Acute Promyelocytic Leukemia Treatment & Management

Patients with acute leukemia should be treated in centers staffed by specially trained physicians and nurses. Availability of supportive care, such as platelet transfusion therapy, and a well-equipped laboratory is also crucial.

Given the frequent abrupt onset of acute promyelocytic leukemia (APL) and the risk of severe hemorrhagic events, immediate institution of all-trans-retinoic acid (ATRA) and/or arsenic trioxide (ATO) treatment and supportive therapy is indicated, to avoid early death. Current recommendations strongly suggest starting these measures upon clinical suspicion of APL and before genetic confirmation of the diagnosis. ^[16]

APL treatment has three phases: induction, consolidation, and maintenance. 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 regimen for relapsed disease. These issues are the subject of ongoing clinical trials (see ClinicalTrials.gov).

ATRA is an important agent in all three phases of APL treatment. ^[22] ATRA can lead to terminal differentiation of malignant promyelocytes into mature neutrophils. However, ATRA alone cannot eradicate the malignant clone. Achievement of complete hematologic and molecular remission requires the addition of ATO or chemotherapy. ^{[23, 24]}

Resistance to ATRA has been seen with cytogenetic variants of APL, especially cases with the PLZF-RARA mutation. However, resistance may also develop as a secondary event in PML-RARA APL.

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) who have heavy vaginal bleeding or who are pregnant at the time of diagnosis.

In patients with acute promyelocytic leukemia (APL) who are at low or intermediate risk (ie, those with a white blood cell count [WBC] of 10,000/μL or less), current guidelines from the National Comprehensive Cancer Network (NCCN) recommend all-trans-retinoic acid (ATRA), 45 mg/m² in divided doses daily until clinical remission, plus arsenic trioxide (ATO), 0.15 mg/kg IV daily until bone marrow remission. Alternative regimens (all category 1) are as follows ^[16] :

• ATRA plus daunorubicin (50 mg/m² x 4 days or 60 mg/m² x 3 days) and cytarabine (200 mg/m² x 7 days)

• ATRA plus idarubicin (12 mg/m² on days 2, 4, 6, and 8)

• ATRA plus ATO (0.3 mg/kg IV on days 1–5 of cycle one and 0.25 mg/kg twice weekly in weeks 2–8 or until clinical remission)

A randomized phase III study by Lo-Coco et al demonstrated that ATRA plus ATO is not inferior to ATRA plus chemotherapy for the induction therapy of patients with low- to intermediate-risk APL. The 2-year disease-free survival rate was 97% (95% confidence index [CI], 94-100%) in the ATRA–ATO group and 90% (95% CI, 84-97%) in the ATRA–chemotherapy group (P = 0.11). The 2-year cumulative incidence of relapse was 1% (95% CI, 0-4%) in the ATRA–ATO group and 6% (95% CI, 0-11%) in the ATRA–chemotherapy group (P = 0.24). ^[25]

In high-risk patients (WBC >10,000/μL), the NCCN recommends the following regimens for induction therapy ^[16] :

• ATRA plus daunorubicin and cytarabine

• ATRA plus age-adjusted idarubicin plus ATO

• ATRA plus idarubicin 

For patients who are unable to tolerate anthracyclines, the NCCN recommends ATRA plus ATO.

Idarubicin has been shown to be slightly more effective than daunorubicin in younger patients with acute myelogenous leukemia (AML). The combination of ATRA with chemotherapy improves long-term survival and results in 85-90% complete remission rates.

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) ^[26] and European APL 2000 ^[27] 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. ^[27]

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. ^[28] These researchers proposed risk stratification based on WBC and platelet count, as follows:

• Low risk - WBC < 10,000/μL and platelets >40,000/μL

• Intermediate risk - WBC < 10,000/μL and platelets < 40,000/μL

• High risk - WBC >10,000/μL and platelets < 40,000/μL

In the PETHEMA study (LPA 96 and 99), 426 patients with newly diagnosed APL were given induction therapy with ATRA and idarubicin (AIDA regimen). The study was started in 1996 and was 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%).

In the French-Belgian-Swiss study (APL 2000)< study, 413 patients younger than age 75 years with newly diagnosed 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 four 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.

