H i g h S u r v i v a l R a t e i n I n f a n t A c u t e L e u k e m i a T r e a t e d W i t h
E a r l y H i g h - D o s e C h e m o t h e r a p y a n d S t e m - C e l l S u p p o r t
By Fernando Marco, Encarna Bureo, Juan J. Ortega, Isabel Badell, Amparo Verdaguer, Ana Martı´nez, Arturo Mun˜oz, Luis Madero, Teresa Olive´, Josep Cubells, Victoria Castel, Ana Sastre, M. Soledad Maldonado, and Miguel A. Dı´az from the Grupo Espan˜ol de Trasplante de Me´dula Ósea en Nin˜os Purpose: Infants with acute leukemia have a poor
are 64% (SE ؍ 9%) and 63% (SE ؍ 10%), respectively.
prognosis when treated with conventional chemother-
Autologous and allogeneic SCT offered similar outcome.
apy. It is still unknown if stem-cell transplantation (SCT)
There was not any transplant-related mortality, and all
can improve the outcome of these patients. In the
deaths were caused by relapse in the first 6 months
present study, we review our experience with SCT in
after SCT. In multivariate analysis, the single factor
infant acute leukemia to clarify this issue.
associated with better DFS was an interval between
Patients and Methods: We report the results of 26
CR1 and SCT of less than 4 months (P < .025).
infants who were submitted to a SCT for acute leukemia.
Conclusion: SCT is a valid option in the treatment of
There were 15 cases of acute myeloid leukemia and 10
infant acute leukemia, and it may overcome the high
cases of acute lymphoid leukemia. One patient had a
risk of relapse with conventional chemotherapy show-
bilineal leukemia. Twenty-two patients were in their first
ing very reduced toxicity. This study suggests that SCT
complete response (CR1), three were in their second CR,
should be performed in CR1 in the early phase of the
and one was in relapse. Eight patients were submitted to
allogeneic SCT, and 18 underwent autologous SCT.
J Clin Oncol 18:3256-3261. 2000 by American
Results: With a median follow-up of 67 months, the
Society of Clinical Oncology.
5-year overall survival and disease-free survival (DFS)
LEUKEMIASTHATdevelopwithinthefirstyearoflife with conventional chemotherapy regimens, but they show a have distinctive biologic and clinical features. Infant high relapse rate, with long-term disease-free survival acute lymphoblastic leukemia (ALL) is characterized by (DFS) ranging from 25% to 43% in large cooperative hyperleukocytosis, hepatosplenomegaly, CNS involvement group studies.8-12 Despite some recent reports showing at diagnosis, and CD19ϩ, CD10Ϫ immunophenotype with an increased DFS for infants with ALL treated with more myeloid-associated antigen expression.1-3 Acute myeloid intensive chemotherapy regimens,13,14 outcome for these leukemia (AML) shows a higher incidence of myelomono- patients is far from being optimal. The prognosis of cytic or monocytic phenotypes (M4 or M5) and is fre- infant AML treated with chemotherapy is not better, with quently associated with hyperleukocytosis and extramedul- reported DFS of 31% to 42%.15,16 Thus, autologous or lary disease.1,4,5 Rearrangements of the MLL gene in allogeneic bone marrow transplantations (BMT) havebeen tried by some groups to reduce the risk of relapse chromosome 11q23, including cases with apparently normal with some encouraging results, although published series karyotype, have been found in 70% to 80% of infant ALL and are associated with a poor outcome.1,6-8 In infant AML, The present study was undertaken to investigate whether this finding is present in nearly 60% of cases and correlates an intensive multiagent chemotherapy with stem-cell sup- with M4 and M5 phenotypes.4 Most infants with ALL port could improve the DFS of infants with acute leukemia.
achieve complete response (CR) when they are first treated We retrospectively analyzed the clinical features, treatmentoutcome, and prognostic variables of 26 patients with infantacute leukemia who underwent stem-cell transplantation From the Hospital Universitario Marque´s de Valdecilla, Santander; (SCT) in hospitals associated with the Grupo Espan˜ol de Hospital Materno-Infantil Vall D’Hebro´n; Hospital de la Santa Creu i Trasplante de Me´dula Osea en Nin˜os.
