Scholarly article on topic 'Pilot Study of Allogeneic G-CSF–Stimulated Bone Marrow Transplantation: Harvest, Engraftment, and Graft-versus-Host Disease'

Pilot Study of Allogeneic G-CSF–Stimulated Bone Marrow Transplantation: Harvest, Engraftment, and Graft-versus-Host Disease Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — M. Ostronoff, F. Ostronoff, P. Souto Maior, C. Matias, R. Calixto, et al.

Abstract Peripheral blood progenitor cell (PBPC) harvests mobilized by granulocyte colony-stimulating factor (G-CSF) contain more CD34+ cells and provide more rapid engraftment than do bone marrow (BM) harvests. However, some reports have suggested a higher risk of chronic graft-versus-host disease (GVHD), possibly because such PBPC harvests contain approximately 10 times more T lymphocytes than do BM harvests. Some groups are attempting to combine the faster engraftment of PBPCs with the lower incidence of GVHD observed after BM transplantation by using G-CSF–primed BM conventionally harvested from iliac crests for allogenic BM transplantation. We report the results of a pilot study of 38 allogeneic transplants using G-CSF–stimulated BM from related donors, with a focus on the harvest composition, engraftment, and incidence of acute and chronic GVHDs.

Academic research paper on topic "Pilot Study of Allogeneic G-CSF–Stimulated Bone Marrow Transplantation: Harvest, Engraftment, and Graft-versus-Host Disease"

Biology of Blood and Marrow Transplantation 12:729-733 (2006) © 2006 American Society for Blood and Marrow Transplantation l083-879l/06/l207-0005$32.00/0 doi:l0.l0l6/j.bbmt.2006.03.006

AS BMI,

American Society for Blood and Marrow Transplantation

Pilot Study of Allogeneic G-CSF-Stimulated Bone Marrow Transplantation: Harvest, Engraftment, and Graft-versus-Host Disease

M. Ostronoff, F. Ostronoff, P. Souto Maior, C. Matias, R. Calixto, A. Sucupira, M. Domingues, R. Florencio, C. Tagliari

Hematology and BMT Unit, Real-Hospital Português, Recife, Pemambuco, Brazil

Correspondence and reprint requests: F. Ostronoff, Al Franca 699, Apt 111, 01422-000 Sao Paulo, SP, Brazil (e-mail: f.ostronoff@uol.com.br).

Received May 29, 2005; accepted March 13, 2006

ABSTRACT

Peripheral blood progenitor cell (PBPC) harvests mobilized by granulocyte colony-stimulating factor (G-CSF) contain more CD34+ cells and provide more rapid engraftment than do bone marrow (BM) harvests. However, some reports have suggested a higher risk of chronic graft-versus-host disease (GVHD), possibly because such PBPC harvests contain approximately 10 times more T lymphocytes than do BM harvests. Some groups are attempting to combine the faster engraftment of PBPCs with the lower incidence of GVHD observed after BM transplantation by using G-CSF-primed BM conventionally harvested from iliac crests for allogenic BM transplantation. We report the results of a pilot study of 38 allogeneic transplants using G-CSF-stimulated BM from related donors, with a focus on the harvest composition, engraftment, and incidence of acute and chronic GVHDs.

© 2006 American Society for Blood and Marrow Transplantation

KEY WORDS

G-CSF • BMT • Harvest • GvHD and engraftment

INTRODUCTION

Bone marrow (BM) has been the accepted source of hematopoietic cells for allogeneic transplantation. However, historical comparisons have shown that peripheral blood progenitor cell (PBPC) transplantation mobilized by granulocyte colony-stimulating factor (G-CSF) offers quicker neutrophil and platelet recovery, apparently with less treatment-related toxicity and mortality [1-4]. This may be due in part to the higher stem cell content of G-CSF-primed PBPCs. G-CSF may also activate quiescent progenitors and hasten their maturation, leading to faster engraftment through qualitative changes in the cellular composition of the harvest [2]. However, some reports have indicated a higher rate of chronic graft-versus-host disease (GVHD) in G-CSF-stimulated PBPC recipients, probably because such PBPC harvests contain approximately 1 log more T lymphocytes than do conventional BM harvests [5-7]. Several groups have examined the use of G-CSF-primed BM for autolo-

gous hematopoietic transplantation and reported granulocyte and platelet recovery times similar to those seen after blood stem cell transplantation [3]. A few teams have studied the use of G-CSF-primed BM for allogeneic BM transplantation (BMT) and reported faster neutrophil engraftment and similar transplant-related complications compared with conventional BMT [8-11].

