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Target Audience : Oncology Fellows, Oncology physicians, Oncologists Archer Board Review Courses www.Ccsworkshop.com ACUTE LYMPHOBLASTIC LEUKEMIA

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ACUTE LYMPHOBLASTIC LEUKEMIA EPIDEMIOLOGY <ul><li>Most common leukemia in children </li></ul><ul><ul><li>60% of ALL patients younger than 20 years of age; most common malignant disease in children </li></ul></ul><ul><ul><li>Accounts for 30% of all childhood cancers </li></ul></ul><ul><li>3830 new cases in the US annually </li></ul><ul><li>Accounts only for 20% of acute leukemia in adults </li></ul><ul><li>More common in males: 62% </li></ul><ul><li>Greatest incidence in the US among Hispanics </li></ul><ul><ul><li>Higher incidence in whites vs blacks </li></ul></ul>

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ALL - EPIDEMIOLOGY <ul><li>Age-Specific Annual Incidence of ALL (1998-2002) </li></ul><ul><ul><li>Peak incidence in childhood, followed by sharp decline in early adolescence </li></ul></ul><ul><ul><li>Increase in incidence during older decades </li></ul></ul>

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ALL - ETIOLOGY <ul><li>Mostly unknown – genetic predisposition is most likely cause. Chrmosomal translocations that occur inutero and post-natally are suggested as major contributors. </li></ul><ul><li>Children with certain genetic and immunodeficiency syndromes are at increased risk: Down syndrome, Klinefilter syndrome, Neurofibromatosis type 1, Bloom syndrome, Fanconi anemia and ataxia telangiectasia. </li></ul><ul><li>Radiation exposure may be associated with increased risk : Survivors of the 1945 atomic bombings of Hiroshima and Nagasaki have an overall relative risk of 9.1 for developing ALL compared with an age-matched controls. </li></ul><ul><li>Chemical toxins : exposure to high levels of benzene. </li></ul><ul><li>Cigarette smoking linked to small increased risk among adults > 60 years of age. </li></ul><ul><li>Secondary ALL may occur after certain chemotherapies ( eg: Topo II inhibitors like VP16 – mode: 11q23 translocation ( MLL gene rearrangements) } </li></ul><ul><li>Viruses : HTLV-1 is implicated in Adult T-cell leukemia/ Lymphoma. Some potential associations were identified between EBV and Burkitt-ALL ( Mature B-Cell ALL) </li></ul>

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ALL - OUTCOME <ul><li>High complete remission rates ( 97%)and Five-Year survival rates (80%) in children. </li></ul><ul><li>Prognosis less favorable in adults. Complete remission rates are high ( 80%) but five-year survival rates still low ( 25% to 50%) </li></ul>

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ALL - CLASSIFICATION <ul><li>FAB ( French-American-British) classification </li></ul><ul><ul><li>Based largely on morphology </li></ul></ul><ul><ul><li>Little prognostic or therapeutic information to help guide treatment decisions. </li></ul></ul><ul><li>WHO ( World Health Organization) classification(WHO) classification </li></ul><ul><ul><li>Revised in 2008 </li></ul></ul><ul><ul><li>Discarded the FAB terms since morphological classification has no clinical or prognostic relevance. </li></ul></ul><ul><ul><li>Changed the classification to reflect increased understanding of the biology and molecular pathogenesis of ALL. </li></ul></ul>

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ALL – CLASSIFICATION FAB

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ALL – CLASSIFICATION FAB

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ALL – CLASSIFICATION WHO <ul><li>Uses immunophenotypic classification : </li></ul><ul><ul><li>Acute lymphoblastic leukemia/lymphoma (Former Fab L1/L2) </li></ul></ul><ul><ul><ul><li>Precursor B acute lymphoblastic leukemia/lymphoma. </li></ul></ul></ul><ul><ul><ul><ul><li>Cytogenetic subtypes: </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>t(12;21)(p12,q22) TEL/AML-1 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>t(1;19)(q23;p13) PBX/E2A </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>t(9;22)(q34;q11) ABL/BCR </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>T(V,11)(V;q23) V/MLL </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Precursor T acute lymphoblastic leukemia/lymphoma </li></ul></ul></ul><ul><ul><li>Burkitt's leukemia/lymphoma (Former FAB L3) </li></ul></ul><ul><ul><li>( mature B cell ALL) </li></ul></ul><ul><ul><li>Biphenotypic acute leukemia ( 2 to 5%) </li></ul></ul>

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ALL IMMUNOPHENOTYPING IN THE DIAGNOSIS AND CLASSIFICATION <ul><li>Leukemic lymphoblasts lack specific morphological and cytochemical features – hence, Immunophenotyping by flow cytometry and Cytogenetics are required for diagnosis and classification. </li></ul><ul><li>Use of a TdT assay and a panel of monoclonal antibodies (MoAbs) to T cell and B cell associated antigens will identify almost all cases of ALL. </li></ul><ul><li>Immunophenotypic categories of acute lymphoblastic leukemia (ALL) </li></ul>Types FAB Class Tdt T cell associate antigen B cell associate antigen c Ig s Ig Precursor B L1,L2 + - + CD10, 19, 20, 22, 24 -/+ - Precursor T L1,L2 + + 2,3,4,5,7,8 - - - B-cell L3 - - + - +

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ALL: IMMUNOPHENOTYPIC CLASSIFICATION <ul><li>Precursor B most frequently observed subtype </li></ul><ul><li>20% to 30% of adults with ALL have aberrant coexpression of myeloid markers </li></ul><ul><ul><li>Only 2% to 5% with true biphenotypic acute leukemia </li></ul></ul>ALL Subtype, % Frequency in Children Frequency in Adults B lineage <ul><li>Precursor B </li></ul>70 55 <ul><li>Pre B </li></ul>10 15 <ul><li>B (FAB L3) </li></ul>5 5 T lineage 15 25

