Successful allogeneic bone marrow transplantation in ... - Nature

Bone Marrow Transplantation, (1998) 21, 1043–1047  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt

Successful allogeneic bone marrow transplantation in selected patients over 50 years of age – a single institution’s experience W Du2, R Dansey2,3–5, EM Abella1,3–5, R Baynes1,3–5, WP Peters1,3–5, J Klein1,3–5, A Akhtar1,3–5, L Cherednikova1,3–5 and C Karanes1,3–5 1 4

Bone Marrow Transplant Unit, 2Biostatistics Unit, 5Barbara Ann Karmanos Cancer Institute, 3Division of Hematology/Oncology, Wayne State University, Detroit, MI, USA

Summary: As allogeneic bone marrow transplantation (BMT) is a procedure with a higher risk of morbidity and mortality in older patients, many institutions place a limit of 50 to 55 years for allogeneic BMT. Consequently, older patients may not be offered potentially curative treatment for otherwise poor prognosis diseases such as AML or myelodysplastic syndrome. We compared the outcome of 59 patients aged over 50, 124 aged 40–50, and 253 aged 18–39 years who underwent allogeneic BMT in our institution between August 1987 and April 1996. Our results show little influence of age on outcome when comparing patients over 50 years with patients 40–50 years. Apart from an initial higher transplant mortality rate, overall survival was not significantly different between the three age groups. The 1-year and 2year overall survival rates were 57% and 48%, 57% and 48%, and 62% and 58% for the ⬎50 years, 40–50 years, and ⬍40 years patients, respectively. The incidence of GVHD was also comparable. We conclude that allogeneic BMT can be performed in selected patients over the age of 50 years with acceptable morbidity and mortality and that older patients should not be denied this treatment based on age alone. Keywords: allogeneic BMT; age; transplant mortality; overall survival

Allogeneic bone marrow transplantation (BMT) has been used successfully in the treatment of many hematological diseases that are otherwise incurable, but its potential benefits must be balanced against its risks. It has been reported that increasing age is a risk factor associated with a higher mortality in allogeneic BMT.1–9 Consequently, many centers in the past have limited the procedure to patients younger than 45 years of age and more recently younger than 55 years of age. This approach tends to exclude older patients who often have poor risk disease and who might yet benefit from an allogeneic BMT. Over the last several years substantial improvements have been made in lowering the transplant-related mortality rate associated with Correspondence: Dr C Karanes, Division of Hematology/Oncology, Harper Hospital, 4 Brush South, 3990 John R, Detroit, MI 48201, USA Received 16 September 1997; accepted 4 December 1997

allogeneic BMT through improved HLA-typing techniques for donor matching, improved infection control and better supportive care.8,9 Several publications have reported that the outcomes of allogeneic and autologous BMT in patients over the age of 40 were comparable to those in younger patients.10–19 Less has been reported on the number of patients transplanted over the age of 50. Although available data suggest no difference, a firm conclusion as to the appropriateness of allogeneic BMT in this group has not been reached. We report an analysis of age effect in a consecutive series of 436 patients, with 253 between 18–39 years of age, 124 between 40–50 years of age, and 59 over 50 years of age who have undergone allogeneic BMT at our institution.

Materials and methods Patients This was a retrospective analysis of 436 adult patients who underwent allogeneic BMT at our institution from August 1987 to April 1996. A comparison of the clinical outcomes of the three age groups of 18–39 years old, 40–50 years old, and over 50 years old was the focus. The minimum follow-up was 1 year post-BMT. Patient diagnoses included CML, AML, myelodysplastic syndrome (MDS), ALL, Hodgkin’s disease or non-Hodgkin’s lymphoma, multiple myeloma and aplastic anemia. All patients were required to have a Karnofsky performance status ⭓70% together with FEV1 and FVC being ⭓60% of predicted values, a cardiac ejection fraction ⭓50%, and a 24-h creatinine clearance of ⭓60 ml/min. Transplant preparative regimens All patients with AML, CML or MDS were treated with BuCy2. Patients who were at higher risk of relapse were given high-dose cytosine arabinoside interposed between the busulfan and cyclophosphamide. All patients with lymphoid malignancies with no prior radiation treatment received Cy/TBI. CBV was used for patients with prior radiation. No T cell depletion was undertaken. Graftversus-host disease prophylaxis initially consisted of cyclosporine and methyl prednisolone but was later changed to cyclosporine and methotrexate, with some patients also receiving tacrolimus in place of cyclosporine. Patients who

