JSH practical guidelines for hematological malignancies, 2018: I. Leukemia—2. Acute promyelocytic leukemia (APL)

Overview

1. Disease concept

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) in which neoplastic proliferation of promyelocytes with unique cellular morphology is observed in bone marrow and peripheral blood. APL is characterized by anemia, infection, and hemorrhage due to suppression of normal hematopoiesis, as well as a strong bleeding tendency due to hyperfibrinolytic disseminated intravascular coagulation (DIC) caused by APL cells. The majority of patients have the PML-RARA chimeric gene produced by t(15;17)(q22:q21).^1,2 APL accounts for 10–15% of AML cases, occurring most commonly in people in their 30–50 s and less commonly in people aged 60 years and older. Secondary APL after anti-cancer therapy is uncommon, but does occur. Treatment outcomes for APL improved dramatically with the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which are molecularly targeted drugs that act on the PML-RARα chimeric protein produced by the chromosomal translocation t(15;17).³

2. Classification

APL corresponds to the M3 and M3 variant (M3v) subtypes in the French–American–British (FAB) classification. M3 is easily diagnosed morphologically by highly irregular nuclei with rich azurophilic granules in cytoplasm, and by the appearance of faggot cells with many Auer rods. M3v is often difficult to diagnose morphologically due to its lack of granules and Auer rods, and many patients have an elevated white blood cell (WBC) count. It is important to suspect M3v in patients with DIC with strongly myeloperoxidase-positive blasts. M3 cells are CD13- and CD33-positive, but HLA-DR- and CD34-negative. M3v cells are often positive for HLA-DR, CD34, and the T cell antigen CD2.

APL is referred to as APL with recurrent cytogenetic abnormality PML-RARA in the WHO classification (2017).¹ The most important factor in treatment of APL is the response to ATRA and ATO. The t(15;17) translocation is detected in 92% of patients with APL diagnosed by cellular morphology. If complex karyotypes are included, the overall percentage with PML-RARA rises to 98%.² Most of the few remaining patients have variant RARA translocations, a subtype in which a specific gene such as ZBTB16 becomes translocated with RARA on chromosome 17 (Table 1).¹ When fluorescence in situ hybridization (FISH) does not detect a PML-RARA fusion signal but does detect 3 RARA signals, it is necessary to suspect the presence of another chimeric gene. Response to ATRA depends on the translocation. It is considered ineffective for t(11;17)/PLZF(ZBTB16)-RARA and t(17;17)/STAT5B-RARA. ATO targets PML, and thus is only effective in patients with PML-RARA. Therefore, early testing for PML-RARA by FISH or reverse transcription polymerase chain reaction (RT-PCR) is critical to the diagnosis of APL. Detection of PML-RARA is essential for the M3v subtype, because it is often difficult to diagnose morphologically.

Table 1 Fusion genes produced by chromosomal translocation in APL and response to ATRA and ATO

Other genetic abnormalities besides t(15;17) translocation are very likely involved in development of APL as well. A recent study in which comprehensive genetic analysis was performed in 165 patients with APL identified FLT3-ITD (27%), FLT3 (16%), WT1 (14%), NRAS (10%), KRAS (4%), ARIA1A (4.8%), and ARID1B (3%) mutations in APL cells at diagnosis.⁴FLT3-ITD is correlated with the M3v subtype, a high WBC count, and the PML breakpoint bcr3. It is believed that these mutations, most of which activate signal transduction pathways, contribute to APL development coordinating with PML-RARA. Interestingly, abnormalities in the genes which are commonly mutated in other forms of AML (e.g., DNMT3A, NPM1, TET2, ASXL1, and IDH1/2) are uncommon in APL.

3. Prognosis

The introduction of ATRA dramatically improved treatment outcomes for APL. ATO is effective for treating relapse after ATRA therapy, and yields a high remission rate after relapse. Recently, combination therapy with ATO and ATRA has been shown to be highly effective in newly diagnosed patients.

ATRA plus chemotherapy can be expected to yield complete remission in 90% or more of patients aged younger than 70 years.³ The main causes of failure to achieve remission are organ hemorrhage caused by DIC and differentiation syndrome (DS). Resistance to primary treatment with ATRA plus chemotherapy is very uncommon. Non-relapse mortality due to infections that develop during the period of myelosuppression in the second to third cycles of consolidation chemotherapy is not rare particularly among elderly patients. The high cumulative incidence of relapse (CIR) of around 25% is also a major issue. Over 80–90% of patients will achieve the second remission with ATO after relapse. The expected relapse-free survival (RFS) rate with ATRA and chemotherapy is 60–80%, and the expected overall survival (OS) rate is around 80%. Elderly patients (≥ 60 or 70 years) have a high rate of complications such as hemorrhage and infection, and remission rate decreases with age. Death from infection during consolidation therapy is more frequent in elderly than young patients.

