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Allogenic stem cell transplantation as salvage therapy for patients relapsing after autologous transplantation: experience from a single institution
Leukemia Research 25 (2001) 379– 384 www.elsevier.com/locate/leukres
Allogenic stem cell transplantation as salvage therapy for patients relapsing after autologous transplantation: experience from a single institution ´ lvaro Urbano-Ispizua, Carmen Martı´nez, Enric Carreras *, Montserrat Rovira, A Jordi Esteve, Franc¸esc Ferna´ndez-Avile´s, Marı´a Perales, Susana Rives, Marta Go´mez, Emilio Montserrat Transplantation Unit, Department of Hematology, Postgraduate School of Hematology ‘Farreras-Valentı´’, Institute of Hematology and Oncology, IDIBAPS Hospital Clı´nic, Uni6ersity of Barcelona, Villarroel 170, 08036 Barcelona, Spain Received 4 July 2000; accepted 20 October 2000
Abstract The prognosis of patients relapsing after an autologous transplant (autoSCT) is very poor. Allogenic stem cell transplantation (alloSCT) offers the possibility of curing some of these patients, at the cost, however, of a high transplant related mortality (TRM). The aim of this study was to analyze the outcome of 14 consecutive patients with hematologic malignancies, from a single institution, who underwent alloSCT for progressive disease after autoSCT. Patients had relapsed at a median of 11.5 months (range 2–72) after autoSCT and they underwent alloSCT at a median of 25.5 months (range 7 – 73) from the first transplant. Ten patients received HLA-identical related peripheral blood progenitor cells, three patients underwent matched-unrelated donor marrow transplants, and one patient received a mismatched related transplant. Conditioning regimens consisted of total body irradiation plus cyclophosphamide (n=5) or melphalan (n= 1), or high-dose combination chemotherapy (n= 8). Cyclosporin A and methothrexate were administered as graft-versus-host disease (GVHD) prophylaxis. Eight patients (57%) developed grade II–IV acute GVHD. All evaluable patients (n =6) presented extensive chronic GVHD. Overall survival at 1 year was 16% (median 3.5 months, 95% CI 0.7–10.3). Ten patients (71%) died from transplant related complications at a median of 3.5 months (range 0.7–11). Only one patient died of recurrent disease. Three patients remain alive and in complete remission at the time of this report (4, 20 and 20 months, respectively). In conclusion, alloSCT offers the possibility of a sustained control of the disease in some patients who relapse after an autoSCT. However, the procedure is associated with a high transplant-related mortality. Better results might be obtained by carefully selecting patients and by reducing the intensity of the preparative regimen. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Autologous transplantation; Relapse; Allogenic transplantation
1. Introduction Hematopoietic stem cell transplants are effective in a variety of hematologic malignancies [1 – 3]. Relapse of the underlying disease after transplantation remains the most frequent cause of treatment failure, particularly with autologous transplants (autoSCT), and is generally Abbre6iations: AlloSCT, allogenic stem cell transplantation; AutoSCT, autologous transplant; GVHD, graft-versus-host disease; TRM, transplant related mortality. * Corresponding author. fax: +34-93-2275428. E-mail address: [email protected] (E. Carreras).
considered to have a poor prognosis. The optimal treatment strategy for these patients is not resolved [4]. Although in some patients a second complete remission can be obtained with conventional chemotherapy, very few patients, if any, are cured with this approach. The role of second transplant in the treatment strategy of patients relapsing after a first transplant is controversial, basically because of the treatment-related toxicity. Allogenic stem cell transplantation (alloSCT) has been employed as a salvage therapy in patients who relapse after a first alloSCT. The results from large series of leukemia patients reported by the both Eu-
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C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384
ropean Group for Blood and Marrow Transplantation and by the International Bone Marrow Transplantation registries have shown that a minority of the patients achieve long-term disease-free survival. However, a substantial proportion of the patients die due to the toxicity related to the procedure or because of the relapse of the disease [5,6]. Treatment results are better in young patients, individuals with a long time interval between the first and the second transplant, and those with good performance status. Experience with alloSCT in patients who relapse after autoSCT is limited, and factors that could predict a favorable outcome in this group of patients have not been fully established [7 – 10]. The purpose of this study was to evaluate the outcome of patients with hematologic malignancies who underwent alloSCT for progressive disease after autoSCT in our institution.
tion chemotherapy in nine (Table 1). The stem cell source for the first transplant was bone marrow (n=3), peripheral blood (n= 10), or both (n = 1). The conditioning regimen for alloSCT consisted of Cy 120 mg/kg and TBI 12–13 Gy in six cases, busulfan (Bu) 16 mg/kg and Cy 120 mg/kg in four, melphalan 140 mg/m2 and TBI 12 Gy in one, Cy 120 mg/kg +Bu 16 mg/kg +etoposide 30 mg/kg in one, and fludarabine 150 mg/m2 + melphalan 140 mg/m2 in two. Ten patients received HLA-identical related (sibling (n=9), father (n= 1)) peripheral blood progenitor cells, three underwent matched-unrelated donor marrow transplants, and one patient received a mismatched related peripheral blood transplant. All patients received cyclosporin A and short course methothrexate as graft-versus-host disease (GVHD) prophylaxis. The diagnosis and grading of acute and chronic GVHD was established according to the Seattle criteria [12]. Chronic GVHD was defined as the presence of GVHD after day 90.
