Saturday, December 4, 2004, 06:00 PM
[886] All-Trans-Retinoic Acid (ATRA) and Arsenic Trioxide-Induced Expression and Regulation of Programmed Cell Death 4 (PDCD4) in Acute Promyelocytic Leukemia.
Session Type: Poster Session 40-I
Bulent Ozpolat, Maribel Tirado-Gomez, Nancy H. Colburn, Gabriel Lopez-Berestein (Intr. by Kapil Mehta). Experimental Therapeutics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA; Experimental Therapeutics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA; Gene Regulation Section,Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA; Experimental Therapeutics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA
All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia (APL) characterized by t(15;17), which leads to expression of PML-RARa and differentiation arrest. ATRA treatment alone results in complete remission (CR) about 90% of APL patients. However these remissions are transient and APL patients commonly become resistant to ATRA therapy. Recently, arsenic trioxide, As(2)O(3), was proven to be highly effective in inducing CRs not only in relapsed after ATRA and primary APL patients. Despite the well documented clinical efficacy ATRA and As(2)O(3) in APL, precise downstream molecular mechanisms of action of these agents and the molecular mechanisms responsible for the resistance largely remain unknown. Recently, employing comprehensive proteomics methods we studied molecular mechanisms of ATRA-induced growth inhibition in APL cells. We reported that ATRA induces translational suppression through multiple posttranscriptional mechanisms involved in translation initiation and elongation phases (Harris &Ozpolat et al, Blood, 104 (5) 2004). We also demonstrated that ATRA inhibits expression translation initiation factors including IF2, eIF4AI, eIF4G, eIF5, eIF6 but upregulates expression of translation inhibitor DAP5/p97/NAT1 in APL cells. Translational control of gene expression has been identified as an important regulatory mechanism for gene products involved in regulation of cell proliferation, differentiation and apoptosis. Programmed cell death 4(PDCD4) inhibits cap-dependent translation and exerts transformation-suppressing activity by inhibiting the helicase activity of eIF4A. . Here we investigated whether PDCD4 plays a role in ATRA-induced growth inhibition and terminal differentiation by mediating translational suppression. We found for the first time that ATRA (1 mM) and As(2)O(3) ( 0.4 mM and 2 mM) induced PDCD4 expression at mRNA and protein level detected by RT-PCR and western blotting analyses, respectively, after 24 h of treatment in NB4 cells. As(2)O(3) induced maximum PDCD4 protein expression at 72 h of treatment in NB4 cells ATRA induced PDCD4 mRNA expression in ATRA responsive human acute myeloid leukemia cells (HL-60) but not in ATRA-resistant HL60 cells (HL-60R), which express a point mutation in ATRA binding domain of RARa, suggesting PDCD4 expression is mediated through retinoid receptor alpha in HL-60 leukemia cells. Overall data suggest that translational control may play a role in ATRA-induced differentiation and As(2)O(3)-induced effects. We are currently determining whether other retinoid receptors are involved in ATRA-induced expression of PDCD4 and testing the hypothesis that whether PDCD4-mediated translational suppression is critical to ATRA-induced APL cell differentiation. Activation of these pathways that lead to translational suppression reveals a novel mechanism of ATRA action and provide novel insights into ATRA-induced differentiation program in APL cells.Better understanding of posttranscriptional control of gene expression may offer targets for the differentiation therapy and chemo preventive strategies.
Abstract #886 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: As2O3|Acute promyelocytic leukemia|ALL-trans retinoic acid (ATRA)
Poster Session: Adult AML and APL (6:00 PM-7:30 PM)
+++++++++++++++++++++++++++++++=
Saturday, December 4, 2004, 06:00 PM
[888] Clinical Observation on the Efficacy of All-Trans Retinoic Acid (ATRA) Combined with Arsenic Trioxide (As2O3) in Newly Diagnosed Acute Promyelocytic Leukemia (APL).
Session Type: Poster Session 42-I
Y.F. Liu, Z.X. Shen, J. Hu, Y.M. Zhu, J.M. Li, J.H. You, Y. Shen, Z.Z. Shi, S.J. Chen, Z. Chen, Z.Y. Wang. Department of Hematology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai, China
PURPOSE: To determine the efficacy of front-line use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) in patients with newly diagnosed acute promyelocytic leukemia (APL).
PATIENTS AND METHODS: Since 2001, 61 patients have received ATRA (25mg/m2) and As2O3 (0.16mg/kg) daily till CR and all patients received 3 consolidation chemotherapy and then received 5 cycles of sequential treatment of ATRA, As2O3 and 6-MP/MTX. The efficacy of treatment protocol in induction remission, molecular response and relapse-free survival were compared with our historical control.