The issues with treatment of APL with ATRA plus chemotherapy are early death of DIC-related organ hemorrhage and DS during induction therapy, death of infection during the period of myelosuppression in consolidation therapy, and relapse. Age and baseline WBC count are prognostic factors for disease-free survival (DFS) in APL. Patients with a baseline WBC count of 10,000/μL or higher are considered high-risk, and account for 25% of all patients.⁵ Patients with a baseline WBC count less than 10,000/μL are considered standard-risk. Patients are sometimes classified by baseline platelet count as low-risk (> 40,000/μL) or intermediate-risk (≤ 40,000/μL),⁶ but the most common approach is to stratify patients for treatment as either high- or standard-risk. Prognostic factors for ATRA and ATO combination therapy in newly diagnosed patients have not been established, but treatment is stratified by risk classification based on WBC count. Positivity of CD56, a cell adhesion factor, is also an unfavorable risk factor for relapse independent of WBC count.⁷ Eleven to fifteen percent of all APL patients are CD56-positive, and CIR after ATRA plus chemotherapy is significantly higher for CD56-positive patients. Extramedullary relapse is also considered to be common in CD56-positive patients.

PML-RARA transcripts in bone marrow cells are useful for assessment of remission at the molecular level. Half of all patients still have PML-RARA transcripts in hematological remission after induction therapy, but must test negative by the end of consolidation therapy.⁸ Reappearance of PML-RARA transcripts during follow-up indicates molecular relapse, and it is recommended to restart treatment in those patients.

It is highly likely that the issues with ATRA and chemotherapy will be reduced by using ATO in primary treatment (not covered by Japanese National Health Insurance [NHI]). ATO only causes mild myelosuppression, and has a low rate of hemorrhage during induction therapy and infection during consolidation therapy. It also promises to reduce CIR due to its synergistic effect with ATRA in breaking down PML-RARα chimeric protein. Some hope that ATRA and ATO might eliminate the need for chemotherapy for APL.

References

• 1. Arber DA, et al. Acute myeloid leukaemia with recurrent genetic abnormalities. Acute promyelocytic leukaemia with PML-RARA. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Lyon, IARC; 2017: pp 134–6. (Textbook)

• 2. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia. 2002; 16(10): 1959–73.

• 3. Sanz MA, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009; 113(9): 1875–91. (Guidelines)

• 4. Madan V, et al. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. Leukemia. 2016; 30(8): 1672–81.

• 5. Asou N, et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. J Clin Oncol. 1998; 16(1): 78–85. (3iiDii)

• 6. Sanz MA, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000; 96(4): 1247–53. (3iiDii)

• 7. Grimwade D, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009; 27(22): 3650–8. (3iiDii)

• 8. Montesinos P, et al. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. Blood. 2011; 117(6): 1799–805. (3iiDii)

Algorithm

Detection of PML-RARA by FISH or RT-PCR is important in the diagnosis of APL (CQ1) because the presence of translocations other than t(15;17) affects response to ATRA and ATO. Coagulation tests must be performed frequently because early death by cerebral or pulmonary hemorrhage associated with coagulopathy in primary treatment for APL is the main cause of failure to achieve remission. Patients with a baseline WBC count of 10,000/μL or higher are considered high-risk in terms of DFS.

ATRA plus chemotherapy is the standard induction therapy (CQ2) for newly diagnosed APL. Resistance to initial induction therapy is very uncommon, and early death from complications such as hemorrhage and DS is the main cause of failure to achieve remission. Therefore, prevention of hemorrhage (CQ3) and management of DS (CQ4) are critical in the treatment of APL. Recently, combination therapy with ATRA and ATO (not covered by Japanese NHI) has been shown to be highly effective in induction and consolidation therapies for newly diagnosed patients (CQ1).

Once hematologic remission is achieved, 2 or 3 cycles of consolidation chemotherapy (CQ5) are performed with the aim of achieving molecular remission, which is evidenced by a negative RQ-PCR result for PML-RARA in bone marrow cells. Various approaches including combination regimens with ATRA and use of ATO have been attempted as consolidation therapy.

Maintenance combination chemotherapy (CQ6) does not improve outcomes. Maintenance therapy with ATRA alone or ATRA plus mercaptopurine (6MP)/methotrexate (MTX) has been reported to be effective, but the effectiveness of these therapies is also influenced by preceding treatments up to consolidation therapy. A study comparing tamibarotene and ATRA for maintenance therapy found that tamibarotene was better in high-risk patients.

