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A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells.

Cocukluk yasi akut myeloblastik losemi ve myelodisplastik sendromunda myeloid losemik hucrelerde farklilasma ve apoptosisi saglayan yuksek doz metilprednizolon ile yeni bir tedavi yaklasimi

Introduction

Glucocorticoids (GCs) have been used successfully in the treatment of childhood acute lymphoblastic leukemia (ALL) since the late 1940's. To enhance their effectiveness, higher doses of GCs (250 to 1000 mg daily) were used, mostly in adults, up to the early 1960's. Massive doses of steroid induced hematologic improvement more rapidly in ALL patients, and the beneficial effect was noted in patients who became resistant to conventional-dose steroid and also in a few patients with acute myeloblastic leukemia (AML) [1-3). However, for a long period, the therapeutic benefits of GCs at higher doses were not evaluated in clinical trials. Recently, in in vitro studies, higher antileukemic activity [4), which may be associated with an increase in apoptosis [5,6), and favorable clinical results were obtained by increasing the dose of GCs in childhood ALL [7-12].

In contrast to ALL, in patients with AML, it is generally believed that GCs in conventional dose have limited or no effect. Despite the favorable results obtained in childhood ALL, progress in the treatment of children with AML with currently used regimens, which mainly depend on the eradication of blast cells by cytotoxic agents, remains unsatisfactory [13,14]. However, the possibility of treatment with agents that induce terminal differentiation of myeloid leukemic cells has long been proposed as a promising approach for improvement in the prognosis of patients with AML. Differentiation-inducing therapy with a derivative of vitamin A, all-trans retinoic acid (ATRA), resulted in significant improvement in the outcome in children with acute promyelocytic leukemia (APL, AML-M3) [15,16]. However, the results in non-APL patients obtained with ATRA are not encouraging. Based on the in vitro studies, which revealed that arsenic trioxide can induce differentiation and apoptosis of APL cell line NB4 and fresh APL cells with t (15;17) dose-dependently [17], it has also been incorporated in the treatment of adult APL patients. However, there are limited data regarding results in children with APL [18].

GC-induced differentiation and/or apoptosis of human myeloid leukemic cells in vitro

Since the early 1970's, a number of experimental studies have shown that prednisolone (PRD) and dexamethasone (Dex) are the most potent agents for inducing differentiation of mouse myeloid leukemic cells into macrophages and granulocytes [19-22]. Moreover, a high concentration of Dex caused complete arrest of mouse myeloid leukemic cell proliferation and prolonged the survival in mice inoculated with sensitive M1 cells [23]. In further studies, differentiation- and/or apoptosis-inducing effects of Dex or methylprednisolone (MP) on human primary AML cells [24-26] and myeloid leukemia cell lines (HL60, NB4, U937, HIMeg and t(8;21)-positive myeloid leukemia cells), in a dose-dependent manner, have been demonstrated in vitro [27-32]. Various effects of steroid on human and mouse myeloid leukemic cells were reviewed previously [33,34].

Other steroid derivative-induced differentiation and/or apoptosis of human myeloid leukemic cells in vitro

Very recently, Chow et al. [35] reported that 2-methoxyestradiol (2ME2), a natural metabolite of 17[beta]-estradiol, can induce apoptosis in different types of AML cell lines (HL-60, NB4 and U937) and in primary human AML cells (M0, M1, M2) in vitro in a dose-dependent manner. Trafalis et al. [36], who evaluated the effects of two homo-aza-steroids (1 androgen and 1 estrogen derivative) on leukemic blasts obtained from patients with various subtypes of AML, indicated the capacity of differentiation. Several aminosteroid compounds have also been shown to inhibit proliferation and/or induce differentiation in HL-60 cells dose-dependently [37,38]. In addition, a cardiotonic steroid, bufalin, has been shown to induce differentiation of human myeloid leukemia-derived cell lines, HL-60, U937 and ML1, and leukemic cells from 4 of 20 AML patients in primary culture [39,40]. In all these studies, therapeutic potential of these different steroid derivatives as possible novel agents in the blood malignancies has been indicated [35-40]. Furthermore, in addition to another steroid derivative, 1[alpha], 25-dihydroxyvitamin [D.sub.3] and its analogs, which is well known to induce differentiation [41], isomeric pregnadienedione steroids (guggulsterones, naturally occurring plant sterols) and 16-dehydroxyprogesterone with increasing concentration have been shown recently to exert antileukemic effect by inducing differentiation and apoptosis in human AML cell lines (HL-60, NB4 and U937) by Samudio et al. [42]. These compounds also induced apoptosis in primary CD34-positive leukemia cells obtained from relapsed patients with AML-M0 and M2 [42]. Interestingly, it has been indicated that the pregnadienedione structure of these steroids could offer the potential for development of novel chemotherapeutics.

