AU618283B2 - The use of GM-CSF in the treatment of a patient requiring high-dose chemo- or radiotherapy for cancer - Google Patents
The use of GM-CSF in the treatment of a patient requiring high-dose chemo- or radiotherapy for cancer Download PDFInfo
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- AU618283B2 AU618283B2 AU23587/88A AU2358788A AU618283B2 AU 618283 B2 AU618283 B2 AU 618283B2 AU 23587/88 A AU23587/88 A AU 23587/88A AU 2358788 A AU2358788 A AU 2358788A AU 618283 B2 AU618283 B2 AU 618283B2
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- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 title claims description 45
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 title claims description 44
- 238000002512 chemotherapy Methods 0.000 title claims description 10
- 238000001959 radiotherapy Methods 0.000 title claims description 10
- 206010028980 Neoplasm Diseases 0.000 title claims description 8
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- 229960004397 cyclophosphamide Drugs 0.000 claims description 23
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical group ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 22
- 210000001185 bone marrow Anatomy 0.000 claims description 21
- 238000001802 infusion Methods 0.000 claims description 21
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- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 8
- 230000001400 myeloablative effect Effects 0.000 claims description 4
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- 238000002360 preparation method Methods 0.000 description 2
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- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 102000046157 human CSF2 Human genes 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
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- 206010024378 leukocytosis Diseases 0.000 description 1
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- 231100001022 leukopenia Toxicity 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010198 maturation time Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/48—Blood cells, e.g. leukemia or lymphoma
Description
61828 3 S COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION NAME ADDRESS OF APPLICANT: Sandoz Ltd.
Lichtstrasse SCH-4002 Basle jSwitzerland
AND
Instituto Nazionale Per Lo Studio e la Cura Dei Tumori S' Via Venezia 1 S 20133 Milano SItaly SNAME(S) OF INVENTOR(S): Stt GIANNI Alessandro M i t t tl I I ADDRESS FOR SERVICE: Iti DAVIES COLLISON j l Patent Attorneys 1 Little Collins Street, Melbourre, 3000.
I l COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: i t"The use of GM-CSF in the treatment of a patient requiring high-dose chemo- or radiotherapy for cancer".
j The following statement is a full description of this invention, including the best method of V "fI performing it known to me/us:t
I
iI^M I IIIIBI i i ll1 i' 118-7383 The present invention relates to a new application, in particular a new pharmaceutical application for the compound granulocyte-macrophage colony stimulating factor. More specifically it pertains to the use, in sequence, of a cytotoxic, but stem cell sparing, agent and granulocytemacrophage colony stimulatihg factor.
Granulocyte-macrophage colony stimulating factor, hereinafter referred to as GM-CSF, is known and has been described, together with processes for its production by recombinant DNA methods, for example in European Patent Publication 0188,479 Application Number 85903275) and equivalents world-wide.
As described in EP 188,478, GM-CSF is known from various animal sources. The present invention however, is particularly concerned with primate GM-CSF and more particularly with human GM-CSF.
The GM-CSF of the present invention may be prepared by any of the means known in the art. For example, as described in the above mentioned EP 188,479, it may be produced as the result of recombinant DNA expression. It may otherwise be isolated from natural sources or produced synthetically.
It is known that GM-CSF is a factor which is required for the survival, proliferation and differentiation of myeloid progenitor cells which are committed to form mature granulocytes and macrophages (CFU- GMs). It has thus been suggested that it be used in the treatment of myelo-suppression caused by chemotherapeutical or irradiation treatment of cancer. Under such circumstances the GM-CSF is administered to a patient, treated with chemo- or irradiation therapy, after the re-infusion of previously removed bone marrow (autologous bone marrow) in order I It I I I~ II -2 -2- 4 a 44 44 4 4 4? 444444 4444 4 44 to stimulate the proliferation and differentiation of the myeloid progenitor cells found in the bone marrow. GM- CSF may also be administered for 3-5 days before the removal of bone marrow for later re-infusion.
The cytotoxic, but stem cell sparing, agent is selected from cyclophosphamide [N,N-Bis(2chloroethyl)tetrahydro-2H-l,3,2-oxazophosphorin-2-amine- 2-oxide)], a known compound whose preparation was first described by Arnold et al (Naturwiss 45 (1957) 64) and etoposicde (VP-16), whose preparation is described by Keller-Justen et al in J Med Chem 14 (1971) 936.
It is known that a dose of a cytotoxic agent, such 15 as cyclophosphamide, has the effect of stopping proliferation of bone marrow cells. However, the cytotoxic effect upon the cells which normally regulate proliferation is longer lasting, so that upon recovery from the treatment, bone marrow proliferation is rapid 20 and uncontrolled. It has therefore been proposed to treat patients with a cytotoxic, but stem cell sparing, agent such as cyclophosphamide 14 days before removal of bone marrow for re-infusion following chemo- or radiotherapy, so that the bone marrow will be in an actively proliferating state when removed.
It has now been found that when the bone marrow is in this actively proliferating state, many progenitor stem cells appear in the peripheral blood circulation.
The differentiation of these circulating stem cells may be stimulated by treatment with GM-CSF in the period following treatment with the cytotoxic agent. It has further been found that if, after cytotoxic agent/GM-CSF treatment, peripheral blood is removed at the same time as bone marrow, and this blood, or leucocytes obtained from this blood, are re-infused together with the bone marrow, myeloid recovery is considerably more rapid than is normally the case.
