- Email: [email protected]
Hematopoietic cell transplantation in first complete remission versus early relapse
Best Practice & Research Clinical Haematology Vol. 19, No. 2, pp. 333–339, 2006 doi:10.1016/j.beha.2005.12.001 available online at http://www.sciencedirect.com
9 Hematopoietic cell transplantation in first complete remission versus early relapse Frederick R. Appelbaum*
MD
Director Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, 1100 Fairview Avenue North, D5-310, P.O. Box 19024, Seattle, WA 98109-1024, USA
S. Frieda Pearce1 PhD Although data from a number of clinical trials can help guide the choice, the decision of whether patients with acute myeloid leukemia (AML) should undergo transplantation while in first remission or should have transplantation withheld until relapse is a particularly difficult one. Current data suggest that patients with AML and unfavorable cytogenetics should undergo allogeneic transplantation while in first remission if at all possible. Patients with AML and good risk cytogenetics can probably forgo transplantation until after first relapse. For patients with intermediate risk disease, the decision of transplantation during first remission versus waiting until first relapse is particularly difficult and should be made only after considering additional individual risk factors. If the decision is made to delay transplantation until first relapse, there are additional steps that physicians should take to ensure that salvage transplantation is possible, including identifying the source of hematopoietic stem cells in advance of relapse and developing a careful monitoring plan for the patient while in first remission. Keywords: transplantation; allogeneic; myeloid leukemia.
A key decision most patients with AML and their physicians will face is whether to undergo hematopoietic cell transplantation (HCT) while in first remission or reserve transplantation until relapse. Nonetheless, no clinical study has ever been performed directly addressing this question. Several large studies have indirectly addressed this issue by treating patients to complete remission and then giving consolidation therapy. Patients were then assigned to an allogeneic HCT if they had a matched sibling donor or randomized to chemotherapy or autologous HCT if they did not (Table 1).1,2,3,16,17 The European Organization for Research and Treatment of Cancer/Acute Myeloid * Corresponding author. Tel.: C1 206 667 4412; Fax: C1 206 667 6936. E-mail address: [email protected] (F.R. Appelbaum). 1 Dr Pearce prepared the first draft of the manuscript based on slides and a transcript of a talk given by Dr Appelbaum.
1521-6926/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
334 F. R. Appelbaum and S. F. Pearce
Table 1. Major randomized trials in adult AML. Study
Question
Patients
Disease-free survival (4 year) Allo (%)
Auto (%)
Chemo (%)
EORTC/GIMEMA AML 81 EORTC/GIMEMA AML 1016 GOELAM3 MRC AML 102 US intergroup17
Allo vs auto vs chemo Allo vs auto
831 1198
55 52
48 42
30
Allo vs auto vs chemo Auto vs chemo Allo vs auto vs chemo
517 1612 740
49
48 54 34
43 40 34
43
Abbreviations: AML, acute myeloid leukemia; Allo, allogeneic; Auto, autologous; Chemo, chemotherapy; EORTC, European organisation for research on treatment of cancer; GIMEMA, Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto; GOELAM, Groupe Ouest Est Leuce´mies Aigue¨s Mye´loblastiques; MRC, medical research council; yr, year(s).
Leukemia (EORTC/AML) 10 trial did not have a chemotherapy arm, while the Medical Research Council AML 10 allogeneic arm was reported separately. The 4-year disease free survival (DFS) for each arm in each trial is presented in Table 1. The first of the studies performed, the EORTC/Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) trial (EORTC/AML 8)1 reported that the allogeneic arm had a 55% 4-year DFS compared to 48% in the autologous arm and 30% for the chemotherapy arm. Similar trends were seen in each of the subsequent trials with DFS higher in the allogeneic arm than in the autologous HCT or the chemotherapy arms. Differences in DFS between the autologous and chemotherapy arms tended to be small and not statistically significant except for the MRC AML 10 trial2 (Table 1). These trials are instructive about the outcome of initial therapy using allogeneic HCT, autologous HCT or consolidation chemotherapy in large patient populations, but they do not take into account individual patient variations in terms of, for example, age, comorbidities, AML disease risk factors and cytomegalovirus serostatus, all of which can affect the outcome of transplantation and chemotherapy unequally. Therefore, these prior studies of large populations are interesting, but they are not entirely informative for choosing how to treat individual patients. Further, these large studies ignored salvage strategies. Thus, none of these trials directly addressed the central question facing most patients; should I be transplanted now or wait until relapse?