Here, the results of our clinical studies with another pregnadienedione steroid derivative, MP, which induces differentiation and apoptosis of myeloid leukemic cells in vivo, will be reviewed.

Short-course HDMP treatment-induced differentiation of myeloid leukemic cells in vivo

Since 1988, we have shown the remarkable antileukemic effects of MP at high doses, in various subtypes of newly diagnosed and relapsed children with AML [43,44]. Children who had no infection were given MP sodium succinate (Prednol-L, MN Pharmaceutical, Turkey) orally, at a single daily dose of 20-30 mg/kg (not exceeding 1 g daily) together with an antacid. Based on the experimental studies on induction of differentiation of mice myeloid leukemic cells, we first demonstrated morphologic evidence of in vivo differentiation of myeloid leukemic cells to mature granulocytes in a boy with AML-M4 treated with HDMP alone in 1991 [45]. In our further studies, short-course (3 to 7 days) high-dose (HD)MP treatment was also shown to induce terminal differentiation of myeloid leukemic cells in children with APL (AML-M3) and in other sub types of AML (AML-M1,-M2,-M4,-M7) [46-49]. In addition to rapid reduction of blast cells, morphologic changes including presence of Auer rods in mature cells (Figure 1) and surface marker analysis of peripheral blood and/or bone marrow cells by flow cytometric studies confirmed the evidence of in vivo differentiation of myeloid leukemic cells. More recently, MP has been shown by Corsello et al. [32] in vitro to induce differentiation of AML cell lines with a t(8;21) in a dose-responsive manner. In this study, treatment of t(8;21)-positive Kasumi-1 cells with MP revealed loss of AML1-ETO protein expression in a proteasome- and GC receptor-dependent manner. Moreover, in three primary patient AML samples, AML1-ETO protein was reduced with in vitro MP treatment. MP could also be the effective agent for the targeted inhibition of dysregulated transcription factors in some other subtypes of AML. It will be interesting to explore whether or not HDMP treatment induces cellular differentiation in some other malignant diseases.

Short-course HDMP treatment-induced apoptosis of myeloid leukemic cells in vivo

Apoptosis (programmed cell death) has been demonstrated in vitro to be the common mode of cell death of differentiated human myeloid leukemic cells (HL-60) [50]. We have also shown that induction of apoptosis of myeloid leukemic cells with or without differentiation is possible with HDMP treatment in vivo and in vitro [26,49,51]. In addition to ultrastructural findings, light microscopic studies revealed the morphologic evidence of apoptosis in bone marrow cells obtained from different subtypes of AML children (AML-M3,-M4 and -M7) who received short-course HDMP (4 days) as a single agent. Incubation of low ([10.sup.-6]M) and high ([10.sup.-3]M) concentration of MP with freshly obtained leukemic cells from AML children resulted in a dose-dependent increase in differentiated cells and in apoptosis [26]. Previously, Blewitt et al. [52] demonstrated that GCs at suprapharmacologic concentration, in contrast to low-dose, showed massive lethal effect possibly by inducing apoptosis in human myeloid leukemic cells in vitro [52]. It was also reported that cytolethal effects of GCs (hydrocortisone, Dex, MP) are dose-dependent, and among the GC preparations tested, the most severe cytolethal effect was obtained in human lymphoid and myeloid leukemic cells when exposed to a suprapharmacologic dose of MP ([10.sup.-3]M) [53]. Dex- and/or MP-induced apoptosis has been demonstrated in AML cell lines (Kasumi-1 and Skno-1 cells) with a t(8;21) [28,32], HL-60 and in human acute megakaryocytic leukemia (AmegL) cell lines in a dose-dependent manner [27,30]. A plant steroid, diosgenin, has also been shown to induce megakaryocytic differentiation and apoptosis in a human erythroleukemia cell line dose-dependently [54]. In addition to the results of in vitro studies and the rapid hematological and morphological improvement detected four days after HDMP treatment via induction of differentiation and apoptosis of leukemic cells, as observed in our patients with AmegL [26,49], it is important to note that addition of HDMP to induction therapy appears to be a very promising treatment approach in these patients who have poor prognosis. Suppression of the Bcl-2 by MP or Dex might indicate the role GCs in inducing apoptosis of myeloid leukemic cells [32,55,56]. Dex has also been shown to significantly suppress expression of c-myc and c-myb genes during Dex-induced differentiation of mouse myeloid leukemic cells [56,57].