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ALL CYTOGENETICS AND FISH – GENETIC SUBTYPES OF ALL

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ALL IN ADULTS CYTOGENETIC AND MOLECULAR ABNORMALITIES

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MOLECULAR AND CYTOGENETIC SUBTYPES OF B-LINEAGE ALL *Most common in infant leukemia (mixed AML-ALL). Bassan R, et al. Crit Rev Oncol Hematol. 2004;50:223-261. Subtype ( Cytogenetics) Karyotype Childhood Frequency, % Adult Frequency, % Childhood EFS, % Adult EFS, % Hyperdiploidy > 50 chr 25 5 80-90 40-50 TEL/AML1 t(12;21) 25 3 85-90 ? MYC t(8;14) 2 5 75-85 60-70 bcr/abl t(9;22) 5 33 20-40 < 10 MLL/AF4* t(4;11) 3 6 30 15

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MOLECULAR AND CYTOGENETIC SUBTYPES T-CELL LINEAGE ALL Armstrong SA, Look AT. J Clin Oncol. 2005;26:6306-6315. Graux C, et al. Leukemia. 2006;20:1496-1510. Subtype (Cytogenetics) Karyotype Childhood Frequency, % Adult Frequency, % Childhood EFS, % Adult EFS, % HOX11 expression -- 3 33 90 60 NOTCH1 mutations -- 50 50 90 -- TCR t(14q11) 15 25 70 60 MLL-ENL t(11;19) 2 2 95 --

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ALL CYTOGENETICS – GENETIC SUBTYPES OF ALL Cytogenetic abnomality Genes Adult Childhood Type Prognosis t(9:22) BCR/ABL 30% 3% Common / Pre B-ALL (CD10+) Azurophilic granules Unfavorable t(v;11q23) or t(4,11) MLL 5% Topoismomerase related 3% Infants with organomegaly Pro B-ALL CD10- Unfavorable - High rate of early treatment failure t(8,14) MYC/IGH 5% 2% Mature B-Cell, FAB L3 t(1,14) TAL1/TCR 3% T-cell disease t(1;19) PBX/E2A 3% 6% (25% Pre B-ALL) Previously unfavorable now normal prognosis with aggressive therapy. t(12;21) TEL/AML1 ( now referred as ETV6/RUNX1) Rare ( 2%) 16-29% ( most common “t” in children) Favorable Hyperdiploidy >50 7% 25% Favorable Hypodiploidy < 44 2% 5% Unfavorable

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ALL <ul><li>CLINICAL FEATURES AND DIAGNOSIS </li></ul>

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ALL CLINICAL PRESENTATION <ul><li>Typical onset of clinical symptoms of ALL is rapid. </li></ul><ul><li>Symptoms reflect bone marrow failure or leukemic infiltration of extramedullary sites . </li></ul><ul><li>Symptoms related to Bone marrow failure: </li></ul><ul><ul><ul><li>Up to 50% have fever or documented infections. ( Neutropenia) </li></ul></ul></ul><ul><ul><ul><li>One third have some type of bleeding at diagnosis.( Thrombocytopenia) </li></ul></ul></ul><ul><ul><ul><li>Fatigue, lethargy, dizziness, dyspnea, and cardiac angina may reflect the severity of anemia. </li></ul></ul></ul><ul><li>Symptoms related to Leukemic blast Infiltration </li></ul><ul><ul><ul><li>Marrow expansion by leukemic blasts may produce bone pain and arthralgias. </li></ul></ul></ul><ul><ul><ul><li>50% of adult patients have hepatomegaly, splenomegaly, or lymphadenopathy at diagnosis. Organomegaly is more common in T-cell ALL and mature B-cell ALL. </li></ul></ul></ul><ul><ul><ul><li>Mediastinal masses ( seen on CXR/ CT scan), occur primarily in T-lineage ALL . ( bulky masses in anterior mediastinum)These also have frequent pleural involvement and may have chest pain. May be associated with pleural effusions. These masses can produce complications : superior vena cava syndrome, tracheal obstruction, and pericardial effusions (with or without tamponade). </li></ul></ul></ul><ul><ul><ul><li>CNS : Fewer than 10% of individuals with newly diagnosed ALL present CNS involvement. Symptoms suggestive of this are : headache, vomiting, neck stiffness, alteration in mental status, and focal neurologic abnormalities. CNS involvement much more frequent in T-cell ALL and Burkitt-ALL ( mature b-cell ALL). </li></ul></ul></ul>

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ALL CLINICAL PRESENTATION

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ALL CLINICAL PRESENTATION <ul><li>“ B-symptoms” such as fever, night sweats, or weight loss can occur in ALL – usually, mild. 50% of T-cell ALL have B-Symptoms. </li></ul><ul><li>Chin numbness : when elicited in the history or an examination, can indicate cranial nerve involvement and is suggestive of mature B-cell ALL. </li></ul><ul><li>Leucocytosis is usually present. Even in the presence of very high WBC counts, symptoms of “Hyperleucocytosis” are rare in ALL. </li></ul><ul><li>Spontaneous Tumor Lysis Syndrome more likely seen with Burkitt ALL. </li></ul><ul><li>A combination of lytic bone lesions and hypercalcemia with “flower” cells in the peripheral blood is more suggestive of Adult T-cell Leukemia/ lymphoma. </li></ul>

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<ul><li>Minimum blast % required to diagnose Acute leukemia is > 20% blats in bone marrow aspirate or peripheral blood sample. </li></ul><ul><li>Diagnosis is made by clinical features and demonstration of blasts in peripheral blood or bone marrow. </li></ul><ul><li>Once blasts are found, lineage must be established ( myeloid, lymphoid or undifferentiated). </li></ul><ul><li>Traditionally, blast lineage has been established by cell morphology and cytochemical staining to MPO ( Myeloid) vs. TDT ( Lymphoid). </li></ul><ul><li>Immunotyping using Flow cytometry : determines blast surface antigens and improves diagnostic accuracy, and the ability to distinguish between lineage subtypes. It is largely used now in ALL DIAGNOSIS AND CLASSIFICATION </li></ul><ul><li>Cytogenetics : must be obtained to help diagnosis of genetic sub-types of ALL and to aid in predicting prognosis </li></ul>ALL DIAGNOSIS