RISK FACTORS AND OUTCOME More than 15 years ago, an analysis of published SWOG trials examined whether variables at diagnosis could identify patients for whom BMT or continued chemotherapy would more likely be of benefit. The enrolled patients (612) were either transplanted or treated with chemotherapy.4 Risk factors that differentially affected transplantation versus chemotherapy outcome included age, gender, white blood cell count, number of induction cycles required to achieve first remission, and the presence of hepatitis. Retrospective analysis showed that age had a very
Transplantation in remission versus early relapse 335
strong effect on the outcome of transplantation, but had only a weak effect on the outcome of chemotherapy. Gender affected transplantation, but had no effect on chemotherapy. White cell count at diagnosis had a strong impact on chemotherapy, but had no impact on transplantation. The number of induction cycles had a strong impact on chemotherapy, but did not affect transplantation outcome. And the presence of hepatitis during induction affected the outcome of transplantation, but did not affect chemotherapy.4 Cytogenetic status was not included in this study because most of the patients were accrued in the 1970s and 1980s when cytogenetics were not routinely obtained. Yet even without cytogenetic analysis, patients could be identified for whom transplantation was predicted to be beneficial and others for whom chemotherapy was predicted to lead to a better outcome, and a mathematical model was developed whereby the comparative outcomes of transplantation and chemotherapy could be predicted for each patient based on individual patient parameters. This sort of analysis has not been repeated, but if it were, it would likely be very informative given increased knowledge of risk factors associated with outcome of chemotherapy and transplantation. Given that cytogenetic risk category is the single most powerful prognostic factor for disease recurrence following chemotherapy, the differential outcomes of transplantation and chemotherapy based on cytogenetics has been studied. In the North American Intergroup trial, only allogeneic transplantation seemed to benefit patients with unfavorable cytogenetic risk, although the numbers of patients were small and the follow-up relatively short. For this high risk group, the 5-year estimated survival was 42% with allogeneic transplant, 13% for autologous HCT and 15% for chemotherapy.5 Similar results have been published by others.6 Cytogenetic status is clearly important in considering transplantation versus chemotherapy, but other risk factors mentioned above, such as age, sex, and white count at diagnosis might also differentially affect the expected outcomes with these interventions. Amalgamating these factors into a single model would be helpful in recommending the best therapy for individual patients. As alternative forms of HCT become acceptable, including unrelated donor and cord blood transplants, identification of high-risk patients will become increasingly important.
SALVAGE THERAPIES Prolonged second remissions can be achieved with chemotherapy in some patients with acute promyelocytic leukemia or AML associated with inv (16), but for the vast majority of AML patients, further chemotherapy offers very little chance for cure after an initial relapse. A report from the International Bone Marrow Transplant Registry (IBMTR) analyzed the probability of survival after allogeneic transplant for AML in second remission in a large number of patients transplanted from either matched siblings (837) or from unrelated donors (567). The probability of survival under these circumstances was about 35% at 5 or more years. The probability of survival with autologous transplantation also in second remission was approximately 25–30% at 5 years and beyond with 380 patients in that group.7 Thus, transplantation can offer prolonged survival in about 30–35% of patients with AML in second remission, a result that appear superior to those achieved with chemotherapy.7,8
336 F. R. Appelbaum and S. F. Pearce
ALLOGENEIC HCT IN FIRST UNTREATED RELAPSE VERSUS SECOND REMISSION Whether patients with AML in first untreated relapse should go directly to transplant or should first be reinduced is an unanswered question. A thought experiment illustrated in Figure 1 would suggest that there might be little benefit of attempted reinduction. If, for example, reinduction were attempted in 100 patients with AML in first relapse, approximately 50% might be expected to achieve second remission. If transplant in second remission yields a 35% cure rate, we would expect 17.5 (.35!50) of these patients to be cured. With reinduction, there will be about a 15–20% early death rate. The 35 patients who do not achieve a second complete remission or die during the attempt could still be transplanted if they do not