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Total-Body Irradiation and Melphalan Is a Safe and Effective Conditioning Regimen for Autologous Bone Marrow Transplantation in Children With Acute Myeloid Leukemia in First Remission

From the Department of Pediatrics, University of Pavia, IRCCS Policlinico San Matteo, Pavia; Department of Pediatrics, University of Bologna, Ospedale Sant'Orsola, Bologna; Department of Pediatrics, University of Padova; Giannina Gaslini Institute, Genova; Department of Pediatrics, University of Turin; and Department of Pediatrics, University of Bari, Bari, Italy.

Address reprint requests to Franco Locatelli, MD, Dipartimento di Scienze Pediatriche, Università di Pavia, IRCCS Policlinico San Matteo, P.le Golgi 2, I-27100 Pavia, Italy; email f.locatelli{at}smatteo.pv.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To evaluate the safety and efficacy of a preparative regimen consisting of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m² in a single dose) in children with acute myeloid leukemia in first complete remission (CR) given autologous bone marrow transplantation (ABMT).

PATIENTS AND METHODS: Fifty-three children (30 males and 23 females; age range, 1.5 to 18 years) were enrolled onto the study. The median time from first CR to ABMT was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from the diagnosis. Forty-five patients received in vitro marrow purging with standard-dose mafosfamide (100 µg/mL), seven patients were treated with interleukin-2 before marrow collection, and in the remaining child, the marrow was unmanipulated. The median infused cell dose was 1.8 x 10⁸/kg (range, 0.4 to 5.8 x 10⁸/kg).

RESULTS: All patients but one achieved hematopoietic engraftment, with a median time to neutrophil recovery of 24 days (range,11 to 66 days). Treatment-related toxicity was moderate and consisted mainly of mucositis. One patient died from cytomegalovirus interstitial pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%) relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65% to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to 81%), with a median follow-up duration of 40 months (range, 7 to 130 months).

CONCLUSIONS: These data suggest that, in our cohort of patients, the combination of total-body irradiation and melphalan is safe and associated with good antileukemia activity, making ABMT an appealing alternative for postremission therapy in children with acute myeloid leukemia in first CR.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
IN THE LAST decade, with the use of recent chemotherapy protocols and better supportive care, approximately 80% of children with acute myeloid leukemia (AML) achieved first complete remission (CR).^1-4 Different therapeutic strategies have been used to consolidate remission, including conventional chemotherapy, allogeneic bone marrow transplantation (BMT), and autologous BMT (ABMT). In general, there has been an evolution toward the use of more aggressive treatments, and several retrospective and prospective analyses have compared the safety and efficacy of these postremission strategies.^5-9

ABMT has been used in patients with AML in first CR who lack an HLA-identical sibling to overcome the limit of marrow toxicity of more intensive consolidation therapy. Disparate incidences of both transplant-related mortality (TRM) and leukemia relapse have been reported in the different analyses concerning the role of ABMT.¹⁰ In particular, it is still not well defined whether the use of total-body irradiation (TBI) can offer an advantage in the cure of these patients, although a better outcome of children treated with radiotherapy has been suggested.¹¹ This issue is of particular relevance considering the radiation-induced sequelae (ie, growth retardation, hypothyroidism, and neuropsychologic complications)^12,13 that can have a particularly deleterious impact on the quality of life of surviving pediatric patients. Because the optimal conditioning regimen for ABMT still needs to be defined, considerable interest remains for the identification of the optimal myeloablative treatment. With the aim of contributing to this question, we evaluated prospectively the safety, tolerability, and antileukemia efficacy of a conditioning regimen that consisted of fractionated TBI (fTBI) and melphalan (L-PAM) in children with AML who underwent ABMT in first CR.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
Between January 1988 and October 1998, 53 pediatric patients (30 males and 23 females) with AML in first CR underwent ABMT using the same conditioning regimen. Patients underwent transplantation in one of the Italian Association for Pediatric Hematology and Oncology (AIEOP) BMT centers participating in this study, and data were collected by the AIEOP-BMT Registry. Transplants were performed in six different centers that reported one to 22 cases (see Appendix). The main contributing center began using this preparative regimen in 1988 for all children with AML who lacked a compatible sibling, and after the publication of the preliminary results,¹⁴ the remaining institutions joined the study in January 1994. Thus, the cohort includes an unselected population of children with AML who reached first CR and who lacked an HLA-identical family donor. All patients were classified as having de novo AML according to the criteria of the French-American-British (FAB) cooperative group,¹⁵ and none of these children had Down's syndrome. Details on patient characteristics, induction therapy allowing patients to enter CR, and the number of consolidation courses or the use of high-dose cytarabine are listed in Table 1.

