Acute Promyelocytic Leukemia Treatment & Management

  • Author: Sandy D Kotiah, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Aug 2, 2011
 

Medical Care

Patients with acute leukemia should be treated in centers staffed by specially trained physicians with access to adequate supportive care, such as platelet transfusion therapy and adequate nursing care. Access to a well equipped laboratory (see Workup Laboratory Studies, Other Tests, Procedures, and Staging) is also crucial.

Acute promyelocytic leukemia (APL) treatment involves induction, consolidation, and maintenance phases. There is debate among experts about the ideal induction therapy, the best initial treatment for the elderly, the subset of patients most likely to benefit from maintenance therapy and the most effective relapse regimen. There are clinical trials ongoing that are looking into these issues (see ClinicalTrials.gov).

At this time, strong evidence suggests that high-risk patients with acute promyelocytic leukemia (APL) (WBC >10,000/μL) should undergo induction and consolidation chemotherapy with an anthracycline, cytarabine, and ATRA (eg, idarubicin, cytarabine, and ATRA). ATRA should be started immediately to control coagulopathy. Chemotherapy can be started within 3 days, but it should be started as soon as possible for high-risk patients. Moderate- to low-risk patients can be treated with an anthracycline and ATRA alone for induction and consolidation.

Four small studies performed in China, India, Iran, and the United States at MD Anderson have investigated the role of ATO with ATRA as induction therapy with complete remission rates from 86-95%.[8] However, a randomized controlled trial is needed to compare chemotherapy with ATRA versus ATO with ATRA to determine which therapy is ideal for induction.

Consolidation therapy usually consists of 2 cycles of anthracycline-based chemotherapy with concurrent ATRA. There are conflicting randomized trials about the role of maintenance therapy. The trials that showed no benefit to maintenance therapy consisted of patients who achieved complete molecular remission after 2 cycles of consolidation therapy. The ideal duration of maintenance therapy is also being investigated. Currently, it consists of 2 years of 6-mercaptopurine (6-MP), methotrexate, and ATRA.

The following sections will discuss the different therapeutic agents and the important clinical trials for these 3 phases of treatment (induction, consolidation, and maintenance). The treatment for the elderly and for relapsed disease will also be reviewed.

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Recommendations

ATRA

ATRA was first demonstrated to be effective in acute promyelocytic leukemia (APL) in China during the mid 1980s. Pharmacologic doses of ATRA (45 mg/m2 divided into bid doses) led to terminal differentiation of malignant promyelocytes to mature neutrophils. However, ATRA alone cannot eradicate the malignant clone. There have been several studies demonstrating the achievement of complete hematologic and molecular remission with the addition of chemotherapy to ATRA. These studies have also shown that extended ATRA treatment improved complete remission rates, improved overall survival, and reduced relapse rates.

ATRA helps to rapidly control the DIC associated with acute promyelocytic leukemia (APL). About 25-50% of patients can develop retinoic acid syndrome (RAS) during treatment with ATRA. This syndrome can occur within the first 21 days of treatment and is characterized by fever, hypotension, weight gain, respiratory distress, serositis with pleural or pericardial effusions, hypoxemia, radiologic infiltrates, acute renal failure, and hepatic dysfunction. RAS is frequently associated with hyperleukocytosis but can occur with normal leukocyte counts. RAS should be treated with intravenous (IV) dexamethasone 10 mg q12h for at least 3 days.

Other side effects of ATRA include headache, nasal stuffiness, dry red skin and, rarely, pseudotumor cerebri. Resistance to ATRA has been seen with the other cytogenetics variants of acute promyelocytic leukemia (APL), especially the PLZF-RAR alpha mutation, but the resistance may also develop as a secondary event in garden variety APL.

It is important to note that the treatment of DIC should also include platelet transfusions to maintain the platelet count at about 20,000/μL and cryoprecipitate to maintain a fibrinogen level at least above 100-150 mg/dL.

In those patients who are not treated initially with chemotherapy, a rapid increase in WBC count may follow ATRA use. These patients should rapidly be treated with chemotherapy to avoid clinical hyperleukocytosis.

