Relapsed Acute Promyelocytic Leukemia Research Articles

Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation.

The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%-30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease.

Long-term follow up of re-induction with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukemia previously treated with all-trans retinoic acid: results of 7 cases from a single institute

Long-term follow up of re-induction with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukemia previously treated with all-<i>trans</i> retinoic acid: results of 7 cases from a single institute

CNS Relapses of Acute Promyelocytic Leukemia After All-trans Retinoic Acid

OBJECTIVE:To review the role of all-trans retinoic acid (ATRA) and arsenic trioxide in central nervous system (CNS) relapses of acute promyelocytic leukemia (APL).CASE SUMMARY:A 69-year-old white man diagnosed with APL presented with bleeding diathesis. His molecular and cytogenetic studies were positive for promyelocytic leukemia—retinoic acid receptorα (PML-RARα) and t(15;17) transformation. Complete molecular and cytogenetic remission was achieved with ATRA, daunorubicin, and cytarabine. Within 6 months, the patient was readmitted for investigation of severe global headaches and an ataxic gait. His peripheral blood and cerebral spinal fluid were positive for PML-RARα fusion protein. Intrathecal chemotherapy and radiation, as well as ATRA, were the main treatment modalities provided. Molecular and cytogenetic remission was again obtained. Three months later, a second relapse occurred in the CNS and the peripheral blood.DISCUSSION:APL is typically treated with anthacycline-based chemotherapy and ATRA. Approximately 85–95% of patients achieve complete remission (CR); however, the relapse rate has been reported to be about 30–40%. A thorough literature search (MEDLINE, EMBASE, CANCERLIT, 1966–January 2002) revealed only 54 cases of extramedullary disease, of which 35 involved the CNS.CONCLUSIONS:The introduction of ATRA has improved patient survival dramatically. APL relapse, in general, has been in part attributable to repetitive or prolonged exposure to ATRA and the possibility of additional chromosomal changes, making the disease more refractory to treat. Given the evidence, one could argue that, with repeated ATRA treatment, CR duration may be shortened. However, limited data are available to guide the appropriate management of APL relapsed to the CNS with either ATRA, chemotherapy, or arsenic trioxide. In our opinion, treatment using arsenic trioxide is an unconventional option worthy of exploring.

Retinoic acid resistance in acute promyelocytic leukemia.

Primary resistance of PML-RARalpha-positive acute promyelocytic leukemia (APL) to the induction of clinical remission (CR) by all-trans retinoic acid (ATRA) is rare but markedly increases in frequency after > or =2 relapses from chemotherapy-induced CRs. Nevertheless, even in de novo cases, the primary response of ATRA-naive cases is variable by several measures, suggesting involvement of heterogeneous molecular elements. Secondary, acquired ATRA resistance occurs in most patients treated with ATRA alone and in many patients who relapse from combination ATRA chemotherapy regimens despite limited ATRA exposure. Although early studies suggested that an adaptive hypercatabolic response to pharmacological ATRA levels is the principal mechanism of ATRA resistance, recent studies suggest that molecular disturbances in APL cells have a predominant role, particularly if disease relapse occurs a few months after discontinuing ATRA therapy. This review summarizes the systemic and APL cellular elements that have been linked to clinical ATRA resistance with emphasis on identifying areas of deficient information and important topics for further investigation. Overall, the subject review strongly supports the hypothesis that, although APL is an infrequent and nearly cured disease, much can be gained by understanding the complex relationship of ATRA resistance to the progression and relapse of APL, which has important implications for other leukemias and malignancies.

Arsenic Trioxide Induces Apoptosis of HL-60 Cells via Activation of Intrinsic Caspase Protease with Mitochondrial Dysfunction.

