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The following case study focuses on a 26-year-old man who presents to the emergency room with a history of fatigue, fevers, and gingival bleeding for the past three days. Test your knowledge by reading the background information below and making the proper selection.

His physical exam reveals a young, pale skin man with notable ecchymosis and gingival bleeding, otherwise unremarkable. The patient’s white blood cell (WBC) count is 17.000/μl, hemoglobin is 9.4g/dl, and platelet count is 72,000/μl. The WBC differential notes 19 percent lymph, 15 percent monocytes, 6 percent eosinophils, and 60 percent others. The peripheral blood smear shows characteristic population with reddish-blue or dark-purplish cytoplasmic granules and creased, folded, or dumb-bell shaped nuclei. The patient is admitted for initiation of treatment. Subsequent FISH analysis documents a t(15;17) translocation.

What would be the optimal treatment plan for this patient?

1. This patient has a favorable prognostic chromosomal translocation and as such should receive standard "7+3" induction chemotherapy alone.
2. This patient should receive ATRA (tretinoin) plus induction chemotherapy. Given his high-risk features as evidenced by the high WBC, an allogeneic transplant should be considered in first CR.
3. The appropriate treatment for this patient includes ATRA plus induction chemotherapy and subsequent ATRA single-agent consolidation.
4. This patient has high-risk features, and as such, will require additional consolidation therapy with either an arsenic trioxide or cytarabine-containing regimen.

Answer

4. This patient has high-risk features, and as such, will require additional consolidation therapy with either an arsenic trioxide or cytarabine-containing regimen.

Explanation

Acute promyelocytic leukemia (APL) is one of the variants of acute myeloid leukemia (AML) and is biologically distinct from the other AML variants. The diagnosis of APL is suggested by the clinical features and the characteristic morphologic findings on the peripheral smear. The presentation with bleeding secondary to disseminated intravascular coagulation is unique to APL.

Almost all cases of APL are defined in molecular genetic terms by the presence of a reciprocal translocation between the long arms of chromosomes 15 and 17 (i.e., t[15;17][q22;q12]), with the creation of a fusion gene, PML/RAR-α.^1,2 The chromosome breakpoint on chromosome 17 has been mapped to the site of the retinoic acid receptor-alpha (RARα) gene.^3,4 Although it is unclear how this translocation results in leukemogenesis, there is evidence that PML/RARα impairs terminal differentiation and subsequent apoptosis of promyelocytes. The impaired interaction between the PML/RARα gene product and endogenous retinoids can be overcome by pharmacologic doses of retinoic acid, constituting the rationale for the use of this agent in the treatment of APL.

In a multivariate analysis of 217 patients with newly diagnosed APL treated in the Italian GIMEMA and the Spanish PETHEMA trials, adverse risk factors were a total WBC count >10,000/microL and a platelet count ≤40,000/microL.⁵ Using these two parameters, three prognostic categories could be distinguished, with the following estimated probabilities of three-year relapse-free survival (RFS):

• Low risk — WBC ≤10,000 and platelets >40,000; RFS 98 percent
• Intermediate — WBC ≤10,000 and platelets ≤40,000; RFS 89 percent
• High risk — WBC > 10,000; RFS 70 percent

Since the diagnosis of APL represents a medical emergency, it is necessary to start treatment as soon as the diagnosis is suspected and before definitive (cyto) genetic confirmation of the diagnosis has been made.

Complete hematologic remissions induced by ATRA alone are rarely associated with complete molecular remissions and have had a median duration of only about 3.5 months.

Thus, remission induction therapy using a combination of ATRA plus cytotoxic chemotherapy appears necessary for long-term survival.

Results from a European randomized controlled study demonstrated the efficacy of ATRA in combination with chemotherapy for initial induction. This trial compared daunorubicin/cytarabine alone or in combination with ATRA.² The study was stopped early when the first interim analysis showed that patients receiving ATRA had a significantly prolonged event-free survival at 12 months (79% vs. 50%) and a reduction in the relapse rate (19% vs. 40%).

