Acute Lymphoblastic Leukaemia

Clinical and economic comparison of allogeneic peripheral blood progenitor cell and bone marrow transplantation for acute lymphoblastic leukemia in children

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Abstract

There is limited experience in the use of peripheral blood progenitor cells (PBPC) for allogeneic transplantation in children. In the present study we compared engraftment kinetics, incidence of acute and chronic graft-versus-host disease (GVHD) and the outcome and economic costs of allogeneic PBPCT vs BMT in children with ALL in a single institution. All children were transplanted in complete remission (CR) with a similar conditioning regimen and the same GVHD prophylaxis. Patients undergoing PBPCT achieved myeloid and platelet engraftment before patients undergoing BMT (P < 0.001). platelet recovery was faster for the pbpct group (P < 0.014 for 50 × 109/l and P < 0.039 for 100 × 109/l). Incidence and severity of acute and chronic GVHD were similar in both groups (acute grade 1–2: 9/13 for PBPCT vs 9/11 for BMT; chronic GVHD: 5/12 for PBPCT vs 3/8 for BMT). Hospital stay was shorter for the PBPCT than for the BMT group (28.8 days vs42.9 days, respectively) and the PBPCT group used less clinical resources, resulting in overall lower cost for PBPCT (US $14046) compared to BMT (US $19840). There was no statistically significant difference in DFS between PBPCT and BMT (68.4% vs 50%, respectively). Bone Marrow Transplantation (2000) 26, 269–273.

Main

Allogeneic bone marrow transplantation (BMT) from genotypically HLA-identical siblings is the treatment of choice for children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) and very high risk first CR.123

A decade ago, several reports456 showed that mobilized peripheral blood progenitor cells (PBPC) could be used for autologous transplantation in pediatric patients. Since then, autologous PBPC have been increasingly used after myeloablative therapy as a source of hematopoietic stem cells. PBPC collected from healthy donors after mobilization with granulocyte colony-stimulating factor (G-CSF) have been used recently in allogeneic transplantation.7 Several reports on adult patients and a few on children, have shown that G-CSF mobilized allogeneic PBPC transplants are safe and well-tolerated.89101112 Compared to BMT, a major advantage derived from the use of PBPC is faster engraftment.1314 Although a high incidence of chronic graft-versus-host disease (GVHD) has been observed after PBPC transplantation, the higher numbers of CD3+ and natural killer (NK) cells in the graft may enhance the graft-versus-leukemia (GVL) effect.81516 Furthermore, PBPCT has been reported to cost less than BMT.17

We compared the engraftment kinetics, incidence of acute and chronic GVHD, outcome and economic costs of allogeneic PBPCT vs BMT for children with ALL in a single institution.

To our knowledge, this is the first study conducted on PBPCT for ALL in children in a single institution that compares this technology with BMT and is the first to include an economic analysis of PBPCT vs BMT in children.

Patients and methods

Study population

Patients were children under 16 with ALL in CR who underwent hematopoietic cell transplantation at the BMT Unit between June 1990 and June 1999. Table 1 summarizes patient characteristics. Informed consent was obtained in each case, according to institutional guidelines.

Table 1  Patient and donor characteristics

Bone marrow collection

Bone marrow was harvested from the posterior iliac crest of HLA-identical donors using standard techniques on the day of transplantation (day 0).

PBPC mobilization, collection and infusion

PBPC donors were HLA-identical siblings. Thirteen healthy donors were mobilized with G-CSF (Neupogen; Amgen, Thousand Oaks, CA, USA) at a dose of 10 μg/kg/day for 4 consecutive days, as previously reported.18

PBPC collections by large volume-leukapheresis (LVL) were performed on day +5 after G-CSF mobilization by a Cobe Spectra blood cell separator (COBE, Denver, CO, USA) using acid-citrate-dextrose (ACD-A) as anticoagulant. Venous access was obtained by venepuncture of both arms in five donors. A central venous catheter was placed in eight very low weight donors in order to achieve adequate flow. Femoral access was chosen for the central line to minimize the catheter insertion-related risk, with adequate measures to prevent or manage potential complications. Details of LVL have been reported elsewhere.19 The CD34+ cell target dose for collection was at least 4 × 106/kg of recipient body weight.

Apheresis products were infused without further manipulation immediately after collection.

Conditioning regimen

Twenty-one patients (10 BMT and 11 PBPCT) were given intravenous cyclophosphamide 60 mg/kg on 2 consecutive days followed by 12 Gy total body irradiation given in six fractions over 3 days.20 Three patients (two BMT and one PBPCT) received busulphan orally at a dose of 16 mg/kg over 4 days and intravenous cyclophosphamide 60 mg/kg on 2 consecutive days.21 One PBPC patient received busulphan orally at a dose of 16 mg/kg over 4 days and melphalan 180 mg/m2 on day −2.22

