Acute promyelocytic leukemia: Clinical and morphologic features and prognostic factors

Acute Promyelocytic Leukemia: Clinical and Morphologic Features and Prognostic Factors GiuseppeAwisuti,

FruncescoLo Coca, und Frunco Mundelli

The most impressive clinical feature of acute promyelocytic leukemia (APL) at diagnosis is the presence in 80% to 90% of patients of a severe hemorrhagic syndrome. Recent data favor a fibrinolytic/proteolytic process rather than a disseminated intravascular coagulation as the mechanism mainly responsible for the hemorrhagic diathesis in APL. Morphologically, two main cytologic variants have been identified: the classical hypegranular APL (M3), which represents the great majority of all APL, and the microgranular variant (M~v), which accounts for about 15% to 20% of all APL. A rare basophilic variant has also been described. With regard to prognosis, it has markedly changed from that of a rapidly fatal acute leukemia to that of a highly curable disease. This revolutionary progress was mainly due to the introduction during the 1990s of all-trans retinoic acid (ATRA) for the treatment of this disease. After the introduction of ATRA, in addition to clinical features such as hyperleukocytosis (white blood cell count > 10 x lO’/L) or thrombocytopenia (platelet count e 10 x 103/L) at presentation, immunophenotype markers and polymerase chain reaction status for promyelocytic leukemia/retinoic acid receptor-a during follow-up also had an impact on prognosis. Semin Hematol38:4-12. Copyright 0 2001 by WA Saunders Company.

INCE ITS FIRST description by Hillestad in 1957*3 and Bernard et al in 1959,li acute promyelocytic leukemia (APL) has become a well-recognized entity among the other acute myelogenous leukemia (AML) subtypes because of its characteristic clinical, morphologic, and biological features.29J5,77

S

Clinical Features The most impressive clinical feature of APL at diagnosis is the presence in 80% to 90% of patients of a severe hemorrhagic syndrome, generally out of proportion with the degree of thrombocytopenia. Mucocutaneous hemorrhages are common, and before the introduction of all-trans retinoic acid (ATRA), the main cause of induction failure in APL was death from cerebral hemorrhage, with a frequency up to 20%.77,79 The laboratory coagulation profile always shows the presence of high levels of fibrinogen/fibrin-degradation products in the From Ematologia, University Campus Bio-Medico and the Department of Biotechnologie Celhlari ed Enzatologia, University La Sapienza, Rome, Italy. Address reprint requests to Gizqbpe Avvisati, MD, PhD, Ematologia, L&era Universitk Campus Bio-Medico, Via Longoni Emilio 83; 00155 Roma, Italy. Copyright 0 2001 by W.B. Saunders Company 0037-1963/01/3801-0002$35.OOlO doi:lO. 1053/shenz.2001.20861

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serum, associated with low levels of fibrinogen.3,79 Moreover, these features are constantly associated with normal antithrombin III levels and reduced a,-plasmin inhibitor (a,PI) levels.* These data, and the normality of protein C (PC)* levels and platelet survival,’ favor a fibrinolytic/proteolytic process rather than a disseminated intravascular coagulation as the main mechanism responsible for the hemorrhagic diathesis in APL. Recently reported data on annexin II expression in APL strongly support this theory. In fact, abnormally high annexin II levels have been detected on leukemic cells from patients with APL and not from those with other AMLs.~I This protein is a cell-surface receptor for plasminogen (Plg) and one of its activators, the tissue plasminogen activator (tPA). Therefore, the linkage of Plg and tPA to annexin II on the cell surface favors the activation of Plg to plasmin, the major fibrinolytic enzyme. Plasmin, once released from the cell surface, activates the fibrinolytic process. To counteract this process, the ol,PI forms an inactive complex with plasmin. However, because of the overexpression of annexin II, plasmin is generated at an abnormally high rate; as a result, a,PI is rapidly consumed, and active plasmin accumulates in the plasma, favoring the hemorrhagic diathesisG1

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APL: Clinics, Morphology, and Prognosis

