ABSTRACT
The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Age Factors , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Cladribine/therapeutic use , Core Binding Factors , Cytarabine/therapeutic use , Daunorubicin/therapeutic use , Gemtuzumab/therapeutic use , Humans , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Maintenance Chemotherapy , Mutation , Myelodysplastic Syndromes/complications , Myeloproliferative Disorders/complications , Neoplasm, Residual , Sulfonamides/therapeutic use , Survival Rate , Translational Research, Biomedical , Tretinoin/therapeutic use , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
OBJECTIVES: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). PATIENTS AND RESULTS: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. CONCLUSIONS: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Adult , Aged , Aged, 80 and over , Anthracyclines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers , Consolidation Chemotherapy , Cytarabine/administration & dosage , Cytogenetic Analysis , Female , Humans , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/mortality , Male , Middle Aged , Neoplasm, Residual/pathology , Recurrence , Remission Induction , Survival Analysis , Treatment Outcome , Tretinoin/administration & dosage , Young AdultABSTRACT
The use of high-dose ascorbate (ASC) for the treatment of human cancer has been attempted several decades ago and has been recently revived by several in vitro and in vivo studies in solid tumors. We tested the cytotoxic effects of ASC, alone or in combination with arsenic trioxide (ATO) in acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). Leukemic cell lines and primary blasts from AML and APL patients were treated with graded concentrations of ASC, alone or in association with standard concentration (1 µM) of ATO. The ASC/ATO combination killed myeloid blasts, including leukemic CD34+ cells, while sparing CD34+ progenitors obtained from normal cord blood and bone marrow. Actually, approximately one-third (11/36) of primary AML cases were highly sensitive to the ASC/ATO combination. The mechanism of cell killing appeared to be related to increased oxidative stress and overproduction of ROS in a non-quantitative fashion, which resulted in induction of apoptosis. These effects were reverted by the addition of the antioxidant N-Acetyl-Cysteine (NAC). In the APL NB4 model, ASC induced direct degradation of the PML and PML/RARA proteins via caspase activation, while the transcriptional repressor DAXX was recruited in re-constituted PML nuclear bodies. Our findings encourage the design of pilot studies to explore the potential clinical benefit of ASC alone or in combination with ATO in advanced AML and APL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenicals/therapeutic use , Ascorbic Acid/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Arsenic Trioxide , Arsenicals/pharmacology , Ascorbic Acid/pharmacology , Humans , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Leukemia, Promyelocytic, Acute/mortality , Leukemia, Promyelocytic, Acute/pathology , Oxides/pharmacology , Reactive Oxygen Species , Survival Analysis , Tumor Cells, CulturedABSTRACT
We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.
Subject(s)
Anthracyclines/administration & dosage , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Adolescent , Child , Child, Preschool , Consolidation Chemotherapy/methods , Cytarabine/administration & dosage , Disease-Free Survival , Humans , Induction Chemotherapy/methods , Infant , Japan , Leukemia, Promyelocytic, Acute/complications , Maintenance Chemotherapy/methods , Male , Prospective Studies , Survival Rate , Treatment Outcome , Tretinoin/administration & dosageABSTRACT
Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high-risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional (n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD-HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide.
