COMMENTARY Treatment of Acute Promyelocytic Leukemia in Children

COMMENTARY

Treatment of acute promyelocytic leukemia in children: arsenic or ATRA

Y Ravindranath1, J Gregory2 and J Feusner3

1Children’s Hospital of Michigan and Wayne State University School of Medicine, Detroit, MI, USA; 2Hackensack University Medical Center and University of Medicine and Dentistry, New Jersey, Hackensack, NJ, USA; and 3University of California-San Francisco and Children’s Hospital of Oakland, Oakland, CA, USA

Leukemia (2004) 18, 1576–1577. doi:10.1038/sj.leu.2403479 prognostic indicator in APL and none had evidence of Published online 9 September 2004 coagulopathy prior to treatment. Treatment consisted of eight cycles of As2O3 at a dose of 0.15 mg/kg/day as an i.v. infusion This invited commentary is addressed at the paper by George over 4 h. During induction As2O3 was administered until the 1 et al on ‘treatment of childen with Acute Promyelocytic remission was achieved or a maximum of 60 days. Six patients Leukemia with arsenic trioxide –’published in this issue of also had hydroxyurea (HU) because of increasing white count Leukemia. Acute Promyelocytic Leukemia (APL) is a unique and one patient in addition received a single dose of mito- disorder, characterized by a translocation involving the PML xantrone. The mean duration to achieve remission was gene on chromosome 15 and the retinoic acid receptor – RARa- 48 days (41–60). One patient died on day 5 of intracranial gene on chromosome 17 giving rise to the classic translocation hemorrhage and the remainder achieved remission. At the time 2 t(15;17)(q22;q21) and the PML-RARa fusion protein. Less of report, eight patients were off therapy and two were still frequent are associations of RARa with PLZF on chromosome on primary treatment. One patient had relapsed 6 months 3 11 giving rise to t(11;17)(q23;q21) and the NPM gene on after completion of therapy and responded to a second course 4 chromosome 5 giving rise to t(5;17)(q35;q21); rarely t(15;17) of arsenic trioxide. With a median duration of follow-up of 5 may not directly involve RARa as in t(15;17)(q13;q12). 30 months (range 3–60), the leukemia free-survival was 81% Morphologic variants include the microgranular variant (M3v) with an overall survival of 91%. There were no cases of ATRA and the agranular variant. All of these cytogenetic and syndrome or pseudo-tumor cerebri. Minor toxicities included morphologic variants have been described in children as well hyperpigmentation of the skin, ichthyosis, mild reversible as in adults and thus from a cytogenetic and morphologic peripheral neuropathy in one patient. Significant cardiotoxicity perspective the disease appears to be homogeneous in adults was not observed but it is not clear if the children were 6 and children. Yet some clinical differences have been monitored by electrocardiograms for prolonged QT intervals. observed, for example, high white counts and the M3v variant These results with essentially single-agent therapy with arsenic 7–9 appears to be more common in children; and internal tandem trioxide are comparable to those reported with ATRA-alone or ATRA duplication of the receptor tyrosine kinase FLT3 (FLT3-ITD) is plus chemotherapy.6,9 In the recently published results of the French 10 less common in childhood. While the overall outcome with APL93 study, 31 children with APL received ATRA7chemotherapy. ATRA-based regimens appears to be the same, there is an The median age of the children was 15 years (range 12 months to 17 increased incidence of headaches and the more ominous years; five children aged 3 years or less); 15/31 children had 9 pseudotumor cerebri in children with ATRA. Additional WBC410 000/ml and 10 had M3v variant. The distribution of the concerns with current APL therapies for children are the risks three different BCR isoforms was nearly equal, while in the study for cardiotoxicity (acute and delayed) associated with the 2 from Vellore, 81.8% had bcr1 isoform. Total daunorubicin dose was high cumulative doses of anthracyclines (up to 600 mg/M of 605 mg/M2 and some patients received maintenance therapy with 6- daunorubicin) included in the chemotherapy component of mercaptopurine and methotrexate for 2 years. In all, 97% obtained some of the combined adult-pediatric