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Journal of Clinical Oncology, Vol 18, Issue 18 (September), 2000: 3256-3261
© 2000 American Society for Clinical Oncology

ORIGINAL ARTICLE

High Survival Rate in Infant Acute Leukemia Treated With Early High-Dose Chemotherapy and Stem-Cell Support

By Fernando Marco, Encarna Bureo, Juan J. Ortega, Isabel Badell, Amparo Verdaguer, Ana Martínez, Arturo Muñoz, Luis Madero, Teresa Olivé, Josep Cubells, Victoria Castel, Ana Sastre, M. Soledad Maldonado, Miguel A. Díaz, from the Grupo Español de Trasplante de Médula Ósea en Niños

From the Hospital Universitario Marqués de Valdecilla, Santander; Hospital Materno-Infantil Vall D’Hebrón; Hospital de la Santa Creu i Sant Pau, Barcelona; Hospital Universitario La Fe, Valencia; Hospital La Paz; Hospital Ramón y Cajal; and Hospital del Niño Jesús, Madrid, Spain.

Address reprint requests to Fernando Marco, MD, Servicio de Hematología, Hospital Universitario Marqués de Valdecilla, Avenida de Valdecilla 1, 39008 Santander, Spain; email fernandomarco{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Infants with acute leukemia have a poor prognosis when treated with conventional chemotherapy. It is still unknown if stem-cell transplantation (SCT) can improve the outcome of these patients. In the present study, we review our experience with SCT in infant acute leukemia to clarify this issue.

PATIENTS AND METHODS: We report the results of 26 infants who were submitted to a SCT for acute leukemia. There were 15 cases of acute myeloid leukemia and 10 cases of acute lymphoid leukemia. One patient had a bilineal leukemia. Twenty-two patients were in their first complete response (CR1), three were in their second CR, and one was in relapse. Eight patients were submitted to allogeneic SCT, and 18 underwent autologous SCT.

RESULTS: With a median follow-up of 67 months, the 5-year overall survival and disease-free survival (DFS) are 64% (SE = 9%) and 63% (SE = 10%), respectively. Autologous and allogeneic SCT offered similar outcome. There was not any transplant-related mortality, and all deaths were caused by relapse in the first 6 months after SCT. In multivariate analysis, the single factor associated with better DFS was an interval between CR1 and SCT of less than 4 months (P < .025).

CONCLUSION: SCT is a valid option in the treatment of infant acute leukemia, and it may overcome the high risk of relapse with conventional chemotherapy showing very reduced toxicity. This study suggests that SCT should be performed in CR1 in the early phase of the disease.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
LEUKEMIAS THAT develop within the first year of life have distinctive biologic and clinical features. Infant acute lymphoblastic leukemia (ALL) is characterized by hyperleukocytosis, hepatosplenomegaly, CNS involvement at diagnosis, and CD19+, CD10- immunophenotype with myeloid-associated antigen expression.1-3 Acute myeloid leukemia (AML) shows a higher incidence of myelomonocytic or monocytic phenotypes (M4 or M5) and is frequently associated with hyperleukocytosis and extramedullary disease.1,4,5 Rearrangements of the MLL gene in chromosome 11q23, including cases with apparently normal karyotype, have been found in 70% to 80% of infant ALL and are associated with a poor outcome.1,6-8 In infant AML, this finding is present in nearly 60% of cases and correlates with M4 and M5 phenotypes.4 Most infants with ALL achieve complete response (CR) when they are first treated with conventional chemotherapy regimens, but they show a high relapse rate, with long-term disease-free survival (DFS) ranging from 25% to 43% in large cooperative group studies.8-12 Despite some recent reports showing an increased DFS for infants with ALL treated with more intensive chemotherapy regimens,13,14 outcome for these patients is far from being optimal. The prognosis of infant AML treated with chemotherapy is not better, with reported DFS of 31% to 42%.15,16 Thus, autologous or allogeneic bone marrow transplantations (BMT) have been tried by some groups to reduce the risk of relapse with some encouraging results, although published series are small.17-20

The present study was undertaken to investigate whether an intensive multiagent chemotherapy with stem-cell support could improve the DFS of infants with acute leukemia. We retrospectively analyzed the clinical features, treatment outcome, and prognostic variables of 26 patients with infant acute leukemia who underwent stem-cell transplantation (SCT) in hospitals associated with the Grupo Español de Trasplante de Médula Osea en Niños.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
From January 1990 to December 1998, 26 SCT were performed in 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 one had bilineal leukemia. Their pretransplant clinical characteristics are listed in Table 1.


