Correspondence

Isotretinoin for Juvenile Chronic Myelogenous Leukemia

N Engl J Med 1995; 332:1520-1521June 1, 1995

Article

To the Editor:

Castleberry and coworkers (Dec. 22 issue)1 report that isotretinoin (13-cis-retinoic acid) may induce long-term responses in some patients with juvenile chronic myelogenous leukemia. In this study of 10 children, isotretinoin induced complete remissions in 2, partial remissions in 3, and a minimal response in 1; the remaining 4 patients had progressive disease. Among the seven patients who did not undergo subsequent bone marrow transplantation, one was still in continuous complete remission 83 months later and two had had stable disease for 36 and 37 months while receiving isotretinoin. The authors could not identify any clinical or laboratory features that predicted whether or not a patient would respond to this agent.

Although clearly warranting further evaluation of isotretinoin, these findings should be interpreted with caution. The median age of the patients was 10 months, and young age is a favorable prognostic feature in juvenile chronic myelogenous leukemia. Indeed, prolonged survival has been noted in many infants who were treated with a variety of chemotherapy regimens.2-4 Owen and colleagues,2 for example, reported that three of six infants less than 6 months of age at diagnosis were alive 10 years or more after the completion of chemotherapy that did not include isotretinoin. In a more recent study, the mean (±SE) survival rate at five years for 10 infants treated with cytotoxic drugs or interferon was 80±35 percent.3

To obtain a better estimate of the influence of age on treatment outcome in this disease, we analyzed updated information on 24 patients in the National Registry for Juvenile Chronic Myelogenous Leukemia in Italy3 and 6 others treated at St. Jude Children's Research Hospital from 1984 to 1994. Therapy consisted of antineoplastic drugs, cytokines, or both. After censoring data on patients who underwent bone marrow transplantation, we found the survival rate for infants to be significantly better than that for children older than one year at diagnosis (mean [±SE], 67±27 percent vs. 0 percent at five years; P = 0.003 by log-rank analysis) (Figure 1Figure 1Probability of Event-free Survival among Infants and Older Children with Juvenile Chronic Myelogenous Leukemia.). None of the six patients who received isotretinoin (100 mg per square meter of body-surface area orally for one to seven months), including one infant, had a clinical response. Thus, infants with juvenile chronic myelogenous leukemia may survive for extended periods after treatment with regimens that exclude isotretinoin, in contrast to older children with this disease, for whom allogeneic bone marrow transplantation is the only known curative treatment.5

Ching-Hon Pui, M.D.
St. Jude Children's Research Hospital, Memphis, TN 38101

Maurizio Aricò, M.D.
University of Pavia, 27100 Pavia, Italy

5 References

1. 1

   Castleberry RP, Emanuel PD, Zuckerman KS, et al. A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med 1994;331:1680-1684
   Full Text | Web of Science | Medline

2. 2

   Owen G, Lewis IJ, Morgan M, Robinson A, Stevens RF. Prognostic factors in juvenile chronic granulocytic leukaemia. Br J Cancer 1992;66:Suppl XVIII:S68-S71
   Web of Science

3. 3

   Arico M, Bossi G, Schiro R, et al. Juvenile chronic myelogenous leukemia: report of the Italian Registry. Haematologica 1993;78:264-269
   Web of Science | Medline

4. 4

   Pui C-H, Kane JR, Crist WM. Biology and treatment of infant leukemias. Leukemia (in press).
   

5. 5

   Sanders JE, Buckner CD, Thomas ED, et al. Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia. Blood 1988;71:1144-1146
   Web of Science | Medline

To the Editor:

Castleberry et al. reported a trial of isotretinoin therapy for patients with juvenile chronic myelogenous leukemia, for which the only effective treatment is bone marrow transplantation.1 Unfortunately, a number of methodologic weaknesses undermine the value of the results. The first problem is the inclusion criteria. The diagnostic criteria agreed on by the French–American–British Committee2 and used in the international literature1,3,4 are as follows: the disease must occur in childhood and involve hyperleukocytosis, monocytosis, negativity for the Philadelphia chromosome, and bone marrow hypercellularity, with marrow blasts not exceeding 25 or 30 percent. Since the authors required that each candidate for the study have a normal karyotype, they effectively excluded all patients with cytogenetic abnormalities and made it difficult to compare their results with published data.