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ALL DIAGNOSIS/ PRE-RX INVESTIGATIONS <ul><li>Complete blood count </li></ul><ul><li>Comprehensive metabolic panel, LDH, Uric acid </li></ul><ul><li>Peripheral Smear </li></ul><ul><li>Bone Marrow Biopsy and aspiration </li></ul><ul><li>Flow Cytometry </li></ul><ul><li>Cytogenetics </li></ul><ul><li>FISH for certain translocations mentioned earlier </li></ul><ul><ul><li>ALL panel in children with new diagnosis includes : t(9;22), BCR/ABL ; t(12;21), TEL/AML1 ; t(1;19), PBX/TCF3; t(11q23;var), MLL; del(9p); and t(14;var), IGH </li></ul></ul><ul><ul><li>Adult patients: FISH for BCR/ABL and MLL are recommended in adult patients with B-cell ALL. </li></ul></ul><ul><li>RT-PCR for rapid identification of BCR/ABL ( Ph chr positivity) in adults </li></ul><ul><li>CMV serology </li></ul><ul><li>HLA Typing if HSCT is planned. </li></ul><ul><li>Lumbar puncture : and CSF evaluation in all cases of ALL at presentation ( most important in T-cell ALL and in Burkitt-ALL) </li></ul><ul><li>MUGA scan, CXR, EKG </li></ul>

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TREATMENT DECISIONS ALL

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ALL: TYPICAL TREATMENT <ul><li>Primary objective : to achieve and maintain a complete remission (CR) </li></ul><ul><li>Induction, consolidation, maintenance phases </li></ul><ul><ul><li>CNS prophylaxis with IT-MTX during induction and consolidation phases </li></ul></ul>Induction Consolidation Maintenance Over a period of months 2-3 years CNS Prophylaxis (IT-MTX)

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ALL – TREATMENT <ul><li>Complete Remission : Those who achieve and maintain Complete Remission have significantly improved survival. </li></ul><ul><li>Criteria for CR include: </li></ul><ul><ul><li>Evidence of normal Bone marrow recovery ( at least > 25% bone marrow cellularity) </li></ul></ul><ul><ul><ul><li>platelet count ≥ 100 x 109/L </li></ul></ul></ul><ul><ul><ul><li>neutrophil count ≥ 1 x 109/L, and </li></ul></ul></ul><ul><ul><li>Evidence of eradication of detectable leukemia cells </li></ul></ul><ul><ul><ul><li>≤ 5% blasts present in the bone marrow. </li></ul></ul></ul><ul><li>Probability of AML recurrence sharply declines to < 10% after 3 years in CR, and patients in continuous CR for 3 or more years - considered “potentially cured”. </li></ul><ul><li>Additional response criteria have been proposed, such as “CR with incomplete platelet recovery” , defined as CR with platelet count > 30 x 109/L, but < 100 x 109/L. </li></ul>

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REMISSION INDUCTION <ul><li>Anti neop lastic treatment </li></ul><ul><ul><ul><li>Drugs: prednisone, vincristine, asparginase, cyclophosphamide, daunorubicin / adr i amycin/epirubicin, and cytosine arabinoside </li></ul></ul></ul><ul><ul><ul><li>Treatment duration: 4-8 weeks </li></ul></ul></ul><ul><ul><ul><li># of courses: 1- 2 </li></ul></ul></ul><ul><li>2. CNS prophylaxis </li></ul><ul><li>3. Supportive care </li></ul><ul><li>4. Treatment of complications </li></ul>

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TREATMENT OF ADULT ALL <ul><li>Most regimens adopted from pediatric protocols </li></ul><ul><li>Almost no randomized clinical trials comparing regimens or individual drugs </li></ul><ul><li>Less intensive protocols </li></ul><ul><li>Adherence to protocol by adult teams usually not as strict as pediatric teams </li></ul><ul><ul><li>Dose and timing of therapy </li></ul></ul>

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ALL INDUCTION <ul><li>BFM regimen : frequently used in Pediatric ALL. Can be used in young adults with good PS. Induction therapy consists of vincristine, daunorubicin, prednisone, asparaginase, intrathecal cytarabine, and intrathecal methotrexate. </li></ul><ul><li>CALGB ALL : used in high-risk pediatric ALL, may use in adults. Uses five drugs – cyclophosphamide, daunorubicin, Vincristine, prednisone and L-asparaginase in induction for 4 weeks. </li></ul><ul><li>HyperCVAD : combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) alternating with high-dose methotrexate and high-dose cytarabine – Also, used in adult ALL. Regimen also includes a risk-stratified schedule of CNS prophylaxis with IT methotrexate and IT cytarabine. The dose-intensive phase spans six to seven months and is followed by two years of maintenance therapy. </li></ul><ul><li>GRALL2003 : another pediatric inspired regimen. Includes high doses of prednisone, vincristine, and asparaginase in combination with daunorubicin, cyclophosphamide, and intrathecal methotrexate. </li></ul>

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TREATMENT OF ALL: BFM-BASED MODEL <ul><li>Induction phase I (4 weeks) </li></ul><ul><ul><li>Prednisone, vincristine, daunorubicin, L-asparaginase </li></ul></ul><ul><ul><li>No benefit to adding cyclophosphamide, high-dose cytarabine, or high-dose anthracycline </li></ul></ul><ul><li>Induction phase II (4 weeks) </li></ul><ul><ul><li>Cyclophosphamide, cytarabine, 6-mercaptopurine </li></ul></ul><ul><li>Consolidation </li></ul><ul><ul><li>4-7 cycles of intensive multiagent chemotherapy </li></ul></ul><ul><ul><li>Delayed reinduction </li></ul></ul>

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HYPER-CVAD REGIMEN <ul><li>Part A </li></ul><ul><ul><li>Dexamethasone, vincristine, doxorubicin, cyclophosphamide </li></ul></ul><ul><li>Part B (after WBC recovery) </li></ul><ul><ul><li>High-dose MTX, high-dose cytarabine </li></ul></ul><ul><ul><li>No asparaginase </li></ul></ul><ul><li>Parts A and B repeated 4 times </li></ul>Kantarjian H, et al. J Clin Oncol. 2000;18:547-561.

