ADVANCES IN MANAGEMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA

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recent advances in management of acute lympoblastic leukemia of children

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Current TREATMENT AND RECENT ADVANCES in all….:

Current TREATMENT AND RECENT ADVANCES in all…. Dr.Shubhankar Mishra

CANCER IS THE MOST DREADED DISEASE IN THE WORLD…….:

CANCER IS THE MOST DREADED DISEASE IN THE WORLD …….

CANCER MOST COMMON CAUSE OF DEATH IN CHILD HOOD………..:

CANCER MOST COMMON CAUSE OF DEATH IN CHILD HOOD………..

LEUKEMIA IS MOST COMMON CAUSE OF ALL THE CHILDHOOD MALIGNANCIES……..:

LEUKEMIA IS MOST COMMON CAUSE OF ALL THE CHILDHOOD MALIGNANCIES……..

AROUND HALF OF ALL THE PEDIATRIC MALIGNANCIES ARE LEUKEMIA…………:

AROUND HALF OF ALL THE PEDIATRIC MALIGNANCIES ARE LEUKEMIA …………

AMONG ALL THE LEUKEMIAS ACUTE LYMPHOBLASTIC LEUKEMIA IS COMMONEST ONE……:

AMONG ALL THE LEUKEMIAS ACUTE LYMPHOBLASTIC LEUKEMIA IS COMMONEST ONE……

ALL : 77% AML : 11% CML :2-3% JMML: 1-2% OTHERS : 5-7% :

ALL : 77% AML : 11% CML :2-3% JMML: 1-2% OTHERS : 5-7%

Classification - ALL:

Classification - ALL

ACCORDING TO ALL-FAB CLASSIFICATION :

ACCORDING TO ALL-FAB CLASSIFICATION ALL-L1 : 80-85% ALL-L2 : 15% ALL-L3 : 1-2%

ALL-L1 HAS BEST PROGNOSIS AMONG ALL THE CHILDHOOD CANCERS……:

ALL-L1 HAS BEST PROGNOSIS AMONG ALL THE CHILDHOOD CANCERS…… ALL –Best Prognosis factors.. Ages 1-9 Females Initial WBC < 10,000 Favorable cytogenetics Early response to treatment

ALL –Poor Prognosis factors…… Ages < 1 year or > 10 years Initial WBC > 50,000 Extramedullary sites CNS Testes Steroid Pre-Treatment Unfavorable cytogenetics Lack of remission after induction treatment :

ALL –Poor Prognosis factors…… Ages < 1 year or > 10 years Initial WBC > 50,000 Extramedullary sites CNS Testes Steroid Pre-Treatment Unfavorable cytogenetics Lack of remission after induction treatment

ALL - Cytogenetics Examples:

ALL - Cytogenetics Examples Favorable Unfavorable Hyperdiploid (extra chromosomes) Hypodiploid (fewer than 54 chromosomes Trisomies 4, 10, 17 t(9;22) BCR/ABL translocation t (12;21)TEL-AML1 t(4;11) MLL rearrangement

RISK GROUPS……… :

RISK GROUPS……… Risk groups vary based on protocols and clinical trials group National Cancer Institute (NCI): –Standard risk—WBC count less than 50,000/ μL and age 1 to younger than 10 years. –High risk—WBC count 50,000/ μL or greater and age 10 years or older.

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TREATMENT STRATEGY IN ALL

TREATMENT OVERVIEW :

TREATMENT OVERVIEW The treatment of ALL can be broken up into categories: –Children Low risk Intermediate risk High risk –Adolescents and young adults

TREATMENT MODALITIES:

TREATMENT MODALITIES -Induction -Consolidation -Maintenance -CNS prophylaxis - Supportive care -Treatment of complications

Induction :

Induction Induction typically lasts 4-6 weeks –Concept: kill leukemia cells quickly before resistance can occur 3 drugs in standard risk – Asparaginase – Vincristine (VCR) weekly for 3-4 weeks – Dexamethasone or prednisone daily 4 drugs in high risk,as general rule –Add daunorubicin

Induction Response :

Induction Response -90-95% of inductions result in a response –Remission monitored using minimal residual disease (MRD) –No clearance of the bone marrow after 4-6 weeks of therapy is deemed a failure -Earlier clearance of lymphoblasts and the presence of MRD at the end of induction therapy is the best indicator of outcome

Minimal Residual Disease (MRD) :

Minimal Residual Disease (MRD)

Consolidation :

Consolidation Consolidation or intensification therapy is the second phase of ALL treatment and is initiated soon after attainment of CR May wait until ANC recovers ≥ 750/ μL and platelets ≥ 75,000/ μL Consolidation therapy usually lasts from four to eight months

Standard risk :

Standard risk VCR 1.5mg/m2 on day 1 Mercaptopurine (6-MP) 75 mg/m2 daily on days 1-28 Intrathecal methotrexate (MTX) 8-15mg dosed based on age on days 1, 8, 15 +/- Leucovorin rescue 5 mg/m2 +/- Asparaginase 2500U/m2 on days 1 and 28

High risk :