Sant Pau, Barcelona; Hospital Universitario La Fe, Valencia; HospitalLa Paz; Hospital Ramo´n y Cajal; and Hospital del Nin˜o Jesu´s, Madrid, Submitted September 2, 1999; accepted May 5, 2000. Address reprint requests to Fernando Marco, MD, Servicio de Hematologı´a, Hospital Universitario Marque´s de Valdecilla, Avenida From January 1990 to December 1998, 26 SCT were performed in de Valdecilla 1, 39008 Santander, Spain; email fernandomarco@ patients diagnosed with acute leukemia in the first year of life in seven Spanish hospitals. Fifteen of these patients had AML, 10 had ALL, and 2000 by American Society of Clinical Oncology. one had bilineal leukemia. Their pretransplant clinical characteristics Journal of Clinical Oncology, Vol 18, No 18 (September 15), 2000: pp 3256-3261 Transplantation
Median age at diagnosis was 7 months (range, 1 to 12 months).
There were 15 males and 11 females. Three patients had CNSinvolvement at diagnosis, and 20 had hepatosplenomegaly. The median leukocyte count was 28 ϫ 109/L (range, 1.3 to 900 ϫ 109/L).
Immunophenotype was CD19ϩ, CD10Ϫ in 50% of ALL patients.
All patients were engrafted with a median time to an Cytogenetic studies were available in 14 patients. Four patients had a absolute neutrophil count of 0.5 ϫ 109/L of 22 days (range, normal karyotype, six showed anomalies of the 11q23 region, and four 10 to 70 days). A platelet count of 20 ϫ 109/L was achieved in a median of 31.5 days (range, 16 to 120 days). One patient, who had received an autologous transplant purgedwith mafosfamide, achieved engraftment only after a second Most ALL patients had been previously treated with multiagent infusion of autologous cells on day ϩ40.
chemotherapy protocols that included doxorubicin, cyclophosphamide,vincristine, prednisone, L-asparaginase, intrathecal therapy, and high- dose methotrexate and cytarabine.21-23 AML patients had been mostlytreated with protocols including at least two cycles of an anthracycline, Eighteen of 26 patients are alive, with a median survival cytarabine, and etoposide. The decision to perform SCT was made at of 67 months. Five-year overall survival and DFS are 64% the discretion of the responsible physician.
(SE ϭ 9%) and 63% (SE ϭ 10%) (Fig 1), respectively. In patients transplanted in CR1, DFS is 71% (SE ϭ 10%),whereas only one of four patients transplanted in more Patient characteristics at the time of BMT are listed in Table 1.
Median time from first CR (CR1) to BMT was 3.5 months (range, 1 to advanced status survives. Patients with ALL had a 5-year 25 months). Disease status at transplant was CR1 in 22 cases, second DFS of 56%, and AML patients had a DFS of 73% (P ϭ not CR (CR2) in three patients, and more advanced disease in one patient.
significant) (Fig 2). Five out of eight recipients of allogeneic Eight patients received an allogeneic transplant. Donors were six transplant and 12 of 18 recipients of autologous transplants HLA-identical siblings, one partially mismatched parent, and one matched unrelated donor. Eighteen patients who had no suitable donorwere submitted to autologous transplant. The source of progenitors was In logistic regression using univariate analysis, signifi- bone marrow in 22 patients, peripheral-blood stem cells in three cant factors associated with greater DFS were leukocyte patients, and umbilical cord blood cells in one patient. Election of the count less than 20 ϫ 109/L at diagnosis (P Ͻ .04) and an conditioning regimen was made at the discretion of the responsible interval between CR1 and SCT of less than 4 months (P Ͻ physician. Twenty patients received conditioning regimens that in- .005) (Fig 3). Factors that showed no significant association cluded busulfan, cyclophosphamide, and, in some patients, etoposide.
Only one patient was treated with total-body irradiation, cytarabine, with DFS included age at diagnosis less than 6 months, and cyclophosphamide, whereas five patients received other chemo- therapy regimens. Phenytoin, phenobarbital, or clonazepam were ad- CD10Ϫ immunophenotype, 11q23 abnormalities in karyo- ministered to patients who received busulfan for prophylaxis ofseizures. Busulfan levels were not targeted in any patient. All alloge-neic transplant recipients received unmanipulated stem cells. Autolo-gous bone marrow was purged ex-vivo with mafosfamide in sixpatients and with monoclonal antibodies in two. Measures to preventinfection varied according to the standard of practice at the time ofSCT. Eight patients received growth factors after transplantation.
