour 42 following cytarabine

IFOSPHAMIDE/ETOPOSIDE :-- Etoposide 100mg/m2/dose iv * 5 doses- Ifosfamide 1.8mg/m2/dose iv * 5doses

INTERIM MAINTENANCE:- commonly employed between consolidation and delayed intensification/reinduction courses.

DELAYED INTENSIFICATION / REINDUCTION :

- Dexamethasone 10mg/m2/d in divided doses PO * 14-28 day - vincristine 1.5mg/m2/dose iv weekly * 5 doses - doxorubicin 25-30mg/m2/dose iv weekly * 3 doses - cyclophosphamide 1000mg/m2/dose iv - 6-thioguanine 60mg/m2/dose PO once daily * 14 days - cytareabine 75mg/m2/dose iv - IT methotrexate * 2 doses

MAINTENANCE /CONTINUATION REGIME :- repeat cycles to complete 24-36 month of total t/t - prednisolone 40-60mg/m2/d or dexamethasone 6mg/m2/d in divided dose PO * 5day every 28 day - vincristine 1.5mg/m2/day iv evry 4 week - mercaptopurine 75mg/m2/dose PO once daily - methotrexate 20mg/m2/dose PO once weekly - IT methotrexate every 4-12 week for 1-2 yr of t/t

INTRATHECAL CHEMOTHERAPY:-

• Single agent IT methotrexate has been the std t/t

• Triple agent IT C.T is sometimes employed especially for those with high risk disease, CNS leukemia or meningeal relapse.

• To facilitate CNS delivery, the volume of CSF removed should equal the volume administered and pt should remain in prone position for 30 min.

INDUCTION SCHEDULE :- - CNS 1 : every 2 week * 2 doses - CNS 2 or CNS 3 : weekly * atleast 4 doses MAINTENANCE SCHEDULE :- - every 4-12 week for 1-2 year of t/t

CONSOLIDATION SCHEDULE :- - every 1-4 week

EXTRAMEDULLARY LEUKEMIA :-

• Current chemotherapy regimen are associated with low rates of extra medullary relapse in both the CNS & testes.

• Pt with extramedullary relapse also require systemic therapy .

• Radiation is currently preserved to treat CNS leukemia

RADIATION GUIDELINES :-

• CNS radiation should be avoided in children <2 year of age

• Radiation dose should be based on specific indication & overall t/t.

SITE TOTAL DOSE (CGY) FRACTIONAL DOSE (CGY) CRANIUM 1200- 2400 150-200 SPINE 600-1200 150-200

MANAGEMENT OF RELAPSE :-

• Chance of cure decreases after relapse.

• Attaining a second remission is critical & often times can be achieved with standard 4 or 5 drug induction regimens.

• For those with bone marrow relapse and CR1 duration of > 18-36 month ,approx 35% will achieve prolonged DFS with intensive re-treatment. ALLOGENIC STEM CELL TRANSPLANTATION:-

• Pt with HLA matched sibling donors , allogenic SCT in 2nd CR is standard care.

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