2. Patients and methods
2.1. Patient population Fourteen alloSCT were performed between March 1995 and December 1999 for the treatment of hematologic malignancies relapsing after autoSCT. Five patients had non-Hodgkin’s lymphoma, four acute leukemia, three Hodgkin’s disease, one multiple myeloma, and one chronic myeloid leukemia. The outcome of two patients with mantle-cell lymphoma allografted after relapsing from an autoSCT has been described in a separate publication [11]. The clinical characteristics of these patients prior to both the first and second transplants are described in Table 1. The median age of patients at the time of alloSCT was 37 years (range 20–57). Nine patients were male and five were female. The median time interval from diagnosis to autoSCT was 15 months (range 4 – 44). Patients had relapsed at a median of 11.5 months (range 2 – 72) after autoSCT. All patients but one were treated with one (n =10) or ]two (n =3) chemotherapy regimens before alloSCT. Only three patients were in complete remission (CR) at the time of the second transplant, and one patient with CML was maintained in the chronic phase. AlloSCT was performed at a median of 25.5 months (range 7 – 73) following autoSCT. The median Karnofsky performance status score prior to alloSCT was 70% (range 40 – 80%).
2.2. Transplantation methods The preparative regimen for autoSCT consisted of cyclophosphamide (Cy) 120 mg/kg and fractionated total body irradiation (TBI) 12 Gy in four patients, melphalan 200 mg/m2 in one, and high-dose combina-
2.3. Statistical methods Median values and ranges for age and time intervals were determined. Survival was measured from the date of alloSCT to the date of death from any cause, or last known follow-up. The method of Kaplan and Meier was used to plot survival and relapse curves. The analysis was performed with SPSS software.
3. Results
3.1. Hematopoietic engraftment One patient died before hematopoietic engraftment. The median time to achieve an absolute neutrophil count of \ 0.5×109/l and \ 1.0× 109/l was 15 days (range 10–23), and 17 days (range 11–25), respectively. The median time to achieve a platelet count \20× 109/l was 15 days (7–38) days; five patients did not achieve this platelet count after transplant. No patient rejected the graft.
3.2. GHVD Eight patients (57%) developed acute GVHD grade II–IV. Six patients survived more than 90 days and were evaluable for chronic GVHD. All of them presented extensive chronic GVHD; this complication was fatal in two cases (patients c3 and c 4). Two patients (cases c2 and c 7) died due to infectious complications associated with immunosuppressive therapy for chronic GVHD (Table 2).
M M F F M M F F M M M M F M
01 02 03 04 05 06 07 08 09 10 11 12 13 14
26 48 27 38 48 36 45 53 57 28 42 24 20 32
Age at alloSCT
AML CML AML NHL MM HD NHL MCL MCL ACL NML ALL HD HD
Diagnosis
11 31 10 44 4 23 35 15 15 10 7 5 23 27
Time to autoSCTb
BM BM BM+PB PB PB PB PB PB PB PB PB BM PB PB
Stem cell source
AutoSCT
CyTBI BuCy BuCy BEAC MLF BEAC BEAC BEAC BEAC CyTBI CyTBI CyTBI BEAC BEAC
Conditioning regimen 72 12 9 10 9 11 24 24 13 7 5 42 15 2
Time to relapseb
73 39 12 26 19 29 33 30 19 11 7 47 25 17
Time between autoSCT– alloSCTb
HLA-matched UNR BM HLA-matched UNR BM HLA-mismatched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched father PB HLA-matched sibling PB HLA-matched UNR BM HLA-matched sibling PB HLA-matched sibling PB
Stem cell source
AlloSCT
BuCY CyTBI CyTBI CyTBI MLFTBI BuCyVP CyTBI CyTBI CyTBI BuCy BuCy BuCyATG FludaraMLF FludaraMLF
Conditioning regimen
80 80 60 80 20 50 60 80 80 60 60 60 90 80
Karnofsky PS
Karnofsky PS, Karnofsky performance status; AML, acute mieloblastic leukemia; CML, chronic mieloid. leukemia; NHL, non-Hodgkin lymphoma; MM, multiple myeloma; HD, Hodgkin disease; MCL, mantle cell lymphoma; ALL, acute lymphoblastic leukemia; Cy, cyclophosphamide; TBI, total body irradiation; Bu, busulfan; BEAC, BCNU, etoposide, ara-C, cyclophosphamide; MLF, melphalan; VP, etoposide, Fludara, fludarabine; UNR, unrelated; BM, bone marrow; PB, peripheral blood. b Months.