We report the results of a pilot study of allogeneic transplantation using G-CSF-stimulated BM from related donors, with a focus on the harvest composition, engraftment, and incidence of acute and chronic GVHDs.

METHODS Patients

Between January 2001 and March 2003, patients eligible for BMT at our center were invited to participate in this study. With their written informed consent and institutional review board approval, 38 pa-

Table 1. Preparatory Regimens According to Diagnosis and Disease Status*

Diagnosis

Preparatory Regimen

Disease Stage

Chronic myeloid leukemia

(first chronic phase) BUS + LPAMf I6

Acute myeloid leukemia

First CR BUS + LPAMf 3

Second CR 2

Acute lymphoid leukemia

First CR FTBI + CTXJ 4

Second CR I

Severe aplastic anemia BUS + CTX§ 9

Paroxysmal nocturnal

hemoglobinuria BUS + LPAMf I

Myelodysplastic syndrome BUS + LPAMf 2

*CR indicates complete remission; BUS, busulfan; LPAM, melpha-lan; CTX, cyclophosphamide; FTBI, fractionated total body irradiation.

tBUS (16 mg/kg orally) + LPAM (140 mg/m2). JFTBI (1200 cGy) + CTX (120 mg/kg). §BUS (4 mg/kg orally) + CTX (200 mg/kg) [22].

tients underwent G-CSF-stimulated HLA-matched sibling BMT. The conditioning protocol depended on diagnosis and disease status (Table 1).

Broad-spectrum antibiotics were administered when patients became neutropenic (absolute neutro-phil count <.5 X 109/L) until neutrophil recovery. Irradiated platelet transfusions were given if the platelet count was <20 X 109/L, and irradiated red blood cells were transfused when the hemoglobin concentration was <9 g/dL. Patients received G-CSF 5-10 ^g • kg-1 • d-1 subcutaneously until hematologic recovery.

GVHD prophylaxis included cyclosporine A (CSA) 2 mg • kg-1 • d-1 and methotrexate (MTX) 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6. Mycophenolate mofetil (MMF) 15 mg • kg-1 • d-1 was also given to 16 patients because of a new institutional protocol started during this study period. For nonmalignant diseases, if GVHD was absent, CSA was then tapered from day 210 until day 240, when the drug was discontinued; for malignant diseases, CSA was tapered from day 150 until day 180. MMF was administered from day 0 until day 120.

Donors and Harvest

With their written informed consent, donors received 5 ^g • kg-1 • d-1 of G-CSF subcutaneously for 5 days before BM harvest (day -4 to day 0; Table 2). All donors were HLA-identical siblings. BM was collected on the fifth day from the posterior iliac crests (target volume, 10-15 mL/kg recipient body weight). CD34+, CD3+, and CD8+ cells were counted by flow cytometry. No manipulations were performed on the product, other than red blood cell or plasma depletion in the event of ABO major discrepancy between donor and

patient, and BM was infused on day 0. This regimen of low- to moderate-dose, short-course G-CSF was used to minimize exposure of normal donors to this growth factor.

Evaluation

The date of neutrophil engraftment was the first of 3 consecutive days with an absolute neutrophil count >.5 X 109/L. The date of platelet engraftment was the first of 7 consecutive days with a platelet count >20 X 109/L without transfusion. GVHD was graded according to published criteria [12].

Descriptive statistics (median and range) were used to describe donor, recipient, and BM characteristics. Times to neutrophil and platelet engraftment and BM cell counts were compared with published historical data [13-16].

RESULTS

Donor and Graft Characteristics

Donors were 26 female and 12 male subjects, with a median age of 26 years (range, 1 to 54). The only immediate adverse effects of G-CSF injections were mild arthralgia and bone pain, which were successfully treated with paracetamol.

BM harvests contained a median of 3.8 X 106 CD34+ cells/kg recipient weight (range, .94 to 13.5), 31 X 106 CD3+ lymphocytes/kg (range, 19 to 62.8), and 12.9 X 106 CD8+ lymphocytes/kg (range, 8 to 30.2).

