Version May 2024
INTRODUCTION — Acute promyelocytic leukemia (APL) is a clinically and biologically distinct variant of acute myeloid leukemia (AML). It was classified as AML-M3 in the older French-American-British (FAB) classification system, and acute promyelocytic leukemia with t(15;17)(q24.1;q21.1);PML-RARA in the World Health Organization classification system. (See "Acute myeloid leukemia: Classification".)
The vast majority of patients with newly diagnosed APL obtain a hematologic complete remission (CR) with induction therapy that incorporates all-trans retinoic acid (ATRA; tretinoin), followed by a molecular CR after consolidation therapy. Using arsenic trioxide (ATO) during consolidation of first CR markedly reduced the relapse rate even in high-risk APL. The current standard of care for the treatment of newly diagnosed APL is the chemotherapy-free combination of ATRA plus ATO, and relapses are quite uncommon after molecular remissions. The predominant cause of induction failure (5 to 10 percent) is death from hemorrhage or infection, and it is extremely uncommon to have primary drug resistance in APL. However, for patients treated with ATRA plus anthracycline chemotherapy, relapse occurs in 5 to 10 percent of patients with APL and in 20 to 30 percent of those with high-risk APL (ie, presentation with a white blood cell count >10,000/microL and a platelet count <40,000/microL). Some of these relapses have occurred after more than five years in remission.
The treatment of relapsed or refractory APL will be reviewed here. The clinical features, diagnosis, and prognosis of APL in adults are presented separately, as is the initial treatment of APL. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)
DEFINITIONS — Resistant or refractory APL is diagnosed in those patients who either fail to attain a cytologic complete remission with induction chemotherapy or fail to attain a complete molecular remission following several cycles of consolidation chemotherapy [1]. Response criteria are presented separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Introduction'.)
We consider patients to have relapsed disease if, after attainment of complete molecular remission, subsequent analyses confirm the loss of such molecular remission or identify extramedullary disease.
OVERVIEW — The treatment of patients with relapsed APL is generally aimed at achieving molecular remission with plans to proceed to high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) in those with chemotherapy-sensitive disease [2]. Allogeneic HCT can be considered if a suitable donor is available, but for APL, allogeneic HCT is not clearly better than autologous HCT, at least in patients who achieve a second complete molecular response. For patients who do not achieve RT-PCR negativity, allogeneic HCT is the preferred treatment in eligible patients with an available donor. The treatment of patients who are not candidates for HCT, who fail to respond to second-line regimens, or who relapse after HCT is generally palliative; enrollment onto a clinical trial should be encouraged. The same approach is followed in patients with refractory disease.
ACHIEVING A SECOND RESPONSE — Several treatment regimens have been used to treat refractory and relapsed disease [3]. These include all-trans retinoic acid (ATRA), anthracyclines, high-dose cytarabine, arsenic trioxide (ATO), and gemtuzumab ozogamicin. The choice of therapy and the likelihood of cure depend in part upon whether ATRA was given together with an anthracycline drug during the first remission, whether ATO was incorporated into induction or post-remission therapy, and whether the relapse occurred while the patient was still receiving therapy.
Long-term follow-up of 380 patients initially treated with ATRA demonstrated that most relapses occur during the first three years [4]. Late relapses are not common, accounting for less than 5 percent of relapses, and are likely to have durable responses with second line therapy.
The molecular pathways involved in relapsed or refractory APL are poorly understood, but likely differ depending upon the type of initial treatment and the timing of relapse in relation to treatment. As an example, in an analysis of 45 patients with relapsed APL following initial treatment with ATRA plus chemotherapy, 18 cases (40 percent) demonstrated point mutations in the ligand binding domain of PML-RARalpha [5]. Patients with PML-RARA point mutations had progressive disease while receiving ATRA therapy (11 cases) or progressed following the completion of ATRA therapy (seven cases), suggesting selection pressure due to both ATRA therapy and ATRA-independent mechanisms of progression. In contrast, patients within the same study who received ATO as part of their initial therapy had a lower rate of progression, perhaps due to elimination of clones containing PML-RARA point mutations. Another study of patients with relapse after ATO identified point mutations within the B2 domain of PML that interacts with ATO upon binding [6]. Some patients with RARA mutations alone responded to subsequent therapy with ATRA plus ATO, while none with both PML and RARA mutations responded.