Arsenic trioxide (As2O3) was introduced into the treatment of refractory or relapsed acute promyelocytic leukemia and showed a striking effectiveness in China and United States multicenter study. However, the mechanistic basis for the carcinogenic or therapeutic effects of arsenics is still poorly understood. So, this study is performed to determine whether As2O3 induces apoptosis through intrinsic caspase cascades in acute promyelocytic leukemia HL-60 cells. HL-60 cells were treated with As2O3 to investigate apoptosis through signaling of caspase cascades and mitochondrial dysfunction. As2O3 (>0.5 uM) decreased the viability of HL-60 cells in a dose-dependent manner, which was revealed as apoptosis shown chromatin condensation and ladder pattern DNA fragmentation. As2O3 increased the catalytic activity of caspase family cysteine proteases including caspase-3 and -9 proteases. Consistently, PARP, an intracellular biosubstrate of caspase-3 protease, was cleaved from 116 kDa to 85 kDa fragments. It also induced the change of mitochondrial membrane potential. Morever, As2O3 resulted in the increase of Bak. These data suggest that As2O3 induces apoptosis of HL-60 cells through activation of intrinsic caspase protease with mitochondrial dysfunction.

Atypical blasts and bone marrow necrosis associated with near-triploid relapse of acute promyelocytic leukemia after arsenic trioxide treatment

The pathologic features of acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) are highly characteristic, which with few exceptions enable a firm diagnosis to be made on morphologic grounds. An APL patient in first relapse presented with large, bizarre circulating blasts and bone marrow necrosis 2 weeks after chemotherapy consolidation for an arsenic trioxide–induced remission. Although a morphologic diagnosis could not be reached, cytogenetic investigations showed a near-triploid clone with t(15;17), confirming APL in second relapse. This case showed that clonal evolution with additional karyotypic aberrations might alter the blast morphology and pathologic features in APL. HUM PATHOL 33:849-851. Copyright 2002, Elsevier Science (USA). All rights reserved.

Inhibition by arsenic trioxide of human hepatoma cell growth

Arsenic trioxide (As2O3) has been shown to be effective for treatment of patients with refractory or relapsed acute promyelocytic leukemia and a variety of other malignant hematopoetic disorders. We studied the effect of this agent on proliferation of human hepatoma-derived cell lines (SK-Hep-1, HepG2, and HuH7). In HuH7 cells, As2O3 reduced proliferation time- and dose-dependently at 1 and 2 μM, while in SK-Hep-1 and HepG2 cells, As2O3 inhibited proliferation at 2 and 4 μM respectively. Cell cycle analysis by flow cytometry showed that As2O3 induced apoptosis in these hepatoma-derived cells as confirmed by appearance of sub-G1 cells. Sensitivity of hepatoma-derived cells to As2O3 was inversely related to their intracellular glutathione (GSH) and intensity of GSH synthesis. Arsenic sensitivity was restored to relatively resistant cell lines when GSH was depleted by l-buthionine sulfoximine (BSO). These results indicate that As2O3 may have therapeutic potential for treatment of hepatocellular carcinoma.

Arsenic trioxide: Mechanisms of action

The chimeric protein encoded by the PML-RARα gene that is pathognomonic of acute promyelocytic leukemia (APL) causes the arrest of myeloid cell development at the promyelocyte stage, leading to an accumulation of abnormal promyelocytes in the bone marrow. Differentiation therapy with all-trans retinoic acid (ATRA) is used routinely in patients with APL, but ATRA is not the only agent in clinical use that promotes differentiation of the abnormal clone. Arsenic trioxide (ATO) has been shown to cause degradation of PML-RARα, promoting differentiation. APL cells are extremely sensitive to ATO, which has shown good clinical activity at low doses in patients with relapsed APL. However, degradation of PML-RARα may not be wholly responsible for the great sensitivity of APL cells to ATO, which also acts through the intracellular environment to influence apoptosis, differentiation, growth arrest, and angiogenesis. ATO can act at several points in mitochondrially induced apoptosis, including degradation of peroxides and interaction with glutathione (GSH)-related enzymes. Subclones that are resistant to ATO have been used to demonstrate that sensitivity can be restored by reducing the cellular GSH content. GSH can be reduced using agents such as buthionine sulfoximine (BSO) and ascorbic acid. The key factors that determine the ATO sensitivity of cells and control ATO-induced apoptosis have not yet been defined. It has been proposed that ATO acts through activation of Jun N-terminal kinase (JNK), activator protein-1, and inhibition of dual-specificity phosphatases, and evidence is accumulating that JNK activation is an important event in arsenic-induced apoptosis. Further research is required to determine the exact pathways through which the cytotoxic actions of ATO are mediated. Semin Hematol 39(suppl 1):3-7. Copyright 2002, Elsevier Science (USA). All rights reserved.