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HYPER-CVAD IN ADULTS WITH ALL <ul><li>5-year CR and survival with hyper-CVAD vs VAD in untreated ALL </li></ul>Kantarjian et al. J Clin Oncol. 2000;18:547-561. Outcome Hyper-CVAD (N = 204) VAD (N = 222) 5-Year CR, % 38 32 5-Year Survival, % 39 21

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ADULT ALL: LARGE CLINICAL TRIALS Clinical Trials N Age Treatment CR, % DFS, % GMALL 02/84 562 28 BFM 75 39 GMALL 05/93 1163 35 BFM, HD-ARA-C, HD-MTX 87 35-40 CALGB 8811 198 35 BFM, ↑ Cy, ↑ ASP 85 36 CALGB 19802 163 41 BFM, ↑ Cy , ↑ DNR 78 35 GIMEMA 778 28 BFM ± Cy 82 29 MRC-UKALL XA 618 > 15 BFM + early intensification 89 -- MRC/ECOG 1521 BFM + HD-MTX ± SCT 91 38 UCSF 8707 84 27 BFM intensified 93 52 Hyper-CVAD 288 40 Cy, D, AD, HD-MTX, HD-ARA-C 92 38

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ADULT ALL: LARGE CLINICAL TRIALS (CONT’D) Study Study Years References GMALL 02/84 84-90 Hoelzer D, et al. Blood. 1998;71:123-131. GMALL 05/93 93-99 Gökbuget N, et al. Blood. 2001;98:802a. CALGB 8811 88-91 Larson R, et al. Blood. 1995;85:2025-2037. CALGB 19802 99-01 Larson RA. Ann Hematol. 2004;83(suppl 1): S127-S128. GIMEMA 88-94 Annino L, et al. Blood. 2002;99:863-871. MRC-UKALL XA Durrant I, et al. Br J Haematol. 1997;99:84-92. MRC/ECOG 93-04 Rowe J, et al. Blood. 2005;106:3760-3767. UCSF 8707 87-98 Linker C, et al. J Clin Oncol. 2002;20:2464-2471. Hyper-CVAD 92-00 Kantarjian H, et al. Cancer. 2004;101:2788-2801.

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ALL - INDUCTION <ul><li>EVALUATION OF RESPONSE </li></ul><ul><ul><li>Bone marrow aspirate and biopsy once adequate values for absolute neutrophil count (>1000/microL) and platelet count (>100,000/microL) are obtained. A core biopsy required to assess marrow cellularity. </li></ul></ul><ul><ul><li>Assess if CR is achieved. </li></ul></ul><ul><ul><ul><ul><li>The importance of achieving a CR was shown in the International ALL trial; patients achieving or not achieving CR had overall survival rates of 45 versus 5 percent, respectively </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Once a CR is achieved, therapy must continue for an extended period of time to eliminate subclinical disease (minimal residual disease) known to contribute to relapse. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>MRD : CR has historically been defined based upon morphologic criteria, However, some propose that an assessment of minimal residual disease using immunological or molecular techniques can better define prognosis  As yet, prospective studies have not demonstrated that altering therapy based upon evidence of minimal residual disease leads to a better outcome . </li></ul></ul></ul></ul>

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CENTRAL NERVOUS SYSTEM PROPHYLAXIS <ul><li>Less than 10% of ALL presents with CNS involvement however, with no CNS prophylaxis  CNS relapse can occur in 60% of patients. </li></ul><ul><li>Risk factors for CNS involvement in adults </li></ul><ul><ul><ul><ul><li>mature B-cell ALL </li></ul></ul></ul></ul><ul><ul><ul><ul><li>high serum lactate dehydrogenase levels > 600 U/L) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>presence of a high proliferative index at diagnosis ( >14% of lymphoblasts in the S and G2/M phase of the cell cycle) </li></ul></ul></ul></ul><ul><li>If symptomatic CNS disease present at diagnosis  concurrent cranial irradiation + IT chemotherapy </li></ul><ul><li>For CNS prophylaxis in all other cases : </li></ul><ul><ul><li>IT-MTX and systemic high-dose MTX or some regimens incorporate “triple” therapy ( IT MTX +ARA-C+Corticosteroids) </li></ul></ul><ul><ul><li>Cranial irradiation </li></ul></ul><ul><ul><ul><li>Probably not necessary with systemic high-dose treatment (MTX, ARA-C) and extended IT-MTX ( cranial irradiation associated with late brain toxicity) </li></ul></ul></ul>

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ALL - SUPPORTIVE CARE <ul><li>Cytopenias : All patients treated with traditional induction will develop cytopenias which may require intervention. </li></ul><ul><ul><li>Transfusion support : Platelets and Packed red cell transfusion when necessary ( leukodepleted and irradiated to prevent GVHD) </li></ul></ul><ul><ul><li>G-CSF Support : Is safe and appears to reduce the number of induction deaths </li></ul></ul><ul><ul><ul><ul><li>When given on day 4 of induction until return of absolute neutrophil count > 1000/L, patients receiving G-CSF , had signifi cantly shorter hospital stays, less time to neutrophil recovery, and fewer severe infections compared with patients who did not receive CSF. CALGB 9111 trial highlighted the benefi t of using this drug in patients prone to diffi culty with hematologic recovery, specifically older patients. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Does not affect DFS or OS but is safe and assists patients to proceed with post-remission therapy </li></ul></ul></ul></ul><ul><li>Prevention of Tumor Lysis Syndrome ( Risk highest in Burkitt-ALL and T-Cell ALL) </li></ul><ul><ul><li>Intravenos hydration 100ml/hr </li></ul></ul><ul><ul><li>Allopurinol </li></ul></ul><ul><ul><li>Rasburicase </li></ul></ul><ul><ul><li>Correction of electrolyte disturbances (Hypocalcemia, Hyperphospahtemia) </li></ul></ul><ul><li>Antibiotic Prophylaxis while on aggressive chemotherapies : </li></ul><ul><ul><li>Acyclovir prophylaxis for all HSV seropositive adults </li></ul></ul><ul><ul><li>Prophylaxis with antibiotics (quinolones) and/or antifungals during neutropenia. </li></ul></ul><ul><ul><li>Trimtheoprim/sulfamethoxazole for PCP prophylaxis </li></ul></ul><ul><ul><li>Ganciclovir prophylaxis for CMV seropositive patients </li></ul></ul>