Patients, Engraftment, and GVHD

The patients were 12 female and 26 male subjects, with a median age of 30 years (range, 3 to 53); 12 patients were <18 years old. Disease status was chronic myeloid leukemia in the first chronic phase in 16 cases; severe aplastic anemia in 9 cases; acute lym-phoblastic leukemia in first complete remission in 4 cases; acute myeloid leukemia in the first complete remission in 3 cases; acute myeloid leukemia in the second complete remission in 2 cases; myelodysplastic syndrome in 2 cases; acute lymphoblastic leukemia and central nervous system relapse in 1 case; and nocturnal paroxysmal hemoglobinuria in 1 case. Eighteen patients had sex-matched donors and 20 had

Table 2. Characteristics of Donors and Harvests*

Age, y Male/female

Female donor/male recipient CD34+/kg recipient weight CD3+/kg recipient weight CD8+/kg recipient weight

26 (1-54) 12/26 17/38

3.8 X I06 (0.94-13.5) 31 X I06 (19-62.8) 12.9 X I06 (8-30.2)

*Data are means (ranges).

Allogenic G-CSF-Stimulated BMT 73l

Table 3. Characteristics of Patients and Outcomes*

Age, y 26 (3-53)

Male/female 26/12

Neutrophil engraftment, d 12 (6-20)

Platelet engraftment, d 21(10-28)

TRM at day 100 23.6%

Overall survival 65.7%

*Data are means (ranges). TRM indicates therapy-related mortality.

Klebsiella pneumoniae, which was susceptible only to imipenem, in 1 case, multidrug-resistant Pseudomonas aeruginosa in 2 cases, and Aspergillosis in 1 case. Therapy-related mortality was 23.6%; causes of death were those included in the overall 100-day mortality in addition to 1 death due to chronic GVHD, which occurred at 1 year. Overall survival and relapse-free survival were 65.7% and 63.1%, respectively.

sex-mismatched donors (female donor/male recipient in 17 cases, 10 with previous pregnancies, and male donor/female recipient in 3 cases; Table 3).

Median duration of follow up was 42 months. Median time to neutrophil recovery was 12 days (range, 6 to 20) and median time to platelet recovery was 21 days (range, 10 to 28). One patient developed graft failure, probably owing to immunologic rejection (multiple previous transfusions, including from her parents). Two patients died before engraftment from veno-occlusive disease. These 3 patients were not assessable for acute GVHD because of early death. Acute GVHD grade <2 occurred in 13 of the remaining 35 patients (37.1%) patients and grade 3/4 acute GVHD occurred in 4 patients (11.4%); the gastrointestinal tract and liver were the main target sites (84% and 38% of cases, respectively). Chronic GVHD (always mild) occurred in 10 of the 29 patients (34.4%) who survived >100 days after transplantation. There were no differences in the incidence of acute or chronic GVHD between the group that received CSA/MTX and the group that received CSA/MTX/ MMF for GVHD prophylaxis. The overall 100-day mortality rate was 23.6% (9 deaths). Causes of death were veno-occlusive disease in 2 cases; infection in 4 cases; acute GVHD in 1 case; relapse in 1 case; and hemorrhagic cystitis in 1 case. Infectious deaths were mainly due to nosocomial infections and included

DISCUSSION

We treated 38 patients with G-CSF-primed allogeneic BMT in this single-center study. The results are compared in Table 4 with published historical data on conventional BMT and PBPC transplantation using or not using MTX for GVHD prophylaxis and G-CSF after transplantation. We found that time for neutrophil engraftment after G-CSF-stimulated BMT was similar to that reported after PBPC transplantation. Time to platelet recovery, however, was similar to that observed after conventional BMT. CD34+ cell counts were similar to those obtained in unstimulated BM and in PBPC harvests. There were 2 cases of CD34+ counts >10 X 106/kg and both were observed with children as donors. CD3 + cell counts were similar to those observed in the conventional BMT setting. The incidence of acute and chronic GVHD was compatible with that observed in other settings. The relatively slow platelet reconstitution observed in the present study confirms that of a recent report based on data from the International Bone Marrow Transplant Registry [17].

