- Email: [email protected]
Is there a role for consolidation therapy pre-transplantation?
Best Practice & Research Clinical Haematology Vol. 19, No. 2, pp. 301–310, 2006 doi:10.1016/j.beha.2005.11.010 available online at http://www.sciencedirect.com
5 Is there a role for consolidation therapy pre-transplantation? Jacob M. Rowe*
MD
Director Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel Technion, Israel Institute of Technology, Haifa 31096, Israel
There is much confusion and uncertainty regarding the need for consolidation therapy before bone marrow transplantation. There are no prospective studies that have established clear guidelines and much of the information has been based on retrospective analyses of data obtained from the international bone marrow transplant registries. These data suggest that there may not be a role for consolidation therapy before an allogeneic transplantation. However, this may not be applicable to transplants performed following reduced intensity conditioning or to transplants performed beyond first remission. The data for autologous transplantation are substantially more confused. Common practice includes the administration of consolidation therapy prior to transplantation, although there is enormous variability in the amount of cycles and in the doses that are given before transplantation. Key words: consolidation therapy pre-transplantation.
One of the unanswered issues in bone marrow transplantation is the question of whether there is a role for consolidation therapy prior to transplantation in acute myelogenous leukemia (AML). Clearly there are different considerations for allogeneic or autologous transplantation but, in both cases, there have been no major prospective studies that have actually looked at this (Table 1). In virtually every large prospective study of AML over the past decade, bone marrow transplantation, whether allogeneic or autologous, usually appears at the tail end of one or more randomizations with varying degrees of prior therapy. There have been registry analyses that provide some important information on this aspect. However, the problem is compounded by the fact that those data that are available may not be generally applicable without considering several factors. First, the intensity of induction therapy may uniquely impact upon the amount of post-
* Tel.: C972 4 854 2541; fax: C972 4 854 2343. E-mail address: [email protected]
1521-6926/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
302 J. M. Rowe
Table 1. Consolidation therapy pre-transplantation. Very little data No prospective studies Some registry analyses Available data may not be generally applicable without considering several factors Intensity of induction therapy Prognostic factors, especially cytogenetic Interval to transplant Conditioning regimen CR1 vs CR2 or beyond
remission therapy that is needed to effect a cure. Second, pre-transplant prognostic factors, especially cytogenetics, may ultimately be crucial in determining how much post-remission therapy is required prior to transplantation.1–3 It is possible that what may be right for favorable or intermediate cytogenetics, may not be applicable for patients with unfavorable cytogenetics. Third, one of the most difficult issues is adjusting for the effect of the interval from diagnosis or from complete remission to transplant. In prospective studies this is usually dealt with by an intent-to-treat analysis from an early time point. However, in retrospective registry analyses, despite some creative statistical models and attempts at adjustments, this still remains a major obstacle in comparing groups of patients. Finally, the conditioning regimen is rarely taken into account. While most investigators agree that there is no major difference in outcome for AML between cyclophosphamide and total body irradiation (TBI) versus busulfan and cyclophosphamide, the new era of reduced intensity conditioning may make a major difference in this consideration. Table 2 summarizes the data from four major prospective studies that have been reported over the past decade comparing allogeneic transplant versus autologous transplant versus chemotherapy in AML in first complete remission. All of these studies showed the lowest relapse rate following an allogeneic transplant, with autologous transplant coming next and the highest relapse rate for patients receiving chemotherapy. However, all of these trials were conducted differently, such that the amount of post-remission therapy pre-transplant is simply not comparable. In the largest reported trial in AML, conducted by the Medical Research Council (MRC) in the United Kingdom5 both the allogeneic and the autologous transplant arms came at the tail end of three intensive courses of consolidation after achievement of CR; in fact, significantly more so than in any other study. In contrast, in the US Intergroup study6 patients went into transplant as early as was considered feasible. Only one course of Table 2. Relapse following post remission therapy.
