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![Diagnosis (Pre-treatment)
• Complete blood count (CBC) with peripheral smear
• Coagulation Profile (prothrombin time [PT], activated partial
thromboplastin time [aPTT], fibrinogen)
• Chemistry profile, U/E/Crs, LFTs , Uric Acids, and,LDH
• Bone marrow aspiration and biopsy – Definitive diagnostic tests
• Cultures; in particular, blood cultures
• Chest radiography
• Chest computed tomography (CT) scan, as indicated by symptoms
• Multiple-gated acquisition (MUGA) scan or echocardiogram
• Lumbar puncture
• HIV,HBSAsg, CMV,EBV
• HLA -typing
10/29/2023 18](https://image.slidesharecdn.com/acutelymphoblasticleukemia-231029155121-22caadc3/75/Acute-Lymphoblastic-Leukemia-pptx-18-2048.jpg)
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Acute Lymphoblastic Leukemia.pptx
- 1. Acute Lymphoblastic Leukemia By DrHaja S Sovula Registrar 10/29/2023 1
- 2. Outline • Overview • Epidemiology •Etiology • Clinical Presentation • Classification and Staging • Diagnosis • Treatment • Summary • References 10/29/2023 2
- 3. Overview • Acute lymphoblasticleukaemia (ALL) is a heterogeneous hematologic disease characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. • Most common childhood malignancy. • Accounts 75%–80% of acute leukemias among children • Was first clearly described by 2 pathologists in 1845 • High complete remission rates ( 97%)and Five-Year survival rates (89%) in children (61%) AYA 10/29/2023 3
- 4. ACUTE LYMPHOBLASTIC LEUKEMIA EPIDEMIOLOGY •Most common leukemia in children. • Accounts for (1/3rd) of childhood Malignancies • 60% of ALL patients are diagnosed younger than 20 years of age. • Peak age 2-5yrs • Boys > girls • 2500-3500 new cases in the US annually • 3.4 cases per 100,000 • Greatest incidence in the US among Hispanics • Higher incidence in whites vs blacks 10/29/2023 4
- 5. Epidemiology contd •Incidence isgenerally low in Africa and a study in Kenya incidence of 1.2/100,000 (<15yrs) •1 case at our oncology unit (5 yr old M died) •ALL is 5 times commoner in children than AML 10/29/2023 5
- 6. Epidemiology contd •Identical twins,the risk to the • second twin if one twin develops leukemia is greater than that in the general population. •The risk is >70% if ALL is diagnosed in the first twin during the 1st yr of life and monochorionic • If the first twin develops ALL by 5-7 yr of age, the risk to the second twin is at least twice that of the general population, regardless of zygosity. •Other siblings 10/29/2023 6
- 7. ALL - ETIOLOGY •Atwo-step process of genetic mutation and exposure to infection play a prominent role. • The first step occurs in utero, when fusion gene formation or hyperdiploidy generates a covert, pre-leukemic clone. •The second step is the acquisition of secondary genetic changes that drive conversion to overt leukemia. •Only 1% of children born with a pre-leukemic clone progress to leukemia. 10/29/2023 7
- 8. ETIOLOGY • Children withcertain genetic and immunodeficiency syndromes are at increased risk: Down syndrome, Klinefilter syndrome, Neurofibromatosis type 1, Bloom syndrome, Fanconi anemia and ataxia telangiectasia. • 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. • Chemical toxins : exposure to high levels of benzene. 10/29/2023 8
- 9. ETIOLOGY Contd •Secondary ALLmay occur after certain chemotherapies ( eg, cyclophosphamide, etoposide doxorubicin) •Viruses : Some potential associations were identified between EBV and Burkitt-ALL ( Mature B- Cell ALL) HTLV-1 10/29/2023 9
- 10. Classification of ALL •FAB ( French-American-British) classification • Based largely on morphology • Little prognostic or therapeutic information to help guide treatment decisions. • WHO ( World Health Organization) classification • Revised in 2008,2016 • Discarded the FAB terms since morphological classification has no clinical or prognostic relevance. • Changed the classification to reflect increased understanding of the biology and molecular pathogenesis of ALL. 10/29/2023 10