Graft-versus-host-disease (GVHD) prophylaxis consisted of cyclospor-ine or short-term methotrexate and cyclosporine. Assessment andgrading of acute and chronic GVHD were performed according tostandard criteria.24 Late adverse effects of SCT, including developmen-tal delay, learning disabilities, and endocrinopathies, were evaluated inall long-term survivors.
Overall survival and DFS were estimated using the Kaplan-Meier method, with differences between groups being analyzed by thetwo-tailed log-rank test. DFS was calculated from the date at SCT torelapse, death, or last contact. Data from second transplants were notincluded in this study, and recipients were censored for overall survivalat time of second transplant. Cox multivariate analysis was performedto estimate the independent effect of various factors in overall survivaland DFS. Only factors at 5% level from the univariate analysis wereassessed in the multivariate analysis. All analyses were performed with Fig 1. Kaplan-Meier estimated DFS for overall group of 26 infants
the NCSS statistical package (NCSS, Kaysville, UT).
transplanted for acute leukemia.
type, allogeneic SCT, and conditioning regimen. In multi-variate analysis, an interval between CR and SCT of lessthan 4 months was the only significant factor associatedwith greater DFS (P Ͻ .025). In patients transplanted duringthe first 4 months after CR1, DFS is 92% (SE ϭ 8%).
No patient died of transplant-related complications. All patients developed fever, neutropenia, and low-grade mu-cositis. One patient presented with reversible veno-occlu-sive disease. Grade III/IV acute GVHD was not seen in anyallogeneic recipient, and none of the six patients whosurvived more than 100 days after an allogeneic SCT hadextensive chronic GVHD. Neuropsychologic developmentwas slightly delayed in one patient only after the patient wassubmitted to a second SCT. No other late effects, such asgrowth retardation, cataracts, endocrinopathies, cardiacfunction impairment, or secondary neoplasias, were de- Fig 3. Kaplan-Meier estimated DFS for patients submitted to SCT within
tected. Long-term survivors are doing intellectually well, the first 4 months after CR compared with patients transplanted after the first
and most are eventually attending school.
4 months after CR. Statistical significance was determined by the log-rank

The only cause of death was leukemic recurrence. Nine finally died from relapse. No other patients were submitted patients relapsed, with a median time of 104 days from SCT to relapse. All relapses were hematologic and occurred inthe first 6 months after SCT. A new remission was obtained in one relapsed patient who received chemotherapy and a Several cooperative group studies have stated the role of second SCT from a different sibling donor. This patient SCT in the treatment of children with AML25,26 or high-riskALL.27,28 Although infants with ALL or AML are consid-ered to have a poorer outcome when compared with olderchildren, a few small noncomparative series of BMT ininfant acute leukemia have been reported.17-20 Thus, theindication of allogeneic or autologous SCT in these patientsis not established yet. Overall survival and DFS in our seriesare improved when compared with historical results inpatients treated with chemotherapy alone.4,8-14 A certainselection bias is possible in our series because we onlyincluded the patients who eventually were submitted toSCT. Nevertheless, characteristics of our series were com-parable with those previously reported in infant acuteleukemia, and poor risk factors, such as 11q23 anomalies,CD10Ϫ phenotype, or high WBC count, were frequentlypresent (Table 1). It was the philosophy of the participatingcenters that all (but not only) poor-risk patients would betransplanted. We found 11q23 anomalies in karyotype fromsix patients and evidence of MLL rearrangement was pro-vided by southern blot analysis in two additional cases, fora total of eight 11q23/MLL(ϩ) patients. Interestingly, four Fig 2. Kaplan-Meier estimated DFS for patients diagnosed with AML
of these eight patients, including two out of four autotrans- compared with patients with ALL. Differences did not reach statistical
significance as determined by the log-rank test.

plants, are long-term disease-free survivors. We are now collecting molecular data in ongoing patients, so it would cokinetics,29 the good performance status of most infants, help to clarify whether the benefit of high-dose chemother- and the immaturity of their immune systems, which mini- apy plus SCT could outweigh the prognostic significance of mizes the risk of GVHD. In the current study, there was not MLL rearrangement. Lack of expression of CD10 in ALL any transplant-related mortality. Most of our patients were patients, which has been associated with poor prognosis, did conditioned with regimens containing busulfan and cyclo- not seem to affect outcome in our series, with three out of phosphamide (BuCy), which have proved to be well toler- five survivors in both CD10ϩ and CD10Ϫ ALL patients.
