Original Article

Bone Marrow Transplantation (2009) 43, 307–314; doi:10.1038/bmt.2008.327; published online 17 November 2008

Pediatric Transplants

Early outcomes after allogeneic hematopoietic SCT in pediatric patients with hematologic malignancies following single fraction TBI

T E Druley1, R Hayashi1, D B Mansur2, Q (Jean) Zhang3, Y Barnes1, K Trinkaus3, S Witty1, T Thomas1, E E Klein2, J F DiPersio4, D Adkins4 and S Shenoy1

  1. 1Division of Pediatric Hematology and Oncology, Department of Pediatrics, Bone Marrow Transplantation and Leukemia Section, Washington University School of Medicine, Saint Louis, MO, USA
  2. 2Department of Radiation Oncology, Bone Marrow Transplantation and Leukemia Section, Washington University School of Medicine, Saint Louis, MO, USA
  3. 3Department of Biostatistics, Bone Marrow Transplantation and Leukemia Section, Washington University School of Medicine, Saint Louis, MO, USA
  4. 4Division of Medical Oncology, Department of Internal Medicine, Bone Marrow Transplantation and Leukemia Section, Washington University School of Medicine, Saint Louis, MO, USA

Correspondence: Dr S Shenoy, Division of Pediatric Hematology and Oncology, Washington University School of Medicine, Box 8116 SLCH, One Children's Place, Saint Louis, MO 63110, USA. E-mail: shenoy@wustl.edu

Received 26 October 2007; Revised 17 August 2008; Accepted 21 August 2008; Published online 17 November 2008.

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Abstract

Fractionated TBI (FTBI) followed by allogeneic hematopoietic SCT results in donor engraftment and improves survival in children with high-risk hematologic malignancies. However, acute toxicities (skin, lung and mucosa) are common after FTBI. Late complications include cataracts, endocrine dysfunction, sterility and impaired neurodevelopment. Instead of FTBI, we used low-dose single fraction TBI (550cGy) with CY as transplant conditioning for pediatric hematologic malignancies. GVHD prophylaxis included CYA and short-course MTX; methylprednisolone was added for unrelated donor transplants. A total of 55 children in first (40%) or second remission and beyond (60%) underwent transplantation from BM (65%) or peripheral blood; 62% from unrelated donors; 22% were mismatched. Median follow-up was 18.5 months (1–68). Overall survival and disease-free survival at 1 year were 60 and 47%, respectively. Acute toxicities included grade 3–4 mucositis (18%), invasive infections (11%), multiorgan failure/shock (11%), hemolytic anemia (7%), veno-occlusive disease (4%) and renal failure (4%). TRM was 11% at 100 days. Non-relapse mortality was 6% thereafter. Graft rejection occurred in 2%. Three patients (5%) died of GVHD. The regimen was well tolerated even in heavily pretreated children and supported donor cell engraftment; long-term follow up is in progress.

Keywords:

hematopoietic cell transplant, children, hematologic malignancies, single-dose TBI, outcomes

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Introduction

Myeloablative conditioning using fractionated TBI (FTBI) with alkylating agents such as CY or melphalan is successful in achieving engraftment of donor hematopoietic stem cells in allogeneic BM transplant recipients and is a preferred transplant option especially in hematologic malignancies.1 Fractionation over several days enables the delivery of a high dose of radiation and eliminates both host hematopoiesis and malignant cells. However, acute toxicities, such as mucositis, interstitial pneumonitis, veno-occlusive disease (VOD), nausea, vomiting and diarrhea, are associated with FTBI resulting in significant morbidity and mortality especially in heavily pretreated patients.2 Delayed toxicities of impaired growth, cognitive development, hormone insufficiency, cataracts, pulmonary fibrosis, sterility are additional concerns especially in young children.3, 4, 5