Fever as a presenting feature is observed be in 15% to 30% of patients and cannot explained by infections.67,70 Organomegaly and/or adenomegaly, as well as leukemic infiltration of the central nervous system and of the skin, are very rare at diagnosis.46,67,70 Peripheral blood count frequently reveals the presence of anemia, thrombocytopenia, and leukopenia. However, a few cases, generally those with the hypogranular morphologic variant, may present hyperleukocytosis at diagnosis.29J5,77 APL also differs epidemiologically from the other AMLs; more than 90% of cases are diagnosed in patients between 15 and 60 years of age, and the male-female ratio is close to l.* Moreover, clusters of APL have been described,14,37 and a higher incidence of APL has been reported in Latinos.26J6 Furthermore, cer-

tain occupations and seem to be associated APL.“O

Morphologic

5

environmental exposures with the development of

Features

Morphologically, APL is not a homogeneous entity, and two main cytological variants have been identified: the classical hypergranular APL (M3)’ represents the great majority of all APL, and the microgranular variant (M~v)~ accounts A rare for about 15% to 20% of all APL.*9355377 basophilic variant has also been described.59l78 The predominant leukemic cells in the classical hypergranular APL are abnormal promyelocytes with an abundant cytoplasm filled with large azurophilic granules (Fig IA). The cytoplasm may be so densely packed with granules

Figure 1. Bone marrow films from patients with APL. (A) Classical APL with numerous hypergranular promyelocytes and a cell in the middle containing numerous Auer rods (faggots). (B) A cell with numerous Auer rods (faggots). (C) Microgranular APL with bilobed nuclei. (D) Basophilic variant of APL. (May-Griinwald-Giemsa stain, original magnification X 1,200. Courtesy of Drs Susanna Fenu and Francesca Mancini.) Color reproduction supported in part by Roche Pharma AG (Schweiz).

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Avvisati, Lo Coca, and Mandelli

that nuclear details are obscured. The nuclear contour is irregular, and in some cells the nuclei have a reniform or bilobed appearance. Auer bodies are commonly found in many cells, and sometimes they are regrouped in bundles to form the so-called faggots (Fig 1A and B). These typical hypergranular leukemic cells are less evident in the peripheral blood, where they may have monocytoid-appearing nuclei with scanty granules. The hypogranular or microgranular variant is characterized by the presence of leukemic cells with bilobed or reniform nuclei with dusty, very minute granules in the cytoplasm that are not readily perceptible on light microscopy (Fig 1C). In these cells, there may be a few isolated Auer rods. A minority of typical hypergranular blasts are associated in variable proportions. The very rare hyperbasophilic APL is characterized by cells with a high nucleuslcytoplasm ratio and strongly basophilic cytoplasms with either no or sparse granules (Fig 1D). Both hypergranular and hypogranular APL have positive reactions for myeloperoxidase, Sudan black, and chloroacetate esterase. Basophilic variant cells stain positively with toluidine blue; this cytologic variant has been associated with hyperhistaminemia with ATRA treatment.48 Recently, a previously unrecognized form of acute leukemia potentially misdiagnosed as APL has been immunologically characterized by the coexpression of the myeloid associated antigen CD33 and the natural killer cell-associated antigen CD56 and by the lack of expression of HLA-DR and CD16 (the immunoglobulin Fey receptor) antigens. However, this new acute leukemia, named the myeloidi natural killer cell acute leukemia, lacks t(15; 17).7* Therefore, although the great majority of APL may be easily recognized by morphologic and cytochemical studies, a definitive diagnosis of APL is possible only through cytogenetic and molecular studies. In cases in which cytogenetic or molecular studies are not available or in the presence of an apparently normal karyotype, an immunocytochemical diagnosis of APL by means of anti-PML monoclonal antibodies has been proposed. 27 This approach allows rapid identification of the APL-specific so-called microspeckled distribution of the PML protein,

which correlates with the PML/RARa gene rearrangement and is also detectable in morphologically atypical APL.

Prognostic Factors The prognosis of APL has changed markedly from that of a rapidly fatal acute leukemia, as it was in the 1960s and 1970s,i” to that of a highly curable disease. 21,55 This revolutionary progress in the prognostic outcome of the disease was attributable mainly to the introduction of the vitamin A derivative ATRA in the treatment of the disease during the 1990~.~~ Therefore, we will analyze the prognostic factors of APL by separating the outcomes of APL into two periods: before and after ATRA.

