Leukemia (Part Four)

Control vs Cure

The survival of each patient with malignant hematologic pathology is determined by age, performance status, disease stage. Consequently, therapy is determined by these factors. For most patients, the treatment aims for a uniform goal; the achievement and maintenance of Complete Remission (CR). CR indicates the deepest possible reduction of the tumor mass in the body, but tumor mass remains (MRD). However, it should be emphasized that this is not a true CR, as most patients will relapse over time. So far, the only possibility for the complete elimination of the tumor mass, hence for the complete cure of the disease, is the successful Allogeneic BMT (Bone Marrow Transplant) (for a number of patients).

Only by achieving CR and maintaining it, as the most important goal of the treatment of hematologic diseases, can the disease and its many complications be controlled.

Chemotherapy

1. Induction (high-intensity chemotherapy) aims for a rapid destruction of measurable leukemic cells and to decrease the limits of minimal residual disease (MRD), thus trying to achieve the greatest possible reduction of the total number of leukemic cells in the body (reduction of the tumor mass). Treatment protocols vary, different clinics prefer different treatment schemes, but for adults there is still no “state of the art” protocol as for the pediatric age.

   The "Therapeutic Aplasia" period. Complete suppression of the Bone Marrow leading to anemia, neutropenia, severe thrombocytopenia with corresponding consequences. Careful, high morbidity and mortality inversely related to age.

   The goal of treatment in AML is to achieve Complete Remission - CR = clinical cure, in bone marrow > 50% cellularity, with the presence of maturation of the three lines and blasts < 5% (< 109cells), normal peripheral blood; without leukemic cells, with neutrophils > 500 mm3 and platelets > 100,000 mm3, without extramedullary involvement, ensured by the destruction of dividing tumor and normal cells, but not cells in G0 (like Normal Hematopoietic Cells and Leukemic Stem Cells).

   If repopulation of the Bone Marrow by normal hematopoietic stem cells is ensured, CR will be achieved, if not Partial Remission or failure. CR is not a biological cure, because tumor cells remain in the Bone Marrow and peripheral blood, (which are not distinguishable in cytological examination with MO), but are distinguishable with EM, immunophenotyping, cytogenetic and molecular examinations. These cells constitute “Minimal Residual Disease” or MRD. To minimize it, post-remission treatment will continue. Chemopreparations that do not cause a reduction of tumor cells less than 109 (thus achieving MRD) consequently do not provide CR.

2. Post – Complete Remission Therapy. For ALL, post-remission therapy in CR consists of using CT for a short time, with relative intensity followed by maintenance therapy – long-term therapy with low doses, BMT (Bone Marrow Transplant). All CRs will fail without post-remission therapy.

   a) Intensification aims to further reduce MRD. The same chemopreparations can be used at high dose as in Induction or high doses of other chemopreparations for a shorter time. When the same chemopreparations are used, it is referred to as consolidation or reinduction.

   b) Continuation (maintenance therapy or therapy continuation). Low dose of chemopreparations for a relatively long time. Aims to keep MRD at the lowest limits, i.e., to keep as small a number of residual leukemic cells as possible. 3 years for male children, 2 years for girls and adults.

   c) Elimination of residual disease, hence molecular level cure and complete disease cure is achieved through Allo-BMT (which can be used as consolidation + Auto-BMT or in case of failure). Careful side effects, cost, relapse. Allo - BMT has a lower incidence of relapses, but both allo-BMT and auto-BMT as post-remission therapy do not offer survival advantages compared to intensive therapy, except for patients with Ph1-positive ALL. The use of allo BMT as primary post-remission therapy is limited due to the difficulty of finding compatible HLA donors and increased mortality in patients in their 5th-6th decade (reaching up to 20% to 40%).

   d) For ALL, meningitis prophylaxis is done with intrathecal chemopreparations, high-dose MTX, radiotherapy. If the testes are affected, radiotherapy is done.

   e) APL (promyelocytic) is treated with All-Trans Retinoic Acid (Vesanoid, ATRA) + Anthracycline at the beginning of treatment and consolidation treatment after achieving Remission with MTX, 6-MP, ATRA. Almost all patients will relapse without consolidation therapy.

   f) Older ages, regimes with monotherapy and low dose (low doses). The possibility of achieving remission is smaller and, if achieved, shorter.

Cure is an achievable goal in ALL, ≥ 94% of pediatric patients have DFS (continuous disease-free survival) for 5 years and are considered cured, while 30–40% of adults have continuous disease-free survival for 5 years.

In AML, 60-70% of patients achieve CR with Induction Therapy. 20-45% of those achieving CR may live over 3 years (considered cured). It should be emphasized that clinical studies in most cases involve young patients who tolerate aggressive therapy. The overall cure rate for AML (including older patients and those who do not tolerate aggressive therapy) is lower. The cure rate for APL reaches up to 98%. The rate of remission and its duration in adult AML is inversely related to age. Secondary AML (post MDS, post AA, PNH, previous CT/RT treatments) the possibility of achieving and duration of remission are smaller than in de novo AML.

In 25-30% of adult ALL cases and 2-10% of pediatric cases and rarely (1-2%) of AML, a cytogenetic disorder indistinguishable from the Philadelphia Chromosome in CML but molecularly distinct is present. Aggressive LA. Treatment with Glivec, Dasatinib.

In cases of failures, relapses, BMT can be applied if not done previously. Immunotherapy is being attempted. If not possible, palliative and symptomatic treatment.

The current treatment is empirical. Systemic chemopreparations that eliminate any cell that is in rapid multiplication (including tumor cells, remaining normal hematopoietic cells, skin and mucosal epithelial cells, spermatogenesis in males) are used. The ideal is to damage tumor cells and as few (or none) normal cells as possible. The future of Acute Leukemia diagnosis will no longer be merely clinical and morphological, it will be molecular diagnosis and personalized therapy, target therapy (elimination of Leukemic Stem Cells through target therapy).