- 11. WHO Classification ofB-lymphoblastic leukemia/lymphoma(WHO-HAEM5R) • B-lymphoblastic leukemia/lymphoma, NOS • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR- ABL1(fusion) • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);ETV6-RUNX1 • B-lymphoblastic leukaemia/lymphoma with ETV6::RUNX1-like features • B-lymphoblastic leukemia/lymphoma with hyperdiploidy 10/29/2023 11
- 12. WHO Classification ofB-lymphoblastic leukemia/lymphoma(5th Edition) • B-lymphoblastic leukemia/lymphoma with hypodiploidy • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3- IGH • B-lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3- PBX1 • B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like* • B-lymphoblastic leukemia/lymphoma with iAMP21* 10/29/2023 12
- 13. WHO Classification ofT-lymphoblastic leukemia/lymphoma • T-lymphoblastic leukaemia / lymphoma, NOS • Early T-precursor lymphoblastic leukaemia / lymphoma 10/29/2023 13
- 14. Clinical Presentation • Fever •Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion • Bleeding • Disseminated intravascular coagulation (DIC) at diagnosis (about 10% of cases) • Blood clots • Palpable lymphadenopathy 10/29/2023 14
- 15. Clinical Presentation • Bonepain (can be severe common in lower limbs) • Left upper quadrant fullness and early satiety due to splenomegaly (about 10% of cases) • Symptoms of leukostasis (eg, respiratory distress, altered mental status) • Kidney failure in patients with a high tumor burden • Infections, including pneumonia • Petechiae (particularly on lower extremities) and ecchymoses • Rashes from skin infiltration with leukemic cells 10/29/2023 15
- 16. Clinical Presentation (LessCommon) • Headache is uncommon (<5 percent of cases), but leukemia involving the central nervous system can present with • headache, vomiting, lethargy, nuchal rigidity, and, rarely, with cranial nerve abnormalities • Testicular enlargement is rare (<1 percent), • but painless unilateral testicular enlargement can be a presenting sign of ALL/LBL. • However, testicular involvement is present in up to 10 percent of boys with relapsed leukemia 10/29/2023 16
- 17. Clinical Presentation (LessCommon) • A mediastinal mass, which is most often associated with T-ALL/LBL, can cause superior vena cava (SVC) syndrome, which may manifest as pain, dysphagia, dyspnea, or swelling of the neck, face, and upper limbs due to obstruction the SVC. • Respiratory distress may result from a mass compressing the trachea. 10/29/2023 17
- 18. Diagnosis (Pre-treatment) • Completeblood count (CBC) with peripheral smear • Coagulation Profile (prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen) • Chemistry profile, U/E/Crs, LFTs , Uric Acids, and,LDH • Bone marrow aspiration and biopsy – Definitive diagnostic tests • Cultures; in particular, blood cultures • Chest radiography • Chest computed tomography (CT) scan, as indicated by symptoms • Multiple-gated acquisition (MUGA) scan or echocardiogram • Lumbar puncture • HIV,HBSAsg, CMV,EBV • HLA -typing 10/29/2023 18
- 19. Confirmatory Diagnosis • ALLis characterized by presence of immature cells – blast cells • of >20% in the -blood picture -bone marrow examination • A negative myeloperoxidase (MPO) stain and a positive and terminal deoxynucleotidyl transferase (TdT) is the hallmark of the diagnosis of most cases of ALL 10/29/2023 19
- 20.
- 21. Acute lymphoblastic leukemia(ALL), peripheral blood of a child, Pappenheim stain, magnification x100 10/29/2023 21
- 22. Diagnosis contd • Thepolymerase chain reaction (PCR) • Fluorescence in situ hybridization(FISH) (to pinpoint molecular genetic abnormalities & can be used to detect small numbers of malignant cells at diagnosis as well as during follow-up.) • DNA microarray ( helps analyze the expression of thousands of genes in the leukemic cell. This technique promises to further enhance the understanding of the fundamental biology and to provide clues to the therapeutic approach of ALL.) • Flow cytometry helps to distinguish B-ALL from T-ALL. 10/29/2023 22
- 23.