GIMEMA, 19957 GOELAM, 19978 MRC, 19985 (excluding children) ECOG/SWOG, 19986
Allogeneic BMT (%)
Autulogous BMT (%)
Chemotherpy (%)
24 28 19 29
40 45 35 48
57 55 53 61
Reproduced with permission from Appelbaum FR et al.4
AML pre-transplant consolidation 303
attenuated consolidation was added; its main purpose was to make sure that patients did not relapse early while waiting for the transplant procedures to be sorted out. In this study—contrary to the MRC study—the aim was to go transplant, both allogeneic and autologous, as early as possible without any significant consolidation. In the study by the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA)7, which was the first major published randomized study of these various treatment options in AML, both the autologous and the allogeneic patients received one course of pretransplant consolidation, although this was not with a typical high-dose cytarabine regimen. What basically characterized all of these early studies was an assumption that the consolidation therapy that needed to be given pre-transplantation should comprise the same total dose whether this was followed by an allogeneic or an autologous transplantation. The one early exception to this was the study by the Groupe Ouest-Est Leucemies Aigues Myeloblastiques (GOELAM)8, where patients who had a matched sibling donor went straight to an allogeneic transplant after achieving complete remission; the idea behind this study design was that you could not compare the allogeneic and the autologous approach and those patients who were randomized to an autologous transplant received additional consolidation pre-transplant. The concept behind this study is much more in line with what the registry data suggest and is also closer to the common practice today in many centers.
ALLOGENEIC BONE MARROW TRANSPLANTATION It is important to differentiate between standard conditioning and reduced intensity conditioning as well as the remission status—first complete remission or a later remission. Most of the registry data that are available for AML patients in first complete remission comprise of patients who received standard conditioning regimen. To date there have been two major analyses from transplant registries. The first attempt to look at this was performed by the European Bone Marrow Transplant Group (EBMTG) who reported their data in 2000.9 This retrospective analysis looked at 826 patients who were transplanted between 1980 and 1995 and who had at least 5 years of follow-up (Table 3). The 154 AML patients in first remission who did not receive any consolidation prior to transplant were compared with patients who received various forms of consolidation with cytarabine (Ara-C)—some with standard dose, which they defined as 100–200 mg/m2 for 5–10 days; high-dose was defined as over 1.5 g/m2 for 4– 6 days and anywhere in between those two was defined as the intermediate-dose Table 3. Pre-transplant consolidation therapy-EBMT data (5years). Allogeneic transplant (nZ826)
n
DFS (%)
Replapse (%)
TRM (%)
No consolidation Consolidation Standard-dose Ara-C Intermediate-dose Ara-C High-dose-Ara-C P
154
51
27
29
393 68 193
56 54 56 0.88
24 21 23 0.72
26 28 27 0.92
DFS, disease free survival; TRM, treatment related mortality. Reproduced with permission from Cahn J-Y et al Table 3.9
304 J. M. Rowe
cytarabine. Although the numbers suggested that there may be a slight advantage in reducing the relapse rate and an improvement in the leukemia-free survival with consolidation, none of these differences were significant and similarly, the transplant-related mortality was not different between patients who did not receive any pre-transplant consolidation and those who received some form of consolidation pretransplant. The conclusion from this EBMT retrospective analysis was that for AML patients in first complete remission receiving an allogeneic transplant, and relying to a large extent on the immunologic effects of the graft-versus-leukemia, there was probably no role for added consolidation therapy after achievement of complete remission. It was recognized that such data did not rule out the need for some form of consolidation therapy in specific subgroups. Although cytogenetics were reviewed in this study, it was simply not possible to include these in the multivariate analysis owing to the small number of patients in each subgroup. At the same time the international bone marrow transplant registry (IBMTR) looked, retrospectively, at the same issue.10 The IBMTR reported on 431 AML patients transplanted between 1989 and 1995 and basically came to the identical conclusion as the one reported by the EBMT, even though there were only about half the patients in this study. There was no difference in the transplant-related mortality (Figure 1), in the incidence of relapse (Figure 2), in the disease-free survival (Figure 3) and in the overall survival (Figure 4). This analysis was as thorough as any retrospective analysis could be conducted and used quite sophisticated stepwise regression analysis to try and correct in multivariate analyses other variables such as the interval from complete remission to a transplant. The conclusion from these two registry analyses was that the data for an allogeneic transplant, although certainly not conclusive, appears to support the increasingly used approach for AML patients in first complete remission who receive standard conditioning regimen that there may not be a need for any consolidation therapy if performed in first complete remission. However, this relies heavily on harnessing the graft-versus-leukemia effect to eradicate minimal residual disease and there are no data as yet to say whether the same conclusion applies if performed beyond first remission. At that point, is it too much to expect from the immune mechanisms of graft-versus-leukemia? Similarly, especially in older patients in whom reduced-intensity conditioning is increasingly performed the question is wide open and there are as yet no comparative data to indicate whether transplant alone may be sufficient in first complete remission.