RESULT: 58 (95.1%) patients achieved CR and all remain relapse free with the current protocol. Though ATRA/As2O3 duet did not improve the hematological/molecular remission rate and reduced the early mortality after induction, it did induce an early hematological response (26.1±4.1 days). During limited follow-up (20 to 39 months), both RFS and OS are significantly increased in patients who received the ATRA/As2O3/ chemotherapy triad as post-remission therapy compared to the historical control. PML-RARa mRNA was retrospectively assessed by quantitative real-time reverse transcription-polymerase chain reaction (RQ-RT-PCR) before treatment, after CR, after consolidation and during follow-up period in 36 patients with ATRA and As2O3 combination treatment. PML-RARa normalized dose was found to be more significantly decreased after remission induction (median fold reduction: 335.8), and after consolidation (median fold reduction: 358362.2), as compared with ATRA or As2O3 mono-therapy. The addition of As2O3 into post-remission therapy can further increase the post-remission molecular response through either qualitative or quantitative RT-PCR measurement. CONCLUSION: Our current follow-up data suggested a potential benefit of front-line combination of ATRA and As2O3, which might translate into better chance of curing the disease.
Abstract #888 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: Arsenic trioxide|Retinoic acid|Acute promyelocytic leukemia
Poster Session: Adult AML and APL (6:00 PM-7:30 PM)
++++++++++++++++++++++++++++++++++++++++++++++
Saturday, December 4, 2004, 06:00 PM
[889] Arsenic Trioxide (As2O3) in the Treatment of Patients with Newly Diagnosed Acute Promyelocytic Leukemia (APML) – Toxicity and Outcome.
Session Type: Poster Session 43-I
Biju George, Vikram Mathews, Auro Vishwabandhya, Alok Srivastava, Mammen Chandy. Haematology, Christian Medical College, Vellore, Tamilnadu, India
There is limited data on outcome and toxicity in newly diagnosed patients with APML treated primarily with arsenic trioxide (As2O3). We have treated 58 patients with APML, who were unable to receive all-trans retinoic acid (ATRA) based therapy, with As2O3 between 1997-2004. As2O3 was administered as follows: 10 mg/day for adults and 0.15 mg/kg/day for children. For remission induction, it was given till hematological remission (CR) was achieved (or maximum of 60 days) followed by a consolidation course of 28 days, 1 month after achieving CR. Maintenance therapy was administered for 10 days every month for 6 months. Hydroxyurea was used to control rising white cell counts. Patients were monitored for blood counts, coagulation profile, liver and renal functions and for cardiac complications. Supportive treatment was provided as necessary. There were 58 patients (30 males, 28 females) with a mean age of 28 years (range: 6 – 60) and a median WBC count at diagnosis of 2.8 x 109/L (range: 0.6 to 163.4). At diagnosis, 34 patients (58.6%) had severe thrombocytopenia < 20 x 109/L, 5 (8.6%) had coagulopathy while 8 (13.7%) had abnormal liver functions. Leukocytosis was seen in 46 patients (79.3%) starting at an average of 5 days (range: 1-20) after starting treatment with As2O3. Only 4 of these went on to developn an ATRA-like syndrome which resolved with treatment in all. The mean WBC count at this time in these patients was 31.5 x 109/L (range: 15.3 to 45.8). In 43 patients, leukocytosis was controlled with hydroxyurea while 3 patients required additional treatment with anthracyclines. Hydroxyurea was given for a mean of 11 days (range: 2 – 28) with temporary discontinuation of As2O3 in 6 patients. Asymptomatic elevation of liver enzymes and mild sensory neuropathy were seen in 9 patients each (15.5%) not requiring discontinuation of As2O3. One patient developed supraventricular tachycardia for which arsenic was temporarily discontinued, but was restarted later with cardiac medication without further complications. Hyperpigmentation and ichythosis of the skin were seen in 8 patients (13.7%). Twenty seven patients (46.5%) had coagulopathy and required corrective infusion of fresh frozen plasma for a median of 4 days (range: 2 – 15). Thirteen patients (22.4%) had >10% weight gain related to fluid retention. Gastrointestinal side effects of dyspepsia and vomiting were seen in 3 patients (5.1%). Minor side effects included myalgia and conjunctival suffusion in 1 patient each (1.7%). Nine patients expired less than 2 weeks into treatment due to intracranial hemorrhage. Response to As2O3 was therefore evaluable in 49 patients. Fortyseven patients (95%) achieved hematological remission. Of the two patients who did not achieve remission, one expired on day 21 due to intracranial bleed while the second died on day 22 due to bacterial sepsis. One patient in hematological remission died due to fungal pneumonia on day 60. Forty six patients have received subsequent courses of As2O3. At a median follow up of 23 months (range: 3 – 79), 4 (8.6%) have relapsed. Of these, 3 have achieved a second remission with As2O3 and ATRA. Presently, 45 patients (77.5%) are alive and in molecular remission with a leukemia free survival of 91.3%. Our data shows that As2O3 alone induces durable remission in a majority of patients with APML with no major toxicity. Long term follow up is required to assess the late effects of As2O3.
Abstract #889 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: Acute promyelocytic leukemia|Arsenic trioxide|Toxicity
Poster Session: Adult AML and APL (6:00 PM-7:30 PM) |