a
Sex
Patient
Table 1 Patient characteristicsa C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384 381
C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384
382 Table 2 Allogenic transplantation outcome Patient
Acute GVHD
Chronic GVHD
Cause of death
Status
01 02 03 04 05 06 07 08 09 10 11 12 13 14
Grade Grade Grade Grade 0 Grade Grade Grade 0 Grade 0 Grade Grade NE
NEa Extensive Extensive NE NE Extensive Extensive Extensive Extensive NV NE NE NE NE
Idiopathic pneumonitis+acute GVHD Bacterial sepsis+chronic GVHD Chronic GVHD Idiopathic pneumonitis Multiorgan failure+fungal infection Chronic GVHD Bacterial sepsis+chronic GVHD
Dead, Dead, Dead, Dead, Dead, Dead, Dead, Alive, Alive, Dead, Dead, Dead, Alive, Dead,
a
III II III I II II II II II III
Viral infection Relapse Viral infection+acute GVHD Idiopathic pneumonitis
day +45 11 months 11 months 2 months day +21 7 months 9 months 20 months 20 months day +107 3 months 2 months 4 months day +22
NE, not evaluable.
3.3. Sur6i6al and cause of death The Kaplan –Meier estimated overall survival at 1 year was 16% (median 3.5 months, 95% CI: 0.7 –10.3) (Fig. 1). One patient died 3 months after transplant due to leukemic relapse. Ten patients (71%) died from transplant related complications at a median of 3.5 months (range 0.7 – 11) after the procedure. As shown in Table 2, causes of death included GVHD in six cases; bacterial, fungal or viral infections in five; idiopathic pneumonitis in three; and multiorgan failure in one. At the time of this report, three patients remain alive (Table 2). Two of them (patients c 8 and c 9) had mantle cell lymphoma and underwent alloSCT in CR and partial remission, respectively. Both developed extensive chronic GVHD remaining in CR 20 months after transplantation with a Karnofsky performance status score of 90%. Patient c13 had a resistant Hodgkin disease with lung involvement. She developed an acute grade III GVHD responding to immunosuppressive therapy. At the time of writing, the patient is in CR, 8 months after the alloSCT and she has developed extensive chronic GVHD. In these patients, the duration of the remission after the second transplant was longer than after the autoSCT.
contamination of the graft and the antitumoral activity mediated by the so-called graft-versus-tumor effect [13 –16]. The outcome of patients receiving an alloSCT after failing an autoSCT has been analyzed in several studies, the majority coming from registries or multiple institutions [7–10]. The largest series analyzed treatment results in patients with acute leukemia and has recently been reported by the European Blood and Marrow Transplantation Registry [7]. In this study, patients relapsing after an autoSCT underwent a second autologous (n= 74) or allogenic (n= 94) transplant as salvage therapy. Transplanted-related mortality (TRM) at 2 years was 51% in recipients of matched alloSCT and 26% following a second autoSCT (P B0.05). Leukemia-free survival (LFS) was not statistically different between the two groups since higher disease progression was observed after autoSCT. In the multivariate analysis, parameters associated with shorter LFS were: age \ 25 years, interval from first autoSCT
4. Discussion Patients with hematological malignancies who relapse after autoSCT have a very poor prognosis with a median survival of less than 1 year [4]. In most cases, a second autoSCT is not feasible due to the resistance of the disease to the therapy, or to the impossibility of collecting enough stem cells. For all these reasons, alloSCT is a potentially interesting salvage therapy offering the advantages of both the lack of tumor
Fig. 1. Overall survival after alloSCT.