AUTOLOGOUS BONE MARROW TRANSPLANT In contrast to allogeneic transplantation, the issue regarding consolidation therapy pre autologous transplantation is much more difficult and a greater degree of uncertainty prevails. The underlying assumption is that there are no major immunologic effects with an autologous transplant and in essence the transplant itself is another form of intensive consolidation. As there are virtually no prospective data, in the non-transplant setting, on the number of cycles of intensive therapy that are needed in AML, it is not surprising that this issue remains open. Figure 5a is a composite of two sets of data that just heighten the level of uncertainty that exists. The data from the City of Hope Medical Center, CA, USA, reported a disease-free survival for a cohort of AML patients in first complete remission (CR1) who received intensive consolidation with high-dose cytarabine prior to the autologous transplant, as is fairly common practice.11 In contrast, these data are virtually
AML pre-transplant consolidation 305
100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3 Years
4
5
6
Figure 1. Transplant-Related Mortality. Reproduced with permission from Tallman MS et al.10
identical to the data published by the Eastern Cooperative Oncology Group (ECOG) (Figure 5b) showing the identical disease-free survival for AML patients in first complete remission who received an autologous transplant right after the achievement of complete remission without any consolidation. Table 4 summarizes the registry data from the EBMT for 846 patients who underwent an autologous transplant with at least a 5-year follow-up. Basically, in this analysis there was no difference whatsoever between patients who received no 100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3
4
5
6
Years Figure 2. Incidence of relapse. Reproduced with permission from Tallman MS et al.10
306 J. M. Rowe
100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3
4
5
6
Years Figure 3. Disease free survival. Reproduced with permission from Tallman MS et al.10
consolidation and the 800 patients who received some form of pre-transplant consolidation and it did not matter whether one looked at the disease-free survival, the relapse or the transplant-related mortality. The problem with these data is the fact that there were only 43 patients who did not receive any form of consolidation, significantly reducing the level of confidence that one can have in the conclusions that were drawn from this analysis. In contrast, the American Blood and Marrow Transplant Registry 100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3 Years
4
5
6
Figure 4. Overall survival. Reproduced with permission from Tallman MS et al.10
AML pre-transplant consolidation 307
Disease Free Survival (%)
(a) 100 80
AML
60
CR
n=44
40
HiDAC
20
ABMT
0 0
1
2
3
4
6
5
Years ECOG-PC486
Disease Free Survival (%)
(b) 100
AML
80 n=39
60 40
CR ABMT
20 0 0
1
2
3
4
5
Years Figure 5. (a) AML in CR1: Autologous transplant with in vivo purging. reproduced with permission from Stein et al11 Figure 2. (b) AML in CR1: Autologous transplant without in vivo purging. Reproduced with permission from Cassileth PA et al12.
(ABMTR) recently reported on the same issue.13 This was an analysis of 639 patients undergoing an autologous transplant for AML in first complete remission between 1989 and 1998 for whom comprehensive data were reported to the ABMTR. 146 patients proceeded to transplant right after achieving first complete remission without any consolidation and 489 patients received some form of consolidation, equally divided between those who received standard dose cytarabine and those who received highdose cytarabine. The data are divided by the method of stem cell harvest, whether this was from the bone marrow or from the peripheral blood. The transplant-related mortality at 3 years was identical among the various groups (Figure 6). However, in contrast to the data from the EBMT, there appeared to be an increased relapse rate among patients not receiving any form of consolidation. (Figure 7). Although the difference was across the board, it reached statistical significance only among patients receiving peripheral blood transplant. Similarly, looking at the leukemia-free survival, there was a major difference in favor of patients receiving some form of consolidation therapy (Figure 8). And finally, most interestingly, there was a statistically significant
308 J. M. Rowe
Table 4. Pre-transplant consolidation therapy-EBMT data (5 years). Allogeneic transplant (nZ826) No consolidation Consolidation Standard-dose Ara-C Intermediate-dose Ara-C High-dose-Ara-C P
n 43 357 158 283
DFS (%)
Replapse (%)
TRM (%)
36
55
21
46 50 46 0.63
47 47 47 0.91
13 6 14 0.39
DFS, disease free survival; TRM, treatment related mortality. Reproduced with permission from Cahn J-Y et al Table 2.9
100 No consolidation vs consolidation BM
80 PERCENT
p =.76 p =.55
No consolidation vs consolidation PBSC
At 3 yrs.