Before ATRA Before ATRA-based chemotherapy, several clinical features were found to influence the APL prognosis. A lower complete remission (CR) rate was observed among older patients17,*Q8 and patients with hyperleukocytosis at diagnosisi7J1 or with the microgranular APL variant.s8 The CR rate was also predicted by albumin levels and fever at diagnosis.17J1 Sanz et al identified fever as well as creatinine levels as important prognostic factors for CR rate.‘O A shorter CR duration was observed in patients with elevated lactate dehydrogenase levels1s~46; however, these patients generally had elevated leukocyte counts.l* Patients with blast counts higher than 500/mm3 in peripheral blood also had shorter CR durations.sl However, failure to achieve CR in these early reports was mainly attributable to fatal hemorrhages of the central nervous system during the first days of treatment. Important prognostic factors for fatal hemorrhages were leukocytosis and low fibrinogen levelsi2Js or thrombocytopenia, elevated absolute blast and promyelocyte count, old age, and anemia. 46 In a retrospective study of the GIMEMA cooperative group, only high blast cell counts on the day of admission were significantly associated with hemorrhagic deaths within the first 10 days.68 However, prognosis was also influenced by the type of induction therapy. A retrospective study of the Southwest Oncology Group indi-

APL: Clinics, Morphology, and Prognosis

cated that aggressive daunomycin therapy influenced survival of patients with APL.42 This result, indicating that high-dose anthracycline drugs are needed in APL, has been confirmed in a prospective randomized study that the Italian cooperative group GIMEMA initiated shortly before the ATRA era. In this study, patients with newly diagnosed APL were randomized to receive the anthracycline drug idarubicin as a single induction agent or the combination of idarubicin and ara-C. After a follow-up period of more than 5 years from the accrual of the last patient, multivariate analysis showed that event-free survival (EFS) was favorably influenced by induction treatment with IDA alone (P = .02) and unfavorably influenced by white blood cell (WBC) count greater than lO,OOO/ PL (P = .01).5 This unique randomized study comparing an anthracycline monochemotherapy with a combination therapy in newly diagnosed APL clearly indicates that anthracycline monochemotherapy is superior to combination therapy in terms of EFS duration in APL. As a consequence, first-line induction treatments for APL should always include anthracycline drugs. Moreover, some studies had indicated that survival in patients who had achieved CR was also influenced by the presence in the therapeutic program of a maintenance treatment based on 6mercaptopurine and methotrexate, two drugs that usually are not effective in the other AML subtypes.47,58

After ATRA The introduction of ATRA for the treatment of APL has improved the CR rate as well as the overall survival of APL patients by rapidly ameliorating the severe coagulopathy present in APL at diagnosis, even though ATRA did not significantly reduce the rate of early (within the first 10 days of induction therapy) fatal hemorin the retrospective rhages. 6,23 In particular, study of Di Bona et al, the rate of early hemorrhagic deaths was 3% in the patients receiving the AIDA (ATRA + idarubicin) compared with 4.1% in those receiving idarubicin alone as induction.23 Therefore, in patients with genetically proven APL receiving standard therapy, including ATRA and anthracycline-containing che-