Chromosome analysis at diagnosis was available in 45 of 53 children. Twenty-nine patients had a normal karyotype, whereas clonal abnormalities were present in the remaining 16 patients. For the purpose of this study, patients with monosomy of chromosomes 5 and 7, anomalies of 11q or translocations 6;9, 8;16, and 1;22 were classified as having poor prognosis (11 cases). Patients with normal karyotype or other cytogenetic abnormalities, as well as those with unavailable cytogenetic data, were assigned to a cytogenetic standard-risk category (42 cases, Table 1).

The median lapse of time from first CR to transplantation was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from diagnosis. Ten patients had also been included in a previously published study.¹⁴

Bone Marrow Processing
Forty-five patients received marrow purged in vitro with an active cyclophosphamide derivative. Briefly, the cell suspension (2 x 10⁷ cells/mL), obtained after centrifugation and resuspension in medium 199 with autologous plasma, was exposed to 4-hydroxazaphosphorine (mafosfamide) at a final concentration of 100 µg/mL for 30 minutes at 37°C.

According to a method described elsewhere,¹⁶ seven patients received a 5-day cycle of interleukin-2 infusion at a dosage of 6 x 10⁶ UI/m²/d before bone marrow collection. The marrow collection was performed within 48 hours from the end of interleukin-2 infusion. In the remaining child, the marrow was unmanipulated. The marrow was cryopreserved in 10% dimethylsulfoxide in 100-mL aliquots using a programmable freezer and stored in the liquid or vapor phase of liquid nitrogen. At the time of ABMT, marrow was reinfused after rapid thawing, with a median cell dose of 1.8 x 10⁸/kg (range, 0.4 to 5.8 x 10⁸/kg).

Conditioning Regimen and Posttransplant Supportive Therapy
The patients' parents gave written informed consent before transplantation. The conditioning regimen consisted of fTBI (12 Gy in six divided doses in 37 cases and 9.9 Gy in three doses in 16 cases) delivered over 3 consecutive days from day -4 to day -2, and L-PAM 140 mg/m² as an intravenous single dose on day -1. Patients older than 5 years received 12 Gy fTBI in six divided fractions, whereas, to spare sedation procedures, children younger than 5 years were given 9.9 Gy fTBI in three fractions. None of the patients received chemotherapy after ABMT.

Supportive therapy and prophylaxis and treatment of infections were substantially homogeneous among participating centers. Patients received oral cotrimoxazole starting from the day of engraftment as Pneumocystis carinii pneumonia prophylaxis. To reduce the risk of infection, children received commercial immunoglobulin preparation intravenously at a dosage of 400 mg/kg/wk, starting 2 days before transplant and ending at day 40 after ABMT. Recombinant human granulocyte colony-stimulating factor was given to 23 patients at a dosage of 5 µg/kg/d from day +5 until stable engraftment.

Empirical broad-spectrum antibiotic therapy was usually started when children became febrile, and antifungal therapy was used in the presence of either clinical evidence of fungal infection or fever persisting after 3 days of antibiotic therapy.

Definitions
Patients were considered to be in CR if they had a normal recovery of hematopoiesis (neutrophil count > 1.5 x 10⁹/L and platelet count >100 x 10⁹/L) in the presence of less than 5% blast cells in a bone marrow smear, in the absence of circulating blasts, and in the absence of extramedullary leukemia cell infiltration.

Myeloid engraftment was defined as the first of 3 consecutive days when the neutrophil count was 0.5 x 10⁹/L, and platelet engraftment was defined as the first of 3 consecutive days with an unsupported platelet count 50 x 10⁹/L.

Children were subdivided into high-risk and standard-risk groups according to the recently described Berlin-Frankfurt-Munster (BFM) criteria based on morphology, karyotype, and blast cell reduction on day +15 after the beginning of induction therapy.¹⁷ In particular, the standard-risk group comprised 17 patients (32%) who had M1 or M2 AML with Auer rods (according to FAB criteria), M3 and M4eo, inversion of chromosome 16 and t(8;21) translocation, and blast cell reduction on day +15 to 5%. All other patients belonged to the high-risk group (36 children; 68% of the overall population). Regimen-related toxicity was graded according to the criteria previously reported by Bearman et al.¹⁸

To evaluate the long-term sequelae of the preparative regimen, we investigated the occurrence of growth impairment, thyroid complications, hypogonadism, cataracts, leukoencephalopathy, and secondary malignancies in the 24 patients who survived in remission more than 2 years after the transplant procedure.