Frequent mutations in the ligand-binding domain of PML-RARα after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-transretinoic acid and histone deacetylase inhibitors in vitro and in vivo

This study identified missense mutations in the ligand binding domain of the oncoprotein PML-RARalpha in 5 of 8 patients with acute promyelocytic leukemia (APL) with 2 or more relapses and 2 or more previous courses of all-trans retinoic acid (RA)-containing therapy. Four mutations were novel (Lys207Asn, Gly289Arg, Arg294Trp, and Pro407Ser), whereas one had been previously identified (Arg272Gln; normal RARalpha1 codon assignment). Five patients were treated with repeat RA plus phenylbutyrate (PB), a histone deacetylase inhibitor, and one patient experienced a prolonged clinical remission. Of the 5 RA + PB-treated patients, 4 had PML-RARalpha mutations. The Gly289Arg mutation in the clinical responder produced the most defective PML-RARalpha function in the presence of RA with or without sodium butyrate (NaB) or trichostatin A. Relapse APL cells from this patient failed to differentiate in response to RA but partially differentiated in response to NaB alone, which was augmented by RA. In contrast, NaB alone had no differentiation effect on APL cells from another mutant case (Pro407Ser) but enhanced differentiation induced by RA. These results indicate that PML-RARalpha mutations occurred with high frequency after multiple RA treatment relapses, indicate that the functional potential of PML-RARalpha was not correlated with clinical response to RA + PB treatment, and suggest that the response to RA + PB therapy in one patient was related to the ability of PB to circumvent the blocked RA-regulated gene response pathway.

Therapy-related myelodysplastic syndrome–acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem

AbstractThe use of all-trans retinoic acid (ATRA) in combination with chemotherapy has markedly improved the prognosis for patients with acute promyelocytic leukemia (APL); the higher complete remission (CR) and survival rates now reported in this disease almost approach those obtained for other highly curable hematologic malignancies. Of 77 patients with APL who were consecutively treated at a single institution and who achieved CR after induction and consolidation therapy, 5 (6.5%) acquired therapy-related myelodysplasia (tMDS), acute myelogenous leukemia (AML), or both (tMDS–AML). Of these, 3 of 46 (6.5%) patients received front-line chemotherapy with or without ATRA and acquired tMDS–AML while in first remission of APL. Two underwent repeated chemotherapy cycles with ATRA because of APL relapse and acquired tMDS–AML while in the second or third remission of APL. In 2 patients, clinical and biologic characteristics of tMDS–AML were as expected for postalkylating forms (long latency, MDS phase preceding AML, karyotypic aberrations involving chromosomes 5 or 7), even though one of them had not previously received alkylating drugs. Three of the 5 patients died shortly after tMDS–AML diagnosis, one is alive with tMDS, and one is alive and in CR after allogeneic bone marrow transplantation. The occurrence of tMDS–AML after successful therapy for APL is an emerging problem. The availability of prognostic score systems at initial diagnosis and monitoring of residual disease by polymerase chain reaction might allow better tailoring of treatment intensity in APL to spare unnecessary toxicity and to minimize the risk for tMDS–AML in patients who are presumably cured.

Arsenic trioxide, a therapeutic agent for APL.

Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the differentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)). Over the past 5 years, it has been well demonstrated that As(2)O(3) induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 85 to 90%). The side effects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As(2)O(3) as post-remission therapy has given better survival than those treated with As(2)O(3) alone. The effect of As(2)O(3) has been shown to be related to the expression of APL-specific PML-RARalpha oncoprotein, and there is a synergistic effect between As(2)O(3) and ATRA in an APL mouse model. Cell biology studies have revealed that As(2)O(3) exerts dose-dependent dual effects on APL cells. Apoptosis is evident when cells are treated with 0.5 approximately 2.0 microM of As(2)O(3) while partial differentiation is observed using low concentrations (0.1 approximately 0.5 microM) of the drug. The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell differentiation induced by low dose arsenic remain to be explored. Interestingly, As(2)O(3) over a wide range of concentration (0.1 approximately 2.0 microM) induces degradation of a key leukemogenic protein, PML-RARalpha, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers.

Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide

Arsenic trioxide has been shown to be effective in treating acute promyelocytic leukemia (APL), with minimal overall toxicity reported to date. A phase I/II study was initiated in June 1998 using arsenic trioxide for relapsed APL to determine the maximum tolerated or minimal effective dose and to determine the efficacy of treatment at that dose. Ten patients received 1 to 4 monthly cycles of treatment with 0.1 mg/kg per day intravenous arsenic trioxide. Six of 7 patients evaluable for response achieved cytogenetic or molecular complete remission. However, 3 patients died suddenly during the first cycle of treatment. Autopsies obtained on 2 of these failed to identify a cause of sudden death, despite evidence of pulmonary hemorrhage in one. A third patient, for whom an autopsy was not performed, became asystolic and died while on continuous cardiac telemetry. These observations suggest that arsenic trioxide may be significantly or even fatally toxic at doses currently used and that caution is warranted in its use.

Clinical Experience of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) has unique clinical, cytogenetic, and molecular features and is one of the most potentially curable human malignancies. The current standard treatment given to patients with newly diagnosed APL con-sists of all-trans retinoic acid and anthracycline-based cytotoxic chemotherapy, which is highly effective for remission induction. However, despite the potential for cure with existing treatments, approximately 20%-30% of patients relapse and require salvage therapy. Reports of the safety and efficacy of arsenic trioxide from centers in China led to a pivotal trial of this agent in the United States for patients with relapsed APL. In an initial pilot study, 11 of 12 patients experienced a complete response, and a subsequent multicenter trial confirmed the efficacy and safety of arsenic trioxide for remission induction in this patient population. Additional trials are under way to evaluate the use of this agent alone or as part of a chemotherapy regimen for consolidation and maintenance of patients with APL.

History of the development of arsenic derivatives in cancer therapy.

Arsenic is a natural substance that has been used medicinally for over 2,400 years. In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century. This multipurpose solution was also primary therapy for the treatment of chronic myelogenous leukemia until replaced by radiation and cytotoxic chemotherapy. The past 100 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline was due to concerns about the toxicity and potential carcinogenicity of chronic arsenic administration. The rebirth of arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide as part of a treatment for acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL. The mechanisms of action of arsenic derivatives in this disease and other malignancies are many and include induction of apoptosis, partial cytodifferentiation, inhibition of proliferation, and inhibition of angiogenesis. Molecular studies and ongoing clinical trials suggest that, as a chemotherapeutic agent, arsenic trioxide shows great promise in the treatment of malignant disease.

Risk/benefit profile of arsenic trioxide.

Approximately 20%-30% of patients with acute promyelocytic leukemia (APL) who are treated with the current standard all-trans retinoic acid and anthracycline-based chemotherapy regimen suffer relapse. In the mid-1990s, studies from China reported the effective use of arsenic trioxide in achieving complete remission in patients with APL. In the United States, a multicenter trial of this agent in 40 patients with relapsed APL following conventional therapy confirmed the positive safety and efficacy outcomes of a smaller 12-patient pilot study. Common adverse events were hyperleukocytosis, APL differentiation syndrome, prolonged QT interval on electrocardiogram, skin rash, and hyperglycemia.

Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukaemia: clinicopathological and molecular features of a pilot study.

