ACUTE LEUKEMIA HABtemu motbY - Copy.pptx

acute leukemia

1. BY:DR Habtamu M.(R1) MODERATOR:DR.Tamiru.A (MD, Ass professor) ACUTE LEUKEMIA 3/15/2022 acute leukemia 1

2. Outlines Introduction Epidemiology Etiology Clinical manifestation Diagnosis Management prognosis References 3/15/2022 acute leukemia 2

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5. Leukemia Is hematologic malignancy with primary involvement of bone marrow and blood by clonally derived myeloid or lymphoid linage cells These leukemias comprise a spectrum of malignancies that, untreated, range from rapidly fatal to slowly growing. The course of leukemias may vary from a few days or weeks to many years. Some hematologic malignancies can change their phenotype with time. This clonal evolution model of cancer development involves gain of function of oncogenes and loss of function of tumor suppressor genes that cooperate to induce fulminant disease Based on their untreated course, the myeloid leukemias have traditionally been designated acute or chronic Introduction definition 3/17/2022 acute leukemia 5

6. Con Introduction definition Leukemias; traditionally classified into four main groups: Acute lymphoblastic leukemia/ALL (includes T cell, B cell, and Null cell) Acute myeloid leukemia/AML includes myeloblastic, promyelocytic, monocytic, myelomonocytic, erythrocytic, and megakaryocytic Chronic lymphocytic leukemia/CLL Chronic myeloid leukemia/CML The incidence of leukemias of all types in the population is approximately 10/100 000 per annum. The relative incidence of the four categories in western populations AML=46% CLL=29% CML=14% ALL=11% 3/15/2022 acute leukemia 6

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8. The incidence of acute myeloid leukemia (AML) is ~3.5 per 100,000 people per year And the age-adjusted incidence is higher in men than in women (4.3 vs 2.9). AML incidence increases with age; 1.7 in individuals aged <65 years and 15.9 in those aged >65 years. In 2016, the estimated number of new AML cases in the United States was 19,950, comprising ~1.2% of all cancer cases. AML is the most common acute leukemia in older patients, with a median age at diagnosis of 67 years . Long-term survival is infrequent; U.S. registry data report that only 27% of patients survive 5 years. AML Incidence 3/15/2022 acute leukemia 8

9. Most cases of AML are idiopathic The following have been implicated in the development of AML Genetic predisposition, radiation chemical/other occupational exposures, and drugs have been implicated in the development of AML AML cases with established etiology are relatively rare. No direct evidence suggests a viral etiology. Etiology 3/15/2022 acute leukemia 9

10. Germline mutations associated with increased risk of developing a myeloid neoplasm include CEBPA , DDX41 , RUNX1 , ANKRD26 , ETV6 , and GATA2 . myeloid neoplasms with germline predisposition are a feature of several well-described clinical syndromes, including bone marrow failure disorders (e.g., Fanconi anemia, Shwachman -Diamond syndrome, Diamond- Blackfan anemia), telomere biology disorders (e.g., dyskeratosis congenita). Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and ataxia-telangiectasia Congenital neutropenia ( Kostmann syndrome) Myeloproliferative d/ rs can also evolve into AML Certain syndromes with somatic cell chromosome aneuploidy Eg. Trisomy 21 noted in Down syndrome Etiology Genetic Predisposition 3/15/2022 acute leukemia 10

11. Down syndrome–associated AML in young children (<4 years) is typically of the acute megakaryocyticsubtype and is associated with mutation in the GATA1 gene. Such patients have excellent clinical outcomes but require dose modification of chemotherapy due to high treatment-related toxicities . Inherited diseases with defective DNA repair (e.g., Fanconi anemia, Bloom syndrome, and ataxia- telangiectasia ) are also associated with AML. Each syndrome is associated with unique clinical features and atypical toxicities with chemotherapy, requiring expert care. Congenital neutropenia ( Kostmann syndrome), due to mutations in the genes encoding the granulocyte colony-stimulating factor receptor and neutrophil elastase , is another disorder that may evolve into AML 3/15/2022 acute leukemia 11

12. drugs are the leading cause of therapy-associated AML. Alkylating agent–associated leukemias occur on average 4–6 years after exposure affected individuals often have multilineage dysplasia and monosomy/ aberrations in chromosomes 5 and 7. Topoisomerase II inhibitor– associated leukemias occur 1–3 years after exposure, and affected individuals often have AML with monocytic features and aberrations involving chromosome 11q23. Exposure to ionizing radiation, benzene, chloramphenicol, phenylbutazone, and other drugs can uncommonly result in bone marrow failure that may evolve into AML. Smoking ,Exposure to petroleum products, paint, ethylene oxide, herbicides, and pesticides Radiation High-dose radiation, like that experienced by survivors of the atomic bombs in Japan or nuclear reactor accidents These increase the risk of myeloid leukemias that peak 5–7 years after exposure. Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people also exposed to alkylating agents Chemical, Radiation, and Other Exposures Anticancer 3/15/2022 acute leukemia 12