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  		Table 1. Patient Characteristics at Diagnosis and Transplantation and Outcome
 
Median age at diagnosis was 7 months (range, 1 to 12 months). There were 15 males and 11 females. Three patients had CNS involvement at diagnosis, and 20 had hepatosplenomegaly. The median leukocyte count was 28 x 109/L (range, 1.3 to 900 x 109/L). Immunophenotype was CD19+, CD10- in 50% of ALL patients. Cytogenetic studies were available in 14 patients. Four patients had a normal karyotype, six showed anomalies of the 11q23 region, and four showed other abnormalities.

Previous Treatment
Most ALL patients had been previously treated with multiagent chemotherapy protocols that included doxorubicin, cyclophosphamide, vincristine, prednisone, L-asparaginase, intrathecal therapy, and high-dose methotrexate and cytarabine.21-23 AML patients had been mostly treated with protocols including at least two cycles of an anthracycline, cytarabine, and etoposide. The decision to perform SCT was made at the discretion of the responsible physician.

Transplantation
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 25 months). Disease status at transplant was CR1 in 22 cases, second CR (CR2) in three patients, and more advanced disease in one patient. Eight patients received an allogeneic transplant. Donors were six HLA-identical siblings, one partially mismatched parent, and one matched unrelated donor. Eighteen patients who had no suitable donor were submitted to autologous transplant. The source of progenitors was bone marrow in 22 patients, peripheral-blood stem cells in three patients, and umbilical cord blood cells in one patient. Election of the conditioning regimen was made at the discretion of the responsible physician. Twenty patients received conditioning regimens that included busulfan, cyclophosphamide, and, in some patients, etoposide. Only one patient was treated with total-body irradiation, cytarabine, and cyclophosphamide, whereas five patients received other chemotherapy regimens. Phenytoin, phenobarbital, or clonazepam were administered to patients who received busulfan for prophylaxis of seizures. Busulfan levels were not targeted in any patient. All allogeneic transplant recipients received unmanipulated stem cells. Autologous bone marrow was purged ex-vivo with mafosfamide in six patients and with monoclonal antibodies in two. Measures to prevent infection varied according to the standard of practice at the time of SCT. Eight patients received growth factors after transplantation. Graft-versus-host-disease (GVHD) prophylaxis consisted of cyclosporine or short-term methotrexate and cyclosporine. Assessment and grading of acute and chronic GVHD were performed according to standard criteria.24 Late adverse effects of SCT, including developmental delay, learning disabilities, and endocrinopathies, were evaluated in all long-term survivors.

Statistics
Overall survival and DFS were estimated using the Kaplan-Meier method, with differences between groups being analyzed by the two-tailed log-rank test. DFS was calculated from the date at SCT to relapse, death, or last contact. Data from second transplants were not included in this study, and recipients were censored for overall survival at time of second transplant. Cox multivariate analysis was performed to estimate the independent effect of various factors in overall survival and DFS. Only factors at 5% level from the univariate analysis were assessed in the multivariate analysis. All analyses were performed with the NCSS statistical package (NCSS, Kaysville, UT).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Engraftment
All patients were engrafted with a median time to an absolute neutrophil count of 0.5 x 109/L of 22 days (range, 10 to 70 days). A platelet count of 20 x 109/L was achieved in a median of 31.5 days (range, 16 to 120 days). One patient, who had received an autologous transplant purged with mafosfamide, achieved engraftment only after a second infusion of autologous cells on day +40.

Survival and DFS
Eighteen of 26 patients are alive, with a median survival of 67 months. Five-year overall survival and DFS are 64% (SE = 9%) and 63% (SE = 10%) (Fig 1), respectively. In patients transplanted in CR1, DFS is 71% (SE = 10%), whereas only one of four patients transplanted in more advanced status survives. Patients with ALL had a 5-year DFS of 56%, and AML patients had a DFS of 73% (P = not significant) (Fig 2). Five out of eight recipients of allogeneic transplant and 12 of 18 recipients of autologous transplants are disease-free survivors.