Supportive care

All patients had a central venous line and were nursed in barrier nursing units with HEPA-filtered air. Prophylaxis for Pneumocystis carinii (cotrimoxazole 8 mg/kg/day from day −7 to 0 and then from +50 to +150 post-transplantation) and for herpes simplex virus and cytomegalovirus (acyclovir 1500 mg/m2 from day −7 to +24) was employed. Non absorbable antibiotics for gut decontamination were routinely administered. Blood products were infused for hematocrit <25% and/or platelet counts <20 × 109/l. All hemoderived transfusion products were irradiated prior use. Patients commenced intravenous broad spectrum antibiotics if their temperature was higher than 38°C and their absolute neutrophil count (ANC) <0.5 × 109/l. Amphotericin (1 mg/kg/day) was added if fever and neutropenia continued 4–5 days after antibiotics were started. GVHD prophylaxis was with cyclosporine and short course methotrexate (MTX, days +1, +3 and +6). Cyclosporine was started on day −1 at a daily intravenous dose of 1–5 mg/kg, and switched to oral administration when tolerated. Central nervous system prophylaxis was with MTX, 12 mg intrathecally, every 15 days, for 2 months.

After hospital discharge patients were assessed weekly, until +100, with clinical examination, a total blood count and biochemical parameters.

Definitions

Neutrophil recovery was defined as the days to achieve an ANC >0.5 × 109/l for 3 consecutive days. Platelet recovery was defined as the time to achieve >50 × 109/l without requiring transfusion. Hospital stay was defined as days from day 0 to day of hospital discharge. GVHD was diagnosed and graded according to the Seattle criteria.23

Economic analysis

Each patient's cost from mobilization or marrow harvest to day +100 was calculated according to inpatient and outpatient information. We included direct expenditure for hospitalization (including medical and paramedical expenditures), conditioning regimen (including total body irradiation), marrow harvest or apheresis, supportive care, laboratory tests, and radiological procedures. Drugs and single-use material costs were valued at the cost price of the institution. Blood product costs were obtained from the Transfusion Regional Center Laboratory and radiological-derived costs were obtained from the institution. Daily hospitalization cost for the university hospital was obtained from the Spanish Health Department. Cost-effectiveness was calculated by dividing the mean total cost of each procedure by the number of saved-life years (calculated by the Kaplan–Meier method). Costs were calculated in US dollars.

Statistical analysis

Data are presented as mean ± mean standard error. Differences in mean values were compared using the Student's t-test. We estimated time to engraftment and disease-free survival by the Kaplan–Meier model, and compared differences in time to engraftment and survival between PBPCT and BMT groups using the log-rank test. The software program Stata (Stata Corporation, College Station, TX, USA) was used for statistical analysis.

Results

PBPC donors

No significant side-effects were observed during the mobilization, except for mild bone pain in four cases. A total of 14 LVL were performed for the 13 donors. No hemorrhagic complications occurred. Minor self-limiting hypocalcemic episodes that manifested as anxiety and perioral tingling were observed in two donors. The mean CD34+ cells harvested were 7.09/kg ± 0.92 (×106).

BM donors

No side-effects related to the harvest were found. The median nucleated cells infused was 3.2 × 108/kg (range 1.8–7.3 × 108).

Hematopoietic recovery

Only one patient who received BMT did not engraft. He died from hepatic veno-occlusive disease (HVOD) on day +17. Patients undergoing PBPCT achieved myeloid engraftment before the patients undergoing BMT, as shown in Figure 1 (P < 0.001). PBPC significantly influenced platelet recovery. Figure 2 shows platelet engraftment probability for both groups.

Figure 1
figure1

Kaplan–Meier probability of achieving >0.5 × 109/l neutrophils in both groups.

Figure 2
figure2

Kaplan–Meier probability of achieving >50 × 109/l (a) and >100 × 109/l (b) platelets in both groups.

Patients in the PBPC group received antibiotics, platelet support and parenteral nutrition for a significantly shorter period of time. On average, patients receiving a PBPC transplant were discharged sooner than those receiving BMT (Table 2).

Table 2  Clinical values (calculated from day 0 to day 100)

Graft-versus-host disease

No differences were found in the incidence of acute or chronic GVHD between either groups (Table 3).

Table 3  Incidence of graft-versus-host disease

Outcome

As of 31 December 1999, 10 patients transplanted with PBPC are alive in CR (mean follow-up 436 days, and DFS was 68.4% ± 15.8%). There were two transplant-related deaths (Bronchiolitis obliterans and aspergillosis in a patient with chronic GVHD). A third patient died after ALL relapse.

DFS for the BMT group was 50% ± 14.4%, at a mean follow-up of 1172 days. Four patients died of ALL relapse, one patient died of HVOD and another died of interstitial pneumonia.

There was no statistically significant difference in survival between groups (Figure 3). DFS at 100 days was 92.3% ± 7.4% vs 58.3% ± 14.2% for PBPCT and BMT, respectively. The 1 and 2-year DFS rates were 82.1% ± 11.7% vs 58.3% ± 14.2% and 68.4% ± 15.8% vs 50% ± 14.4% (PBPCT vs BMT).

Figure 3
figure3

DFS in both groups.