- 24. Phenotypically Based on surfacemarkers ALL derived from • B lineage (85 percent), B-lymphoblastic leukemia • T lineage ( 15 percent), T-lymphoblastic leukemia • Mature B cells(1 percent) Burkitt leukemia 10/29/2023 24
- 25.
- 26. Key Terminology intreatment • Complete Remission : Criteria for CR include: • Evidence of eradication of detectable leukemia cells • ≤ 5% blasts present in the bone marrow. • Evidence of normal Bone marrow recovery ( at least > 25% bone marrow cellularity) • platelet count ≥ 100 x 109/L • neutrophil count ≥ 1 x 109/L. • Minimal Residual Disease (MRD): Refers to residual leukemic cells that remain following the achievement of CR, but are below the limits of detection using conventional morphologic assessment. 10/29/2023 26
- 27. RELAPSE • Reappearance ofblast at any site in the body after initial remission during chemotherapy or after completing chemo. • Marrow relapse-poor outcome (15-20%) • Hyper CVAD regimen • Allogenic BM transplant • CNS relapse –(<5%) • Triple IT –alternate days till CSF clears, then twice weekly 6 doses. then one dose every week 6 doses. • cranial irradiation • Testicular relapse -chemotherapy plus b/l testicular radiation 10/29/2023 27
- 28. Risk-directed therapy • isthe standard of current ALL treatment and accounts • for age at diagnosis, initial WBC count, immunophenotypic and cytogenetic characteristics of blast populations, rapidity of early treatment response and assessment of Minimal Residual Disease MRD at the end of induction therapy. • Pt are categorised as having • STANDARD RISK- age 1-10 yr and a leukocyte count<50,000/µL are used by the National Cancer Institute (NCI) • High RISK- Children who are younger than 1 yr or older than 10 yr or who have an • initial leukocyte count of >50,000/µL are considered to be high risk. 10/29/2023 28
- 29.
- 30. Prognostic Factors contd •Characteristics that adversely affect outcome include T-cell immunophenotype or a slow response to initial therapy. • Chromosomal abnormalities, including hypodiploidy, the Philadelphia chromosome, and KMT2A (MLL) gene rearrangements, mutation in IKZF1 portend a poorer outcome. • More favourable characteristics include a rapid response to therapy, hyperdiploidy, trisomy of • specific chromosomes (4, 10, and 17), and rearrangements of the ETV6-RUNX1. 10/29/2023 30
- 31. ALL: TYPICAL TREATMENT 10/29/202331 Induction Consolidation Maintenance Over a period of months 2-3 years CNS Prophylaxis (IT-MTX) • Primary objective : to achieve and maintain a complete remission (CR) • Induction, consolidation, maintenance phases • CNS prophylaxis with IT-MTX during induction and consolidation phases
- 32. Remission induction • isdesigned to eradicate the leukemic cells from the bone marrow. • 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. • CALGB ALL : used in high-risk pediatric ALL, mostly AYA. Uses five drugs – cyclophosphamide, daunorubicin, Vincristine, prednisone and L- asparaginase in induction for 4 weeks. • HyperCVAD : combination of hyperfractionated cyclophosphamide, vincristine, Adramycin (doxorubicin) and dexamethasone alternating with high-dose methotrexate and high-dose cytarabine – 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. • Kasili Protocol: Vincristine, doxorubicin,prednisone, IT MTX (induction) Cytarabine, cyclophosphamide in Consolidation 10/29/2023 32
- 33.