Induction therapy

Induction therapy consists of ATRA with an anthracycline and cytarabine. Idarubicin has been shown to be slightly more efficacious in younger patients with AML versus daunorubicin. The combination of ATRA with chemotherapy improves long-term survival and has 85-90% complete remission rates.

ATRA should be started immediately to control DIC, and chemotherapy can be started concurrently. A randomized North American Intergroup APL trial showed that the 5-year disease-free survival was highest (74%) in patients receiving ATRA plus chemotherapy, followed by 2 cycles of consolidation and maintenance with ATRA.[9]

The most effective and least toxic induction chemotherapy combination with ATRA has not been established. The PETHEMA (Programa de Estudio y Tratamiento de las Hemopatías Malignas)[10] and European APL 2000[11] groups showed comparable and high complete remission rates with different induction chemotherapy regimens. The main difference was the addition of cytarabine by the APL 2000 group. The addition of cytarabine causes more myelosuppression, but the APL 2000 group reported a higher relapse risk when it was omitted.[11] Please note the following points:

  • Prognostic factors were identified in 2000 by the Italian Group for Adult Hematologic Diseases (GINEMA) and Spanish PETHEMA group in a 217-patient multivariate analysis based on WBC count and platelet count.[12] The low-risk group had WBC < 10,000/μL and platelets >40,000/μL, the intermediate-risk group had WBC < 10,000/μL and platelets < 40,000/μL, and the high-risk group had WBC >10,000/μL and platelets < 40,000/μL.
  • The PETHEMA study (LPA 96 and 99) – 426 patients with newly diagnosed acute promyelocytic leukemia (APL) were given induction therapy with ATRA and idarubicin (AIDA regimen). The study was started in 1996 and called LPA 96. However, the study was modified after 1999 (LPA 99) to give intermediate- and high-risk patients consolidation with ATRA and higher doses of anthracyclines. The complete remission rate was 90%. All of the patients received 2 years of maintenance therapy. The 3-year risk of relapse was lower in the LPA 99 arm (8.7% vs 20.1%).
  • The French-Belgian-Swiss study (APL 2000) – 413 patients younger than age 75 years with new diagnosed acute promyelocytic leukemia (APL) were randomized to ATRA, followed by chemotherapy versus ATRA with concurrent chemotherapy. The first arm had to achieve remission with ATRA before chemotherapy, with 7 days of cytarabine at 200 mg/m2 and 3 days of daunorubicin at 60 mg/m2. The second arm had chemotherapy added on day 3. These patients were then randomized to 4 different maintenance arms: observation, ATRA, chemotherapy, or ATRA with chemotherapy. The complete remission rate was 92%. The results revealed that the early addition of chemotherapy lead to significantly better survival, and the lowest relapse risk was seen in patients with ATRA and chemotherapy maintenance.
  • A joint analysis was performed by Ades et al that compared results of the French-Belgian-Swiss group and the PETHEMA group for patients younger than 65 years.[13] The investigators concluded that the 3-year survival rate was similar in both groups in patients with WBC < 10,000/μL. However, for patients with WBC >10,000/μL, the complete remission rates and 3-year free survival rates were higher in the APL 2000 trial, as well as a lower risk of relapse. These findings were statistically significant and suggested a beneficial role to the addition of cytarabine for induction chemotherapy in high-risk patients.

De la Serna et al reported on the incidence, time of occurrence, and prognostic factors of induction failure in a population of 732 patients with acute promyelocytic leukemia (APL).[14] The most common causes of induction failure included hemorrhage, infection, and APL differentiation syndrome. A multivariate analysis showed that certain pretreatment factors correlated with these adverse events. For example, elevated creatinine levels, presence of high peripheral blood blasts, and coagulopathy increased the risk of death.

Infection was seen more frequently in male patients older than 60 years and those who had fever at presentation.[14] Acute promyelocytic leukemia (APL) differentiation syndrome (a rapid rise in WBC count during APL treatment, resulting in hyperleukocytosis) was linked to a lower serum albumin level and an Eastern Cooperative Oncology Group (ECOG) score >1.