Statistical Analysis
Data were analyzed as of March 31, 1999. Disease-free survival (DFS), TRM, relapse rate, and neutrophil and platelet engraftment curves after transplantation (starting point) were calculated by the Kaplan-Meier method and compared using the log-rank test. DFS analysis included both relapse and death in remission from any cause as treatment failures, whereas relapse rate analysis considered only disease relapse, and TRM analysis considered only deaths from any transplant-related cause as failures. Results are expressed as probability (%) and 95% confidence limits. The impact of the different disease-, patient-, and BMT-related variables on clinical outcome was tested in univariate analysis. Because of the limited number of patients studied, no multivariate analysis was performed. The SAS package (SAS Institute, Cary, NC) was used for the statistical analysis of the data.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Engraftment
All patients but one achieved hematopoietic engraftment, and the median time to achieve neutrophil recovery was 24 days (range, 11 to 66 days). By contrast, the median time to obtain a self-sustained platelet count more than 50 x 10⁹/L was 60 days (range, 30 to 213 days).

The use of hematopoietic growth factors did not favor a faster recovery of neutrophil count. In fact, median time for myeloid recovery in patients who did or did not receive hematopoietic growth factors was 21 days (range, 14 to 66 days) and 24 days (range, 11 to 46 days), respectively (P = not significant [NS]). Patients who underwent transplantation with marrow cells purged in vitro with mafosfamide had an earlier recovery of neutrophil count (median, 21 days; range, 11 to 66 days) compared with those treated in vivo with interleukin-2 (median, 30 days; range, 21 to 40 days; P = .065). The number of cells infused, as well as the number of chemotherapy courses before bone marrow collection or transplantation, did not have any influence on the kinetics of hematopoietic recovery.

Regimen-Related Toxicity
Details on specific organ toxicity are listed in Table 2. Regimen-related toxicity was moderate and largely restricted to oral and gastrointestinal mucositis. Otherwise, the aplastic period was generally well tolerated. Two patients died: one from cytomegalovirus interstitial pneumonia and one from pulmonary hemorrhage. The 1-year overall probability of TRM was 4% (95% confidence interval [CI], 0% to 9%; Fig 1).

View larger version (20K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimate of transplant-related mortality, relapse probability, and disease-free survival for the 53 patients enrolled onto the study.

Patient Outcome
Fourteen patients (26%) experienced leukemia relapse at a median time of 6 months after transplant (range, 2 to 17 months). Five of the 14 patients who relapsed died from disease progression, whereas three more children died from transplant-related complications after a subsequent allograft from an unrelated donor. The remaining six children are alive, four of whom are in second continuous CR after an unrelated BMT or cord-blood allogeneic transplantation. Figure 1 shows a 5-year cumulative probability of relapse of 29% (95% CI, 16% to 42%) for the entire group of children.

The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (95% CI, 65% to 90%). Thirty-seven of the 53 patients (70%) are alive and in CR, with a median observation time of 40 months from transplantation (range, 7 to 130 months). The cumulative DFS at 5 years was 68% (95% CI, 55% to 81%; Fig 1). DFS of patients who underwent transplantation before or after the median lapse of time between first CR and ABMT was 57% and 94%, respectively (P = .01). Because a long time interval between diagnosis and transplant can determine a favorable selection of patients, we evaluated the posttransplant outcome of our children who underwent transplantation within or beyond 6 months from diagnosis. Children who underwent transplantation within 6 months from diagnosis had a 5-year DFS of 63% (95% CI, 48% to 77%), whereas all eight patients who underwent ABMT after this interval are alive and well (P = .07; Fig 2).

View larger version (16K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimate of disease-free survival according to the time interval between first CR and ABMT.

DFS of patients in the standard- and high-risk groups according to BFM criteria was 77% and 63%, respectively (P = NS). The 5-year Kaplan-Meier DFS estimate of patients in the favorable and unfavorable cytogenetic risk groups was 75% and 67%, respectively (P = NS). In univariate analysis, sex, age at diagnosis, FAB subtype, age at transplant, leukocyte count at diagnosis, first-line chemotherapy protocol, number of induction courses to achieve first CR, use of high-dose cytarabine during consolidation therapy, total dose of fTBI, and the number of cells infused did not influence the clinical outcome of the patients (data not shown). Likewise, these variables did not have any impact on relapse rate (data not shown).

