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© 1999 American Society for Clinical Oncology Total Body Irradiation, Thiotepa, and Cyclophosphamide as a Conditioning Regimen for Children With Acute Lymphoblastic Leukemia in First or Second Remission Undergoing Bone Marrow Transplantation With HLA-Identical SiblingsFrom 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, Padova; Department of Pediatrics, University of Pisa, Pisa; Department of Pediatrics, University of Brescia, Spedali Civili, Brescia; and Department of Pediatrics, Ospedale Silvestrini, Perugia, Italy. Address reprint requests to Marco Zecca, MD, Dipartimento di Scienze Pediatriche, Università di Pavia, IRCCS Policlinico San Matteo, P.le Golgi 2, I-27100 Pavia, Italy; email m.zecca{at}smatteo.pv.it
PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-identical siblings can be used to treat children with acute lymphoblastic leukemia (ALL). However, a significant proportion of patients with ALL who undergo HSCT relapse. For this reason, we prospectively evaluated a preparative regimen that included total body irradiation (TBI), thiotepa (TT), and cyclophosphamide (CY) in patients with high-risk ALL in first complete remission (CR) and in children with ALL in second CR. PATIENTS AND METHODS: Forty children (median age, 9 years; range, 1 to 18 years) with ALL in first or second CR who underwent allogeneic HSCT from HLA-identical siblings were conditioned with a combination of fractionated TBI, TT (10 mg/kg), and CY (120 mg/kg over 2 days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine administered intravenously at a dose of 1 to 3 mg/kg/d for the first 21 days and subsequently orally at a dose of 6 mg/kg/d. RESULTS: All assessable patients were engrafted, with a median time of 11 and 24 days for neutrophil and platelet recovery, respectively. The preparative regimen was well tolerated. Only one patient died as a result of regimen-related causes. Eight patients relapsed at a median time of 8 months after transplantation (range, 3 to 9 months), and this determined a cumulative probability of relapse of 23%. Twenty-six of 40 patients (65%) are alive and in complete hematologic remission, with a median observation time of 36 months (range, 14 to 57 months), which results in a disease-free survival (DFS) at 3 years of 65%. The 13 patients who underwent transplantation in first CR had a DFS of 85%, whereas the 27 patients who underwent HSCT in second CR had a DFS of 56%. CONCLUSION: These data suggest that TT is an effective cytotoxic drug that can be safely added to the classical TBI-CY regimen. Because of its cell cycle–independent action, good CNS diffusion, and limited extramedullary toxicity, TT may contribute to increasing the percentage of children with ALL who are successfully cured with allogeneic BMT.
ACUTE LYMPHOBLASTIC leukemia (ALL) represents the most common neoplasm in childhood, with an incidence per year of approximately 40 cases per one million children younger than 15 years.1 Although nowadays more than 70% of children affected by ALL can be cured by the modern chemotherapy protocols,2-6 a significant proportion of patients ultimately undergo an allogeneic hematopoietic stem cell transplantation (HSCT), either in second complete remission (CR) after disease relapse, or in first CR because of the presence of unfavorable prognostic factors.7-9 According to the last European Blood and Marrow Transplantation Group survey, more than 850 patients (including both children and adults) underwent allogeneic HSCT in Europe during 1995 as part of ALL treatment.10 Leukemia relapse is still the most frequent cause of treatment failure after HSCT for childhood ALL in first or second CR, with an incidence ranging from 20% to 50% in different reports.11-16 For this reason, considerable interest remains for the evaluation of new approaches aimed at improving the antileukemia efficacy of the procedure and increasing the probability of disease-free survival (DFS) after transplantation. Different combinations of cytotoxic drugs, with or without total body irradiation (TBI), have been proposed for the conditioning regimen of children with ALL,13,14,16-18 the association of high-dose cyclophosphamide (CY) (60 mg/kg/d for 2 consecutive days) and TBI being the standard of comparison for all other preparative regimens. Thiotepa (TT) (N, N', N''-triethylene thiophosphoramide) is an alkylating agent with proved immunosuppressive and antineoplastic activity,19-21 and it has recently been tested as part of the myeloablative treatment administered before allogeneic and autologous bone marrow transplantation (BMT) for various diseases.22-25 In this study, we prospectively evaluated the safety, tolerability, and antileukemic efficacy of TT added to the classical TBI-CY pretransplantation conditioning regimen in a group of pediatric patients with either high-risk ALL in first CR or ALL in second CR who underwent allogeneic HSCT with an HLA-identical sibling.