The recognition of radiation-induced toxicities has resulted in the development of alternative preparative regimens using either high-dose chemotherapy combinations or immunosuppressive non-myeloablative agents.2, 6, 7, 8 Unfortunately, alternative regimens that have avoided radiation are associated with higher rates of relapse and treatment failure when compared with FTBI-based regimen, especially in lymphoid malignancies.8, 9 High-dose chemotherapy-containing regimens also result in organ dysfunction specific to the agents involved and contribute to TRM and mortality.8, 9, 10

A lower total radiation dose can be effectively administered in a single fraction at a high dose rate to achieve myeloablation (SDTBI). Delivering radiation at a high dose rate in a single large fraction is presumed to have equivalent myelosuppressive effects as FTBI at lower dose rates. This approach resulted in lower incidence of organ toxicity and TRM when tested in animal models.11, 12 Successful transplant outcomes using a single fraction at a dose of 550cGy were reported in adult transplant recipients with hematologic malignancies, myelodysplastic syndrome and non-Hodgkin's lymphoma.13, 14, 15, 16 In adults, TRM, engraftment and survival were similar or even superior to outcomes following FTBI.

A similar conditioning strategy was adopted in 1998 for pediatric hematologic malignancies—acute leukemia and non-Hodgkin's lymphoma. We report transplant outcomes in 55 consecutive children less than 21 years of age who received matched related donor (MRD) or unrelated donor (URD) hematopoietic cell transplants (HCT) following SDTBI and CY between March 1998 and December 2005.

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Patients and methods

A total of 55 consecutive children transplanted between March 1998 and January 2006 are reported. All provided signed consent for the transplant regimen. Patient characteristics are summarized in Table 1. Two patients were undergoing a second HCT; one after a previous autologous transplant (BCNU, etoposide, cytosine arabinoside and melphalan conditioning) for relapsed Burkitt's lymphoma 6 weeks prior to allogeneic HCT; the second with AML who relapsed after MRD HCT (BU and CY conditioning; BM as stem cell source) and underwent the second transplant 22 months later with MRD PBSC. Outcome measurements include overall survival (OS), disease-free survival (DFS), TRM, the incidence of acute and chronic GVHD, engraftment and toxicities.


Class I HLA antigens (A, B and C) were typed by serology until May 2000, by low-resolution molecular typing between June 2000 and October 2001, and subsequently by high-resolution typing. HLA-DRB1 alleles were typed by high resolution in all patients. Of 36 URD donor/recipient pairs, 24 were matched at all 8/8 loci. Of 12 mismatched pairs (33%), 6 were mismatched at a single class I locus, 4 were mismatched at two class I loci, 1 was mismatched at three class I loci and 1 was mismatched at a single class I and class II locus.

Conditioning regimen

Conditioning included CY at a dose of 60mg/kg intravenously on days −3 and −2 and SDTBI (550cGy) on day −1. SDTBI was delivered in parallel-opposed lateral field with a 6-MV linear accelerator (Clinac 600 CD; Varian Medical Systems, Palo Alto, CA, USA). General anesthesia was used if necessary. Patients were treated in the seated-supine (‘fetal’) position with a 300-cm source-to-midline distance. The point-of-dose prescription was a single point, midline in the body, at the level of the umbilicus. A large Lucite plate was placed in the beam near the patient to increase the superficial dose, and a missing tissue compensator was used to keep the midline dose to the head and neck within 110% of the prescription dose. The lateral position of the arms provided partial lung shielding. No additional lung shielding was used. Both ion chamber and diodes placed on different parts of the body were used to ensure that the measured and calculated doses were within acceptable limits. The median actual dose rate was 31.6cGy/min (range 27–38.1). Twelve patients were treated with a fractionated external beam ‘boost’ in the few days prior to TBI. Of these, three patients were treated with cranial irradiation (800–900cGy), and seven with craniospinal irradiation (cranial 800–1260cGy and spinal 540–1260cGy) for central nervous system leukemia. Two patients with testicular disease were treated with 1000–1260cGy boost to this region.