Long-Term Side Effects
Twenty-four of the 53 patients, with a follow-up duration greater than 24 months, were evaluated for the occurrence of long-term side effects of the transplant procedure. A decrease in growth velocity was the most frequent alteration in this subgroup of children and was observed in 11 patients at a median of 3.7 years after ABMT (range, 1.6 to 5.3 years). In four cases, replacement therapy with recombinant human growth hormone was started after the demonstration of growth hormone–secretion deficiency. Overt or compensated hypothyroidism was diagnosed in seven children after a median of 3 years after transplantation (range, 2 to 5 years). Four children are receiving substitutive therapy with L-thyroxin. Hypogonadism or delayed puberty occurred in five patients. Four children experienced cataracts at a median of 3 years after ABMT (range, 2.5 to 5 years); however, none of them needed surgical repair. No patient developed leukoencephalopathy or secondary malignancies.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Adequate postremission therapy is essential to reduce the risk of leukemia relapse and to obtain the definitive cure for children with AML. Although ABMT is a recognized therapy to consolidate the remission state of patients with AML, few studies have specifically focused on pediatric patients.^4-6,11,14

Our results indicate that the preparative regimen used is effective, because more than two thirds of children included in this study are cured. This result is clearly superior to that previously achieved in a group of Italian children with AML who were prepared for ABMT with the carmustine, amsacrine, etoposide, and cytarabine regimen in the context of a multicenter prospective randomized trial.⁴ In fact, patients who underwent ABMT after this regimen enjoyed a DFS probability at 3 years after transplantation of only 28%, compared with the 68% observed in our cohort of patients. Our data confirm and extend the results of a previously published retrospective analysis in Italian children with AML given autologous transplantation in first CR¹¹ that suggested an advantage in favor of TBI. Moreover, both the overall survival and TRM we observed are comparable to those recently described in ABMT recipients by the 10th trial of the Medical Research Council in childhood AML.⁴ Also in this group of patients, fTBI, coupled with cyclophosphamide, was used as part of the preparative regimen.

The 4% TRM probability documented in our patients is lower than the value of 15% reported by the Pediatric Oncology Group in the arm randomized to receive an autologous transplant.⁵ In that prospective multicenter study, patients were prepared for ABMT with the combination of busulfan and cyclophosphamide and, compared with patients given conventional chemotherapy, the lower relapse incidence in the ABMT arm was counterbalanced by a higher TRM, determining similar DFS.

Further support to the feasibility and safety of our preparative regimen is also given by the mild to moderate organ-specific morbidity observed. Moreover, the possibility of obtaining a new remission after relapse in four ABMT recipients by means of an allogeneic BMT also indicates that the toxicity associated with our protocol does not preclude a subsequent allograft.

Several drugs have been used in combination with radiotherapy during the preparative regimen with the aim of increasing specific leukemia eradication. We chose to use L-PAM with TBI on the basis of the following considerations: (1) L-PAM is an alkylating agent with a non—cell cycle—specific activity that can further increase the killing of malignant progenitors dormant out of cell cycle; (2) the relapse rate after marrow transplantation has been reported to be reduced in patients given TBI and L-PAM compared with those treated with TBI and cyclophosphamide¹⁹; (3) because L-PAM is usually not included in chemotherapy protocols, its use during myeloablative therapy minimizes the risk of prior exposure and resistance to this drug; and (4) the use of high-dose L-PAM in children with solid tumors was demonstrated to be associated with a limited and acceptable extramedullary toxicity.²⁰ Recently published studies provide further evidence in favor of the use of high-dose L-PAM for ABMT in children with AML. In fact, Tiedemann et al²¹ updated their initial results, reporting a 10-year event-free survival of 69% in 49 children treated with an intensive induction-consolidation therapy and given unpurged ABMT using L-PAM alone (180 mg/m²) as a preparative regimen.²² Yaniv et al²³ documented a 2-year event-free survival of 83% in 13 pediatric patients given high-dose L-PAM before autologous transplantation, used as final consolidation after a BFM-like protocol. These two studies suggest that, in children with AML in first CR, a preparative regimen consisting of high-dose L-PAM alone may be as effective as the combination of L-PAM with fTBI. If this hypothesis is proved in a prospective, controlled trial, the short- and long-term morbidity associated with radiotherapy could be avoided. In this regard, endocrine complications, which sometimes require hormonal replacement therapy, were the most frequent long-term side effects of our patients. By contrast, although the observation time is limited, we did not observe secondary malignancies and neuropsychologic abnormalities.