Subject(s)
Leukemia, Promyelocytic, Acute/epidemiology , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide , Arsenicals/administration & dosage , Bone Marrow/pathology , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Disease-Free Survival , Female , Follow-Up Studies , Germany/epidemiology , Humans , Kaplan-Meier Estimate , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/mortality , Leukocyte Count , Maintenance Chemotherapy , Male , Middle Aged , Mitoxantrone/administration & dosage , Multicenter Studies as Topic/statistics & numerical data , Oxides/administration & dosage , Prognosis , Randomized Controlled Trials as Topic/statistics & numerical data , Remission Induction , Risk , Thioguanine/administration & dosage , Treatment Outcome , Tretinoin/administration & dosageABSTRACT
The purpose of the study was to evaluate event-free survival (EFS), overall survival (OS) and safety for early addition of arsenic trioxide (As(2)O(3)) as frontline consolidation therapy compared to high-dose arabinoside (HiDAC) in adult patients with de novo acute promyelocytic leukemia (APL). 271 patients (aged 17-65 years) received consolidation therapy containing As(2)O(3) (two 21-day courses) or HiDAC regimen. EFS at 5 years was 75% versus 54% (P < 0.001), and OS at 5 years was 83% versus 71% (P = 0.002) in As(2)O(3) and HiDAC treatment arms. 139 patients treated with As(2)O(3), EFS at 5 years reached 79% versus 56% (P = 0.014), but OS at 5 years was 77% versus 84% (P = 0.32) in low-risk (WBC ≤ 10 × 10(9)/L) and high-risk (WBC > 10 × 10(9)/L) cohorts. Further, patients treated with As(2)O(3) rarely incurred agranulocytosis (1.4%, P < 0.001), or severe infection (0.7%, P < 0.001). It is still very well tolerated compared to HiDAC. We confirmed that As(2)O(3) as a first-line consolidation regimen provided significant benefits of OS to patients with APL. The As(2)O(3) regimen made low-risk patients gain more EFS benefits than high-risk group. The high-risk cohort receiving As(2)O(3) overcame the negative impact, yielding OS similar to that for with the low-risk patients treated with As(2)O(3).
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Consolidation Chemotherapy/methods , Cytarabine/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols , Arsenic Trioxide , Arsenicals/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Leukemia, Promyelocytic, Acute/mortality , Male , Middle Aged , Oxides/adverse effects , Tretinoin/therapeutic use , Young AdultABSTRACT
AIM: To analyze the specific features of recurrences of acute promyelocytic leukemia (APL) in children after standard therapy with daunorubicin, cytosine arabinoside (Ara-C), all-trans retinoic acid (ATRA) and to develop further programmed treatment policy. SUBJECTS AND METHODS: The study included 9 patients with recurrent APL. The recurrences developed significantly more frequently in a very high-risk group (patients with minimal residual disease being preserved after the intensive therapy phase). Induction used arsenic trioxide (ATO) and/or standard chemotherapy + ATRA; ATO monotherapy was in consolidation. CD34+ cells were mobilized until molecular remission was achieved with high-dose Ara-C and granulocyte colony-stimulating factor. Pretransplantation conditioning involved melfalan as a basic drug in combination with high-dose AraC (5 pts), treosulfan (1 pt) or bisulfan (1 pt). Six patients received gemtusumab ozogamicin, 3-9 mg/m2, at different stages of therapy. RESULTS: Before therapy one patient died; 8 patients achieved the second molecular remission; CD34+ cell mobilization and sampling were effective in 7 cases. Five patients were in long-term molecular remission after autologous hemopoietic stem cell transplantation (autoHSCT). Follow-up was 23-40 months. One patient is being prepared for transplantation. Following autoHSCT, another patient with a developed repeat recurrence died from complications due to related partially compatible transplantation. Visceral, including cardiological, toxicity of therapy was insignificant. In the APL-2003 protocol, overall and event-free survival rates were 93 +/- 3 and 76 +/- 6%, respectively. CONCLUSION; The application of ATO and autoHSCT in recurrent APL makes it possible to achieve and preserve the second molecular remission in case of insignificant extrahematological toxicity. Russian clinics should have access to ATO.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Leukemia, Promyelocytic, Acute/prevention & control , Transplantation Conditioning/methods , Adolescent , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Arsenic Trioxide , Arsenicals/administration & dosage , Arsenicals/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Disease-Free Survival , Humans , Infant , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Leukemia, Promyelocytic, Acute/surgery , Oxides/administration & dosage , Oxides/therapeutic use , Remission Induction , Secondary Prevention , Transplantation, AutologousABSTRACT
The objective of this study for newly diagnosed acute promyelocytic leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretreatment white blood cell (WBC) count < and > or =10 x 10(9)/l (low/intermediate and high risk according to the Sanz score), our patients received uniform therapy. From 1994 to 2005, 142 patients (age, 16-60 years) were enrolled. In the low/intermediate (n=105) vs high (n=37) WBC group, the rates of complete remission were 95.2 vs 83.8%, of induction death were 4.8 vs 16.2% (P=0.05) and of molecular remission were 87.5 vs 91.3% (P=1). Long-term overall survival was 84.4 vs 73.0% (P=0.12), event free survival was 78.3 vs 67.3% (P=0.11), relapse free survival was 82.1 vs 80.0% (P=0.83) and the cumulative incidence of relapse was 7.4 vs 11.4% (P=0.46). No relapse or death occurred after 4.7 years. ATRA and intensified chemotherapy including HD ara-C followed by prolonged maintenance therapy reduced the relapse risk in high risk patients. Pretreatment WBC count > or =10 x 10(9)/l count was no relevant prognostic factor for relapse.