The treatment of choice for relapsed APL (CQ7) is ATO. As hematologic relapse is frequently complicated by hemorrhage and DS, it is best to start treatment immediately after detecting molecular relapse by a positive PML-RARA result, rather than waiting for hematologic relapse. It is recommended to perform consolidation therapy with ATO after achieving remission (CQ8), followed by allogeneic hematopoietic stem cell transplantation (HSCT) if PML-RARA is detected in bone marrow or autologous HSCT if it is not detected. If HSCT is not indicated, gemtuzumab ozogamicin (GO) is recommended because it is also effective for patients with APL who have relapsed after treatment with ATO.

Treatment of APL in elderly patients (CQ9) will also be discussed below.

CQ 1 What tests should be performed and what prognostic factors should be assessed before starting treatment for newly diagnosed APL?

Explanation

The most important factor in treatment of APL is response to ATRA and ATO.¹ Most patients with APL diagnosed by cellular morphology or chemistry have the t(15;17) translocation. If complex karyotypes and other masked variants are included, the overall percentage of patients with PML-RARA responsive to both ATRA and ATO rises to 98%. Most of the few remaining patients have subtypes in which a specific gene such as ZBTB16 becomes translocated with RARA on chromosome 17.² Response to ATRA depends on the translocation. It is considered ineffective for t(11;17)/PLZF(ZBTB16)-RARA and t(17;17)/STAT5B-RARA. ATO targets PML, and thus is only effective in patients with PML-RARA. Therefore, early testing for PML-RARA by FISH or RT-PCR is critical to the diagnosis and treatment of APL. Detection of PML-RARA is essential for diagnosis of the M3v subtype because it is often difficult to diagnose morphologically. PML-RARA is also essential in subsequent detection of minimal residual disease (MRD). Testing for PML-RARA at the time of diagnosis is necessary because its presence after consolidation therapy is a critical prognostic factor that determines the course of treatment.³

Resistance to ATRA plus chemotherapy for newly diagnosed APL is very uncommon, and early death from complications such as hemorrhage and DS is the main cause of failure to achieve remission.¹ No predictors of DS have been identified, but it is necessary to make efforts to detect it early and to treat it early (CQ3). Prevention of hemorrhage by frequent testing for coagulopathy is also important (CQ4).

Baseline WBC count is the prognostic factor for DFS in APL. Patients with a WBC count of 10,000/μL or higher are considered high-risk in stratification for ATRA plus chemotherapy.^4,5 Patients are sometimes classified by baseline platelet count as low-risk (≥ 40,000/μL) or intermediate-risk (< 40,000/μL),⁵ but the most common approach is to stratify patients for treatment as either high- or standard-risk. Prognostic factors for ATRA and ATO combination therapy in newly diagnosed patients have not been established, but treatment is stratified by risk classification based on WBC count. Positive CD56 is also an adverse risk factor for relapse independently of WBC count.^6,7 Eleven to fifteen percent of all APL patients are CD56-positive, and CIR after ATRA plus chemotherapy is significantly higher for CD56-positive patients than CD56-negative patients.

References

• 1. Sanz MA, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009; 113(9): 1875–91. (Guidelines)

• 2. Grimwade D, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d’Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action “Molecular Cytogenetic Diagnosis in Haematological Malignancies”. Blood. 2000; 96(4): 1297–308. (3iiDiv)

• 3. Grimwade D, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009; 27(22): 3650–8. (3iiDii)

• 4. Asou N, et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. J Clin Oncol. 1998; 16(1): 78–85. (3iiDii)

• 5. Sanz MA, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000; 96(4): 1247–53. (3iiDii)

• 6. Ferrara F, et al. CD56 expression is an indicator of poor clinical outcome in patients with acute promyelocytic leukemia treated with simultaneous all-trans-retinoic acid and chemotherapy. J Clin Oncol. 2000; 18(6): 1295–300. (3iiA)

• 7. Montesinos P, et al. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. Blood. 2011; 117(6): 1799–805. (3iiDii)

CQ 2 What induction therapy regimen is recommended for newly diagnosed APL?

Explanation

After a study from a Shanghai-based research group found that ATRA monotherapy yields a high complete remission rate in patients with APL,¹ large clinical trials from Europe, the United States, and Japan confirmed its superior treatment outcomes.^2–4 Since then, ATRA plus chemotherapy has become established as the standard therapy for newly diagnosed APL. Combination of ATRA with an anthracycline-based chemotherapy regimen yields a CR rate of 90–95% for initial induction therapy for newly diagnosed APL.