ABMTR Data
60 40 Consolidation, BM (n = 291)
20
Consolidation, PBSC (n = 198)
No consolidation, PBSC (n = 37) No consolidation, BM (n = 120)
0 0
1
2
3
4
5
Years Figure 6. Transplant–related mortality. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
ABMT R Data
100 No consolidation vs consolidation BM p = .15 No consolidation vs consolidation PBSC p = .05
PERCENT
80
At 3 yrs.
No conso lid ation , PBSC (n = 37)
60
No consolidation, BM (n = 120)
40 Consolidation, PB SC (n = 198)
20 0
Consolidation, B M (n = 291)
0
1
2
3
4
5
YEARS
Figure 7. Relapse. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
AML pre-transplant consolidation 309 No consolidation vs consolidation BM p = .16 No consolidation vs consolidation PBSC p = <.01
100
At 3 yrs.
80 PERCENT
Consolidation, PBSC (n = 191)
60
Consolidation, BM (n = 286) No consolidation, BM (n = 118)
40
No consolidation, PBSC (n = 37)
20 0 0
1
2
3
4
5
YEARS
Figure 8. Leukemia-free Survival. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
difference in the overall survival irrespective of whether bone marrow or peripheral blood was used, in favor of patients who received any type of consolidation therapy, although in this particular retrospective study it did not matter what form of consolidation therapy was given; whether this was high-dose cytarabine or intermediate dose cytarabine (Figure 8). In contrast to the EBMT, the conclusion from these data was that patients with AML in first remission who were going to an autologous transplant should receive some form of consolidation. The data from the ABMTR have the strength of numbers in that the patients who did not receive any consolidation therapy comprised a respectable group of 157 patients which lend greater confidence to this analysis. A cautious conclusion from these data, based primarily on the ABMTR analysis (Figure 9), support the current practice of administering some form of consolidation therapy prior to an autologous transplant in AML. However, the type and number of cycles are unknown and is much in line with the general uncertainty that prevails also in the non-transplant post-remission therapy.14 No consolidation vs consolidation BM p = .01 No consolidation vs consolidation PBSC p = <.01
100
PERCENT
80
At 3 yrs.
Consolidation, PBSC (n = 198) Consolidation, BM (n = 291)
60 No consolidation, BM (n = 120)
40 No consolidation, PBSC (n = 37)
20 0 0
1
2
3
4
5
YEARS Figure 9. Overall Survival. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
310 J. M. Rowe
REFERENCES 1. Byrd JC, Mrozek K, Dodge RK et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from cancer and leukemia group B (CALGB 8461). Blood 2002; 100: 4325–4336. 2. Grimwade D, Walker H, Oliver F et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukaemia working parties. Blood 1998; 92: 2322–2333. 3. Slovak ML, Kopecky KJ, Cassileth PA et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a southwest oncology group/ eastern cooperative oncology group study. Blood 2000; 96: 4075–4083. 4. Appelbaum FR, Rowe JM, Radich J & Dick JE. Acute myeloid leukemia. Hematology (American Society Hematology Education Program) 2001; 62–86. 5. Burnett AK, Goldstone AH, Stevens RM et al. Randomised comparison of addition of autologous bonemarrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK medical research council adult and children’s leukaemia working parties. Lancet 1998; 351: 700–708. 6. Cassileth PA, Harrington D, Appelbaum FR et al. A comparison of chemotherapy versus autologous bone marrow transplantation versus allogeneic bone marrow. transplantation in first remission of adult acute myeloid leukemia: an intergroup study. E3489). N Engl J Med 1998; 339: 1649–1656. 7. Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European organization for research and treatment of cancer (EORTC) and the gruppo italiano malattie ematologiche maligne dell’adulto (GIMEMA) leukemia cooperative groups. N Engl J Med 1995; 332(4): 217–223. 8. Harousseau JL, Cahn JY, Pignon B et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The groupe ouest est leucemies aigues myeloblastiques (GOELAM). Blood 1997; 90: 2978–2986. 9. Cahn JY, Labopin M, Sierra J et al. No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission. Acute leukaemia working party of the European group for blood and marrow transplantation (EBMT). Br J Haematol 2000; 110: 308–314. 10. Tallman MS, Rowlings PA, Milone G et al. Effect of post remission chemotherapy prior to HLA-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 2000; 96: 1254– 1258. 11. Stein AS, O’Donnell MR, Chai A et al. In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. J Clin Oncol 1996; 14: 2206–2216. 12. Cassileth PA, Andersen J, Lazarus HM et al. Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol 1993; 11: 314–319. 13. Tallman MS, Perez WS, Lazarus HM, et al Pretransplant consolidation chemotherapy decreases leukemia relapse after autologous blood and marrow transplant for acute myelogenous leukemia in first remission. Biol Blood Marrow Transpl 2006, in press. 14. Rowe JM. Uncertainties in the standard care of acute myelogenous leukemia. State-of-the-art mini-review. Leukemia 2001; 15: 677–679.