Consolidation therapy

Consolidation therapy should be given with 2-3 cycles of anthracycline-based chemotherapy. Molecular remission is achieved in 90-99% of cases. The benefit of ATRA with consolidation therapy has not been proven in randomized studies. However, historical comparisons of the independent groups GINEMA and PETHEMA showed statistically improved outcomes when ATRA was added to chemotherapy for 15 days. The PETHEMA group used 3 cycles of consolidation with idarubicin to mitoxantrone to idarubicin, but they increased the doses of idarubicin for intermediate- to high-risk patients. The APL 2000 group used daunorubicin and cytarabine in differing doses for 2 cycles of consolidation.

Montesinos et al analyzed data from 918 patients who underwent induction and consolidation therapy with ATRA and anthracycline-based chemotherapy. Of the 918 patients, 17 patients who achieved complete remission developed therapy-related myeloid neoplasms (t-MN) or secondary AML.[15] The 6-year cumulative incidence overall was 2.2%. In subgroups of APL in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. The study shows that t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment of APL with ATRA and anthracycline-based regimens.

Powell et al investigated the role of arsenic trioxide in consolidation therapy.[16] In their study, 481 patients all underwent the same induction regimen with daunorubicin, cytarabine, and tretinoin. They were then randomized to consolidation treatment with either 2 cycles of daunorubicin and tretinoin or two 25-day courses of arsenic trioxide. This study also randomized patients to different maintenance arms, but the data were analyzed at 3 years. It was shown that event-free survival and disease-free survival were significantly better for the arsenic trioxide consolidation arm (p< 0.0001), but overall survival was not statistically significant (p=0.59).

Maintenance therapy

In 2000, the US Intergroup Trial demonstrated that ATRA maintenance improved 5-year survival rates from 36% to 61%. The regimen also reduced relapse rates from 25-30% to 10-15%. However, there were some groups using more intensive consolidation regimens that did not find benefit to maintenance therapy in the patients. Therefore, the ideal maintenance regimen or patient population has not been established.

The European APL group randomized patients to intermittent ATRA alone, ATRA plus 6-MP and methotrexate, or observation. They found an improved overall survival in patients receiving ATRA or ATRA plus chemotherapy. Currently, the 3-drug regimen of ATRA 45 mg/m2 daily given 15 days every 3 months, oral (PO) 6-MP 60 mg/m2 once daily, and methotrexate 20 mg/m2 PO once weekly are administered for 2 years. Patients should be monitored for abnormal liver function and myelosuppression during this time period.

Acute promyelocytic leukemia (APL) disease monitoring is usually done by RT-PCR assay for the PML-RAR alpha fusion transcript.[17] The RT-PCR assay can establish the diagnosis of APL when cytogenetics and FISH fail. The assay is useful for detecting minimal residual disease (MRD). The recommendation by the International Working Group is that the goal of treatment is complete molecular remission. This is evidenced by the absence of the fusion transcript using RT-PCR at a sensitivity threshold of 10(-4).

It is expected that bone marrow remission can take up to 40-50 days, but it can also be as long as 90 days. Therefore, bone marrow biopsy should not be repeated until consolidation is complete to avoid confusion. Due to the lower sensitivity of the RT-PCR assay, it is necessary to monitor the peripheral blood RT-PCR every 3 months for the first 2 years. Then, the assay can be performed every 3-6 months for the next 3 years. The highest risk of relapse is in the first 2 years. Bone marrow samples may be more sensitive to detecting MRD, but peripheral blood samples are considered equivalent.