develop significant complication during the reinduction attempt. If they were transplanted, a generous estimate of cure would be 15%. That would amount to another five patients (.15!35). So from 100 patients, 22.5 patients would be cured (schema shown in Figure 1). Alternatively, if the same 100 patients were not reinduced but transplanted immediately, the cure rate would likely be in excess of 22.5%. Although there are little data in the literature about the cure rate after first relapse without reinduction, the Seattle group has looked at this issue. An initial study published in 1983 reported that of 17 patients who received allogeneic transplantation in untreated first relapse, the 3-year DFS was 29%.9 A follow-up was published in 1992, and in 126 patients transplanted in untreated first relapse, the 3-year DFS was 28%.10 A further analysis of patients transplanted in untreated first relapse between 1992 and 1998 shows that 33% of them are alive without disease. One study from outside Seattle has reported in this issue. Brown et al from the St Louis group reported a 28–30% survival rate at O5 years for matched related donor transplants in untreated first relapse.12 A finding of interest from their study is that graft-versus-host disease has an important effect on outcome. Patients who did not develop any graft-versus-host disease had a very high relapse rate, while those who did had a much lower relapse rate. This is similar to the finding of the Seattle study, in which developing graft-versus-host disease was important for disease control when patients were transplanted in untreated first relapse with a matched sibling donor.10 100 Patients Reinduction
BMT (.25)
15 ED
35 NR
50 CR
25 patients cured BMT (.15)
BMT (.35)
5 patients + 17.5 patients cured Figure 1. Should patients with AML be reinduced prior to bone marrow transplant? A theoretical calculation can be performed to determine the percentage of patients who will survive transplant without or with attempted reinduction. Abbreviations: BMT, bone marrow transplant; CR, complete remission; ED, early death; NR, not reinduced.
Transplantation in remission versus early relapse 337
UNRELATED DONOR HCT IN UNTREATED FIRST RELAPSE There are essentially no published data of unrelated donor transplants for patients with AML in untreated first relapse. We searched the database at the Fred Hutchinson Cancer Research Center and could find only 18 adult patients who had received unrelated donor transplants for AML in untreated first relapse in the last 6 years. Of those, eight are disease-free survivors at 1.5–5 years with four and six cases of relapse and nonrelapse mortality, respectively. It is not surprising that there are so few patients in this category given that it has taken, on average, 3 months to find an unrelated donor. Currently, as more donors in the registry have been completely typed, accelerated searches for donors are being carried out more frequently, and donors can now be found for some patients in 6 weeks or less. The new accelerated approaches that the National Marrow Donor Program have developed make it conceivable to carry out unrelated donor transplants in untreated first relapse if relapse is detected very early, for example as a rise in a marker of minimal residual disease. Similarly, the possibility of unrelated cord blood transplants in adults13,14 provides another option for performing an allogeneic transplant in untreated first relapse for patients without matched siblings.
AUTOLOGOUS HCT FOR UNTREATED FIRST RELAPSE Little data have been published about the use of autologous HCT for AML in untreated first relapse. In Seattle, we conducted a study in which patients with AML in first remission but without matched siblings had stem cells stored for transplantation in first relapse, should disease recur.11 Of 100 patients whose stem cells were stored, 34 never relapsed. Twenty-eight patients relapsed but were not transplanted in untreated first relapse because the patient and/or referring physician opted for reinduction. Eight of these 28 patients were transplanted in second remission and two of them are long-term survivors. The other 20 patients in whom reinduction was attempted either failed to enter second remission or died during the attempt. Autologous transplantation was conducted in 38 patients in untreated first relapse and eight survive disease-free at 15–114 months. This group received a preparative regimen of busulfan and cyclophosphamide followed by autologous transplants and posttransplant were treated with IL-2 or IL-2 plus lymphokine-activated killer cells. While comparisons with other approaches are not possible given the uncontrolled nature of this trial, the study does suggest that a strategy of stem cell storage in first remission with autologous transplantation in first relapse is feasible and can lead to long-term survival in some patients.
