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?
- This patient has a favorable prognostic
chromosomal translocation and as such should receive standard "7+3"
induction chemotherapy alone.
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.
appropriate treatment for this patient includes ATRA plus induction
chemotherapy and subsequent ATRA single-agent consolidation.
patient has high-risk features, and as such, will require additional
consolidation therapy with either an arsenic trioxide or
This patient has high-risk
features, and as such, will require additional consolidation therapy
with either an arsenic trioxide or cytarabine-containing regimen.
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
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
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
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
- Kakizuka A, Miller WH Jr, Umesono K, et al. Chromosomal
translocation t(15;17) in human acute promyelocytic leukemia fuses RAR
alpha with a novel putative transcription factor, PML. Cell. 1991;66:663-74.
- Fenaux P, Le Deley MC, Castaigne S, 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;82:3241-9.
- Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood. 2005;105:3019-25.
- Collins SJ. Acute promyelocytic leukemia: relieving repression induces remission. Blood. 1998;91:2631-3.
- Sanz MA, Lo Coco F, Martín G, 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;96:1247-53.
- Cheson BD, Bennett JM, Kopecky KJ, et al. Revised
recommendations of the International Working Group for Diagnosis,
Standardization of Response Criteria, Treatment Outcomes, and Reporting
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642-9.
- Sanz MA, Martín G, González M, 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;103:1237-43.
- Adès L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008;111:1078-84.
- Breccia M, Diverio D, Noguera NI, et al. Clinico-biological
features and outcome of acute promyelocytic leukemia patients with
persistent polymerase chain reaction-detectable disease after the AIDA
front-line induction and consolidation therapy. Haematologica. 2004;89:29-33.
- Sanz MA, Grimwade D, Tallman MS, et al. Guidelines
on the management of acute promyelocytic leukemia: Recommendations from
an expert panel on behalf of the European LeukemiaNet. Blood. 2008. [Epub ahead of print]
- Mathews V, George B, Lakshmi KM, et al. Single-agent
arsenic trioxide in the treatment of newly diagnosed acute
promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006;107:2627-32.
- Powell BL, Moser B, Stock W, et al. Preliminary results from the north american acute promyelocytic leukemia (APL) study C9710. Blood (Annual Meeting Abstracts). 2006;108:566.
- Burnett AK, Wheatley K, Goldstone AH, et al. The
value of allogeneic bone marrow transplant in patients with acute
myeloid leukaemia at differing risk of relapse: results of the UK MRC
AML 10 trial. Br J Haematol. 2002;118:385-400.
Case study submitted by Tahamtan Ahmadi, MD, PhD, Hospital of University of Pennsylvania.
back to top