Autografting in Children

Successive double high-dose chemotherapy with peripheral blood stem cell rescue collected during a single leukapheresis round in patients with high-risk pediatric solid tumors: a pilot study in a single center

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Summary:

In total, 18 of 26 double high-dose chemotherapies (HDCT) in pediatric solid tumors were rescued with peripheral blood stem cells collected during a single leukapheresis round (single-harvest group, SHG). In the remaining eight HDCT, additional leukapheresis were necessary after the first HDCT (HDCT1) to rescue the second HDCT (HDCT2) (double-harvest group, DHG). Stem cell collection after HDCT1 was inefficient and delayed in patients who had received prior chemotherapy before HDCT1. The interval between HDCT1 and HDCT2 was shorter in SHG than in DHG (median 62.5 days vs 178.5 days, P-value=0.002). Hematologic recovery in HDCT2 was delayed compared to HDCT1. However, there was no difference in hematologic recovery between SHG and DHG. A high rate of treatment-related mortality (TRM) was recorded during HDCT2, but there was no evidence that the shorter interval caused a higher rate of TRM (P-value=0.454). The probability of disease-free survival at 2 years after HDCT2 in the SHG and DHG were 66.7 and 25.0%, respectively (P-value=0.031). Therefore, to administer the second HDCT earlier in double HDCT, and thus to improve the survival of patients with high-risk solid tumors, the single-harvest approach is recommended rather than the double-harvest approach.

Main

Survival of patients with high-risk pediatric solid tumors including high-risk neuroblastoma has improved with the introduction of high-dose chemotherapy (HDCT) and autologous stem cell rescue.1,2,3 However, in many patients, complete remission (CR) is not achieved even after HDCT or tumor relapse. Therefore, new therapeutic approaches such as double HDCT are necessary for treatment of patients with high-risk pediatric solid tumors. Double HDCT is a novel way to further increase dose intensity to treat chemosensitive high-risk tumors, and this strategy has been evaluated in various tumors including malignant lymphoma, breast cancer, and neuroblastoma.4,5,6,7

We believe that the second HDCT in double HDCT should be given as soon as possible after the first HDCT to eradicate possible residual tumor and to reduce relapse after HDCT. However, because stem cell collection after the first HDCT is possible only when the bone marrow has fully recovered after the first HDCT and a lot of time is needed for sufficient recovery, the second HDCT may be delayed if precryopreserved stem cells are not available. In this study, to give the second HDCT earlier in double HDCT, peripheral blood stem cells (PBSCs) collected during a single leukapheresis round before the first HDCT were used to rescue successive double HDCT in pediatric patients with high-risk solid tumors.

Patients and methods

Patient characteristics

In all, 26 patients who did not achieve CR even after the first HDCT or were considered to have a high probability of treatment failure with a single HDCT received double HDCT at Samsung Medical Center in Seoul from April 1998 to July 2001. Of the 26, 18 double HDCT were rescued with PBSCs collected during a single leukapheresis round before the first HDCT (single-harvest group, SHG). In the remaining eight HDCT, an additional or more rounds of leukapheresis were necessary after the first HDCT to rescue the second HDCT (double-harvest group, DHG).

In total, 10 high-risk neuroblastomas (10 older than 1 year, nine multiple metastases, eight N-myc amplifications), three younger age or high-risk medulloblastomas, three inoperable tumors (rhabdoid tumor, malignant fibrous histiocytoma, and primitive neuroectodermal tumor), one relapsed clear cell sarcoma, and one relapsed glioblastoma multiforme were included in the SHG. Five high-risk neuroblastomas (five older than 1 year, five multiple metastases, four N-myc amplifications), one astrocytoma with severe brain stem invasion, and two brain stem gliomas were included in the DHG. All of the 26 patients included in this study were in partial remission (PR) or stable disease (SD) before initiation of the first HDCT (Table 1).