Patients Forty consecutive patients with high-risk ALL in first CR or with ALL in second CR who underwent allogeneic HSCT with an HLA-identical sibling between June 1992 and May 1997 were enrolled onto the study. 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. Transplantations were performed in six different centers, each of which reported from one to 20 cases (see Appendix). Patient characteristics are listed in Table 1.
Twenty-five patients were male and 15 were female; the median age at diagnosis was 6.4 years (range, 0.5 to 17 years), whereas the median age at transplantation was 9 years (range, 1 to 18 years). Twenty-two patients had common ALL, two had pre-pre-B ALL, six had pre-B ALL, one had B ALL, and nine had T-phenotype ALL. The t(9;22) translocation was present in three cases, whereas the t(4;11) translocation was demonstrated in one patient, and multiple chromosomal abnormalities were observed in seven other children. Twenty-five children had a normal cytogenetic analysis at diagnosis, whereas the karyotype was not available in the remaining four patients. First-line chemotherapy treatment was administered according to the AIEOP ALL 87 protocol26 in three patients, the AIEOP ALL 88 protocol27 in three patients, the AIEOP ALL 91 protocol28 in 28 patients, and the AIEOP ALL 95 protocol in three patients. Notably, the latter three protocols have a Berlin-Frankfurt-Munster (BFM)–like backbone. The remaining three patients did not receive an AIEOP chemotherapy schedule as first-line chemotherapy. Briefly, enrolled patients usually underwent a three-drug remission induction regimen with prednisone, vincristine, and asparaginase at standard dosage, plus anthracyclines for average- and high-risk patients. A continuing multiple-agent chemotherapy treatment with appropriate CNS prophylaxis that included systemic high-dose and intrathecal methotrexate and/or cranial irradiation was delivered until the completion of 2 years of treatment. Thirteen children with high-risk ALL underwent HSCT in first CR. The median time from CR to transplantation was 4.3 months (range, 1.7 to 13 months). Indication for HSCT in first remission differed slightly among the different chemotherapy protocols but included unfavorable chromosomal abnormalities, ie, t(9;22) translocation; resistance to corticosteroid treatment (> 1 x 109/L blasts in peripheral blood after 7 days of prednisone administration) with elevated blast count in the peripheral blood at diagnosis or T immunophenotype; and lack of remission at the end of the induction phase.29-33 Details regarding this subgroup of patients are listed in Table 1. Twenty-seven patients underwent the transplantation procedure in second CR, after a bone marrow relapse in 20 cases, a combined bone marrow and testis relapse in four cases, and an isolated CNS relapse in three cases. The median time from diagnosis to the first relapse was 28 months (range, 3 to 69 months), whereas the median time from second CR to transplantation was 2.5 months (range, 0.5 to 13 months).
Conditioning Regimen, Prophylaxis for Graft-Versus-Host Disease, and Posttransplantation Supportive Therapy Donor marrow was infused on day 0, and the median bone marrow nucleated cell dose was 4 x 108/kg (range, 1.6 to 11.1 x 108/kg). Three patients underwent cord-blood transplantation (CBT); the nucleated cell doses were 1.8, 2.1, and 3.5 x 107/kg. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine administered intravenously for the first 3 weeks at the dose of 1 to 3 mg/kg/d and, subsequently, given orally at a dosage of 6 mg/kg/d for an additional 3 to 6 months. Supportive therapy, as well as prophylaxis for and treatment of infections, was substantially homogeneous among centers participating in this study. As Pneumocystis carinii pneumonia prophylaxis, patients received oral cotrimoxazole, starting from the day of engraftment. In the majority of patients, the expression of pp65 cytomegalovirus matrix protein was monitored in order to detect viral reactivation. Recombinant human granulocyte colony-stimulating factor was given to 29 patients. Usually, empirical broad-spectrum antibiotic therapy was started when patients became febrile, and antifungal therapy was used in the presence of clinical evidence of fungal infection or fever persisting after 3 days of antibiotic therapy.
