Second allogeneic hematopoietic stem cell transplantation as ... - Nature

Bone Marrow Transplantation (2000) 25, 41–45  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant IW Blau, N Basara, M Bischoff, S Gu¨nzelmann, E Ro¨mer, D Kirsten, B Schmetzer, MG Kiehl and AA Fauser Clinic for Bone Marrow Transplantation and Hematology/Oncology, Idar-Oberstein, Germany

Summary: We report 27 patients with relapsed acute or chronic leukemia who underwent a second hematopoietic stem cell transplant (HSCT) from a related or unrelated donor. Seventeen patients were diagnosed with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL) and four with chronic myeloid leukemia (CML). Ages ranged from 22 to 49 years (median 37); 13 patients were female and 14 male. Relapse was diagnosed between 1 and 45 months after the first HSCT. Sixteen patients who relapsed had received an autologous transplant initially and 11 an allogeneic transplant. Ten patients relapsed within 6 months and 17 patients later than 6 months. Chemotherapy was used as reinduction for relapse after HSCT in 16 patients who had received an autologous transplant and in three who had received an allogeneic transplant, since the latter did not respond to reduction of immunosuppression to induce a graft-versus-leukemia (GVL) reaction. Five of these 19 patients (26%) achieved complete remission (CR), seven patients did not respond to chemotherapy and seven achieved a partial remission (PR). The stem cell source for the second HSCT included bone marrow (n = 12) and PBSC (n = 4) from genotypically identical unrelated donors, PBSC (n = 7) and bone marrow (n = 3) from related donors. Currently eight of the 27 patients are alive and diseasefree after the second HSCT. One patient is alive and disease-free after two allogeneic transplants (day +1538), eight patients, who relapsed after an autologous transplant followed by an allogeneic transplant (days +248 to +1140), acute myeloid leukaemia (n = 6) and chronic myeloid leukemia (n = 2) are alive and diseasefree. The overall disease-free survival is 30% (8/27). The overall disease-free survival of autologous transplant patients subsequently undergoing an allogeneic transplant is 43% (P = 0.049). It is suggested that a second HSCT is possible for patients with leukemia relapse following the first autologous transplant. A second transplant might also be offered to patients relapsing after the first allogeneic HSCT. Bone Marrow Transplantation (2000) 25, 41–45. Correspondence: Dr IW Blau, Clinic of Bone Marrow Transplantation and Hematology/Oncology, Dr Ottmar-Kohler Str 2, 55743 Idar Oberstein, Germany Received 18 November 1998; accepted 13 May 1999

Keywords: second allogeneic bone marrow transplant; conditioning regimen; relapse rate; acute leukemia; diseasefree survival

The relapse rate in patients transplanted for acute or chronic leukemia still ranges from 20–60%, accounting for one important cause of treatment failure.1,2 Relapse rate correlates with diagnosis and stage of disease,3,4 since patients transplanted either in relapse or after chemotherapy induction failure demonstrated a significantly higher risk for relapse compared to patients transplanted in complete remission.5 The management of patients relapsing after HSCT is still controversial.6,7 The therapeutic modalities for the treatment of leukemia relapse following allogeneic transplantation have been reviewed recently.8–10 Options such as immunotherapy, donor lymphocyte infusion (DLI) or a second allograft after myeloablative conditioning have been explored.10 Despite the high treatment-related mortality with a second HSC transplant, this may be considered for some patients, in particular those with AML. Data concerning therapeutic approaches for treating leukemia relapse after an autologous transplant are still unclear. Chiang et al11 describing the outcome for 23 patients receiving matched sibling or unrelated bone marrow, reported four patients who relapsed after an autologous transplant and received a second unrelated HSCT. Tsai et al12 analyzed 20 patients with malignant lymphoma (n = 14), and AML (n = 6), who underwent alloHSCT after failing autologous HSCT. The outcome was very poor with a median survival of 2 months and 17 patients died from transplant-related complications. We report 27 leukemia patients, who relapsed after their first transplant and underwent a second HSCT from either a related or unrelated donor. The purpose of our study was to evaluate clinical outcome, engraftment, treatment-related toxicities, and overall survival time in leukemia patients undergoing a second allogeneic transplant. We assessed these factors with regard to source of hematopoietic stem cells, ie autologous vs allogeneic and peripheral blood stem cells vs bone marrow, time to relapse and age in order to identify patients who might profit from a second HSC transplant.