5 Is there a role for consolidation therapy pre-transplantation? Jacob M. Rowe*
MD
Director Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel Technion, Israel Institute of Technology, Haifa 31096, Israel
There is much confusion and uncertainty regarding the need for consolidation therapy before bone marrow transplantation. There are no prospective studies that have established clear guidelines and much of the information has been based on retrospective analyses of data obtained from the international bone marrow transplant registries. These data suggest that there may not be a role for consolidation therapy before an allogeneic transplantation. However, this may not be applicable to transplants performed following reduced intensity conditioning or to transplants performed beyond first remission. The data for autologous transplantation are substantially more confused. Common practice includes the administration of consolidation therapy prior to transplantation, although there is enormous variability in the amount of cycles and in the doses that are given before transplantation. Key words: consolidation therapy pre-transplantation.
One of the unanswered issues in bone marrow transplantation is the question of whether there is a role for consolidation therapy prior to transplantation in acute myelogenous leukemia (AML). Clearly there are different considerations for allogeneic or autologous transplantation but, in both cases, there have been no major prospective studies that have actually looked at this (Table 1). In virtually every large prospective study of AML over the past decade, bone marrow transplantation, whether allogeneic or autologous, usually appears at the tail end of one or more randomizations with varying degrees of prior therapy. There have been registry analyses that provide some important information on this aspect. However, the problem is compounded by the fact that those data that are available may not be generally applicable without considering several factors. First, the intensity of induction therapy may uniquely impact upon the amount of post-
* Tel.: C972 4 854 2541; fax: C972 4 854 2343. E-mail address: [email protected]
1521-6926/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
302 J. M. Rowe
Table 1. Consolidation therapy pre-transplantation. Very little data No prospective studies Some registry analyses Available data may not be generally applicable without considering several factors Intensity of induction therapy Prognostic factors, especially cytogenetic Interval to transplant Conditioning regimen CR1 vs CR2 or beyond
remission therapy that is needed to effect a cure. Second, pre-transplant prognostic factors, especially cytogenetics, may ultimately be crucial in determining how much post-remission therapy is required prior to transplantation.1–3 It is possible that what may be right for favorable or intermediate cytogenetics, may not be applicable for patients with unfavorable cytogenetics. Third, one of the most difficult issues is adjusting for the effect of the interval from diagnosis or from complete remission to transplant. In prospective studies this is usually dealt with by an intent-to-treat analysis from an early time point. However, in retrospective registry analyses, despite some creative statistical models and attempts at adjustments, this still remains a major obstacle in comparing groups of patients. Finally, the conditioning regimen is rarely taken into account. While most investigators agree that there is no major difference in outcome for AML between cyclophosphamide and total body irradiation (TBI) versus busulfan and cyclophosphamide, the new era of reduced intensity conditioning may make a major difference in this consideration. Table 2 summarizes the data from four major prospective studies that have been reported over the past decade comparing allogeneic transplant versus autologous transplant versus chemotherapy in AML in first complete remission. All of these studies showed the lowest relapse rate following an allogeneic transplant, with autologous transplant coming next and the highest relapse rate for patients receiving chemotherapy. However, all of these trials were conducted differently, such that the amount of post-remission therapy pre-transplant is simply not comparable. In the largest reported trial in AML, conducted by the Medical Research Council (MRC) in the United Kingdom5 both the allogeneic and the autologous transplant arms came at the tail end of three intensive courses of consolidation after achievement of CR; in fact, significantly more so than in any other study. In contrast, in the US Intergroup study6 patients went into transplant as early as was considered feasible. Only one course of Table 2. Relapse following post remission therapy.