Cell dose

Graft details are outlined in Table 1. The median total nucleated cells infused was 4.3 × 108 per kg recipient weight (range 1.4–41.2). The median number of CD34+ cells infused was 3.8 × 106 per kg recipient weight (range 1.3–44.7). PBSC when used were collected after either G-CSF (n=15) or a combination of G-CSF and GM-CSF (n=4) according to a separate study. All BM and PBSC products were infused fresh and without manipulation.

GVHD prophylaxis

GVHD prophylaxis included CYA and short-course MTX (three doses). Methylprednisolone was added for URD HCT recipients. CYA levels were maintained between 250 and 350ng/ml until taper between days +100 and +180 in the absence of GVHD. MTX was administered intravenously at 10mg/m2 on day +1 and 7.5mg/m2 on days +3 and +6. Methylprednisolone or an oral equivalent was administered at 1mg/kg/day between days +7 and +28 and weaned between days +28 and +54 in the absence of GVHD.

Supportive care

G-CSF at a dose of 5μg/kg/day was administered between day +7 and recovery of ANC (greater than or equal to1500/μl × 2). CMV seronegative blood products were administered in CMV seronegative recipients. Seropositivity for varicella–zoster virus and/or herpes simplex virus was treated with acyclovir at a dose of 750mg/m2/day for 6 months. Ampicillin prophylaxis was administered intravenously until neutrophil engraftment unless broad-spectrum antibiotics were indicated. Fluconazole prophylaxis was administered until day +75. All patients received prophylaxis against Pneumocystis jiroveci, with trimethoprim–sulfamethoxazole for 1 year or until the withdrawal of immunosuppression. Blood was tested for CMV reactivation (PCR or shell vial culture) weekly after neutrophil engraftment until day +100.

Outcome measurements

Neutrophil and plt engraftment were the first of three consecutive days in which the ANC was >500/μl and plt count greater than 20000/μl occurring at least seven days after the most recent plt transfusion respectively. Donor cell engraftment was determined by short tandem repeat polymorphisms. Full donor chimerism was greater than or equal to90% of marrow cells. Between 10 and 90% donor cells were termed mixed chimerism. In the absence of disease relapse, graft rejection was defined as the failure to achieve an ANC >500/μl or <10% donor cells greater than or equal to45 days post transplant. Acute and chronic GVHD were graded according to previously published criteria.17, 18 Mucositis grading was performed according to previously published criteria.19 Total parenteral nutrition was administered only to patients with grade IV mucositis and not used prophylactically. Organ toxicities were recorded based on physical examination and laboratory criteria. Relapse was defined as >25% blasts in peripheral blood or BM. DFS was defined as the number of days between HCT and relapse. TRM was death in the absence of relapse <100 days after HCT. Non-relapse mortality was >100 days after HCT. Basic immune reconstitution was determined by peripheral blood lymphocyte subpopulation analysis by flow cytometry and PHA-induced lymphocyte blastogenesis at days +100 (N=20), +180 (N=9) and +365 (N=9). Lymphocyte subpopulations are reported as absolute numbers and PHA-induced stimulation index as a percentage of normal control.

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Results

Outcomes are reported following mean and median follow-up times post transplant of 23.2 and 18.5 months, respectively (range 4–68). Twenty-three (42%) patients were followed for greater than or equal to24 months.

Engraftment and chimerism

The median in-patient stay for all patients was 19 days (range 17–66). The cumulative incidence of neutrophil and plt engraftment, and donor chimerism at days +100 and +365 are listed in Table 2. At day +100, 85% of evaluated patients had full donor chimerism, 9% had mixed chimerism. Of the five patients with mixed chimerism, four (two with ALL, two with AML; two MRD, two matched URD) relapsed between days +118 and +218 and died. The fifth patient with Ph-positive ALL remains in remission and has 100% donor chimerism 1 year after one donor lymphocyte infusion. Of four additional patients who failed to engraft neutrophils, one patient had graft rejection (2%); three others died within 30 days prior to engraftment. The single patient with graft rejection was transplanted for ALL in third remission with a mismatched URD BM product. This patient subsequently relapsed 100 days post transplant and died of disease. On day +365, all patients tested (N=24) had full donor chimerism.