Second HSC for patients with relapsed AL IW Blau et al

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Patients and methods

Table 2

Patient characteristics

Donor

Between May 1994 and December 1998, 280 allogeneic and autologous HSC (150 related and 130 unrelated) were performed at our institution. Twenty-seven patients were eligible for a second transplant with HSC (BM, n = 17 and PBSC, n = 10), having relapsed after the first transplant. Informed consent was approved by the institutional review board (CTRB) to obtain a second graft from the same donors. Patient characteristics are given in Table 1. Diagnoses at first transplant of the 27 patients included in this study were 17 with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL) and four with chronic myeloid leukemia (CML). One patient with CML had been diagnosed with AML five years prior to his diagnosis of CML. Ages ranged from 22 to 49 years (median 37); 13 patients were female and 14 male. Relapse occurred between 1 and 45 months after the first HSCT with a median time interval of 8 months. Ten patients relapsed within 6 months, and 17 later than 6 months. Sixteen patients who relapsed had initially received an autologous transplant, one a syngeneic and 10 an allogeneic transplant. Patients analyzed in this study did not respond to reduction of immunosuppressive therapy to induce a GVL reaction. Chemotherapy was administered for the relapse in 19 patients. Eight patients who relapsed underwent the second transplant without prior induction therapy. Five of 19 patients receiving chemotherapy achieved subsequent complete remission (CR), seven patients did not respond to chemotherapy and seven patients achieved a partial remission (PR). Conditioning regimens Preparative regimens for the first HSCT are given in Table 2. Nine patients received cyclophosphamide (CY) 60 mg/kg BW i.v. on 2 consecutive days or total body irradiation (TBI) 13.5 Gy on 3 days with a daily dose of 4.5 Gy in two fractions. Seven patients were treated with busulfan (BU) 4 mg/kg BW daily every 6 h for 4 days orally and with CY 120 mg/kg BW. Nine patients were treated with a VP-16 containing regimen as described.13 Three patients Table 1

Patient characteristics Patients

No. of patients Age (years) 21–30 31–40 41–50 Male Female Diagnosis: AML ALL CML

Autologous Matched sibling BM PBSC Matched unrelated BM PBSC Preparative regimen TBI + CY CT alone GVHD prophylaxis CsA + P CsA + P + MTX No Autologous

BMT 1

BMT 2

16

0

7 0

5 6

4 0

12 4

9 18

11 16

7 4 0 16

10 15 2 0

BM = bone marrow; PBSC = peripheral blood stem cells; TBI = total body irradiation; CY = cyclophosphamide; CsA = cyclosporine A; CT = chemotherapy; P = prednisolone; MTX = methotrexate.

received chemotherapy alone. Nine patients received autologous bone marrow and seven patients peripheral blood stem cells (PBSC). Syngeneic bone marrow was given in one patient, genotypic identical marrow (n = 4) or PBSC (n = 2) from a related donor; HLA-matched marrow (n = 3) or PBSC (n = 1) from unrelated donors (MUD) to the others. Graft-versus-host disease prophylaxis (GVHD) for the initial transplant consisted of cyclosporin A (CsA) 5 mg/kg BW daily starting on day −3 and prednisolone at a dose of 0.5 mg/kg BW daily from day +7. Methotrexate (MTX) was given on day +1 at a dose of 15 mg/m2 and on days +3 and +6 at a dose of 10 mg/m2, in patients receiving MUD transplants and non-identical sibling transplants. The preparative regimen for second HSCT was BU days −7 to −4 and VP-16 (60 mg/kg BW) day −3 in eight patients, BU/CY or TBI/CY14 in 17 patients, respectively, CY/high-dose methylprednisolone/ATG in two patients. The second HSCT was performed using bone marrow (n = 12) or PBSC (n = 4) from genotypically identical unrelated donors, PBSC (n = 7) or bone marrow (n = 3) from related donors. Twelve of 16 patients, initially transplanted with autologous stem cells, received a MUD and four patients a related donor transplant. GVHD prophylaxis for recipients of a second allogeneic HSCT was CsA/prednisolone/MTX (n = 13) and CsA/prednisolone in eight patients, three of whom had an unrelated donor; two patients did not receive any prophylaxis for GVHD.

27 9 10 8 14 13 17 6 4

AML = acute myeloid leukemia; ALL = acute lymphocytic leukemia; CML = chronic myeloid leukemia. Bone Marrow Transplantation

Transplant-related data

Evaluation and definition Engraftment was assessed according to published criteria.14 Briefly, myeloid engraftment was defined as the first of 3 consecutive days when the absolute neutrophil count was higher than 0.5 × 109/l. Platelet engraftment was defined as the first of 7 consecutive days when the platelet count exceeded 20 × 109/l without transfusions. Transplant-related mortality (TRM) was defined as death in the absence of relapse.