7

motherapy, the CR rate is negatively influenced by early death, the latter being mainly due to severe hemorrhage. 6 Clinical features affecting the early death rate are the presence of purpura and low platelet number at diagnosisi as well as high blast count at diagnosis and severity of hemorrhagic symptoms.23 Prognostic factors for CR rate, which by extension influence EFS, are older age and elevated WBCi,l’ as it was before ATRA. However, although before ATRA the EFS rate of these patients was very low, after ATRA it reached considerable levels of 50% to 60%.50,71 As to remission duration and relapse risk, WBC count above 10 X lO”/L at presentation was the only factor that correlated with increased relapse risk in all reported series.15,30,71 In addition, this factor retained its significance in the multivariate model in the JALSG, MRC, and GIMEMA and PETHEMA studies.1,15,71 The European APL 913O and a combined analysis of the GIMEMA and PETHEMA groups7i confirmed the prognostic value of this factor. Moreover, the multivariate analysis performed by these cooperative groups indicated that also an initial platelet count below 50 X lO”/L in the European APL 91 or 40 X lO’/L in the GIMEMA and PETHEMA combined analysis negatively affected the relapse risk. In particular, platelet count below 40 X lO’/L was an independent variable associated with increased relapse risk in the combined GIMEMA and PETHEMA study.‘l This finding led to the use of this parameter, in conjunction with WBC count, to build a relapse risk model in APL patients receiving “AIDA-like” regimens (as in the GIMEMA and PETHEMA studies). The model segregated patients into low- (WBC count < 10 X lO”/L and platelet count > 40 X lO’/L), intermediate- (WBC count < 10 X 109/L and platelet count < 40 X 109/L), and high- (WBC count > 10 X 109/L) risk groups, with distinctive relapse-free survival curves (P < .0001).71 This in turn provides a rationale for the design of risk-adapted therapies, which are currently being adopted by the PETHEMA and GIMEMA groups. As for the influence of induction and maintenance therapy on prognosis, results accumulated to date indicate that ATRA, in induction,

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Awisdti, Lo Coca,and Mad&

should be combined with simultaneous standard chemotherapy15~28J7~72 and always included in the maintenance programs.28,*0

Biological

Features and Prognosis

In addition to clinical features, since the introduction of ATRA a number of biological characteristics have been analyzed for their impact on prognosis, including immunophenotype markers,32,41,64 additional karyotypic lesions 19,44,73,75 type of PML/RAR~Y isoform,15,33,35,36,57,76,81 kinetics of molecular remission,i5 and polymerase chain reaction results for PMLiRARa during followUP.

24,25,34,40,45,49,53,54,62,63,66,69

Immunophenotype Markers Immunophenotype is potentially useful for clearer discrimination of prognostic groups in uniformly diagnosed and treated APL cases. APL blasts have an immunophenotype that is different from those of the other AMLs. They are consistently positive for CD13 and CD33 myeloid antigens and for CD9, whereas they lack the HLA-DR antigen and have low frequency of CD34, CD7, CDllb, and CD14 antigen expression.20,41,51,65 These data indicate that APL cells probably derive from a more mature myeloid progenitor than other AML cells. Previous reports on the expression of the T cell-associated antigen CD2 on APL blasts indicated that it was variably associated with PMLiRARa bcr3 typel” or with microgranular M3v morphology but not with any PML gene breakpoint.i3 A recent study of Guglielmi et al*l on 196 cases of pediatric and adult molecularly confirmed APL, showed the presence of CD2 in 45 of 160 tested cases (28%). Of these CD2positive APLs, 58% (P < .OOl) had an M3v morphology and 52% (P < .OOl) had a PML bcr3 breakpoint. Moreover, the expression of CD34 on APL cells was also significantly associated with M3v morphology (P < ,002) and a PML bcr3 breakpoint (P < ,001); whereas the CD19 expression was directly correlated with WBC counts. However, from this large retrospective study it was concluded that only CD2 expression positively influenced CR rate and EFS.41

Two recent studies indicate that CD56 (the natural killer cell-associated antigen) would be associated with a lower CR rate and inferior overall survival or inferior CR duration and overall surviva1.32s64 In one such study conducted in patients treated with upfront ATRA and idarubicin, CD56 expression was shown to be an independent marker of poorer survival in the multivariate analysis.32 However, further studies are needed to better clarify the prognostic value of this marker because this antigen has only recently been introduced in the diagnostic characterization panel of the acute leukemias, and therefore only a minority of APL patients have been characterized for CD56 expression. These controversial results on the prognostic significance of the immunophenotype need to be confirmed in prospective studies in which all patients are treated with the same protocol.