APL studies. Thus, further complete remission; ATRA syndrome occurred in four children, improvements are necessary in the therapy of APL in children. headaches were reported in 12 children (39%) and pseudotumor cerebri in five children (16%). Seven patients had relapsed after 4– 36 months with 5 year EFS of 71% and OS of 90%. Despite the high Critique doses of daunorubicin, cardiotoxicity was not observed within the duration of follow-up of up to 36 months. In this issue of the journal, Dr George et al1 from Vellore, India, More relevant is the recent report describing the results from describe their experience in 11 children with newly diagnosed a study of adolescent and adult APL patients, comparing ATRA vs 11 APL treated with arsenic trioxide (As2O3), with virtually no arsenic vs ATRA plus arsenic. Like in other studies of APL up to additional chemotherapy. The age ranged from 6 to 14 years 60% of patients on study also received HU or idarubicin/ and all had molecular documentation of PML-RAR. None of the cytarabine. The age range was 14–74 years. In all, three groups children had had WBC410 000/ml, a well-recognized poor CRrateswerehigh(X90%).ThemediantimetoCRintheATRA- alone group was 40.5 days, As2O3-alone group was 31 days and Correspondence: Y Ravindranath, Georgie Ginopolis Chair for for the group with both ATRA and As2O3 was 25.5 days and the Pediatric Cancer and Hematology, Wayne State University School of difference was statistically significant in favor of arsenic vs ATRA Medicine, Children’s Hospital of Michigan-2M34, 3901 Beaubien and combined therapy vs monotherapy. The median leukemia- Boulevard, Detroit, MI 48201, USA; Fax: þ 313 745 5237; E-mail: [email protected] free survivals were 13, 16 and 20 months for ATRA-alone, arsenic- Received 27 June 2004; accepted 12 July 2004; Published online alone, or combined therapy respectively; these differences were 9 September 2004 also statistically significant in favor of combined therapy. Commentary 1577 For George et al, the primary reason for a clinical trial with delayed toxicity (especially neurologic); and how long does arsenic was cost of ATRA in the Indian setting. It appears that arsenic remain in the body. Clearly, there is a need for a this is a significant issue not only in India but certain other parts pediatric age group-based APL study to determine not only the of the world as well (anecdotal information from Dr Harrif efficacy/safety of ATRA vs AS2O3, but also questions arising Mhamed, Casablanca). George et al report that the cost of from earlier ATRA þ chemotherapy studies, that is, how best to treatment with arsenic trioxide was CUSD $2000/per patient, reduce the risk for pseudotumor cerebri; special oral formula- a fraction compared to the estimated cost with ATRA (USD tions of ATRA for children who cannot swallow capsules; what $15 000). Is this cost differential real and is it applicable to other is the optimal cumulative dose of daunorubicin (does one need parts of the world? In part, Dr George et al were able to reduce to give 600 mg/M2 with its attendant risk for cardiotoxicity, the costs of providing arsenic trioxide to their patients because acute as well as delayed); what is the basis for the increased of their ingenuity and creativity. They obtained reagent grade incidence of M3v in children; what is the prognostic importance As2O3 from a chemical manufacturer and solubilized it locally of bcr isoforms; what is the impact of FLT3-ITD in pediatric in their own institution with the help of a highly sophisticated APL; is there a role for cAMP modulators in the treatment of hospital pharmacy. So the cost estimates are based on the costs childhood APL12 and most importantly can some children with of wholesale arsenic trioxide, but do not necessarily include the APL be cured without exposure to cytotoxic chemotherapy. cost for formulation within the pharmacy. We calculated an estimated cost in the USA for a 3-year-old child with APL (BSA References 2 0.77/m and weight 20 kg) for ATRA vs As2O3. Based on wholesale pricing, the cost for a daily dose of ATRA at a dose of 1 George BMV, Ponkuzhali B, Shaji RV, Srivastava A, Chandy M. 2 C 45 mg/m /day would be $43.65 per dose, and for AS2O3 Treatment of children with newly diagnosed acute promyelocytic $93.06 (0.15 