Arsenic trioxide (As2O3) effectively induces remissions in relapsed acute promyelocytic leukaemia (APL), but the safety of its long-term administration is unknown. The anthracycline idarubicin is highly active alone or in combination chemotherapy for the treatment of APL. To minimize arsenic exposure and based on the high sensitivity of APL cells to anthracyclines, we conducted a prospective study to evaluate induction with As2O3 followed by consolidation with idarubicin in the treatment of APL in relapse. Eight patients were treated with As2O3 at a daily dose of 10 mg until remission, followed by three monthly courses of idarubicin, at 6 mg/m(2)/day for 5 days in the first course and 6 mg/m(2)/day for 2 days in the subsequent two courses. All patients achieved morphological but not molecular remission after As2O3 treatment. During As2O3 therapy, an increase in white cell count peaking at a median of 17 days occurred in all the cases. Serial flow cytometric analysis of apoptosis, with mitochondrial APO2.7 antigen expression and the sub-G1 cell fraction on DNA histogram as markers, showed induction of apoptosis of APL cells in vivo. With both qualitative and real-time quantitative polymerase chain reaction, all patients were shown to attain molecular remission after subsequent idarubicin treatment. With a median follow up of 13 months, seven of eight patients have remained in complete clinical remission, with six patients in molecular remission as well. One patient who was in third remission became PCR-positive after being transiently negative. One patient died from an intracranial extramedullary relapse after achieving marrow molecular remission. We conclude that As2O3 induction followed by idarubicin consolidation is an effective therapy for APL in relapse. This regimen avoids the possible long-term toxicities of As2O3 and mutagenicity of combination chemotherapy, a strategy that might be suitable for this potentially curable leukaemia.

Treatment of acute promyelocytic leukemia with arsenic compounds: In vitro and in vivo studies

Arsenic compounds, Including arsenic trioxide (As2O3) and arsenic sulfide (As4S4), have recently been shown to be effective in the treatment of acute promyelocytic leukemia (APL). In vitro, As2O3 exerts a dose-dependent dual effect: it triggers apoptosis at relatively high concentrations (0.5 to 2.0 micromol/L) and induces partial differentiation at low concentrations (0.1 to 0.5 micromol/L). The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the retinoic acid signaling is required for APL cell differentiation. As2O3 over a wide range of concentrations (0.1 to 2.0 micromol/L) Induces degradation of PML-RARalpha as well as the wild-type PML and enhances the acetylation of histone, a process important for the transcriptional activation of genes. In vivo, As2O3 induces a high complete remission (CR) rate in patients with both primary and relapsed APL (around 85% to 90%). Side effects, such as skin reaction, gastrointestinal symptoms, electrocardiographic (EKG) changes, neuropathy, and liver dysfunction, are mild to moderate in relapsed patients, and severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As2O3 as postremission therapy has yielded better survival than treatment with As2O3 alone. This is in line with the observation that remission induction with As2O3 is not sufficient in most cases to obtain a molecular remission as Judged by reverse-transcriptase polymerase chain reaction for PML-RARalpha fusion transcripts. The in vivo effect of As2O3 seems to be related to the expression of APL-specific PML-RARalpha oncoprotein, and a synergistic effect between As2O3 and ATRA has been shown in the APL mouse model. Besides As2O3, other arsenic compounds such as As4S4 also show a therapeutic effect in APL. Because the toxic effects of arsenic treatment in primary APL need to be investigated further, we propose use of ATRA as a first-line drug for remission induction in primary APL, whereas As2O3 can be incorporated into multidrug postremission therapy or used as rescue for relapsed APL patients.