PROGNOSTIC FACTORS FOR HCT IN UNTREATED FIRST RELAPSE Patients who can be transplanted in untreated first relapse may represent an unusual subset of patients, with disease caught very early or with only slowly progressive disease. In our study of allogeneic HCT for AML in first relapse and in the St Louis study, the extent of relapse did not appear to have a major impact on outcome. There was no demonstrable difference in outcome based on blast content, i.e. whether there were more or less than 30% blasts in the bone marrow when transplanted. Further, there was no impact on the duration of first remission on the outcome of subsequent transplantation in untreated first relapse in either our study or the St Louis study of
338 F. R. Appelbaum and S. F. Pearce
allogeneic transplantation.12,15 To date, in large part because so few patients have been transplanted, no conclusion can be drawn about the factors affecting the outcome of patients transplanted in untreated first relapse with unrelated donors. For autologous transplantation, the risk factor assessment is somewhat different. In our studies, the extent of relapse appeared to correlate with outcome. Those who had greater than 30% blasts in their bone marrow at the time of autologous transplant in untreated first relapse did more poorly than those who were transplanted earlier in the course of relapse. Also, the duration of first remission had an impact: those who had an autologous transplant after a long first remission tended to do better than those with a short first remission. Once again, these conclusions are not entirely robust because of limited data.
PROPOSED TREATMENT FOR AN INDIVIDUAL PATIENT For the patient who decides not to be transplanted in first remission, the patient and the family should nonetheless be HLA typed to plan for future therapy. If the patient has a matched sibling, monitoring complete blood counts every week or every other week may be warranted. A subtle change in peripheral blood values should signal for a bone marrow examination including morphology, flow cytometry, and, if appropriate, cytogenetics and fluorescent in situ hybridization. If residual leukemic blasts are found, proceeding straight to transplant in untreated early relapse can be recommended. For the patients without a matched sibling, storage of autologous cells after consolidation might be considered. Additionally, a brief survey of the unrelated donor population should be done. Patients can then be monitored in a manner similar to the patient with a matched sibling. If patients relapse during the first year of remission, autologous transplantation is less likely to be of benefit and efforts should be made to rapidly move to an unrelated donor transplant or possibly a cord blood transplant. However, if relapse occurs after a longer first remission, autologous transplantation using stem cells stored in first remission might be considered.
CONCLUSION Based on available data, and assuming patients are not already enrolled on a well-conceived clinical trial, patients with cytogenetically determined unfavorable risk AML should consider allogeneic transplantation in first remission, if possible. In contrast, patients with good risk disease should probably forgo transplantation until after an initial relapse. For patients with intermediate risk disease, the decision should probably be more individualized. For example, young patients in good health with matched siblings should consider allogeneic HCT in first remission, while older patients with medical comorbidities and without matched siblings might consider delaying transplantation until relapse. There are few easy answers to this decision making process, and we run the risk of ignoring the complexity of individual patient variability in trying to simplify the process too much.
ACKNOWLEDGEMENTS This work was supported in part by grants number CA 18029, CA 15704, CA 78902, and HL 36444, from the National Institutes of Health, DHHS.
