Acute promylocytic leukemiaALP is a malignant leukocytic disease that can affect patients of different ages and is a specific subtype of AML, accounting for approximately 5-15% of AML. APL is apparently characterized by some kind of chromosomal abnormality genetic transformation, a translocation of chromosomes 15 and 17.
This genetic alteration leads to inhibition of normal cell growth and impairment of the maturation of leukocyte precursors in the bone marrow, which eventually leads to cancer.
APL is rarely associated with splenomegaly at initial diagnosis, a high bleeding tendency, a high incidence of DIC, and approximately 10 to 30% of ALP patients die from bleeding before or during induction therapy. high WBCs predispose to renal failure and respiratory failure. Early mortality is high when remission is induced with cytotoxic drugs. Since all-trans retinoic acid and arsenious acid have been used successfully to induce remission in ALP, but the induction of remission takes longer. In recent years, we treated 13 cases of APL with “small triad”: retinoic acid, arsenious acid, and low-dose chemotherapy, which shortened the induction remission time of APL, significantly accelerated the time to complete remission, and significantly accelerated cell differentiation and apoptosis, and also reduced the occurrence of various comorbidities such as DIC.
Clinical data.
I. Cases: 13 cases of APL were all patients treated in our department for the first time. There were 8 male cases and 5 female cases. The ages ranged from 3 to 39 years, with a mean age of 23 years. All cases met the diagnostic criteria of the 1987 National Symposium on Leukemia Chemotherapy Treatment.
Second, treatment: retinoic acid: 50 mg/m2 /d-, three oral doses, continued to induce the end. Arsenious acid: 0.15 mg/kg/d-, intravenous drip for a total of 15 days. HAC triple chemotherapy: high triptan: 1 mg/d- intravenous drip for 1 to 7 days. Cytarabine: 150mg/ d-, IV drip for 1-7 days. Cyclophosphamide: 600mg/ d-, IV drip for 1, 3 and 5 days. 15 days is a course of treatment, and intensive therapy is started after one course of treatment for those with complete re-bone marrow. Then sequential therapy was carried out, with arsenious acid, retinoic acid and mini-chemotherapy applied alternately, with the first year of “mini-trim” being treated at one-month intervals, the second year at two-month intervals, and the third year at three-month intervals.
All 13 cases of APL were treated with arsenious acid, retinoic acid and small doses of chemotherapy simultaneously. The observed results were as follows.
13 days: DIC was lifted and all coagulation indexes were normal.
7 days: total leukocyte count started to drop, 20×109/L every other day.
Day 14: The average leukocyte decreased to 2.5×109/L.
Day 9: The coarse asplenophilic granules in the early granulocytes in the bone marrow began to decrease, and the nuclei were divided, lacunar, and mononuclear-like —- differentiation was accelerated.
13 days: blood picture in remission.
Average 15-day bone marrow remission. Early 13-day remission.
Discussion.
Acute promyelocytic leukemiaAPL is a malignant leukocytic disease that can affect patients of different ages and is a specific subtype of AML, accounting for approximately 5% to 15% of AML.APL apparently has some kind of chromosomal abnormal genetic transformation – there is a translocation of chromosomes 15 and 17, and this genetic alteration leads to inhibition of normal cell growth. The maturation of leukocyte precursors in the bone marrow is hindered, which eventually leads to cancer.
APL is rarely associated with organomegaly at the time of initial diagnosis, with a high bleeding tendency and a high incidence of DIC. approximately 10% – 30% of APL patients die from bleeding before or during induction therapy. high WBC predispose to renal failure and respiratory failure. Early mortality is high when remission is induced with cytotoxic drugs. Since the success of all-trans retinoic acid and suberin for the induction of remission in APL, but the time to induction of remission is longer, triple therapy for APL is better than single retinoic acid for induction of differentiation. Data suggest that initial M3 remission with ATRA can be achieved in 70-90% of patients with a mean time to remission of more than 30 days, but 20-30% still relapse, and some studies have shown that patients have difficulty achieving remission when relapsing back on ATRA and chemotherapy. There is information that the duration of remission with single use of arsenious acid is >30 days long. Moreover, arsenious acid has side effects such as nephrotoxicity, hepatotoxicity, shortness of breath, fever, and muscle pain. Reducing the duration of arsenious acid use is undoubtedly to alleviate the above side effects. More especially than single chemotherapy, DIC did not occur, and the mechanism is thought to be three different mechanisms acting on the pathological cells, thus accelerating their differentiation and regulation, in the treatment observation statistics megakaryocytes are not reduced, platelets recovered signal fast. In the treatment observation statistics, there was no reduction of megakaryocytes, platelets recovered rapidly, red lineage proliferation followed, coarse asplenophilic granules in the cytoplasm of early juvenile granulocytes disappeared completely in 9 days, cells were isodisintegrated and formed obese 2- to 5-lobular nuclei, obese lobular nuclei granulocytes gradually decreased and granulocytes differentiated from normal stem cells took their place. 13 cases of APL did not show any serious infection. Analysis: M3 obese lobular nucleus granulocytes in lysis apoptosis, cytoplasmic non-specific particles reduced, its tropism, phagocytosis, killing, and other anti-inflammatory functions may be incomplete, but not completely lost, to be continued observation and exploration.
Mechanism of action of triple therapy: There are three main pathways of action of retinoic acid.
(i) Induction of differentiation, which can lead to differentiation of naïve leukemic cells morphologically and partially functionally towards mature granulocytes, and then death, and eventually remission by the appearance of normal hematopoiesis.
(ii) Induction of programmed death: programmed death, also known as apoptosis, is a form of non-pathological cell death. It is mainly manifested by nuclear chromatin agglutination, nuclear fragmentation, cytoplasmic vacuolar degeneration and the appearance of regulatory vesicles with increased specificity of nuclear endonucleases.
(iii) Inhibition of leukemic cell growth, in vitro studies have shown that retinoic acid inhibits HC-L60 cell growth. The number of bone marrow Cfu-L colonies decreased in APL patients who applied retinoic acid to reach CR, and the number of Cfu-GM colonies, which had been inhibited, rebounded significantly. cell cycle kinetic studies revealed that RA inhibited DNA synthesis, causing an increase in the number of cells in GO/G1 phase, a decrease in the number of cells in G1 and G2/M phases, and a decrease in the ability of cells to synthesize proteins.
The main mechanism of action of arsenious acid is induced by a process known as apoptosis, where tumor cell extinction causes DNA damage and alters cell conductance chemistry, decreasing PML-RARα fusion and leading to leukemic cell differentiation and apoptosis; effects on the hematopoietic microenvironment, in vitro and animal tests showed non-PML-RARα-dependent anti-leukemic effects by downregulating adhesion molecules and selectively blocking blood vessels supplying tumor cells. In vitro tests showed reactive oxygen species, in vitro tests showed linear steric damage and stimulated apoptosis of endothelial cells in the blood supply vessels of tumor cells. Consolidation therapy may suggest genetic remission with a unique therapeutic mechanism without post-chemotherapy-induced side effects.
The addition of small doses of chemotherapy resulted in significantly earlier induction of remission in APL. Cell differentiation apoptosis is significantly accelerated. Mitigation and reduction of toxic side effects caused by single, retinoic acid and arsenious acid treatment, resulting in shorter time of patient suffering and better success rate in clinical practice. It is also a new way to treat leukemia by combining ancient arsenic agents with modern medicine.