Subject(s)
Cytarabine/administration & dosage , Leukemia, Promyelocytic, Acute/drug therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Germany , Humans , Leukemia, Promyelocytic, Acute/mortality , Longitudinal Studies , Lymphocyte Count , Middle Aged , Prognosis , Remission Induction , Survival Analysis , Treatment Outcome , Tretinoin/administration & dosage , Young AdultABSTRACT
OBJECTIVE: Acute promyelocytic leukemia (APL) is now highly curable, except in many developing countries. Introduction of current treatment strategies may improve the outcome for children with APL in these countries. METHODS: The diagnosis was based on the FAB classification and detection of PML-RAR alpha rearrangement. From December 1999 to September 2004, 16 eligible children were treated with an intensive in-house protocol including high-dose AraC and anthracycline. Subsequently, 14 cases were treated with a less intensive protocol modified from the PETHEMA LPA99. RESULTS: The 3.5 years event-free survival (EFS) was 37.5% (95% CI, 13.8-61.2%) for patients treated on initial protocol. The treatment failures were: six patients abandoned treatment (37.5%), two who died of intracranial hemorrhage at diagnosis (6.3%) and sepsis in remission (6.3%) respectively, and two who relapsed (12.5%). Those treated on modified PETHEMA had a 3.5 years EFS of 79.6% (95% CI, 52.9-106.3%). Treatment failures included: one who died of intracranial hemorrhage at diagnosis (7.1%) and one who relapsed (7.1%). The patients on modified PETHEMA had a significantly higher EFS (P = 0.012), lower frequency of sepsis during treatment (7.7% vs. 77.8%; P = 0.0015), and lower hospitalization cost (median US$ 4,700 vs. US$ 20,000; P < 0.0001) than those on in-house protocol. CONCLUSION: Treatment with the less intensive protocol based on the PETHEMA LPA99 study of childhood APL successfully reduced chemotherapy toxicity and lowered hospitalization costs without increasing relapses. This led to decreases in treatment-related morbidity and the treatment abandonment rate, thus improving overall outcome.