A European registry reported outcomes of 155 patients who were treated with ATO for first relapse of APL [7]. Responses varied with the type of relapse:
●Hematological relapse (104 patients): 91 percent achieved hematological complete remission (CR), 74 percent molecular (m)CR, 27 percent had differentiation syndrome, 7 percent induction death, 2 percent treatment resistance, 68 percent three-year overall survival (OS), 41 percent second relapse
●Molecular relapse (40 patients): 62 percent achieved mCR, no deaths or side effects of ATO, 66 percent three-year OS, 48 percent second relapse
●Extramedullary relapse (11 patients): 100 percent hematological CR and mCR, 90 percent three-year OS, 11 percent second relapse
●Multivariate analysis reported the following were associated with favorable OS and leukemia-free survival: first CR duration ≥1.5 years, achievement of mCR, autologous or allogeneic HCT in second remission
Arsenic trioxide (ATO)
Efficacy — In many areas of the world, ATO is available for frontline treatment of APL. It is also the treatment of choice for most patients with relapsed APL following initial therapy with ATRA plus chemotherapy. Complete remission (CR) can be obtained in 85 to 88 percent of patients. It is unclear whether adding ATRA to ATO is better than ATO alone. ATO is able to penetrate the blood-brain barrier and so can be used in patients with central nervous system involvement [8]. This therapy is then followed by consolidation treatment, which is selected based upon the depth of response and patient characteristics:
●If a second remission is obtained and reverse transcription polymerase chain reaction (RT-PCR) testing is negative for the PML/RARA transcript, consolidation with either autologous hematopoietic cell transplantation (HCT), allogeneic HCT, or further ATO is given. Autologous HCT is usually preferred because of its association with less toxicity and morbidity. However, if the patient is young (eg, <30 years of age) and without comorbid conditions, allogeneic HCT is an equally effective choice with a potential, yet unproven improvement in disease control.
●If PCR negativity is not obtained, allogeneic HCT is the favored treatment, but alternative treatments such as gemtuzumab ozogamicin are acceptable options.
A number of studies have shown a high response rate following therapy with ATO in patients with relapsed APL [9-15].
●A case series included 26 patients with relapsed APL who received induction therapy with ATO (0.06 to 0.2 mg/kg per day) [11,12]. CR was achieved in 88 percent at a median time of 47 days. A rising white blood cell count (WBC) >10,000/microL was noted during ATO treatment in 15 patients, with the WBC >100,000/microL in three. Eight patients (31 percent) developed "differentiation syndrome" (a cytokine release mediated phenomenon) at a mean time of 17 days (range 7 to 24 days), and required treatment with corticosteroids. This syndrome was only noted during induction therapy with ATO; neither leukocytosis nor the differentiation syndrome was seen during any postremission courses. Three patients remained positive for the PML/RARA transcript and relapsed early [11].
●In a larger series, 47 patients with relapsed APL (43 in first relapse and two each in second and third relapse) received ATO with or without other agents; 31 with ATO alone, 11 with ATO and moderate chemotherapy, and 5 with ATO and ATRA [9]. CR was obtained in 85 percent, with median disease-free and overall survival rates of 17 and 25 months, respectively. More than two-thirds of the patients treated with ATO alone or chemotherapy alone after attaining CR subsequently relapsed, as compared with only 2 of 11 patients treated with ATO and chemotherapy after attaining CR. Most of the side effects (liver, GI, skin, cardiac) were modest and responded to symptomatic treatment.
●In a multicenter trial of 40 patients with APL in first or second relapse, CR following treatment with ATO was attained in 85 percent, 91 percent of whom had negative post-treatment cytogenetic tests for t(15;17) [14]. Overall and relapse-free survival rates at 18 months were 66 and 56 percent, respectively. Ten patients developed the "APL differentiation syndrome" and were effectively treated with dexamethasone. Prolongation of the QT interval was seen in 63 percent; one patient had an asymptomatic 7-beat run of torsades de pointes. There were two deaths during induction, unrelated to drug treatment.
For patients with resistant or relapsed disease, we suggest treatment with one or two cycles of arsenic trioxide 0.15 mg/kg per day IV for 25 consecutive doses (or five doses per week for five weeks), followed by autologous HCT in patients who achieve a CR and are RT-PCR negative. Allogeneic HCT can be considered if a suitable donor is available, but for APL, allogeneic HCT is not clearly better than autologous HCT. For patients who do not achieve RT-PCR negativity, allogeneic HCT is the preferred treatment in eligible patients with an available donor.