Furthermore, the main end point in the determination of efficacy was the cytologic response, together with the disappearance of organ enlargement. These measures provide no information on the duration of the response or the effect on survival, which are the most relevant end points in a disease that often has a transient response to chemotherapy and in which survival can exceed two years.4 As a result, it is hazardous to state that a patient who died 54 months after diagnosis, with progressive disease, had a complete response. With regard to the only patient who survived for a long period (83 months) without bone marrow transplantation, the response to only 1 year of treatment appears too perfect. Indeed, it is well known3 that these patients can survive spontaneously or with limited therapy (e.g., mercaptopurine). Castro-Malaspina et al.3 identified factors associated with a poor prognosis (age of more than two years, thrombocytopenia, and increased circulating blast-cell counts). It would have been interesting to know the characteristics of the long-term survivor in the study by Castleberry et al. In the absence of such data it remains to be proved that isotretinoin is any more effective than mercaptopurine or even no treatment at all.

Jean Donadieu, M.D.
Centre Hospitalier Régional, 45000 Orléans, France

4 References

1. 1

   Donadieu J, Stephan JL, Blanche S, et al. Treatment of juvenile chronic myelomonocytic leukemia by allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;13:777-782
   Web of Science | Medline

2. 2

   Chessels JM. Myelodysplasia. Baillieres Clin Haematol 1991;4:459-482
   CrossRef | Medline

3. 3

   Castro-Malaspina H, Schaison G, Passe S, et al. Subacute and chronic myelomonocytic leukemia in children (juvenile CML): clinical and hematologic observations, and identification of prognostic factors. Cancer 1984;54:675-686
   CrossRef | Web of Science | Medline

4. 4

   Chan HS, Estrov Z, Weitzman SS, Freedman MH. The value of intensive combination chemotherapy for juvenile chronic myelogenous leukemia. J Clin Oncol 1987;5:1960-1967
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In their critical review of our pilot study of isotretinoin in juvenile chronic myelogenous leukemia, Drs. Pui and Aricò suggest that the responses observed may relate more to the patients' age and less to the effect of isotretinoin. We recognize the well-known relation between age and outcome in juvenile chronic myelogenous leukemia. The ages at diagnosis of the patients who had a partial remission or better were 1, 4, 4, 6, and 16 months, and all had progression of leukocytosis and organomegaly before isotretinoin therapy. The ages at diagnosis of those who had a minimal response or disease progression were 6, 12, 24, 48, and 72 months. Since a response and lack of response were observed in both infants and older patients, the responses to isotretinoin appear to be real in selected patients without the need for chemotherapy. Drs. Pui and Aricò also noted that six patients in their series had no response to isotretinoin. Since it was implied that their patients had received prior therapy with antineoplastic drugs, cytokines, or both, these six patients assuredly had progressive leukemia at the time retinoids were given. We, too, have noted similar poor responses to isotretinoin in more than 25 previously treated patients (unpublished data).

Dr. Donadieu criticized our diagnostic criteria for juvenile chronic myelogenous leukemia. With the exception of the cytogenetic requirement, there is no substantial difference between the criteria drawn up by the French–American–British Committee and those listed in our study. Our requirement that no chromosomal abnormalities be present was included to ensure that none of the patients had Philadelphia chromosome–positive chronic myelogenous leukemia; we were unsure at the initiation of the trial whether monosomy 7 would be appropriately included in this group. In the subsequent phase 2 trial of isotretinoin in juvenile chronic myelogenous leukemia now being conducted by the Pediatric Oncology Group, patients with monosomy 7 are eligible. The information regarding the duration of response and survival is in Table 3 of our article. We concur that the response of the longest surviving patient may be too perfect and we have some concern that, although he fulfilled the entry criteria for the study, this patient may not have had juvenile chronic myelogenous leukemia. With respect to the prognostic variables of Castro-Malaspina et al., in our series two patients were older than two years of age (neither of whom had a response), eight had thrombocytopenia (six of whom had a response), and none had substantial numbers of circulating blasts.