Ades et al compared results of the French-Belgian-Swiss group and the PETHEMA group for patients younger than 65 years and concluded that in both groups, patients with WBC < 10,000/μL had similar 3-year survival rates. ^[29] 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, and risk of relapse was lower. These findings were statistically significant and suggested a beneficial role for 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 APL. ^[30] The most common causes of induction failure included hemorrhage, infection, and APL differentiation syndrome (a rapid rise in WBC count during APL treatment, resulting in hyperleukocytosis). 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 men older than 60 years and patients who had fever at presentation. ^[30] APL differentiation syndrome was linked to a lower serum albumin level and an Eastern Cooperative Oncology Group (ECOG) score >1.

In low- and intermediate-risk patients, the NCCN recommends continuing induction therapy until count recovery occurs, then proceeding to consolidation therapy. In high-risk patients receiving ATRA/ATO, induction is continued until count recovery and bone marrow remission are demonstrated. In high-risk patients receiving other regimens, count recovery and lumbar puncture results are indications for proceeding to consolidation therapy. ^[16]

For consolidation therapy in acute promyelocytic leukemia (APL), the National Comprehensive Cancer Network (NCCN) recommends basing the choice of regimen on the agents used for induction therapy. For example, patients who received all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) would continue to receive ATRA/ATO, while those treated with ATRA plus chemotherapy would for the most part continue to receive those agents. In some cases, mitoxantrone may be added. ^[16] Another consolidation regimen consists of 2 years of 6-mercaptopurine (6-MP), methotrexate, and ATRA.

Retrospective studies by the independent groups GINEMA and PETHEMA showed statistically improved outcomes when ATRA was added to chemotherapy for 15 days. The PETHEMA group used three cycles of consolidation with idarubicin to mitoxantrone to idarubicin, but with higher doses of idarubicin for intermediate- to high-risk patients. The APL 2000 group used daunorubicin and cytarabine in differing doses for two cycles of consolidation.

Montesinos et al reported that of 918 patients who achieved complete remission with induction and consolidation therapy with ATRA and anthracycline-based chemotherapy, 17 patients developed therapy-related myeloid neoplasms (t-MN) or secondary acute myelogenous leukemia. ^[31]

The 6-year cumulative incidence of these complications 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. ^[31]

Powell et al investigated the role of ATO in consolidation therapy. ^[32] In their study, 481 patients all underwent the same induction regimen with daunorubicin, cytarabine, and ATRA. They were then randomized to consolidation treatment with either two cycles of daunorubicin and ATRA or two 25-day courses of ATO. At 3 years, event-free survival and disease-free survival were significantly better for the ATO consolidation arm (P< 0.0001), but the difference in overall survival was not statistically significant (P = 0.59).

The role of maintenance therapy remains uncertain, especially for patients with low-risk APL who achieve molecular remission at the end of consolidation treatment. Most of the studies demonstrating benefit from maintenance therapy were conducted before the introduction of ATRA, ATO, or cytarabine for consolidation. ^[16]

The European APL group randomized patients to intermittent ATRA alone, ATRA plus 6-mercaptopurine (6-MP) and methotrexate, or observation. They found an improved overall survival in patients receiving ATRA or ATRA plus chemotherapy. Currently, the three-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.

APL disease monitoring is usually done by reverse transcription polymerase chain reaction (RT-PCR) assay for the PML-RARA fusion transcript. ^[33] The RT-PCR assay can establish the diagnosis of APL when cytogenetics and fluorescence in situ hybridization (FISH) fail. The assay is useful for detecting minimal residual disease (MRD). The International Working Group recommends that the goal of treatment is complete molecular remission, which is evidenced by the absence of the fusion transcript using RT-PCR at a sensitivity threshold of 10^-4.

Due to the lower sensitivity of the RT-PCR assay, the peripheral blood RT-PCR needs to be monitored 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 for 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-RARA negative on RT-PCR) at the end of consolidation. In this study, 586 patients who were RT-PCR negative after consolidation were then randomized to four maintenance arms: (1) oral 6-MP and intramuscular methotrexate, (2) ATRA, (3) alternating oral 6-MP and intramuscular methotrexate with ATRA, or (4) observation alone. After 4 years, the chemotherapy alone arm was discontinued. ^[34]

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. ^[34]

Patients have resistant APL 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 by RT-PCR assay shows positivity on consecutive samples. This can occur in up to 30% of patients. ATO is recommended in relapsed or refractory APL. ^[35]

In relapsed APL, ATO shows high antileukemic 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 of 52-96% with ATO monotherapy in relapsed APL. Soignet et al showed a complete remission rate of 85% in a multicenter study of 40 patients with APL. ^[36] After two cycles of ATO, 78% of patients had no evidence of the leukemic clone.