Transplant-related toxicities

Of 31 deaths, 18 (58%) died of relapsed disease and 13 died of non-relapse causes. Three patients died prior to neutrophil engraftment; the first with AML in CR2 died on day +19 with refractory VOD. The second also with AML in CR2 expired on day +13 following initial renal and subsequently multiorgan failure. Although aspergillosis and herpes simplex virus infection were pre-transplant complications, no infectious etiology was identified post transplant. The third patient with acute undifferentiated hypodiploid leukemia in CR1 died on day +30 of candida infection.

Four patients died between days +67 and +730 of GVHD and related complications. All four patients developed gut involvement; three of four also developed fungal infection that contributed to death.

One patient who was lost to follow-up died of an undetermined cause. Four patients died of late infections after day +100 (days 100–1227). Organisms included Mucor mycosis, Pneumocystis jiroveci, Paecilomyces variotii+Candida glabrata and BK virus+CMV+Streptococcus pneumoniae bacteremia/meningitis. One child transplanted for Burkitt's lymphoma subsequently developed Hodgkin's lymphoma 3 years later and died of infection 3 weeks after reinduction chemotherapy.

Despite being a heavily pretreated group of transplant recipients, only nine (16%) developed grade III mucositis and one (2%) developed grade IV mucositis. Non-fatal infectious complications included Gram-negative bacteremia (4%), mycobacterial bacteremia (2%), candidemia (5%) and CMV reactivation (9%) between 14 and 100 days post transplant. Non-fatal organ toxicities included VOD in two (4%), infection-induced organ dysfunction in six (11%) and hemolytic anemia in four (7%). No patient developed primary radiation-induced acute pneumonitis.

GVHD

The cumulative incidence of acute and chronic GVHD is shown in Table 2. Of the 27% of patients with grade II–IV acute GVHD, the majority (87%) had received an URD transplant. The most common grade/site was greater than or equal tograde III acute GVHD of the gastrointestinal tract (n=9). One patient had grade IV GVHD, which involved the liver.

Of 40% of patients who developed chronic GVHD, 77% had received URD HCT. The skin and gastrointestinal tract were affected most frequently. One patient with biopsy-proven severe, extensive chronic GVHD of the skin and gastrointestinal tract went on to develop bronchiolitis obliterans with organizing pneumonia diagnosed by open lung biopsy 139 days after transplant. Chronic GVHD is attributable to both the use of PBSC as a stem cell source and the acceptance of HLA mismatched donors in this series.

Immune reconstitution

Table 3 demonstrates that lymphocyte subpopulations and function returned to normal values by day 365 post transplant.


OS, DFS and TRM

OS for the entire cohort was 44% (24 of 55) with a median survival time of 757 days.

For recipients in CR1 or CR2 at the time of transplant, OS at 1 year was 63% (95% CI: 48–75) for lymphoid malignancies (pre-B ALL, pre-T ALL, peripheral T-cell lymphoma, Burkitt's lymphoma, T-cell lymphoblastic lymphoma, biphenotypic leukemia). Cumulative DFS was 51% (36–64) and TRM was 14% (6–27). OS for patients receiving URD and MRD stem cells was 90% (66–97) and 53% (23–75), respectively (Figure 1a). DFS at 1 year for URD and MRD transplants was 70% (45–85) and 46% (19–70), respectively (Figure 1b). TRM for URD and MRD transplants was 15% (4–43) and 5% (1–24), respectively (Figure 1c). There was no statistical difference in survival between URD and MRD HCT recipients (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Kaplan–Meier plots for overall survival (a) and disease-free survival (b). Matched related donors (MRD, solid line) or unrelated donors (URD, dashed line) are indicated. TRM (c) in patients with lymphoid malignancies who were in CR1 or CR2 at the time of HCT. Numbers indicate the cumulative percentage of patients. The P-value was calculated using Fisher's exact test. The 95% confidence interval is included in parentheses.