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  		Fig 1. Kaplan-Meier estimated DFS for overall group of 26 infants transplanted for acute leukemia.

 


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  		Fig 2. Kaplan-Meier estimated DFS for patients diagnosed with AML compared with patients with ALL. Differences did not reach statistical significance as determined by the log-rank test.

 
In logistic regression using univariate analysis, significant factors associated with greater DFS were leukocyte count less than 20 x 109/L at diagnosis (P < .04) and an interval between CR1 and SCT of less than 4 months (P < .005) (Fig 3). Factors that showed no significant association with DFS included age at diagnosis less than 6 months, French-American-British leukemia classification type, CD10- immunophenotype, 11q23 abnormalities in karyotype, allogeneic SCT, and conditioning regimen. In multivariate analysis, an interval between CR and SCT of less than 4 months was the only significant factor associated with greater DFS (P < .025). In patients transplanted during the first 4 months after CR1, DFS is 92% (SE = 8%).



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  		Fig 3. Kaplan-Meier estimated DFS for patients submitted to SCT within the first 4 months after CR compared with patients transplanted after the first 4 months after CR. Statistical significance was determined by the log-rank test.

 
Transplant-Related Toxicity
No patient died of transplant-related complications. All patients developed fever, neutropenia, and low-grade mucositis. One patient presented with reversible veno-occlusive disease. Grade III/IV acute GVHD was not seen in any allogeneic recipient, and none of the six patients who survived more than 100 days after an allogeneic SCT had extensive chronic GVHD. Neuropsychologic development was slightly delayed in one patient only after the patient was submitted to a second SCT. No other late effects, such as growth retardation, cataracts, endocrinopathies, cardiac function impairment, or secondary neoplasias, were detected. Long-term survivors are doing intellectually well, and most are eventually attending school.

Relapse
The only cause of death was leukemic recurrence. Nine patients relapsed, with a median time of 104 days from SCT to relapse. All relapses were hematologic and occurred in the first 6 months after SCT. A new remission was obtained in one relapsed patient who received chemotherapy and a second SCT from a different sibling donor. This patient finally died from relapse. No other patients were submitted to second SCT.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Several cooperative group studies have stated the role of SCT in the treatment of children with AML25,26 or high-risk ALL.27,28 Although infants with ALL or AML are considered to have a poorer outcome when compared with older children, a few small noncomparative series of BMT in infant acute leukemia have been reported.17-20 Thus, the indication of allogeneic or autologous SCT in these patients is not established yet. Overall survival and DFS in our series are improved when compared with historical results in patients treated with chemotherapy alone.4,8-14 A certain selection bias is possible in our series because we only included the patients who eventually were submitted to SCT. Nevertheless, characteristics of our series were comparable with those previously reported in infant acute leukemia, and poor risk factors, such as 11q23 anomalies, CD10- phenotype, or high WBC count, were frequently present (Table 1). It was the philosophy of the participating centers that all (but not only) poor-risk patients would be transplanted. We found 11q23 anomalies in karyotype from six patients and evidence of MLL rearrangement was provided by southern blot analysis in two additional cases, for a total of eight 11q23/MLL(+) patients. Interestingly, four of these eight patients, including two out of four autotransplants, are long-term disease-free survivors. We are now collecting molecular data in ongoing patients, so it would help to clarify whether the benefit of high-dose chemotherapy plus SCT could outweigh the prognostic significance of MLL rearrangement. Lack of expression of CD10 in ALL patients, which has been associated with poor prognosis, did not seem to affect outcome in our series, with three out of five survivors in both CD10+ and CD10- ALL patients. Our good results with autologous SCT put the stress in the importance of high-dose chemotherapy more than in providing a graft-versus-leukemia effect by an allogeneic transplant. It is remarkable that none of our patients developed extensive chronic GVHD, which could be theoretically associated with a graft-versus-leukemia effect. Moreover, previous series of BMT in infant acute leukemia did not demonstrate significant differences in outcome between autologous and allogeneic BMT .17,19,20 Our results also suggest that intensification should be early because a short interval between CR and SCT was the only significant factor associated with a better prognosis in multivariate analysis. When transplantation was delayed more than 4 months from CR1, DFS was dramatically reduced from 92% (SE = 7%) to 38% (SE = 17%). An increased rate of relapse in delayed transplants could be related to emergence of resistance leukemia phenotypes while on maintenance therapy.

