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Acute Lymphoblastic Leukemia (ALL)
Acute Lymphoblastic Leukemia (ALL) is a cancer of the lymphatic system that most often affects children. It is diagnosed based on bone marrow morphology and immunophenotyping. Treatment involves intensive chemotherapy based on pediatric protocols including steroids, vincristine, asparaginase, and methotrexate, along with central nervous system prophylaxis and monitoring of minimal residual disease. Outcomes have improved with targeted therapies for high-risk features and relapses, though relapsed ALL still carries a poor prognosis. Long-term effects of intensive treatment require ongoing monitoring.
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Acute Lymphoblastic Leukemia (ALL)
- 1. Acute Lymphoblastic Leukemia (ALL) DR.SUBHASH THAKUR CLINICAL ONCOLOGIST, CMC
- 2. Definition oAcute Lymphoblastic Leukemia: oMostcommon Leukemia oMost common cancer in children oMore immature Lymphoid Lineage Cells
- 3. Common In RiskFactors a. Antineoplastic agents b. Ionizing Radiation c. Hodgkins Lymphoma d. Benzene e. Multiple Myeloma Down Syndrome (Trisomy 21)
- 4. oALL is amalignant disease of precursor cells of the lymphatic system oDefined by more than 25% infiltration of the bone marrow with lymphatic blast cells oPhysiological B and T Cell lymphopoiesis is disrupted by the malignant event, and immature blasts accumulate Lymphoblast Proliferate and a. Replace most of bone marrow b. Enter the peripheral blood: Leukostasis c. Metastasize throughout the body: Liver, Spleen, Testis
- 6. ALL ischaracterized by small- to medium-sized leukemic blasts. The cytoplasmic rim tends to be basophilic. Lymphoblasts a. No granules b. Increased N/C ratio c. Scanty Cytoplasm d. Less prominent nucleoli
- 7. Essential diagnostic proceduresin ALL oConfirmation of diagnosis: ◦ • Cytomorphology, immunophenotyping o Identification of risk factors: ◦ • Cytogenetics / molecular genetics oIdentification of therapy targets: ◦ • CD19, CD20, CD22, CD33, CD52 ◦ • BCR-ABL ◦ • Establishment of MRD (minimal residual disease) assay ◦ • Biobanking
- 8. oImmunophenotype is subdividedinto T and B Cells o Seventy-five percent of cases are B-precursor ALL oEach phenotype is associated with distinct cytogenetic and molecular aberrations and clinical features oThe most frequent cytogenetic aberration is the translocation t(9;22) with the corresponding fusion gene BCR-ABL, which occurs in B-precursor ALL only, with an overall incidence of 25%– 50%, depending on age
- 10. Unfavorable Prognostic Factors oConsiderBMT oAge>60 years oWBCs>100,000 oMature B or early T Cell type oPhiladelphia +, t(9:22) ot(4:11), MLL-AF4 fusion gene oALL is not a uniform disease but shows differences in outcome, defined by prognostic factors ranging from 30%–40% for high-risk B-precursor and T cell ALL (T-ALL) to 60%–70% for standard-risk B cell ALL (B-ALL) and T-ALL, and 70%–80% for mature B-ALL. The relevance of prognostic factors depends on the treatment protocol. oClinical and genetic prognostic factors can be identified at diagnosis, and potential criteria are different for Band T-precursor A
- 11. oAge is ahighly relevant prognostic factor in all subgroups of ALL. With increasing age, the incidence of poor prognostic factors increases, and therapy is less well tolerated. Patients are at increased risk of early mortality, mortality in remission, and relapse. oResponse to treatment is essential for prognosis. Prognosis is poor in patients without complete response (CR) after induction and/or with persistent MRD. oMRD is defined as the persistence of leukemic blasts below the detection level of microscopy (5%).
- 12. Definition of CRin bone marrow • Complete hematological remission: <5% blasts • MRD: 1% to 0.01% blasts • Complete molecular remission: <0.01% blasts
- 13. oPatients who donot achieve a negative MRD status (MRD failure) or show newly detected MRD during treatment (MRD relapse) have a high risk for relapse despite continued treatment oPrognostic factors relevant for treatment decisions: • Age-adapted therapy • Intensified therapy with stem cell transplantation (SCT) • Utilization of targeted and experimental drugs
- 14. Clinical presentation andsupportive care oALL is often associated with a rapid deterioration of the general condition. oSymptoms are usually unspecific: ◦ fatigue due to anemia, ◦ bleeding due to thrombocytopenia, ◦ infections due to granulocytopenia. ◦ Bone pain may also occur. Additional symptoms may occur, due to infiltration of organs. oT-ALL patients frequently show mediastinal tumors, whereas patients with mature B-ALL show other organ involvement
- 16. Mediastinal tumors canlead to emergency situations with dyspnea and upper venous compression.
- 17. oTo diagnose ALL,a bone marrow aspirate is necessary. Sufficient material for different diagnostic procedures should be obtained. oAnalysis of cerebrospinal fluid (CSF) is an essential part of the initial workup. In ALL, it should be associated with first intrathecal prophylaxis, usually consisting of methotrexate (MTX) or a combination of MTX, cytarabine, and steroids. oAdvice for fertility preservation should be offered in all applicable cases
- 18. Most ALL patientsshow cytopenias of different lineages and immature lymphatic blasts in the peripheral blood. The absence of blast cells and normal blood counts do not exclude ALL
- 19. Supportive Therapy Supportive therapyshould be started at first diagnosis, including hydration, tumor lysis prophylaxis, and infection prophylaxis.
