Manual de etiquetado

Ann Hematol (1995) 71:65-70

9 Springer-Verlag 1995

A. Torres G6mez 9 M. A. Jimenez 9 M. A. Alvarez A. Rodriguez 9 C. Martin 9 M. J. Garcia 9 R. Flores J. Sanchez 9 M. J. de la Torre 9 C. Herrera J. Roman 9 P. Gomez 9 F. Martinez

Optimal timing of granulocyte colony-stimulating factor (G-CSF) administration after bone marrow transplantation A prospective randomized study Received: 3 March 1995 / Accepted: 8 June 1995

Abstract The positive role of G-CSF in hastening the myeloid recovery of patients undergoing allogeneic bone marrow transplantation ( A L L O - B M T ) or autologous bone marrow transplantation (ABMT) has recently been established. Considerable knowledge about adequate doses and route of administration has been accumulated in the past few years. Nonetheless, the optimal time to start growth-factor administration remains undetermined. We have performed a stratified study according to the source of hematopoietic progenitors ( A L L O - B M T or ABMT), underlying disease and its stage, and acute graft-versus-host disease (GVHD) prophylaxis regimen and randomized patients in two arms: group A, which started G-CSF on day 0 (36 patients), and group B, which started on day + 7 post-BMT (39 patients). The same dose (5 ixg/kg/day) and route of administration were employed in both groups. We found no significant differences in the time to reach an absolute neutrophil count (ANC) of 0.1, 0.5, and l x 109/1 and 50• 109 platelets/1 (medians: 10 and 11, 14.5 and 14, 17 and 16, 23 and 24 days, respectively, in groups A and B). We did not find differences in the days of fever or days on antibiotic treatment with less than 1 x 109/1 ANC, rate of bacteriemia, or days of hospitalization in both groups. In contrast, a considerable saving of GCSF in B group was found (mean days of infusion in group A, 18, versus 11 in group B) (p 5 0 x l 0 / L

PROBABILITY TO REACH an A N C > l x I O / L

,8

DAY O - DAY +7 . . . .

15

b)

S

P = 0.0725

to

J~

.4

"" " " ' :

5 C,)

10

DAY o - DAY +7 . . . .

DAY 0 - -

i

,2

DAY +7 . . . .

15

20 D

A

Y

25

30

S

10

35

20

d)

30 D

40 A

50

Y

60

70

S

Table 5 Transplant-related infectious morbidity G-CSF start

Days of fever and ANC < 1 x 109/1

Days on antibiotics and ANC < 1 x 1 0 9 / 1

Rate of bacteremias a

Days to discharge

Day 0 Day +7 p value

4 (0-18) 3 (0-15) n.s.

11.5 (0-26) 11 (0-17) n.s.

13/36 (36.1%) 11/39 (28.2%) n.s.

34.5 (23-57) 35 (23-70) n.s.

a Number of cases with documented bacteremia/total number of cases Table 6 Hematological recovery in ALLO-BMT (53 cases): influence of prophylaxis regimen independent of the day of G-CSF start (median, range) Regimen

Days to ANC > 0.1 x 109/1

Days to ANC > 0.5 x 109/1

Days to ANC > 1,0 x 109/1

Days to platelets > 50 x 109/1

CsA

9 (7-14)

11 (9-17)

12 (10-24)

21.5 (14-49)

12 (6-21)

16 (11-23)

18 (12-25)

25 (12-40)

0.0001

0.0009

CsA + MTX

p value

0.0004

one A L L O - B M T patient of g r o u p B was a m p h o t e r i c i n B a d d e d for 5 days. T h e days of hospitalization do not differ significantly b e t w e e n the two groups (medians: 34.5 days in g r o u p A versus 35 days in g r o u p B).

n.s.

h e m a t o p o i e t i c r e c o v e r y a m o n g patients receiving M T X + C s A versus C s A alone as G V H D prophylaxis ( i n d e p e n d e n t of the day w h e n G - C S F was started), we o b s e r v e d that g r o u p B was significantly faster in reaching granulocyte counts of 0.1, 0.5, and i x 109/1, but not platelets > 50 x 109/1 (see Table 6).