Table 1 Characteristics of patients, and summary of treatment and results

Collection of PBSCs

In 25 out of a total of 36 rounds of leukapheresis, 5–10 μg/kg of G-CSF was infused daily for mobilization of stem cells from the day when the absolute neutrophil count (ANC) fell below 0.5 × 109/l after different chemotherapy regimens. Collection of PBSCs began from the day when the white blood cell count exceeded 1.0 × 109/l after the nadir. In the remaining 11 rounds, stem cells were mobilized from a steady state with 5–10 μg/kg of G-CSF only, without preceding chemotherapy and the collection of PBSCs began from the 4th day of G-CSF administration. The COBE Spectra (Gambro, USA) was used for leukapheresis, and the numbers of total nucleated cells, mononuclear cells, CD34+ cells, and colony-forming cells were counted. We attempted to collect as many PBSCs as possible during the first leukapheresis round to rescue the successive double HDCT.

HDCT

Various HDCT regimens were used (Table 1). When metastatic disease was present before the first HDCT, total-body irradiation (TBI) was included in the first HDCT regimen. The second HDCT was given when the platelet count exceeded 50 × 109/l without transfusion, and the general patient condition was satisfactory with no evidence of organ dysfunction.

G-CSF was used to accelerate neutrophil recovery from day 0 to the day when the ANC exceeded 1.0 × 109/l for 3 consecutive days. Acyclovir, fluconazole, and oral ciprofloxacin were used from day −1 to the first day when the ANC exceeded 1.0 × 109/l, according to the common protocol of Samsung Medical Center. Total parenteral nutrition was given until patients had an adequate food intake. Heparin was used from the beginning of HDCT to prevent veno-occlusive disease.

Post-HDCT treatment

After the first HDCT, local radiotherapy was given to five patients, and surgery was carried out in two patients in whom tumors were inoperable before the first HDCT; reduced-dose conventional chemotherapy was given to four patients. After the second HDCT, local radiotherapy was given to one patient, surgery to one patient, and reduced-dose conventional chemotherapy and 131-metaiodobenzylguanidine (MIBG) therapy to one patient (Table 1). Interleukin-2 (IL-2)8,9 and 13-cis-retinoic acid (CRA)10 were used after the second HDCT in patients with neuroblastoma to eradicate possible minimal residual disease. These two drugs were used simultaneously because their major toxicities do not overlap, and their different mechanisms of action may synergize in the eradication of minimal residual disease. Immunotherapy using IL-2 was initiated when the platelet count exceeded 50 × 109/l without transfusion, after the second HDCT.

Response and toxicity criteria

CR was defined as the disappearance of all known disease on radiologic and radioisotope examination (99Tc bone scan, and 131-MIBG scan in neuroblastoma), without the appearance of a new lesion. Two cases (patient number 2 and 6) with a small (<2 cm diameter) remaining soft tissue lesion to which radiotherapy had been applied previously and where size change had been absent for more than 3 years, with no evidence of viable tumor on 131-MIBG scan and/or 99Tc bone scan were regarded as in CR. PR was defined as a reduction of greater than 50% in the sum of the products of the longest diameters of all measurable lesions, without the appearance of a new lesion. SD was defined as a reduction of less than 50% or an increase of less than 25% in the sum of the products of the longest diameters of all measurable lesions. All other cases were considered as progressive disease.

Toxicities during HDCT were graded according to the National Cancer Institute common toxicity criteria.

Statistics

Continuous variables, and categorical variables in the data were summarized with median values and frequencies (percentage), respectively. Ranges of continuous variables were also presented. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan–Meier method. Completely observed continuous variables between the two different groups were compared by the Mann–Whitney test. Censored continuous variables between the two different groups were compared by Gehan's test. Censored continuous variables between the paired groups were compared by a paired Prentice–Wilcoxon test. Frequencies of toxicity between the two different groups were compared by Fisher's exact test. Statistical significance was declared at P<0.05.

Results

Collection of PBSCs

In the SHG, a single round of leukapheresis (median 3, range 2–10 leukapheresis) was done at a median of 6 months (range 1–11) after diagnosis or relapse. In the DHG, the first round of leukapheresis (median 4, range 2–7 leukapheresis) was done at a median of 6.5 months (range 2–11) after diagnosis, and the second round of leukapheresis (median 5, range 2–13 leukapheresis) was done at a median of 6 months (range 2–9) after the first HDCT. Stem cell collection after the first HDCT was inefficient and delayed in patients who had received previous chemotherapy before the first HDCT. Less CD34+ cells were collected during the second round of leukapheresis than during the first round (P-value=0.012) in the DHG (Table 2).