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ALL RISK STRATIFICATION <ul><li>Induction therapy substantially reduces the total body leukemia cell population. However, a significant burden of leukemic cells remain undetected ( “minimal residual” disease) leading to relapse if no further therapy is given  hence, post-remission therapy. </li></ul><ul><li>After induction of complete remission (CR), patients must be risk-stratified in order to identify the best post-remission strategy ( Consolidation therapy) </li></ul>

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PROGNOSTIC INDICATORS

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ALL - CONSOLIDATION <ul><li>Standard risk ALL in CR1 </li></ul><ul><ul><li>Proceed with consolidation and maintenance chemotherapy rather than either allogeneic or autologous HCT . </li></ul></ul><ul><ul><li>This preference places a relatively high value on avoiding the higher short-term mortality and long-term morbidity associated with HCT and a low value on the potential, but uncertain, ability of the more intensive transplant therapy to eliminate residual disease. </li></ul></ul><ul><li>High Risk ALL </li></ul><ul><ul><li>For young patients with high-risk ALL in CR1 who have an HLA-matched donor : allogeneic HCT preferred rather than consolidation chemotherapy or autologous HCT </li></ul></ul><ul><ul><li>For patients with high-risk ALL in CR1 who are not candidates for allogeneic HCT ( older adults, co-morbidities), consolidation chemotherapy preferred than autologous HCT . </li></ul></ul><ul><ul><li>For patients with Philadelphia chromosome positive ALL in CR1, a matched sibling HCT preferred than consolidation chemotherapy or autologous HCT . In patients without an HLA-identical sibling, unrelated donor marrow transplantation is an effective option. </li></ul></ul><ul><li>For patients who are still in CR after completing consolidation chemotherapy  proceed with two to three years of maintenance chemotherapy rather than observation The most commonly used regimen is daily 6-mercaptopurine , weekly methotrexate, and monthly pulses of vincristine and prednisone </li></ul><ul><li>(ie, POMP ) or dexamethasone for three years. </li></ul>

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STEM CELL TRANSPLANTATION (SCT): CIMBTR RECOMMENDATIONS <ul><li>First CR </li></ul><ul><ul><li>Allo SCT or MUD in high-risk patients </li></ul></ul><ul><ul><li>Role in standard-risk patients unclear but not recommended </li></ul></ul><ul><ul><li>Auto SCT: no benefit over chemotherapy </li></ul></ul><ul><li>Second CR ( the CR after relapse) </li></ul><ul><ul><li>Allo SCT </li></ul></ul>. CIBMTR, Center for International Blood and Marrow Transplant Research

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ALL: SCT AT FIRST CR Several trials comparing chemotherapy vs. autologous stem cell transplant vs. Allo-SCT reveal improved survival with allo-SCT in High Risk patients as shown above. Study Endpoint CHT Auto SCT Allo SCT Improved Outcome CIBMTR vs German studies LFS 32% -- 34% NS JALSG 93 OS 40% -- 46% NS LALA 87 OS 35% 48% NS LALA 87 SR OS 45% 51% NS LALA 87 HR OS 20% 44% Allo LALA 94 HR OS 35% 44% 51% Allo GOELAL02 HR OS -- 40% 75% Allo

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ALLO BMT VS AUTO BMT IN PATIENTS WITH PH- ALL: MRC UKALL XII/ECOG E2993 Rowe JM, et al. ASH 2006. Abstract 2. Patients with Ph- ALL aged < 55 yrs in complete remission after induction therapy (N = 919) Sibling Allo BMT (n = 389) High-Dose Methotrexate (3 doses) HLA-matched sibling donor available? Yes High-Dose Methotrexate (3 doses) Auto BMT Consolidation/Maintenance Chemotherapy: 2.5 years (n = 530) No

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ALLO BMT VS AUTO BMT IN PATIENTS WITH PH- ALL: 5-YEAR RESULTS MRC/UK-ALL <ul><li>Improved OS with allo BMT vs auto BMT or postinduction chemotherapy in standard-risk Ph- patients </li></ul><ul><ul><li>5-year OS for allo BMT vs chemotherapy only: 54% vs 44%, respectively ( P < .02) </li></ul></ul><ul><ul><li>No advantage in high-risk patients ( older patients, WBC > 30,000 [B cell] or > 100,000 [T cell]) </li></ul></ul>Rowe JM, et al. ASH 2006. Abstract 2. Outcome by Risk Group, % Donor (n = 389) No Donor (n = 530) P Value Overall 5-yr survival 53 45 .02 <ul><li>High risk </li></ul>40 36 .50 <ul><li>Standard risk </li></ul>63 51 .01 10-yr relapse rate <ul><li>High risk </li></ul>39 62 < .0001 <ul><li>Standard risk </li></ul>27 50 < .0001

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ALLO BMT VS AUTO BMT IN PATIENTS WITH PH- ALL: 5-YEAR RESULTS ( (MRC/UKALL CONT’D) <ul><li>Better EFS, OS with consolidation/maintenance chemotherapy vs auto BMT </li></ul><ul><ul><li>No role for auto BMT in postremission Ph-negative ALL </li></ul></ul><ul><ul><li>Allo BMT treatment of choice in standard-risk patients ( contradicts LALA Trial results) </li></ul></ul>Rowe JM, et al. ASH 2006. Abstract 2. Outcome by Risk Group, % Chemotherapy Auto BMT P Value Overall 5-yr survival 47 37 .06 <ul><li>High risk </li></ul>40 32 .2 <ul><li>Standard risk </li></ul>49 41 .2 Overall EFS 42 33 .02