There is no consensus regarding the need to add cytarabine to ATRA plus an anthracycline. The European APL2000 study, which compared treatment with and without addition of cytarabine in newly diagnosed patients with a baseline WBC count of less than 10,000/μL, found that addition of cytarabine yielded a comparable CR rate, but significantly better 2-year CIR, EFS rate, and OS rate.⁵ However, an integrated analysis of the APL2000 study and the PETHEMA study, which investigated ATRA with anthracycline-only chemotherapy (AIDA regimen) showed that 3-year CIR in patients with a WBC count of less than 10,000/μL was significantly lower with the PETHEMA regimen.⁶

The APL204 study conducted by the Japan Adult Leukemia Study Group (JALSG) obtained favorable treatment outcomes by stratifying the chemotherapy regimen used with ATRA for induction therapy based on baseline WBC count and peripheral blood APL cell count (myeloblasts and promyelocytes). The protocol used in the study is currently considered the standard therapy for newly diagnosed APL in Japan. However, a better treatment approach must be established for high-risk patients because the protocol was not adequately effective in patients with a baseline WBC count of 10,000/μL or higher.⁷

Recently, two research groups released results from phase III controlled trials to verify the efficacy and safety of ATRA plus ATO. A group led by GIMEMA investigated the non-inferiority of ATRA plus ATO versus the AIDA regimen in low- to intermediate-risk patients aged 18–71 years with newly diagnosed APL. They found that ATRA plus ATO did not improve the CR rate, but yielded non-inferior 2-year EFS rate, and significantly better 50-month EFS rate, OS rate, and CIR even in direct comparison. Patients who received ATO had lower incidences of hematologic toxicity and infection, and higher incidences of QTc prolongation and hepatotoxicity.^8,9 The British Medical Research Council conducted a similar controlled trial in patients with newly diagnosed APL aged 16–77 years from all risk groups. They found that ATRA plus ATO did not improve the CR rate, but yielded significantly better 4-year CIR after hematologic remission.¹⁰ Another study by M.D. Anderson Cancer Center also found favorable treatment outcomes with ATRA plus ATO for newly diagnosed APL.¹¹ Although ATO is not covered by Japanese NHI for newly diagnosed APL as of December 2017, ATRA plus ATO can be considered non-inferior to ATRA plus anthracycline-based chemotherapy.

References

• 1. Huang ME, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988; 72(2): 567–72. (3iiDiv)

• 2. Fenaux P, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood. 1993; 82(11): 3241–9. (1iiDi)

• 3. Tallman MS, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997; 337(15): 1021–8. (1iiA)

• 4. Kanamaru A, et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group. Blood. 1995; 85(5): 1202–6. (2Di)

• 5. Adès L, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006; 24(36): 5703–10. (1iiDii)

• 6. Adès L, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008; 111(3): 1078–84. (3iiiDi)

• 7. Shinagawa K, et al. Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial. J Clin Oncol. 2014; 32(33): 3729–35. (1iiDiv)

• 8. Lo-Coco F, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013; 369(2): 111–21. (1iiDi)

• 9. Platzbecker U, et al. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017; 35(6): 605–12. (1iiDi)

• 10. Burnett AK, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015; 16(13): 1295–305. (1iiDi)

• 11. Abaza Y, et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017; 129(10): 1275–83. (3iiA)

CQ 3 What approaches are recommended for management of DIC during induction therapy for newly diagnosed APL?

Explanation

In APL, tissue factors and cancer procoagulants in APL cells activate the extrinsic coagulation pathway, and high expression of annexin II on the cell surface simultaneously activates fibrinolysis. As a result, hyperfibrinolytic DIC with a strong bleeding tendency mainly occurs.

The main cause of failure to achieve remission by induction therapy in newly diagnosed APL is organ hemorrhage caused by DIC. More than half of the failures to achieve remission in the JALSG APL97 study were due to early death from organ hemorrhage such as cerebral hemorrhage.¹ A Swedish epidemiological study also reported that many early deaths from organ hemorrhage occur in patients with newly diagnosed APL.²

In the subanalysis of JALSG APL97 study, hypofibrinogenemia (< 100 mg/dL), high WBC count (> 20,000/μL), and performance status of 2 or 3 were identified as high-risk factors for organ hemorrhage.¹ Platelet transfusions to maintain platelet count at 30,000–50,000/μL or higher and replacement therapy with fresh frozen plasma to maintain fibrinogen at 150 mg/dL or higher are recommended for DIC in patients with APL.

