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1988 72: 834-836

Use of recombinant human granulocyte-macrophage colony-stimulating factor in autologous marrow transplantation for lymphoid malignancies
J Nemunaitis, JW Singer, CD Buckner, R Hill, R Storb, ED Thomas and FR Appelbaum
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CONCISE

REPORT

Use of Factor

By John
Recombinant in Autologous

Nemunaitis, Jack

Human Marrow

W. Singer, and

Granulocyte-Macrophage Transplantation for
C. Dean Frederick Buckner, Roger A. Appelbaum
with was rhGM-CSF was compared 86
Colony-Stimulating Lymphoid Malignancies
Rainer Storb, E. Donnall Thomas,
The marrow explored given tolerated
recombinant factor a phase up I/Il to 240 for infusion
human (rhGM-CSF) lymphoid dose
granulocyte-macrophage following malignancies study. 14 When days for escalation autologous
disease-matched patients neutrophil days sooner. with and fever,

and receiving

treatment-matched 60 were sg/m2/day counts more discharged
historirhGM-CSF rapidly. from had the
colony-stimulating in as a at

cal controls.

recovered fewer hospital well a 1988
transplantation 2-hour doses

platelet and

daily sg/m2/day.

by Grune

& Stratton,
RANULOCYTE-MACROPHAGE ing factor (GM-CSF) necessary for the survival, myeloid production cells. of Recombinant sufficient to is enhanced
colony-stimulatis a regulatory glycoprotein proliferation, and maturation DNA quantities technology2 of recombinant has allowed human

for the

minimum week study prior was

after and

marrow

infusion.

Weekly

obtained of Study

during design. patients at a dose

radiographs

The were of

electrocardiograms

weekly

thereafter.

to transplant a phase I/Il enrolled

escalation

in groups [specific

of activthree

consecutively rhGM-CSF
GM-CSF (rhGM-CSF) trials. Myelopoiesis
of clinical ity - 5 x l0 colony-forming units/mg (CFU/mg)] for 14 days. is given to Subsequent groups of three patients were entered, and the dose for normal monkeys,3 and monkeys that receive rhGM-CSF each group was doubled, until either intolerable toxicity occurred or following autologous marrow transplantation recover neutro- biologic activity was suggested. Biologic activity was defined as phil counts more quickly.4 Initial studies in patients withrecovery of neutrophils to >500 cells/zL before 14 in two day of three patients at a given dose. This definition was based on our AIDs-associated neutropenia also demonstrated stimulation

experience with 86 patients given autologous grafts for in response to rhGM- previous malignancies, when only four patients (<5%) achieved this dose escalation trial lymphoid level ofneutrophils by day l4. Ifno significant toxicity occurred at a of rhGM-CSF in patients with lymphoid malignancies dose with suggested biologic activity, we planned to investigate two undergoing autologous marrow transplantation.6 rhG Mmore dose escalations before closing the study. rhGM-CSF was CSF (Immunex, Seattle) given as a 2-hour infusion once a
enable performance when rhGM-CSF

starting

5 g/m2/day of I
of myelopoiesis with minimal CSF.5 This report describes

toxicity a phase

day for tg/m2/day, tion

days was and biologic

well tolerated activity was
at doses up to suggested by observa-

240 within

administered

a single

2-hour

intravenous

infusion

I hour

(designated
Patients. nancy qualifying
of completion of as day 0) and repeated

Fifteen

the autologous marrow infusion daily for a total of 14 days.
patients or with syngeneic lymphoid marrow maligtransplant

of accelerated

engraftment.

MATERIALS AND

consecutive for autologous
METHODS malignancies, disease, autologous or or includnon-Hodgsyngeneic

Patient ing kins acute

selection. lymphocytic

Patients

lymphoid Hodgkins

were studied. There were

conditioning

The mean six females

regimen,

age and

was 32 years nine males.

of marrow

(range Diagnosis,

transplant,

13 to 61 years). disease state,

and marrow

leukemia, who were
purging are listed by patient in Table. AllI patients with a fever were treated uniformly according to Fred Hutchinson marrow transplant after standard preparative regimens were eligible (T > 38#{176}C) Research Center protocol with empiric antibiotic therapy for study. Signed informed consent conforming to FDA and institu- Cancer and without granulocyte transfusions. tion review guidelines was required. No exclusions were made for
lymphoma, undergoing disease state or monitoring. monitored stage, All at counts, prior therapy, were every urine 6 or Karnofsky daily Complete performance and had blood cell Hematologic responses. RESULTS

scores.