Statistical analysis The Kaplan–Meier method was used to estimate probability of overall survival. The difference between groups was compared using Wilcoxon and logrank-tests.15 The following risk factors were analyzed: BM group, PBSC group, age, time to relapse. Results Engraftment Sustained engraftment (ANC ⬎0.5 × 109/l) occurred in all patients after the first transplant. Time to ANC ⬎0.5 × 109/l was 12–37 days, median 18 days. Time to reach platelets ⬎20 × 109/l without platelet transfusion was 12–50 days, median 21 days. After the second transplant sustained engraftment (ANC ⬎0.5 × 109/l) was achieved in 26 of 27 patients. One patient died before engraftment. Time to ANC ⬎0.5 × 109/l was 10–42 days, median 19 days. Time to platelet count ⬎20 × 109/l without platelet transfusion was 11–52 days, median 21 days.

geneic transplant after relapse (days +248, +310, +337, +370, +502, +1119 and +1140) with acute myeloid leukemia (n = 6) and with chronic myeloid leukemia (n = 2). Overall survival was 30% (Figure 1). The overall survival rate of patients undergoing a second HSCT after a first autologous transplant was 43%. This difference with regard to the survival rate is significant depending on the source of hematopoietic stem cells given for the first transplant, autologous vs allogeneic (P = 0.049; log rank test). Eight of 18 patients with remissions lasting more than 6 months are alive with a median follow-up of 249 days. On the contrary no patient with a remission duration ⬍6 months is alive (median 69 days). This difference is highly significant (P = 0.012 log rank test) (Figure 2). Twelve patients, 45% died from relapse after the second transplant. The median time period from relapse to death after the second allogeneic HSCT was 128 days (17–249). Four patients died with recurrent acute lymphocytic leukemia (one additional patient with ALL died from septicemia, one patient with ALL died due to MOF after HSCT), no

43

1.0

Transplant-related mortality Seven of 27 patients died due to TRM complications between days 16 and 190 without any evidence of recurrent disease. Three patients died from multiorgan failure (MOF), four patients died with infectious complications, of whom one had pulmonary aspergillosis.

Survival rate

0.8 0.6

0.4 0.2

Outcome and relapse rate

0.0

Eight patients are alive and disease-free after a second BMT (Table 3). These include one patient who received two allogeneic transplants (day +1538), and seven patients who had initially an autologous, followed by a second allo-

0

200

400

600

800

1000

1200

1400

1600

Time (days) Figure 1 Overall survival in all patients (n = 27) with a second HSCT; 29%.

Table 3 Treatment and clinical outcomes of long-term disease-free survivors Age/Sex Diagnosis at 1. Tx

Months to 2. Tx

Diagnosis at 2. Tx

GVHD prophylaxis 1. Tx

2. Tx

Survival (days)

Engraftment (days)

Conditioning regimen

Donor

to 1. Tx

to 2. Tx

1. Tx

2. Tx

TBI/CY

auto

MUD

TBI/CY

auto PBSC auto PBSC auto

MUD

MMR

auto PBSC auto PBSC MR auto

MR PBSC MUD PBSC MR MUD

43/M

AML, 2.rel.

52

CR

no

MAP

1140

20

45/F

AML, 2.CR

11

CR

no

MAP

502

18

CY/VP16/ Ara-C BU/CY

36/F

AML, 2.CR

13

CR

no

MAP

370

18

BU/CY

BU/CY

36/M

AML, 2.rel.

9

Relapse

no

MAP

1119

17

TBI/CY

26/F

AML, 2.CR

8

Relapse

no

MP

310

14

44/M

AML, 1.rel.

24

Relapse

no

MAP

248

26

38/F 33/M

CML, CP CML, CP

24 53

Relapse SAML

AP no

AP MAP

1538 337

12 26

CY/VP16/ Ara-C CY/VP16/ Ara-C CY/VP16/ Ara-C TBI/CY CY/VP16/ Ara-C

BU/CY TBI/CY BU/VP-16 BU/CY

MUD

Tx = transplant; MR = matched related marrow; PBSC = peripheral blood stem cells; Auto = autologous marrow; MUD = matched unrelated marrow; MAP = methotrexate, cyclosporin A, prednisolone; AP = cyclosporin A, prednisolone. Bone Marrow Transplantation


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1.0

Survival rate

0.8

P = 0.012 (logrank test) P = 0.015 (Wilcoxon test)

0.6 0.4

Duration of remission >6 months Duration of remission ⭐6 months

0.2 0.0 0

200

400

600

800

1000

1200

1400

1600

Time (days) Figure 2 Overall survival in relation to duration of remission after first transplant.

