The therapy of ALL is divided into several phases: Induction, consolidation and maintenance therapy. The goal of induction therapy is the induction of a complete remission (CR) of the disease. The achievement of a CR is a prerequisite for long-term survival or cure of the disease. The therapy phases consolidation and maintenance therapy serve to maintain the complete remission and are summarized under the term post-remission therapy.
Pre-phase therapy: Pre-phase therapy (dexamethasone, cyclophosphamide) should be given to all patients to avoid tumor lysis syndrome. Even in patients with hyperleukocytosis, pre-phase therapy is generally sufficient for gentle cell reduction.
Induction therapy in patients under 55 years of age with ALL or LBL: Standard drugs for the actual induction therapy are vincristine and dexamethasone in combination with an anthracycline derivative (usually dauno/doxorubicin). In addition, asparaginase is used in induction therapy; the substance is specifically effective in ALL and differs from other cytostatics in terms of mechanism of action, resistance and side effect spectrum.
After induction phase I, remission control with MRD determination is performed. If a complete remission (blast percentage <5%) is not achieved according to cytological findings, the patient must be assigned to the high-risk group. In case of borderline cytological findings, the MRD result should be awaited for the final classification. The sole detection of CD10/CD19-positive cells in the flow cytometry can neither be interpreted as an unequivocal blast detection nor as an MRD detection, since especially in the regenerating bone marrow they can also be hematogones. If extramedullary involvement is initially detected, it should be followed up by appropriate imaging and included in the overall assessment of remission.
Induction phase II involves the addition of further drugs - cyclophosphamide, cytosine arabinoside, 6-mercaptopurine and intrathecal prophylaxis with methotrexate. Usually, induction phase II again causes a significant decrease in minimal residual disease (Gökbuget N et al (2012).
Consolidation therapy: The implementation of an intensive consolidation therapy is standard in the therapy of ALL. Very different concepts exist internationally for consolidation therapy and the efficacy of individual elements can hardly be proven individually. However, the available data suggest that cyclic consolidation therapy with changing substances and especially the intensive use of high-dose methotrexate, high-dose cytarabine, increased dose intensity for asparaginase as well as the repetition of induction therapy (reinduction) is beneficial. It is essential that the therapeutic blocks in consolidation therapy are administered as promptly as possible.
Maintenance therapy: For all ALL patients (except for patients with mature B-ALL/Burkitt's leukemia) who do not receive SCT, maintenance therapy is the standard of care after completion of the consolidation and intensification cycles. All studies in which maintenance therapy was omitted have had significantly less favorable overall results. In maintenance therapy, methotrexate is administered orally weekly and mercaptopurine daily. Dosages are adjusted to blood counts.
Stem cell transplantation (SCT): Allogeneic SCT is an essential component of post-remission therapy in adult ALL. Both family and unrelated donors are used, with twice as many unrelated as family donor transplants now being performed due to excellent donor registries. The results are comparable. Autologous SCT is now performed only in rare individual cases after further consolidation therapy. The indication for SZT in first remission varies internationally. The majority of study groups follow a risk-adapted indication for SZT in first remission (Giebel S et al. 2019). In all patients with high-risk features, transplantation is targeted in first CR. Standard-risk patients are not targeted for transplantation in first remission, as they achieve survival rates above 60% even with conventional chemotherapy. The indication for SCT in standard risk patients is molecular relapse or treatment failure.
CNS prophylaxis: The implementation of effective prophylaxis of CNS recurrences is of critical importance in the treatment of ALL. Risk factors for the development of CNS relapse include T-ALL, mature B-ALL/Burkitt's leukemia, and a high leukocyte count at diagnosis. Treatment modalities include intrathecal therapy with methotrexate, with a triple combination (methotrexate, cytarabine, steroid), systemic high-dose therapy with methotrexate and/or cytarabine, and whole-brain radiation (24 Gy). With initial CNS involvement, intensified intrathecal therapy with 2- to 3-times weekly administrations until blast clearance and 1-2 additional consolidation administrations must be performed. In case of frequent intrathecal instillation of methotrexate, a leucovorin rescue should be performed for mucositis prophylaxis.
Therapy of Ph/BCR-ABL-positive ALL: The Philadelphia (Ph) chromosome or corresponding fusion transcript BCR-ABL is the most common recurrent aberration in ALL, with an incidence of 30-50% within B-precursor ALL. The incidence increases with age. The use of tyrosine kinase (TK) inhibitors, particularly imatinib, has significantly improved the prognosis of this subgroup (Ravandi F 2019).In younger patients, imatinib is used in combination with chemotherapy . Remission rates of over 90% are achieved; molecular remission rates are over 50%.
Because of the development of resistance and relapse with chemotherapy in combination with TKIs, stem cell transplantation appears to remain the only option for achieving long-term remission in Ph+ ALL. Further improvement seems possible with the administration of imatinib after transplantation.
In older patients with Ph+ ALL, the approach of induction therapy with imatinib as monotherapy has been predominantly tested in trials. This therapy, which can often be performed on an outpatient basis, achieves a CR in 90% of patients and is thus superior to intensive induction chemotherapy in combination with imatinib (Ottmann OG et al. (2007).
Crucial for therapy management is the quantitative measurement of MRD and, in case of MRD detection, the measurement of resistance-inducing mutations with the highest possible sensitivity.
Recurrence: The probability of recurrence is highest in the first two years after achieving CR. Early relapses with primary remission duration less than 18 months and refractory relapses are prognostically unfavorable. The main goal in the management of relapsed patients is the achievement of a complete remission and subsequent stem cell transplantation, if the patients are individually suitable for this. Achieving CR is a prerequisite for stabilization of the patient with hematologic remission and usually for subsequent transplantation. Molecular remission should be sought if possible, although the prognostic significance of MRD after relapse is less clear than in first-line therapy. Overall survival of ALL after relapse is <10% in published studies (Gökbuget N et al 2012). Increasingly, consistent MRD determination is successful in identifying the increase in leukemia burden prior to the occurrence of cytologic relapse and initiating treatment in the MRD setting. In the treatment of early relapses and refractory relapses of B-precursor ALL, standard chemotherapies produce significantly worse results than the new immunotherapies with blinatumomab or inotuzumab (Kantarjian HM et al. 2016).
CAR-T:Promising data exist for the use of genetically engineered T cells. The so-called chimeric antigen receptor T cells (CAR-T) are engineered ex-vivo from patient T cells with an antigen receptor against leukemia cell surface markers and various signal transduction elements (Majzner RG et al. 2019). Chimeric antigen receptor-modified T cell (CART) therapy has significantly improved the treatment of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) (Yang M et al 2020)
Comment: Lymphoblastic lymphoma (bone marrow involvement < 25%) can be treated very successfully with adapted regimens for ALL.