Table 2 Number of infused hematopoietic cells and hematologic recovery in successive double HDCT

Interval between the first and second HDCT

In the SHG, the first HDCT was given at a median of 7 months (range 2–11) after diagnosis or relapse, and the second HDCT at a median of 62 days (range 46–105) after the first HDCT. In the DHG, the first HDCT was given at a median of 7.5 months (range 3–14) after diagnosis, and the second HDCT at a median of 178.5 days (range 72–329) after the first HDCT. The interval between the first and second HDCT was shorter in the SHG than in the DHG (P-value=0.002).

Hematologic recovery

Hematologic recovery after the second HDCT was delayed compared to the first HDCT in both the SHG and DHG. There was no statistical difference in hematologic recovery after the first and second HDCT between the SHG and DHG (Table 2). However, when analysis was confined to tumors other than brain tumors, in which no chemotherapy or only very short-term chemotherapy had been given before the first HDCT, platelet recovery in the second HDCT was significantly delayed in the DHG (P-value=0.037) compared to platelet recovery in the SHG (Figure 1).

Figure1
figure1

Probability of platelet recovery (>50 × 109/l) in the second HDCT in tumors other than brain tumor. Platelet recovery was more rapid in the single-harvest group than in the double-harvest group (P-value=0.037).

Toxicity

Grade 3–4 toxicities related to the second HDCT are listed in Table 3. The most common toxicity was diarrhea and elevation of liver enzymes. Five renal insufficiencies were recorded in the SHG. However, no patient required dialysis, and azotemia resolved in all patients. A total of five (19.2%) treatment-related mortalities (TRM) occurred during the second HDCT. Four occurred in the SHG and one in the DHG. In the analysis of 26 double HDCT, there was no evidence that a shorter interval between the first and second HDCT resulted in a higher rate of TRM during the second HDCT (P-value=0.454). Causes of TRM were two cases of veno-occlusive disease, one multiorgan failure and one pulmonary hemorrhage before platelet recovery in the SHG and one pneumonia in the DHG.

Table 3 Grade 3–4 toxicities during the second HDCT

Response and survival of patients

In the SHG, four of the 18 patients achieved CR after the first HDCT, but two of these four patients died because of TRM during the second HDCT. Among 14 patients who could not achieve CR even after the first HDCT, eight achieved CR after the second HDCT, and two other patients (patient number 8 and 13) who were still in PR just after the second HDCT became disease-free with post-HDCT treatment. In total, 12 of the 18 patients including six of the 10 patients with high-risk neuroblastoma are still disease free without relapse.

In the DHG, none of the eight patients achieved CR after the first HDCT. Two patients achieved CR after the second HDCT and they are still disease free. Another two patients (patient number 22 and 26) who were still in PR just after the second HDCT became disease free with post-HDCT treatment; however, their tumors relapsed 6 and 7 months after the second HDCT, respectively. The intervals between the first and second HDCT in these two patients were 329 and 279 days, respectively.

In total, 17 of the 26 patients are still alive with a median follow-up of 21 months (range 13–49) after the second HDCT and 14 are still disease free. OS at 2 years after the second HDCT in the SHG and DHG were 72.2 and 50.0%, respectively (P-value=0.393) and DFS at 2 years after the second HDCT in the SHG and DHG were 66.7 and 25.0%, respectively (P-value=0.031) (Figure 2).

Figure2
figure2

Kaplan–Meier probability of disease-free survival (DFS) after double HDCT. DFS at 2 years after the second HDCT in the single- and double-harvest group were 66.7 and 25.0%, respectively (P-value=0.031).