A retrospective analysis comparing platelet and fibrinogen replacement alone, anticoagulant therapy with heparin, and antifibrinolytic therapy with drugs such as tranexamic acid for prevention of organ hemorrhage, which was conducted during the time period before the introduction of ATRA when APL was treated with chemotherapy alone, showed no differences in remission rates or the early death rate from hemorrhage.³ A PETHEMA study showed that combination of tranexamic acid with ATRA increased the risk of thrombosis.⁴ Anticoagulant therapy with low-molecular-weight heparin, danaparoid sodium, or synthetic protease inhibitors such as gabexate mesilate, or nafamostat mesilate has never been evaluated in large case reports or controlled trials.

Recombinant thrombomodulin is widely used to treat APL-induced DIC in practice. Recombinant thrombomodulin reduces expression of annexin II on the surface of APL cells and activates protein C in the presence of thrombin, which suppresses the coagulation, and is therefore a logical choice for treating APL-induced DIC. A small retrospective study reported that recombinant thrombomodulin resolved DIC at an early stage and reduced transfusion volume.⁵

In addition, as ATRA itself directly and indirectly corrects coagulopathy in APL, another strategy for preventing hemorrhage is to promptly start treatment with ATRA without waiting for PML-RARA results when clinical findings are suggestive of APL.⁶

References

• 1. Yanada M, et al. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. Eur J Haematol. 2007; 78(3): 213–9. (3iiDi)

• 2. Lehmann S, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011; 25(7): 1128–34. (3iiDiv)

• 3. Rodeghiero F, et al. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood. 1990; 75(11): 2112–7. (3iiiB)

• 4. Brown JE et al. All-trans retinoic acid (ATRA) and tranexamic acid: a potentially fatal combination in acute promyelocytic leukaemia. Br J Haematol. 2000; 110(4): 1010–2. (3iiA)

• 5. Ikezoe T, et al. Recombinant human soluble thrombomodulin safely and effectively rescues acute promyelocytic leukemia patients from disseminated intravascular coagulation. Leukemia Res. 2012; 36(11): 1398–402. (3iiiDiv)

• 6. Di Bona E, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000; 108(4): 689–95. (2A)

CQ 4 What treatments are recommended for differentiation syndrome?

Explanation

It is believed that enhanced migration of APL cells to tissues by overexpression of integrins on APL cells due to treatment with ATRA or ATO and release of various chemokines induced by differentiation of APL cells cause organ damage, resulting in development of DS. The incidence of DS ranges from 2.5 to 26% and overall mortality from 0 to 3.4% in newly diagnosed APL. The median number of days before onset (diagnosis) of DS is 7–11 days (range 0–47 days) after the start of treatment. The most common signs and symptoms are (1) tachypnea, dyspnea, and hypoxemia (decreased SpO2); (2) fever of unknown origin; (3) weight gain; (4) edema; (5) decreased blood pressure; (6) acute renal failure and congestive heart failure, and (7) pulmonary consolidation, pleural effusion, and pericardial effusion (on chest X-ray or CT).^1–3

Chemotherapy should be promptly added to ATRA upon detecting an increase in WBC count in patients undergoing single-agent induction therapy with ATRA who had a low baseline WBC count. The correlation of baseline WBC count with DS incidence is unclear. In the integrated analysis of LPA96 and LPA99 studies, a baseline WBC count of 10,000/μL or higher was considered a significant risk factor for moderate DS, and a baseline WBC count of 5000/μL or higher a risk factor for severe DS.¹ However, baseline WBC count was not a significant risk factor in the APL93 and Intergroup 0129 studies.^2,3 High body mass index is a significant risk factor for DS.⁴

To treat DS, it is important to start intravenous administration of dexamethasone 10 mg twice daily as soon as possible. Treatment with ATRA or ATO should be interrupted if DS manifests with respiratory symptoms or imaging findings or if dexamethasone is not effective.⁵ ATRA or ATO should be restarted only after symptoms disappear completely. Treatment should be restarted at 75% of the initial dose and then increased to the full initial dose 3–5 days later after confirming that symptoms have not re-appeared.

Patients in the APL2000 study with a baseline WBC count higher than 10,000/μL who were treated with dexamethasone 10 mg twice daily for at least 3 days during induction therapy with ATRA had a lower mortality rate from DS than patients in the APL93 study who received ATRA without dexamethasone.⁶ The LPA99 study investigated the efficacy of oral prednisolone 0.5 mg/kg/day on days 1 through 15 in preventing DS, and found lower incidence than that in the prior LPA96 study.¹ Corticosteroids are considered effective for prevention of DS during induction therapy, but care should be taken not to use them indiscriminately as they can make patients prone to infection.