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ADULT ALL: MAINTENANCE THERAPY <ul><li>Weekly methotrexate + daily 6-mercaptopurine </li></ul><ul><ul><li>Monthly Vincristine/prednisone pulses </li></ul></ul><ul><li>Duration: 2-3 years </li></ul><ul><li>Appropriate for all cases except B-cell and Ph+ ALL </li></ul><ul><li>Poor outcome if omitted </li></ul><ul><li>No randomized trials in adults </li></ul>

46.
ADULT ALL: MAINTENANCE THERAPY (CONT’D) <ul><li>6-mercaptopurine dose varies </li></ul><ul><ul><li>Higher sensitivity in patients with inherited deficiency of thiopurine methyltransferase. If excess toxicity such as severe and prolonged myelosuppression with 6-MP  Stop 6-MP and check for this enzyme. </li></ul></ul><ul><li>Elevation of liver enzymes </li></ul><ul><ul><li>Recovery after discontinuation of therapy </li></ul></ul><ul><ul><li>No need to withhold or reduce dose in absence of severe liver toxicity </li></ul></ul>

47.
L-ASPARAGINASE IN ALL <ul><li>Used only in ALL </li></ul><ul><li>Derived from bacterial enzyme </li></ul><ul><li>Enzyme that depletes serum L-asparagine ( Normal cells can reproduce their own asparagine by asparagine synthetase but ALL cells can not and therefore, dependent on plasma asparagine  depletion of plasma asparagine causes protein synthesis inhibition  depletes synthesis of RNA and DNA  apoptotic cell death of leukemic cells). </li></ul><ul><li>Activity related to serum L-asparagine depletion </li></ul><ul><li>No myelosuppression </li></ul><ul><li>No late effects </li></ul><ul><li>Unique adverse effects </li></ul>

48.
L-ASPARAGINASE: MECHANISM OF ACTION* *Sensitivity of ALL cells to asparaginase due to low asparagine synthetase in leukemic cells. Blood L-asparagine L-asparaginase NH3 + L-aspartate Cell L-asparagine Asparagine synthetase Glutamine L-aspartate L-asparagine + Glutamate +

49.
L-ASPARAGINASE IN ADULT ALL <ul><li>No randomized trials in adults </li></ul><ul><li>Well tolerated in adults </li></ul><ul><ul><li>Usually given at lower total doses than in children </li></ul></ul><ul><li>Importance in childhood disease suggests benefit of increased treatment and longer schedules in adults </li></ul><ul><li>Antibody formation unknown </li></ul>

50.
L-ASPARAGINASE: TOXICITY <ul><li>Hypersensitivity </li></ul><ul><ul><li>Neutralizing antibodies </li></ul></ul><ul><li>Liver dysfunction </li></ul><ul><ul><li>Liver enzymes, bilirubin, low albumin </li></ul></ul><ul><li>Hemostasis </li></ul><ul><ul><li>Bleeding: low clotting factors </li></ul></ul><ul><ul><li>Clotting: low antithrombin III, protein S </li></ul></ul><ul><li>Pancreatitis , diabetes mellitus, CNS effects (lethargy, somnolence) </li></ul>

51.
ALL -SPECIAL GROUPS <ul><li>ALL IN OLDER ADULTS </li></ul><ul><li>PH+ ALL </li></ul><ul><li>MATURE B-CELL / BURKITT- ALL (L3) </li></ul><ul><li>T-CELL ALL </li></ul>

52.
ALL IN OLDER ADULTS <ul><li>Low CR and survival rates </li></ul><ul><li>Lower rate of T-cell ALL </li></ul><ul><li>High rate of Ph-positive ALL ( more than 50% of ALL in age > 65) </li></ul><ul><li>Often excluded from clinical trials </li></ul><ul><li>Often receive attenuated chemotherapy </li></ul>

53.
COMPLICATIONS OBSERVED IN OLDER ADULTS WITH ALL <ul><li>Comorbid conditions </li></ul><ul><li>More severe mucositis related to pain medications </li></ul><ul><li>Events associated with specific chemotherapies </li></ul><ul><ul><li>Vincristine: neuropathy, constipation </li></ul></ul><ul><ul><li>Steroids: hyperglycemia, infections </li></ul></ul><ul><ul><li>L-asparaginase: encephalopathy ( more lethargy and somnolence occur in older adults) </li></ul></ul><ul><li>Low marrow reserve </li></ul><ul><ul><li>Adding G-CSF improves CR rate </li></ul></ul>

54.
PHILADELPHIA CHROMOSOME (PH+) ALL <ul><li>t(9;22) bcr/abl translocation </li></ul><ul><li>Precursor B cell </li></ul><ul><li>Incidence continuously increasing with age </li></ul><ul><ul><li>Rare in children; 50% incidence in ALL patients older than 55 years of age </li></ul></ul><ul><li>Associated with very poor outcome </li></ul><ul><ul><li>No cure with intensive ALL chemotherapy (all ages). Despite intensive chemotherapy, long term survival < 10% </li></ul></ul><ul><ul><li>Cure with SCT possible </li></ul></ul><ul><ul><ul><li>Allo SCT is recommended for all patients with PH+ ALL who achieve a CR. </li></ul></ul></ul><ul><ul><ul><li>Lower cure rate than other ALL subtypes </li></ul></ul></ul>

55.
IMATINIB IN PH+ ALL <ul><li>Induces high response rate as single agent </li></ul><ul><ul><li>Response generally not durable </li></ul></ul><ul><li>In combination with ALL chemotherapy ( preferred choice)for induction </li></ul><ul><ul><li>Higher CR rate: 90% to 97% and improved outcome compared with chemotherapy alone ( in a study, 2-year disease-free survival rate was 87% with the hyper-CVAD regimen plus imatinib vs 28% with hyper-CVAD alone in Ph+ ALL ) </li></ul></ul><ul><ul><li>Increased access to transplantation for more patients </li></ul></ul><ul><ul><li>Improves outcome of subsequent SCT </li></ul></ul><ul><ul><li>Concurrent administration of imatinib + chemotherapy superior to alternating schedule </li></ul></ul>