Full figure and legend (99K)

Sixteen patients with AML were in CR1 or CR2. For patients with AML, OS was 38% (15–60%), DFS was 31% (11–54%) and TRM was 25% (7–52%) in this heavily pretreated population.

Five patients were in CR3 (lymphoid malignancies) and one patient (AML) in PR (Table 1) at the time of HCT. Despite intense therapy prior to transplant, all tolerated the conditioning regimen well. Four of the five patients in CR3 engrafted neutrophils and plts, and three patients remained engrafted 365 days post transplant. All four, however, eventually died of relapse between 122 and 801 days post transplant. One patient died of multiorgan failure of unclear etiology 1 year after HCT and had no detectable malignancy or GVHD at the time of death. The patient with AML in PR relapsed at day 30 and expired on day 39 without donor engraftment.

Median survival time was not statistically different between URD and MRD subgroups (641 vs 811 days) (P=0.52). Of the 24 survivors, 8 (33%) received PBSC and 16 (67%) received BM transplants. This difference is similar to the overall percentage difference in the utilization of each type of product within the cohort, and we were unable to detect a survival advantage based on stem cell source. The overall relapse rate for patients in CR1 and CR2 was 33% with a median time to relapse of 109 days (range 62–350). When divided between lymphoid and AML subgroups, 33% of patients with lymphoid malignancies relapsed at a median of 96 days (range 62–350) and 31% of patients with myeloid malignancies relapsed at a median of 129 days (range 68–179).

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Discussion

This report is a retrospective analysis of outcomes of allogeneic HCT in children with acute hematologic malignancies using a novel myeloablative conditioning strategy of a low total single fraction (550cGy) TBI combined with CY. This method of radiation was adopted in an effort to increase tolerability of the regimen. The duration of conditioning was shortened significantly to only 3 days with this strategy. Our group had reported earlier that this strategy was well tolerated, and had good outcomes in adult patients with malignant disorders.13, 14, 15, 16

The conditioning regimen supported engraftment of PBSC and BM cells, and full donor chimerism was present at day +100 in 85% of evaluated recipients (30% MRD and 55% URD). This is comparable with adult recipients who received similar conditioning using either MRD for CML or best-available donor for hematologic malignancies where complete donor chimerism was present on day +100 in 92 and 76%, respectively. Time to neutrophil and plt engraftment (13 and 18 days, respectively) was also similar to that reported in adult patients undergoing similar conditioning (11 and 14 days, respectively).13, 16

URD HCT (62%) was performed more frequently than MRD HCT, 22% received HLA mismatched transplants. The majority were patients in CR2 (51%) or CR3 (9%). Despite extensive prior chemotherapy±cranial/craniospinal irradiation (10 patients), this regimen was tolerated well. A distinct advantage to administering radiation in a single fraction was a reduction in the number of days of conditioning and sedation often required for FTBI in children. The incidence of severe mucositis was low (16%) as were early invasive infections (11%). No acute pulmonary toxicity was encountered after radiation in contrast to reports of pulmonary toxicity with standard TBI-based regimens.19, 20, 21 The incidence of liver toxicity (VOD) was low (4%). No patient developed hemorrhagic cystitis. However, late complications of myeloablative preparative regimen targeting growth, fertility, endocrine function, cataracts, neurodevelopment and the risk of second malignancies are of special concern in pediatric recipients and are reported with both TBI- and BU-based regimens.2, 3, 4, 5, 9 Although no late complications are apparent to date, the follow-up period is too short, and long-term effects after SDTBI will need to be determined. Of particular interest are growth, endocrine function, neurocognitive development and fertility. The toxicity profile and the ease of administration of the conditioning regimen make this approach an attractive option in children.