Transplantation in remission versus early relapse 339
REFERENCES *1. 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. New England Journal of Medicine 1995; 332: 217–223. *2. 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. *3. 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. *4. Tallman MS, Kopecky KJ, Amos D et al. Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission. Journal of Clinical Oncology 1989; 7: 326–337. *5. 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. 6. Willemze R, Suciu S, Mandelli F et al. Autologous versus allogeneic stem cell transplantation in acute myeloid leukemia. Annals of Hematology 2004; 83(supplement 1): S134. 7. http://www.ibmtr.org 8. Gale RP, Horowitz MM, Rees JK et al. Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia 1996; 10: 13–19. 9. Appelbaum FR, Clift RA, Buckner CD et al. Allogeneic marrow transplantation for acute nonlymphoblastic leukemia after first relapse. Blood 1983; 61: 949–953. *10. Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. Journal of Clinical Oncology 1992; 10: 1723–1729. *11. Schiffman K, Clift R, Appelbaum FR et al. Consequences of cryopreserving first remission autologous marrow for use after relapse in patients with acute myeloid leukemia. Bone Marrow Transplantation 1993; 11: 227–232. *12. Brown RA, Wolff SN, Fay JW et al. High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American marrow transplant group. Blood 1995; 85: 1391–1395. 13. Wagner JE, Barker JN, DeFor TE et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100: 1611–1618. 14. Laughlin MJ, Eapen M, Rubinstein P et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. New England Journal of Medicine 2004; 351: 2265–2275. 15. Appelbaum FR. Allogeneic hematopoietic stem cell transplantation for acute leukemia. Seminars in Oncology 1997; 24: 114–123. *16. Suciu S, Mandelli F, de Witte T et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood 2003; 102: 1232–1240. *17. Cassileth PA, Harrington DP, Appelbaum FR et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. New England Journal Medicine 1998; 339: 1649–1656.
9 Hematopoietic cell transplantation in first complete remission versus early relapse Frederick R. Appelbaum*
MD
Director Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, 1100 Fairview Avenue North, D5-310, P.O. Box 19024, Seattle, WA 98109-1024, USA
S. Frieda Pearce1 PhD Although data from a number of clinical trials can help guide the choice, the decision of whether patients with acute myeloid leukemia (AML) should undergo transplantation while in first remission or should have transplantation withheld until relapse is a particularly difficult one. Current data suggest that patients with AML and unfavorable cytogenetics should undergo allogeneic transplantation while in first remission if at all possible. Patients with AML and good risk cytogenetics can probably forgo transplantation until after first relapse. For patients with intermediate risk disease, the decision of transplantation during first remission versus waiting until first relapse is particularly difficult and should be made only after considering additional individual risk factors. If the decision is made to delay transplantation until first relapse, there are additional steps that physicians should take to ensure that salvage transplantation is possible, including identifying the source of hematopoietic stem cells in advance of relapse and developing a careful monitoring plan for the patient while in first remission. Keywords: transplantation; allogeneic; myeloid leukemia.
A key decision most patients with AML and their physicians will face is whether to undergo hematopoietic cell transplantation (HCT) while in first remission or reserve transplantation until relapse. Nonetheless, no clinical study has ever been performed directly addressing this question. Several large studies have indirectly addressed this issue by treating patients to complete remission and then giving consolidation therapy. Patients were then assigned to an allogeneic HCT if they had a matched sibling donor or randomized to chemotherapy or autologous HCT if they did not (Table 1).1,2,3,16,17 The European Organization for Research and Treatment of Cancer/Acute Myeloid * Corresponding author. Tel.: C1 206 667 4412; Fax: C1 206 667 6936. E-mail address: [email protected] (F.R. Appelbaum). 1 Dr Pearce prepared the first draft of the manuscript based on slides and a transcript of a talk given by Dr Appelbaum.
1521-6926/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
334 F. R. Appelbaum and S. F. Pearce
Table 1. Major randomized trials in adult AML. Study
Question
Patients
Disease-free survival (4 year) Allo (%)
Auto (%)
Chemo (%)
EORTC/GIMEMA AML 81 EORTC/GIMEMA AML 1016 GOELAM3 MRC AML 102 US intergroup17
Allo vs auto vs chemo Allo vs auto
831 1198
55 52
48 42
30
Allo vs auto vs chemo Auto vs chemo Allo vs auto vs chemo
517 1612 740
49
48 54 34
43 40 34
43
Abbreviations: AML, acute myeloid leukemia; Allo, allogeneic; Auto, autologous; Chemo, chemotherapy; EORTC, European organisation for research on treatment of cancer; GIMEMA, Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto; GOELAM, Groupe Ouest Est Leuce´mies Aigue¨s Mye´loblastiques; MRC, medical research council; yr, year(s).