- 34. Prognosis • The outcomefor patients at higher risk can be improved by administration of more intensive therapy despite the greater toxicity of such therapy. • Infants with ALL, along with patients who present with specific chromosomal abnormalities, such as t(4;11), have an even higher risk of relapse despite intensive therapy. • Higher levels of MRD present at the end of induction suggest a poorer prognosis and higher risk of subsequent relapse. MRD of >0.01% on the marrow on day 29 of induction is a significant risk factor for shorter event-free survival for all risk categories, compared with patients with negative MRD. 10/29/2023 34
- 35. Imatinib • Imatinib isan agent specifically designed to inhibit the BCR-ABL kinase resulting from the translocation • The poor outcome of Philadelphia chromosome–positive ALL with t(9;22) has been dramatically changed by the addition of imatinib to an intensive chemotherapy backbone. • With this approach, the event-free survival has improved from 30% to 70%. • For patients with CD20 positive B-lymphoblastic leukemia, rituximab can be added 10/29/2023 35
- 36. Nelarabine • Current therapiesfor T-cell acute lymphoblastic leukemia (ALL) produce high responses, but approximately one half of patients will relapse within 2 years. • Nelarabine demonstrates antineoplastic activity in patients with relapsed/refractory T-cell ALL. The Cancer and Leukemia Group B, nelarabine treatment produced complete remission rates of 26% with minimal toxicities in relapsed/refractory ALL patients. 10/29/2023 36
- 37. Supportive Therapy • Cytopenias: All patients treated with traditional induction will develop cytopenias which may require intervention. Transfusion support : Platelets and Packed red cell transfusion when necessary. • Prevention of Tumor Lysis Syndrome ( Risk highest in Burkitt-ALL and T-Cell ALL) • Intravenous hydration • Allopurinol • Rasburicase • Correction of electrolyte disturbances (Hypocalcemia, Hyperphospahtemia) • Antibiotic Prophylaxis while on aggressive chemotherapies : 10/29/2023 37
- 38. Complications following Treatmentof ALL • Late complications of therapy • Brain tumors (cerebral irradiation) • Secondary AML from topoisomerase inhibitors and alkylating agents • Cardiomyopathy (anthracyclines) • Osteoporosis/Osteonecrosis (corticosteroids) • Growth disturbances • Thyroid dysfunction (cranial irradiation) • Obesity (uncertain etiology) • Neuropsychiatric disturbances and seizures (IT MTX and cranial irradiation) • Emotional problems 10/29/2023 38
- 39. In Conclusion • Acutelymphoblastic leukemia (ALL) is the most common cancer in children but also occurs in adults. • Can either B/T lymphoblastic leukemia • WHO classification predominantly used. • Treatment involves 3 phases can last 2-3yrs • Central nervous system (CNS) involvement is common; most patients receive intrathecal chemotherapy and corticosteroids and sometimes CNS radiation therapy. • Response to treatment is good in children, with cure possible in > 80% of children but in < 50% of adults. • Repeat induction chemotherapy, immunotherapy, and stem cell transplantation may be helpful for relapse. 10/29/2023 39
- 40.
- 41. References • Nelson’s paediatrics21st edition • Medscape • Up to date • https://www.nature.com/articles/s41375-022-01620-2 • https://www.msdmanuals.com/professional/hematology-and- oncology/leukemias/acute-lymphoblastic-leukemia-all • http://erepository.uonbi.ac.ke/bitstream/handle/11295/28663/Agwa ta_ 10/29/2023 41
Editor's Notes
- #4 German –Rudilf Virchow and Britsh John Bennet. The SEER database cure rates and survival outcomes for pediatric patients with ALL have improved dramatically over the past several decades. Improvements are largely due to advances in the understanding of the molecular genetics and pathogenesis of the disease, the incorporation of risk-adapted therapy, the advent of new targeted agents, and the use of allogeneic hematopoietic stem cell transplantation (HSCT). Analyses from the SEER database have shown improvements in survival for children and adolescent and young adult (AYA) patients, with 5-year overall survival (OS) rates of 89% and 61%, respectively.
- #5 The incidence varies worldwide but this may be influenced, in part, by diagnostic and reporting difference
- #6 The incidence varies worldwide but this may be influenced, in part, by diagnostic and reporting difference
- #8 Etiology is generally unknown , however genetic n environmental factors are associated with childhood leukemia .Most cases of ALL are thought to occur due to a 2 step
- #9 Trisomy 21, Males with etra x chro, mutatation in neurofibrin , mutations in the BLM gene , is a rare inherited bone marrow failure syndromes. a rare genetic condition that targets the nervous system, immune system and other systems
- #10 HTLV-1 is implicated in Adult T-cell leukemiaS
- #11 Classification of ALL depends on characterizing the malignant cells in the bone marrow to determine the morphology, phenotype as measured by cell membrane markers, and cytogenetic and molecular genetic features.
