Epidemiology and diagnosis

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with peculiar morphologic, cytogenetic, and biomolecular characteristics (1). Most patients are young, present with leukopenia, and exhibit a life-threatening coagulopathy, which is the most relevant manifestation of the disease at diagnosis (2). The disease is relatively rare in adults, accounting for only 10-15% of adults diagnosed with AML and, at variance with most AML subtypes, is more frequent in the Latin Hispanic race than in Caucasians (3). In most cases, the presumptive diagnosis of APL can easily be made by review of the peripheral blood smear alone or with the bone marrow aspirate by an experienced hematologist. The peripheral blood smear often shows leukopenia with circulating promyelocytes, which usually have abundant, often irregular-appearing primary azurophilic granules; bundles of Auer rods may be found and are identified only in APL (Fig 1, panel A). At variance with classical APL, APL variant (APLv) displays minimal granulation, relative scarcity of cells with heavy granulation and cells containing multiple Auer rods. The nucleus of most cells in the peripheral blood is bilobed, multilobed or reniform, but the majority of cells are either devoid of granules or contain only a few fine azurophil granules (Fig 1, panel B). However, at least a few cells with all the cytoplasmic features of typical APL are present (4). APLv is often associated with a high white blood cell count (WBC > 10 x 109/l) and more all-trans retinoic acid (ATRA)-related toxicities, particularly pseudotumor cerebri (5). Appreciation of these details of morphology features in APL by practicing hematologists is critical because this is the one subtype of AML for which immediate treatment with all-trans retinoic acid (ATRA) and intensive blood product support must begin in order to reduce early mortality when the disease is first suspected, before confirmation of the diagnosis at immunophenotypic, cytogenetic and molecular level (6). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML-RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein, but may not be readily available (7).

 

Ferrara_approfondimento_ACUTE_PROMYELOCYTIC_LEUKEMIA_IN_ADULT_PATIENTS_Figure_

Figure I – Panel A: morphology of atypical promyelocytes showing abundant, often irregular-appearing primary azurophilic granules and bundles of Auer rods (classical APL).
Panel B: Atypical promyelocytes displays cytoplasma with minimal granulation; the nucleus of most cells in the peripheral blood is bilobed, multilobed or reniform.

 

 

Immunophentypic features

APL has also been the subject of immunophenotypic studies, which have yielded results that included positive staining for CD33, CD13, and CD19 antigens, an absence of HLA-DR expression, and low-frequency occurrence of CD7, CD11b, and CD14 expression. Aberrant surface antigens, including CD2 and CD34, have also been identified (8,9). Although the clinical relevance of these surface antigens is not yet well understood, several research groups have demonstrated that the expression of CD2 is associated with APLv morphology and the bcr3 PML-RARα isoform, and that of CD34 with an immature form of APL (10,11). In addition, the presence of the neural cell adhesion molecule CD56 has been shown to be predictive of poor outcome in patients treated with ATRA in combination with chemotherapy (12). More recently, data has been reported suggesting that the presence of FLT3/ITD mutation is closely related to aberrant CD2 expression and high expression levels of FLT3 mRNA (13).

 

Genetic and molecular characteristics

Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, that is, t(15;17)(q22;q21), which results in the fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor (RARalpha) (fig.2). Because the efficacy of differentiation treatment based on retinoids and/or arsenic derivatives is strictly dependent on the presence of the PML-RARalpha fusion gene in leukemia cells, genetic confirmation of this specific lesion is mandatory in all cases (14-16). In addition, the hybrid gene is extremely important for the monitoring of therapeutic results, APL being the only AML subtype in which molecular remission, defined by the absence of the leukemic transcript, represents the main indication of therapeutic efficacy (17,18). Of note, molecular CR should be evaluated by real-time polymerase chain reaction (RT-PCR) at the end of consolidation and after at least two cycles after hematologic CR has been achieved (19). Re-appearance of the PML-RARAalpha gene, demonstrated in two examinations repeated at an interval of one month, defines molecular relapse, which is invariably followed by hematological relapse. APL is therefore unique, in that a relapse at the molecular level should be treated no differently from hematologic relapse, therefore standardized RT-PCR evaluation of the PML-RARAalpha gene represents a powerful and reproducible tool for prospective monitoring of minimal residual disease (14-19).