- 20. Initial workup inALL includes oclinical assessment and anamnesis, ocomorbidity scoring, olaboratory analysis including CSF examination, omicrobial assessments, oimaging procedures for extramedullary involvement, ocardiac function testing, oHLA (human leukocyte antigen) typing for potential bone marrow donors.
- 21. Treatment of newlydiagnosed ALL oMost successful treatment protocols are based on pediatric treatment strategies. oProtocols are adapted for adult patients in order to improve tolerability. oMature B-ALL is treated like Burkitt’s lymphoma. A. First Stabilize then: o Induction o Consolidation followed by maintenance o CNS Prophylaxis
- 22. Stabilize the Patient a.Thrombocytopenia: Platelet transfusion b. Fever and granulocytopenia: blood culture + antibiotics c. Leukostasis: Leukapheresis d. Prevent tumor Lysis Syndrome: hydrate and allopurinol
- 23. Induction Target: to reduceblast cells to an undetectable level and restore normal marrow function Prednisolone, Vincristine, Daunorubicin and L-Asparaginase Consolidation High dose methotrexate, Cyclophosphamide and Cytarabine Maintenance 6-Mercaptopurine and Methotrexate (Low dose)
- 24. Prophylaxis for CNSand testes Intrathecal methotrexate +/- Cranial Irradiation Ph+ ALL : TKI: Imatinib
- 25. ALL outcome ismost favorable in children and young adults. In older patients, the incidence of early mortality increases significantly
- 26. ALL treatment consistsof several cycles of combination therapies accompanied by intrathecal therapy for central nervous system (CNS) relapse prophylaxis.
- 27. CNS relapse prophylaxisis essential in ALL. oIt consists of ointrathecal therapy, osystemic high-dose therapy (MTX, cytarabine), and, oin several protocols, CNS irradiation.
- 28. Targeted therapies areadded to chemotherapy (ChT) if possible. The most important approaches are: imatinib in BCR-ABL-positive ALL and rituximab in CD20- positive ALL
- 29. SCT is anessential part of ALL management. Outcomes are similar for matched siblings and matched unrelated donors. Mortality increases with age oMost study groups establish a risk-based indication for SCT: high-risk prognostic factors, persistent MRD and any situation after relapse
- 30. Treatment of relapseand aftercare oRelapse in ALL is an emergency. For optimal management, extramedullary involvement, subtype, potential target structures, previous remission duration, and prior treatment must be considered. oALL at relapse has a poor prognosis with remission rates of only 40% for first salvage and a median survival of 6 months.
- 31. The goal ofrelapse therapy is to achieve a CR including MRD response and to offer an SCT. Continuous MRD assessment gives the opportunity to detect upcoming relapse and treat earlier. The incidence of SCT in CR after first salvage was 28% in one international trial. SCT in CR offers a chance of cure in relapsed ALL
- 32. Early relapses duringongoing treatment and refractory relapses show profound ChT resistance. Alternative, targeted therapies should be considered. Due to the low incidence of molecular targets in ALL, immunotherapies are the most important new compounds under development for ALL.
- 33. In randomised trials,conjugated antibodies to CD22 such as inotuzumab or bispecific antibodies to CD19 such as blinatumomab showed superior CR rates and survival compared with standard of care.
- 34. Immunotherapies in ALLinclude antibodies and genetically modified chimeric antigen receptor T cells (CAR-T cells). CD19 and CD22 are the preferred surface target
- 35. Increasing cure ratesraise the focus on patient aftercare. Patients should be screened for long-term effects such as ◦ immune dysfunction, ◦ neuropsychological disorders, ◦ endocrine disorders or aseptic bone necrosis.
- 36. Complications of ALLTreatment ALL: high cell turn over: ◦ Folate deficiency ◦ Increased uric acid ◦ Increased potassium ◦ Increase phosphate Chemotherapy ◦ Tumor Lysis Syndrome: increased K+ , increased uric acid, increase phosphate Intrathecal Methotrexate ◦ Neurocognitive disorders Radiation ◦ To testis: infertility, consider sperm banking ◦ To CNS: neurocognitive disorders
- 37. Prevention oSupplementing Folic acidduring pregnancy
- 38. Summary: • Diagnosis ofALL is based on morphology, immunophenotyping, cyto- and molecular genetics • Intensified ChT based on pediatric protocols is possible in adults and leads to improved survival • Treatment compliance is essential; the most important drugs are steroids, vincristine, asparaginase, high-dose MTX, and maintenance therapy with mercaptopurine/MTX • MRD assessment should be performed in all patients since MRD persistence or recurrence is the most relevant poor prognostic factor • Targeted treatment with tyrosine kinase inhibitors in BCR-ABL-positive ALL or rituximab in CD20-positive ALL has improved prognosis
- 39. • Patients withhigh-risk features are candidates for an SCT, depending on the protocol • Relapsed patients have a poor prognosis, but new immunotherapies yield superior response and survival rates compared with standard ChT • ALL should be treated in specialized centers • With improving outcomes, patients should be screened for long-term effects of treatment