[FIGURE 1 OMITTED]

Therapeutic effects of HDMP in children with AML Effect of HDMP on blast cells

During our long-term clinical studies, in a short-period (24 or 48 hours) after administration of HDMP treatment alone, dramatic clinical improvement (improved activities; resolution of bone pain and unexplained high fever) was observed in most of the AML children who had not received HDMP previously. In addition, rapid decrease in blast cells in both peripheral blood and bone marrow with a concomitant increase in the number of maturing and mature myeloid cells (metamyelocytes and polymorphonuclear leukocytes) was detected after short-course (4 to 7 days) HDMP without using any other antileukemic agents in different subtypes of AML children [43-49,58,59]. Changes in marrow blasts 4-7 days after HDMP treatment alone or two weeks after HDMP combined with cytosine arabinoside (Ara-c) are shown in Table 1. Marked decrease in marrow blasts was also detected in relapsed children [44]. In a patient with refractory AML, complete remission (CR) was also described by Sugawara et al. [60] using HDMP combined with granulocyte colony-stimulating factor (G-CSF). Although a similar effect was not obtained in our patients who previously received HDMP, it is important to note that 3-4 months after its discontinuation, some of the patients responded again to HDMP.

Effect of HDMP on extramedullary infiltration

More importantly, dramatic decreases in the size of extramedullary leukemic infiltration (orbita, gingiva and soft tissue) were detected in 24 hours to 7 days after initiation of HDMP treatment [43-45,58,61]. Rapid decreases in orbital and spinal mass following the administration of HDMP treatment alone were also reported by others in children with AML-M2 and t(8;21) translocation [62,63]. Furthermore, we demonstrated complete resolution of pleural effusion and marked decrease in pericardial effusion in children with chronic myelomonocytic leukemia (CMML) four days after HDMP treatment alone, which also induced differentiation and apoptosis of malignant cells in the pleural effusion [64]. Based on these results, we can suggest that addition of short-course HDMP to initial treatment would be a very effective approach for the treatment of patients presenting with extramedullary infiltration

Combined HDMP with cytotoxic chemotherapy

In our previous study reported in 1992, addition of HDMP to mild antileukemia regimens (adriamycin and Ara-c) increased the CR rate to 84.6% in 26 newly diagnosed AML children with or without extramedullary infiltration when compared to the CR rate (62%) of historical controls [59.65], and reduced the number of early relapses occurring within 12 months (45% vs 78%) and 24 months (76% vs 90%), respectively. However, difference in five-year disease-free survival (DFS) rate was not significant (18% vs 10%). In our subsequent studies with two different treatment protocols reported in 2004, the CR rate was 87% and 89% in 23 and 45 children, respectively, who had no extramedullary infiltration at presentation [58]. By using intensive maintenance therapy, improved outcome was achieved and the five-year DFS rate was 44% and 35%, respectively. In this study, in a small number of children (n=7) who presented with myeloblastoma, five-year DFS rate was 71% [58]. However, this improvement was not noted in children with gingival infiltration. We believe that further studies in these heterogeneous group of AML patients who have large differences in outcome should be explored with combined HDMP and more intensive chemotherapy than used in our studies, in an effort to improve the outcome. HDMP treatment was well tolerated, HDMP-related toxicity was mild, and no life-threatening events occurred [58,59]. During induction therapy, after the addition of cytotoxic agents to HDMP, mortality rate was 4% in 112 children with AML [58]. However, unlike with cytotoxic agents, in a short period after initiation of HDMP, increase in white blood cell (WBC) count, which was controlled by the administration of cytotoxic drugs, was observed in 25% of the AML children and in children with myelodysplastic syndrome (MDS) as well [58,66]. This increase was not associated with the increase in peripheral blast cells. Rapid increase in WBC count following massive-dose steroid therapy was also noted in some patients with AML in previous studies [2,3]. Therefore, patients with WBC count >25 x [10.sup.9]/L at diagnosis were given chemotherapy concomitantly with HDMP administration.