An oral formulation of ATO has been shown to be effective for treating relapsed APL [16]. Seventy-three patients with APL in first relapse received oral ATO-based reinduction and all achieved CR2, irrespective of previous ATO exposure. All patients received oral ATO-based maintenance in CR2. At a median follow-up of 94 months (range, 9 to 205 months), 43 patients (59 percent) were still in CR2, and 49 (67 percent) had finished the planned two-year CR2 maintenance with ATRA, oral ATO, and ascorbic acid. Reinduction and maintenance treatments were well tolerated. Grade 1 and 2 headache occurred in 20 patients (27 percent). Transaminase elevation occurred in 35 patients (48 percent; grade 3 and 4 in 12 percent). Three patients had self-limiting QTc prolongation. The 10-year leukemia-free survival rate was 57 percent.
In some areas of the world, oral arsenic (realgar-indigo naturalis formula; RIF) is commercially available [17]. It has been shown to be as effective as intravenous arsenic trioxide for both newly diagnosed APL and those with relapsed disease. Experience in China suggests that it displays a better safety profile, improved quality of life, and lower medical costs for patients. This agent is not approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA).
Studies of combination therapy with other agents are ongoing and have mixed preliminary results. As an example, a small randomized study of 20 patients with APL relapsed after initial treatment with ATRA and anthracycline-based chemotherapy, found no benefit with the addition of ATRA to ATO [18]. Another small pilot study suggested additional benefit when gemtuzumab ozogamicin was added as consolidation after ATO [19].
Toxicity — Serious adverse events attributed to treatment with ATO include fluid retention, the "differentiation syndrome" (similar to that seen with retinoic acid), peripheral sensory neuropathy, electrocardiographic abnormalities (eg, QT interval prolongation and complete atrioventricular block) and sudden death [20-26]. (See "Differentiation syndrome associated with treatment of acute leukemia".)
In an initial report, all eight patients treated with this agent developed QT prolongation and four developed nonsustained ventricular tachycardia requiring treatment with antiarrhythmic agents [23]. A lower risk was noted in a much larger series of 99 patients [22]. Reversible prolongation of the QT interval to >500 msec occurred in 38 patients; the risk was increased in patients with hypokalemia, with one hypokalemic patient developing torsades de pointes. Hyperglycemia has also been noted.
Labeling instructions for this agent recommend that, during therapy, serum potassium concentrations should be kept >4.0 meq/L and magnesium concentrations >1.8 mg/dL [27]. Maintaining an adequate hemoglobin level and oxygenation may also be important to reduce cardiac toxicity. ATO should be held if the absolute QT interval exceeds 500 msec or if the patient develops syncope or an irregular heartbeat. ATO can be reinstated if these symptoms resolve and the absolute QT interval decreases to 460 msec or below. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
Approximately half of patients will develop a leukocytosis that peaks at approximately day 20 and usually resolves at a median of 10.5 days after the peak, despite continuation of ATO therapy [28].
ATO is eliminated mainly by renal excretion. Accordingly, uremic patients are considered unsuitable for treatment with this agent. However, one patient with relapsed APL and chronic renal failure, who was receiving continuous ambulatory peritoneal dialysis, has been successfully treated with ATO, although at a reduced dose [29].
Gemtuzumab — Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody conjugated with the cytotoxic agent calicheamicin. The CD33 antigen is strongly expressed on APL cells. Clinical trials are evaluating its benefit in combination with ATRA and/or ATO for newly diagnosed patients with APL. The US Food and Drug Administration has approved GO based on multiple trials in patients with newly diagnosed and relapsed acute myeloid leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Immunophenotype'.)
Case reports and small case series have reported on the successful use of single agent GO in the treatment of patients with relapsed APL [30-33]. As an example, in one study, 14 of 16 patients with APL in molecular relapse responded to treatment with GO (6 mg/m2 by IV infusion over two hours) [34]. Of the 13 patients receiving three doses of this agent, all attained a new molecular remission. In addition, GO has demonstrated activity when administered in combination with ATRA and ATO in patients with relapsed APL [19].
Chemotherapy and ATRA for relapse — Patients who have received ATRA plus anthracycline treatment during first remission are less likely to be cured by reinstitution of the same treatment at the time of relapse, although a second remission can often be achieved [3]. The best outcomes in these patients are likely to follow HCT, either at the time of relapse or, preferably, soon after a second CR has been obtained.
In one study, 35 patients treated after first relapse or primary induction failure received one course of chemotherapy combining an anthracycline and cytarabine with or without ATRA [35]. CR was achieved in 29 of 38 patients. Four of five patients who had initially received ATRA achieved a second CR when retreated with ATRA. The only factor predictive of poor prognosis for overall survival was the absence of ATRA therapy at the time of relapse.
