hematology and oncology
Acute Lymphoblastic Leukemia (ALL)
Treatment of ALL
Systemic chemotherapy Prophylactic CNS chemotherapy and sometimes CNS radiation For Ph+ ALL, also a tyrosine kinase inhibitor Supportive care Sometimes Immune Therapy , Treatment for newly diagnosed acute lymphoblastic leukemia generally consists of 3 to 4 cycles of chemotherapy blocks of non–cross-resistant chemotherapy for the first 9 to 12 months, followed by 2.5 to 3 years of maintenance chemotherapy. The4 general phases of chemotherapyfor acute lymphoblastic leukemia include Remission induction Postremission consolidation Interim maintenance and intensification Maintenance /L), and no need for blood transfusion. In patients with complete remission, a low measurable residual disease (also known as minimal residual disease or MRD) is the most important prognostic factor ( Treatment references ). Measurable or minimal residual disease is microscopic disease that is not detected by standard assays but can be measured by more sensitive assays. A low measurable residual disease (MRD negativity) is defined variably (based on the assay used) as < 0.01 to 0.1% leukemic cells in bone marrow. Components ofinduction therapyinclude A high-dose corticosteroid (eg,dexamethasone,prednisone) An anthracycline (eg,daunorubicin,doxorubicin,idarubicin) Vincristine Some regimens use a corticosteroid to reduce disease burden prior to intensive induction. In younger adults, a regimen that includes asparaginase and/orcyclophosphamidefor induction, similar to treatment protocols used in children, may increase rates of response and achievement of undetectable minimal residual disease. If complete remission is not achieved after induction, some regimens recommend a second induction course to try to get more patients to complete remission before consolidation. For patients with Philadelphia chromosome–positive (Ph+) ALL, a tyrosine kinase inhibitor (eg,imatinib,dasatinib) can be added to the drug regimen. For patients with CD20 positive B-lymphoblastic leukemia,rituximabcan be added. is to prevent leukemic regrowth. Consolidation therapy usually lasts a few months and combines regimen-specific courses of non–cross-resistant drugs that have different mechanisms of action. For adults with Ph+ ALL, allogeneic Hematopoietic Stem Cell Transplantation is recommended as consolidation therapy. Interim maintenance and late/delayed intensification therapyare used after consolidation therapy. These phases of therapy incorporate a variety of chemotherapeutic agents with different doses and schedules that are less intense than induction and consolidation. Most regimens includemaintenance therapywith monthlyvincristine, weeklymethotrexate, dailymercaptopurine, and 5 days/month corticosteroid. Therapy duration is usually 2½ to 3 years. CNS prophylaxisstarts during induction and continues throughout all phases of treatment. Because lymphoblasts often infiltrate the cerebrospinal fluid and meninges, all regimens include CNS prophylaxis and treatment with intrathecalmethotrexate,cytarabine, andhydrocortisonein combination or as monotherapy. High doses of systemicmethotrexateand/orcytarabinepenetrate the CNS, providing extra CNS prophylaxis if regimens include these drugs. Cranial nerve or whole-brain irradiation was previously often done for patients at high risk of CNS disease (eg, high WBC count, high serum lactate dehydrogenase, B-cell phenotype), but its use has been decreasing in recent years. About one third of patients with acute lymphoblastic leukemia are older adults (> 65). Older ALL patients are more likely to have precursor B-cell ALL and have higher risk and more complex cytogenetics, including Philadelphia chromosome positive (Ph+) or t(v;11q23)MLLorKMT2Arearranged disease. ) plus corticosteroids given with either low-intensity or no chemotherapy have resulted in 95 to 100% complete remission rate, with a 45 to 50% 2-year relapse free survival and about 70% 2-year overall survival. For older patients with ALL who are in their first complete remission, nonmyeloablative or reduced-intensity conditioning allogeneic Hematopoietic Stem Cell Transplantation is an option. Targeted immunotherapy drugs that are available for treatment of relapsed or refractory ALL are increasingly used for treatment of older patients with ALL in clinical trials or clinical practice. Older patients with ALL probably tolerate asparaginase more poorly than younger patients do. Leukemic cells may reappear in the bone marrow, CNS, testes, or other sites. Bone marrow relapse is particularly ominous. Although a new round of chemotherapy may induce a second remission in the majority of children and about one third of adults, subsequent remissions tend to be brief. Chemotherapy helps only a few patients with early bone marrow relapse to achieve long disease-free second remissions or cure. , that bring T cells into close proximity to leukemic blasts demonstrate activity in relapsed ALL. Modified T cells (CAR-T) cells, engineered and generated from the patient's T cells, induce remission in patients with relapsed ALL with remarkable efficacy, albeit with significant toxicity ( Available immunotherapies for relapsed or refractory ALL include Blinatumomab Inotuzumab ozogamicin Tisagenlecleucel a biospecific CD19-directed CD3 T-cell engager, prolongs overall survival for children and adults with relapsed or refractory B-cell precursor ALL, whether Ph+ or Ph-. Life-threatening toxicities may include Cytokine release syndrome and neurologic toxicities (eg, seizures, encephalopathy with altered consciousness, and disordered speech, coordination, and/or balance). Interrupting or stopping than with standard chemotherapy ( Treatment references ). Inotuzumab may cause hepatotoxicity, including fatal and life-threatening veno-occlusive disease and is associated with higher post-transplant non-relapse mortality. a CD19-directed genetically modified autologous T-cell immunotherapy, is available for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in a 2nd or later relapse. Life-threatening toxicities may include Cytokine release syndrome and neurologic toxicities ( , a CD19-directed genetically modified autologous T cell immunotherapy, can be used to treat adult patients with relapsed or refractory B-cell precursor ALL. Complications, including Cytokine release syndrome and neurologic toxicities, may be life threatening. Other agentshave been available, but clinically meaningful outcomes have not been convincingly demonstrated (ie, the approvals were based upon response rate but there were no trials verifying an improvement in disease-related symptoms or increased survival) for these. Examples include: Liposomalvincristine(a vinca alkaloid): For adults with Ph- ALL in at least 2nd relapse or that has progressed despite ≥ 2 antileukemia therapy—marketing has been discontinued Clofarabine(a purine nucleoside analog): For patients age 1 to 21 years with relapsed or refractory ALL after ≥ 2 prior regimens Nelarabine(a purine nucleoside) analog prodrug of guanosine arabinoside: For T-cell ALL that has not responded to or has relapsed after ≥ 2 prior regimens Hematopoietic Stem Cell Transplantation None CNS relapsetreatment includes intrathecalmethotrexate(with or withoutcytarabineor corticosteroids) twice weekly until all signs disappear. The role of continued intrathecal drug use or CNS irradiation is unclear. Testicular relapsemay be evidenced clinically by painless firm swelling of a testis or may be identified on biopsy. If unilateral testicular involvement is clinically evident, the apparently uninvolved testis should undergo biopsy. Treatment is radiation therapy of the involved testis and administration of systemic reinduction therapy. Supportive care is similar in the acute leukemias and may include Transfusions Antimicrobials Hydration and urine alkalinization Psychologic support Transfusionsof red blood cells and sometimes platelets are administered as needed to patients with bleeding or anemia. Prophylactic platelet transfusion is done when platelets fall to<10,000/mcL (< 10 × 109/L). Anemia (hemoglobin<7 or 8 g/dL [< 70 to 80 g/L]) is treated with transfusions of packed red blood cells. Granulocyte transfusions are not routinely used. , which is commonly used in all ALL treatment regimens, and azole antifungals. In patients with refractory pneumonitis, Pneumocystis jirovecii Pneumonia or a viral infection should be suspected and confirmed by bronchoscopy and bronchoalveolar lavage and treated appropriately. Posaconazole, a 2nd-generation triazole antifungal drug, is indicated for primary prophylaxis in patients age > 13 years who are at high risk of developing invasiveAspergillusandCandidainfections because of immunosuppression (eg, hematopoietic stem cell transplant recipients with graft-versus-host disease). In patients with drug-induced immunosuppression (eg, prolonged use of corticosteroids for ALL treatment), sulfamethoxazole/trimethoprim(TMP/SMX),dapsone,atovaquone, orpentamidineis indicated to preventP. jiroveciipneumonia.Acyclovirorvalacyclovirprophylaxis is generally recommended for all patients. can prevent and treat the hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia (ie, Tumor Lysis and Cytokine Release Syndromes ) caused by the rapid lysis of leukemic cells during initial therapy in ALL. Hyperuricemia is minimized by reducing the conversion of xanthine to uric acid by giving Psychologic supportmay help patients and their families with the shock of illness and the rigors of treatment for a potentially life-threatening condition. 1.Berry DA, Zhou S, Higley H, et al: Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: A meta-analysis.JAMA Oncol3(7): e170580, 2017. doi:10.1001/jamaoncol.2017.0580 2.Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.Lancet385(9967) :517–528, 2015. 3.Kantarjian H, Stein A, Gökbuget N, et al:Blinatumomabversus chemotherapy for advanced acute lymphoblastic leukemia.N Engl J Med376(9):836–847, 2017. 4.Kantarjian HM, DeAngelo DJ, Stelljes M, et al:Inotuzumab ozogamicinversus standard therapy for acute lymphoblastic leukemia.N Engl J Med375(8):740–753, 2016. 5.Maude SL, Laetsch TW, Buechner J, et al:Tisagenlecleucelin children and young adults with B-cell lymphoblastic leukemia.N Engl J Med378(5):439–448, 2018. 