 

Ferrara_approfondimento_ACUTE_PROMYELOCYTIC_LEUKEMIA_IN_ADULT_PATIENTS_Figure_2

Figure II. Balanced reciprocal translocation between chromosomes 15 and 17, that is, t(15;17)(q22;q21), which results in the fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor (RARalpha)

 

 

Prognostic factors

The most suitable parameters for risk stratification in APL are still under debate. It was discussed whether patients with APLv might have higher rates of early death because of hemorrhagic complications when compared to patients with the classical APL morphology, however the outcomes of patients with the two FAB subtypes did not differ significantly when adjustment for WBC counts or relapse risk scores was made. The Sanz score subdivides APL patients according to peripheral blood counts into three risk groups: low (WBC ≤10×109/L and platelet count >40×109/L), intermediate (WBC ≤10×109/L and platelet count ≤40×109/L), and high (WBC >10×109/L) (20). High-risk APL patients with a WBC count greater than 10×109/L were reported to achieve higher complete remission rates and better survival outcomes when cytarabine (ARA-C) was included in the chemotherapy regimens, whereas for patients with a WBC count less than 10×109/L all-trans retinoic acid in combination with anthracyclines might be sufficient. In fact, the APLv subtype has been associated with higher frequencies of FLT3-internal tandem duplications (ITD), which may have a negative prognostic impact (21,22) FLT3-ITD occur in 12–38% of all APL patients and tyrosine kinase domain (TKD) mutations in 2–20%. The presence of an FLT3-ITD was reported to worsen prognosis in APL and to be associated with higher WBC counts and higher early death rate by several study groups, but others found no adverse prognostic impact of this molecular marker in APL (23-25). In fact, there were too few patients in many studies in order to be able to draw final conclusions, and it remains unclear whether FLT3-ITD mutation status should be incorporated into risk-adapted therapeutic algorithms for APL patients (26). Other parameters, such as FLT3-ITD mutation level or length, FLT3-ITD/wild-type mutation load and PML-RARalpha expression level have been described to be of prognostic relevance in APL; notwithstanding, either in daily practice or in clinical trials the Sanz score remains the most commonly used tool for prognostic stratification.

 

Pathogenesis of APL

Although the molecular and cellular mechanisms involved in APL pathogenesis and response to treatment have been largely clarified, some aspects are still controversial. The classical APL pathogenetic model describes the PLM-RARalpha fusion product as acting as a dominant negative of RARalpha by forming homodimers, recruiting co-repressors, and inhibiting the expression of target genes necessary for granulocytic differentiation. Furthermore, the PML-RARalpha product might also inhibit the normal function of the PML protein as a tumor suppressor, and therefore act as a dominant negative against both proteins. PML is the organizer of nuclear domains known as PML nuclear bodies (NB). Pharmacological concentrations of all-trans retinoic acid (ATRA) lead to a conformation change of the multifunctional complex around PML-RARalpha. Co-repressors are released, normal regulation of RAR-alpha-responsive genes is restored, and hence terminal differentiation of APL cells is induced (27). Arsenic trioxide (ATO) also elicits PML/RARA degradation and nuclear bodies reformation, but it acts via the PML rather than the RARA moiety of PML/RARA (28). Indeed, like RA, which degrades RARalpha, ATO degrades normal PML and, thus, PML/RARalpha oncoprotein. This unexpected convergence between two clinically active agents, discovered by chance, supports the idea that PML/RARA degradation, and hence PML NB reformation, together contribute to clinical remissions (28,29).