Clinical vital signs patients least and examined hours.

on which

patients

counts

times,

differentials,

platelet

reticulocyte

counts,

analyses

chemistries,

were done

prothromdaily
achieved just cells/iL patient achieved of eight
an absolute and platelet receiving an ANC evaluable five
neutrophil independence rhGM-CSF at
count (ANC) of >500 are shown in Table I. No 15 or 30 g/m2/day five so.
From Submitted Supported CA tute, /8029.

Fred by and

Hutchinson 18, Public 15704 US CA
Cancer 1988; Health awarded and Human
Research April Service by the
Center, 20, Grants National No.

Seattle. 1988. CA Cancer

February

accepted

>500 cel1s/L before day I 4, whereas patients receiving 60 ,g/m2/day did to

26828, Of

Department

ofHealth

Services,
Address reprint requests ogy, Veterans Administration Way, The charge indicate
to John J. Nemunaitis, Medical Center. of this article with Inc. article must /8 were U.S.C. defrayed
Insti- 14, four Bethesda, MD. within 24 MD. 111 Oncol- maximum /Columbian in part be hereby /734 by page marked solely
patients who reached 500 neutrophils/tL temporarily decreased their ANC to 72 hours after stopping rhGM-CSF. reduction tg/m2/day) the retrospective 30 ttg/m2/day 60 recovery of ANC after stopping was 35% (4% control group7 and g/m2/day than 60 ig/m2/day showed the days with transfusions
by day <500/FL The mean Table patients granulocontrol 2

rhGM-CSF

Seattle, publication payment. this
98108. costs This therefore section
(dose 60 compares receiving
to 63%). with study earlier a

rhGM-CSF.

advertisement
in accordance fact. & Stratton. by Grune
receiving to Patients cyte and platelet group. The 38.0#{176}C and

retrospective

0006-4971/88/7202-0043$3.00/0
average number of the number of platelet

Blood,

Vol 72,

temperature in the first

pp 834-836

2 (August),

GM-CSF

IN AUTOLOGOUS

MARROW

TRANSPLANTATION

1. Day

of Myeloid

Megakaryocytic

Engraftment

in rhGM-CSF-Treated

Marrow

Unique

Conditioning

Patient No.

Diagnosis/Disease State

Regimen TBI Dose (cGy)/days

Dose rhGM-C5F

Day After

)nfusion >500

Cells/zL.

Pizging

(ig/m2)
Patient Independent of Platelet Transfusion

)nfusion

NHL/relapse

ALL/relapse

NHL/remission
NHL/re)apse NHL/relapse NHL/re)apse

None None None

3918 3935
NHL/relapse NHL/relapse NHL/remission NHL/relapse ALL/relapse NHL/relapse NHL/remission ALL/relapse non-Hodgkins lymphoma; regimens ALL, included

200 O acute

x 6 x x

A A A S

Pan B None None
None None None None A, x autologous; 2 days). TB),

5, syngeneic. total body

3992 3908

NHL, AIl

lymphocytic (60

leukemia; mg/kg/day

cyclophosphamide

irradiation

delivered

opposing

cobalt

source. Marrow

Patient

received

was with

treated

by linear

with cell

accelerator.

tg/mL antibody

Busulfan

(4 mg/kg/day

x 4 days)

no TBI.

tAutologous on day
4-hydroperoxycyclophosphamide. complement.

in vitro 8.

a pan-B
30 days receiving Two had of

transplantation

appeared of rhGM-CSF. patients (UPN Both (UPN

to be 3990 3810) (B MT)

least not s30 now without
in patients evaluable) jg/m2/day 100
60 g/m2/day of 14 evaluable engraftment. One marrow

(UPN sient

3647) developed in creatinine
acute tubular necrosis with to mg/dL 2.5 believed to be caused

a tranby

incomplete rhGM-CSF.

patient,

a rapid infusion of acyclovir. He was also receiving rhGMCSF at the time. The rhGM-CSF was held for 2 days and dayswas restarted without recurrence of renal function abnormalof reaching positive Patient ( 1 3%) an blood patients ANC cultures 3990 abscess died found septicemia had occurred with an positive UPNs in the ANC blood (3990 first cultures and week 3945). after on to of a positive of septithan one

post-bone

transplantation to have an ANC >1,000 patient >2,000 (-well receiving reconstitution. was

evidence

for relapse, continues initially reaching an post-BMT. row All plete and evaluable hematopoietic rhGM-CSF Toxicity. No patient of suspected rhGM-CSF has The an other ANC hydroperoxycyclophosphamide occasional platelet patients
ANC of cells/tL 3647) but weeks) zg/m2/day bone
400/zL on received marstill
ities. after Two day 24 before a Both 4transplant.