13. FAB Vs WHO Classifications FAB criteria Morphology Cytochemistry WHO criteria Clinical feature Morphology Immunophenotyping Genetic features Karyotyping Molecular testing 3/15/2022 acute leukemia 13

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19. Marrow (or blood) blast count of ≥20% is required to establish the diagnosis of AML, except for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv (16), or t(16;16). In contrast to the previously used French-American-British (FAB) schema , the WHO classification places limited reliance on cytochemistr 3/15/2022 acute leukemia 19

20. Gum infiltration is also characteristic of acute monocytic leukemia ( AMoL )- Leukemia cutis manifesting as subcutaneous nodules 3/15/2022 acute leukemia 20

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22. Once the diagnosis of AML is suspected, a rapid evaluation and initiation of appropriate therapy should follow clarifying the subtype of leukemia evaluate the overall functional integrity of the major organ systems, including the cardiovascular, pulmonary, hepatic, and renal systems. cytogenetics and molecular markers Leukemic cells should be obtained from all patients and cryopreserved All patients should be evaluated for infection Replacement of the appropriate blood components, if necessary, should begin promptly About 50% of patients have a mild to moderate elevation of serum uric acid at presentation so rx hyperurecemia Pretreatment Evaluation 3/15/2022 acute leukemia 22

23. Prognosis of aml Prognostic Factors include Pretreatment Factors Presence of clinically significant residual disease Age the multidrug resistance 1 (MDR1) efflux pump Duration of symptoms before diagnosis High presenting WBC count Cytogenetics and/or molecular genetic aberrations t(15;17)- Very good prognosis (~85% cured) t(8;21) & inv(16)- Good prognosis (~55% cured) No cytogenetic abnormality- Moderately favorable outcome (approximately 40% cured) Complex karyotype, t(6;9), inv(3), or -7 have a very poor prognosis than those requiring multiple cycles Cytogenetics and/or molecular genetic aberrations For those patients lacking prognostic cytogenetic abnormalities, utilizes molecular genetic abnormalities. Favorable prognosis NPM1 mutations without concurrent presence of FLT3-ITD CEBPA mutations, especially if concurrently present in two different alleles, have been shown to predict favorable outcome Poor prognosis FLT3-ITD predicts poor outcome . Treatment Factors Achievement of CR. Patients who achieve CR after one induction cycle have longer CR durations 3/15/2022 acute leukemia 23

24. Many factors influence the likelihood of entering CR, the length of CR, and the curability of AML. Following administration of therapy, achievement of CR is associated with better outcome and longer survival CR is defined after examination of both blood and bone marrow. Neutrophil count > 1000/ μ L Platelet count > 100,000/ μ L. Hemoglobin concentration is not considered in determining CR. Circulating blasts should be absent . While rare blasts may be detected in the blood during marrow regeneration, they should disappear on successive studies. The bone marrow should contain <5% blasts, and Auer rods should be absent . Extramedullary leukemia should not be present Prognostic Factors 3/15/2022 acute leukemia 24

25. SUPPORTIVE CARE ANTI-LEUKEMIC THERAPY SUPPORTIVE CARE Treatment or prevention of metabolic and infectious complications Rational use of blood products Other therapies Use of indwelling catheters, Amelioration of nausea and vomiting, Pain control, and Continuous psychosocial support for the patient and family Treatment of Aml 3/15/2022 acute leukemia 25

26. Blood Products Adequate and prompt blood bank support is critical to therapy of AML Platelet transfusions should be given as needed to maintain a platelet count ≥10,000/ μ L. The platelet count should be kept at higher levels in febrile patients and during episodes of active bleeding or DIC Patients with poor posttransfusion platelet count increments may benefit from administration of platelets from HLA-matched donors. RBC transfusions To keep the hemoglobin level >70–80 g/L (7–8 g/dL) in the absence of active bleeding, DIC, or congestive heart failure, which require higher hemoglobin levels. Blood products leukodepleted by filtration should be used to avert or delay alloimmunization as well as febrile reactions. Blood products should also be irradiated to prevent transfusion-associated GVHD. Cytomegalovirus (CMV)-negative blood products should be used for CMV-seronegative patients who are potential candidates for allogeneic HSCT . Leukodepleted products are also effective for these patients if CMV-negative products are not available Treatment- Supportive Care 3/15/2022 acute leukemia 26