 

Treatment of APL

Induction therapy

As mentioned above, treatment with ATRA should be initiated without waiting for genetic or immunofluorescence confirmation of the diagnosis the same day that diagnosis is suggested by morphologic examination of blood and/or bone marrow. This recommendation is justified with the favorable risk-benefit ratio associated with this approach (30); moreover, ATRA is unlikely to have any deleterious effect should genetic assessment fail to confirm the diagnosis of APL in that ATRA has no severe adverse side effects and might be administered without any complications to any AML patient. Conversely, there are some suggestions for the potential utility of the drug in AML with NPM1 mutations (31). ATRA is known to improve the biologic signs of APL coagulopathy rapidly; hence early initiation of this agent is likely to decrease the risk of severe bleeding. Overall, APL treatment involves induction, consolidation, and maintenance phases. Unanswered questions still exist and concern the ideal induction therapy, the best initial treatment for older patients, the subset of patients most likely to benefit from maintenance therapy and the most effective relapse regimen. Although treatment with single-agent ATRA results in a CR rate of > 85 – 90%, there is unanimous consent that induction therapy should be based on the combination of ATRA + chemotherapy. There are two reasons for this: the first relies on the better quality of CR induced by ATRA + chemotherapy (early studies demonstrated that most patients initially treated with ATRA alone did ultimately relapse), the second postulates that the combination is more effective in controlling ATRA-induced leukocytosis, which is often indicative of APL syndrome occurrence (see below). The CR rate achieved with the simultaneous combination is > 90% in large multicenter studies. Of note, the most frequent cause of therapeutic failure, which is probably underestimated in clinical trials, is early death due to fatal cerebral hemorrhage, whereas infections due to neutropenia account for induction failure in a very small minority of patients (32-34). Of note, higher early death rate has been recorded in an older APL patient population (35,36). Resistance to therapy in APL is extremely rare or absent and would generate the suspicion of incorrect diagnosis. The addition of ATRA is clearly associated with a relevant reduction of mortality due to APL coagulopathy, so that no additional measure is currently indicated for this potentially fatal complication (37). One unresolved question regards the type of chemotherapy that should be added to ATRA. Outside of a clinical trial, our current approach is based on the use of idarubicin (IDA), independently from the initial white blood cell (WBC) count, given that in a series of 95 patients with APL we achieved a CR rate of 96%. No difference was observed by considering different Sanz risk groups (38). In the literature, comparable CR rates have been reported using ATRA + daunorubicin and cytarabine or ATRA + IDA alone, with no apparent advantage observed by adding ARA-C. However, many clinicians (especially in the US) still use ARA-C in combination with ATRA and anthracyclines (39). Of interest, a recent randomized clinical trial from the United Kingdom did demonstrate that additional chemotherapy, Ara-C in particular, is not required in induction therapy of APL, whatever the risk at diagnosis (40). As to the type of anthracycline, we prefer IDA but no data has definitively demonstrated an advantage in comparison to daunorubicin. While simultaneous ATRA and chemotherapy is the current gold standard for newly diagnosed APL resulting in ~80% cure rates, ATO in variable combinations including ± ATRA ± CHT has also been tested as front-line therapy yielding encouraging results in several pilot studies as well as in two phase III studies conducted in China and the US (41). A recent trial conducted in Italy and Germany firstly compared ATO + ATRA vs. ATRA + IDA and definitively demonstrated that for patients with newly diagnosed non-high-risk APL the front-line CHT-free ATO+ATRA combination is at least not inferior for 2 year EFS (42), potentially leading to a new standard of care in non high risk patients.

 

Ferrara_approfondimenti_LEUCEMIA_MIELOIDE_ACUTA_Tabella_1

Table I – Therapeutic options for APL

 

