Bone Marrow Transplantation, (1997) 19, 455–460  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Allogeneic blood stem cell transplantation in advanced hematologic cancers D Przepiorka1, P Anderlini1, C Ippoliti1 , I Khouri1, T Fietz1, P Thall2, R Mehra1, S Giralt1 , J Gajewski1, AB Deisseroth1, K Cleary3 , R Champlin1, K van Besien1, B Andersson1 and M Ko¨rbling1 Departments of 1Hematology, 2 Biomathematics and 3Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Summary: Allogeneic bone marrow transplantation for advanced hematologic cancer is associated with a high risk of early treatment-related morbidity and mortality. To determine the short-term benefits of allogeneic blood stem cell transplants when compared to bone marrow transplants, we reviewed outcomes of 74 adults with advanced hematologic cancer transplanted from HLAmatched related donors after conditioning with thiotepa, busulfan and cyclophosphamide. There were three cohorts: group 1 received bone marrow transplants with cyclosporine (CsA) and methotrexate (MTX) for GVHD prophylaxis; group 2 received bone marrow transplants with CsA and methylprednisolone (MP); and group 3 received blood stem cells with CsA and MP. All patients received filgrastim post-transplant. Median times (range) to neutrophils >0.5 3 109/l were 17 (8– 30), 9 (8–16) and 10 (8–13) days post-transplant, and to platelets >20 3 109/l were 28 (14–1001), 19 (13–1001) and 14 (9–86) days post-transplant for groups 1, 2 and 3, respectively (P , 0.05 only for group 1 vs group 3 for both outcomes). Blood stem cell recipients had the least regimen-related toxicity, fewest early deaths and earliest discharge. There was no significant difference in acute GVHD between the three groups. One hundred and eighty-day survivals (95% CI) were 53% (35–72%), 32% (10–53%), and 68% (49–87%) for groups 1, 2 and 3, respectively (P , 0.05 only for group 2 vs group 3). For allogeneic transplantation, use of blood stem cell grafts has substantial advantages over marrow grafts. Keywords: allogeneic blood stem cell transplant; leukemia; treatment-related mortality

We1 and others2,3 have reported that allogeneic blood stem cell transplantation results in rapid hematopoietic reconstitution without excessive acute GVHD. Here we compare engraftment, regimen-related toxicity, GVHD and survival

Correspondence: Dr D Przepiorka, The UT MD Anderson Cancer Center, Section of Blood and Marrow Transplantation, 1515 Holcombe Boulevard Box 065, Houston, TX 77030, USA Received 8 February 1996; accepted 1 November 1996

in recipients of allogeneic bone marrow or blood stem cell transplants.

Materials and methods Patients From March 1992 to March 1995, 74 adults with advanced hematologic cancer and HLA-matched related donors received allogeneic transplants after conditioning with high-dose thiotepa, busulfan and cyclophosphamide. Eligibility criteria are described. 4 Patient characteristics are listed in Table 1. There were 36 males and 38 females. Median age was 38 years (range 17–57 years). Eighty-five percent of patients were not in remission, and 34% had disease resistant to chemotherapy. Three patients had undergone allogeneic marrow transplantation and two had undergone autologous marrow transplantation previously. Data were analyzed for three cohorts of patients treated on two prospective studies (Table 1). Group 1 received bone marrow transplants with cyclosporine (CsA) and methotrexate (MTX) as GVHD prophylaxis; group 2 received bone marrow transplants with CsA and methylprednisolone (MP) as GVHD prophylaxis; and group 3 received blood stem cell transplants with CsA and MP as GVHD prophylaxis. The groups did not differ significantly with regard to any of the pretreatment characteristics (Table 1). All protocols were approved by the Institutional Review Board of the MD Anderson Cancer Center, and written informed consent was obtained from each participant.

Preparative regimen The preparative regimen consisted of thiotepa 250 mg/m2 i.v. on days 29, 28 and 27, busulfan 1 mg/kg orally q 6 h for 12 doses on days 26, 25 and 24, and cyclophosphamide 60 mg/kg i.v. on days 23 and 22. Busulfan was dosed on ideal body weight. For patients more than 20% above ideal body weight, thiotepa and cyclophosphamide were dosed on adjusted body weight (ideal 1 0.4 (actualideal)); otherwise, cyclophosphamide was dosed on actual body weight.

