Original Article
Reasons That Patients with Acute Myelogenous Leukemia Do Not Undergo Allogeneic Bone Marrow Transplantation
N Engl J Med 1992; 326:156-160January 16, 1992
- Abstract
- Abstract
Background
Numerous reports suggest that allogeneic bone marrow transplantation prolongs the survival of adult patients with acute myelogenous leukemia (AML) in first remission. However, it is unclear how many such patients actually undergo this procedure.
Methods
We reviewed the case records of 350 consecutive adult patients with AML treated with chemotherapy at a single institution from 1979 (when the policy of offering allogeneic transplantation to all such patients in first remission was introduced) through 1990. The criteria for exclusion before transplantation included age greater than 40 and, beginning in 1984, a diagnosis of acute promyelocytic leukemia.
Results
One hundred forty-two patients (41 percent of the study population) were 40 years of age or younger. HLA testing was performed for 120 of these patients (85 percent). Sixty-seven patients (47 percent) had an HLA-identical sibling as a potential donor. One hundred three patients (73 percent) entered remission during treatment according to one of five chemotherapy protocols. Of the 52 patients who both entered remission and had an HLA match, 30 underwent transplantation while they were in first remission. These 30 patients constituted 21 percent of all study patients 40 years old or younger, 29 percent of all patients 40 or under who entered remission, 45 percent of all patients with an HLA match, 58 percent of all patients who had both a remission and a match, and 9 percent of all patients treated according to a protocol. Among patients with a match who did not undergo transplantation, those with primary refractory disease were the largest subgroup.
Conclusions
These findings suggest that allogeneic bone marrow transplantation is performed in less than 60 percent of adult patients with AML who are potentially eligible for the procedure. (N Engl J Med 1992;326: 156–60.)
Media in This Article
Figure 1
Characteristics of Patients with AML Studied with Respect to Potential Allogeneic Bone Marrow Transplantation, 1979 through 1990.Figure 2
Percentages of Patients with AML Who Underwent Bone Marrow Transplantation (BMT) in Three Studies.Article Activity
- Article
ALLOGENEIC bone marrow transplantation has become an important treatment for adults with acute myelogenous leukemia (AML). A number of programs now report rates of disease-free survival exceeding 45 percent for patients undergoing transplantation in the first or second remission.1 2 3 4 5 6 7 However, it is difficult to determine how often this procedure is useful for patients with this disease, since many transplantation centers serve wide-ranging, referral-based populations.
Because a single institution with both an active program of chemotherapy for leukemia and a transplant unit would be able to examine this question more closely and provide more generalizable data, we retrospectively analyzed all consecutive adult patients with previously untreated AML who were given chemotherapy at Memorial Hospital from January 1979 through June 1990. We chose 1979 as the year in which to start the evaluation, because it was then that the policy was implemented to offer all eligible patients in first remission allogeneic transplantation.
In this study, we evaluated the number of patients under the age of 40 (the age that until recently was generally considered the maximal age for bone marrow transplantation); the number of patients for whom HLA testing was performed; the number of patients who were found to have an HLA-identical sibling donor; the number of patients who underwent allogeneic bone marrow transplantation in first remission; and the reasons why some patients with an HLA-identical match did not undergo the procedure. The results of this analysis demonstrated that although the proportion of patients who had an HLA-identical match was relatively high, fewer than 60 percent of the potential candidates actually underwent the procedure.
Methods
Beginning in 1979, the Leukemia Service at Memorial Hospital offered allogeneic bone marrow transplantation to all patients 40 years of age or under who were in a first complete remission. The only exception to this policy was made in 1984, when it was decided to continue treating patients with acute promyelocytic leukemia with chemotherapy because of the relatively favorable results observed after chemotherapy alone for leukemia in this category of the French—American—British classification.8 9 10 To determine the number of patients who were treated with chemotherapy and thus were possible candidates for transplantation during this period, we reviewed a computer-generated list of all adult patients with newly diagnosed AML who had been treated according to one of five protocols at Memorial Hospital from January 1979 through June 1990. A subgroup consisting of patients 40 years of age or younger was then created. Patients who had HLA testing performed were identified, and those with an HLA-identical family member were noted. The charts of the patients who had an HLA-identical sibling were then reviewed with the Bone Marrow Transplant Service to determine whether allogeneic bone marrow transplantation had been performed during a documented first remission. The charts of patients for whom an HLA-identical sibling donor had been identified but who had not undergone transplantation were then reviewed to determine why the procedure had not been performed. The charts of patients who entered remission but who did not undergo HLA typing were examined to determine why typing had not been done.
A first complete remission was defined as a remission occurring after one or two courses of induction therapy, as outlined in each protocol. Two patients who did not enter remission after this treatment but who did so after additional "salvage" therapy and then underwent transplantation were not included in this analysis. Two patients who had primary refractory disease at the time of transplantation were also excluded. Beginning in 1984, 19 patients with acute promyelocytic leukemia were also excluded from all categories except that of the number of patients in each protocol, because these patients were no longer part of the pool of potential candidates for transplantation.
