Recurrence 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 treatment of relapses. Compared with the results of treatment of primary patients, survival of children with relapses of acute lymphocytic leukemia remains low, 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. Separate and combined, bone marrow and extramedullary (with the defeat of the central nervous system, testicular, with infiltration of other organs), very early (within 6 months from the establishment diagnosis), early (up to 18 months after diagnosis) and later (18 months after diagnosis) relapses. Unlike the treatment of primary acute lymphoblastic leukemia, the world experience of chemotherapeutic treatment of relapses is extremely limited. In a few publications, groups of no more than 50-100 patients were analyzed. The only exception is a series of studies of the German BFM group, which began in 1983. By March 1997, within the framework of these studies, the results of treatment of over a thousand patients with the first relapse of acute lymphoblastic leukemia were analyzed. Patients were allocated to risk groups only depending on the localization of relapse. Chemotherapy programs for the treatment of relapses have been developed taking into account the knowledge gained in the treatment of primary patients with acute lymphocytic leukemia both under the ALL-BFM series protocols and other international protocols, as well as taking into account the world experience in conducting intensive chemotherapy in oncology. Treatment was based on the use of two different high-dose combinations of cytostatics - therapeutic elements (blocks) alternating with each other at intervals of 2-3 weeks from the beginning of one to the beginning of another. Each chemotherapy block included high doses of methotrexate (HD-MTX) in combination with 4-5 other chemotherapeutics (the so-called therapeutic elements R1 and R2). In the study ALL-REZ-BFM-90, a new therapeutic element R, (high doses of cytarabine) was added. The results of these studies are published. Below are their main provisions.

• The most important factors determining the prognosis for the first relapse of acute lymphoblastic leukemia are the temporary point of relapse with respect to the initial diagnosis and the end of maintenance therapy (very early, early and late relapse), localization (isolated bone marrow, extramedullary and combined) and immunophenotype of leukemia cells.
• Depending on the time of occurrence, a 10-year survival rate is 38% for a late relapse. At early - 17%, at very early - 10%.
• Depending on the location, the 10-year survival rate is 44% for extramedullary relapse, and 34% for the combined relapse. With isolated bone marrow - 15%.
• With the recurrence of T-cell acute lymphocytic leukemia, long-term survival is 9%, with recurrence of acute lymphocytic leukemia with any other immunophenotype - 26%.
• Differences in the results of treatment with different regimens of high-dose methotrexate (1 g / m ² for 36 h and 5 g / m ² for 24 h) were not detected.
• The introduction of the therapeutic element R, (high doses of cytarabine) in the ALL-REZ-BFM-90 study did not improve the results of treatment.
• Preventive cranial irradiation with isolated late bone marrow relapses significantly increases survival by 20-25%.

In the ALL-REZ-BFM-90 study, the effect of chemotherapy intensity, namely, the duration of interruptions between the blocks (between the onset of one and the beginning of the next therapeutic element, according to the protocol, should not take more than 21 days) was shown for the first time reliably. In 66 patients with a break between the first and second block for less than 21 days, survival 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 the modification of doses, but also by the density of the therapeutic elements.

Multivariate analysis of the results of treatment of more than 1000 patients using the ALL-REZ-BFM-83 and ALL-REZ-BFM-90 protocols showed that stratification into risk groups and, accordingly, treatment options should be reviewed. A small group of patients with a good prognosis can be identified (group S, in the new study ALL-REZ-BFM-95). These are patients with late isolated extramedullary relapses, representing no more than 5-6% of all patients (60 of 1188) with the first relapse of ALL. Survival in this group is 77%. About 15% (175 of 1188) are patients of the unfavorable prognosis group with early isolated bone marrow relapses (group S ₃ ). They should be distinguished from the group of patients with a particularly unfavorable prediction: with very early bone marrow (isolated and combined) relapses and bone marrow recurrence 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 results of treatment are equally bad in both groups, there are significant differences in the level of achievement of remission and the level of therapeutically caused mortality in the period of induction. If in group S ₃ remission reaches 80% of patients, then in group S ₄ - only in 50%. In addition to the high frequency of refractory cases and relapses, very many patients in the S ₄ group , in contrast to the S ₃ group , 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 a second remission rarely exceeding 8 months. The most numerous group is represented by patients with intermediate prognosis (group S ₂ ). These are patients with late isolated and combined bone marrow relapses, with early extramedullary relapses and extramedullary recurrence of T-cell leukemia (652 out of 1188 or 55% of all patients). Survival in this group is an average of 36% (from 30 to 50%).

This stratification into risk groups underlies the protocol ALL-REZ-BFM-95. 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 due to a decrease in total dose loads of cytotoxic drugs. To this end, the first two therapeutic elements R ₁ and R _{2 have} been replaced by less intense blocks F1 and F2 "the therapeutic element R3is excluded. Treatment of patients with a particularly unfavorable prognosis (group S ₄ ) also underwent a change. Its essence is an attempt to overcome drug resistance of tumor cells with the help of new test combinations of cytostatics. Including idarubicin and thiotepu. High-dose intensive chemotherapy in these patients is excluded completely. The decision on whether to continue chemotherapy after each therapeutic element is taken individually in each specific case.

New approaches to the therapy of relapses of acute lymphoblastic leukemia (bone marrow transplantation, immunotherapy, etc.) are being developed. Studies of the BFM group showed that the optimal method for treating children with late relapse is polychemotherapy. Bone marrow transplantation is best performed with early (very early) or repeated relapse, provided that the tumor is sensitive to therapy, since good results in the treatment of late relapse with polychemotherapy take precedence over the toxicity of conditioning regimens for cosmic brain transplantation.

[1], [2], [3], [4], [5], [6], [7], [8], [9],