The two major biases of nonrandomized studies on patients given marrow transplantation are the so-called time censoring effect (ie, patients who undergo transplantation late after achievement of CR may be at lower risk of relapse, by virtue of having remained in remission a time long enough for a transplantation to be performed) and the possibility that patients selected for ABMT have a different intrinsic prognosis compared with those who are not. We cannot exclude that both these factors have influenced our results. However, 85% of our patients underwent transplantation within 6 months after diagnosis, and the stratification into standard- or high-risk group according to the BFM criteria (68% v 32%) completely reflected that recently reported by Creutzig et al.¹⁷ Notably, in our cohort of patients, the use of fTBI and L-PAM allowed us to abolish the prognostic value of this stratification, with the results observed in the high-risk group being particularly encouraging. In contrast, because more than 70% of standard-risk patients have been reported to be alive after treatment with the BFM protocols,^7,17,24 in this subgroup, ABMT could be reserved to children who experienced a relapse and who lacked a compatible relative.

Our results are not inferior to those reported in children given an allogeneic BMT from a compatible sibling^4-6,9,25,26 and are in accord with a previously published analysis by the Children Cancer Study Group, which documented comparable DFS in allogeneic and autologous BMT recipients.²⁷ This consideration raises the question of the need and opportunity of exposing all children with AML in first CR both to the increased morbidity associated with an allograft and to the risk of developing extensive chronic graft-versus-host disease, which has a particularly detrimental impact on a growing organism.

In this study, the bone marrow of most patients was purged in vitro with standard-dose mafosfamide. Because it has been demonstrated that leukemia cells collected with the autologous graft at least may contribute to posttransplant relapse,²⁸ there is a strong rationale for supporting our policy, as well as those of many other investigators,^10,29,30 to perform in vitro marrow purging before ABMT. In the absence of a prospective randomized study, we cannot formally document that purging improved the clinical outcome of our patients. The use of mafosfamide did not affect the rate of engraftment: the kinetics of both neutrophil and platelet recovery were in the range reported for patients with AML in first CR given an unpurged ABMT.³¹ A greater reserve of normal hematopoietic progenitors surviving after chemotherapy in children could account for this finding. Notably, we have been unable to document any favorable impact of granulocyte colony-stimulating factor on myeloid recovery, which raises some doubt, given its cost, on the opportunity of an indiscriminate use of this cytokine in children given ABMT for AML in first CR.

In summary, our data suggest that the combination of TBI and high-dose L-PAM is safe and associated with good antileukemia activity. This conditioning regimen, together with in vitro marrow purging, could increase the probability of patients with AML in first CR to be maintained in sustained remission, making ABMT an appealing alternative for postremission therapy.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
AIEOP-BMT Group Centers that participated in the study: A. Pession, A. Prete, R. Rondelli, and G. Paolucci, BMT Unit, Department of Pediatrics, University of Bologna, Policlinico Sant'Orsola, Bologna; C. Messina, S. Cesaro, and L. Zanesco, BMT Unit, Department of Pediatrics, University of Padova, Padova; F. Locatelli, F. Bonetti, M. Zecca, G. Giorgiani, P. De Stefano, and F. Severi, Department of Pediatrics, University of Pavia, IRCCS Policlinico San Matteo, Pavia; F. Fagioli, E. Madon, and A. Busca, BMT Unit, Department of Pediatrics, University of Turin, Turin; E. Lanino, G. Dini, and A. Dallorso, BMT Unit, Giannina Gaslini Institute, Genova; C. Favre and P.L. Macchia, BMT Unit, Department of Pediatrics, University of Pisa, Pisa, Italy.

	ACKNOWLEDGMENTS

 
Supported in part by the Associazione Italiana per la Ricerca sul Cancro, Milan, and IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico) Policlinico San Matteo, Pavia, Italy (to F.L).

We thank Dr. Patrizia Comoli, Eugenia Giraldi, and Rita Maccario for valuable help and continuous support, and Dr. Carmelo Carlo-Stella for critical revision of the manuscript.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted May 6, 1999; accepted July 22, 1999.

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				D. Montagna, R. Maccario, F. Locatelli, E. Montini, S. Pagani, F. Bonetti, L. Daudt, I. Turin, D. Lisini, C. Garavaglia, et al. Emergence of antitumor cytolytic T cells is associated with maintenance of hematologic remission in children with acute myeloid leukemia Blood, December 1, 2006; 108(12): 3843 - 3850. [Abstract] [Full Text] [PDF]

				F. Locatelli, M. Labopin, J. Ortega, G. Meloni, G. Dini, C. Messina, I. Yaniv, F. Fagioli, V. Castel, P. J. Shaw, et al. Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission Blood, February 15, 2003; 101(4): 1611 - 1619. [Abstract] [Full Text] [PDF]

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