C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384
to relapse of 8 months or less, and TBI used as part of the preparative regimen in the first autoSCT. The role of second transplants in the management of patients with lymphoid malignancies has not been widely investigated [9,10,17 – 19]. Tsai et al. [9] analyzed 20 patients, 14 of them with lymphoma, who underwent alloSCT after failing autoSCT. In this study, the median survival was only 2 months; all the deaths were due to transplant-related complications that included bacterial or fungal infection, veno-occlusive disease of the liver, idiopathic interstitial pneumonitis and chronic GVHD. Only three patients were alive at the time of this report. Similar results have been shown in patients with multiple myeloma having relapsed after autoSCT [10,20]. Thus, Mehta et al. [10] performed a case-matched study comparing patients who underwent an alloSCT or a second autoSCT for relapsed or refractory multiple myeloma. The conclusions of this study were that while autoSCT might be superior to alloSCT when considering overall survival (54 vs. 29%, respectively, P =0.01), the event-free survival was comparable given the significantly lower disease progression after alloSCT (72 vs. 31%, respectively, P = 0.03). In our single institution study, which included all patients that had received an alloSCT after having relapsed from an autoSCT, alloSCT resulted in prompt engraftment. However, TRM due to toxicity, and the incidence of GVHD and infections were extremely high. Although the series is small, the proportion of long-term survivors does not appear to be different from that found in other series. It should be noted that, although most patients had relapsed after 8 months from autoSCT and only four received TBI as part of the preparation regimen for the first transplant, a great proportion of them were over 25 and had been heavily pretreated, factors which have been associated with poor outcome [7 – 10]. The last two patients of the series received low-intensity conditioning regimens in order to reduce the toxicity associated to the procedure. One of them is alive and in CR at the time of this report In summary, in patients who relapse after an autoSCT, salvage therapy with alloSCT is associated with a high TRM, but a proportion of patients may experience prolonged disease-free survival. The most important problem with this procedure is TRM. This could be diminished by a careful selection of the patients and, particularly, by reducing the intensity of the conditioning regimen, an avenue that is being actively investigated [21,22]. Taking into account the dismal prognosis of patients relapsing after a first transplant, as well as the high TRM associated with second regular transplants, the so-called ‘mini-transplants’ (or transplants with non-myeloablative regimens) are worth investigation.
383
Acknowledgements This work has been supported in part by grants SGR 1998/00111 from the Comissionat per a Universitats i Recerca (Generalitat Catalunya), FISS-98/995, 98/0380, and 99/0189 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, Spanish Ministry of Health, and FIJC-00/P-CR and FIJC-00/ P-EM from the Jose´ Carreras International Foundation. We wish to thank Anna Bauer for the English grammar review of the manuscript. References [1] Foon KA, Gale RP. Therapy of acute myelogenous leukemia. Blood Rev 1992;6:15. [2] Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. New Engl J Med 1995;333:1540. [3] Haioun C, Lepage E, Gisselbrecht C, et al. Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade nonHodgkin’s lymphoma in first complete remission: a study of 464 patients. J Clin Oncol 1994;12:2543. [4] Vose JM, Bierman PJ, Anderson JR, et al. Progressive disease after high-dose chemotherapy and autologous marrow transplantation for lymphoid malignancy: clinical course and patient follow-up. Blood 1992;80:2142. [5] Mrsı´c M, Horowitz MM, Atkinson K, et al. Second HLA-identical sibling transplants for leukemia recurrence. Bone Marrow Transplant 1992;9:269. [6] Barret AJ, Locatelli F, Treleaven JG, Gratwohl A, Szydlo R, Zwaan FE. Second transplants for leukaemic relapse after bone marrow transplantation: high early mortality but favourable effect of chronic GVHD on continued remission. Br J Haematol 1991;79:567. [7] Ringde´n O, Labopin M, Frassoni F, et al. Allogeneic bone marrow transplant or second autograft in patients with acute leukemia who relapse after an autograft. Bone Marrow Transplant 1999;24:389. [8] Blau IW, Basara N, Bischoff M, et al. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant. Bone Marrow Transplant 2000;25:41. [9] Tsai T, Goodman S, Saez R, et al. Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant 1997;20:859. [10] Mehta J, Tricot G, Jagannath S, et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant 1998;21:887. [11] Martı´nez C, Carreras E, Rovira M, et al. Patients with mantlecell lymphoma relapsing after autologous stem cell transplantation may be rescued by allogeneic transplantation. Bone Marrow Transplant 2000;26:677– 9. [12] Thomas ED, Storb R, Clift RA, et al. Bone marrow transplantation. New Engl J Med 1975;292:832. [13] Horowitz MM, Gale RP, Sondel PM, et al. Graft-versusleukemia reactions after bone marrow transplantation. Blood 1990;75:555. [14] Jones RJ, Ambinder RF, Piantadosi S, Santos DW. Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 1991;77:649.
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[15] Verdonck LF, Dekker AW, Lokhorst HM, Petersen EJ, Nieuwenhuis HK. Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade nonHodgkin’s lymphoma. Blood 1997;90:4201. [16] van Besien KW, de Lima M, Giralt SA, et al. Management of lymphoma recurrence after allogeneic transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 1997;19:977. [17] Schouten HC, Armitage JO, Klassen LW, et al. Allogeneic bone marrow transplantation in patients with lymphoma relapsing after autologous marrow transplantation. Bone Marrow Transplant 1989;4:119. [18] Moreau P, Me´chinaud F, Mahe´ B, et al. Successful allogeneic bone marrow transplantation for early relapse after autologous bone marrow transplantation in two cases of aggressive highgrade non-Hodgkin’s lymphoma. Bone Marrow Transplant 1996;18:665.