27. Prophylactic agents Neutropenia (neutrophils <500/ μL or <1000/ μL and predicted to decline to <500/ μL over the next 48 h) can be part of the initial presentation and/or a side effect of the chemotherapy treatment in AML patients. Thus, infectious complications remain the major cause of morbidity and death during induction and postremission chemotherapy for AML Antibacterial (i.e., quinolones) and antifungal (i.e., posaconazole ) prophylaxis in the absence of fever is likely to be beneficial especially in conjunction with regimens that cause mucositis, is beneficial . For patients who are herpes simplex virus or varicellazoster seropositive , antiviral prophylaxis should be initiated (e.g., acyclovir, valacyclovir). Treatment of Infections Fever develops in most patients with AML, but infections are documented in only half of febrile patients. Early initiation of empirical broad-spectrum antibacterial and antifungal antibiotics has significantly reduced the number of patients dying of infectious complications* Caspofungin (or a similar echinocandin), voriconazole, or liposomal amphotericin B should be considered for antifungal treatment if fever persists for 4–7 days following initiation of empiric antibiotic therapy Treatment- Supportive Care 3/15/2022 acute leukemia 27

28. The most commonly used CR induction regimens (for patients other than those with APL) consist of combination chemotherapy with cytarabine and an anthracycline. Cytarabine is a cell cycle S-phase–specific antimetabolite that becomes phosphorylated intracellularly to an active triphosphate form that interferes with DNA synthesis. Anthracyclines are DNA intercalators . Their primary mode of action is thought to be inhibition of topoisomerase II, leading to DNA breaks. Cytarabine is usually administered as a continuous intravenous infusion for 7 days Anthracycline therapy generally consists of daunorubicin intravenously on days 1, 2, and 3 (the 7 and 3 regimen) Treatment with idarubicin for 3 days in conjunction with cytarabine by 7-day continuous infusion is at least as effective as daunorubicin in younger patients The addition of etoposide may improve the CR duration. When combined with cytarabine in a 7 and 3 regimen, a higher dose of anthracycline (i.e., daunorubicin 90 mg/m 2 ) improves outcome compared with a lower dose (i.e., daunorubicin 45 mg/m 2 ) Treatment- Induction 3/15/2022 acute leukemia 28

29. A dose-response effect for cytarabine in patients with AML who were aged < 60 years was demonstrated High-dose cytarabine significantly prolonged CR and increased the fraction cured in patients with favorable [t(8;21) and inv(16)] and normal cytogenetics, but it had no significant effect on patients with other abnormal karyotypes. For older patients, exploration of attenuated intensive therapy that includes either chemotherapy or reduced-intensity allogeneic HSCT has been pursued. Postremission therapy is a setting for introduction of new agents Allogeneic HSCT is used in patients ages <70–75 years with an HLA-compatible donor who have high-risk cytogenetics. high-risk molecular features such as FLT3 -ITD, allogeneic HSCT is best applied in the context of clinical trials, as the impact of aggressive therapy on outcome is unknown. Relapse following allogeneic HSCT occurs in only a small fraction of patients, but treatment-related toxicity is relatively high; complications include venoocclusive disease, GVHD, and infections. Treatment- Post- Remissison Therapy 3/15/2022 acute leukemia 29

30. Class of Drugs Examples of Agents in Class Tyrosine kinase inhibitors PKC412, MLN518, SU11248, CHIR-258, imatinib (STI571, Gleevec), dasatinib, AMN107 Demethylating agents Decitabine, 5-azacytidine Histone deacetylase inhibitors Suberoylanilide hydroxamic acid (SAHA), MS275, LBH589, valproic acid Heavy metals Arsenic trioxide Farnesyl transferase inhibitors R115777, SCH66336 HSP-90 antagonists 17-allylaminogeldanamycin (17-AAG), DMAG, or derivatives Cell cycle inhibitors Flavopiridol, CYC202 (R-Roscovitine), SNS-032 Nucleoside analogues Clofarabine, troxacitabine Humanized antibodies Anti-CD33 (SGN33), anti-KIR Toxin-conjugated antibodies Gemtuzumab ozogamicin Proteasome inhibitors Bortezomib Aurora inhibitors AZD1152, MLN-8237, AT9283 Immunomodulatory Lenalidomide , IL-2, histamine dihydrochloride 3/15/2022 acute leukemia 30

31. Autologous HSCT can be administered in young and older patients and uses the same preparative regimens. Patients subsequently receive their own stem cells collected while in remission. The toxicity is relatively low with autologous HSCT (5% mortality rate), but the relapse rate is higher than with allogeneic HSCT, due to the absence of the graft-versus-leukemia (GVL) effect seen with allogeneic HSCT and possible contamination of the autologous stem cells with residual tumor cells. Trials comparing allogeneic HCT with intensive chemotherapy or autologous HCT have shown improved duration of remission with allogeneic HCT. However, the relapse risk reduction that is observed with allogeneic HCT is partially offset by the increase in fatal Treatment- Post- Remissison Therapy 3/15/2022 acute leukemia 31