Post-induction therapy

As mentioned above, molecular CR must be the final endpoint of induction/consolidation therapy. The conventional approach is based on the administration of two or three courses of chemotherapy, including anthracyclines with or without ARA-C. Given that any consolidation course induces substantial myelotoxicity resulting in prolonged pancytopenia, the possibility of reducing the intensity of consolidation has been considered according to a ‘less is better’ approach (43). As in induction, the role of cytarabine in consolidation remains somehow controversial, but at least in low and intermediate risk patients, risks deriving from more intensive consolidation are not balanced by any clinical benefit; on the contrary, a trend in favor of cytarabine administration was observed for high-risk patients (44). My recommendation is to use only anthracyclines and to avoid ARA-C in low and intermediate risk patients, retaining the combination only in patients with an initial WBC count > 10,000/mL, who are at major risk of relapse. More recently, data from the Italian GIMEMA cooperative group, showed a statistically significant reduction in relapse risk by adding ATRA at standard dose in conjunction with three courses of consolidation chemotherapy (45). This approach is currently adopted at our institution, by giving ATRA 45mg/m2 for 15 days at each consolidation course. Recently, aiming at elimination of chemotherapy as well as reinforcement of ATRA efficacy, ATO has emerged as a powerful post-induction treatment of APL. Apart from phase 2 trials on a relatively small number of patients (41), the use of ATO as post-remission treatment has been supported by a large, randomized study by the US Intergroup. In this trial, patients before the standard consolidation regimen with two more courses of ATRA + daunorubicin, were randomized to receive or not two courses of 25 days of ATO (5 days a week for 5 weeks) immediately after CR achievement [46]. The administration of ATO resulted in a significantly better EFS and OS, providing further evidence for the use of ATO in consolidation. Even so, patients in the control arm experienced relatively low survival as compared to results by other investigators, who employed ATRA and anthracycline chemotherapy-based schedules.
The question of maintenance therapy for APL patients with molecular negative disease at the end of consolidation is still an unresolved question (47). Two recent randomized studies showed no benefit for these patients, either when using ATRA, 6-mercaptopurine, and methotrexate (the Italian approach) or when using six courses of intensified therapy (the Japanese approach) (48,49). Furthermore, in our experience, tolerance to chemotherapy is poor and more than half of patients discontinue the treatment because of gastrointestinal or hepatic toxicity. Our current approach is to administer ATRA for 15 days at intervals of 3 months for 2 years.

 

Treatment of relapse

Relapse occurs in approximately 5 – 30% of APL patients and is almost exclusively limited to those with high-risk disease at presentation (50). Approximately 3 – 5% of APL patients develop extramedullary relapse. In most cases, the CNS is involved, but other sites might also be implicated (51). Finally, a small group of patients (< 3%) experience isolated molecular relapse. Therapeutic options should take into account different characteristics of patients at relapse, which are independent from Sanz initial categorization. In particular, the length of the first CR, the WBC count, the number of previous relapses, and the achievement or not of molecular remission after hematological remission (52). Patients presenting with none of these factors would be considered as low risk, all others as high risk. For patients treated in induction/consolidation with ATRA + chemotherapy, there is no doubt that single-agent ATO represents the treatment of choice (53). Data from the US multicenter study suggested a CR rate of 85% and a molecular remission rate of 78%, clearly showing that ATO is the most powerful inducer of molecular remission (54). We suggest two or three additional courses after CR achievement. High-risk patients aged < 45 – 50 years could be considered for allogeneic stem cell transplantation (allo-SCT), whereas patients who do not have a donor and those older than 50 would be candidates for autologous SCT (ASCT), provided that they had a molecularly negative graft (peripheral blood stem cell) and were in molecular remission (55-57). The obvious objection to this approach is that there are no randomized studies demonstrating that ASCT is really useful for patients in second molecular CR and therefore potentially cured before transplantation.

However, our experience is very favorable in relapsed patients receiving ASCT in the absence of transplant-related mortality; long-term survival exceeds 80% (58). With regard to allo-SCT, there is unanimous consent that it has no role to play in APL for patients in first molecular CR (59,60). The only indication for allo-SCT includes patients who do not achieve molecular CR at the end of consolidation (5% or less) or those who experience early relapse (first CR duration less than 18 – 24 months). Obviously, allo-SCT must also be considered for patients in their second or further relapse. A therapeutic algorithm for relapsed patients is suggested in Figure 2.