Avissati et al published the results of a 12 year follow-up for different maintenance regimens among patients who achieved a complete molecular remission (PML-RAR alpha RT-PCR negative) at the end of consolidation. Eight hundred and seven patients received the AIDA regimen and 3 doses of consolidative chemotherapy. Five hundred and eighty six patients who were RT-PCR negative were then randomized to maintenance with oral 6-MP and intramuscular methotrexate versus ATRA alone versus alternating oral 6-MP and intramuscular methotrexate with ATRA or observation alone. After 4 years, the chemotherapy alone arm was discontinued. The estimated 12-year disease-free survival was 68.9%, no difference in disease-free survival was found among all of the arms. This study raises the question of whether maintenance therapy should be done in patients who achieve a complete molecular remission at the end of consolidation and will likely change the design of future maintenance trials.[18]

Relapsed/refractory disease

Patients have resistant acute promyelocytic leukemia (APL) disease if they have not achieved complete molecular remission at the end of consolidation therapy. Individuals have relapsed disease if they achieve molecular remission, but monitoring of the RT-PCR assay shows positivity on consecutive samples. This can occur in up to 30% of patients. ATO is recommended in relapsed or refractory acute promyelocytic leukemia (APL), as was gemtuzumab ozogamicin until it was withdrawn from the US Market in June 2010 (see below).

Arsenic trioxide

ATO induces differentiation of acute promyelocytic leukemia (APL) cells at low concentrations and apoptosis at higher concentrations by interacting with the PML-RAR alpha protein.[19] ATO has been studied as part of induction therapy and in the relapsed setting. In 2004, Shen et al randomized 61 patients to ATRA versus ATO versus ATO and ATRA.[20] All groups demonstrated high complete remission rates (>90%), but the combination group had the fastest time to complete remission, greater molecular reduction of disease, and lower relapse rates.[20] However, ATO has not yet been compared to standard induction or consolidation chemotherapy in a randomized clinical trial. It is recommended that ATO is used in first-line setting if the patient cannot tolerate chemotherapy.

In relapsed APL, ATO shows high leukemic activity, especially for patients who have a relapse within 1 year of receiving ATRA. Several studies in China from 1996 to 1999 showed complete remission rates from 52-96% with ATO monotherapy in relapsed acute promyelocytic leukemia (APL). Soignet et al showed a complete remission rate of 85% in a multicenter study of 40 patients with acute promyelocytic leukemia (APL).[21] After 2 cycles of ATO, 78% of patients had no evidence of the leukemic clone.

Analysis of 72 patients with APL treated with ATO alone shows a good overall survival in the good-risk group, as defined in the study, at 100% for the study period. Single-agent ATO in the management of newly diagnosed cases of low-risk APL is safe and is associated with durable responses compared with standard therapy with anthracyclines, as these agents likely would be required in high-risk cases.[22]

These studies evaluated ATO only as a treatment for these patients. ATO is well tolerated in elderly persons and low doses have antileukemic effects. Side effects of ATO include prolongation of the QTc interval, hepatotoxicity, nausea and vomiting, fluid retention, itching and rash, and APL differentiation syndrome.

For induction or relapsed therapy, ATO is given 0.15 mg/kg/day until bone marrow remission, with a maximum of 60 doses. For consolidation, ATO is given at the same dose for 5 weeks, for a total of 25 doses maximum.

Gemtuzumab ozogamicin (withdrawn from the US Market in June 2010)

Gemtuzumab ozogamicin is a humanized anti-CD33 antibody linked to N-acetyl calicheamicin, 1,2-dimethyl hydrazine (CalichDMH) chloride, an antitumor antibiotic.[23] This drug was initially approved in May 2000 for first recurrence of AML but was withdrawn in June 2010 when no improvement in clinical benefit was observed and after a greater number of deaths occurred in the group of patients who received gemtuzumab compared with those receiving chemotherapy alone. In addition, the rate of veno-occlusive disease (VOD) was shown to be increased in the postmarket setting.

Prior to withdrawal of this agent, treatment with gemtuzumab ozogamicin monotherapy had been highly effective in molecular or overt relapsed acute promyelocytic leukemia (APL). Lo Coco et al reported 9 of 11 patients achieved molecular remission after 2 doses of gemtuzumab ozogamicin at 6 mg/m2.[24] After a third dose was administered, 13 of 13 patients achieved molecular remission. Estey et al showed that gemtuzumab ozogamicin (9 mg/m2) with ATRA led to an 84% complete remission.[25] The adverse effects of gemtuzumab ozogamicin included infusion-related events with fever, hypotension, chills, and nausea, as well as myelosuppression, thrombocytopenia, hepatic toxicity, or VOD of the liver.