32. In patients who relapse after achieving CR, the length of first CR is predictive of response to salvage chemotherapy treatment; Early first relapse (<12 months) Poor outcome It is justified (for patients without HLA-compatible donors) to explore innovative approaches, such as new drugs or immunotherapies Longer first CR (>12 months) Generally relapse with drug-sensitive disease Have a higher chance of attaining a CR. Cure, however, is uncommon Treatment with novel approaches should be considered if allogeneic HSCT is not possible. Similar to patients with refractory disease, patients with relapsed disease are rarely cured by salvage chemotherapy treatments Therefore, patients who eventually achieve a second CR and are eligible for allogeneic HCT should be transplanted. However, there is no consensus on optimal treatment for patients who relapse after allogeneic HCT ; outcomes in this setting are very poor. Once relapse occurs, patients are rarely cured with further standard-dose chemotherapy. Patients eligible for allogeneic HSCT should receive transplants expeditiously at the first sign of relapse. Long-term disease-free survival is approximately the same (30–50%) with allogeneic HSCT in first relapse or in second remission. TREATMENT FOR REFRACTORY OR RELAPSED AML 3/15/2022 acute leukemia 32

33. For elderly patients (age >60 years) for whom clinical trials are not available, gemtuzumab ozogamicin is another alternative. CR rate with this agent is ~30%. However, its effectiveness in early relapsing (<6 months) or refractory AML patients is limited, possibly due to calicheamicin being a potent MDR1 substrate Toxicity, including myelosuppression, infusion toxicity, and venoocclusive disease, can be observed with gemtuzumab ozogamicin . Pretreatment with glucocorticoids can diminish many of the associated infusion reactions Relapse 3/15/2022 acute leukemia 33

34. Tretinoin is an oral drug that induces the differentiation of leukemic cells bearing the t(15;17). APL is responsive to cytarabine and daunorubicin, but about 10% of patients treated with these drugs die from DIC induced by the release of granule components by dying tumor cells . Tretinoin does not produce DIC but produces another complication called the APL differentiation syndrome . Tretinoin plus anthracycline-based chemoRx Among the most effective treatments for APL Leads to CR rates of 90–95%. Arsenic trioxide has antileukemic activity and may be used in tretinoin refractory cases. It is also under investigation for combination chemotherapy. ATO remains the preferred reinduction therapy for patients who relapse. Achievement of CR2 should be followed by consolidation with autologous HCT (for patients who achieve RT-PCR negative status) Sequential monitoring of RT-PCR for t(15;17) is now considered standard for postremission monitoring of APL. Disappearance  A ssociated with long-term disease-free survival Persistence: two consecutive tests performed 2 weeks apart invariably predicts relapse Treatment- INDUCTION APL 3/15/2022 acute leukemia 34

35. Sequential monitoring of RT-PCR for t(15;17) is now considered standard for postremission monitoring of APL. Disappearance  A ssociated with long-term disease-free survival Persistence: two consecutive tests performed 2 weeks apart invariably predicts relapse Patients who continue in molecular remission may benefit from maintenance therapy with tretinoin. Patients in molecular, cytogenetic, or clinical relapse should be salvaged with arsenic trioxide It produces meaningful responses in up to 85% of patients and can be followed by HSCT Arsenic trioxide has antileukemic activity and may be used in tretinoin refractory cases. It is also under investigation for combination chemotherapy. ATO remains the preferred reinduction therapy for patients who relapse. Achievement of CR2 should be followed by consolidation with autologous HCT (for patients who achieve RT-PCR negative status). In the minority who do not achieve negative RT-PCR or who relapse again, allogeneic HCT may still be potentially curative Treatment- INDUCTION APL 3/15/2022 acute leukemia 35

36. In acute lymphoblastic leukemia (ALL), the malignant clone arises from hematopoietic progenitors in the bone marrow or lymphatic system resulting in an increase of immature nonfunctioning leukemic cells. The immunophenotype of leukemic cells at diagnosis reflects the level of differentiation achieved by the dominant clone ALL Introduction 3/15/2022 acute leukemia 36

37. INCIDENCE ALL is the most frequent neoplastic disease in children with an early peak at the age of 3–4 years Median age at diagnosis= 14 60% occur in those < 20years age 24% diagnosed at > 45years 11% diagnosed at > 65years Represents 75-80% of childhood leukemias 20% of adult leukemias Most cases of ALL occur in children, but most deaths from ALL (approximately four of five) occur in adults. 3/15/2022 acute leukemia 37

38. In most cases, no etiologic factors are discernible. Favored theory: Leukemogenesis reflects the interaction between host pharmacogenetics (susceptibility) and environmental factors* Environmental agents, such as ionizing radiation and chemical mutagens, have been implicated in the induction of ALL in some patients but less than AML. Initiation and progression of ALL is driven by successive mutations that alter cellular functions, including . Etiology & Pathogenesis 3/15/2022 acute leukemia 38