Since an early blast cell clearance by remission induction therapy is a major independent prognostic factor, the improved outcome in our patients could be related with the initial striking decrease in leukemic cells in the bone marrow and in the extramedullary site obtained with HDMP as a differentiating- and apoptosis-inducing agent. In addition, administration of short-course (4 days) HDMP treatment during induction therapy resulted in a rapid increase in T4+, T8+ T-cells and natural killer (NK) cells, possibly due to stimulation of marrow CD34+ cells, which may also contribute to the antileukemic effect of HDMP [67]. It has also been shown by Vitale et al. [68] that pharmacological concentration of MP can induce preferential and rapid in vitro differentiation of CD34+ hematopoietic precursors to NK cells.

Recently, dramatic selective blast cell reduction associated with apoptosis and improved outcome were reported by Suzuki et al. [69] in elderly patients (63-89 years) with AML secondary to MDS treated with MP alone (125 mg, body). Significant blast reduction with hematological and cytogenetic remission following HDMP (1000 mg/day) treatment alone was also demonstrated by Shimohakamada et al [70] in an adult AML patient who had pulmonary infection. However, the optimal dose of MP in inducing differentiation and apoptosis remains unknown.

The stimulation of normal myelopoiesis with HDMP treatment would be an additional benefit in the treatment of these patients. Short-course (3-5 days) HDMP treatment shortens the chemotherapy-induced neutropenic period in children with AML and ALL during induction and maintenance therapy, possibly by stimulating the CD34+ hematopoietic progenitor cells [71-73]. Pretreatment with short-course HDMP, before high-dose consolidation therapy, reduced the duration and severity of neutropenia in children with AML [74]. We suggest that the effect of short-course HDMP should be evaluated in non-leukemic malignancies in order to stimulate neutrophil recovery.

Therapeutic effects of HDMP in children with MDS

Although significant progress has been achieved in the treatment of children with MDS who could have received hematopoietic stem cell transplantation, treatment results with standard chemotherapy regimens have been generally unsatisfactory [75,76]. Since progressive impairment in differentiation of hematopoietic cell lineages is the main pathophysiological feature, there has been great interest in using differentiation-inducing agents in MDS. However, results with retinoic acid and vitamin D3 are not encouraging [77].

On the other hand, we obtained promising results in children with various subtypes of MDS (refractory anemia with excess blast (RAEB), RAEB in transformation, juvenile myelomonocytic leukemia (JMML) and CMML) with the addition of HDMP to cytotoxic chemotherapy [66,78,79], with the exception of patients with JMML and monosomy 7. As observed in AML children, a marked decrease in blast cells both in peripheral blood and bone marrow was also detected after HDMP treatment (Table 1). In addition, dramatic resolution of extramedullary infiltration (orbital, spinal and pleural), possibly due to its differentiation- and apoptosis-inducing effects, was also noted in these children [66,79]. With the use of combined HDMP and mild cytotoxic chemotherapy, higher CR rate (70%) was achieved in 17 of 25 children with different subtypes of MDS [79]. Improvement in the outcome in these children, especially in children with CMML, seems to be promising. Our preliminary data showed that short-course HDMP treatment might also be beneficial by remarkably increasing serum levels of interleukin-2 in children with CMML [80]. As obtained with anti-thymocyte globulin and cyclosporin A, modulation of immune response by HDMP might contribute to its beneficial effect in some patients with MDS. In contrast to other immunosuppressive agents, an advantage of the use of short-course HDMP and its favorable effects have been indicated in adult patients with refractory anemia [81-83]. Decrease in serum tumor necrosis factor-alpha after short-course HDMP therapy observed in children with AML and ALL might indicate that it is also effective in MDS, leading to hematologic improvements [84]. In addition, an inhibitory effect of steroids (PRD and Dex) has been shown in vitro on the production of leukemia-associated inhibitor from human myeloid leukemic cells, which has been suggested by Olofsson et al. [85] as being responsible for the suppression of normal hematopoiesis. The possibility of HDMP-induced suppression of inhibitory activity of MDS abnormal clones [86] may also contribute to its effect in MDS. These possibilities might explain the favorable response to short-course HDMP treatment obtained in our patient with hypoplastic MDS as well as in a case with hypoplastic AML [87,88].