- #12 NOS NOT OTHERWISE SPECIFIED. In addition, newly added from 4th edition in green. Those with translocation now fusion. The classification based on these groups remains largely unchanged from WHO-HAEM4R; however, the nomenclature focuses on the molecular events rather than cytogenetic alterations, to allow for the application of differing techniques for their detection
- #13 Red they have distinct genetic signatures that are associated with adverse prognosis
- #14 NK-lymphoblastic leukaemia/lymphoma has been deleted as an entity it used to be part of 4th edition classification
- #15 Typical onset of clinical symptoms of ALL is rapid. Symptoms reflect bone marrow failure or leukemic infiltration of extramedullary sites. Fever is one of the most common signs of ALL, and patients with ALL often have fever without any other evidence of infection. However, in these patients, one must assume that all fevers are from infections until proved otherwise, because a failure to treat infections promptly and aggressively can be fatal. Typical lymphadenopathy associated with ALL/LBL is nontender, firm, rubbery, and matted. neutropropenia
- #16 Young children with bone pain may present with a limp or refusal to bear weight . Leco = >50-10x109 Infiltration of the marrow by massive numbers of leukemic cells frequently manifests as bone pain. This pain can be severe and is often atypical in distribution. About 10-20% of ALL patients may present with left upper quadrant fullness and early satiety due to splenomegaly. Although patients may present with symptoms of leukostasis (eg, respiratory distress, altered mental status) because of the presence of large numbers of lymphoblasts in the peripheral circulation, leukostasis is much less common in people with ALL than those with acute myelogenous leukemia (AML), and it occurs only in patients with the highest WBC counts (ie, several hundred thousand per μL). Patients with a high tumor burden, particularly those with severe hyperuricemia, can present in renal failure.
- #19 It is important that thorough hx n examination is done n all studies necessary to confirm a diagnosis and adequately classify the type of leukemia be performed before treatment as this would help with prognostication checking remission etc Cardiac evaluation – Echocardiogram or cardiac scan should be performed to assess cardiac function in anticipation of treatment that includes an anthracycline. Some experts perform HLA typing in the event that hematopoietic cell transplantation will be required for later management. ●CT of chest – For patients who are diagnosed with T-ALL/LBL, a CT scan of the chest, with contrast if possible, should be performed to evaluate the presence of a mediastinal mass.All children who are diagnosed with ALL/LBL must undergo a lumbar puncture (LP) prior to beginning therapy to evaluate potential leukemic involvement of the central nervous system (CNS) and concomitantly administer the first dose of intrathecal therapy, as described separately.
- #21 Features of blast cells very high N:C ratio ,large cells with large nuclei absence of cytoplasmic granules presence of round or convoluted nuclei
- #27 These subclinical levels of residual leukemia are thought to be responsible for relapse after initial disease response.
- #28 Triple IT (Methotrexate/Hydrocortisone/Cytarabine) Chimeric antigen receptor (CAR) T-cell technology will have an increasing role in the treatment of patients who have experienced a relapse of ALL CNS HAS DECREASES TO LESS THAN 5% SINECE COMMENCEMENT OF PROPHYLACTIC CNS THERAPY
- #31 IKZF1 gene, have been shown to be associated with a poor prognosis and may become important in treatment algorithms in the future
- #32 single most important prognostic factor in ALL is the treatment: without effective therapy, the disease is fatal
- #33 Berlin-Frankfurt-Münster. (Cancer and leukemia group B) Hyper Cvd for highly aggressive Newer modifications of the hyper-CVAD regimen include the addition of a tyrosine kinase inhibitor in patients whose leukemia is Ph+, and of rituximab in patients whose leukemia is CD20 positive Both of these approaches have resulted in improvements in disease-free survival.
- #35 Infants younger than age 12 months with 11q23 abnormalities are at high risk of CNS relapse but because of their young age are usually treated without cranial irradiation, using intensified systemic and intrathecal chemotherapy to treat the CNS.
- #37 How ever a recent trial of 28 pediatric patients with relapsed or refractory T-ALL who were treated with single-agent nelarabine, the overall response rate was 39.3% (cited Zwaan et al. as referen state that the combination of nelarabine, cyclophosphamide, and etoposide has also been used in patients with relapsed or refractory T-ALL, with response rates comparable to single-agent nelarabine