Discussion

HDCT has been used to improve the survival of patients with high-risk pediatric solid tumors, but is still not satisfactory. PR before HDCT and the presence of multiple poor prognostic factors at diagnosis are risk factors for treatment failure after HDCT.11,12 With this background, double HDCT have been undertaken in an attempt to improve survival of patients with high-risk solid tumors.4,5,6,7

We believe that the second HDCT in double HDCT should be given as soon as possible after the first HDCT to eradicate possible residual tumor. However, because stem cell collection after the first HDCT is possible only when the bone marrow has fully recovered after the first HDCT, it tends to be delayed as in our patients in the DHG. Delayed second HDCT may be a cause of relapse. Therefore, in this study, to give the second HDCT earlier, PBSCs collected during a single leukapheresis round before the first HDCT were used to rescue successive double HDCT in 18 of the 26 double HDCT.

The interval between the first and second HDCT in the SHG was shorter than in the DHG. We believe that the shorter interval resulted in a higher survival in the SHG than in the DHG, although tumors in this study were somewhat heterogenous. While tumors relapsed in two of the four patients with neuroblastoma in the DHG, there have been no relapses to date in the SHG. This suggests that the second HDCT should be undertaken as soon as possible after the first HDCT, if needed.

Hematologic recovery, especially platelet recovery after the second HDCT was delayed compared to recovery after the first HDCT. There was no statistical difference in hematologic recovery between the SHG and DHG. However, in tumors other than brain tumors for which no chemotherapy or only very short-term chemotherapy was used before the first HDCT, platelet recovery after the second HDCT was significantly delayed in the DHG compared to recovery in the SHG (P-value=0.037). Further damage in the bone marrow by the first HDCT, especially when this included TBI, is a possible explanation for the inefficient collection of PBSCs after the first HDCT in the DHG and the delayed platelet recovery after the second HDCT. Therefore, we believe that the second round of leukapheresis should be conducted before the first HDCT, if sufficient number of PBSCs could not be collected during the single round of leukapheresis in patients who are destined to receive double HDCT.

A high rate of TRM (19.2%) was recorded in the second HDCT. However, there was no evidence suggesting that a shorter interval between the first and second HDCT caused a higher rate of TRM during the second HDCT. This finding also suggests that the second HDCT should be given as soon as possible, if needed. Philip et al6 also reported a high toxic death rate during the second HDCT. In their report, a high rate of TRM during the second HDCT was a critical issue despite the encouraging survival. We consider that the intense HDCT regimen in this study compared with other studies using double HDCT4,5,6,7 might be a cause of the high rate of TRM in this study and therefore, the dose intensity might need to be adjusted to minimize TRM with second HDCT, especially in patients in whom CR was achieved after the first HDCT.

In this study, we used melphalan, carboplatin, and etoposide-based regimens in most of the first HDCT, and one to two of these drugs were used again in the second HDCT because an effective regimen that does not include any one of these drugs is rare at present, especially in neuroblastoma. If other effective drugs that had not been used for the first HDCT had been used in the second HDCT, the rate of TRM in the second HDCT would have decreased and the rate of response might have increased. More consideration in the selection of a HDCT regimen is necessary for less toxic and more effective double HDCT.

In summary, the second HDCT could be applied earlier by using the single-harvest approach without a further increase in TRM during the second HDCT and thus, a higher rate of survival was possible in patients with high-risk pediatric solid tumors, especially in those where CR could not be achieved even after the first HDCT. We consider these results in the SHG to be encouraging despite limitations in the study because of the disease's heterogeneity, small patient numbers, and short duration of follow-up. Therefore, to give the second HDCT earlier in double HDCT and thus to improve the survival of patients with high-risk solid tumors, the single-harvest approach rather than the double-harvest approach is recommended.

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Correspondence to H H Koo.

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Sung, K., Yoo, K., Chung, E. et al. Successive double high-dose chemotherapy with peripheral blood stem cell rescue collected during a single leukapheresis round in patients with high-risk pediatric solid tumors: a pilot study in a single center. Bone Marrow Transplant 31, 447–452 (2003) doi:10.1038/sj.bmt.1703869

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Keywords

  • double high-dose chemotherapy
  • high-risk pediatric solid tumors
  • autologous hematopoietic stem cell transplantation

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