Definitions Acute and chronic GVHD were classified according to previously described criteria.34,35 Children with sustained donor engraftment who survived more than 14 days and more than 100 days after the transplantation were evaluated for occurrence and severity of acute and chronic GVHD, respectively. Toxicity related to the transplantation procedure was graded according to the criteria proposed by Bearman et al.36,37
Statistical Analysis The SAS package (SAS Institute, Cary, NC) was used for the statistical analysis of the data.
Engraftment All patients who survived more than 7 days after HSCT and who were assessable for engraftment (39 of 40) showed a complete hematologic reconstitution. The median time to achieve neutrophil recovery was 11 days (range, 7 to 23 days), whereas the median time for a self-sustained platelet count of more than 50 x 109/L was 24 days (range, 12 to 60 days). Patients who were given hematopoietic growth factors had a faster recovery of neutrophil count compared with those who did not receive hematopoietic support (data not shown).
Regimen-Related Toxicity
GVHD
Chronic GVHD was observed in 11 of the 35 assessable patients. Nine patients presented limited skin chronic GVHD and two presented the extensive form of the disease. Ten of the 11 patients with chronic GVHD had previously experienced acute GVHD. The median time from transplantation to chronic GVHD appearance was 3.9 months (range, 3 to 7 months). The 3-year Kaplan-Meier estimate of chronic GVHD was 31% (95% CI, 15% to 47%).
Patient Outcome
On the whole, six patients (15%) died as a result of nonleukemic transplantation-related causes. Acute GVHD was the cause of death in two cases, whereas, as previously mentioned, one patient died of idiopathic interstitial pneumonia 3 months after BMT and three patients (7.5%) died as a result of infectious complications—Streptococcus pneumoniae sepsis, Candida albicans pneumonia, and cytomegalovirus pneumonia—5 days, 10 days, and 8 months after transplantation, respectively. Figure 1 shows the cumulative probability of TRM for the overall population, which was 15% (95% CI, 4% to 26%). Children who underwent HSCT in first CR had a cumulative probability of TRM of 8% (95% CI, 0% to 22%), whereas TRM was 19% (95% CI, 4% to 33%) for the patients who underwent transplantation in second CR (P = NS). Twenty-six (65%) of the 40 patients are alive and in complete hematologic remission with a median observation time of 36 months from transplantation (range, 14 to 57 months). The cumulative DFS at 3 years was 65% (95% CI, 50% to 80%) (Fig 1). The DFS of the 13 patients who underwent transplantation in first CR was 85% (95% CI, 65% to 100%), whereas the value for the 27 patients who underwent HSCT in second CR was 56% (95% CI, 37% to 74%) (P = NS) (Fig 3). Excluding the three patients who presented an isolated CNS relapse, the DFS of the 24 patients who underwent transplantation in second CR after an isolated or combined bone marrow relapse was 54% (95% CI, 34% to 73%).
Considering only the cohort of children who underwent transplantation in second CR, patients who presented the first relapse within 6 months after cessation of therapy had a DFS of 57% (95% CI, 31% to 83%) as compared with a value of 54% (95% CI, 27% to 81%) for the children who experienced the first relapse more than 6 months after treatment discontinuation (P = NS). No significant correlation was observed between sex, age at diagnosis, age at transplantation, leukocyte count at diagnosis, immunophenotype, or interval CR-transplantation and the clinical outcome of the patients (data not shown). Finally, DFS was not influenced by GVHD occurrence. In fact, considering the 38 patient who were assessable for acute GVHD, patients without or with grade 1 acute GVHD and those with grade 2 to 4 GVHD had an identical DSF (68%, 95% CI, 48% to 89%). DFS for the 24 patients without chronic GVHD was 75% (95% CI, 61% to 89%), whereas the 11 patients with chronic GVHD had a DFS of 73% (95% CI, 52% to 94%) (P = NS).