In our experience with SCT in infants, engraftment was 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 patients.17-20 This may be because of differences in pharmacokinetics,29 the good performance status of most infants, and the immaturity of their immune systems, which minimizes the risk of GVHD. In the current study, there was not any transplant-related mortality. Most of our patients were conditioned with regimens containing busulfan and cyclophosphamide (BuCy), which have proved to be well tolerated in infants, avoiding the risk of neuropsychologic sequelae and other late effects associated with total-body irradiation.17,18 Although toxicity may not be a major problem in infant SCT, relapse remains the first cause of failure. To increase the tumoricidal action of the BuCy regimen, we added etoposide in 14 patients; 11 of them remain disease-free survivors. Etoposide has been reported as an especially effective agent in AML.30 However, in our series, good results with BuCy plus etoposide are not restricted to myeloid leukemia but are also obtained in ALL infants (Table 1). Other strategies that could be attempted to reduce the risk of relapse, such as more intensified preparative regimens or posttransplantation immune modulation,19,31,32 need to be assessed in prospective comparative studies.

In conclusion, our study supports the recommendation of early intensification with autologous or allogeneic SCT rescue for infants with acute leukemia in CR1. An excellent DFS rate is achieved in patients transplanted within the first 4 months after CR1, with very little transplant-related toxicity.


   ACKNOWLEDGMENTS
 
We thank Dr Carlos Richard for critical review of the manuscript.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Pui C-H, Kane JR, Crist WM: Biology and treatment of infant leukemias. Leukemia 9: 762-769, 1995[Medline]

2. Pui C-H, Evans WE: Acute lymphoblastic leukemia in infants. J Clin Oncol 17: 438-440, 1999 (editorial)[Free Full Text]

3. Basso G, Rondelli R, Covezzoli A, et al: The role of immunophenotype in acute lymphoblastic leukemia of infant age. Leuk Lymph 15: 51-60, 1994[Medline]

4. Sorensen PHB, Chen C-S, Smith FO, et al: Molecular rearrangements on the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. J Clin Invest 93: 429-437, 1994

5. Pui C-H, Kalwinsky DK, Schell MJ, et al: Acute nonlymphoblastic leukemia in infants: Clinical presentation and outcome. J Clin Oncol 6: 1008-1013, 1988[Abstract/Free Full Text]

6. Chen C-S, Sorensen PHB, Domer PH, et al: Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 81: 2386-2393, 1993[Abstract/Free Full Text]

7. Rubnitz JE, Link MP, Shuster JJ, et al: Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 84: 570-573, 1994[Abstract/Free Full Text]

8. Pui C-H, Behm FG, Downing JR, et al: 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. J Clin Oncol 12: 909-915, 1994[Abstract/Free Full Text]

9. Reaman GH, Sposto R, Sensel MG, et al: Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children’s Cancer Group. J Clin Oncol 17: 445-455, 1999[Abstract/Free Full Text]

10. Frankel LS, Ochs J, Shuster JJ, et al: Therapeutic trial for infant acute lymphoblastic leukemia: The Pediatric Oncology Group experience (POG 8493). J Pediatr Hematol/Oncol 19: 35-42, 1997[Medline]

11. Chessells JM, Eden OB, Bailey CC, et al: Acute lymphoblastic leukemia in infancy: Experience in MRC UKALL trials—Report from the Medical Research Council Working Party on childhood leukemia. Leukemia 8: 1275-1279, 1994[Medline]

12. Ferster A, Bertrand Y, Benoit Y, et al: Improved survival for acute lymphoblastic leukemia in infancy: The experience of EORTC-Childhood Leukemia Cooperative Group. Br J Haematol 86: 284-290, 1994[Medline]

13. Silverman LB, McLean TW, Gelber RD, et al: Intensified therapy for infants with acute lymphoblastic leukemia: Results from Dana-Farber Cancer Institute Consortium. Cancer 80: 2285-2295, 1997[Medline]