GIMEMA, 19957 GOELAM, 19978 MRC, 19985 (excluding children) ECOG/SWOG, 19986
Allogeneic BMT (%)
Autulogous BMT (%)
Chemotherpy (%)
24 28 19 29
40 45 35 48
57 55 53 61
Reproduced with permission from Appelbaum FR et al.4
AML pre-transplant consolidation 303
attenuated consolidation was added; its main purpose was to make sure that patients did not relapse early while waiting for the transplant procedures to be sorted out. In this study—contrary to the MRC study—the aim was to go transplant, both allogeneic and autologous, as early as possible without any significant consolidation. In the study by the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA)7, which was the first major published randomized study of these various treatment options in AML, both the autologous and the allogeneic patients received one course of pretransplant consolidation, although this was not with a typical high-dose cytarabine regimen. What basically characterized all of these early studies was an assumption that the consolidation therapy that needed to be given pre-transplantation should comprise the same total dose whether this was followed by an allogeneic or an autologous transplantation. The one early exception to this was the study by the Groupe Ouest-Est Leucemies Aigues Myeloblastiques (GOELAM)8, where patients who had a matched sibling donor went straight to an allogeneic transplant after achieving complete remission; the idea behind this study design was that you could not compare the allogeneic and the autologous approach and those patients who were randomized to an autologous transplant received additional consolidation pre-transplant. The concept behind this study is much more in line with what the registry data suggest and is also closer to the common practice today in many centers.
ALLOGENEIC BONE MARROW TRANSPLANTATION It is important to differentiate between standard conditioning and reduced intensity conditioning as well as the remission status—first complete remission or a later remission. Most of the registry data that are available for AML patients in first complete remission comprise of patients who received standard conditioning regimen. To date there have been two major analyses from transplant registries. The first attempt to look at this was performed by the European Bone Marrow Transplant Group (EBMTG) who reported their data in 2000.9 This retrospective analysis looked at 826 patients who were transplanted between 1980 and 1995 and who had at least 5 years of follow-up (Table 3). The 154 AML patients in first remission who did not receive any consolidation prior to transplant were compared with patients who received various forms of consolidation with cytarabine (Ara-C)—some with standard dose, which they defined as 100–200 mg/m2 for 5–10 days; high-dose was defined as over 1.5 g/m2 for 4– 6 days and anywhere in between those two was defined as the intermediate-dose Table 3. Pre-transplant consolidation therapy-EBMT data (5years). Allogeneic transplant (nZ826)
n
DFS (%)
Replapse (%)
TRM (%)
No consolidation Consolidation Standard-dose Ara-C Intermediate-dose Ara-C High-dose-Ara-C P
154
51
27
29
393 68 193
56 54 56 0.88
24 21 23 0.72
26 28 27 0.92
DFS, disease free survival; TRM, treatment related mortality. Reproduced with permission from Cahn J-Y et al Table 3.9
304 J. M. Rowe
cytarabine. Although the numbers suggested that there may be a slight advantage in reducing the relapse rate and an improvement in the leukemia-free survival with consolidation, none of these differences were significant and similarly, the transplant-related mortality was not different between patients who did not receive any pre-transplant consolidation and those who received some form of consolidation pretransplant. The conclusion from this EBMT retrospective analysis was that for AML patients in first complete remission receiving an allogeneic transplant, and relying to a large extent on the immunologic effects of the graft-versus-leukemia, there was probably no role for added consolidation therapy after achievement of complete remission. It was recognized that such data did not rule out the need for some form of consolidation therapy in specific subgroups. Although cytogenetics were reviewed in this study, it was simply not possible to include these in the multivariate analysis owing to the small number of patients in each subgroup. At the same time the international bone marrow transplant registry (IBMTR) looked, retrospectively, at the same issue.10 The IBMTR reported on 431 AML patients transplanted between 1989 and 1995 and basically came to the identical conclusion as the one reported by the EBMT, even though