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Table 1

Patient and donor characteristics

Transplant: GVHD prophylaxis: No. of patients Patient sex (male/female) Patient median age (years) Range Diagnosis Chronic myelogenous leukemia Acute myelogenous leukemia Myelodysplastic syndrome Acute lymphoblastic leukemia Other Disease status Relapse Remission Disease sensitivity Untreated Resistant Sensitive Prior transplant Allogeneic Autologous Donor sex (male/female) Donor median age (years) Range Sex-mismatched Pair CMV-seronegative Median follow-up (months) Range

Marrow and blood stem cell collection Donors were HLA-matched and related. Blood stem cells were collected from filgrastim-treated donors by apheresis as described.1,5 Apheresis was continued until a minimum of 4 3 106 CD341 cells/kg recipient body weight were collected.

Group 1 BMT CsA/MTX

Group 2 BMT CsA/MP

Group 3 SCT CsA/MP

30 16/14 39 (18–53)

19 6/13 32 (18–52)

25 14/11 43 (17–57)

6 12 5 6 1

6 4 3 3 3

9 8 2 4 2

25 5

17 2

21 4

16 9 5

10 7 2

12 9 4

1 2 15/15 42 (7–65) 11 1 25 (12–31)

1 0 10/9 31 (19–56) 7 2 38 (33–42)

1 0 14/11 38 (14–60) 8 1 9 (6–20)

prophylactic ganciclovir from engraftment to day 100. The discharge criteria were the same for all three groups; for discharge, the patients had to be ambulatory, afebrile, tolerating oral medications, eating 1000 kcal daily, and drinking 1 l of fluid daily. GVHD prophylaxis and treatment

Supportive care Filgrastim 5 mg/kg/day subcutaneously was given from day 7 for 10 patients in group 1 and from day 1 for the remaining 64 patients. Groups 1 and 2 received filgrastim until the neutrophil count exceeded 1.5 3 109/l for 3 days, and group 3 received filgrastim until the day the neutrophil count exceeded 1.0 3 109/l. All blood products were irradiated and filtered. Patients were given 2 units of red blood cells for hemoglobin ,80 g/l and 4 units of platelets (or one single-donor pack equivalent to 6 units) for platelet count ,20 3 109/l. Infection prophylaxis during the peritransplant period consisted of nonabsorbable antibiotics orally, vancomycin 1 g intravenously daily, fluconazole 200 mg intravenously every 12 h, and acyclovir 5 mg/kg intravenously every 8 h. All patients received broad spectrum antibiotics for neutropenic fever and hyperalimentation when needed. Intravenous immunoglobulin 200–500 mg/kg was given weekly to day 100 and monthly thereafter to 1 year. Once engrafted, the patients also received twice-weekly trimethoprim-sulfamethoxazole orally or pentamidine by inhalation every 3 weeks, and CMV-seropositive patients received

CsA was administered at 3 mg/kg/day i.v. continuous infusion from day 22, and doses were adjusted to maintain whole blood steady state or trough levels at 250–350 ng/ml by RIA for parent drug. Eighteen patients in group 1 received MTX at 10 mg/m2 i.v. on days 1, 3 and 6, and the other 12 patients received MTX at 15 mg/m2 i.v. on day 1, and 10 mg/m2 i.v. on days 3, 6 and 11. The patients in group 2 received MP at 0.5 mg/kg/day beginning on day 7 with an increase to 1.0 mg/kg/day on day 15 and a taper thereafter.4 The patients in group 3 received MP at 1.0 mg/kg/day beginning day 5 with a taper thereafter.1 Patients who developed grade 2 GVHD were treated initially with MP at 0.5 mg/kg i.v. q 6 h. Antithymocyte globulin 10 mg/kg/day i.v. was given to some patients with gastrointestinal involvement at the onset of GVHD and to patients with steroid-refractory GVHD (unresponsive to MP at 2 mg/kg/day 3 3). Toxicity grading Regimen-related toxicity (RRT) was graded as described6 except that deaths after day 28 resulting from RRT occur-

Allogeneic SCT for advanced hematologic cancers D Przepiorka et al

Table 2

457

Hematopoietic recovery and support Group 1 BMT CsA/MTX

Transplant: GVHD prophylaxis:

Hematopoietic recovery mean (range) Day neutrophils .0.5 3 109 /l Day neutrophils .1.0 3 109 /l Day platelets .20 3 109/l Day platelets .50 3 109/l

17 18 28 32

(8–30)a (9–46) (14–1001) (16–1001)

Transfusions to day 100 Platelet units/patient Red blood cell units/patient Platelet units/day b Red blood cell units/day

92 12 1.6 0.2

(24–532) (0–61) (0.2–6.7) (0–1.3)

a

Group 2 BMT CsA/MP

Group 3 SCT CsA/MP

9 10 19 25

(8–16) (8–19) (13–1001) (13–1001)

10 10 14 18

(8–13) (9–13) (9–86) (10–1001)

142 22 3.0 0.4

(36–494) (2–93) (0.4–11.8) (0–4.2)