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[19] de Lima M, van Besien KW, Giralt SA, et al. Bone marrow transplantation after failure of autologous transplant for nonHodgkin’s lymphoma. Bone Marrow Transplant 1997;19:121. [20] Toor A, Morris C, Spencer H, et al. Allogeneic stem cell transplantation as salvage or consolidation therapy after prior melphalan based autotransplantation for poor risk multiple myeloma. Blood 1999;10(Suppl. 1):346a. [21] Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998;91:756. [22] Khouri IF, Keating M, Ko¨rbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998;16:2817.
Allogenic stem cell transplantation as salvage therapy for patients relapsing after autologous transplantation: experience from a single institution ´ lvaro Urbano-Ispizua, Carmen Martı´nez, Enric Carreras *, Montserrat Rovira, A Jordi Esteve, Franc¸esc Ferna´ndez-Avile´s, Marı´a Perales, Susana Rives, Marta Go´mez, Emilio Montserrat Transplantation Unit, Department of Hematology, Postgraduate School of Hematology ‘Farreras-Valentı´’, Institute of Hematology and Oncology, IDIBAPS Hospital Clı´nic, Uni6ersity of Barcelona, Villarroel 170, 08036 Barcelona, Spain Received 4 July 2000; accepted 20 October 2000
Abstract The prognosis of patients relapsing after an autologous transplant (autoSCT) is very poor. Allogenic stem cell transplantation (alloSCT) offers the possibility of curing some of these patients, at the cost, however, of a high transplant related mortality (TRM). The aim of this study was to analyze the outcome of 14 consecutive patients with hematologic malignancies, from a single institution, who underwent alloSCT for progressive disease after autoSCT. Patients had relapsed at a median of 11.5 months (range 2–72) after autoSCT and they underwent alloSCT at a median of 25.5 months (range 7 – 73) from the first transplant. Ten patients received HLA-identical related peripheral blood progenitor cells, three patients underwent matched-unrelated donor marrow transplants, and one patient received a mismatched related transplant. Conditioning regimens consisted of total body irradiation plus cyclophosphamide (n=5) or melphalan (n= 1), or high-dose combination chemotherapy (n= 8). Cyclosporin A and methothrexate were administered as graft-versus-host disease (GVHD) prophylaxis. Eight patients (57%) developed grade II–IV acute GVHD. All evaluable patients (n =6) presented extensive chronic GVHD. Overall survival at 1 year was 16% (median 3.5 months, 95% CI 0.7–10.3). Ten patients (71%) died from transplant related complications at a median of 3.5 months (range 0.7–11). Only one patient died of recurrent disease. Three patients remain alive and in complete remission at the time of this report (4, 20 and 20 months, respectively). In conclusion, alloSCT offers the possibility of a sustained control of the disease in some patients who relapse after an autoSCT. However, the procedure is associated with a high transplant-related mortality. Better results might be obtained by carefully selecting patients and by reducing the intensity of the preparative regimen. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Autologous transplantation; Relapse; Allogenic transplantation
1. Introduction Hematopoietic stem cell transplants are effective in a variety of hematologic malignancies [1 – 3]. Relapse of the underlying disease after transplantation remains the most frequent cause of treatment failure, particularly with autologous transplants (autoSCT), and is generally Abbre6iations: AlloSCT, allogenic stem cell transplantation; AutoSCT, autologous transplant; GVHD, graft-versus-host disease; TRM, transplant related mortality. * Corresponding author. fax: +34-93-2275428. E-mail address: [email protected] (E. Carreras).
considered to have a poor prognosis. The optimal treatment strategy for these patients is not resolved [4]. Although in some patients a second complete remission can be obtained with conventional chemotherapy, very few patients, if any, are cured with this approach. The role of second transplant in the treatment strategy of patients relapsing after a first transplant is controversial, basically because of the treatment-related toxicity. Allogenic stem cell transplantation (alloSCT) has been employed as a salvage therapy in patients who relapse after a first alloSCT. The results from large series of leukemia patients reported by the both Eu-
0145-2126/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 0 ) 0 0 1 4 6 - 6
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C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384
ropean Group for Blood and Marrow Transplantation and by the International Bone Marrow Transplantation registries have shown that a minority of the patients achieve long-term disease-free survival. However, a substantial proportion of the patients die due to the toxicity related to the procedure or because of the relapse of the disease [5,6]. Treatment results are better in young patients, individuals with a long time interval between the first and the second transplant, and those with good performance status. Experience with alloSCT in patients who relapse after autoSCT is limited, and factors that could predict a favorable outcome in this group of patients have not been fully established [7 – 10]. The purpose of this study was to evaluate the outcome of patients with hematologic malignancies who underwent alloSCT for progressive disease after autoSCT in our institution.