there were only about half the patients in this study. There was no difference in the transplant-related mortality (Figure 1), in the incidence of relapse (Figure 2), in the disease-free survival (Figure 3) and in the overall survival (Figure 4). This analysis was as thorough as any retrospective analysis could be conducted and used quite sophisticated stepwise regression analysis to try and correct in multivariate analyses other variables such as the interval from complete remission to a transplant. The conclusion from these two registry analyses was that the data for an allogeneic transplant, although certainly not conclusive, appears to support the increasingly used approach for AML patients in first complete remission who receive standard conditioning regimen that there may not be a need for any consolidation therapy if performed in first complete remission. However, this relies heavily on harnessing the graft-versus-leukemia effect to eradicate minimal residual disease and there are no data as yet to say whether the same conclusion applies if performed beyond first remission. At that point, is it too much to expect from the immune mechanisms of graft-versus-leukemia? Similarly, especially in older patients in whom reduced-intensity conditioning is increasingly performed the question is wide open and there are as yet no comparative data to indicate whether transplant alone may be sufficient in first complete remission.
AUTOLOGOUS BONE MARROW TRANSPLANT In contrast to allogeneic transplantation, the issue regarding consolidation therapy pre autologous transplantation is much more difficult and a greater degree of uncertainty prevails. The underlying assumption is that there are no major immunologic effects with an autologous transplant and in essence the transplant itself is another form of intensive consolidation. As there are virtually no prospective data, in the non-transplant setting, on the number of cycles of intensive therapy that are needed in AML, it is not surprising that this issue remains open. Figure 5a is a composite of two sets of data that just heighten the level of uncertainty that exists. The data from the City of Hope Medical Center, CA, USA, reported a disease-free survival for a cohort of AML patients in first complete remission (CR1) who received intensive consolidation with high-dose cytarabine prior to the autologous transplant, as is fairly common practice.11 In contrast, these data are virtually
AML pre-transplant consolidation 305
100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3 Years
4
5
6
Figure 1. Transplant-Related Mortality. Reproduced with permission from Tallman MS et al.10
identical to the data published by the Eastern Cooperative Oncology Group (ECOG) (Figure 5b) showing the identical disease-free survival for AML patients in first complete remission who received an autologous transplant right after the achievement of complete remission without any consolidation. Table 4 summarizes the registry data from the EBMT for 846 patients who underwent an autologous transplant with at least a 5-year follow-up. Basically, in this analysis there was no difference whatsoever between patients who received no 100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3
4
5
6
Years Figure 2. Incidence of relapse. Reproduced with permission from Tallman MS et al.10
306 J. M. Rowe
100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3
4
5
6
Years Figure 3. Disease free survival. Reproduced with permission from Tallman MS et al.10
consolidation and the 800 patients who received some form of pre-transplant consolidation and it did not matter whether one looked at the disease-free survival, the relapse or the transplant-related mortality. The problem with these data is the fact that there were only 43 patients who did not receive any form of consolidation, significantly reducing the level of confidence that one can have in the conclusions that were drawn from this analysis. In contrast, the American Blood and Marrow Transplant Registry 100
None Standard Dose HiDAC
Percent
80
n=62 n=222 n=147
IBMTR Data
60
40
20
0 0
1
2
3 Years
4
5
6
Figure 4. Overall survival. Reproduced with permission from Tallman MS et al.10
AML pre-transplant consolidation 307
Disease Free Survival (%)
(a) 100 80
AML
60
CR
n=44
40
HiDAC
20
ABMT
0 0
1
2
3
4
6
5
Years ECOG-PC486
Disease Free Survival (%)
(b) 100
AML
80 n=39
60 40
CR ABMT
20 0 0
1
2
3
4
5
Years Figure 5. (a) AML in CR1: Autologous transplant with in vivo purging. reproduced with permission from Stein et al11 Figure 2. (b) AML in CR1: Autologous transplant without in vivo purging. Reproduced with permission from Cassileth PA et al12.