Subject(s)
Leukemia, Promyelocytic, Acute/drug therapy , Adolescent , Anthracyclines/therapeutic use , Child , Child, Preschool , Cytarabine/therapeutic use , Female , Health Care Costs , Humans , Infant , Leukemia, Promyelocytic, Acute/mortality , Male , Treatment Outcome , Tretinoin/adverse effectsABSTRACT
To determine prognosis of acute promyelocytic leukemia (APL) failing to front-line therapy with all-trans retinoic acid (ATRA) and anthracyclines, outcome of 52 patients (32 M/20 F; age: 37, 3-72) included in PETHEMA trials LPA96 and LPA99 who presented with either molecular failure (MOLrel, n=16) or hematological relapse (HEMrel, n=36) was analyzed. Salvage therapy consisted of ATRA and high-dose ara-C-based chemotherapy (HDAC) in most cases (83%), followed by stem-cell transplantation (autologous, 18; allogeneic, 10; syngeneic, 1). Fourteen patients with MOLrel (88%) achieved second molecular complete response (molCR), whereas 81% HEMrel patients responded to second-line treatment, with 58% molCR. After median follow-up of 45 months, four MOLrel and 18 HEMrel patients, respectively, experienced a second relapse. Outcome after MOLrel compared favorably to HEMrel, with longer survival (5-year survival: 64+/-14 vs 24+/-8%, P=0.01) and lower relapse risk (5-year relapse risk: 30+/-13 vs 64+/-9%; P=0.044). Additionally, age Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
, Leukemia, Promyelocytic, Acute/drug therapy
, Salvage Therapy
, Adolescent
, Adult
, Aged
, Antineoplastic Combined Chemotherapy Protocols/administration & dosage
, Biomarkers, Tumor/blood
, Child
, Child, Preschool
, Combined Modality Therapy
, Cytarabine/administration & dosage
, Etoposide/administration & dosage
, Female
, Hematopoietic Stem Cell Transplantation
, Humans
, Idarubicin/administration & dosage
, Kaplan-Meier Estimate
, Leukemia, Promyelocytic, Acute/blood
, Leukemia, Promyelocytic, Acute/mortality
, Leukemia, Promyelocytic, Acute/pathology
, Leukemia, Promyelocytic, Acute/surgery
, Liposomes/administration & dosage
, Male
, Middle Aged
, Mitoxantrone/administration & dosage
, Neoplasm, Residual
, Oncogene Proteins, Fusion/blood
, Prognosis
, Recurrence
, Remission Induction
, Survival Analysis
, Time Factors
, Treatment Outcome
, Tretinoin/administration & dosage
ABSTRACT
The objective of our study was to evaluate high-dose cytarabine in consolidation therapy in patients with newly diagnosed acute promyelocytic leukemia (APL). Patients (age 16-60 years) received induction therapy according to the AIDA protocol (all-trans retinoic acid, idarubicin) followed by one cycle of ICE (idarubicin, cytarabine, etoposide) and two cycles of HAM (cytarabine 3 g/m(2) q12h, days 1-3; mitoxantrone 10 mg/m(2), days 2 and 3). From 1995 to 2003, 82 patients were enrolled. In total, 72 patients (88%) achieved a complete remission, and 10 patients (12%) died from early/hypoplastic death (ED/HD). A total of 71 patients received at least one cycle of HAM. Relapse-free survival (RFS) and overall survival (OS) after 46 months were 83 and 82%, respectively. White blood cell count above 10.0 x 10(9)/l at diagnosis and additional chromosomal aberrations were unfavorable prognostic markers for OS, whereas no prognostic markers for RFS were identified including FLT3 mutations. In conclusion, high-dose cytarabine in consolidation therapy for patients with newly diagnosed APL is an effective treatment approach.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cytarabine/administration & dosage , Idarubicin/administration & dosage , Leukemia, Promyelocytic, Acute/drug therapy , Mitoxantrone/administration & dosage , Tretinoin/administration & dosage , Adolescent , Adult , Female , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/mortality , Male , Middle Aged , Prognosis , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Remission Induction , fms-Like Tyrosine Kinase 3ABSTRACT