Couban et al [10] reported a single-arm study of 29 patients who received G-CSF-primed BM. Gran-ulocyte and platelet recovery was faster in the G-CSF group than in historical controls, but this did not improve secondary endpoints such as the length of hospital stay. Isola et al [8] compared 17 patients who

Table 4. Comparison of Stem Cell Sources*

Characteristic Allogenic PBPC Allogenic BM G-CSF-Primed BM

CD34+ cells X l06/kg recipient weight 7.3 (l-29.8)f 2.4 (0.8-l0.4)f 3.8 (0.94-l3.5)

CD3+ cells X l06/kg recipient weight 279 (l43-788)f 23.8 (5.4-347)f 3l (l9-62.8)

Neutrophil engraftment, d 16 (ll-29)f 2l (l3-36)f l2 (6-20)

14 (10-40)$ l9 (ll-35)$

11 (9-20)§ l6 (l4-27)

Platelet engraftment, d 13 (5-4l)f l9 (7-74)f 2l (l0-28)

18 (l3-68)$ 25 (l2-87)$

l3 (9-35)§ 27 (l7-ll0)||

aGVHD (grade 2) 64%f 57%f 37.l%

40%$ 35%$

48%§ 8%|

cGVHD 46%f 35%f 34.4%

65%$ 53%$

*aGVHD indicates acute GVHD; cGVHD, chronic GVHD. tAdapted from Bensinger et al [13]. ^Adapted from Champlin et al [14].

§Adapted from Bishop et al [15] who used G-CSF after transplantation and CSA/MTX for GVHD prophylaxis. ¡Adapted from Schriber et al [16] who used G-CSF after transplantation and CSA/MTX for GVHD prophylaxis.

received G-CSF-primed BMT with controls who received conventional BMT and associated more rapid

neutrophil recovery with a shorter hospital stay, although the incidence of GVHD or death was not increased. Platelet engraftment was not improved.

In a Chinese study, Shuquan et al [11] compared harvest content, engraftment, and GVHD between patients who received stimulated BM and those who received conventional BMT. They found that stimulated BM contained a larger number of granulocyte-macrophage colony-forming units and CD34+ cells, and that patients who received this harvest demonstrated faster engraftment. The incidence of chronic GVHD and relapse did not differ between groups.

Serody et al [9] reported a nonrandomized study of patients who received G-CSF-mobilized PBPC or G-CSF-stimulated BM and found a 1-log lower T-cell dose in the group that received BM. Granulo-cyte recovery was similar in the 2 groups, but there was a trend toward faster platelet recovery in the PBPC group. Patients who received primed BM had significantly less chronic GVHD. A randomized study by Morton et al [18] compared outcomes after stem cell transplantation in patients who received PBSC or BM from donors treated with G-CSF. They found that, compared with recipients of G-CSF-primed BM, patients undergoing PBSC transplantation were more likely to develop severe acute GVHD refractory to prednisone and chronic GVHD, with a need for prolonged immunosuppressive therapy to control symptoms.

In these studies, the dose of G-CSF for BM priming ranged from 3 to 12 ^g ■ kg-1 ■ d-1 and the length of G-CSF treatment ranged from 2 to 7 days.

In a recent study, Ringden et al [19] of the European Group for Blood and Marrow Transplantation reported a retrospective analysis of the use of G-CSF after allogeneic stem cell transplantation and found a shortening of neutropenia but a lengthening of thrombocytopenia. Importantly, when BM was the source of stem cells, G-CSF after transplantation increased incidences of acute and chronic GVHDs and treatment-related mortality. These adverse effects of G-CSF were not seen in recipients of PBPC [19]. Whether these findings also apply to G-CSF-primed BMT remains to be seen.

In the present study, G-CSF was administered until hematologic recovery, which may have contributed to the faster recovery of neutrophil and the relatively slow recovery of platelets [15].

Because of a new institutional protocol started during the study period, MMF was given to 16 patients. A few phase II clinical studies have been conducted on the combination of MMF and CSA for GVHD prophylaxis, and it is not completely understood if MMF affects engraftment kinetics. A recent study found that median time to engraftment in pa-

tients who received MMF and CSA for GVHD prophylaxis was similar to that in patients who received GVHD prophylaxis with CSA and MTX [20].

Another possible use of G-CSF priming is in non-myeloablative allogeneic BMT, for which a high stem cell dose is needed to compensate for less intense induction therapy, as shown in animal models [21]. The lower incidence of chronic GVHD associated with the higher CD34+ cell counts obtained in G-CSF-primed BMT could be beneficial for this mode of transplantation.

It is important to note that this study was performed in a developing country, where infection during neutropenia remains a major problem, and means of accelerating neutrophil recovery are therefore of great interest.

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