39. Molecular abnormalities can be grouped according to the functional consequence of oncogenic mutation. BCR-ABL Acquired constitutive activation of the ABL protein kinase by rearrangement with the BCR gene is an example of a mutation that confers a proliferative advantage The fusion gene is the consequence of the t(9;22)(q34;q11) balanced chromosomal translocation, This is the most common cytogenetic abnormality in adult ALL. . NOTCH1 More recently, aberrant expression of NOTCH1 has been linked to ALL leukemogenesis. NOTCH1 encodes a transmembrane receptor that regulates normal T-cell development. Genetic Syndromes Only a minority (5%) of cases are associated with inherited, predisposing genetic syndromes. Down’s Syndrome 10 to 30 times greater risk of leukemia; acute megakaryoblastic leukemia predominates in patients younger than 3 years, and ALL is predominant in older age groups Autosomal recessive genetic diseases: Ataxia-telangiectasia, Nijmegen breakage syndrome, and Bloom Environmental Factors In utero radiation exposure Pesticide exposure Parental cigarette smoking before or during pregnancy have been suggested causes of childhood ALL Infectious agents syndrome 3/15/2022 acute leukemia 39

40. Symptoms Symptoms may appear insidiously or acutely Fever: ~50% of patients Often is induced by pyrogenic cytokines (e.g., IL-1, IL-6, and TNF) released from leukemic cells In these patients, fever resolves within 72 hours after the start of antileukemic therapy. Fatigue, lethargy, dyspnea, angina, and dizziness: due to Anemia Limping, bone pain, arthralgia, or an unwillingness to walk: Because of leukemic infiltration of the periosteum, bone, or joint or because of expansion of the marrow cavity by leukemic cells Arthralgia and bone pain are less severe in adults Less common signs and symptoms include headache, vomiting, altered mental function, oliguria, and anuria. Occasionally, patients present with a life-threatening infection or bleeding (e.g., intracranial hematoma). Usually, intracranial hemorrhage occurs mainly in patients with an initial WBC count> 400 x 10 9 /liter . Very rarely, ALL produces no signs or symptoms and is detected during routine examination. Clinical Features 3/15/2022 acute leukemia 40

41. Signs Common: pallor, petechiae, and ecchymosis in the skin and mucous membranes and bone tenderness The latter is as a result of leukemic infiltration, microvascular obstruction with infarction or hemorrhage that stretches the periosteum Liver, spleen, and lymph nodes are the most common sites of extramedullary involvement ~50% of adults (NCCN 2014: in only 20% of patients) The degree of organomegaly is more pronounced in children than in adults. An anterior mediastinal (thymic) mass is present in 7 to 10 % of childhood cases and 15 % of adult cases* More commonly seen T cell ALL Painless scrotal swelling Can be due to testicular leukemia or hydrocele The latter resulting from lymphatic obstruction Overt testicular disease is relatively rare, generally seen in infants or patients with T cell leukemia with hyperleukocytosis , and does not require radiation therapy Other uncommon presenting features include Ocular involvement (leukemic infiltration of the orbit, optic nerve, retina, iris, cornea, or conjunctiva), Subcutaneous nodules (leukemia cutis), Enlarged salivary glands ( Mikulicz syndrome ), Cranial nerve palsy, and Priapism (resulting from leukostasis of the corpora cavernosa and dorsal veins or sacral nerve involvement). Epidural spinal cord compression 3/17/2022 acute leukemia 41

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43. Chest x-ray film of a 12-year-old black male with T cell ALL and an anterior mediastinal mass 3/17/2022 acute leukemia 43

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45. Mediastinal masses are detected by chest radiographs or computed tomography scans primarily in patients with T-lineage ALL, who also frequently have pleural involvement and may complain of chest pain So Chest CT scans are warranted in cases of T cell ALL Chest radiography is needed to detect enlargement of the thymus or mediastinal nodes, with or without pleural effusion. Spinal roentgenography is useful in patients with suspected vertebral collapse. WHO 2008 The term ALL is used if there are >20 % bone marrow blasts, with or without a mass lesion. For cases with a mass lesion and less than 20 % bone marrow involvement, the term lymphoblastic lymphoma is used Imaging 3/17/2022 acute leukemia 45

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47. Immunophenotyping Among children B-cell lineage ALL constitute 88% of cases In adults Sub types of B-cell ALL- 75% Including mature B cell which accounts for 5% T-cell ALL- 25% Cytogenetic studies The frequency certain subtypes differ among children and adults, which partially explains the differences in outcomes between the two patient populations Hyperdiploidy (25% in children vs 7%)---- Favorable TEL-AML1 (22% in children vs 2% in adults)--- Favorable BCR-ABL (3% in children vs 25% in adults)---- Unfavorable In addition children (1-9yrs) with philadelphia positive ALL have a better prognosis than Adolescents with the same subtype Cytogenetic studies The frequency of Philadelphia positive ALL increases with age 10% in 15-39yrs 25% in 40-49yrs 20-40% in > 50yrs 3/17/2022 acute leukemia 47