Arsenic trioxide (As2O3) was recently identified as a very potent agent against acute promyelocytic leukemia (APL). Intravenous infusion of 10 mg As2O3 daily for one to two months can induce significant complete remission (CR) of APL, and there is no cross drug-resistance between As2O3 and other antileukemic agents, including all-trans retinoic acid (ATRA). The CR rate of relapsed and/or refractory APL patients who received As2O3 treatment ranged from 52.3% to 93.3%. The median duration to CR ranged from 38 to 51 days, with accumulative As2O3 dosage of 340-430 mg. Although most adverse reactions of As2O3 treatment were tolerable, certain infrequent but severe toxicities related to As2O3 were observed, including renal failure, hepatic damage, cardiac arrhythmia and chronic neuromuscular degeneration, which should be monitored carefully. As2O3 can induce partial differentiation and subsequent apoptosis of APL cells through degradation of wild type PML and PML/RAR alpha chimeric proteins and possible anti-mitochondrial effects. Like the treatment of ATRA in APL, early relapses from As2O3 treatment within a few months were not infrequently seen, indicating that rapid emerging resistance to As2O3 can occur. Nevertheless, the PML/RAR alpha fusion protein was reported to disappear in some APL patients who received As2O3, and who might earn long-survival. However, the follow-up is still too short to draw the conclusion. Intriguingly, it has been shown that As2O3 can also induce apoptosis of other non-APL tumor cells with clinical achievable concentrations. However, the detailed molecular mechanisms are not yet fully understood. Further studies regarding to the pharmacological characters, clinical efficacies, toxicities, apoptogenic mechanisms, and spectrum of anti-tumor activity of As2O3 are warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Salvage Therapy , Acute Kidney Injury/chemically induced , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Arrhythmias, Cardiac/chemically induced , Arsenic Trioxide , Arsenicals/adverse effects , Arsenicals/pharmacology , Cell Differentiation/drug effects , Chemical and Drug Induced Liver Injury/etiology , Drug Evaluation , Drug Screening Assays, Antitumor , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/pathology , Humans , Leukemia, Promyelocytic, Acute/mortality , Leukemia, Promyelocytic, Acute/pathology , Life Tables , Medicine, Chinese Traditional , Mitochondria/drug effects , Models, Biological , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/drug effects , Neuromuscular Diseases/chemically induced , Oncogene Proteins, Fusion/antagonists & inhibitors , Oncogene Proteins, Fusion/metabolism , Oxides/adverse effects , Oxides/pharmacology , Remission Induction , Survival Analysis , Treatment Outcome , Tumor Cells, Cultured/drug effects , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: The incidence of acute myeloid leukemia is 3 cases per 100,000 inhabitants/year and its five years event free survival is 15 to 20%. Since the incorporation of trans retinoic acid, event free survival of M3 acute myeloid leukemia is 80%. AIM: To report the results of acute myeloid leukemia treatment at the Hospital del Salvador, between 1990 and 1998. PATIENTS AND METHODS: The medical records of 117 patients (66 female, mean age 48.2 years), treated between 1990 and 1998 using PANDA protocol, were retrospectively reviewed. Immunophenotyping was done in 69 patients and cytogenetic studies were done in 65. RESULTS: Sixteen percent of patients had M3 acute myeloid leukemia. The most frequent phenotype was the association of DR, CD34 plus a panmyeloid marker. DR and CD34 were negative in seven of nine patients with M3 acute myeloid leukemia. Cariotype was abnormal in 78% of patients. Complete remission was achieved in 65% of cases with a 13% of failures. Early mortality was 21.3% and decreased to 6.1% in the last three years. Infections and coagulation disorders were the main causes of death. Mean survival was 10.5 months. Five years event free survival was 11%. In M3 acute myeloid leukemia, the figure is 50%. CONCLUSIONS: Treatment results are less effective than protocols that consider more aggressive chemotherapeutic protocols or bone marrow transplantation. The reduction in early mortality is due to a better management of febrile neutropenia.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Adolescent , Adult , Aged , Chemotherapy, Adjuvant , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Disease-Free Survival , Female , Humans , Idarubicin/therapeutic use , Immunophenotyping , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/mortality , Male , Middle Aged , Mitoxantrone/therapeutic use , Prognosis , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome. METHODS: Three hundred forty-six patients with previously untreated acute promyelocytic leukemia were randomly assigned to receive all-trans-retinoic acid or daunorubicin plus cytarabine as induction treatment. Patients who had a complete remission received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy, then