74 10 0.8 0.1

(12–482) (2–55) (0.2–6.4) (0–1.4)

P values for group 1 vs 3

2 vs 3

,0.001 ,0.001 ,0.001 0.08

NS NS NS NS

NS NS NS NS

0.04 0.08 0.03 0.05

Median (range). Based on number of days alive to day 100.

b

Between-group comparisons of demographic data, regimenrelated toxicity, and development of steroid-resistant GVHD were made by x2 analysis or log-likelihood ratio. Actuarial estimates of time to engraftment, discharge, GVHD, and death were calculated according to the method of Kaplan and Meier. Comparisons of time to event were made using the Peto and Peto Gehan–Wilcoxon test. The z-test of endpoints was used to compare 180-day survivals. Logistic regression was used to identify factors independently affecting 180-day survival. P values were two-tailed with corrections made for multiple comparisons by Bonferroni adjustment.

Absolute neutrophil count

8

6

4

2

Results

0 0

2

4

6

8

10

12

14

16

18

20

Day after transplantation

Engraftment

Neutrophil recovery was defined as the first of 3 consecutive days with an absolute neutrophil count >0.5 3 109/l, and platelet recovery was defined as the day the platelet count was >20 3 109/l with no platelet transfusions the following week. Hematopoietic chimerism was evaluated by conventional cytogenetics for sex-mismatched patient– donor pairs and by DNA restriction fragment length polymorphisms.7 Diagnosis of GVHD was based on clinical and histologic data.8 GVHD was graded according to the consensus criteria.9

One patient in group 1 failed to achieve remission and expired on day 50 without hematopoietic recovery. The remaining patients engrafted. Median times to hematopoietic recovery were 11 days to neutrophils >0.5 3 109/l, 12 days to neutrophils >1.0 3 109/l, 21 days to platelets >20 3 109/l, and 27 days to platelets >50 3 109/l. Hematopoietic recovery differed between treatment groups. Hematopoietic recovery was significantly earlier for patients receiving CsA/MP as GVHD prophylaxis when compared to those receiving CsA/MTX (Table 2). At the time of engraftment, the CsA/MP (groups 2 and 3) recipients had a rapid onset of neutrophilia that lasted several days past the last dose of filgrastim (Figure 1). No patient developed graft rejection. Hematopoiesis was shown to be donor in origin in all patients except for those with impending (within 3 months) or active relapse. Platelet transfusions expressed as units per day survived to day 100 were significantly less for blood stem cell recipients than for marrow recipients receiving CsA/MP and similar to that for patients receiving CsA/MT (Table 2).

Statistical considerations

Regimen-related toxicity

At the time of analysis, median time from transplantation was 24 months (range, 6–42 months) for all subjects.

Grade 2–4 RRT in at least one organ occurred in 72% of patients, and grade 3–4 RRT in 12% of patients. Blood

Figure 1 Daily median absolute neutrophil count (310 23/l) for patients in groups 1 (dotted line), 2 (dashed line) and 3 (solid line).

ring before day 28 were also scored as grade 4. Adverse events attributed to culture-documented infection, bleeding or medications were not scored as RRT. Assessment of engraftment and GVHD

Allogeneic SCT for advanced hematologic cancers D Przepiorka et al

Regimen-related toxicitya

Table 3

Group 1 BMT CsA/MTX

Transplant: GVHD prophylaxis:

a

Group 2 BMT CsA/MP

21 (70) a 10 (33) 27 (90) 2 (7) 1 (3)

Grade 2–4 stomatitis Grade 2–4 hepatotoxicity Grade 2–4 maximum toxicity Grade 3–4 maximum toxicity Cumulative score >7

10 6 16 6 4

(53) (32) (84) (32) (21)

Group 3 SCT CsA/MP

8 5 10 1 1

(32) (20) (40) (4) (4)

P values for group 1 vs 3

2 vs 3

0.01 NS ,0.01 NS NS

NS NS 0.01 NS NS

Number of patients (percentage of treatment group).

a

Acute graft-versus-host disease

1

Actuarial rate (95% CI) of grades 2–4 acute GVHD was 51% (38–63%), and grades 3–4 acute GVHD, 21% (11– 32%). Grades 2–4 GVHD occurred in 49% (27–71%), 66% (42–91%) and 42% (22–63%) of groups 1, 2 and 3, respectively, and grades 3–4 GVHD occurred in 13% (0–28%), 33% (8–58%) and 22% (4–39%), respectively (Figure 2). There were no significant differences between treatment groups. Steroid refractory acute GVHD occurred in 7% of group 1, 21% of group 2, and 20% of group 3 (P 5 NS).

