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

Abstract

Introduction

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.

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 may be effective salvage therapy in some patients who relapse after an initial transplant. To date, most studies

Keywords: childhood leukemia, second transplant, disease status at transplant

Correspondence to: Akira Kikuchi MD, PhD, Division of Hematology/Oncology, Saitama Children’s Medical Center, 2100 Magome Iwatsuki-ku, Saitama-shi Saitama 339-8551, Japan. Tel: +81 48 7581811, Fax: +81 48 7581818, E-mail: [email protected]

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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 KaplanMeier 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 2 1/M ALL R- BM R- PB 3 3/M ALL U- BM U- CB 4 6/F ALL U- BM U- BM 5 16/M ALL MSD-PB MSD-PB 6 0/M ALL U- CB U- CB 7 11/F ALL R- BM R- PB 8 1/M ALL U- CB U- BM 9 4/M ALL U- BM U- BM 10 11/F ALL R- PB R- PB 11 0/F ALL U- CB U- BM 12 0/M ALL U- CB U- BM 13 2/F ALL U- BM U- BM 14 8/M ALL U- BM U- BM 15 10/F AML MSD-BM MSD-PB 16 6/M AML R- BM R-PB 17 6/M AML U- BM R-PB 18 8/F AML R- BM MSD-BM 19 14/F AML U- BM R- PB 20 3/M AML U- CB U- BM 21 5/F CML MSD-BM MSD-PB

3 5 5 14 8 17 3 3 7 3 9 7 5 5 3 27 13 29 3 3 60

6 RL 13 RL 9 RL 21 RL 11 CR 23 CR 4 RL 14 CR 13 CR 7 RL 46 CR 12 CR 13 CR 16 CR 25 CR 33 RL 16 RL 33 CR 5 RL 11 RL 62 CP

2 0 1 3 1 0 2 NE 2 2 3 2 0 0 1 0 2 2 0 1 0 2 1 1 1 1 3 0 0 0 2 2 1 2 0 1 2 4 0 0 0 2

18 DOD 7 DOD 16 DOD 1 DOD 23 DOD 60+ NA 1 DOD 9 BO 11 DOD 3 MOF 2+ NA 16+ NA 8+ NA 3+ NA 20 DOD 27 DOD 7 MOF 24+ NA 4 GVHD 8 DOD 95+ NA

Abbreviations: MSD = matched sibling donor; BM = bone marrow; R = related; U = unrelated; PB = peripheral blood stem cell; CB = cord blood; RL=relapse; CR= complete remission; CP= chronic phase; DOD = died of disease; BO= bronchiolitis obliterans; MOF = multiple organ failure; GVHD = graft versus host disease; NE= not evaluable; NA = not applicable. * Age is indicated in years. All periods are indicated in months. Plus sign indicates the patient is still alive.

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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

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.

The Experience ofunderwent Caring For the first HSCT, sixteen patients total for a Person with a Mental body irradiation (TBI). The remaining five patients Illness: Grounded Theory Study received busulfan(BU). Five patients, who received BU ASurvival 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

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 the second HSCT showed a better survival rate.

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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 HLApartially 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 nonremission 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.

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