Allogeneic BMT in patients ⬎50 years W Du et al

1044

developed grade 2–4 acute GVHD were treated with corticosteroids. Patients without evidence of GVHD were taken off immune suppression by day 180 post-transplant. All patients received prophylactic anti-microbial therapy with norfloxacin and fluconazole from admission until engraftment. Prophylactic ganciclovir for the first 100 days post-BMT was given to patients who were sero-positive for cytomegalovirus or who had received marrow from a donor who was sero-positive. Patients were housed in private rooms with HEPA-filtered air. Standard hand-washing techniques and masks were used. Statistical methods Univariate comparisons on patient baseline characteristics and outcomes of the oldest group vs the two younger groups were performed using two-sided Fisher’s exact, Student’s t, or normal (z) test. Preparative regimens were classified by whether or not TBI was included. Patients were classified as good risk if they were in first chronic phase (CP1) of CML or if they were in first remission of any other diagnosis at transplant, while all other assessment categories were considered poor risk. The outcomes examined were transplant-related mortality, disease relapse, overall survival, time to engraftment, in-hospital length of stay, incidence of acute and chronic GVHD and preparative regimen toxicity. The first three outcomes listed are each measured as time from the date of BMT. Survival curves and actuarial rates were generated using the Kaplan–Meier method. Log-rank tests were used to compare survival curves while two-sided normal (z) tests were used to compare actuarial rates. Lastly, multivariate Cox proportional hazards regression analysis was performed on survival data to adjust for the differences in patient pre-transplant characteristics. All statistical analyses were performed using SAS version 6.10. Results Patient characteristics Among the 436 adult patients, 59 (14%) were above 50, 124 (28%) were between 40 and 50 and 253 (58%) were below 40 years of age. The median age of the greater than 50 years old patients was 53.7 years with a range of 50 to 62 years, and 62% of them were less than 55 years of age. Table 1 compares pretransplant clinical and demographic characteristics. The older patient group included more sibling HLA-matched transplants (91% vs 80% vs 74%) and patients were also more likely to have received methotrexate (63% vs 43% vs 32%) as GVHD prophylaxis. Multiple myeloma (10% vs 8% vs 2%) and MDS (22% vs 10% vs 9%) were more common and the median follow-up was shorter (16 months vs 18 vs 28 months) in the older patient groups.

Table 1

Patient characteristics

Characteristics

Age ⬍40 (n = 253)

Age 40–50 (n = 124)

Age ⬎50 (n = 50)

Male (%) White (%) Diagnosis (%) AML ALL MDS CML Lymphoma Multiple myeloma Aplastic anemia Preparative regimen with TBI (%) MTX use (%) HLA-matched sibling donor (%) No. of prior chemotherapy ⭓2 (%) Disease status at BMT (%) Good risk (CR1+CP1) Months from Dx to BMT Median (range) Patient follow-up in months Median (range)

151 (60) 209 (83)

64 (52) 105 (85)

30 (51) 51 (86)

93 27 24 65 43 4 17 64

(29) (11)a (9)a (26) (17) (2)b (7) (25)

24 4 12 48 23 10 3 37

(19) (3) (10)a (39) (19) (8) (2) (30)

13 1 13 18 6 6 2 12

(22) (2) (22) (31) (10) (10) (3) (20)

81 (32)c 185 (74)b

52 (43)a 97 (80)

35 (63) 51 (91)

59 (26)

33 (29)

11 (23)

86 (37)

56 (48)

21 (38)

18 (1–256)

10 (1–234)

7 (1–144)

28b (0–113)

18 (0–118)

16 (0–79)

Only the P values for the ⬎50 years patients vs each of two younger patient groups are given. a P value between 0.01 and 0.05. b P value between 0.001 and 0.01. c P value ⬍0.001.

Table 2

Primary patient outcomes

Patient outcomes

Transplant-related mortality rate (%) 1-month 3-month 1-year Relapse rate (%) 1-year 2-year Overall survival rate (%) 1-year 2-year

Age ⬍40 (n = 253)

Age 40–50 (n = 124)

Age ⬎50 (n = 59)

5a 18 33

11 21 32

15 24 36

11 13

13 18

16 20

62 58

57 48

57 48

Only the P values for the ⬎50 years patients vs each of two younger patient groups are given here. a P value between 0.01 and 0.05. b P value between 0.001 and 0.01. c P value ⬍0.001.

points up to 2 years were not significantly different between the three age groups, with the exception that 1-month posttransplant mortality was significantly higher in the ⬎50 years group when compared with the ⬍40 years group (15% vs 5%, P ⬍ 0.05).

Transplant-related mortality, relapse, and overall survival

Other patient outcomes

As shown in Table 2 and Figure 1, transplant-related mortality, relapse and overall survival at a number of time

The rates of GVHD were the same by age group including grade 2–4 acute GVHD and extensive GVHD (see Table 3).