Economic analysis

The distribution of resources used are shown in Table 4. Mean harvest costs were significantly higher for PBPCT. These differences are related to the G-CSF mobilization and the leukapheresis procedures. Conditioning regimen costs were similar in both groups. All costs related to the post-transplant period were significantly lower for the PBPCT group. Due to faster engraftment and shorter hospital stay, patients in the PBPCT group used less resources than did those in the BMT group. The total cost savings for the PBPCT group were related to lower costs of every supportive care item, namely blood products (a saving of US $877), parenteral nutrition (a saving of US $488) and antibiotics (a saving of US $234). Monitoring costs were also significantly lower for the PBPCT group, with a saving of US $354 when compared to the BMT group. Intensive care unit-related costs were lower for the PBPCT group than for the BMT group, but the difference was not statistically significant. Costs for hospitalization were US $2686 less for the PBPCT group than for the BMT group. The mean overall cost of PBCPT was US $14146 vs US $19840 for the BMT (P = 0.047). Cost-effectiveness was lower in the PBPCT group at the time-points evaluated (100 days, 1 and 2 years after transplantation: 153.25, 172.4, 206.87 vs 340.14, 356.81, 396.81, respectively (Table 4)).

Table 4  Economic analysis

Discussion

The ability of blood derived progenitors to engraft in the allogeneic setting was first demonstrated by Russell et al in 1993.24 Since then allogeneic PBPC transplants have been widely used, to the extent that 22% of allogeneic transplants registered by the EBMT and North America Blood and Marrow Transplant Registry in 1997 used PBPC as the source of stem cells.25 However, experience in the mobilization and collection of PBPC for allogeneic transplantation in children is still limited.10111226

Confirming our initial report,18 in the present study we successfully obtained sufficient progenitor cells from pediatric donors for allogeneic transplantation by LVL without major side-effects. PBPC collection after G-CSF mobilization is a safe procedure that causes less discomfort than bone marrow harvest and avoids general anesthesia. The use of minors as PBPC donors represents an ethical dilemma, which from our point of view is no greater than that posed by bone marrow donation for a relative. The only limiting factor to more widespread use of this approach is the ethical dilemma in administering G-CSF to the healthy pediatric donors.

Hematological recovery after allogeneic PBPCT is significantly faster than after BMT in adults.131427 Although there is less experience in children our results are similar to those reported in adults. The faster reconstitution of children receiving alloPBPCT may be due to the high number of CD34+ cells transplanted in our study (7.09 ± 106 CD34+/kg).

One of the major concerns in the use of PBPC is the higher incidence and severity of GVHD related to the higher number of T-lymphocytes in PBPC collections vs conventional marrow harvest. There is no definitive evidence of a higher incidence and severity of acute GVHD in PBPCT, but there are some reports suggesting a higher incidence of chronic GVHD.7916 Although experience in children is limited, in our study we found no differences in the incidence of grade II acute or chronic GVHD between the PBPCT and BMT groups.

As other authors have reported,28 relapse rate was also lower in our PBPCT (one patient) than in our BMT group (four patients). Although our series is small, difference in relapse rate would be of interest because all patients were transplanted in the same institution in CR with a similar conditioning regimen and the same GVHD prophylaxis.

Our study includes an economic comparison of the costs of PBPCT vs alloBMT in children with ALL from the perspective of the Spanish health care system. To our knowledge, this is the first study that analyzes cost of PBPCT vs BMT in children. We found that PBPCT was significantly less expensive than alloBMT, in the early post-transplant period. Similar results were reported by Bennett et al,17 although there are reports with a different conclusion.29

Analysis of different resource areas showed differences between the two technologies. Mobilization and apheresis costs were significantly more expensive than was the marrow harvest. On the other hand, supportive care (including cyclosporine, blood products, parenteral nutrition, inotropics, morphics and antibiotics) and monitoring costs were significantly more expensive in the BMT group. The shorter hospital stay for the PBPCT group resulted in an overall economic saving, as reported by Bennett et al.17

Although our overall cost for PBPCT is lower than other reports on the subject, it is very difficult to establish comparisons because of the differences in institutions, protocols, diseases, and salaries for medical and paramedical personnel. The lower cost can be due to the following: (1) the mean weight of our patients was 33 kg; (2) we performed a single apheresis to achieve the CD34+ cell target dose of at least 4 × 106/kg recipient weight in 12 of 13 cases; (3) we did not use hematopoietic growth factors after transplant; and (4) we did not evaluate indirect costs.

Cost-effectiveness is considered to be one of the most useful economic indices.30 In our study the cost per year of life saved was lower in the PBPCT group, since our overall cost is lower and DFS was better in these patients.

We conclude that PBPCT is a safe and effective procedure in children with ALL, and achieves faster hematological recovery than does BMT. The incidence and severity of acute and chronic GVHD did not differ between groups. Finally, the overall cost is lower for PBPCT and the cost-effectiveness for this technology is better than for BMT.

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Madero, L., Vicent, M., Ramirez, M. et al. Clinical and economic comparison of allogeneic peripheral blood progenitor cell and bone marrow transplantation for acute lymphoblastic leukemia in children. Bone Marrow Transplant 26, 269–273 (2000) doi:10.1038/sj.bmt.1702516

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Keywords

  • allogeneic PBPCT
  • cost analysis
  • children

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