Results
Between January 1979 and June 1990, 350 patients with AML who were ≥15 years of age were treated according to one of five chemotherapy protocols (Table 1Table 1
Status of the 350 Patients Studied with Respect to Potential Allogeneic Bone Marrow Transplantation.*). No upper age limit was established for treatment according to the first three protocols, but beginning with the fourth protocol in 1984, patients over the age of 60 were not included. Between 48 and 99 patients were assigned to each protocol; the accrual of patients is shown in Table 1. The details of each protocol have been described elsewhere.11 One hundred forty-two patients, or 41 percent of the entire study population, were 40 years old or younger (Fig. 1Figure 1Characteristics of Patients with AML Studied with Respect to Potential Allogeneic Bone Marrow Transplantation, 1979 through 1990.).HLA typing was performed for a relatively large proportion of these 142 patients (120 patients, or 85 percent) (Table 1). The reasons for patients' not being typed were as follows: nine patients had primary refractory leukemia and either died during therapy (one patient) or had an insufficient number of cells for HLA analysis (eight patients); two patients who entered remission were adopted; two patients in remission had no siblings; six patients in remission had at least one sibling, but there was no recorded reason to account for their lack of HLA testing; for one patient in remission, HLA typing was incomplete because of technical difficulties; and for two patients data were incomplete. Sixty-seven patients, or 47 percent of those tested, were found to have an HLA-matched sibling donor.
One hundred three of the 142 patients who were 40 years old or younger (73 percent) entered a complete remission after one or two courses of chemotherapy administered according to protocol (Table 1). Fifty-two patients (37 percent) had both a complete remission and an HLA match. Thirty patients underwent allogeneic bone marrow transplantation during a first complete remission. To determine what proportion of patients they represented, we calculated the percentage with five different denominators: first, as a percentage of all patients who had both a remission and a match; second, as a percentage of all patients with an identified HLA match; third, as a percentage of all patients who entered remission; fourth, as a percentage of all patients 40 years old or younger; and finally, as a percentage of all patients assigned to the protocol. The data were also analyzed separately for each protocol to determine whether there was any bias during the administration of a particular chemotherapy protocol (Table 2Table 2
Incidence of Bone Marrow Transplantation during a First Complete Remission in Relation to Specific Groups among the 350 Patients Studied.*).There were no major differences among the protocols in the rates of transplantation when the data were analyzed as described above. The 30 patients who underwent transplantation made up 58 percent of all patients who had both a remission and a match, 45 percent of all patients with an HLA match, 29 percent of all patients who entered a complete remission, 21 percent of all patients 40 years old or younger, and 9 percent of all patients assigned to the protocol. The overall pattern of accrual is shown in Figure 1.
Thirty-seven of the HLA-matched patients (54 percent) did not undergo transplantation (Table 3Table 3
Reasons for Which Patients ≤40 Years Old Who Had an HLA Match Did Not Undergo Bone Marrow Transplantation.). Among these 37 patients, the 15 patients with primary refractory disease were the largest subgroup; these patients accounted for 41 percent of the patients who had an HLA-identical donor but who did not undergo transplantation. The next largest group consisted of nine patients (24 percent) whose disease relapsed before transplantation could be scheduled; this usually occurred within an interval of three months between the time of a documented remission and the time of scheduling. There were seven patients (19 percent) who declined the procedure and five patients (14 percent) for whom there was no documented reason to account for the lack of transplantation.The data were also analyzed according to sex. The 142 patients 40 years old or younger comprised 64 men (45 percent) and 78 women (55 percent). Fifty-two of the men (81 percent) had HLA typing, as did 68 of the women (87 percent). Forty-three men entered remission; they represented 67 percent of the men 40 years old or younger and 42 percent of all patients with a remission. Sixty women entered remission; they represented 77 percent of the women 40 years old or younger and 58 percent of all patients with a remission. Of the 30 patients who underwent transplantation, 11 (37 percent) were men, and 19 (63 percent) were women.
No patient was denied HLA testing or bone marrow transplantation because of financial constraints.
Discussion
That bone marrow transplantation may offer a survival advantage for adult patients with AML in a first complete remission has been suggested by a number of recently reported trials.1 2 3 4 5 6 7 However, the selection of patients for this procedure is an important, infrequently addressed factor. To determine the overall applicability of the procedure, we reviewed all adult patients with AML treated according to one of five chemotherapy protocols at a single institution, beginning at the time allogeneic transplantation was first offered as an alternative to continued chemotherapy. Despite the presumed advantage of such a study in a single center, the number of patients who underwent the procedure during a first complete remission was relatively small, regardless of the denominator used in the calculation (Fig. 1).