1045

100

50 years

90

80

Percent survival

70

60

50

40

30

20

10

0 0

12

24

36

48

60

72

84

96

108

Overall survival (months) Figure 1 Kaplan–Meier survival curves for the 436 allogeneic BMT patients of which 253 were aged below 40, 124 aged 40–50, and 59 over 50. The P value is 0.1952 for the ⬍40 group vs the ⬎50 group and 0.8790 for the 40–50 group vs the ⬎50 group. P values were derived by two-sided logrank tests.

Table 3

Other patient outcomes

Patient outcomes

Acute GVHD (%) Acute GVHD (grade ⭓2) Chronic GVHD (%) Extensive chronic GVHD (%) Engraftment (median, range) Days to ANC ⬎500 Days to platelet ⬎25 Length of stay (days) Regimen toxicity (grade ⭓1) (%) CNS bladder cardiac diarrhea mucositis hepatic pulmonary renal skin

Age ⬍40 (n = 253)

Age 40–50 (n = 124)

Age ⬍50 (n = 59)

52 25 40 20

48 26 40 20

51 20 46 20

14 (7–42) 15 (8–35) 15 (8–31) 16 (8–123) 16 (10–164) 19/(11–132) 38 (11–207) 39 (13–148) 39 (20–110) 1 3 7a 34a 51b 14b 5 4c 12

2 6 9 47 51a 15a 10 8b 14

2 7 16 52 71 30 13 23 18

A number of ⭓grade 1 regimen-related toxicities (Bearman toxicity scale20) including cardiac, gastrointestinal, oral, hepatic and renal toxicities were more frequently observed in older patients (see Table 3). The incidence rate of any severe events (⭓grade 3) were 20% vs 10% vs 3% for the ⬎50 years, 40–50 years, and ⬍40 years group. Engraftment times and length of hospital stay did not differ between the three age groups. Prognostic factors Multivariate Cox’s regression was performed on the survival data (see Table 4). The results showed that sibling HLA-matched transplant, the use of methotrexate, a good risk classification before transplant and a diagnosis of MDS were associated with longer overall survival, while a diagnosis of ALL was associated with shorter survival. The relative risk of death after adjusting for all other prognostic factors was 1.331 (P = 0.101) for patients aged 40–50 and 1.654 (P = 0.038) for patients aged over 50 years when compared with the ⬍40 years group. Discussion

Only the P values for the ⬎50 years patients vs each of two younger patient groups are given. a P value between 0.01 and 0.05. b P value between 0.001 and 0.01. c P value ⬍0.001. ANC = absolute neutrophil count.

Age limits in transplant protocols are placed because of the concern that older patients will not tolerate the intensive transplant procedure and will experience excessively high morbidity and mortality compared to a younger patient


1046

Table 4

Multivariate results

Patient characteristic

Number of prior chemo ⭓2 Disease status at BMT Good risk (CP1 or CR1) Sibling HLA-matched BMT Methotrexate use Diagnosisa ALL MDS CML Lymphoma Multiple myeloma AML Dx to BMT ⬎1 year Ageb Age ⬍40 Age 40–50 Age ⬎50

Overall survival risk ratio 1.221 0.446e 0.611d 0.692c 2.164e 0.556c 1.076 1.091 1.531 1.000 0.907 1.000 1.331 1.654c

a

The reference group for diagnosis is AML. The reference group for age is the ⬎50 years group. c P value between 0.01 and 0.05. d P value between 0.001 and 0.01. e P value ⬍0.001. b

population, but there are no data defining a maximum tolerated age. Questions such as whether there is a definable maximum age without excessive transplant-related mortality and what an acceptable definition of excessive mortality would be for a procedure such as an allogeneic transplant are unanswered at this time. Early reports recommended limiting allogeneic transplantation to patients under the age of 45 years9 and more recently between 50 and 55 years.9,10–15 Several studies on patients ⭓40 years have shown that there is no significant difference in transplant mortality, disease-free survival or overall survival when compared to younger adults.10,14,16 Successful allogeneic transplants have also been performed in patients up to the age of 60.12,15 The determination of a precise upperage limit from these data is difficult as the limit appears to be moving upward. For the last several years we have adopted an open approach to age eligibility for allogeneic transplantation. Each patient is carefully assessed, and if the Karnofsky score and performance status are ⭓70% and organ function is normal, transplantation is offered provided all other protocol eligibility criteria are satisfied. We have shown with this retrospective analysis that our approach appears justified. The most pertinent result is that overall survival is 48% at 2 years for both older age groups above 40 years. Although the death rate was significantly higher with increasing age in the first month after transplantation, which likely reflects the effects of the preparative regimen, by the end of the first year this difference had diminished to statistical insignificance. As could be predicted from the early higher death rate, regimen-related toxicity was also more common in the older patient groups. Unfortunately the retrospective nature of the data was such that confirming the early transplant-related mortality as being mostly due to regimen toxicity was not possible. The higher frequency