patient with a second transplant for ALL survived. Two patients with CML at an advanced stage at the time of transplant also died due to recurrent disease. Ten patients received a peripheral blood stem cell transplant; 17 patients had bone marrow as the source of hematopoietic stem cells. There was no statistical difference regarding bone marrow vs peripheral blood stem cells (P = 0.71, Wilcoxon test). Age (40 years) was also tested as a risk factor, and was not found to be significant (P = 0.7, Wilcoxon test). Discussion Optimal management of transplant recipients experiencing leukemia relapse after autologous or allogeneic transplant is one of the most controversial issues. We treated 27 patients with a second allogeneic HSCT after relapse following the first HSCT. Patients receiving an allogeneic HSCT after initial autologous HSCT survived significantly longer than did patients receiving a second allogeneic HSCT after a first allogeneic HSCT. Five patients are still alive and disease-free after receiving an unrelated HSC for their second transplant, which contrasts with a recent study11 evaluating the outcome of patients with hematological malignancies undergoing allogeneic HSCT for disease relapse after autologous HSCT. Most patients (17/20) in the study of Tsai et al12 died; only three were alive with severe complications at the time of writing. In our study, 26 out of 27 patients (96%) achieved myeloid engraftment within a similar time frame as observed after the first transplant. Eight patients are alive at present with a median follow-up of more than 2 years. Ten patients received unrelated donor cells for the second HSCT demonstrating that a second HSCT can be performed from an unrelated donor after an initial autologous transplant. Five of the long-term survivors were transplanted with hematopoietic stem cells from an unrelated donor. Our results show a survival rate of 30% with patients doing particularly well after a first autologous transplant. Those undergoing two allogeneic transplants include four patients who received a second HSCT from an unrelated donor after a first MUD transplant. However none of these patients survived. Bone Marrow Transplantation

Multicenter studies reported different results regarding the 2-year probability of leukemia-free survival after a second BMT. Mrsic et al16 reported a 34% 2-year probability of leukemia-free survival for patients in remission and only a 2% survival rate for patients in relapse. In contrast, Barrett et al6 demonstrated no significant differences for patients transplanted in relapse or in complete remission. Nevertheless, there was a trend to a more favorable outcome with regard to leukemia-free survival, namely 17% for good risk patients and 6% in poor risk patients. Other studies, however, revealed no evidence of longer survival with a second transplant performed in complete remission.14 Many single institutions and BMT programs have reported on the outcome of a second HSCT as treatment for relapse,11,16,17 finding a high relapse rate (30% to 65%), and a high incidence of HSCT-related complications, with a probability of a leukemia-free relapse survival of 20%. The mortality related to the toxicity of the preparative regimen for these patients was 19%, which is comparable to our data. Despite the high incidence for early mortality, it has been shown that the probability of relapse is lower after the second transplant compared to the first transplant, which might be explained by a GVHD-mediated GVL effect in the allogeneic setting.6,18,19 Adoptive immunotherapy with DLI might be considered beneficial for patients in relapse after HSCT, and results in approximately 30– 40% complete remissions when given to patients with relapsed CML.20,21 However, in patients with acute leukemia, in particular with ALL, this approach appears to be less satisfactory.10 In all patients in our study who relapsed after the first allogeneic transplant, GVHD prophylaxis was reduced in order to achieve GVL. Moreover, this approach failed in all relapsed patients with ALL. Therefore, for these patients therapeutic options such as a second allogeneic transplant or a mini-transplant22 might be considered. In conclusion, we suggest that a second HSCT as treatment for relapse of acute or chronic myeloid leukemia after first HSCT might be considered in patients relapsing after an autologous transplant. An unrelated donor for the second transplant might also be considered for patients with relapse after a first autologous transplant. Our data might also contribute to the further evaluation of unrelated donors as the source for a second HSCT. Treatment of patients with relapsed ALL appears to be very difficult, since none of our patients derived benefit from a second transplant. Therefore, a second transplant for ALL patients relapsing after a first transplant is probably not the treatment of choice. References 1 Donney K, Fisher LD, Appelbaum F. Treatment of adult acute lymphoblastic leukemia with allogenic bone marrow transplantation. Multivariate analysis of factors affecting acute graft-versus-host disease, relapse and relapse free survival. Bone Marrow Transplant 1991; 7: 453–459 2 Wingard JR, Piantadosi S, Santos WG. Allogeneic bone marrow transplant for patients with high risk acute lymphoblastic leukemia. J Clin Oncol 1991; 8: 820–830. 3 Gale RP, Kersey JH, Bortin MM et al. Bone marrow trans-


4

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7 8 9

10

11

12 13

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