Bone marrow transplantation (BMT)

BMT should be offered to patients in the relapsed setting.[26] The cure rate for acute promyelocytic leukemia (APL) is high, such that BMT is not the first option. There is also significant transplant-related mortality, especially with allogeneic transplants. Patients who achieve molecular remission with salvage therapy should be offered high-dose chemotherapy, followed by autologous stem cell transplantation (SCT) for consolidation. Patients who have persistent molecular or hematologic disease after salvage therapy should be offered allogeneic SCT if they have a good performance status and an HLA-matched donor can be found.

Other alternatives would include enrollment in a clinical trial if transplantation is not an option. The Center for International Blood and Marrow Transplant Research (CIBMTR) data show that the majority of patients undergo SCT in the second or subsequent remissions. Three-year overall survival (OS) was 73% for autologous SCT and 61% for allogeneic SCT. The role of maintenance therapy after SCT has not been established. Transplantation-related mortality is improving over time with improved techniques and conditioning regimens. The role of transplantation in high-risk patients (WBC >10,000/μL) will need further investigation.

Intrathecal chemotherapy

For patients who have CNS involvement or who are at higher risk for CNS relapse, intrathecal chemotherapy is usually given in 5 doses. The chemotherapy is a combination of cytarabine (50 mg), methotrexate (15 mg), and hydrocortisone (30 mg); it is given weekly for 5 weeks. For prophylaxis, a dose is given during induction, and 4 doses are given during consolidation.[27]

Treatment in the elderly

Although acute promyelocytic leukemia (APL) is sensitive to chemotherapy in elderly patients older than age 60 years, these patients have higher death rates in complete remission.[28] The PETHEMA group omitted one dose of idarubicin for induction chemotherapy in patients older than age 70 years. In the European APL93 trial, 18.6% of elderly patients with acute promyelocytic leukemia (APL) died mainly from sepsis during consolidation or maintenance treatment. Although these patients can be treated with ATRA and a less intensive dose of chemotherapy, consolidation should be altered to liposomal ATRA, ATO, or GO. These drugs can also be used in combination.

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Surgical Care

Surgery does not have a role in acute promyelocytic leukemia (APL).

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Consultations

An interventional radiology consultation should be made for placement of a peripherally inserted central catheter (PICC) line. A gynecology consultation should be obtained for women with acute promyelocytic leukemia (APL) and heavy vaginal bleeding or who are pregnant at the time of diagnosis.

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Diet

A neutropenic diet should be ordered for leukopenic or neutropenic patients. No fresh fruits or flowers should be allowed in the patient's room.

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Activity

The patient's activity should be limited in cases of severe thrombocytopenia (platelets < 10,000/μ L). The risk of spontaneous bleeding increases, and the risk for falls should be minimized.

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Contributor Information and Disclosures
Author

Sandy D Kotiah, MD  Fellow in Hematology Oncology, Thomas Jefferson University Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Specialty Editor Board

Clarence Sarkodee-Adoo, MD  Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Disclosure: Takeda Millenium Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Sacher, MB, BCh, MD, FRCPC  Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgments

I would like to acknowledge Dr. Emmanuel Besa for allowing me the opportunity to write this article.

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Bone marrow aspirate hybridized with the RARA dual color break-apart probe set (Abbott-Vysis). The cell to the left shows a normal cell with 2 fusion signals, as the 5'RARA probe (orange) and the 3'RARA probe (green) are not separated. The cell on the right shows split signals for one RARA gene, indicating a chromosomal rearrangement disrupting the RARA gene. Image courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
Bone marrow aspirate hybridized with PML/RARA dual color translocation probe set (Abbott-Vysis). The cell to the right shows a normal cell with 2 separate PML (orange) and RARA (green) signals each. The cell to the left shows an abnormal cell characterized by a single fusion signal juxtaposing the PML and RARA signals, suggestive of a translocation of the 2 genes. Images courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
Hypogranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
 
 
 
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