References

• 1. Montesinos P, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009; 113(4): 775–83. (3iiiDiv)

• 2. De Botton S, et al. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. Blood. 1998; 92(8): 2712–8. (3iiiDiv)

• 3. Tallman MS, et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood. 2000; 95(1): 90–5. (3iiiDiv)

• 4. Breccia M, et al. Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols. Blood. 2012; 119(1): 49–54. (3iiiDiv)

• 5. Sanz MA, et al. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014; 123(18): 2777–82. (Review)

• 6. Sanz MA, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004; 103(4): 1237–43. (3iiiDiv)

CQ 5 What is the optimal consolidation therapy regimen following induction with ATRA plus chemotherapy for newly diagnosed APL?

Explanation

Consolidation therapy with 3 cycles of anthracycline and cytarabine combination therapy as postremission therapy was shown to yield high OS in the JALSG APL97 and APL204 studies.¹

Recently published studies have shown that addition of ATO to induction or consolidation therapy for newly diagnosed APL improves EFS. The North American Leukemia Intergroup Study C9710, a randomized controlled trial investigating postremission therapy with and without ATO in 481 patients with newly diagnosed APL, found that the 3-year EFS rate was significantly better with addition of ATO (80% vs. 63%).² A similar study by a group from Shanghai, China, compared consolidation therapy with and without ATO in 109 patients. They found that addition of ATO significantly extended 5-year EFS (94.4% vs. 54.8%, p = 0.0001) and OS (95.7% vs. 64.1%, p = 0.003) rates.^3,4

Results of the Italian–German APL0406 trial also suggest that chemotherapy-free treatment is safer and causes fewer adverse events in low-risk patients.⁵ This is good news for elderly patients, as they are particularly prone to experiencing adverse events with chemotherapy. Therefore, it is considered advantageous to select ATO plus ATRA as postremission therapy for newly diagnosed APL in patients not suitable for intensive chemotherapy due to comorbidities. (It should be noted that ATO has not been approved for consolidation therapy for newly diagnosed APL in Japan as of May 2018.)

Currently, consolidation therapy regimens are anthracycline-based (idarubicin, daunorubicin, or mitoxantrone),⁶ and are combined with cytarabine or ATRA. In the Italian AIDA2000 study, which used a modified version of the treatment protocol for the prior AIDA0493 study with addition of ATRA for all patients and addition of cytarabine for high-risk patients in consolidation phase, the relapse rate for the high-risk group decreased significantly.⁷

References

• 1. Shinagawa K, et al.: Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial. J Clin Oncol. 2014; 32(33): 3729–35. (1iiDiv)

• 2. Powell BL, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010; 116(19): 3751–7. (1iiDi)

• 3. Shen ZX, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004; 101(15): 5328–35. (1iiDi)

• 4. Lou Y, et al. Long-term efficacy of low-dose all-trans retinoic acid plus minimal chemotherapy induction followed by the addition of intravenous arsenic trioxide post-remission therapy in newly diagnosed acute promyelocytic leukaemia. Hematol Oncol. 2014; 32(1): 40–6. (2Di)

• 5. Platzbecker U, et al. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 Trial. J Clin Oncol. 2017; 35(6): 605–12. (1iiDi)

• 6. Adès L, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008; 111(3): 1078–84. (3iiiDi)

• 7. Lo-Coco F, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010; 116(17): 3171–9. (3iiiDii)

CQ 6 What is the optimal maintenance therapy regimen for newly diagnosed APL in remission?

Explanation

Maintenance therapy should be selected taking into account induction and consolidation therapies. The Italian AIDA 0493 study compared ATRA, ATRA/MTX/6MP, MTX/6MP, and no maintenance therapy, and found no significant difference in 12-year DFS rate between the four groups.¹ The French APL93 study compared the same four groups and found that 10-year CIR was lowest for the ATRA/MTX/6MP group, and that this treatment was particularly effective in patients with a high baseline WBC count (> 5000/μL).² ATRA monotherapy and MTX/6MP were also more effective than no maintenance therapy. In the JALSG APL97 study, a prospective study comparing 6 cycles of infusional combination maintenance chemotherapy with observation,³ there was no significant difference in 6-year DFS between groups, and outcomes for the chemotherapy group were actually worse in 6-year OS. This indicates that combination chemotherapy is not recommended as maintenance therapy. In summary, although the optimal maintenance therapy regimens for low-risk (WBC count ≤ 10,000/μL, platelet count > 40,000/μL) and intermediate-risk (WBC count ≤ 10,000/μL, platelet count ≤ 40,000/μL) patients still need to be established, ATRA-based maintenance therapy should be considered for high-risk patients (WBC count > 10,000/μL).

