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Second Allogeneic Hematopoietic Stem Cell Transplantation for Relapse after Initial Allogeneic Transplant in Childhood Leukemia - A Single Center Experience

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Second Allogeneic Hematopoietic Stem Cell

Transplantation for Relapse after Initial Allogeneic

Transplant in Childhood Leukemia

- A Single Center Experience

Akira Kikuchi, Ryoji Hanada Division of Hematology / Oncology, Saitama Children’s Medical Center

Keywords: childhood leukemia, second transplant, disease

status at transplant

AbstrAct

To evaluate the efficacy of second allogeneic hematopoietic stem cell transplantation (HSCT) for relapse after initial allogeneic transplant in childhood leukemia, we reviewed twenty-one patients who received second allogeneic HSCT for recurrent acute lymphoblastic leukemia (n=14), acute myelogenous leukemia (n=6) or chronic myelogenous leukemia (n=1). Of twenty-one patients, seven patients survived after the second HSCT with a median time of 16 months (range 2-95). Among several clinical characteristics, complete remission or chronic phase at the second HSCT showed a significant impact on better survival (46.9 +/- 18.7 % versus 0%, p=0.0012). Although the outcome might be dismal especially in the patients who received second HSCT while in non-remission status, if remission of relapse is obtained after initial HSCT, a second HSCT should be considered as a curative treatment strategy for these patients.

IntroductIon

Allogeneic hematopoietic stem cell transplantation (Hsct) is an established curative treatment for children with hematological malignancies refractory to or relapsing after conventional chemotherapy although more than 80% of childhood leukemia patients can be cured only by modern chemotherapy.1 However,

patients experiencing relapse after Hsct have a very poor prognosis and an optimal salvage therapy has yet to be established. current treatment options include chemotherapy, donor leukocyte infusion (dLI)2 and

second Hsct.3-11 Intensive chemotherapeutic regimens

can induce remission in some patients with recurrent leukemia, but remission durations are short, and most patients die of uncontrolled leukemia or infectious complications. Although dLI results in durable clinical and molecular remission in chronic myelogenous leukemia (cML), results of dLI for acute leukemia are less encouraging.2 second allogeneic transplantation

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of second transplants for recurrent leukemia are limited in adult patients and there are no reports on second Hsct in childhood leukemia. In this article, we analyzed results of second Hsct for leukemia relapse after initial transplants at our center.

PAtIents And MetHods

between May 1992 and June 2008 at saitama children’s Medical center, twenty-one patients received second allogeneic Hsct for recurrent acute lymphoblastic leukemia (ALL; n=14), acute myelogenous leukemia (AML; n=6) or cML (n=1). clinical characteristics of these patients prior to the first and the second Hsct are described in table 1. Median patient age at Hsct was 5 years (range 0-16). Median time from first Hsct

to relapse was 5 months (range 3-60), median time from relapse to second Hsct was 6 months (range 1-22 ) and median interval between first and second Hsct was 13 months (range 3-62 ).0several clinical characteristics were compared between surviving and non-surviving patients. survival curves were calculated by the Kaplan-Meier method12 and differences of survival curves were

evaluated by log rank test.

resuLts

stem cell source

treatment and clinical outcomes of the second Hsct are shown in table 1. stem cell sources for the second

Table 1. Patient characteristics and outcomes

UPN Age/Sex Diagnosis Donor for HSCT1 to HSCT1 to Disease acute Survival Cause of