The success of allogeneic HSCT in eradicating leukemia depends on the following two factors: (1) the ability of the chemoradiotherapy administered as myeloablative treatment to reduce or, at best, to eliminate clonogenic malignant cells, and (2) the graft-versus-leukemia effect mediated by donor lymphocytes infused with the stem-cell inoculum.39,40 As far as the first point is concerned, the relevant relapse risk after HSCT in ALL patients has stimulated the evaluation of several combinations of cytotoxic drugs and radiotherapy designed to increase the antileukemic efficacy of the pretransplantation myeloablative treatment.13,14,16,17,41-44 Although some authors reported promising results, none of these studies were conducted in a randomized way and none documented unquestionable advantages over the standard TBI-CY schedule. The best results were reported in the oldest studies,42-44 in which patients who underwent transplantation, having received less intensive first-line chemotherapy than that adopted in more recent years, reasonably had a greater probability of benefiting from BMT. Moreover, the regimens that include higher doses of fractionated TBI or that substitute or add either cytarabine, etoposide, or melphalan to CY may result in lower relapse rates but are frequently associated with increased regimen-related toxicity. In this regard, two studies have evaluated the efficacy of the combination of TBI, cytarabine, and melphalan in children with ALL in second CR.41,45 Both reports demonstrated a good efficacy, with a DFS in of approximately 65%. However, toxicity was not negligible; TRM of the first study on a limited cohort of patients was 35%,41 and 22% of patients in the latter study, which included patients who underwent transplantation over a wide time period, died as a result of causes unrelated to leukemia.45 Likewise, Carpenter et al16 reported a 42% TRM and a 27% DSF in a group of 26 patients with ALL who underwent allogeneic BMT after receiving a conditioning regimen that consisted of busulfan, CY, and melphalan. To our knowledge, this is the first prospective study to evaluate the tolerability and efficacy of a new conditioning regimen based on the combination of TBI, TT, and CY in a homogeneous group of children with ALL. The addition of TT, a cell cycle–independent alkylating agent with good CNS diffusion and limited extramedullary toxicity, to the TBI-CY regimen was well tolerated, as proved by the overall TRM of 15%. Moreover, only one patient died as a result of strictly regimen-related causes (idiopathic interstitial pneumonia), although it cannot be excluded that some of the GVHD-related deaths were favored by the cytokine storm induced by the myeloablative therapy. The low TRM we observed provides further evidence of the safety of this combination, which was recently documented by Papadopoulos et al46 in a cohort of adult patients with acute myeloid leukemia who underwent T-cell–depleted BMT, and also favorably compares with other previously published reports on Italian children with ALL who underwent transplantation in first or second CR after receiving a conditioning regimen that included TBI, vincristine, and CY.12,17 Although it was obtained in a small cohort, the 85% DFS probability for children enrolled onto this prospective study who underwent transplantation in first CR is of particular value, because all 13 patients presented multiple, well-known, adverse prognostic factors, such as t(9;22) translocation or day +7 poor corticosteroid response associated with T-cell immunophenotype or hyperleukocytosis. On this basis, in our population, a selection bias could be reasonably excluded. Patients with this subset of childhood ALL frequently present early relapse, and the results of salvage chemotherapy are usually poor.4,47 Our data favorably compare with the 69% DFS described by the MRC UKALL X trial in 1992.48 Moreover, these results are similar to those recently reported by Saarinen et al,49 who observed in a retrospective analysis a 73% DFS in 22 children with very high-risk ALL who underwent BMT with HLA-identical siblings, and to those published in 1989 by a French cooperative group50 that documented an 84% DFS in a group of pediatric patients with high-risk ALL who underwent allogeneic BMT in first CR. The low cumulative TRM and relapse probability we observed (both 8%) after the TBI, TT, and CY conditioning regimen suggests a further evaluation of this therapy in a larger cohort of patients with high-risk ALL in first CR. We also believe that the 56% DFS documented in