(ABMTR) recently reported on the same issue.13 This was an analysis of 639 patients undergoing an autologous transplant for AML in first complete remission between 1989 and 1998 for whom comprehensive data were reported to the ABMTR. 146 patients proceeded to transplant right after achieving first complete remission without any consolidation and 489 patients received some form of consolidation, equally divided between those who received standard dose cytarabine and those who received highdose cytarabine. The data are divided by the method of stem cell harvest, whether this was from the bone marrow or from the peripheral blood. The transplant-related mortality at 3 years was identical among the various groups (Figure 6). However, in contrast to the data from the EBMT, there appeared to be an increased relapse rate among patients not receiving any form of consolidation. (Figure 7). Although the difference was across the board, it reached statistical significance only among patients receiving peripheral blood transplant. Similarly, looking at the leukemia-free survival, there was a major difference in favor of patients receiving some form of consolidation therapy (Figure 8). And finally, most interestingly, there was a statistically significant
308 J. M. Rowe
Table 4. Pre-transplant consolidation therapy-EBMT data (5 years). Allogeneic transplant (nZ826) No consolidation Consolidation Standard-dose Ara-C Intermediate-dose Ara-C High-dose-Ara-C P
n 43 357 158 283
DFS (%)
Replapse (%)
TRM (%)
36
55
21
46 50 46 0.63
47 47 47 0.91
13 6 14 0.39
DFS, disease free survival; TRM, treatment related mortality. Reproduced with permission from Cahn J-Y et al Table 2.9
100 No consolidation vs consolidation BM
80 PERCENT
p =.76 p =.55
No consolidation vs consolidation PBSC
At 3 yrs.
ABMTR Data
60 40 Consolidation, BM (n = 291)
20
Consolidation, PBSC (n = 198)
No consolidation, PBSC (n = 37) No consolidation, BM (n = 120)
0 0
1
2
3
4
5
Years Figure 6. Transplant–related mortality. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
ABMT R Data
100 No consolidation vs consolidation BM p = .15 No consolidation vs consolidation PBSC p = .05
PERCENT
80
At 3 yrs.
No conso lid ation , PBSC (n = 37)
60
No consolidation, BM (n = 120)
40 Consolidation, PB SC (n = 198)
20 0
Consolidation, B M (n = 291)
0
1
2
3
4
5
YEARS
Figure 7. Relapse. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
AML pre-transplant consolidation 309 No consolidation vs consolidation BM p = .16 No consolidation vs consolidation PBSC p = <.01
100
At 3 yrs.
80 PERCENT
Consolidation, PBSC (n = 191)
60
Consolidation, BM (n = 286) No consolidation, BM (n = 118)
40
No consolidation, PBSC (n = 37)
20 0 0
1
2
3
4
5
YEARS
Figure 8. Leukemia-free Survival. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
difference in the overall survival irrespective of whether bone marrow or peripheral blood was used, in favor of patients who received any type of consolidation therapy, although in this particular retrospective study it did not matter what form of consolidation therapy was given; whether this was high-dose cytarabine or intermediate dose cytarabine (Figure 8). In contrast to the EBMT, the conclusion from these data was that patients with AML in first remission who were going to an autologous transplant should receive some form of consolidation. The data from the ABMTR have the strength of numbers in that the patients who did not receive any consolidation therapy comprised a respectable group of 157 patients which lend greater confidence to this analysis. A cautious conclusion from these data, based primarily on the ABMTR analysis (Figure 9), support the current practice of administering some form of consolidation therapy prior to an autologous transplant in AML. However, the type and number of cycles are unknown and is much in line with the general uncertainty that prevails also in the non-transplant post-remission therapy.14 No consolidation vs consolidation BM p = .01 No consolidation vs consolidation PBSC p = <.01
100
PERCENT
80
At 3 yrs.
Consolidation, PBSC (n = 198) Consolidation, BM (n = 291)
60 No consolidation, BM (n = 120)
40 No consolidation, PBSC (n = 37)
20 0 0
1
2
3
4
5
YEARS Figure 9. Overall Survival. BM—stem cell harvested from the bone marrow. PBSC—stem cell harvested from the peripheral blood. Reproduced with permission from Tallman MS et al.13
310 J. M. Rowe
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