The achievement of molecular remission rates of about 95 percent in patients receiving at least two further cycles of anthracycline-based chemotherapy after induction has led to adoption of this strategy as the standard for consolidation³ and supports the clinical paradigm of achieving molecular remission as recommended by the International Working group.⁶

The role for cytarabine in the treatment of APL has been controversial. A recent randomized study of the European APL Group⁷ reported an increased risk of relapse when cytarabine was omitted from a schedule containing daunorubicin. A joint analysis of the PETHEMA group and European APL group⁸ noted a trend in favor of cytarabine for high-risk patients with a WBC higher than 10x109/L. In keeping with these results, the most recent Italian study suggests a benefit for cytarabine in combination with ATRA in patients with high-risk disease.^9,10

Arsenic trioxide has differentiation, inductive, and apoptotic effects on APL cells in vitro and has been shown to induce a high rate of complete remissions (CRs) in patients with recurrent APL. Arsenic trioxide degrades PML-RARα transcripts in the cell, but also acts through a PML-RARα independent cytotoxic mechanism.

Various smaller studies have reported on the use of arsenic trioxide in previously untreated patients. In one study, single-agent arsenic trioxide produced a high rate of CR and these remissions were shown to be durable in a significant number of patients.¹¹ These results underscore the strong therapeutic effect of this drug.

A randomized North American Intergroup trial (CALGB 9710) investigated the safety and utility of adding two courses of arsenic trioxide (0.15 mg/kg per day for 5 days each week for 5 weeks) as a first consolidation treatment in 518 adults with newly diagnosed APL achieving CR or partial remission (PR) following a standard induction program. While the overall CR with 89 percent did not differ between the standard arm and the Arsenic arm, high-risk patients who received arsenic had improved DFS than those who did not receive arsenic.¹² This study does not yet provide a definitive answer in regard to the place of arsenic trioxide in the current management of APL.

However, these recent studies investigating various risk-adapted treatment approaches in APL do suggest additional benefit for intensified consolidation with either arsenic or cytarabine for patients with high-risk features.

It is worth noting that, while a WBC>10.000 does define high risk for APL, the overall prognosis for these patients is still favorable compared to most otherAMLs.

The UK MRC investigated the role for allogeneic transplant in patients with high-risk features in APL in first CR in the pre-ATRA era and failed to show any benefit.¹³

References

1. Kakizuka A, Miller WH Jr, Umesono K, et al. . Cell. 1991;66:663-74.
2. Fenaux P, Le Deley MC, Castaigne S, et al. . Blood. 1993;82:3241-9.
3. Sanz MA, Tallman MS, Lo-Coco F. . Blood. 2005;105:3019-25.
4. Collins SJ. . Blood. 1998;91:2631-3.
5. Sanz MA, Lo Coco F, Martín G, et al. . Blood. 2000;96:1247-53.
6. Cheson BD, Bennett JM, Kopecky KJ, et al. . J Clin Oncol. 2003;21:4642-9.
7. Sanz MA, Martín G, González M, et al. . Blood. 2004;103:1237-43.
8. Adès L, Sanz MA, Chevret S, et al. . Blood. 2008;111:1078-84.
9. Breccia M, Diverio D, Noguera NI, et al. . Haematologica. 2004;89:29-33.
10. Sanz MA, Grimwade D, Tallman MS, et al. . Blood. 2008. [Epub ahead of print]
11. Mathews V, George B, Lakshmi KM, et al. . Blood. 2006;107:2627-32.
12. Powell BL, Moser B, Stock W, et al. . Blood (Annual Meeting Abstracts). 2006;108:566.
13. Burnett AK, Wheatley K, Goldstone AH, et al. . Br J Haematol. 2002;118:385-400.

Case study submitted by Tahamtan Ahmadi, MD, PhD, Hospital of University of Pennsylvania.