Identification of responsive MDS patients to GC therapy by in vitro technique was first reported by Bagby et al. [89]. In that study, it was suggested that if therapeutically achievable concentrations of cortisol enhance colony growth of marrow cells and if the colonial cells are well differentiated (granulocyte maturation was observed in 2 patients), the patients will likely respond favorably to PRD therapy. Interestingly, they described responses when higher doses of PRD were used in patients who were considered in vitro non-responders. Beneficial effects of high-dose steroid in patients with MDS were also reported by others [90-94]. Based on these studies, HDMP combined with chemotherapy followed by autologous stem cell transplantation can be considered as an alternative therapeutic approach in children with MDS who are not suitable for bone marrow transplantation.

In conclusion, our clinical studies indicate that addition of short-course HDMP as a differentiation- and apoptosis-inducing agent to cytotoxic chemotherapy regimens represents a promising approach in the treatment of children with AML and MDS. In further studies, its effective dosage, duration of administration and role in maintenance therapy should be evaluated. Although the factors involved in the mechanisms of HDMP effect in inducing differentiation, apoptosis and stimulation of myelopoiesis are not well known, it may be effective through complex mechanisms to target several antileukemic pathways. Further studies, enhancing the understanding of the metabolic and molecular basis of these effects, could provide important therapeutic benefit in children with AML and MDS. Based on the results of our clinical studies, short-course HDMP also deserves evaluation regarding its effect in the treatment of some other malignancies.

Acknowledgements

I would like to particularly thank Prof. Dr. M. Cetin and all my colleagues who made valuable contributions during these studies, as indicated in the list of cited references of the published papers. I also warmly thank all doctors, nurses and the technical personnel who also made valuable contributions during the long clinical follow-up period of these children. I would like to acknowledge Prof. Dr. E. Erdemli and Prof. Dr. M. Tekelioglu from the Department of Histology at Ankara University for providing electron microscopic studies.

Conflict of interest

No author of this paper has a conflict of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included in this manuscript.

Received: November 8, 2009 Accepted: November 19, 22009

Gelis tarihi: 8 Kasim 2009 Kabul tarihi: 19 Kasim 2009

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Gonul Hicsonmez

Department of Hematology, Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey

Address for Correspondence: Gonul Hicsonmez, MD, Department of Hematology, Ihsan Dogramaci Children's Hospital Hacettepe University, Ankara 06100, Turkey Phone: +90 312-238 11 19 Fax: +90 312-324 49 90 E-mail: gsonmez@hacettepe.edu.tr
Table 1. Decrease in percent of marrow blasts after HDMP alone or HDMP
combined with Ara-c in children with newly diagnosed AML and MDS

 Duration of Blast cells%
No. of treatment
Patients Treatment (day) <5% 0-15% References

37 * HDMP 4-7 12(32%) 20(54%) 58
26 * HDMP+ Ara-c 15 7(27%) 17(61%) 59
4 ** HDMP+LD-Ara-c 4(100%) --
8 ** HDMP 4 7(88%) 8(100%) 79

* AML, ** RAEB and RAEB-t, Ara-c (3mg/kg, 3 days a week), LD Ara-c
(10 mg/[m.sup.2])

HDMP: High-dose methylprednisolone; LD Ara-c: Low-dose cytosine
arabinoside; AML: Acute myeloblastic leukemia; MDS: Myelodysplastic
syndrome; RAEB: Refractory anemia with excess of blasts; RAEB-t: RAEB
in transformation
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Date:Mar 1, 2010
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