HSCT status GVHD death

HSCT1 HSCT2 Relapse HSCT2 at HSCT2 HSCT1 HSCT2 after HSCT2

1 3/M ALL Msd-bM Msd-bM 3 6 rL 2 0 18 dod 2 1/M ALL r- bM r- Pb 5 13 rL 1 3 7 dod 3 3/M ALL u- bM u- cb 5 9 rL 1 0 16 dod 4 6/F ALL u- bM u- bM 14 21 rL 2 ne 1 dod 5 16/M ALL Msd-Pb Msd-Pb 8 11 cr 2 2 23 dod 6 0/M ALL u- cb u- cb 17 23 cr 3 2 60+ nA 7 11/F ALL r- bM r- Pb 3 4 rL 0 0 1 dod 8 1/M ALL u- cb u- bM 3 14 cr 1 0 9 bo 9 4/M ALL u- bM u- bM 7 13 cr 2 2 11 dod 10 11/F ALL r- Pb r- Pb 3 7 rL 0 1 3 MoF 11 0/F ALL u- cb u- bM 9 46 cr 0 2 2+ nA 12 0/M ALL u- cb u- bM 7 12 cr 1 1 16+ nA 13 2/F ALL u- bM u- bM 5 13 cr 1 1 8+ nA 14 8/M ALL u- bM u- bM 5 16 cr 3 0 3+ nA 15 10/F AML Msd-bM Msd-Pb 3 25 cr 0 0 20 dod 16 6/M AML r- bM r-Pb 27 33 rL 2 2 27 dod 17 6/M AML u- bM r-Pb 13 16 rL 1 2 7 MoF 18 8/F AML r- bM Msd-bM 29 33 cr 0 1 24+ nA 19 14/F AML u- bM r- Pb 3 5 rL 2 4 4 GVHd 20 3/M AML u- cb u- bM 3 11 rL 0 0 8 dod 21 5/F cML Msd-bM Msd-Pb 60 62 cP 0 2 95+ nA

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Hsct were bM in 10 (Msd=2, unrelated=8), Pb in 9 (Msd=3, related other than Msd=6) and cb in 2 (unrelated=2).

conditioning regimen

For the first Hsct, sixteen patients underwent total body irradiation (tbI). the remaining five patients received busulfan(bu). Five patients, who received bu for the first Hsct, received tbI for the second Hsct. reduced intensity conditioning (nontbI, nonbu) was used for four patients for the second Hsct.

engraftment

one patient died before engraftment was evaluable. For the remaining twenty patients, engraftment was prompt and durable. there was no late graft failure.

Graft versus host disease

Among twenty evaluable patients, thirteen patients

developed acute GVHd, with nine having grade 2-4 disease. Fourteen patients developed acute GVHd after their first Hsct. nine of these fourteen patients also had acute GVHd after their second Hsct. conversely, among seven patients with no acute GVHd after the first Hsct, four developed acute GVHd after the second Hsct.

survival

of twenty-one patients, seven patients survived after the second Hsct with a median follow-up of 16 months (range 2-95). the cause of death was relapse in 10, MoF in 2, bo in 1 and GVHd in 1. overall survival rate after the second Hsct was calculated as 21.6 +/- 10.2 %. We compared several characteristics between survivors and non-survivors. Among clinical characteristics such as remission duration after the first Hsct, stem cell source for the second Hsct, disease status at the second Hsct, conditioning regimen for the second Hsct or GVHd after the second Hsct, complete remission or chronic phase at the second Hsct showed a significant impact on better survival as shown in Fig.1 (remission or chronic phase versus non-remission: 46.9 +/- 18.7

Fig. 1. survival curves after the second Hsct according to the disease status. Patients in complete remission or chronic phase at

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% versus 0 %, p=0.0012). remission duration of more than 12 months after the first Hsct showed marginal significance (more than 12 months versus 12 month or less: 51.4 +/- 20.4 % versus 17.5 +/- 11.2 %, p=0.119). stem cell source for the second Hsct, conditioning regimen for the second Hsct or GVHd after the second Hsct did not show any significant impact on better survival (data not shown).

dIscussIon

the use of dose-intensive chemotherapy regimens followed by allogeneic Hsct is an established curative treatment for patients with hematological malignancies refractory to or relapsing after conventional chemotherapy. However, patients experiencing relapse after Hsct have a very poor prognosis. currently, the best curative option for these patients is second allogeneic Hsct. to date, most studies of second transplants for recurrent leukemia have been limited in adult patients and there are no reports on second Hsct in childhood leukemia. In this article, we report the outcome of twenty-one patients who received second Hsct for leukemia relapse after initial transplants at our center.

the overall survival rate of these patients was 21.6 +/- 10.2 %. this figure is obviously low compared with the survival rate after the first line Hsct for childhood leukemia. the cause of death in fourteen died patients was relapse in 10, MoF in 2, bo in 1 and GVHd in 1. considering the high rate of relapse as the cause of death among these patients, the most important factor for successful second Hsct is good control of primary disease. compared with Hsct in adults, transplantation mortality rate is relatively low in childhood Hsct, therefore uncontrollable primary disease is the most serious problem. In fact, among the remaining four patients who died, three patients had received allogeneic peripheral blood stem cell transplantation from HLA-partially mismatched parents at non-remission status. Although they died of transplantation related toxicity, such poor Hsct conditions might have influenced these outcomes.