tion chemotherapy in nine (Table 1). The stem cell source for the first transplant was bone marrow (n=3), peripheral blood (n= 10), or both (n = 1). The conditioning regimen for alloSCT consisted of Cy 120 mg/kg and TBI 12–13 Gy in six cases, busulfan (Bu) 16 mg/kg and Cy 120 mg/kg in four, melphalan 140 mg/m2 and TBI 12 Gy in one, Cy 120 mg/kg +Bu 16 mg/kg +etoposide 30 mg/kg in one, and fludarabine 150 mg/m2 + melphalan 140 mg/m2 in two. Ten patients received HLA-identical related (sibling (n=9), father (n= 1)) peripheral blood progenitor cells, three underwent matched-unrelated donor marrow transplants, and one patient received a mismatched related peripheral blood transplant. All patients received cyclosporin A and short course methothrexate as graft-versus-host disease (GVHD) prophylaxis. The diagnosis and grading of acute and chronic GVHD was established according to the Seattle criteria [12]. Chronic GVHD was defined as the presence of GVHD after day 90.
2. Patients and methods
2.1. Patient population Fourteen alloSCT were performed between March 1995 and December 1999 for the treatment of hematologic malignancies relapsing after autoSCT. Five patients had non-Hodgkin’s lymphoma, four acute leukemia, three Hodgkin’s disease, one multiple myeloma, and one chronic myeloid leukemia. The outcome of two patients with mantle-cell lymphoma allografted after relapsing from an autoSCT has been described in a separate publication [11]. The clinical characteristics of these patients prior to both the first and second transplants are described in Table 1. The median age of patients at the time of alloSCT was 37 years (range 20–57). Nine patients were male and five were female. The median time interval from diagnosis to autoSCT was 15 months (range 4 – 44). Patients had relapsed at a median of 11.5 months (range 2 – 72) after autoSCT. All patients but one were treated with one (n =10) or ]two (n =3) chemotherapy regimens before alloSCT. Only three patients were in complete remission (CR) at the time of the second transplant, and one patient with CML was maintained in the chronic phase. AlloSCT was performed at a median of 25.5 months (range 7 – 73) following autoSCT. The median Karnofsky performance status score prior to alloSCT was 70% (range 40 – 80%).
2.2. Transplantation methods The preparative regimen for autoSCT consisted of cyclophosphamide (Cy) 120 mg/kg and fractionated total body irradiation (TBI) 12 Gy in four patients, melphalan 200 mg/m2 in one, and high-dose combina-
2.3. Statistical methods Median values and ranges for age and time intervals were determined. Survival was measured from the date of alloSCT to the date of death from any cause, or last known follow-up. The method of Kaplan and Meier was used to plot survival and relapse curves. The analysis was performed with SPSS software.
3. Results
3.1. Hematopoietic engraftment One patient died before hematopoietic engraftment. The median time to achieve an absolute neutrophil count of \ 0.5×109/l and \ 1.0× 109/l was 15 days (range 10–23), and 17 days (range 11–25), respectively. The median time to achieve a platelet count \20× 109/l was 15 days (7–38) days; five patients did not achieve this platelet count after transplant. No patient rejected the graft.
3.2. GHVD Eight patients (57%) developed acute GVHD grade II–IV. Six patients survived more than 90 days and were evaluable for chronic GVHD. All of them presented extensive chronic GVHD; this complication was fatal in two cases (patients c3 and c 4). Two patients (cases c2 and c 7) died due to infectious complications associated with immunosuppressive therapy for chronic GVHD (Table 2).
M M F F M M F F M M M M F M
01 02 03 04 05 06 07 08 09 10 11 12 13 14
26 48 27 38 48 36 45 53 57 28 42 24 20 32
Age at alloSCT
AML CML AML NHL MM HD NHL MCL MCL ACL NML ALL HD HD
Diagnosis
11 31 10 44 4 23 35 15 15 10 7 5 23 27
Time to autoSCTb
BM BM BM+PB PB PB PB PB PB PB PB PB BM PB PB
Stem cell source
AutoSCT
CyTBI BuCy BuCy BEAC MLF BEAC BEAC BEAC BEAC CyTBI CyTBI CyTBI BEAC BEAC
Conditioning regimen 72 12 9 10 9 11 24 24 13 7 5 42 15 2
Time to relapseb
73 39 12 26 19 29 33 30 19 11 7 47 25 17
Time between autoSCT– alloSCTb
HLA-matched UNR BM HLA-matched UNR BM HLA-mismatched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched sibling PB HLA-matched father PB HLA-matched sibling PB HLA-matched UNR BM HLA-matched sibling PB HLA-matched sibling PB
Stem cell source
AlloSCT
BuCY CyTBI CyTBI CyTBI MLFTBI BuCyVP CyTBI CyTBI CyTBI BuCy BuCy BuCyATG FludaraMLF FludaraMLF
Conditioning regimen
80 80 60 80 20 50 60 80 80 60 60 60 90 80
Karnofsky PS
Karnofsky PS, Karnofsky performance status; AML, acute mieloblastic leukemia; CML, chronic mieloid. leukemia; NHL, non-Hodgkin lymphoma; MM, multiple myeloma; HD, Hodgkin disease; MCL, mantle cell lymphoma; ALL, acute lymphoblastic leukemia; Cy, cyclophosphamide; TBI, total body irradiation; Bu, busulfan; BEAC, BCNU, etoposide, ara-C, cyclophosphamide; MLF, melphalan; VP, etoposide, Fludara, fludarabine; UNR, unrelated; BM, bone marrow; PB, peripheral blood. b Months.