Survival was better for children with lymphoid malignancies than those with myeloid cancers. Previously reported outcomes after allogeneic transplantation for pediatric hematologic malignancies are listed in Table 4 for comparison. Children undergoing HCT from URDs for hematologic malignancies have an OS of 47–51% and a DFS of 43–51%.26 Retrospective studies comparing the efficacy of BU and CY (Bu/CY) and FTBI/CY conditioning in pediatric patients with ALL suggest that TBI-based regimens had better outcomes than chemotherapy alone.22, 23, 24, 25 Bu/CY-containing regimens were also associated with a higher incidence of death because of systemic infection, interstitial pneumonitis and VOD.8 Standard myeloablative HCT for ALL has an OS of 39–68%, DFS of 31–58% and TRM of 9–31%.8, 9, 10, 22, 27 Our survival rates were comparable with SDTBI. TRM for lymphoid malignancies was 15% in URD HCT and 5% in MRD HCT. Patients with lymphoid malignancies undergoing URD HCT in CR1 or CR2 had a 1 year OS of 90%, whereas similar patients undergoing MRD HCT had a 1 year OS of 53%. Similarly, DFS was 68 and 46% in URD and MRD HCT, respectively. Owing to wide confidence intervals, this was not of statistical significance and can just be described as a trend. However, similar results are described by Gassas et al.28 with an attribution to a GVL effect. In children with AML, outcomes are similar following Bu/CY- and TBI/CY-based conditioning when the total dose of CY combined with BU was 200mg/kg.29 Previous reports describe a DFS of 51% in CR2 and 38% TRM for AML and URD transplants.22, 24, 30 The DFS for AML patients in our group, the majority of which were URD transplants, was 31% and TRM was 33%. The morbidity of transplant is exacerbated by the intensity of previous therapies, and pediatric protocols for AML therapy are dose-intensive. Transplant timing and approach for AML need further optimization, and the SDTBI approach seems comparable with other transplant methods with room for improvement.31 For all patients, the OS following SDTBI-based conditioning was 44% with a median survival time of 757 days.


Previously described GVHD rates are 30% for grade 2–4 acute and 40% for chronic in children.32 Grade 2–4 acute GVHD developed in 26% of our patients and resulted in three deaths (5%) despite URD HCT and mismatched transplants (Table 1). These findings compare favorably with a GVHD-related mortality of 10% for FTBI/CY and 11% for Bu/CY in children receiving MRD HCT8 and a 26% incidence of acute GVHD after MRD HCT in children.9 Grade 3–4 acute GVHD was 18% in our patient cohort. Extensive chronic GVHD was developed in 27% of patients. GVHD rates are similar for acute GVHD and lower for chronic GVHD when compared with adult patients transplanted using this regimen.13, 16 This may be attributed to patient age and stem cell source differences.

In conclusion, SDTBI was easy to administer, well tolerated and resulted in successful donor cell engraftment in patients receiving MRD or URD HCT. Early transplant outcomes were comparable to pediatric patients receiving classic myeloablative conditioning and were better for lymphoid malignancies than for the myeloid group. The incidence of GVHD was comparable despite HLA mismatching. The advantages of delivering SDTBI included shortened conditioning time (3 days), easy delivery, early neutrophil recovery and consequently a shorter period of hospitalization that could translate into lowered in-patient hospitalization costs. The single fraction of radiation was technically easier to deliver and simplified anesthesia requirements in the young. The incidence of early toxicities, such as mucositis and interstitial pneumonitis, was low despite a heavily pretreated population and the preponderance of URD HCT. These observations make SDTBI an attractive option for pediatric transplant recipients, especially in lymphoid malignancies where radiation therapy-based conditioning is likely to provide benefit. Longer follow up, as well as a prospective comparison between fractionated and SDTBI, is necessary to better define late outcomes. Follow-up studies are in progress to determine late outcomes and side effects of this regimen.

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Conflict of interest

The authors declare no competing financial interests.

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Acknowledgements

This work was supported in part by the National Institutes of Health under the Ruth L Kirschstein National Research Service Award T32 HD 007499 from the NICHD (TED).