Leukemia (EORTC/AML) 10 trial did not have a chemotherapy arm, while the Medical Research Council AML 10 allogeneic arm was reported separately. The 4-year disease free survival (DFS) for each arm in each trial is presented in Table 1. The first of the studies performed, the EORTC/Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) trial (EORTC/AML 8)1 reported that the allogeneic arm had a 55% 4-year DFS compared to 48% in the autologous arm and 30% for the chemotherapy arm. Similar trends were seen in each of the subsequent trials with DFS higher in the allogeneic arm than in the autologous HCT or the chemotherapy arms. Differences in DFS between the autologous and chemotherapy arms tended to be small and not statistically significant except for the MRC AML 10 trial2 (Table 1). These trials are instructive about the outcome of initial therapy using allogeneic HCT, autologous HCT or consolidation chemotherapy in large patient populations, but they do not take into account individual patient variations in terms of, for example, age, comorbidities, AML disease risk factors and cytomegalovirus serostatus, all of which can affect the outcome of transplantation and chemotherapy unequally. Therefore, these prior studies of large populations are interesting, but they are not entirely informative for choosing how to treat individual patients. Further, these large studies ignored salvage strategies. Thus, none of these trials directly addressed the central question facing most patients; should I be transplanted now or wait until relapse?
RISK FACTORS AND OUTCOME More than 15 years ago, an analysis of published SWOG trials examined whether variables at diagnosis could identify patients for whom BMT or continued chemotherapy would more likely be of benefit. The enrolled patients (612) were either transplanted or treated with chemotherapy.4 Risk factors that differentially affected transplantation versus chemotherapy outcome included age, gender, white blood cell count, number of induction cycles required to achieve first remission, and the presence of hepatitis. Retrospective analysis showed that age had a very
Transplantation in remission versus early relapse 335
strong effect on the outcome of transplantation, but had only a weak effect on the outcome of chemotherapy. Gender affected transplantation, but had no effect on chemotherapy. White cell count at diagnosis had a strong impact on chemotherapy, but had no impact on transplantation. The number of induction cycles had a strong impact on chemotherapy, but did not affect transplantation outcome. And the presence of hepatitis during induction affected the outcome of transplantation, but did not affect chemotherapy.4 Cytogenetic status was not included in this study because most of the patients were accrued in the 1970s and 1980s when cytogenetics were not routinely obtained. Yet even without cytogenetic analysis, patients could be identified for whom transplantation was predicted to be beneficial and others for whom chemotherapy was predicted to lead to a better outcome, and a mathematical model was developed whereby the comparative outcomes of transplantation and chemotherapy could be predicted for each patient based on individual patient parameters. This sort of analysis has not been repeated, but if it were, it would likely be very informative given increased knowledge of risk factors associated with outcome of chemotherapy and transplantation. Given that cytogenetic risk category is the single most powerful prognostic factor for disease recurrence following chemotherapy, the differential outcomes of transplantation and chemotherapy based on cytogenetics has been studied. In the North American Intergroup trial, only allogeneic transplantation seemed to benefit patients with unfavorable cytogenetic risk, although the numbers of patients were small and the follow-up relatively short. For this high risk group, the 5-year estimated survival was 42% with allogeneic transplant, 13% for autologous HCT and 15% for chemotherapy.5 Similar results have been published by others.6 Cytogenetic status is clearly important in considering transplantation versus chemotherapy, but other risk factors mentioned above, such as age, sex, and white count at diagnosis might also differentially affect the expected outcomes with these interventions. Amalgamating these factors into a single model would be helpful in recommending the best therapy for individual patients. As alternative forms of HCT become acceptable, including unrelated donor and cord blood transplants, identification of high-risk patients will become increasingly important.