Proportion

0.8

0.6

0.4

0.2

Outcome 0 0

10

20

30

40

50

60

70

80

90

100

Day after transplantation b

1

0.8

Proportion

458

0.6

0.4

0.2

0 0

10

20

30

40

50

60

70

80

90

100

Day after transplantation

Nineteen patients (26%) died prior to first discharge posttransplant; 67% of group 1, 74% of group 2, and 84% of group 3 patients were discharged (P 5 NS). The median time to discharge was day 29 for group 1, day 19 for group 2, and day 15 for group 3 (P , 0.001 for group 1 vs group 3, and P 5 0.006 for group 2 vs group 3). Twenty-six patients died prior to day 100 with no significant differences between treatment groups (Table 4). One hundred and eighty-day survival was 51% (95% CI, 40–63%) for all patients. Blood stem cell recipients had the best survival (Figure 3). One hundred and eighty-day survival (95% CI) was 53% (35–72%) for group 1, 32% (10– 53%) for group 2, and 68% (49–87%) for group 3. There was a significant survival advantage at 180 days for blood stem cell recipients only in comparison to bone marrow recipients receiving CsA/MP (P 5 0.02), and this difference remained significant in the logistic regression analysis adjusting for age .40 years, female donor, sex-mismatched donor, diagnosis, and response to reinduction pretransplant (P 5 0.04). The 2-year survival for all patients was 28% (95% CI, 15–40%).

Figure 2 Probabilities of grades 2–4 (a) and grades 3–4 (b) acute GVHD for patients in groups 1 (dotted line), 2 (dashed line) and 3 (solid line). There are no significant differences between groups.

Discussion

stem cell recipients had the least RRT (Table 3). Individual organ toxicities included stomatitis (53%), hepatotoxicity (28%), cardiac toxicity (9%), cystitis (8%), pulmonary toxicity (4%), nephrotoxicity (3%), gastrointestinal toxicity (3%), and neurologic toxicity (1%). Blood stem cell recipients had significantly less grade 2–4 stomatitis (Table 3), but individual organ toxicity did not otherwise differ significantly between the three treatment groups.

In this study, we found that allogeneic blood stem cell recipients had rapid hematopoietic recovery, a low incidence of toxicity, early discharge, and no increase in acute GVHD. Such results parallel the advantages of blood stem cell transplants over bone marrow transplants in the autologous setting.10–12 The salutory effects were associated with improvement in 180-day survival for blood stem cell recipients compared to bone marrow recipients receiving

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Causes of death prior to day 100a

Table 4

Transplant: GVHD prophylaxis:

Group 1 BMT CsA/MT

Number of deaths Infection GVHD 1 infection Relapse Regimen-related toxicity Other

11 (37) a 8 (27) 0 (0) 2 (7) 0 (0) 1 (3)

a

Group 2 BMT CsA/MP 8 3 0 1 3 1

(42) (16) (0) (5) (16) (5)

Group 3 SCT CsA/MP 7 3 3 0 0 1

(28) (12) (12) (0) (0) (4)

Total

26 14 3 3 3 3

(35) (19) (4) (4) (4) (4)

Number of patients (percentage of treatment group).

CsA and MP as GVHD prophylaxis, but outcome was no better than for bone marrow recipients receiving CsA and MTX. Neutrophil and platelet recoveries were slowest in the group receiving CsA/MTX for GVHD prophylaxis, and this probably resulted from the myelosuppressive effects of MTX. Hematopoietic recoveries were essentially identical for the two groups receiving CsA/MP, although platelet recovery was most rapid in the blood stem cell recipients, which may reflect the higher number of megakaryocytic progenitors in blood stem cell grafts. 13 Owens and Santos 14 showed in a murine transplant model a linear relationship between GVHD and numbers of T cells infused. Since blood stem cell grafts contain about 10-fold more T cells than bone marrow grafts, 15 there has been concern that the risk of acute GVHD might be higher with allogeneic blood stem cells, but this is not what we observed. Whether chronic GVHD and long-term survival is altered with allogeneic blood stem cell transplantation requires a controlled study with longer follow-up. Acknowledgement We are grateful to the Transplant Clinical Nurse Specialists and Clinical Pharmacists for expert care of our patients. The study 1

Proportion

0.8

0.6

0.4

0.2

0 0

20

40

60

80

100

120

140

160

180

Day after transplantation Figure 3 Probability of survival for patients in groups 1 (dotted line), 2 (dashed line) and 3 (solid line). For group 1 vs 3, P 5 NS; for group 2 vs 3, P 5 0.02.

was supported in part by the American Cyanamid Corporation, the Tony Anderson Fund, and grant No. CA 16672 from the National Institutes of Health.

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