the 27 patients who underwent transplantation in second CR is noteworthy for two main reasons. First, only three of 27 patients underwent the transplantation procedure after a previous isolated CNS relapse, and the DFS was not modified by their exclusion from the analysis. Second, the escalation of intensity of the last-generation first-line chemotherapy protocols that were administered to the great majority of our patients (23 of 27 second CR patients, as well as 11 of 13 first CR patients, received intensive BFM-like treatment as first-line chemotherapy) may have led to an unfavorable selection of relapsed patients, who were more likely to harbor refractory disease and more prone to develop severe toxicity after an aggressive pretransplantation conditioning regimen. Allogeneic HSCT has been demonstrated to be a successful therapeutic strategy for children affected by ALL in second CR, with an advantage when compared with chemotherapy or autologous HSCT, especially for patients who experienced an early relapse.4,11,13,51 Patients who underwent transplantation after an early relapse (ie, < 30 months from diagnosis) had an outcome similar to that of children with a late relapse (approximately 55%). This observation is in agreement with both the BFM study published by Dopfer et al13 and the large analysis recently published by Barrett et al,11 demonstrating that when an HLA-identical family donor is available, allogeneic HSCT can abrogate or greatly reduce the impact of duration of first remission on the patient's outcome. Myelosuppression is the major dose-limiting toxicity of TT52; for this reason, there has been considerable interest in studying the antineoplastic efficacy of this drug in escalating-dose trials for autologous BMT.22,23,25 On the other hand, studies in the allogeneic setting of HSCT have evaluated mainly the capacity of TT to promote donor-cell engraftment.21,24 Terenzi et al20 demonstrated, in an experimental model of fully mismatched transplantation, an enhanced engraftment of donor stem cells when TT was added to TBI. The authors related this result mainly to a reduction of stem-cell competition by the additional myeloablation effect of the new drug. More recently, Down et al19 confirmed the improved engraftment rate induced by the addition of TT to TBI, but this effect was attributed mainly to the powerful immunosuppressive properties of the drug. Given that TT is not currently part of first- or second-line chemotherapy protocols for childhood ALL, the addition to the TBI-CY schedule of this alkylating agent could minimize the risk of a previously acquired drug resistance of the leukemic blasts. Moreover, owing to its effect on enhancing engraftment of donor stem cells, TT could be of particular value in critical situations characterized by a high risk of graft failure, such as cord-blood transplantation or unrelated or mismatched donor transplantation. In conclusion, in our experience, the combination of TBI, TT, and CY as a conditioning regimen for children with ALL in first or second CR was demonstrated to be safe, well tolerated, and associated with a promising DFS. Because of the rather small number of patients included in this analysis, further prospective, controlled, randomized studies are warranted to compare, in pediatric patients affected by ALL both in first and second CR, the efficacy of this preparative regimen with respect to the classical TBI-CY regimen or other alternative myeloablative therapy.
BMT Unit, Department of Pediatrics, University of Bologna, Policlinico Sant'Orsola, Bologna, Italy: A. Pession, A. Prete, R. Rondelli, G. Paolucci. BMT Unit, Department of Pediatrics, University of Brescia, Spedali Civili, Brescia, Italy: F. Porta, A.G. Ugazio. BMT Unit, Department of Pediatrics, University of Padova, Padova, Italy: C. Messina, S. Cesaro, L. Zanesco. Department of Pediatrics, University of Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy: F. Locatelli, F. Bonetti, M. Zecca, G. Giorgiani, P. De Stefano, F. Severi. BMT Unit, Department of Pediatrics, Ospedale Silvestrini, Perugia, Italy: I. Mazzarino, C. Almici. BMT Unit, Department of Pediatrics, University of Pisa, Pisa, Italy: C. Favre, P.L. Macchia.
Supported in part by grants from Associazione Italiana per la Ricerca sul Cancro (no. 815) and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo (no. 390RFN 97/01) to F.L. We thank Dr Patrizia Comoli, Piero DeStefano, Rita Maccario, and Daniela Montagna for their valuable help and continuous support.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