48. NCCN Recommendation on risk assessments Given the poor prognosis associated with Ph positive ALL and the wide availablity of agents that can target the BCR-ABL kinase, initial risk stratification for all patients with ALL (AYA and Adults) is based on the presence or absence of t(9,22) chromosomal translocation and the BCR/ABL fusion protein Ph positive- High risk Ph negative High risk: Hypodiploidy (<44 chromosomes) MLL rearrangement Complex Karyotypes ( > 5 chromosomal abnormality) Age <1 or >10 WBC count (>30.000 for B cell or >100,000 for T cell) Standard risk Absence of any of the high risk features Prognostic Factors and Risk Stratification 3/17/2022 acute leukemia 48

49. Recommendation on risk assessments- Adults Ph positive- High risk Ph negative: Age> 65 or serious comorbidities vs < 65yrs (no substantial comorbidities) High risk: Hypodiploidy (<44 chromosomes) MLL rearrangement Complex Karyotypes ( > 5 chromosomal abnormality) WBC count (>30.000 for B cell or >100,000 for T cell)- doesn’t apply for those with >65yrs age Standard risk Absence of any of the high risk features Prognostic Factors and Risk Stratification 3/17/2022 acute leukemia 49

50. SUPPORTIVE CARE ANTI-LEUKEMIC THERAPY Treatment for leukemias affecting the B cell precursor and T cell lineages consists of three standard phases: Remission induction, Intensification (consolidation), and Prolonged continuation therapy. CNS-directed therapy, which overlaps other treatments, is started early It is given for different lengths of time, depending on the patient's risk of relapse and the intensity of the primary systemic regimen . Treatment 3/17/2022 acute leukemia 50

51. Remission Induction The first goal of therapy for patients with leukemia is inducing a complete remission and restore normal hematopoiesis. The induction regimen invariably includes a glucocorticoid (prednisone, prednisolone, or dexamethasone), vincristine, and L-asparaginase for children or an anthracycline for adults. Children with high- or very-high-risk ALL and nearly all young adults with ALL receive all four drugs during remission induction in contemporary clinical trial Remission induction ctd Improvements in chemotherapy and supportive care have resulted in complete remission rates of approximately 98 % for children and approximately 85 % for adults. When a complete clinical remission is induced, patients have various degrees of residual leukemia, and some can still have as many as 10 billion leukemic cells a "molecular" or "immunologic" remission, defined as leukemic involvement of less than 0.01 % of nucleated marrow cell s Treatment- Anti-Leukemic Rx 3/17/2022 acute leukemia 51

52. Intensification/Consolidation Rx When normal hematopoiesis is restored, patients in remission become candidates for intensification therapy. Such treatment, administered shortly after remission induction, refers to high doses of multiple agents not used during the induction phase or to readministration of the induction regimen More commonly used regimens for childhood ALL High-dose methotrexate with or without mercaptopurine, high-dose L-asparaginase given for an extended period , or A combination of dexamethasone, vincristine, L-asparaginase, and doxorubicin, followed by thioguanine, cytarabine, and cyclophosphamide This phase of therapy has improved outcome, even of patients with low-risk ALL The value of intensification treatment is less certain in adults with ALL Two randomised trials did not show better clinical outcomes but several non randomised trials showed better patient oucomes In cases of T cell ALL , the benefit is derived from cyclophosphamide and cytarabine. In other cases of standard-risk and high-risk ALL , the benefit is derived from high-dose cytarabine Treatment- Anti-Leukemic Rx 3/17/2022 acute leukemia 52

53. CNS Therapy In the 1970s, the cornerstone of ALL therapy was cranial irradiation (2400 cGy ) plus methotrexate administered intrathecally after complete remission was induced Concern that cranial irradiation could cause second cancer, late neurocognitive deficits, and endocrinopathy stimulated efforts to replace cranial irradiation with early intensification of intrathecal and systemic chemotherapy. Whether certain groups of patients would still benefit from cranial irradiation is unclear It is contended that with effective systemic and intrathecal therapy, the need for cranial irradiation can be eliminated in all patients by adhering to the following guidelines. Avoid traumatic lumbar puncture Coincide intrathecal therapy with the diagnostic LP and should be intensified in patients with any amount of identifiable leukemic cells in their CSF and in patients who experience traumatic lumbar puncture or have other high-risk features Patients should remain in a prone position for at least 30 minutes after the procedur Treatment- Anti-Leukemic Rx 3/17/2022 acute leukemia 53