high-dose cytarabine plus daunorubicin. Patients still in complete remission after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with all-trans-retinoic acid or to observation. RESULTS: Of the 174 patients treated with chemotherapy, 120 (69 percent) had a complete remission, as did 124 of the 172 (72 percent) given all-trans-retinoic acid (P=0.56). When both induction and maintenance treatments were taken into account, the estimated rates of disease-free survival at one, two, and three years were 77, 61, and 55 percent, respectively, for patients assigned to chemotherapy then all-trans-retinoic acid; 86, 75, and 75 percent for all-trans-retinoic acid then all-trans-retinoic acid; 75, 60, and 60 percent for all-trans-retinoic acid then observation; and 29, 18, and 18 percent for chemotherapy then observation. By intention-to-treat analysis, the rates of overall survival at one, two, and three years after entry into the study were 75, 57, and 50 percent, respectively, among patients assigned to chemotherapy, and 82, 72, and 67 percent among those assigned to all-trans-retinoic acid (P= 0.003). CONCLUSIONS: All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Tretinoin/therapeutic use , Adolescent , Adult , Antineoplastic Agents/adverse effects , Child , Child, Preschool , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin/administration & dosage , Daunorubicin/adverse effects , Disease-Free Survival , Female , Humans , Leukemia, Promyelocytic, Acute/mortality , Male , Middle Aged , Remission Induction/methods , Survival Rate , Treatment Failure , Tretinoin/adverse effectsABSTRACT
A clinical trial was conducted in order to evaluate the therapeutic effect and side-effects of low-dose ATRA in the treatment of acute promyelocytic leukemia (APL). We compared the pharmacokinetic features in normal individuals with single oral ATRA at 15 mg/m2 and 45 mg/m2, respectively. The results showed that maximal plasma concentration (Cpmax) with oral 15 mg/m2 ATRA was high enough (10(-6) M) to induce APL cell differentiation. Based on these results, 27 cases of de novo APL patients were treated with continuous oral ATRA at the dose of 15-20 mg/m2/day and 24/26 evaluable cases (92%) achieved clinical CR after 13 to 67 days of ATRA treatment. No patient experienced RAS and DIC. The Cpmax with a single dose of ATRA on day 1 of treatment and immediately at CR obtained with continuous ATRA in three cases demonstrated similar values in one patient and an approximately two-fold decrease in two patients. More importantly, compared with a relatively well-matched historic group of 20 APL patients treated with high-dose ATRA, our results suggest that low-dose ATRA is as effective as high-dose in treating APL patients and may provide advantages through decreased hyperleukocytosis and other side-effects.
Subject(s)
Immunologic Factors/pharmacokinetics , Leukemia, Promyelocytic, Acute/therapy , Tretinoin/pharmacokinetics , Administration, Oral , Adult , Female , Half-Life , Humans , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , Leukemia, Promyelocytic, Acute/mortality , Leukocytosis/chemically induced , Male , Middle Aged , Remission Induction , Tretinoin/administration & dosage , Tretinoin/adverse effects , Tretinoin/therapeutic useABSTRACT
The Southwest Oncology Group analyzed outcome with cytotoxic chemotherapy for previously untreated acute myeloblastic leukemia (AML) from 1982 through 1986. Results with acute promyelocytic leukemia (APL) prompted comparison with patients from 1986 through 1991 and analysis of factors contributing to APL results. Patient and disease characteristics and treatment outcome were compared for all evaluable patients, with more detailed analysis of factors affecting APL treatment outcome. From 1982 through 1986, median survival and disease-free survival in 45 APL patients were 106 months and greater than 105 months, respectively, versus 6 and 14 months for 417 other AML patients. Such differences were not seen from 1986 through 1991. In the 141 APL patients from 1982 through 1991, after adjusting for significant patient and disease characteristics, higher daunomycin (DNR) doses during induction were significantly associated with higher complete remission rates (P < .0001), longer survival (P < .0001), and longer DFS (P < .0001). Cytosine arabinoside (Ara-C) induction dose, the inclusion of other chemotherapy agents in induction, postremission therapy (consolidation, maintenance, or