14. Luciano M, Cimino G, Angioni A, et al: A retrospective evaluation of infant patients with acute lymphoblastic leukemia treated at a single institution. Haematologica 84: 464-465, 1999[Free Full Text]

15. Pui C-H, Ribeiro RC, Campana D, et al: Prognostic factors in the acute lymphoid and myeloid leukemias of infants. Leukemia 10: 952-956, 1996[Medline]

16. Satake N, Maseki N, Nishiyama M, et al: Chromosome abnormalities and MLL rearrangement in acute myeloid leukemia of infants. Leukemia 13: 1013-1017, 1999[Medline]

17. Emminger W, Emminger-Schmidmeier W, Haas OA, et al: Treatment of infant leukemia with busulfan, cyclophosphamide ± etoposide and bone marrow transplantation. Bone Marrow Transplant 9: 313-318, 1992[Medline]

18. von Bueltzingsloewen A, Esperou-Bourdeau H, Souillet G, et al: Allogeneic bone marrow transplantation following a busulfan-based conditioning regimen in young children with acute lymphoblastic leukemia: A Cooperative Study of the Société Francaise de Greffe de Moelle. Bone Marrow Transplant 16: 521-527, 1995[Medline]

19. Woolfrey AE, Gooley TA, Sievers EL, et al: Bone marrow transplantation for children less than 2 years of age with acute myelogenous leukemia or myelodysplastic syndrome. Blood 92: 3546-3556, 1998[Abstract/Free Full Text]

20. Pirich L, Haut P, Morgan E, et al: Total body irradiation, cyclophosphamide and etoposide with stem cell transplant as treatment for infants with acute lymphocytic leukemia. Med Pediatr Oncol 32: 1-6, 1999[Medline]

21. Reiter A, Schrappe M, Ludwig WD, et al: Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: Results and conclusions of the multi-center trial ALL-BFM 86. Blood 84: 3122-3133, 1994[Abstract/Free Full Text]

22. Bezanilla JL, Cubells J, Muñoz A, et al: Treatment of acute lymphoblastic leukemia with the Spanish SHOP 89 Protocol: Preliminary results. Med Pediatr Oncol 20: 407, 1997 (abstr P-63)

23. Ortega JJ: PETHEMA protocols in acute lymphoblastic leukemias. Sangre 39: 475-477, 1994

24. Glucksberg J, Storb R, Fefer A, et al: Clinical manifestation of GVHD in human recipients of marrow from HLA matched sibling donors. Transplantation 18: 295-304, 1989

25. Michel G, Leverger G, Leblanc T, et al: Allogeneic bone marrow transplantation vs aggressive post-remission chemotherapy for children with acute myeloid leukemia in first complete remission: A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP). Bone Marrow Transplant 17: 191-196, 1996[Medline]

26. Tiedemann K, Waters KD, Tauro GP, et al: Results of intensive therapy in childhood acute myeloid leukemia, incorporating high-dose melphalan and autologous bone marrow transplantation in first complete remission. Blood 82: 3730-3738, 1993[Abstract/Free Full Text]

27. Saarinen UM, Mellander L, Nysom K, et al: Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: A retrospective case-control study in the Nordic countries—Nordic Society for Pediatric Hematology and Oncology (NOPHO). Bone Marrow Transplant 17: 357-363, 1996[Medline]

28. Maldonado MS, Díaz-Heredia C, Badell I, et al: Autologous bone marrow transplantation with monoclonal antibody purged marrow for children with acute lymphoblastic leukemia in second remission. Bone Marrow Transplant 22: 1043-1047, 1998[Medline]

29. Vassal G, Gouyette A, Hartmann O, et al: Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol 24: 386-390, 1992

30. Bishop JF: Etoposide in the treatment of leukemias. Semin Oncol 19: 33–38, 1992 (suppl 13)

31. Messina C, Zambello R, Rossetti F, et al: Interleukin-2 before and/or after autologous bone marrow transplantation for pediatric acute leukemia patients. Bone Marrow Transplant 17: 729-735, 1996[Medline]

32. Atra A, Millar B, Shepherd V, et al: Donor lymphocyte infusion for childhood acute lymphoblastic leukemia relapsing after bone marrow transplantation. Br J Haematol 97: 165-168, 1997[Medline]

Submitted September 2, 1999; accepted May 5, 2000.




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