several prognostic factors have been reported to predict the outcome of second Hsct. Among several clinical characteristics such as remission duration after the first Hsct,6, 10, 11 stem cell source for the

second Hsct,10 disease status at the second Hsct,10

conditioning regimen for the second Hsct10 or GVHd

after the second Hsct,3 only complete remission or

chronic phase at the second Hsct showed a significant impact on better survival (Fig.1). Again, the importance of primary disease control was reconfirmed. Indeed, all of the ten patients who received second Hsct while in a non-remission status died; in particular, seven of these ten died within 8 months after Hsct. For patients whose disease does not respond to remission induction therapy for relapse after initial Hsct, a quite novel treatment strategy is needed. otherwise, palliative therapy might be indicated to preserve the quality of life for these patients. However, the survival rate of patients who received the second Hsct while in complete remission or chronic phase was 46.9 +/- 18.7 % although some patients still have a short observation period. We think this survival rate is very encouraging and comparable with adult data.9-11 If remission is obtained for relapse

after initial Hsct, the second Hsct should be considered as a curative treatment strategy for these patients. We could not evaluate the significance of stem cell source or conditioning regimen because of the heterogeneity in this retrospective analysis. evaluation of the significance of stem cell source is difficult because of the limitation of allogeneic donor availability. to evaluate the significance of conditioning regimen, a uniform conditioning regimen designed especially for second Hsct will be required.11 one patient, who

received the second Hsct during second complete remission, died of bo. this is the only patient who died while in remission. because receiving full dose Hsct twice can induce serious complications in some patients, reduced intensity Hsct might be indicated for selected patients in remission as reported in adult patients.9,11

In this article, we reported twenty-one patients who received second allogeneic Hsct for relapse after initial allogeneic transplant in childhood leukemia at our center. the outcome might be dismal especially in patients who received second Hsct while in a non-remission status, however, the outcomes of patients who received second Hsct during remission was encouraging. Further study is needed to establish a safe and efficient treatment strategy for relapse after initial allogeneic transplant in childhood leukemia.

reFerences

1 Pui cH, relling MV, downing Jr: Acute lymphoblastic leukemia. n engl J Med 2006; 350: 1535-1548.

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sibling transplants for leukemia recurrence. bone Marrow transplantation 1992; 9: 269-275.

4 radich JP, sanders Je, buckner cd et al.: second marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens. J clin oncol 1993; 11 : 304-311.

5 Kumar L: Management of relapse after allogeneic bone marrow transplantation. J clin oncol 1994;7: 50-57.

6 chiang KY, Weisdorf dJ, davies sM et al.: outcome of second bone marrow transplantation following a uniform conditioning regimen as a therapy for malignant relapse. bone Marrow transplant 1996;17: 39-42.

7 basara n, bischoff M, blau IW et al. A second unrelated bone marrow transplant with an unrelated donor marrow: treatment of a patient with relapsed leukemia. bone Marrow transplant 1998;21: 291-293.

8 bosi A, Laszlo d, Labopin M et al.: second allogeneic bone marrow

transplantation in acute leukemia: results of a survey by the european cooperative group blood and marrow transplantation. J clin oncol 2001;9: 3675-3684.

9 Fernstein Lc, sandmaier bM, Maloney dG et al. Allografting after nonmyeloablative conditioning as a treatment after a failed conventional hematopoietic cell transplant. biol blood Marrow transplant 2003;9: 266-272.

10 eapen M, Giralt sA, Horowitz MM et al.: second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. bone Marrow transplant 2004; 34: 721-727. 11 Grullich c, bertz H, spyridonidis A et al.: A fludarabine, thiotepa

reduced toxicity conditioning regimen designed specifically for allogeneic second hematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation. bone Marrow transplant 2008; 41: 845-850.

Figure

Table 1. Patient characteristics and outcomes
Fig. 1.  survival curves after the second Hsct according to the disease status. Patients in complete remission or chronic phase at the second Hsct showed a better survival rate

References

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