bone marrow transplantation) other than DNR, APL subtype, and patient age did not appear to significantly affect outcome of APL, except for a significant detrimental effect of high-dose Ara-C in consolidation (P = .0042). Morphologic AML subtypes other than APL did not affect outcome. We conclude that high-dose DNR selectively increases survival in APL. This good survival is important for evaluation of combined all-trans retinoic acid (ATRA)/chemotherapy protocols and for planning future combinations of chemotherapy and ATRA. These results illustrate the need to individualize chemotherapy for subtypes of AML. Therapeutic response of APL is independent of age. Except for APL, morphologic subclassification of AML contributed little prognostic information.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Adolescent , Adult , Aged , Cytarabine/therapeutic use , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Leukemia, Promyelocytic, Acute/mortality , Leukemia, Promyelocytic, Acute/radiotherapy , Male , Middle Aged , Remission Induction , Retrospective Studies , Survival Rate , Time Factors , Treatment Outcome , Whole-Body IrradiationABSTRACT
A high hemorrhagic risk and a complete response to the differentiative agent all-trans-retinoic acid (ATRA) are the main clinical features of acute promyelocytic leukemia (APL), two distinct subtypes of which have been recognized, the common hypergranular leukopenic form (M3) and a microgranular hyperleukocytic variant (M3v). We analyzed, with emphasis on both disease- and therapy-related prognostic factors, the results from a 9-year trial in 65 adults with M3 and M3v APL, treated homogenously with a short-term therapy (STT) program excluding maintenance. STT comprised a maximum of six courses with doxorubicin, cytosine arabinoside (ara-C), and 6-thioguanine. Sixty-five APL patients formed the study group, M3v accounting for 25% of cases. In M3v, the absolute blast cell count was significantly higher (p < 0.0001) and early hemorrhagic deaths were more frequent (p = 0.05). The blast count correlated inversely with the probability of remission (p = 0.005), poor-risk patients being those with > 10 x 10(9)/l blast cells. During the study, the median survival improved from 0.1 to 2.7 years (p = < 0.005). In first place, response to chemotherapy increased from 42 to 84% (p = 0.006), by giving daily prophylactic platelet transfusions (to > 30 x 10(9)/l) and no heparin (course I), and by avoiding too toxic high-dose ara-C and deferring treatment in infected/neutropenic patients showing the atypical differentiative bone marrow pattern (course II). Secondly, the probability of first unmaintained remission differed significantly between patients given intentionally more than four total chemotherapy courses or intermediate/high-dose ara-C consolidation (0.59 at 5 years) and those treated less intensively (0.21) (p < 0.005). Intensive STT was very effective for the management of adult APL patients at standard hemorrhagic risk and receiving optimal supportive care. In high-risk patients with hyperleukocytosis and M3v, induction results could be improved by the concomitant use of ATRA. M3v in adults must be recognized promptly because of the very high early hemorrhagic risk.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Adolescent , Adult , Age Factors , Bone Marrow Transplantation , Combined Modality Therapy , Cytarabine/administration & dosage , Cytoplasmic Granules/ultrastructure , Disease-Free Survival , Disseminated Intravascular Coagulation/etiology , Doxorubicin/administration & dosage , Female , Hemorrhage/etiology , Hemorrhage/mortality , Humans , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/classification , Leukemia, Promyelocytic, Acute/complications , Leukemia, Promyelocytic, Acute/mortality , Leukemia, Promyelocytic, Acute/therapy , Life Tables , Male , Middle Aged , Prospective Studies , Remission Induction , Survival Analysis , Thioguanine/administration & dosage , Treatment OutcomeABSTRACT
All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans RA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy. Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. Initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .05) as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type "A" isoform of PML/RAR-alpha (also known as bcr3 or "short") was associated with a significantly shorter duration of relapse-free and overall survival (P = .005).(ABSTRACT TRUNCATED AT 400 WORDS)