a
Sex
Patient
Table 1 Patient characteristicsa C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384 381
C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384
382 Table 2 Allogenic transplantation outcome Patient
Acute GVHD
Chronic GVHD
Cause of death
Status
01 02 03 04 05 06 07 08 09 10 11 12 13 14
Grade Grade Grade Grade 0 Grade Grade Grade 0 Grade 0 Grade Grade NE
NEa Extensive Extensive NE NE Extensive Extensive Extensive Extensive NV NE NE NE NE
Idiopathic pneumonitis+acute GVHD Bacterial sepsis+chronic GVHD Chronic GVHD Idiopathic pneumonitis Multiorgan failure+fungal infection Chronic GVHD Bacterial sepsis+chronic GVHD
Dead, Dead, Dead, Dead, Dead, Dead, Dead, Alive, Alive, Dead, Dead, Dead, Alive, Dead,
a
III II III I II II II II II III
Viral infection Relapse Viral infection+acute GVHD Idiopathic pneumonitis
day +45 11 months 11 months 2 months day +21 7 months 9 months 20 months 20 months day +107 3 months 2 months 4 months day +22
NE, not evaluable.
3.3. Sur6i6al and cause of death The Kaplan –Meier estimated overall survival at 1 year was 16% (median 3.5 months, 95% CI: 0.7 –10.3) (Fig. 1). One patient died 3 months after transplant due to leukemic relapse. Ten patients (71%) died from transplant related complications at a median of 3.5 months (range 0.7 – 11) after the procedure. As shown in Table 2, causes of death included GVHD in six cases; bacterial, fungal or viral infections in five; idiopathic pneumonitis in three; and multiorgan failure in one. At the time of this report, three patients remain alive (Table 2). Two of them (patients c 8 and c 9) had mantle cell lymphoma and underwent alloSCT in CR and partial remission, respectively. Both developed extensive chronic GVHD remaining in CR 20 months after transplantation with a Karnofsky performance status score of 90%. Patient c13 had a resistant Hodgkin disease with lung involvement. She developed an acute grade III GVHD responding to immunosuppressive therapy. At the time of writing, the patient is in CR, 8 months after the alloSCT and she has developed extensive chronic GVHD. In these patients, the duration of the remission after the second transplant was longer than after the autoSCT.
contamination of the graft and the antitumoral activity mediated by the so-called graft-versus-tumor effect [13 –16]. The outcome of patients receiving an alloSCT after failing an autoSCT has been analyzed in several studies, the majority coming from registries or multiple institutions [7–10]. The largest series analyzed treatment results in patients with acute leukemia and has recently been reported by the European Blood and Marrow Transplantation Registry [7]. In this study, patients relapsing after an autoSCT underwent a second autologous (n= 74) or allogenic (n= 94) transplant as salvage therapy. Transplanted-related mortality (TRM) at 2 years was 51% in recipients of matched alloSCT and 26% following a second autoSCT (P B0.05). Leukemia-free survival (LFS) was not statistically different between the two groups since higher disease progression was observed after autoSCT. In the multivariate analysis, parameters associated with shorter LFS were: age \ 25 years, interval from first autoSCT
4. Discussion Patients with hematological malignancies who relapse after autoSCT have a very poor prognosis with a median survival of less than 1 year [4]. In most cases, a second autoSCT is not feasible due to the resistance of the disease to the therapy, or to the impossibility of collecting enough stem cells. For all these reasons, alloSCT is a potentially interesting salvage therapy offering the advantages of both the lack of tumor
Fig. 1. Overall survival after alloSCT.