 

APL differentiation syndrome

The APL differentiation syndrome (DS), formerly known as retinoic acid syndrome, is an unpredictable but frequent complication that may develop after administration of ATRA and/or ATO in patients with APL (61). DS is reported in 2.5 – 30% of APL patients who receive induction therapy with ATRA and/or ATO, while it is present neither during consolidation or maintenance therapy with both compounds nor during ATRA treatment in non-APL malignancies, implicating that the leukemic APL cells play a crucial role in the development of DS (62). The wide range of incidence probably depends on the different criteria used for the diagnosis, as well as on the effects on the incidence and severity of the syndrome and differences in induction therapy and supportive measures. Furthermore, as none of the aforementioned symptoms is pathognomonic of the syndrome – and might be due to concurrent medical problems such as bacteremia, sepsis, pneumonia, pulmonary hemorrhage, or congestive heart failure – DS may be under or over diagnosed. On clinical grounds, the syndrome should be suspected in the presence of one of the following symptoms and signs: dyspnea, unexplained fever, weight gain, peripheral edema, unexplained hypotension, acute renal failure or congestive heart failure, and particularly if a chest radiograph demonstrates interstitial pulmonary infiltrates or pleuropericardial effusion. Risk factors for developing DS are not well understood but may include high WBC count, rapidly increasing WBC count, and the expression of cell-surface antigens (63,64). Of interest, in patients treated with combination of ATRA and Idarubicin, an increased body mass index correlates with incidence of DS (65). The syndrome is recognized as a distinct complication and a potential life-threatening adverse reaction. Therefore, we usually administer specific therapy with dexamethasone at a dose of 10 mg daily by intravenous injection when one symptom is present. In the presence of a high WBC count (>100×109/L), our policy is to include the administration of 500 mg ARA-C, even though the risk of myelotoxicity increases substantially. A temporary discontinuation of ATRA and/or ATO is indicated in cases of severe DS, in particular in the presence of acute renal failure or respiratory distress syndrome requiring admission to an intensive care unit.

 

Indications to individualized approach in APL

While inclusion in clinical trials remains the best option for patients with APL, in special situations stringent inclusion criteria of the studies represent reasons of exclusion. Furthermore, in specific situations the optimal approach consisting of the combination of ATRA + anthracyclines may be contra-indicated because of concomitant disease or poor performance status, unrelated to APL.

APL in pregnancy

Given the teratogenic potential of chemotherapy, ATRA, and ATO on the fetus, the overall treatment of the pregnant patient with APL should include a discussion about pregnancy termination, especially if APL is diagnosed in the first trimester (66). In this setting, we favor therapeutic abortion after inducing CR with ATRA plus IDA. After abortion, therapy should be continued on the basis of Sanz risk, as in standard patients. If the pregnancy is to continue due to religious faith or insuppressible patient’s desire, then an appropriate chemotherapy regimen needs to be determined, avoiding either ATRA or ATO. In this regard, daunorubicin might be preferred because this agent is known to be effective in APL and there is more published experience of its use in pregnancy (67). The patient should be informed about high risk of hemorrhage deriving from the lack of ATRA in the therapeutic program. For APL occurring during the second and third trimesters of pregnancy, management should not differ from that used in daily practice. Notwithstanding, frequent fetal monitoring, along with aggressive management of potential APL-related complications, is necessary to allow for optimal maternal and fetal outcomes.

 

APL in older patients

At variance with other AML subtypes, the hematological, cytogenetic, and molecular features of APL in advanced age are substantially similar to those of young adults, and older APL patients seem to be as sensitive to specific APL therapy as younger individuals. However, the prognosis of the disease steadily worsens with increasing age since induction therapy based on ATRA and anthracyclin can be contraindicated by cardiomyopathy or other severe organ dysfunction (68,69). In addition early death rates are significantly higher: a population-based study from the USA reported an early death rate of 24% in APL patients aged 55 years or older. In the Swedish Adult Leukemia Registry, the ED rate of 105 unselected APL patients of all age groups was 29%, while it was 50% in patients over 60 years (33,34). Furthermore, consolidation therapy is in turn associated with significant morbidity and mortality (70). Nonetheless, patients who satisfy inclusion criteria for multicenter clinical trials achieve CR rates and survival similar to young adult APL patients (71,72). On this basis, it appears reasonable to manage fit, elderly patients with therapeutic programs similar to those used in younger patients, slightly attenuated in dose intensity. However, those with severe comorbidities and unfit for chemotherapy (especially anthracyclines) are ideal candidates to receive single-agent ATO, since the combination ATRA plus ATO, despite potential better antileukemic activity, could be associated with a considerably higher risk of APL syndrome occurrence. The attenuated induction regimen could be followed, after CR achievement, by a molecularly driven post-CR approach aimed at molecular remission achievement. In this setting, Gemtuzumab-ozogamycin, an anti-CD33 antibody conjugated with the cytotoxic agent chalicheamycin, could have a pivotal role (73).