ated in infants, avoiding the risk of neuropsychologic Our good results with autologous SCT put the stress in the sequelae and other late effects associated with total-body importance of high-dose chemotherapy more than in pro- irradiation.17,18 Although toxicity may not be a major viding a graft-versus-leukemia effect by an allogeneic problem in infant SCT, relapse remains the first cause of transplant. It is remarkable that none of our patients devel- failure. To increase the tumoricidal action of the BuCy oped extensive chronic GVHD, which could be theoreti- regimen, we added etoposide in 14 patients; 11 of them cally associated with a graft-versus-leukemia effect. More- remain disease-free survivors. Etoposide has been reported over, previous series of BMT in infant acute leukemia did as an especially effective agent in AML.30 However, in our not demonstrate significant differences in outcome between series, good results with BuCy plus etoposide are not autologous and allogeneic BMT .17,19,20 Our results also restricted to myeloid leukemia but are also obtained in ALL suggest that intensification should be early because a short infants (Table 1). Other strategies that could be attempted to interval between CR and SCT was the only significant reduce the risk of relapse, such as more intensified prepar- factor associated with a better prognosis in multivariate ative regimens or posttransplantation immune modula- analysis. When transplantation was delayed more than 4 tion,19,31,32 need to be assessed in prospective comparative months from CR1, DFS was dramatically reduced from 92% (SE ϭ 7%) to 38% (SE ϭ 17%). An increased rate of In conclusion, our study supports the recommendation of relapse in delayed transplants could be related to emergence early intensification with autologous or allogeneic SCT of resistance leukemia phenotypes while on maintenance rescue for infants with acute leukemia in CR1. An excellent DFS rate is achieved in patients transplanted within the first In our experience with SCT in infants, engraftment was 4 months after CR1, with very little transplant-related good and toxicity was very low. This finding has been previously reported in other series, suggesting that infants tolerate the intensification regimens better than older pa-tients.17-20 This may be because of differences in pharma- We thank Dr Carlos Richard for critical review of the manuscript.
1. Pui C-H, Kane JR, Crist WM: Biology and treatment of infant 8. Pui C-H, Behm FG, Downing JR, et al: 11q23/MLL rearrange- ment confers a poor prognosis in infants with acute lymphoblastic 2. Pui C-H, Evans WE: Acute lymphoblastic leukemia in infants.
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6. Chen C-S, Sorensen PHB, Domer PH, et al: Molecular rearrange- 12. Ferster A, Bertrand Y, Benoit Y, et al: Improved survival for ments on chromosome 11q23 predominate in infant acute lymphoblas- acute lymphoblastic leukemia in infancy: The experience of EORTC- tic leukemia and are associated with specific biologic variables and Childhood Leukemia Cooperative Group. Br J Haematol 86:284-290, 7. Rubnitz JE, Link MP, Shuster JJ, et al: Frequency and prognostic 13. Silverman LB, McLean TW, Gelber RD, et al: Intensified significance of HRX rearrangements in infant acute lymphoblastic therapy for infants with acute lymphoblastic leukemia: Results from leukemia: A Pediatric Oncology Group study. Blood 84:570-573, 1994 Dana-Farber Cancer Institute Consortium. Cancer 80:2285-2295, 1997 14. Luciano M, Cimino G, Angioni A, et al: A retrospective 24. Glucksberg J, Storb R, Fefer A, et al: Clinical manifestation of evaluation of infant patients with acute lymphoblastic leukemia treated GVHD in human recipients of marrow from HLA matched sibling at a single institution. Haematologica 84:464-465, 1999 15. Pui C-H, Ribeiro RC, Campana D, et al: Prognostic factors in 25. Michel G, Leverger G, Leblanc T, et al: Allogeneic bone the acute lymphoid and myeloid leukemias of infants. Leukemia marrow transplantation vs aggressive post-remission chemotherapy for children with acute myeloid leukemia in first complete remis- 16. Satake N, Maseki N, Nishiyama M, et al: Chromosome abnor- sion: A prospective study from the French Society of Pediatric malities and MLL rearrangement in acute myeloid leukemia of infants.
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BARRY H. SCHWAB, PH.D. EDUCATION Ph.D. Biostatistics, Medical College of Virginia, Richmond, Virginia, 1984 B.A. Statistics, State University of New York, College at Oneonta, 1980 Undergraduate Study Abroad, Tel Aviv University, Israel (1978 – 1979) EMPLOYMENT HISTORY 1984-present Janssen Research & Development, LLC (a J&J company) Vice President, Clinical

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