56.
TREATMENT OF RELAPSED PH+ ALL: DASATINIB Coutre S, et al. ASCO 2006. Abstract 6528 Ph+ ALL CML (Chronic Phase) Patients, N 36 186 Imatinib status, % <ul><li>Resistant </li></ul>94 68 <ul><li>Intolerant </li></ul>6 32 Response, % <ul><li>CHR </li></ul>31 90 <ul><li>NEL </li></ul>11 <ul><li>McyR </li></ul>58 45 <ul><li>CcyR </li></ul>58 33 Median duration of response, mos 4.8 > 6.0

57.
B-CELL ALL (FAB L3): BURKITT’S LEUKEMIA <ul><li>Rapid cell proliferation and very high LDH </li></ul><ul><li>t(8;14), t(2;8), t(8;22) </li></ul><ul><ul><li>Rearrangement of myc protooncogene (ch 8) with Ig heavy chains (ch 14) or light chains (ch 2 or 22) </li></ul></ul><ul><li>High expression of CD20 </li></ul><ul><li>Treatment option : Short intensive chemotherapy </li></ul><ul><ul><li>High-dose MTX and cyclophosphamide </li></ul></ul><ul><ul><li>CALGB regimens </li></ul></ul><ul><ul><li>Role of anti-CD20 : Addition of rituximab to hyper-CVAD improves remission duration and survival compared with hyper-CVAD without rituximab.[Hyper-CVAD plus rituximab increased the amount of patients with complete responses sustained through 3 years (70% vs 38% with hyper-CVAD alone; P < .001). Survival was also improved with hyper-CVAD plus rituximab (75% vs 47% with hyper-CVAD alone; P = .003) </li></ul></ul><ul><li>Intensive CNS prophylaxis </li></ul><ul><li>No maintenance required ( high cure rates after intensive chemotherapy) </li></ul><ul><li>Cure rate: 60%; relapses are rare 6 months after CR </li></ul>

58.
ALL MINIMAL RESIDUAL DISEASE <ul><li>Refers to residual leukemic cells that remain following the achievement of CR, but are below the limits of detection using conventional morphologic assessment. These subclinical levels of residual leukemia are thought to be responsible for relapse after initial disease response. </li></ul><ul><li>Methods of detection : </li></ul><ul><ul><li>Multicolor flow cytometry or PCR </li></ul></ul><ul><ul><li>Fusion transcripts </li></ul></ul><ul><ul><li>Rearranged immunoglobulin and T-cell receptor genes </li></ul></ul><ul><li>Effect on prognosis — 80 percent of adults with ALL will have MRD detectable immediately following the completion of induction therapy. Multiple studies have shown that patients with detectable MRD have significantly higher relapse rates. </li></ul><ul><ul><li>Prognostic levels defined for children; prognostic time points and levels yet to determined for adults. </li></ul></ul>Time of Evaluation Minimum Residual Disease Prognosis Children <ul><li>At CR </li></ul>< 0.01% Excellent outcome <ul><li>After CR </li></ul>> 0.1% High relapse risk

59.
ALL MINIMAL RESIDUAL DISEASE <ul><li>Ongoing trials : </li></ul><ul><ul><li>Whether MRD at CR1 measurements can be used to modify therapy to improve clinical outcomes? Ongoing trials are evaluating the escalation of therapy intensity in MRD positive cases and the reduction of therapy intensity in MRD negative cases. </li></ul></ul><ul><ul><li>It is not clear whether MRD measurement should play a role in the long-term surveillance of patients who have completed therapy. </li></ul></ul>

60.
T-CELL ALL <ul><li>Current therapies for T-cell acute lymphoblastic leukemia (ALL) produce high responses, but approximately one half of patients will relapse within 2 years. </li></ul><ul><li>Nelarabine demonstrates antineoplastic activity in patients with relapsed/refractory T-cell ALL. In a recent study by the Cancer and Leukemia Group B, nelarabine treatment produced complete remission rates of 26% with minimal toxicities in relapsed/refractory ALL patients. </li></ul>

61.
NELARABINE IN RELAPSED/REFRACTORY ADULT T-ALL/T-LBL 1. Goekbuget N, et al. Blood. 2005;106:47a. Abstract 150. 2. DeAngelo D, et al. Blood. 2002;100:198a. Abstract 743. Study CR PR OS Toxicity GMALL (N = 53) [1] 47% 13% 16% Myelosuppression Neurotoxicity (n = 2) CALGB (N = 38) [2] 26% 5% 32% at Yr 1 Myelosuppression Elevated LFT Neurotoxicity (n = 1)

62.
LATE COMPLICATIONS OF THERAPY <ul><li>Late complications of therapy </li></ul><ul><ul><ul><li>Brain tumors (cerebral irradiation) </li></ul></ul></ul><ul><ul><ul><li>Secondary AML from topoisomerase inhibitors and alkylating agents </li></ul></ul></ul><ul><ul><ul><li>Cardiomyopathy (anthracyclines) </li></ul></ul></ul><ul><ul><ul><li>Osteoporosis (corticosteroids) </li></ul></ul></ul><ul><ul><ul><li>Growth disturbances </li></ul></ul></ul><ul><ul><ul><li>Thyroid dysfunction (cranial irradiation) </li></ul></ul></ul><ul><ul><ul><li>Obesity (uncertain etiology) </li></ul></ul></ul><ul><ul><ul><li>Neuropsychiatric disturbances and seizures (IT MTX and cranial irradiation) </li></ul></ul></ul><ul><ul><ul><li>Emotional problems </li></ul></ul></ul><ul><ul><ul><li>Discrimination with insurance, job applications and military service </li></ul></ul></ul>