of methotrexate administration post-transplant in the older patient groups may have contributed to the increased mucositis rate and may also have been a factor contributing to the increased hepatic and renal toxicity. There was no evidence that older patients had any problems with engraftment nor was the utilization of resources any higher as the in-patient days were similar for all three age groups. We were encouraged to note that GVHD was not more frequent or more severe in older patients. The multivariate survival analysis demonstrated a significantly higher relative risk of death in the oldest patients when compared to patients less than 40 years old, but no significant difference when compared to patients between 40 and 50 years. This result is as expected since these 59 older patients were the product of a degree of selection and the multivariate regression is likely to adjust for some of that effect. However, the fact remains that the transplantrelated mortality, relapse and overall survival rates for patients aged 40–50 and for patients over 50 are very similar and both remain within the accepted range of transplantation outcomes reported for younger adults. We contend that the decision to transplant patients should be based upon careful assessment of the individual’s biology together with chronologic age, rather than on chronologic age alone.

Acknowledgements The authors would like to thank Daryn Smith for providing the statistical analysis and survival curves for this work. This study was supported in part by a Cancer Center Support Grant CA22453 from NIH.

References 1 Barrett AJ, Horowitz MM, Gale RP et al. Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 1989; 74: 862–871. 2 Bortin MM, Gale RP, Rimm AA. Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia. JAMA 1981; 245: 1132–1139. 3 Gale RP, Horowitz MM, Biggs JC. Transplantation or chemotherapy in acute myelogenous leukemia. Lancet 1989; 1: 1119–1122. 4 Goldman JM, Gale RP, Horowitz MM et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: increased risk for relapse associated with T cell depletion. Ann Intern Med 1988; 108: 806–814. 5 Ringden O, Zwaan F, Hermans J et al. European experience of bone marrow transplantation for leukemia. Transplant Proc 1987; 19: 2600–2604. 6 Ringden O, Nilsson B. Death by graft-versus-host disease associated with HLA mismatch, high tecipient age, low marrow cell dose, and splenectomy. Transplantation 1985; 40: 39–44. 7 Storb R, Prentice RL, Sullivan N et al. Predictive factors in graft-versus host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings. Ann Intern Med 1983; 98: 461–466. 8 Weiner RS, Bortin MM, Gale RP et al. Interstitial pneumonitis following bone marrow transplantation: assessment of risk factors. Ann Intern Med 1986; 104: 168–175.


9 Klingemann HG, Storb R, Fefer A et al. Bone marrow transplantation in patients aged 45 years and older. Blood. 1986; 67: 770–776. 10 Bar BMAM, Witte D, Schattenberg A et al. Favourable outcome of patients older than 40 years of age after transplantation with marrow grafts depleted of lymphocytes by counterflow centrifugation. Br J Haematol 1990; 74: 53–60. 11 Beelen DW, Quabeck K, Mahmoud HK et al. Allogeneic bone marrow transplantation for acute leukaemia or chronic myeloid leukaemia in the fifth decade of life. Eur J Cancer Clin Oncol 1987; 23: 1665–1671. 12 Clift RA, Buchner CD, Storb R et al. The influence of patient age on the outcome of transplantation during chronic phase (CP) of chronic myeloid leukemia. Blood Proc 1996; 86 (Suppl. 1): 617. 13 Copelan EA, Kapoor N, Berliner M et al. Bone marrow transplantation without total-body irradiation in patients aged 40 and older. Transplantation 1989; 48: 65–68. 14 Rapoport AP, DiPersio JF, Martin BA et al. Patients ⬎ or = age 40 years undergoing autologous or allogeneic BMT have regimen-related mortality rates and event-free survivals comparable to patients ⬍ age 40 years. Bone Marrow Transplant 1995; 15: 523–530.

15 Ringden O, Horowitz MM, Gale RP et al. Outcome after allogeneic bone marrow transplant for leukemia in old adults. JAMA 1993; 270: 57–60. 16 Copelan E, Bolwell B, Lazarus H et al. Analysis of age as a predictor of survival following allogeneic and autologous marrow transplantation. ASCO Proc 1996; 15: 86. 17 Cahn JY, Labopin M, Mandelli F et al. Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: a retrospective analysis of the European Bone Marrow Transplant Group. Blood 1995; 85: 575–579. 18 Kusnierz-Glaz CR, Schlegel PG, Wong RM et al. Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies. J Clin Oncol 1997; 15: 18–25. 19 Miller CB, Piantados S, Vogelsang GB et al. Impact of age on outcome of patients with cancer undergoing autologous bone marrow transplant. J Clin Oncol 1996; 14: 1327–1332. 20 Bearman SI, Appelbaum FR, Buckner CD et al. Regimenrelated toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

1047