High risk -VCR 1.5mg/m2 on day 15,22,43,50 -6-MP 75 mg/m2 daily on days 1-14 and 29-42 -IV MTX 1000mg/m2 weekly +/- Leucovorin rescue 5 mg/m2 - Asparaginase 2500U/m2 on Days 15 and 43

Interim maintenance:

Interim maintenance -In interim maintenance, nonmyelosuppressive chemotherapy ( eg , vincristine and intravenous MTX) are administered to maintain remission and allow the bone marrow to recover. -This occurs for 4-8 weeks

Delayed intensification:

Delayed intensification -Is aimed at treating any remaining resistant leukemia cells. -Two components -intensive reinduction - reconsolidation -

Maintenance:

Maintenance -The last and longest phase of treatment -Backbone: daily 6MP & weekly MTX for 2-3 years –Doses adjusted based on WBC counts -Pulses of VCR q28 days and/or steroid may be added depending on protocol -If ANC is <500/ μL or platelets < 50,000/ μL , therapy held to allow counts to recover –Repeat blood counts ~q4 days

CNS Prophylaxis:

CNS Prophylaxis - CNS involvement at diagnosis <5% –Without prophylaxis, over 80% of patients in CR will relapse in the CNS –With prophylaxis, less than 5% have CNS relapse - Intrathecal chemotherapy is now the mainstay –Sample intermediate risk regimen: IT MTX alone or “triple therapy”: IT cytarabine Day 1 of CR followed by MTX/hydrocortisone/ cytarabine

Grades of CNS disease:

Grades of CNS disease ---CNS 1 - Absence of blasts on cytospin preparation of cerebrospinal fluid (CSF), regardless of the number of white blood cells (WBCs) ---CNS 2 - WBC count of less than 5/ mL and blasts on cytospin findings, or WBC count of more than 5/ mL but negative by Steinherz-Bleyer algorithm findings (if traumatic tap) ---CNS 3 - WBC count of 5/ mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia , such as facial nerve palsy, brain/eye involvement, and hypothalamic syndrome (Additional intrathecal therapy is only given for CNS 3 disease.)

Cranial Radiation:

Cranial Radiation -Sometimes used in higher risk ALL patients –Controversy exists which patients receive -Associated with increased toxicities, especially at doses >18 Gy –Secondary brain tumors –Impaired cognitive development -Altered white matter development

The INDIAN perspective:

The INDIAN perspective -Adapting effective therapy to countries with limited resources requires careful balance of the available resources and the intensity of therapy. - Compared to the Western focus on risk-refinement and adapted therapy, the thrust in India should be on both: - Intensifying Therapy to decrease relapses!, as well as - indigenous , regionally relevant, interventions to minimize toxic deaths.

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Modified MCP:

Modified MCP

Other recent protocols:

Other recent protocols - BFM 90:Berlin-Frankfurt-Mu ̈ nster - CCG 1961-02:Children care group - DFCI 02: Dana - Farber Cancer Institute - I-BFM 95: Intensified Berlin-Frankfurt-Mu ̈ nster - St. Judes TXV -U K protocol

Philadelphia chromosome (Ph)positive ALL :

Philadelphia chromosome (Ph)positive ALL -prognosis for patients with Ph+ ALL is very poor -Ph+ ALL is characterized by the BCR-ABL fusion, which is a target of several tyrosine kinase inhibitors -Fortunately it is rare in paediatric age group. 5% of pediatric ALL, -Currently, imatinib , dasatinib , and ponatinib are tyrosine kinase inhibitors approved by the FDA for treatment of Ph+ ALL

Infant ALL:

Infant ALL -ALL diagnosed in children <365 days old -Majority of cases have absence of CD10 on flow cytometry -t(4;11) (MLL rearrangement) is seen in 75% of cases *MLL blasts express high levels of FLT3 -FLT3 is a tyrosine kinase oncogene implicated in ALL and AML *Associated with poorer outcome -Age <90 days also carries higher risk -Universally poor prognosis with EFS of 50% in past studies *Infants with without MLL rearrangement do better (5 year EFS 60-70%)

T315I-positive, Ph+ ALL:

T315I-positive, Ph+ ALL -Rare mutation ALL -Very resistant to treatment. -Very high risk - Ponatinib has shown a major hematologic response in Ph+ ALL with the T315I mutation

CD-20-positive ALL :

CD-20-positive ALL -Rare in pediatric age group.. -High risk ,bad prognosis. - Rituximab is a monoclonal antibody that targets CD20 -It is in trial phase in adults ALL.

Role of stem cell transplantation :

Role of stem cell transplantation - Stem cell transplantation has good outcome in adults -In pediatric age group it is in experimental phase -It has shown improved outcome in T-cell ALL. -some centers recommend allogeneic stem cell transplantation (SCT) soon after first remission is achieved. - But a trial on subset of patients with BCR-ABL gene rearrangement, the addition of imatinib to intensified chemotherapy produced survival results equivalent to allogeneic SCT.