C. Martı´nez et al. / Leukemia Research 25 (2001) 379–384
to relapse of 8 months or less, and TBI used as part of the preparative regimen in the first autoSCT. The role of second transplants in the management of patients with lymphoid malignancies has not been widely investigated [9,10,17 – 19]. Tsai et al. [9] analyzed 20 patients, 14 of them with lymphoma, who underwent alloSCT after failing autoSCT. In this study, the median survival was only 2 months; all the deaths were due to transplant-related complications that included bacterial or fungal infection, veno-occlusive disease of the liver, idiopathic interstitial pneumonitis and chronic GVHD. Only three patients were alive at the time of this report. Similar results have been shown in patients with multiple myeloma having relapsed after autoSCT [10,20]. Thus, Mehta et al. [10] performed a case-matched study comparing patients who underwent an alloSCT or a second autoSCT for relapsed or refractory multiple myeloma. The conclusions of this study were that while autoSCT might be superior to alloSCT when considering overall survival (54 vs. 29%, respectively, P =0.01), the event-free survival was comparable given the significantly lower disease progression after alloSCT (72 vs. 31%, respectively, P = 0.03). In our single institution study, which included all patients that had received an alloSCT after having relapsed from an autoSCT, alloSCT resulted in prompt engraftment. However, TRM due to toxicity, and the incidence of GVHD and infections were extremely high. Although the series is small, the proportion of long-term survivors does not appear to be different from that found in other series. It should be noted that, although most patients had relapsed after 8 months from autoSCT and only four received TBI as part of the preparation regimen for the first transplant, a great proportion of them were over 25 and had been heavily pretreated, factors which have been associated with poor outcome [7 – 10]. The last two patients of the series received low-intensity conditioning regimens in order to reduce the toxicity associated to the procedure. One of them is alive and in CR at the time of this report In summary, in patients who relapse after an autoSCT, salvage therapy with alloSCT is associated with a high TRM, but a proportion of patients may experience prolonged disease-free survival. The most important problem with this procedure is TRM. This could be diminished by a careful selection of the patients and, particularly, by reducing the intensity of the conditioning regimen, an avenue that is being actively investigated [21,22]. Taking into account the dismal prognosis of patients relapsing after a first transplant, as well as the high TRM associated with second regular transplants, the so-called ‘mini-transplants’ (or transplants with non-myeloablative regimens) are worth investigation.
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Acknowledgements This work has been supported in part by grants SGR 1998/00111 from the Comissionat per a Universitats i Recerca (Generalitat Catalunya), FISS-98/995, 98/0380, and 99/0189 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, Spanish Ministry of Health, and FIJC-00/P-CR and FIJC-00/ P-EM from the Jose´ Carreras International Foundation. We wish to thank Anna Bauer for the English grammar review of the manuscript. References [1] Foon KA, Gale RP. Therapy of acute myelogenous leukemia. Blood Rev 1992;6:15. [2] Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. New Engl J Med 1995;333:1540. [3] Haioun C, Lepage E, Gisselbrecht C, et al. Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade nonHodgkin’s lymphoma in first complete remission: a study of 464 patients. J Clin Oncol 1994;12:2543. [4] Vose JM, Bierman PJ, Anderson JR, et al. Progressive disease after high-dose chemotherapy and autologous marrow transplantation for lymphoid malignancy: clinical course and patient follow-up. Blood 1992;80:2142. [5] Mrsı´c M, Horowitz MM, Atkinson K, et al. Second HLA-identical sibling transplants for leukemia recurrence. Bone Marrow Transplant 1992;9:269. [6] Barret AJ, Locatelli F, Treleaven JG, Gratwohl A, Szydlo R, Zwaan FE. Second transplants for leukaemic relapse after bone marrow transplantation: high early mortality but favourable effect of chronic GVHD on continued remission. Br J Haematol 1991;79:567. [7] Ringde´n O, Labopin M, Frassoni F, et al. Allogeneic bone marrow transplant or second autograft in patients with acute leukemia who relapse after an autograft. Bone Marrow Transplant 1999;24:389. [8] Blau IW, Basara N, Bischoff M, et al. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant. Bone Marrow Transplant 2000;25:41. [9] Tsai T, Goodman S, Saez R, et al. Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant 1997;20:859. [10] Mehta J, Tricot G, Jagannath S, et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant 1998;21:887. [11] Martı´nez C, Carreras E, Rovira M, et al. Patients with mantlecell lymphoma relapsing after autologous stem cell transplantation may be rescued by allogeneic transplantation. Bone Marrow Transplant 2000;26:677– 9. [12] Thomas ED, Storb R, Clift RA, et al. Bone marrow transplantation. New Engl J Med 1975;292:832. [13] Horowitz MM, Gale RP, Sondel PM, et al. Graft-versusleukemia reactions after bone marrow transplantation. Blood 1990;75:555. [14] Jones RJ, Ambinder RF, Piantadosi S, Santos DW. Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 1991;77:649.
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