of 500/tL

(UPN (4-HC)-treated cells/jzL U/2
of 20 cells/zL secondary Thirty percent

transfusions

requires day 8 of Pseudomonas at day 100.an intestinal wall had com- the retrospective patients. bacterial/fungal cemia or the before

presumably at autopsy.

tolerated

by all

control group of patients had blood culture with clinical evidence same organism isolated on more reaching an ANC of 500/sL.
failed to complete toxicity. The were observed:

courses following Three

of rhGM-CSF toxicities patients associated low-grade was associated pulmonary, However,

Tab Ic 2.

because occasion related to abdominal the rhGM-CSF only with temperature only one

DISCUSSION

cramps, two of whom first dose. One patient that patient first cardiac, dose resolved had or when bilateral renal
had symptoms had a constant rhGM-CSF shoulder No pain hepatic, occurred.
was IV eight at doses before

Parameters

well infusion
tolerated in patients for lymphoid

g/m2 Further-

given marrow One the more,

by slow five cells/tL of

undergoing malignancy. 14 only days 5% of achieved
autologous treated an 86 ANC patients with of
discontinued. with neurologic,
transplantation patients 60 day
surviving jzg/m2/day I 4. Because

of rhGM-CSF. toxicities

patient 500

Valu es of Study

rhGM-CSF Dose (ig/m/day) No. of Patients Day AGN 10

>

Day 100 AGN 14

AGN 22

1.30 29
Day Pat&et Transfusion ndependent

Day of Discherge 29

No. of Febrile Days IT 3ac) Until Engaftment 12*
No. of PIat&st Units Transfused (From day 0 to day 30) 1) 67

30 60t

SD (range). controt who died goup
6(8-41) 5 (8-22) 2 (8-13)
10(10-60) 10 (14-41) 2 (12-18)
11 (17-84) 13 (21-53) 4 (20-24)
20(13-118) 22 (13-70) 5 (14-31)

25(18-129)

7(0.30)
41 (22-170) 48 (32-154) 18 (52-90)

(22-41)

(18-51)

6 (3-20)

3 (2-1

fRetrospective

*Patient

of comparebty

matched

patients end is not

)ymphoid

ma)ignancy

underwent

autologous MT at FHCRC B

to the

of this

study.

on day 8 was

unevaluable

included.

NEMUNAITIS
treated this strongly trolled level
in a similar before suggested. trial will be day
fashion 14, necessary However,

but biologic

without activity a
rhGM-CSF at this. influence whether have when with have autologous addition, two these

reached the wastion

further of early for

concern

rhGM-CSF and interfere reconstitution.

may with

cause the Metcalf
differentiaself-renewal and in given with col-

prospective

placebo-con-

required

stem cells long-term
to prove had an determine studies
rhGM-CSF may recovery. However, direct stimulation which other shortened monkeys patients independent other could growth platelet treated with or indirect of
also have we cannot effect. In vitro
leagues reported data in mice showing cellularity after on platelet GM and bone marrow this was intraperitoneal a GM-CSF.3 Third, the mildon tumor cell were regrowth excluded to transplant receptors, in this is unknown. from this on receptors rhGM-CSF have malignancies we GM-CSF leukemia
reductions mice were effect Patients of because

CFUdaily

rhGM-CSF myeloid myeloid

suggested combined

megakaryocyte factors.89 recovery with Other times rhGM-CSF.4
proliferation augmented researchers after In

be significantly

with tumors have rhGM-CSF of exposure reported the effects BMT tumor in cells most rhGM-CSF the molecule after lymphoid
their cell surface and on possible surviving not are been not determined. believed to to some
myelodysplasia after treatment with normal
became platelet with rhGM-CSF.#{176} baseline platelet
of eight Because express transfusion in explore

considered setting.