54. Allogeneic Stem Cell Transplantation Hematopoietic stem cell transplantation during first remission remains controversial. In adult ALL, long-term event-free survival rates range from 30 to 40 % with chemotherapy alone and from 40 to 60 % with allogeneic transplantation. Because of their unfavorable prognosis, patients with the Philadelphia chromosome or those with a poor initial response to induction therapy commonly undergo allogeneic stem cell transplantation during the first remission The indications for transplantation in first remission should be reevaluated as chemotherapy and transplantation continue to improve. Treatment- Anti-Leukemic Rx 3/17/2022 acute leukemia 54

55. Relapse Relapse is defined as the reappearance of leukemic cells at any site in the body. Most relapses occur during treatment or within the first 2 years after its completio n, although initial relapses have been observed 10 or more years after diagnosis Leukemic relapse occasionally occurs at other extramedullary sites, including the eye, ear, ovary, uterus, bone, muscle, tonsil, kidney, mediastinum, pleura, and paranasal sinus. Marrow relapse, with or without extramedullary involvement, portends a poor outcome for most patients. Factors indicating an especially POOR PROGNOSIS Relapse while on therapy or after a short initial remission, T cell immunophenotype, Presence of the Philadelphia chromosome, and An isolated hematologic relapse Course & Prognosis 3/17/2022 acute leukemia 55

56. AYA with Ph+ve ALL These patients should be treated in an appropriate clinical trial if possible No clinical trial  Multi-agent chemotherapy + TKIs CNS prophylaxis should always be included For patients achieving CR after induction Consider allogenic HSCT, if there is donor In AYA <21y/o, emerging data suggest that allogenic HSCT may not confer an advantage over multiagent chemotherapy plus TKIs After HSCT, maintenance therapy for 2-3 years with a TKI with or without monthly pulses of vincristine/prednisolone is recommended Weekly methotrexate and daily MP may be added to maintenance HSCT not possible (No donor) Consolidation with multiagent chemo + TKI Post consolidation chemo with a regimen than contains a TKI For patients achieving less than a CR after induction i.e. having a primary refractory disease Treatment is the same as refractory/relapsed disease Treatment 3/17/2022 acute leukemia 56

57. Adults with Ph+ve ALL Age< 65y/o and No substantial comorbidity Similar to AYA with Ph+ve ALL For patients achieving CR after induction Consider allogenic HSCT, if there is donor In AYA <21y/o, emerging data suggest that allogenic HSCT may not confer an advantage over multiagent chemotherapy plus TKIs After HSCT, maintenance therapy for 2-3 years with a TKI with or without monthly pulses of vincristine/prednisolone is recommended Weekly methotrexate and daily MP may be added to maintenance HSCT not possible (No donor) Consolidation with multiagent chemo + TKI Post consolidation chemo with a regimen than contains a TKI For patients achieving less than a CR after induction i.e. having a primary refractory disease Treatment is the same as refractory/relapsed disease Con Treatment 3/17/2022 acute leukemia 57

58. Adults with Ph+ve ALL Age> 65y/o and/or substantial comorbidity TKI + Corticosteroid OR TKI + Chemotherapy Doses of chemo agents may have to be reduced Maintenance therapy for 2-3 years with a TKI with or without monthly pulses of vincristine/prednisolone is recommended Weekly methotrexate and daily MP may be added to maintenance, as tolerated Age> 65y/o and/or substantial comorbidity For patients achieving less than a CR after induction i.e. having a primary refractory disease Treatment is the same as refractory/relapsed disease Con Treatment 3/17/2022 acute leukemia 58

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60. AYA with Ph- ve ALL Recommendation is treatment in a clinical trial (regardless of the risk status) No clinical trial Pediatric inspired multiagent chemotherapy Regimens: CALGB-8811 (Larson regimen), Lineker regimen, Hyper-CVAD (with or without Rituximab) or the MRC UKALL XII/ECOG 2993 study CNS prophylaxis should always be included For patients achieving CR Consider monitoring for MRD Continue multiagent chemotherapy for consolidation and maintenance therapy (especially for patients with MRD-negative remission) If a matched donor is available, consolidation with HSCT is recommended, particularly in Residual disease by MRD assays High risk disease features ( eg. WBC>30k for Bcell or >100k for Tcell , hypodiploidy or MLL rearrangement) For patients achieving less than a CR after induction i.e. having a primary refractory disease Treatment is the same as refractory/relapsed disease Con 3/17/2022 acute leukemia 60

61. Adults with Ph-ve ALL Age< 65y/o and No substantial comorbidity Test for TMPT gene polymorphism especially for those who develop sever myelosuppression after MP is started Similar to AYA with Ph-ve ALL Regimens: CALGB-8811 (Larson regimen), Lineker regimen, Hyper-CVAD (with or without Rituximab) or the MRC UKALL XII/ECOG 2993 study For patients achieving CR after induction Consider monitoring for MRD Continue multiagent chemotherapy for consolidation and maintenance therapy (especially for patients with MRD-negative remission) If a matched donor is available, consolidation with HSCT is recommended, particularly in Residual disease by MRD assays High risk cytogenetic features ( eg . Hypodiploidy, MLL rearrangement or complex karyotype) For patients achieving less than a CR after induction i.e. having a primary refractory disease Treatment is the same as refractory/relapsed disease Con 3/17/2022 acute leukemia 61