Tumor Lysis Syndrome :

Tumor Lysis Syndrome -Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome -Primary features of tumor lysis syndrome include - hyperuricemia (due to metabolism of purines ) - hyperphosphatemia - hypocalcemia - hyperkalemia - Hyperuricemia can lead to crystal formation with tubular obstruction and acute renal failure

Tumor Lysis Syndrome :

Tumor Lysis Syndrome MANAGEMENT: - Intravenous (IV) fluids at twice the maintenance rates, without potassium - Sodium bicarbonate may be added to the IV fluid to achieve moderate alkalinization of the urine (pH level, 7.5-8) to enhance the excretion of uric acid - Allopurinol -By blocking the enzyme xanthine oxidase , allopurinol blocks uric acid formation - Rasburicase , a recombinant urate oxidase , has demonstrated increased efficacy in pediatric patients at high risk for tumor lysis by catalyzing the enzymatic oxidation of uric acid to a much more urine soluble product, allantoin . -Calcium to stabilize cardiac membrane -Decrease serum potassium-- Kayexylate , diuretics, insulin, dialysis

Leukapheresis:

Leukapheresis --Patients with a markedly elevated WBC count, especially > 100,000/mm 3 , are at risk for leukostasis --Symptoms include dyspnea due to pulmonary infiltration and altered mental status due to CNS effects; patients should receive emergency leukapheresis to rapidly reduce the WBC count

Treatment of infections:

Treatment of infections -Most patients are neutropenic and immunocompromised - Afebrile patients usually receive prophylactic antibiotics - Febrile neutropenic patients require prompt initiation of broad-spectrum antibiotics.Suggested regimens include a third- or fourth-generation cephalosporin or carbapenem with or without vancomycin .

Pneumocystis Pneumonia:

Pneumocystis Pneumonia -Presentation Fever Tachypnea Hypoxia Ground glass appearance on CXR -Prophylaxis Bactrim ( Trimethoprim – Sulfa) – firstline regimen Dapsone Pentamidine Atovaquone

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Blood transfusion is always needed to counteract anemia and neutropenia ………

Treatment of Relapse :

Treatment of Relapse - Marrow Relapse <36 months from diagnosis (20-30% survival) High dose chemotherapy followed by best matched BM >36 months from diagnosis (40-50% survival) High dose chemotherapy only unless sibling match is available for BMT -CNS Relapse <18 months from diagnosis (40-50% survival) High dose chemotherapy + cranial XRT unless sibling match is available for BMT >18 months from diagnosis (70-80% survival) High dose chemotherapy + cranial XRT

Late Effects of ALL Therapy:

Late Effects of ALL Therapy -Long courses of steroids Obesity Low bone density Osteonecrosis - Anthracyclines Cardiomyopathy -CNS directed therapy Slower processing speed

Proteosome inhibitors :

Proteosome inhibitors Bortezomib -- Proteosome inhibitor used in multiple myeloma ---Is effective in inducing CR in pediatric patients with B-Cell precursor ALL --–Combined with VCR, Peg- Asparaginase , Dexamethasone , and anthracycline after 2nd relapse ---Not effective in T-Cell precursor ALL

Monoclonal antibodies:

Monoclonal antibodies Blinatumomab (MT103) --Novel mechanism enabling patient’s T cells to recognize malignant B cells -–The drug serves as a link between B and T Cells, allowing for T cell cytotoxic activity --Phase 2 studies in adult B Cell precursor ALL after second (or higher) relapse -- Monotherapy during consolidation or maintenance cycles or in combination with chemotherapy in younger patients

Liposomal drugs:

Liposomal drugs Liposomal Vincristine (MARQIBO®) --Approved in late 2012 for the treatment of relapsed/refractory ALL after at least 2 prior anti-leukemic regimens --Dosing: 2.25 mg/m2 IV over 1 hour every 7 days

New tyrosine kinase inhibitor for infant ALL:

New tyrosine kinase inhibitor for infant ALL Lestaurtinib -Inhibits both tyrosine kinase and janus kinase . -Phase-III trial for INFANT ALL

Immunotherapy she is emma.She had several relapse of ALL, and doctors had run out of options. Desperate to save her, her parents sought an experimental treatment at the Children’s Hospital of Philadelphia, one that had never before been tried in a child, or in anyone with the type of leukemia Emma had. The experiment, in used a disabled form of the HIV virus to reprogram Emma’s immune system genetically to kill cancer cells. The treatment very nearly killed her. But she emerged from it cancer-free, and about seven months later is still in complete remission. She is the first child and one of the first humans ever in whom new techniques have achieved a long-sought goal giving a patient’s own immune system the lasting ability to fight cancer. :

Immunotherapy she is emma.She had several relapse of ALL, and doctors had run out of options. Desperate to save her, her parents sought an experimental treatment at the Children’s Hospital of Philadelphia, one that had never before been tried in a child, or in anyone with the type of leukemia Emma had. The experiment, in used a disabled form of the HIV virus to reprogram Emma’s immune system genetically to kill cancer cells. The treatment very nearly killed her. But she emerged from it cancer-free, and about seven months later is still in complete remission. She is the first child and one of the first humans ever in whom new techniques have achieved a long-sought goal giving a patient’s own immune system the lasting ability to fight cancer.

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SO LET ‘S FIGHT ALL

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