Three points should be noted about the study population. First, 41 percent of the patients with AML were 40 years old or less, in contrast to the median age (60 years) of patients with AML in the general population.12 This may partly be due to the upper age limit of 60, which was imposed beginning with our fourth protocol in 1984. Second, it is possible that in general younger patients were referred to Memorial Hospital, whereas older patients were kept in community hospitals. This would be difficult to determine without knowing the total number of patients with the disease during the same period in New York, New Jersey, and Connecticut, the states from which the vast majority of the patients were referred. Finally, for a rather high percentage of patients — 47 percent of those 40 or younger and 56 percent of those with HLA testing — an HLA match was identified (Table 1). That HLA-identical matches for patients with AML may be found within the family at a frequency higher than expected has been noted by Chan et al.,13 who studied 104 families of such patients. The frequency with which there were two, one, or no shared haplo-types was 35, 46.3, and 18.7 percent, respectively, as compared with the expected distribution of 25, 50, and 25 percent (P<0.005). In the same study, no such pattern was seen in the families of patients with acute lymphocytic leukemia. The probability calculated by Chan et al. of finding an HLA match within the family of a patient with AML would be increased from 35 percent to 48 percent.13 Our value of 47 percent for patients 40 or younger who had a match was within this range.
Analysis of the data according to sex in relation to the total number of patients treated with chemotherapy, the likelihood of entering remission, the probability of having HLA testing performed, and the probability of undergoing transplantation revealed no pattern of sex-related bias, in contrast to a recent report that more men than women are offered aggressive therapeutic procedures and subsequently undergo them.14
It is difficult to interpret this study in relation to other large transplantation series. Few reports of allogeneic bone marrow transplantation involving adults with AML in a first complete remission have followed patients from the start of chemotherapy to the time of the procedure; thus, series such as that of Hermans et al.15 focus on selected populations of patients. Another problem is that a mixed population of patients under-going bone marrow transplantation has sometimes been studied as a single group. For example, Zander et al.16 considered patients with acute lymphoblastic leukemia and AML together; therefore, the number of patients with AML who had primary refractory disease or who had a relapse before the procedure could be performed could not be determined. Other studies have explained in detail why transplantation was not performed but have included potential candidates for both autologous and allogeneic transplantation.17 , 18
Figure 2Figure 2
Percentages of Patients with AML Who Underwent Bone Marrow Transplantation (BMT) in Three Studies. shows the difficulty of comparing our study with two other relatively large series1 , 2 of patients with AML who were followed to the time of allogeneic transplantation. The studies varied with respect to the base line chosen for evaluation — i.e., all patients with AML, all patients at or below a maximal age, or all patients who entered a complete remission. Of our 142 patients who were 40 years of age or younger, 73 percent entered a complete remission with chemotherapy, as compared with 81 percent in a study conducted in Seattle1 and similar figures in other chemotherapy series.19 20 21 22 In a study at the University of California at Los Angeles (UCLA), only patients in a first remission were considered, so information regarding their response to chemotherapy was not available. Other differences among these studies complicate direct comparison, such as the exclusion of patients with acute promyelocytic leukemia in our study and the inclusion of patients in early relapse in the Seattle study. The series we studied contained the largest number of HLA-matched patients (67, as compared with 44 in Seattle and 23 at UCLA).In our study, some eligible patients did not undergo transplantation for a variety of reasons (Table 3). The incidence of refractory disease in our patients who were 40 years of age or younger (11 percent) was similar to that reported in the Seattle study1 (9 percent) and was comparable to values from other chemotherapy studies.23 24 25 In our series, such patients constituted 22 percent of those with an HLA match. Seventeen percent of our patients had a short complete remission and a relapse before transplantation (Table 3), as compared with 15 percent (5 of 33 potential candidates for bone marrow transplantation) in the Seattle study.
Patients who declined to undergo transplantation or who did not undergo it and for whom there was no obvious documented reason to account for the decision constituted 10 percent and 7 percent, respectively, of the patients with an identified HLA match (Table 3). In Seattle, 11 percent of the HLA-matched population (5 of 44 patients) declined transplantation, and an additional 14 percent did not undergo the procedure because of medical or financial reasons.1 One of 23 HLA-matched patients at UCLA declined transplantation.2
When the three studies are considered together, 29 percent to 37 percent of patients who entered remission were able to undergo allogeneic bone marrow transplantation (Fig. 2). A more precise knowledge of the fraction of patients who undergo transplantation and the reasons that others do not may permit a more complete understanding of survival curves after transplantation.
Supported in part by a Career Development Award (89–124) to Dr. Berman from the American Cancer Society.
We are indebted to Dr. Colin Begg for his many helpful comments and to Mr. Duane Jones for his expert assistance in the preparation of the manuscript.
Source Information
From the Leukemia Service, Department of Medicine (E.B., C.L., T.G., B.C.), and the Bone Marrow Transplantation Service (R.O.), Memorial Sloan—Kettering Cancer Center, New York. Address reprint requests to Dr. Berman at the Leukemia Service, Memorial Sloan—Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
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