62. Adults with Ph-ve ALL Age> 65y/o and/or substantial comorbidity Multiagent chemotherapy OR Doses of chemo agents may have to be reduced Steroids Maintenance therapy with typical chemotherapeutic agents should continue for 2-3 years (Weekly methotrexate and daily MP may be added to maintenance, as tolerated and monthly pulses of vincristine/prednisolone) Weekly methotrexate and daily MP may be added to maintenance, as tolerated Age> 65y/o and/or substantial comorbidity For patients achieving less than a CR after induction i.e. having a primary refractory disease Treatment is the same as refractory/relapsed disease Con 3/15/2022 acute leukemia 62

63. Evaluation and treatment of CNS involvement at prentation among children with ALL is only 3-7% but eventually a substantial proportion (>50%) of patients will develop CNS disease Defn : CNS leukemia is defined as CSF leukocyte count of > 5/ micL with presence of lymphoblasts LP should be done at the time of diagnosis and the first dose of intrathecal chemotherapy should be given at the time Classification of CNS status CNS-1: No lymphoblasts in CSF regardless of WBC count CNS-2: <5WBCs/ micL with presence of lymphoblasts CNS-3: > 5WBCs/ micL with presence of lymphoblasts If leukemic cells are present in the peripheral blood and LP is traumatic (with>5leukocytes/ micL with Blasts), compare the WBC/RBC ration in the CSF to WBC/RBC ration in blood: If ratio is > 2  CNS-3 If ratio is <2 CNS-2 Among adults, factors associated with increased risk of CNS leukemia are Mature B immunophenotype T cell immunophenotype High WBC count on presentation High serum LDH level Among adults, CSF leukemia on presentation is associated with High risk of CNS relapse No significant change in the 5 year EFS (when compared with those with no CNS leukemia at diagnosis) Extramedullary disease 3/15/2022 acute leukemia 63

64. Evaluation and treatment of Extramedullary disease CNS directed therapy includes Cranial irradiation Intrathecal chemotherapy (methotrexate, cytarabin , dexamethasone) and/or High dose systemic chemotherapy(methotrexate, cytarabin , 6-MP, L- Asparginase ) CNS prophylaxis is given throughout the induction, consolidation and maintenance therapy For those patients who present of CNS involvement at diagnosis (i.e. CNS- 3 and/or CN involvement) 18cGy cranial irradiation should be given In addition, patients with CNS leukemia at diagnosis should receive adequate systemic PLUS intrathecal chemotherapy that contains methotrexate throughout the treatment course Adequate systemic chemotherapy should also be given to patients with isolated CNS or testicular relapse In younger AYA patients with high risk ALL ( Bcr - Abl [t(9;22) ]or MLL[t(4;11)] or T cell ALL, use of prophylactic cranial irradiation can be considered A testicular examination should be done for all patients with ALL at diagnostic workup Testicular involvement is particularly common in patients with T-cell ALL No testicular involv’t  Nothing needed Cranial Irradiation vs Chemotherapy* Studies conducted to check if CNS irradiation can be avoided Children studies: with IT and/or Systemic chemo alone 5 year cumulative CNS relapse alone: 3-4% Any CNS relapse: 4-5% Adult studies: IT + Systemic chemo alone Overall CNS relapse rate: 2-6% Therefore the use of cranial irradiation can be reserved for more advanced cases NCCN Recommendations 3/15/2022 acute leukemia 64

65. Surveillance Surveillance at regular intervals after completion of maintenance therapy is recommended 1 st year after completion Monthly P/E and blood tests (CBC with diff.) LFT every 2 months until normal findings are achieved BMA, CSF and Echo- as clinically indicated If BMA is done  Comprehensive cytogenetics (including FISH), Flow cytometry and molecular tests should be considered 2 nd year after completion P/E (including testicular exam for all male patients) and Blood tests (CBC with diff) every 3 months 3 rd year (and beyond) after completion P/E (including testicular exam for all male patients) and Blood tests (CBC with diff) every 6months or as clinically indicated NCCN Recommendations 3/15/2022 acute leukemia 65

66. William’s Hematology 9 th ed. NCCN ALL guidelines, 2014 Harrison 20th edition Uptodate 2018 and 2021 Wintrobes clinical hematology 2th edition Hoffman hematology 7 th edition WHO AML and ALL guidelines References 3/15/2022 acute leukemia 66

67. Thank You! 3/15/2022 acute leukemia 67