63.
ALL – SALVAGE THERAPY

64.
RELAPSED/ REFRACTORY ALL PROGNOSTIC FACTORS Independent prognostic factors associated with achieving CR during salvage therapy include duration of first CR and platelet count. Several factors are associated with poor survival rates : - short duration of first CR, thrombocytopenia, elevated percent bone marrow blasts, and low albumin level Poor Prognostic Factors for CR Poor Prognostic Factors for Survival Albumin level < 3 g/L* Albumin level < 3 g/L* Duration of first CR < 36 mos* Duration of first CR < 36 mos* Hemoglobin level < 10 g/dL Hemoglobin level < 10 g/dL Platelet count ≤ 50 x 10 9 /L* Platelet count ≤ 50 x 10 9 /L* Percent bone marrow blasts > 50% Percent bone marrow blasts > 50%* Peripheral blood blasts ≥ 1% Percent peripheral blood blasts ≥ 1% White blood cell count > 20 x 10 9 /L

65.
ALL: NEW CHEMOTHERAPIES <ul><li>Antimetabolites </li></ul><ul><ul><li>Nelarabine (relapsed T-ALL) </li></ul></ul><ul><ul><li>Clofarabine </li></ul></ul><ul><ul><li>Trimetrexate (dihydrofolate reductase inhibitor) </li></ul></ul><ul><li>Liposomal or pegylated agents </li></ul><ul><ul><li>Pegylated L-asparaginase </li></ul></ul><ul><ul><li>Liposomal daunorubicin </li></ul></ul><ul><ul><li>Liposomal vincristine </li></ul></ul><ul><li>Cytarabine liposome injection (IT) </li></ul>

66.
PEGYLATED ASPARAGINASE <ul><li>Pegylated E. coli L-asparaginase </li></ul><ul><li>Less immunogenic </li></ul><ul><li>Long half-life </li></ul><ul><ul><li>Less frequent dosing </li></ul></ul><ul><ul><li>Continuous asparagine depletion </li></ul></ul><ul><li>In children </li></ul><ul><ul><li>More rapid reduction in marrow blasts during induction </li></ul></ul><ul><ul><li>Lower incidence of neutralizing antibodies </li></ul></ul><ul><ul><li>Similar safety profile as native form </li></ul></ul><ul><li>In adults </li></ul><ul><ul><li>Similar toxicity to native form after single and multiple doses </li></ul></ul>.

67.
CLOFARABINE IN ALL <ul><li>Approved in relapsed or refractory Pediatric ALL </li></ul><ul><li>Children (N = 61) [1] ; median of 3 prior regimens </li></ul><ul><ul><li>52 mg/m 2 on Days 1-5 </li></ul></ul><ul><ul><ul><li>CR + CRp in 12 patients ( 20% ); PR in 6 patients (10%) </li></ul></ul></ul><ul><ul><ul><li>Median survival:13 weeks </li></ul></ul></ul><ul><ul><ul><li>9 responders proceeded to SCT </li></ul></ul></ul><ul><li>Adults (N = 12) [2] </li></ul><ul><ul><li>Dose 40 mg/m 2 on Days 1-5 </li></ul></ul><ul><ul><li>CR in 2 patients ( 17% ) </li></ul></ul><ul><li>Toxicity : hepatotoxicity, palmarplantar erythrodysesthesia, druf fever, rash </li></ul>1. Jeha S, et al. J Clin Oncol. 2006;24:1917-1923. 2. Kantarjian H, et al. Blood. 2003;102:2379-2386.

68.
T-CELL ALL: GAMMA SECRETASE INHIBITOR MK 0752 <ul><li>NOTCH 1 gain-of-function mutations in 50% of T-ALL </li></ul><ul><li>Gamma secretase inhibitors abrogate stimulatory effects of NOTCH 1 </li></ul><ul><li>Phase I trial </li></ul><ul><ul><li>Gamma secretase inhibitor MK-0752 </li></ul></ul><ul><ul><li>4 patients: NOTCH1 activated mutations </li></ul></ul><ul><ul><li>1 patient: decrease in size of mediastinal mass </li></ul></ul>DeAngelo D, et al. ASCO 2006. Abstract 6585.

69.
ALL: TARGETED TREATMENTS <ul><li>Targets include BCR/ABL, CD 20, and FLT3 overexpression, among others </li></ul>ALL Subtype Target Treatment Ph+ BCR/ABL Imatinib, dasatinib, nilotinib T cell NUP214-ABL1 NOTCH1 mutation Imatinib, dasatinib, nilotinib Gamma secretase inhibitor Mature B cell CD20 Rituximab Precursor B cell CD20 Rituximab All subtypes CD52 Alemtuzumab MLL and hyperdiploidly FLT3 overexpression CEP701, PKC 212

70.
ALL: NOVEL MANAGEMENT APPROACHES <ul><li>Minimal residual disease evaluation </li></ul><ul><ul><li>Define prognostic groups for treatment selection </li></ul></ul><ul><li>Microarray analysis (gene expression profiles) </li></ul><ul><ul><li>Prognosis </li></ul></ul><ul><ul><li>Identify new targets </li></ul></ul>

71.
ALL <ul><li>SUMMARY AND FUTURE </li></ul>

72.
TREATMENT OF ALL: SUMMARY AND FUTURE DIRECTIONS <ul><li>Preferable to treat adult patients in clinical trials </li></ul><ul><li>Trials for young adults and adolescents needed </li></ul><ul><li>For patients not in trials, a number of existing chemotherapy regimens available </li></ul><ul><li>Adult patients with Ph-positive ALL: imatinib </li></ul><ul><ul><li>Options in imatinib-resistant disease now available </li></ul></ul><ul><li>Allo SCT appropriate in high-risk ALL </li></ul><ul><ul><li>Role of auto SCT not yet defined </li></ul></ul>

73.
TREATMENT OF ALL: SUMMARY AND FUTURE DIRECTIONS (CONT’D) <ul><li>Future treatment decision may be based on evaluation of MRD at critical time points </li></ul><ul><ul><li>At CR and after CR </li></ul></ul><ul><li>Therapy selection through gene expression profiling </li></ul><ul><li>Molecular markers with possible prognostic significance currently being investigated </li></ul>