Additional Karyotype Lesions Some (30% to 40%) APL patients show other chromosome aberrations in addition to t(15; 17). The role of these secondary cytogenetic abnormalities in prognosis is still unclear. A study performed in the United Kingdom suggested that complex abnormalities were associated with a poorer outcome.44 However, a major bias of this study was that the 54 patients under investigation were treated during a period of more than 15 years (from 1979 to 1996). Therefore, the different therapeutic options used during this period could have played an important role in the outcome of these patients. In fact, a second study performed in Germany did not show any influence of secondary chromosome anomalies on prognosis.73 Finally, in the most recent study from the United States, among SO patients treated solely with chemotherapy, the presence of a secondary chromosome abnormality was associated with longer CR duration (29.9 v 15.7 months; P = .03) and longer EFS duration (17.0 v 12.2 months; P = .03).75 Whether or not additional chromosomal lesions influence the prognosis of APL is still unknown. It would be useful if cytogeneticists participating in cooperative studies could produce a meta-analysis of their data considering

APL:

that present more uniform

Clinics,

protocols for APL treatment than those used in the past.

Morphology,

are

Type of PML/RARa Isoform Except for an early study in patients treated with ATRA alone,s2 the association of bcr3 isoform with poorer outcome was not statistically significant in all recent trials of ATRA plus chemotherapy. 15,28,33,36,71 Unfortunately, the majority of US and European studies used methodologies that fail to distinguish the bcrl from bcr2 PMLiRARa isoforms (the latter is also referred to as “variant” form). Thus, the impact of including bcr2 patients in the long transcript group is unknown, even though bcr2 patients account for only 8% of APL cases.39755 A decreased sensitivity to ATRA in vitro was initially reported for bcr2 patients,35 whereas a subsequent in vivo study in patients enrolled in the US intergroup trial did not entirely clarify this issue because of the low number of patients and because half of them received chemotherapy alone as induction.T6

Kinetics of Molecular Remission Slow kinetics of molecular remission, as well as persistence or conversion to PCR positivity for the PML/RARa after consolidation, has been correlated with increased risk of hematologic relapse. l5 In particular, in this study the relapse rate was 57% if the results of reverse-transcriptase PCR (RT-PCR) were positive after the end of consolidation, whereas it was 27% when RT-PCR results were negative (P = .OOG).

PCRStatus of PMVRARa During Follow-up The PMLIRARcx RT-PCR technique, apart from its value for diagnostic refinement, offers a powerful tool for sensitive assessment of response to treatment.40J4,63 Initial retrospective studies24,4i,j4,63 suggested the clinical utility of PCR monitoring in APL, and the significance of sequential PCR analysis has since been prospectively evaluated by several cooperative groups in patients receiving uniform therapies.15,25,j7,72 Via PCR tests with sensitivity levels of lo-*, it was determined that approximately 50% of patients in hematologic remission after induction had detectable PMLiRARa transcript in

and

Prognosis

9

their marrow cells in the GIMEMA, MRC, and PETHEMA studies.15,57,72 Therefore, no correlations were found between PCR status at the time of remission achievement after induction and relapse risk. On the contrary, after completion of consolidation, 90% to 95% of patients tested PCR negative in the MRC, GIMEMA, and PETHEMA series.15J7,72 In the MRC analysis, detection of residual disease at the end of the third chemotherapy course (of four in total) predicted an increased relapse risk.i5 Posttreatment monitoring was prospectively performed at pre-established time intervals in patients enrolled in the GIMEMA study. The results indicated that conversion from PCR negativity to PCR positivity after consolidation therapy was uniformly associated with subsequent hematologic relapse, leading the Italian study group to anticipate salvage therapy in these patients.25,52 The above results are based on prospective studies performed in the context of uniform clinical trials using PCR tests with lo-* sensitivity. Therefore, although there is general agreement on the value of PCR positivity during remission as a predictor of relapse,40a5i,62 several cautionary issues must be considered before therapeutic decisions are based on molecular tests. First, the persistence of residual disease in long-term remission using more sensitive assays has been reported occasionally.8 l Second, the occurrence of contamination must be ruled out; therefore, confirmation of molecular relapse in an additional marrow sample should be required before initiation of salvage therapy.‘* Third, one major limitation of the assays used is their failure to precisely quantitate the amount of residual disease, which in turn makes it difficult to compare the reported studies.*OJ3 It is conceivable that newly developed methods, such as the real-time PCR technology, will provide better information on the quantitative level of the PML/RARo!, thereby allowing more objective comparison of therapeutic results.

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