CONSOLIDATION — The treatment of patients with relapsed or refractory APL is generally aimed at achieving a second molecular complete remission (CR) with plans to proceed to high dose chemotherapy and hematopoietic cell transplantation (HCT) in those with chemotherapy-sensitive disease. Allogeneic HCT can be considered if a suitable donor is available, but for APL, allogeneic HCT is not clearly better than autologous HCT. For patients who do not achieve reverse transcription polymerase chain reaction (RT-PCR) negativity, allogeneic HCT is the preferred treatment in eligible patients with an available donor.
Autologous transplantation — Studies of autologous HCT performed in second remission suggest that there is prognostic relevance to pretransplant minimal disease assessment by RT-PCR.
●In one study, all seven PCR-positive patients relapsed at a median time of five months following HCT and nine months from the time of second CR. Of the eight PCR-negative patients, one relapsed at 10 months following HCT, one died of a secondary leukemia, and six remained in hematologic and molecular CR at a median time of 28 months [36].
●A second, larger study evaluated results in 50 patients with APL who received autologous HCT while in second CR [3]. Treatment-related mortality was 6 percent. For patients in molecular remission at the time of stem cell collection, the seven-year relapse-free survival was 87 percent.
●A third study of autologous HCT in 51 patients with de novo acute myeloid leukemia in second CR included 12 patients (24 percent) with APL [37]. Treatment consisted of consolidation chemotherapy with high dose cytarabine plus etoposide to mobilize stem cells for collection, followed by a busulfan plus etoposide preparative regimen and autologous HCT. The subset of patients with APL demonstrated five-year disease-free and overall survival rates of 67 percent each with this treatment approach.
●In a Japanese trial of 35 patients with APL in relapse following ATRA-based therapy, reinduction and consolidation with ATO plus chemotherapy resulted in a CR in 81 percent [15]. Autologous HCT was performed in 23 patients who attained PCR negativity. There were no transplant-related deaths and three patients relapsed after HCT. At a median follow-up of five years, the estimated event-free and overall survival rates at five years were 65 and 77 percent, respectively, for the entire cohort.
●A retrospective survey reported 207 patients with APL in second CR who received ATO alone for post-remission therapy (67 patients) versus autologous HCT (140 patients) [38]. Compared with ATO-only, five-year overall survival was superior with autologous HCT (78 versus 42 percent). Improved overall survival was also associated with longer duration of first CR, but not with disease risk status at diagnosis. These data suggest that autologous HCT for APL patients in second CR results in better overall survival than ATO-based therapy alone.
These studies support the use of autologous HCT in patients who achieve a second molecular CR and discourage its use in those who do not.
Allogeneic transplantation — Allogeneic HCT is capable of producing long-term remissions in patients with APL who have achieved a second CR. In an EBMT survey of 137 such patients, five-year leukemia-free survival was 59 percent [39].
However, high rates of non-relapse mortality have been a problem, the rates of which vary depending on risk factors such as age and comorbid conditions. In one series, treatment-related mortality was 39 percent [40], while non-relapse mortality was 32 percent in another [41]. In contrast to the results with autologous HCT, molecular CR at the time of allogeneic HCT may be less important. In two studies, only 3 of 12 PCR-positive patients relapsed following allogeneic HCT [3,41].
MANAGEMENT OF EXTRAMEDULLARY DISEASE — Up to 10 percent of patients with relapsed APL will demonstrate involvement of the central nervous system (CNS) [28]. This may be less common in patients treated with arsenic trioxide (ATO), which can penetrate the CNS. In addition, 3 to 5 percent of patients will have extramedullary disease at other sites, in the form of myeloid sarcoma [28]. There are limited data on the treatment of these patients and most experts extrapolate from their experience treating patients with acute lymphoblastic leukemia (ALL) or other forms of AML.
Central nervous system involvement — All patients with relapsed APL should have a lumbar puncture to assess involvement of the cerebrospinal fluid (CSF). Patients with CNS involvement at the time of relapse require both therapy directed at the CNS and systemic therapy as given to all patients with relapse. It should be noted that ATO does penetrate into CSF [8]. CNS-directed therapy is largely extrapolated from experience with patients with ALL. This is described in more detail separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)
Myeloid sarcoma — Myeloid sarcoma (also called granulocytic sarcoma or chloroma) is defined by prominent extramedullary sites of leukemia, most commonly related to either cutaneous or nodal infiltration by leukemic cells, but any organ can be involved. Although some experts advocate treatment of localized myeloid sarcoma in relapsed APL with local radiation to the extramedullary disease site, most often, systemic therapy for relapsed disease is required as well.