Acute GVHD G - C S F administration and savings T h e r e were no significant differences in the incidence of acute G V H D (grades I I - I V ) b e t w e e n g r o u p A (18%) and g r o u p B (19%). Nevertheless, c o m p a r i n g

T h e m e a n n u m b e r s of days of G - C S F administration in A L L O - B M T and A B M T are significantly lower in

69 Table 7 Days of G-CSF administration and savings (mean, range)

ALLO-BMT Day 0 Day +7 ABMT Day 0 Day +7 Total series Day 0

Days of G-CSF administration

Total units G-CSF x 106

Savings (US$)

18 (13-26)** 12 (6-17)**

577 (180-1000) 392 (144-602)

1100

17 (13-29)*** 9 (8-18)***

510 (300-1120) 270 (126-540)

1300

18 (13-29)**

550 (180-1120)

** p = 0.00001 *** p = 0.0031

group B (12 and 9 days, respectively) than in group A (18 and 17 days, respectively) (p=0.00001 and 0.0031), with an important saving of the costs of 7 days' treatment with growth factor (approximately 1120 SUS; see Table 7).

Discussion It has been well established in both randomized and pilot studies in comparison with historical series that the treatment with G-CSF or other HGFs is capable of shortening the period of neutrophil recovery after A B M T or A L L O - B M T [1-3, 6, 8, 10, 14, 16, 17, 19-21]. Empirically, in all these studies, G-CSF was started on the same day as or the day following marrow infusion. However, in a recent pilot study of a group of malignant lymphoma patients who underwent ABMT, treatment with G-CSF was delayed until 8 days after transplantion, and a significant shortening of the time to reach an A N C of 0.5 x 109/1 was found in comparison with a historical series without growth factor use [7]. Also, a lower number of days under i.v. antibiotics was observed. In our study we found no significant difference in the duration of the neutropenic period in patients undergoing A B M T and A L L O - B M T who received GCSF on day 0 versus day + 7 post-BMT in a controlled, randomized, stratified form. This is consistent with the observation that the endogenous G-CSF levels are high and in the same range as the levels which can be obtained by exogenous administration during the first week after BMT [4]. In fact, there are no differences in the days to reach more than 0.1, 0.5, and l x 109/1 A N C between both groups. Moreover, we have not found differences in the days of fever with less than 1. 109/I ANC, rate of bacteremias, or duration of treatment with parenteral antibiotics. This agrees with previous observations in which most positive blood cultures were isolated in the absolute granulocytopenic period (less than 0.1•

ANC) [7]. The interval of absolute granulocytopenia ranges between 8 and 12 days and does not seem to be modified by early treatment with HGFs and, particularly, by G-CSF [7, 9, 13, 16, 22]. Our results confirm those recently presented by Vey et al. [22] and obtained in patients with malignant lymphomas and solid tumors undergoing ABMT, in whom G-CSF was used on day + 1 versus + 6 post-transplant without there being significant advantages for a particular group. They reported a savings of 1100 $US for patients of the D6 over the D1 group, a result very similar to ours. These observations support previous reports that described that a variable period of time (a fixed period of approximately 8 days) is necessary for the transplanted stem cells to respond to cytokines. During this time, seeding, self-renewal, commitment, and differentiation to a cell capable of responding to the later cytokines take place [5, 13, 151 . In our series, in accordance with others, no difference in the acute G V H D incidences between the groups was noted [8, 9, 13, 20]. Moreover, the incidence in the A L L O - B M T group is lower than that observed in our recent historical cases in which growth factors were not employed (data no shown). However, other therapeutic agents (i.e., high-dose intravenous immunoglobulins) might have played an additional role in this decrease. As our results show, the use of acute G V H D prophylaxis regimens containing methotrexate can delay engraftment, independent of the day on which growth factor administration is started. Therefore, the stratification employed by us seems to be necessary in future investigations about growth factor effects on A L L O BMT, in order to avoid erroneous results. In conclusion, the early use of G-CSF does not shorten the absolute granulocytopenic period after A B M T or A L L O - B M T in comparison with delayed administration. Therefore, the early use of G-CSF immediately after transplantation is useless and more expensive, offering no clear advantage over delayed administration.

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