The JALSG APL204 study compared ATRA with tamibarotene as maintenance therapy after induction therapy and 3 cycles of consolidation therapy in newly diagnosed APL. The 4-year RFS rate was 84% with ATRA and 91% with tamibarotene, and was significantly higher with tamibarotene among high-risk patients.⁴

References

• 1. Avvisati G, et al. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011; 117(18): 4716–25. (1iiDii)

• 2. Adès L, et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010; 115(9): 1690–6. (1iiDii)

• 3. Asou N, et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Blood. 2007; 110(1): 59–66. (1iiDii)

• 4. Katsuji Shinagawa, Masamitsu Yanada et al.: Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial. J Clin Oncol. 2014; 32(33): 3729–35. (1iiDi)

CQ 7 What is the optimal reinduction therapy regimen for relapsed APL?

Explanation

Although the introduction of ATRA plus chemotherapy improved outcomes for primary therapy for APL, approximately 15–20% of patients relapse. The regimen used for primary therapy must be considered when selecting the regimen to use after relapse. New primary therapy regimens that use ATRA and ATO in combination are now being described in the literature, and it can be assumed that the characteristics of relapsed patients will continue to change with such advances.

Treatment with ATO achieves molecular remission in 80–90% of patients who have relapsed after ATRA-based induction therapy.^1–4 The JALSG APL205R protocol, in which autologous HSCT is performed after induction therapy with ATO for relapsed APL, yielded a CR rate of 81%, 5-year EFS rate of 65%, and 5-year OS rate of 77%.⁵

ATO and ATRA are known to act synergistically against APL cells in vitro. However, a small-scale randomized controlled trial in relapsed patients who underwent primary therapy with ATRA found no improvement in survival when ATRA was added to ATO. This indicates that there is little significance to adding ATRA to ATO in patients who have relapsed after treatment with ATRA.⁶

If ATO is not indicated, GO is the drug of choice. In one study, two doses of single-agent therapy with GO achieved molecular remission in 81.8% of patients in molecular relapse.⁷ As GO can cause hepatic sinusoidal obstruction syndrome after HSCT, use of GO should be avoided or transplantation should be delayed in patients scheduled for HSCT. The synthetic retinoid tamibarotene achieved remission in 58% of patients in relapse after treatment with ATRA in a phase II study,⁸ but is currently considered a secondary treatment option after ATO and GO.

Central nervous system (CNS) involvement is observed in at least 5% of relapsed patients, and thus CNS prophylaxis should always be considered when formulating a treatment plan. CNS relapse is sometimes detected by cerebrospinal fluid analysis in patients who do not have symptoms such as headache. CNS relapse occurs in patients with hematological relapse in many cases, but some cases of CNS relapse in patients with only molecular relapse were reported. A study by the European APL Group reported CNS involvement in 5.3% of relapsed patients. Age of 45 years or younger at diagnosis and a WBC count of 10,000/μL or higher have been identified as risk factors for CNS relapse.⁹

CNS relapse is treated by once- to twice-weekly intrathecal injections of methotrexate, cytarabine, and hydrocortisone until disappearance of blasts in cerebrospinal fluid, followed by approximately 6 additional cycles of the regimen as consolidation therapy. Craniospinal irradiation or high-dose cytarabine should be considered if no improvement is seen with intrathecal therapy.

References

• 1. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (AFL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997; 89(9): 3354–60. (3iiDiv)

• 2. Soignet SL, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001; 19(18): 3852–60. (3iiiA)

• 3. Niu C, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999; 94(10): 3315–24. (3iiiDii)

• 4. Shigeno K, et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol. 2005; 82(3): 224–9. (3iiiA)

• 5. Yanada M, et al. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013; 121(16): 3095–102. (2Di)

• 6. Raffoux E, et al. Combined treatment with arsenic trioxide and all-trans retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol. 2003; 21(12): 2326–34. (1iiDiv)

• 7. Lo-Coco F, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004; 104(7): 1995–9. (3iiiDiv)

• 8. Tobita T, et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997; 90(3): 967–73. (3iiDiv)

• 9. de Botton S, et al.: Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006: 20(1), 35–41. (3iDii)

CQ 8 What postremission therapy is recommended for APL in second remission after treatment with ATO?