MONITORING DURING THERAPY AND SUPPORTIVE CARE — The management of cytopenias, infections, tumor lysis, bleeding, menorrhagia, and other complications common to all patients with acute myeloid leukemia (AML) are presented separately. (See "Management of menorrhagia during chemotherapy" and "Acute myeloid leukemia: Overview of complications" and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome' and "Acute myeloid leukemia: Induction therapy in medically fit adults".)
The management of coagulopathy, differentiation syndrome, and leukocytosis are also presented separately. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Monitoring during therapy and supportive care' and "Differentiation syndrome associated with treatment of acute leukemia".)
An electrocardiogram (ECG) should be obtained prior to initiating ATO therapy to assess for congenital QT prolongation or the pharmacologic effects of concomitant medications. ECG monitoring should then be repeated after several days on treatment, at the initiation of subsequent courses of ATO, and after beginning treatment with other medications known to prolong the QT interval. Alternatively, some centers assess weekly ECGs to monitor the QT interval. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)
THERAPY RELATED MYELOID NEOPLASMS AFTER APL — A number of reports of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML) following successful treatment of APL have appeared in the literature [42-44]. In a single institution report of 88 consecutively diagnosed and treated patients with APL, of whom 77 obtained hematologic and molecular remission, MDS and/or AML developed in five patients 24 to 48 months after diagnosis [45]. All five had negative PML/RARA status when this complication occurred; new chromosomal changes included monosomy 7 and del(5q-) in one patient each, consistent with therapy-related MDS/AML. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 'Therapy-related myeloid neoplasms'.)
Patients with MDS or AML after treatment for APL should be studied for germline predisposition mutations, if their family histories suggest a familial basis for myeloid neoplasms. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.
Clinical trials are evaluating various oral arsenic trioxide formulations. In China, there are four types of oral arsenic formulations: tetra-arsenic tetrasulfide (As4S4; isolated from a mined ore known as realgar); ATO (As2O3); Qinghuang powder (realgar and indigo naturalis); and RIF (realgar, indigo naturalis, radix salviae miltiorrhizae, and radix pseudostellariae) [17]. Oral RIF has been administered as induction and consolidation therapy for newly diagnosed APL and for relapsed disease in >5000 patients with APL, which led to approval of RIF by the Chinese Food and Drug Administration.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute promyelocytic leukemia".)
SUMMARY AND RECOMMENDATIONS
●The vast majority of patients with newly diagnosed acute promyelocytic leukemia (APL) can obtain a complete remission (CR) with induction therapy that incorporates all-trans retinoic acid (ATRA; tretinoin) together with arsenic trioxide (ATO) preferably or together with chemotherapy, followed by a molecular CR after consolidation therapy. The cure rate is high when ATO is included in the induction regimen or the consolidation sequence. Despite this, relapse occurs in 5 to 10 percent of patients with APL overall, and in approximately 20 to 30 percent of those with high-risk APL (ie, presentation with a white blood cell count >10,000/microL and a platelet count <40,000/microL). However, initial therapy that includes ATO has proven remarkably effective at reducing the relapse rate even in high-risk APL.
●We consider patients in first hematologic CR to have resistant disease if they have not achieved molecular CR following two to three cycles of consolidation chemotherapy. We consider patients to have relapsed disease if, after attainment of molecular CR, subsequent analyses confirm the loss of such molecular remission. (See 'Definitions' above.)
●For patients with resistant or relapsed disease, we suggest treatment with ATRA plus two courses of arsenic trioxide 0.15 mg/kg per day IV for 25 consecutive doses (or five doses per week for five weeks), followed by autologous hematopoietic cell transplantation (HCT) in patients who achieve a CR and are reverse transcription polymerase chain reaction (RT-PCR) negative (Grade 2B). Allogeneic HCT can be considered if a suitable donor is available, but in the setting of APL, allogeneic HCT is not clearly better than autologous HCT. (See 'Arsenic trioxide (ATO)' above.)
●APL cells have high expression of CD33. Where available, the anti-CD33 monoclonal antibody conjugate gemtuzumab ozogamicin can effectively control disease in patients with APL who have had a molecular relapse. (See 'Gemtuzumab' above.)
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