it reasonable Nonetheless,

However, counts,

tumor cells may express rhGM-CSF receptors or GM- lymphoid rhGM-CSF may influence tumor growth indirectly. CSF had no effect on platelet counts.5 Erythroid stimulation This study evaluated the short-term effects of rhGM-CSF has also been observed in vitro and in animals with increased after autologous BMT for lymphoid malignancy. rhGMerythropoietin levels.7 No clear effect of rhGM-CSF on CSF was well tolerated and appeared to have biologic erythropoiesis was observed in our study. activity when compared with a retrospective control group at Toxicity with rhGM-CSF was mild and predominantly patients limited toxicity production Our to muscle are unknown. by cramps macrophages.2 concerns. cells/zL the last with of First, a temporary occurred in four dose of rhGM-CSF. studies recovery. and GM-CSF bone may pain. induce The mechanisms prostaglandin of doses 60 mg/m2/day given as a 2-hour daily infusion. We cannot E conclude tion regimen, by this trial marrow-purging whether a particular cytoreductechnique, or underlying disto III therapeutic and to rhGM-CSF. are and needed economic any Larger to prodefine advanserious trials
study raised three tion in ANC to <500 within 1 to 3 days after observation is consistent short stimulatory effect patients had sustained
affects the responsiveness reduc- ease randomized phase patients spective This more precisely the possible the tages offered by all untoward effects. this

previous rhGM-CSF.

showing Second, not This

molecule

uncover

hematopoietic

raises

REFERENCES

autologous bone marrow transplantation (ABMT). Blood 68:276a, I. Metcalf D: The granulocyte-macrophage colony stimulating 1986 (abstract) factors. Science 229:16, 1985 2. Cantrell MA, Anderson D, Cerretti DP, Price V, McKereghan 8. Broxmeyer HE, Williams DE, Hangoc G, Cooper 5, Gillis 5, K, Tushinski Ri, Mochizuki DY, Larsen A, Grabstein K, Gillis 5, Shadduck RK, Bicknell DC: Synergistic myelopoietic actions vivo in Cosman D: Cloning, sequence, and expression of a human granulo- after administration to mice of combination of purified natural cyte/macrophage colony-stimulating factor. Proc Natl Acad Scimurine colony-stimulatory factor , recombinant I murine interleukin USA 82:6250, 1985 3, and recombinant murine granulocyte/macrophage colony stimuR, Wang GG, lating factor. Proc Natl Acad Sci USA 84:3871, 1987 of hematopoiesis in 9. Robinson BE, McGrath HE, Quesenberry PJ: Recombinant GM-CSF. Nature murine granulocyte macrophage colony-stimulating factor has 321:872, 1986 megakaryocyte colony-stimulating activity and augments mega4. Nienhuis AW, Donahue RE, Karisson 5, Clark SC, Agricola karyocyte colony stimulation by interleukin 3. J Clin Invest 79:1648, B, Antihoff N, Pierce JE, Turner P. Anderson WF, Nathan DG:1987 Recombinant human granulocyte-macrophage colony stimulating 10. Vadhein-Raj 5, Keating M, LeMaistre A, Hittelman WN, factor (GM-CSF) shortens the period of neutropenia after autoloMcCredie K, Trujillo JM, Broxmeyer HE, Henney C, Gutterman gous bone marrow transplantation in a primate model. J Clin Invest JU: Effects of recombinant human granulocyte macrophage colony 80:573, 1987 stimulating factor in patients with myelodysplastic syndromes. N 5. Groopman JE, Mitsuyasu RT, DeLeo i, M Oette DH, Golde Engl J Med 317:1545, 1987 DW: Effect of recombinant human granulocyte macrophage colony I 1. Metcalf D, Johnson GR, Burgess AW: Direct stimulation by stimulating factor on myelopoiesis in the acquired immunodefipurified GM-CSF of the proliferation of multipotential and cryciency syndrome. N Engl J Med 317:593, 1987 throid precursor cells. Blood 55: I 38, 1980 6. Appelbaum FR, Buckner CD: Overview of the clinical rele12. Kurland JI, Brockman RS, Broxmeyer HE, Moore MA: vance of autologous bone marrow transplantation. In: Goldstone AH Limitation of excessive myelopoiesis by the intrinsic modulation of (ed): Clinics in Haematology: Autologous Bone Marrow Transplanmacrophage-derived prostaglandin E. Science 199:557, 1978 tation. Saunders, Salem, MA, 1986 3. Donahue RE, Wang EA, Stone DK, Kamen

Sehgal primates

PK, Nathan D, Clark SC: Stimulation by continuous infusion of recombinant
7. Hill RS, Still B, Sanders
Mazza P. Buckner CD, Appelbaum FR, Amos D, 13. Metcalf D, Begley CG, marter J, Mermod ii, Thatcher J, Stewart P. Chard R, Livingston R, Berenson R, responses in mice injected with Bensinger W, Clift R, oney D K, Singer J,Witherspoon RP, Thomas ED: Engraftment in 86 patients with lymphoid malignancy after CSF. Exp Hematol 15:1, 1987

Williamson

D, Schmidt

Di, recombinant

EC, murine

DeLaGM-

Hemopoietic

purified

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