We consider our results compelling but reiterate that the small number of patients studied prohibits meaningful analyses relating to prognostic variables. Since the study was not designed to compare isotretinoin therapy with any chemotherapy or cytokine regimen but rather to establish the rate and duration of response to isotretinoin in juvenile chronic myelogenous leukemia, the study objectives were achieved. That other infants and children with juvenile chronic myelogenous leukemia respond and survive after chemotherapy does not weaken our observations. Our pilot trial clearly warrants both careful interpretation and corroboration.

Robert P. Castleberry, M.D.
Peter D. Emanuel, M.D.
University of Alabama at Birmingham, Birmingham, AL 35294

Citing Articles (10)

Citing Articles

1. 1

   Ayami Yoshimi, Seiji Kojima, Naoto Hirano. (2010) Juvenile Myelomonocytic Leukemia. Pediatric Drugs 12:1, 11-21
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2. 2

   Rupert Handgretinger, Joanne Kurtzberg, R. Maarten Egeler. (2008) Indications and Donor Selections for Allogeneic Stem Cell Transplantation in Children with Hematologic Malignancies. Pediatric Clinics of North America 55:1, 71-96
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3. 3

   C. Flotho, C. P. Kratz, E. Bergstrasser, H. Hasle, J. Stary, M. Trebo, M. M. van den Heuvel-Eibrink, D. Wojcik, M. Zecca, F. Locatelli, C. M. Niemeyer, . (2008) Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. Blood 111:2, 966-967
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4. 4

   Eva Bergstraesser, Henrik Hasle, Tim Rogge, Alexandra Fischer, Martin Zimmermann, Peter Noellke, Charlotte M. Niemeyer. (2007) Non-hematopoietic stem cell transplantation treatment of juvenile myelomonocytic leukemia: A retrospective analysis and definition of response criteria. Pediatric Blood & Cancer 49:5, 629-633
   CrossRef

5. 5

   Toshihiko Imamura, Satoshi Matsuo, Takao Yoshihara, Tomohiro Chiyonobu, Kanako Mori, Hiroyuki Ishida, Yasutaka Nishimura, Yasuo Kasubuchi, Mayumi Naya, Akira Morimoto, Shigeyoshi Hibi, Shinsaku Imashuku. (2004) Granulocytic Sarcoma Presenting with Severe Adenopathy (Cervical Lymph Nodes, Tonsils, and Adenoids) in a Child with Juvenile Myelomonocytic Leukemia and Successful Treatment with Allogeneic Bone Marrow Transplantation. International Journal of Hematology 80:2, 186-189
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6. 6

   Hyoung Jin Kang, Hee Young Shin, Hyoung Soo Choi, Hyo Seop Ahn. (2004) Novel regimen for the treatment of juvenile myelomonocytic leukemia (JMML). Leukemia Research 28:2, 167-170
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7. 7

   Charlotte Marie Niemeyer, Christian Kratz. (2003) Juvenile myelomonocytic leukemia. Current Oncology Reports 5:6, 510-515
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8. 8

   Charlotte Marie Niemeyer, Christian Kratz. (2003) Juvenile myelomonocytic leukemia. Current Treatment Options in Oncology 4:3, 203-210
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9. 9

   Cristina Díaz de Heredia, Juan J. Ortega, María T. Coll, Pilar Bastida, Teresa Olivé. (1998) Results of intensive chemotherapy in children with juvenile chronic myelomonocytic leukemia: A pilot study. Medical and Pediatric Oncology 31:6, 516-520
   CrossRef

10. 10

    Patrizia Tosi, Giuseppe Visani, Emanuela Ottaviani, Davide Gibellini, Annalisa Pellacani, Sante Tura. (1997) Reduction of heat-shock protein-70 after prolonged treatment with retinoids: Biological and clinical implications. American Journal of Hematology 56:3, 143-150
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