Treatment of acute promyelocytic leukemia with arsenic compounds: In vitro and in vivo studies

Arsenic compounds, including arsenic trioxide (As 2O 3) and arsenic sulfide (As 4S 4), have recently been shown to be effective in the treatment of acute promyelocytic leukemia (APL). In vitro, As 2O 3 exerts a dosedependent dual effect: it triggers apoptosis at relatively high concentrations (0.5 to 2.0 μmol/L) and induces partial differentiation at low concentrations (0.1 to 0.5 μmmol/L). The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the retinoic acid signaling is required for APL cell differentiation. As 2O 3 over a wide range of concentrations (0.1 to 2.0 μmol/L) induces degradation of PML-RARα as well as the wild-type PML and enhances the acetylation of histone, a process important for the transcriptional activation of genes. In vivo, As 2O 3 induces a high complete remission (CR) rate in patients with both primary and relapsed APL (around 85% to 90%). Side effects, such as skin reaction, gastrointestinal symptoms, electrocardiographic (EKG) changes, neuropathy, and liver dysfunction, are mild to moderate in relapsed patients, and severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As 2O 3 as postremission therapy has yielded better survival than treatment with As 2O 3 alone. This is in line with the observation that remission induction with As 2O 3 is not sufficient in most cases to obtain a molecular remission as judged by reverse-transcriptase polymerase chain reaction for PML-RARα fusion transcripts. The in vivo effect of As 2O 3 seems to be related to the expression of APL-specific PML-RARα oncoprotein, and a synergistic effect between As 2O 3 and ATRA has been shown in the APL mouse model. Besides As 2O 3, other arsenic compounds such as As 4S 4 also show a therapeutic effect in APL. Because the toxic effects of arsenic treatment in primary APL need to be investigated further, we propose use of ATRA as a first-line drug for remission induction in primary APL, whereas As 2O 3 can be incorporated into multidrug postremission therapy or used as rescue for relapsed APL patients.

Pathologic, Cytogenetic and Molecular Assessment of Acute Promyelocytic Leukemia Patients Treated with Arsenic Trioxide (As2O3)

Arsenic trioxide (As2O3) shows great promise as an effective therapy for patients with all-trans retinoic acid (ATRA)-resistant acute promyelocytic leukemia (APL). Little data is available addressing the pathology of As2O3 treated APL and whether the antileukemic mechanism of As2O3 is primarily cytolysis or through stimulation of cell differentiation. In this report, we made a morphologic, cytogenetic, and molecular evaluation of five ATRA-refractory APL patients who were treated with As2O3. Four of the five patients had morphologic responses after one or two cycles of As2O3 treatment. Of the four responders based on bone marrow morphology, two achieved molecular remission (negative RT-PCR for PML- RARα fusion transcripts) by the end of the second and third cycles of As2O3 therapy. Two patients exhibited marked leukocytosis during the first cycle of As2O3, and at that time point the APL cells were largely replaced by the cells showing partial differentiation towards myelocytes with co-expression of CD11b and CD33. Nevertheless, these “myelocyte-like” cells that showed the t(15;17) translocation eventually disappeared with continuous As2O3 therapy. As2O3 treatment appears to be effective therapy for the patients with relapsed APL after the failure of conventional chemotherapy and ATRA therapy. The pathologic findings in these five cases suggest that at low doses As2O3 primarily induces differentiation of the APL cells, generating abnormal myelocytes resembling APL cells treated with ATRA, whereas at higher doses As2O3 induces marrow necrosis.

Acute Promyelocytic Leukemia Relapsing into FAB-M2 Acute Myeloid Leukemia with Trisomy 8

Acute promyelocytic leukemia was diagnosed in a 48-year-old man; the karyotype was normal, whereas reverse transcriptase polymerase chain reaction (RT-PCR) analysis identified PML/RAR α chimeric transcripts of the bcr3 type. Rather unexpectedly, the patient did not respond to all-trans retinoic acid administration; he attained complete remission with conventional chemotherapy and became PML/RAR α negative. Two years later, while PML/RAR α negative on RT-PCR, he presented with thrombocytopenia. Bone marrow examination was compatible with myelodysplasia of the RAEB type; the karyotype was normal. Then, after 10 months, he developed overt acute myeloid leukemia with PML/RAR α negative, French–American–British M2 blasts; karyotypic analysis revealed mosaicism for trisomy 8.