SALVAGE THERAPIES Prolonged second remissions can be achieved with chemotherapy in some patients with acute promyelocytic leukemia or AML associated with inv (16), but for the vast majority of AML patients, further chemotherapy offers very little chance for cure after an initial relapse. A report from the International Bone Marrow Transplant Registry (IBMTR) analyzed the probability of survival after allogeneic transplant for AML in second remission in a large number of patients transplanted from either matched siblings (837) or from unrelated donors (567). The probability of survival under these circumstances was about 35% at 5 or more years. The probability of survival with autologous transplantation also in second remission was approximately 25–30% at 5 years and beyond with 380 patients in that group.7 Thus, transplantation can offer prolonged survival in about 30–35% of patients with AML in second remission, a result that appear superior to those achieved with chemotherapy.7,8
336 F. R. Appelbaum and S. F. Pearce
ALLOGENEIC HCT IN FIRST UNTREATED RELAPSE VERSUS SECOND REMISSION Whether patients with AML in first untreated relapse should go directly to transplant or should first be reinduced is an unanswered question. A thought experiment illustrated in Figure 1 would suggest that there might be little benefit of attempted reinduction. If, for example, reinduction were attempted in 100 patients with AML in first relapse, approximately 50% might be expected to achieve second remission. If transplant in second remission yields a 35% cure rate, we would expect 17.5 (.35!50) of these patients to be cured. With reinduction, there will be about a 15–20% early death rate. The 35 patients who do not achieve a second complete remission or die during the attempt could still be transplanted if they do not develop significant complication during the reinduction attempt. If they were transplanted, a generous estimate of cure would be 15%. That would amount to another five patients (.15!35). So from 100 patients, 22.5 patients would be cured (schema shown in Figure 1). Alternatively, if the same 100 patients were not reinduced but transplanted immediately, the cure rate would likely be in excess of 22.5%. Although there are little data in the literature about the cure rate after first relapse without reinduction, the Seattle group has looked at this issue. An initial study published in 1983 reported that of 17 patients who received allogeneic transplantation in untreated first relapse, the 3-year DFS was 29%.9 A follow-up was published in 1992, and in 126 patients transplanted in untreated first relapse, the 3-year DFS was 28%.10 A further analysis of patients transplanted in untreated first relapse between 1992 and 1998 shows that 33% of them are alive without disease. One study from outside Seattle has reported in this issue. Brown et al from the St Louis group reported a 28–30% survival rate at O5 years for matched related donor transplants in untreated first relapse.12 A finding of interest from their study is that graft-versus-host disease has an important effect on outcome. Patients who did not develop any graft-versus-host disease had a very high relapse rate, while those who did had a much lower relapse rate. This is similar to the finding of the Seattle study, in which developing graft-versus-host disease was important for disease control when patients were transplanted in untreated first relapse with a matched sibling donor.10 100 Patients Reinduction
BMT (.25)
15 ED
35 NR
50 CR
25 patients cured BMT (.15)
BMT (.35)
5 patients + 17.5 patients cured Figure 1. Should patients with AML be reinduced prior to bone marrow transplant? A theoretical calculation can be performed to determine the percentage of patients who will survive transplant without or with attempted reinduction. Abbreviations: BMT, bone marrow transplant; CR, complete remission; ED, early death; NR, not reinduced.
Transplantation in remission versus early relapse 337
UNRELATED DONOR HCT IN UNTREATED FIRST RELAPSE There are essentially no published data of unrelated donor transplants for patients with AML in untreated first relapse. We searched the database at the Fred Hutchinson Cancer Research Center and could find only 18 adult patients who had received unrelated donor transplants for AML in untreated first relapse in the last 6 years. Of those, eight are disease-free survivors at 1.5–5 years with four and six cases of relapse and nonrelapse mortality, respectively. It is not surprising that there are so few patients in this category given that it has taken, on average, 3 months to find an unrelated donor. Currently, as more donors in the registry have been completely typed, accelerated searches for donors are being carried out more frequently, and donors can now be found for some patients in 6 weeks or less. The new accelerated approaches that the National Marrow Donor Program have developed make it conceivable to carry out unrelated donor transplants in untreated first relapse if relapse is detected very early, for example as a rise in a marker of minimal residual disease. Similarly, the possibility of unrelated cord blood transplants in adults13,14 provides another option for performing an allogeneic transplant in untreated first relapse for patients without matched siblings.