Explanation

Performing ATO-based postremission therapy after reinduction with ATO yields somewhat long survival (1.5-year OS rate: 66%, RFS rate: 56%), but the relapse rate is also relatively high.¹ A study by a Shanghai research group showed that OS for ATO plus chemotherapy for consolidation therapy after reinduction with ATO was superior to that for ATO monotherapy.² Consolidation therapy with HSCT is effective as postremission therapy. An Indian study in patients with relapsed APL found that addition of autologous HSCT after induction therapy with ATO alone or ATO plus ATRA significantly extended EFS (83.3% vs. 34.5%).³ If HSCT is not indicated after reinduction therapy with ATO, GO is recommended because it is also effective for APL patients who have relapsed after treatment with ATO.⁴

Before ATO became available, reinduction therapy was performed with ATRA plus chemotherapy. The European APL91 and APL93 studies, which compared autologous and allogeneic HSCT during second remission after reinduction therapy, found that autologous HSCT yielded superior 7-year OS rate to allogeneic HSCT (59.8% vs. 51.8%).⁵ Although allogeneic HSCT yielded better RFS rate (79.4% vs. 92.3%), it also had higher treatment-related mortality (6% vs. 39%). An analysis (n = 625) by the European Group for Blood and Marrow Transplantation (EBMT) showed that the 5-year DFS rate for patients in second CR was 51% for autologous HSCT and 59% for allogeneic HSCT.⁶

The above evidence indicates that either autologous or allogeneic HSCT should be performed after assessment of MRD in bone marrow cells after remission. Allogeneic HSCT is recommended for patients who relapse within 1 year of remission or have MRD, whereas autologous HSCT is recommended for patients who relapse more than 1 year after remission and have no MRD. Consolidation therapy with ATO is often continued in patients judged likely to be intolerant of HSCT.

The protocol used in the JALSG APL205R study is currently considered the standard therapy for relapsed APL in Japan.⁷ It is a curative therapy protocol for APL relapsed after treatment with ATRA plus chemotherapy that incorporates induction therapy with ATO, consolidation therapy with ATO, harvest of peripheral blood stem cells, and autologous HSCT. High-dose cytarabine is used as the harvest regimen; and cells can be collected once or twice during days 18–22 of treatment, and autologous HSCT has been performed safely.

References

• 1. Soignet SL, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001; 19(18): 3852–60. (3iiiA)

• 2. Niu C, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999; 94(10): 3315–24. (3iiiDii/2Dii)

• 3. Thirugnanam R, et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant. 2009; 15(11): 1479–84. (2Di)

• 4. Lo-Coco F, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004; 104(7): 1995–9. (3iiiDiv)

• 5. de Botton S, et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol. 2005; 23(1): 120–6. (3iiA)

• 6. Sanz MA, et al. Hematopoietic stem cell transplantation for adults with acute promyelocytic leukemia in the ATRA era: a survey of the European Cooperative Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2007; 39(8): 461–9. (3iiiDii)

• 7. Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, et al. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013; 121(16): 3095–102. (2Di)

CQ 9 What is the optimal treatment approach for APL in elderly patients?

Explanation

Most elderly patients with APL fall into the low-risk group with a low baseline WBC count, and respond to treatment just as well as younger patients. However, many die from complications such as infection. Therefore, reducing the intensity of chemotherapy should yield better therapeutic outcomes in elderly patients with APL.

The PETHEMA group did not set an age limit for their LPA96 and LPA99 pooled studies, in which patients received induction therapy with ATRA plus idarubicin and anthracycline-based consolidation therapy. The remission rate among patients aged 60 years and older was favorable, but there was a high rate of early death by infection.¹ The GIMEMA group found that, in AIDA protocol, decreasing consolidation therapy from 3 cycles to one course in patients aged 60 years and older reduced treatment-related adverse events but still yielded similar treatment outcomes.²

ATO causes few age-dependent adverse reactions and shows promise for use in elderly patients with APL. The Leukemia Intergroup Study C9710 showed that addition of single-agent ATO consolidation therapy significantly improved survival outcomes in elderly patients aged 61–79 years.³ A group from M.D. Anderson Cancer Center investigated combination therapy with ATO and ATRA for induction and consolidation therapies and obtained favorable results in patients aged 60 years and older.⁴ ATO-based therapy is a reasonable choice for elderly patients because it is associated with fewer fatal adverse events than typical anticancer drugs. However, ATO is not covered by Japanese NHI for this indication as of May 2018.

References

• 1. Sanz MA, et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood. 2004; 104(12): 3490–3. (3iiDii)

• 2. Mandelli F, et al. Treatment of elderly patients (> or = 60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols. Leukemia. 2003; 17(6): 1085–90. (1iiA)

• 3. Powell BL, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010; 116(19): 3751–7. (1iiDi)

• 4. Estey E, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006; 107(9): 3469–73. (3iiDiv)