Relapse of acute lymphoblastic leukemia

A victorious point in the treatment of acute lymphoblastic leukemia in children can be put only after a significant improvement in the results of treating relapses. Compared with the results of treating primary patients, the survival rate of children with relapses of acute lymphoblastic leukemia remains low, the 5-year survival of these patients does not exceed 35-40%. The chances of recovery directly depend on the development of new approaches in polychemotherapy, options for bone marrow transplantation, etc. There are isolated and combined, bone marrow and extramedullary (with CNS damage, testicular, with infiltration of other organs), very early (within 6 months from diagnosis), early (up to 18 months after diagnosis) and late (18 months after diagnosis) relapses. Unlike the treatment of primary acute lymphoblastic leukemia, world experience in chemotherapeutic treatment of relapses is extremely limited. Few publications have analyzed groups of no more than 50-100 patients. The only exception is a series of studies by the German BFM group, which began in 1983. By March 1997, these studies had analyzed the treatment results of over a thousand patients with the first relapse of acute lymphoblastic leukemia. Patients were divided into risk groups only depending on the localization of the relapse. Chemotherapy programs for the treatment of relapses were developed taking into account the knowledge gained in the course of treating primary patients with acute lymphocytic leukemia both according to the ALL-BFM series protocols and other international protocols, as well as taking into account the world experience of intensive chemotherapy in oncology. The treatment was based on the use of two different high-dose combinations of cytostatics - therapeutic elements (blocks), alternating with each other at an interval of 2-3 weeks from the beginning of one to the beginning of the other. Each chemotherapy block included high-dose methotrexate (HD MTX) in combination with 4-5 other chemotherapy drugs (called R1 and R2 therapeutic elements). The ALL-REZ-BFM-90 trial added a new R therapeutic element (high-dose cytarabine). The results of these studies have been published. The following are their main findings.

• The most important factors determining the prognosis in the first relapse of acute lymphoblastic leukemia are the time point of relapse in relation to the initial diagnosis and to the end of maintenance therapy (very early, early and late relapse), localization (isolated bone marrow, extramedullary and combined) and the immunophenotype of leukemic cells.
• Depending on the moment of occurrence, the 10-year survival rate is 38% for a late relapse, 17% for an early relapse, and 10% for a very early relapse.
• Depending on the localization, the 10-year survival rate is 44% for extramedullary relapse, 34% for combined relapse, and 15% for isolated bone marrow relapse.
• In relapsed T-cell acute lymphocytic leukemia, long-term survival is 9%, and in relapsed acute lymphocytic leukemia with any other immunophenotype, it is 26%.
• No differences in treatment outcomes were found when using different regimens of high-dose methotrexate (1 g/ ^m2 for 36 h and 5 g/m2 ^for 24 h).
• The introduction of the therapeutic element R (high dose cytarabine) in the ALL-REZ-BFM-90 study did not improve treatment outcomes.
• Prophylactic cranial irradiation for isolated late bone marrow relapses significantly increases survival by 20-25%.

The ALL-REZ-BFM-90 study reliably demonstrated for the first time the effect of chemotherapy intensity, namely the duration of breaks between blocks (between the start of one and the start of the next therapeutic element, according to the protocol, no more than 21 days should pass). In 66 patients with a break between the first and second block of less than 21 days, the survival rate was 40%, and in 65 patients with a break of more than 25 days - 20%. Thus, the intensity of chemotherapy is determined not only by dose modification, but also by the density of therapeutic elements.

Multivariate analysis of treatment outcomes in over 1,000 patients treated under the ALL-REZ-BFM-83 and ALL-REZ-BFM-90 protocols showed that risk group stratification and, accordingly, treatment options should be revised. A small group of patients with a good prognosis can be identified (group S in the new ALL-REZ-BFM-95 study). These are patients with late isolated extramedullary relapses, accounting for no more than 5-6% of all patients (60 out of 1,188) with the first relapse of ALL. Survival in this group is 77%. About 15% (175 out of 1,188) are patients in the unfavorable prognosis group with early isolated bone marrow relapses (group S ₃ ). It is necessary to distinguish from them a group of patients with a particularly unfavorable prognosis: with very early bone marrow (isolated and combined) relapses and bone marrow relapses of T-cell leukemia (25% of all patients - 301 of 1188). This is group S _4. Survival in groups S ₃ and S ₄ is only 1-4%. Although the treatment results are equally poor in both groups, there are significant differences between them in the level of achieving remission and the level of therapy-induced mortality during the induction period. If in group S ₃ remission is achieved in 80% of patients, then in group S ₄ - only in 50%. In addition to the high frequency of refractory cases and relapses, a great many patients in group S ₄, unlike group S ₃, die from the toxic effects of therapeutic drugs. At the same time, in group S, low survival is associated with a high level of repeated relapses and a short duration of the second remission, rarely exceeding 8 months. The most numerous group is represented by patients with an intermediate prognosis (group S ₂ ). These are patients with late isolated and combined bone marrow relapses, with early extramedullary relapses and with extramedullary relapses of T-cell leukemia (652 of 1188 or 55% of all patients). Survival in this group averages 36% (from 30 to 50%).

This stratification into risk groups is the basis of the ALL-REZ-BFM-95 protocol. The main therapeutic idea of this study for patients in groups S ₃ and S ₄ is a more intensive timing of chemotherapy during the induction period and a decrease in toxicity by reducing the total dose loads of cytostatic drugs. For this purpose, the first two therapeutic elements R ₁ and R. ₂ were replaced by less intensive blocks F1 and F2, therapeutic element R3excluded. Treatment of patients with a particularly unfavorable prognosis (group S ₄ ) has also undergone a change. Its essence is an attempt to overcome the drug resistance of tumor cells using new test combinations of cytostatics, including idarubicin and thiotepa. High-dose intensive chemotherapy in these patients is completely excluded. The decision on the advisability of continuing chemotherapy after each therapeutic element is made individually in each specific case.

New approaches to the treatment of relapses of acute lymphoblastic leukemia (bone marrow transplantation, immunotherapy, etc.) are being developed. Research by the BFM group has shown that the optimal method of treating children with late relapse is polychemotherapy. Bone marrow transplantation is best performed in case of early (very early) or repeated relapse, provided that the tumor is sensitive to therapy, since good results in the treatment of late relapses using polychemotherapy have an advantage over the toxicity of conditioning regimens in bone marrow transplantation.

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