Analysis of 72 patients with APL treated with ATO alone showed 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, which likely would be required in high-risk cases. ^[37]

ATO is well tolerated in elderly persons and has antileukemic effects at low doses. Adverse effects of ATO include the following ^[38] :

• Prolongation of the QTc interval
• Hepatotoxicity
• Nausea and vomiting
• Fluid retention
• Itching and rash
• APL differentiation syndrome

Gemtuzumab ozogamicin, a humanized anti-CD33 antibody linked to an antitumor antibiotic, ^[39] was approved in May 2000 for first recurrence of AML but was withdrawn from the US market 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 was shown to be increased in the postmarket setting. Gemtuzumab ozogamicin had been highly effective in molecular or overt relapsed APL. ^{[40, 41]}

Bone marrow transplantation

Because the cure rate for acute APL is high, bone marrow transplantation (BMT) is not the first option for these patients, but it should be offered to those with relapsed APL. ^{[42, 43]} BMT is associated with 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. Date from the Center for International Blood and Marrow Transplant Research (CIBMTR) 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.

In patients who have central nervous system (CNS) involvement or who are at higher risk for CNS relapse, intrathecal chemotherapy is usually given in five doses. The regimen is a combination of cytarabine (50 mg), methotrexate (15 mg), and hydrocortisone (30 mg), given weekly for 5 weeks. For prophylaxis, one dose is given during induction, and four doses are given during consolidation. ^[44]

Although APL in patients older than 60 years is sensitive to chemotherapy, these patients have higher death rates in complete remission. ^{[45, 46]} 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 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, the consolidation regimen should be altered to liposomal ATRA or ATO. These drugs can also be used in combination.

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

The patient's activity should be limited in cases of severe thrombocytopenia (platelet count < 10,000/μL). These patients are at increased risk of spontaneous bleeding, and the potential for falls should be minimized.

The most important complications of acute promyelocytic leukemia (APL) are bleeding diathesis secondary to underlying coagulopathy (5%), infection (2.3%), and differentiation syndrome (1.4%). ^[30] The coagulopathy should be monitored closely to prevent early mortality. Infection can occur at any time and should be treated promptly with antibiotics. Patients with differentiation syndrome should be treated with intravenous steroids to prevent treatment-related mortality.

ATRA helps to rapidly control the disseminated intravascular coagulation (DIC) associated with APL. It is important to note that the treatment of disseminated intravascular coagulation (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. ^{[16, 12]}

About 25-50% of patients who receive ATRA develop differentiation syndrome, typically within the first 21 days of treatment. This disorder was initially termed retinoic acid syndrome (RAS), but was subsequently found to occur in APL patients treated with ATO or other cytotoxic drugs. Differentiation syndrome is characterized by the following:

• Fever
• Hypotension
• Weight gain
• Respiratory distress
• Serositis with pleural or pericardial effusions
• Hypoxemia
• Radiologic infiltrates
• Acute kidney injury
• Hepatic dysfunction

For high risk patients (WBC >10,000/μL), prophylaxis against differentiation syndrome is with corticosteroids (prednisone or dexamethasone) with the dose tapered over several days.

A high degree of clinical suspicion for differentiation syndrome should always lead to initiation of dexamethasone therapy at the first sign of symptoms of respiratory compromise. Temporary discontinuation of ATRA therapy should be considered until hypoxia resolves. Cytoreduction, hydroxyurea, and anthracycline are recommended for difficult-to-treat differentiation syndrome. ^[16]

Hyperleukocytosis is common in differentiation syndrome, but leukocyte counts may also be normal. Gemtuzumab or anthracyclines (idarubicin and daunorubicin) can be used to control the leukocyte count if necessary. ^[12]

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

Other side effects of ATRA include the following:

• Headache
• Nasal stuffiness
• Dry, red skin
• Pseudotumor cerebri (rare)

No risk factor has been identified for primary acute promyelocytic leukemia (APL). It is still unclear whether there are certain forms of environmental or occupational exposure that predispose susceptible individuals to APL.

Secondary APL may follow treatment with cytotoxic agents (especially mitoxantrone) or radiotherapy. Secondary APL accounts for 10-20% of cases. The evolution of treatment strategies for primary cancers has reduced the incidence of secondary APL in breast cancer patients but increased it in prostate cancer patients. Characteristics and outcomes of secondary APL are similar to those of primary APL. ^[47]