mg/kg/dose $31.18/mg of AS2O3). In the US, leukemia with arsenic trioxide: a single center experience. Leukemia 2004; 18: 1587–1590. AS2O3 is commercially available, and individual formulation such as employed in Vellore would not be possible. Moreover, 2 de The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the there may be other hidden costs from the need of administering retinoic acid receptor alpha gene to a novel transcribed locus. AS2O3 in a hospital/clinic setting and from the need for ECG Nature 1990; 347: 558–561. monitoring. Thus, in the US, AS2O3 would actually be more 3 Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY et al. expensive. For a 3-year-old child, AS2O3 would have one clear PLZF-RAR alpha fusion proteins generated from the variant advantage, which is that it comes as a solution for i.v. infusion, t(11;17)(q23;q21) translocation in acute promyelocytic leukemia whereas ATRA capsules would require special formulation to be inhibit ligand-dependent transactivation of wild-type retinoic acid receptors. Proc Natl Acad Sci USA 1994; 91: 1178–1182. administered as a solution PO. 4 Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) So, what should be the choice for targeted therapy in APL in variant of acute promyelocytic leukemia expresses a nucleophosmin- children? The answer is not clear. Most of the clinical data are retinoic acid receptor fusion. Blood 1996; 87: 882–886. based on ATRA-based studies. However, ATRA administration 5 Kurian S, Hogan TF, Bleigh OC, Dowdy YG, Merghoub T, Pandolfi in infants and children who cannot swallow the large capsules PP et al. Atypical t(15;17)(q13;q12) in a patient with all-trans are problematic. Although there are formulas for solubilization, retinoic acid refractory secondary acute promyelocytic leukemia: a case report and review of the literature. Cancer Genet Cytogenet there are no pharmacokinetic studies to date using such formu- 2002; 138: 143–148. lations and thus there is no standardized data for bioavailability 6 Gregory Jr J, Feusner J. Acute promyelocytic leukaemia in children. and comparability. An alternative in the US would be liposomal Best Pract Res Clin Haematol 2003; 16: 483–494. ATRA, but the costs are unknown as the drug is not commer- 7 Rovelli A, Biondi A, Cantu Rajnoldi A, Conter V, Giudici G, cially available and there are no pediatric studies. In the US, Jankovic M et al. Microgranular variant of acute promyelocytic AS O is not approved for children under 15 years of age, but leukemia in children. J Clin Oncol 1992; 10: 1413–1418. 2 3 8 Biondi A, Rovelli A, Cantu-Rajnoldi A, Fenu S, Basso G, Luciano A since the drug is commercially available off-label use would et al. Acute promyelocytic leukemia in children: experience of the be permitted under the existing rules. Studies by George et al Italian Pediatric Hematology and Oncology Group (AIEOP). and as well, the studies of Shen et al11 would suggest that Leukemia 1994; 8: 1264–1268. there may be an advantage with AS2O3 because of the lower 9 de Botton S, Coiteux V, Chevret S, Rayon C, Vilmer E, Sanz M et al. risk for pseudotumor cerebri. In the French study although Outcome of childhood acute promyelocytic leukemia with the incidence of ATRA syndrome was no different in children all-trans-retinoic acid and chemotherapy. J Clin Oncol 2004; 22: 1404–1412. vs adult, there was a trend towards a higher frequency of 10 Liang DC, Shih LY, Hung IJ, Yang CP, Chen SH, Jaing TH et al. pseudotumor cerebri in children compared to adults. Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia. Cancer 2002; 94: 3292–3298. Conclusions 11 Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Thus, the emerging data on AS2O3 are provocative as well as appealing. Several questions however remain with AS O use in Proc Natl Acad Sci USA 2004; 101: 5328–5335. 2 3 12 Guillemin MC, Raffoux E, Vitoux D, Kogan S, Soilihi H, children – what is the frequency of cardiac toxicity (prolonged Lallemand-Breitenbach V et al. In vivo activation of cAMP QT interval, risk for torsades de pointes); what is the safe signaling induces growth arrest and differentiation in acute cumulative AS2O3 dosage; is there any risk for significant promyelocytic leukemia. J Exp Med 2002; 196: 1373–1380.

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