 

Treatment-related APL (t-APL)

It is well recognized that treatment-related AML (t-AML), defined as AML occurring after chemo or radiotherapy for previous cancer, is characterized by poorer prognosis as compared to de novo cases (74). As more patients survive their primary cancers, secondary leukemias are becoming an increasing healthcare problem. The majority of t-APL cases arise in patients who have undergone treatment for breast cancer, where topoisomerase II inhibitors such as mitoxantrone (MTZ) and epirubicin have been widely used, followed by lymphoma, with a large predominance of non-Hodgkin lymphoma compared with Hodgkin disease, whereas other tumor types were found with lower incidence (75). In the past few years, however, an increasing number of reports on t-APL occurring in multiple sclerosis MS in patients given MTZ have been published (76). Overall, secondary and de novo APL had abnormal promyelocytes with similar morphologic and immunophenotypic features, comparable cytogenetic findings, comparable rates of FLT3 mutations, and similar rates of recurrent disease and death, suggesting that t-APL is similar to de novo APL and, thus, should be considered distinct from other secondary acute myeloid neoplasms (75). No prospective studies have specifically addressed the outcome of patients with t-APL, and literature data demonstrates a favorable prognosis not significantly different from de novo cases. Accordingly, treatment should not differ with the possible exception of patients given high dose anthracyclines for antecedent malignancies, in whom single agent ATO or combination of ATRA and ATO could be considered.

 

Conclusions

While APL represents a paradigm of therapeutic success in clinical hematology, treatment still needs to be improved. The time has come to approach low risk patients with ATRA and ATO, either in induction or consolidation, avoiding any chemotherapy according to a ‘less is better’ philosophy. In more detail, the combination ATRA/ATO could be used as induction (with careful attention to the APL syndrome), followed by between four and six courses of ATO as consolidation. For high-risk patients, the combination of ATRA plus anthracyclines remains the induction treatment of choice; two or three courses of ARA-C combined with anthracyclines represents the current standard of consolidation therapy, even though data from the MRC trial suggests that it is acceptable to de-escalate treatment by removing non-anthracycline treatment irrespective of the risk group. The benefits may not be in overall survival but in reduced myelosuppression and its consequences, mainly in terms of reduced hospitalization and improved quality of life. Notwithstanding this, ATO could represent an attractive alternative option to be further explored in randomized clinical trials. Furthermore, ATO represents the ideal therapy for older frail APL patients as well as for those previously treated with anthracyclines because of previous malignancies; in these cases consolidation with GO could offer the best risk:benefit ratio. Finally, any effort should be made to minimize early hemorrhagic mortality, which still accounts for over 10-15% of all newly diagnosed patients including in developed countries. Physicians caring for patients with APL treated with ATRA or ATO should be aware of early symptoms or signs suggestive of the APL differentiation syndrome. Although a definite diagnosis of this syndrome can be difficult, it must be considered a life-threatening complication, therefore specific treatment with dexamethasone should be started promptly at the very earliest symptom or sign. Finally, it is to be considered that current tools for diagnosis and treatment may not be available in many developing countries, including some in Latin America, where the disease may be particularly common. Recently, an International Consortium (IC-APL) was established with the aim of creating a network in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The establishment of the IC-APL network resulted in a nearly 50% decrease in early mortality and a 30% improvement in survival compared to historical controls, resulting in outcome similar to those reported in developed countries (77). These commendable results were achieved by dissemination of essential clinical management guidelines and increased awareness of APL, coupled with a simple method for rapid diagnosis and the implementation of internet tools for the exchange of clinical expertise.

 

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