AUTOLOGOUS HCT FOR UNTREATED FIRST RELAPSE Little data have been published about the use of autologous HCT for AML in untreated first relapse. In Seattle, we conducted a study in which patients with AML in first remission but without matched siblings had stem cells stored for transplantation in first relapse, should disease recur.11 Of 100 patients whose stem cells were stored, 34 never relapsed. Twenty-eight patients relapsed but were not transplanted in untreated first relapse because the patient and/or referring physician opted for reinduction. Eight of these 28 patients were transplanted in second remission and two of them are long-term survivors. The other 20 patients in whom reinduction was attempted either failed to enter second remission or died during the attempt. Autologous transplantation was conducted in 38 patients in untreated first relapse and eight survive disease-free at 15–114 months. This group received a preparative regimen of busulfan and cyclophosphamide followed by autologous transplants and posttransplant were treated with IL-2 or IL-2 plus lymphokine-activated killer cells. While comparisons with other approaches are not possible given the uncontrolled nature of this trial, the study does suggest that a strategy of stem cell storage in first remission with autologous transplantation in first relapse is feasible and can lead to long-term survival in some patients.
PROGNOSTIC FACTORS FOR HCT IN UNTREATED FIRST RELAPSE Patients who can be transplanted in untreated first relapse may represent an unusual subset of patients, with disease caught very early or with only slowly progressive disease. In our study of allogeneic HCT for AML in first relapse and in the St Louis study, the extent of relapse did not appear to have a major impact on outcome. There was no demonstrable difference in outcome based on blast content, i.e. whether there were more or less than 30% blasts in the bone marrow when transplanted. Further, there was no impact on the duration of first remission on the outcome of subsequent transplantation in untreated first relapse in either our study or the St Louis study of
338 F. R. Appelbaum and S. F. Pearce
allogeneic transplantation.12,15 To date, in large part because so few patients have been transplanted, no conclusion can be drawn about the factors affecting the outcome of patients transplanted in untreated first relapse with unrelated donors. For autologous transplantation, the risk factor assessment is somewhat different. In our studies, the extent of relapse appeared to correlate with outcome. Those who had greater than 30% blasts in their bone marrow at the time of autologous transplant in untreated first relapse did more poorly than those who were transplanted earlier in the course of relapse. Also, the duration of first remission had an impact: those who had an autologous transplant after a long first remission tended to do better than those with a short first remission. Once again, these conclusions are not entirely robust because of limited data.
PROPOSED TREATMENT FOR AN INDIVIDUAL PATIENT For the patient who decides not to be transplanted in first remission, the patient and the family should nonetheless be HLA typed to plan for future therapy. If the patient has a matched sibling, monitoring complete blood counts every week or every other week may be warranted. A subtle change in peripheral blood values should signal for a bone marrow examination including morphology, flow cytometry, and, if appropriate, cytogenetics and fluorescent in situ hybridization. If residual leukemic blasts are found, proceeding straight to transplant in untreated early relapse can be recommended. For the patients without a matched sibling, storage of autologous cells after consolidation might be considered. Additionally, a brief survey of the unrelated donor population should be done. Patients can then be monitored in a manner similar to the patient with a matched sibling. If patients relapse during the first year of remission, autologous transplantation is less likely to be of benefit and efforts should be made to rapidly move to an unrelated donor transplant or possibly a cord blood transplant. However, if relapse occurs after a longer first remission, autologous transplantation using stem cells stored in first remission might be considered.
CONCLUSION Based on available data, and assuming patients are not already enrolled on a well-conceived clinical trial, patients with cytogenetically determined unfavorable risk AML should consider allogeneic transplantation in first remission, if possible. In contrast, patients with good risk disease should probably forgo transplantation until after an initial relapse. For patients with intermediate risk disease, the decision should probably be more individualized. For example, young patients in good health with matched siblings should consider allogeneic HCT in first remission, while older patients with medical comorbidities and without matched siblings might consider delaying transplantation until relapse. There are few easy answers to this decision making process, and we run the risk of ignoring the complexity of individual patient variability in trying to simplify the process too much.
ACKNOWLEDGEMENTS This work was supported in part by grants number CA 18029, CA 15704, CA 78902, and HL 36444, from the National Institutes of Health, DHHS.
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