911009,dbdaLO85,23587.res,2 rT c -I 118-7383 -3- DESCRIPTION OF THE DRAWINGS Figure 1: granulocyte numbers (average values) following high-dose cyclophosphamide (7 g/m 2 on day 0) in 14 control patients and in patients treated with GM-CSF (8 ug/Kg/day from day 1 to day 10 or day 14). Upper panel: linear scale; lower panel: log scale.
Figure 2: distribution of neutropenia duration measured from the end of treatment (cyclophosphamide, 7 g/m 2 on day 0) in 14 control patients (a) and in 5 patients treated with GM-CSF Curves represent the cumulative proportions of patients reaching, within the indicated interval, more than 1000 neutrophils (upper panel) and more than 2500 neutrophils, respectively (lower panel).
Figure 3: effect of GM-CSF or placebo infusion on circulating CFU-GM proportion (upper panel) and blood concentration (lower panel).
tt GM-CSF was continuously infused for 10 days, starting on day 1 following cyclophosphamide (7 g/m 2 Figure 4: granulocyte (I3 and platelet counts in two patients following myeloablative treatment and autografting of bone marrow plus peripheral blood stem cells. Patient A received melphalan alone (200 mg/m 2 patient B total body irradiation (12.5 Gy, fractionated over 3 days) plus melphalan (160 mg/m 2 Circulating stem cells were harvested twice for each patient, following prior high dose cyclophosphamide and GM-CSF infusion (see examples).
i tt i r i- 118-7383 -4- DETAILED DESCRIPTION The present invention provides a method of treatment of a patient requiring high-dose chemo- or radiotherapy for cancer, with rescue by autologous bone marrow transplantation comprising the steps of: a) administering a high dose of a cytotoxic, but stem cell sparing, agent selecied Cfro cycr-oospa.,de and e4(os;de b) over a subsequent period administering GM-CSF i c) when the bone marrow is in an actively proliferating state and precursor stem cells are present in the peripheral blood, removing bone marrow and a volume of peripheral blood or leucocytes obtained therefrom d) administering a fully myeloablative regimen of chemo- or radio- Stherapy i e) shortly therafter, re-infusing bone marrow and peripheral blood, or leucocytes obtained therefrom; and optionally, f) continuing administration of GM-CSF for a period of time until myeloid recovery has occurred.
In a preferred embodiment of the present invention the cytotoxic, but stem cell sparing, agent is cyclophosphamide.
It is surprisingly found that if bone marrow cells are supplemented with a small amount of circulating stem cells, the myeloid recovery, post chemo or radio therapy, occurs after an average of 10 days instead of 14 days or more. Although not yet fully understood, it is believed that the GM-CSF acts on the progenitor cells in the peripheral blood, stimulating them to differentiate, such that 12-21 days after treatment with the cytotoxic, but stem cell sparing, agent, the committed precursors (CFU-GM's) are present in extremely high numbers. These CFU-GM's give rise, in in vitro culture, to mature progeny after 7-10 days. The re-infusion of this cytotoxic agent/GM-CSF treated peripheral blood retS
I"
J ^A 118-7383 suits in the e tremely rapid recovery period.
The present invention also envisages the use of a GM-CSF infusion after peripheral blood and bone marrow transplantation. As CFU-GMs are the main target of GM-CSF, it is anticipated that a further acceleration in the circulating granulocyte appearance would result from such a posttransplant infusion. Such activity of the GM-CSF on infused CFU-GMs is expected to prevent the circulating granulocytes from falling below the safety level of 500/il. This result is not expected to occur after infusion of bone marrow alone, as the precursors found in the bone marrow are predominantly early progenitors which have a longer maturation time.
The use of GM-CSF according to the present invention is particularly suitable after the chemo- or radio-therapy of refractory cancers, ie in those patients who have been through the normal cancer treatment programmes and whose cancer was not eliminated thereby. It is envisaged that such use may be performed after treatment of solid tumours, eg breast cancer; lymphomas; and leukaemia.
o O* 4 S* o o4 4 *4 4 44 4 4; 4 4 In step a), phosphamide is 1.4 g/m 2 (final with cyclophosphamide as the cytotoxic agent, the cyclosuitably administered in 4-5 injections, at dosages of dose 6-7g/m 2 41 4 *44444 44 44t S0 *P 4 In step GM-CSF is suitably administered as a continuous intravenous infusion for 10 to 14 days, with dosages ranging between 6 and 24 pg/Kg/day and preferably 8 ug/Kg/day. A subcutaneous route of infusion may be equally suitable.
In step peripheral blood leukocytes are preferably removed by leukapheresis using a continuous flow blood cell separator (IBM 2997 or the like). The circulating stem cells are preferably harvested when the leucocytes exceed 1000/pl and the platelets exceed 100,000/ul. A total 118-7383 -6of 2 to 4 leukaphereses are performed during the early recovery phase following cyclophosphamide and GM-CSF infusion (usually between day 14 and day 21 post-cyclophosphamide). The total blood volume processed per run is approximately 5-10 litres at a flow rate of 35-70 mL/min.
The chemo- or radiotherapy given in step d) may be any standard or experimental regime, for example TBI 12.5 Gy plus melphalan 160 mg/m 2 After 3-24 hours the bone marrow plus leucocytes is re-infused (step e).
SSuitably the same course of GM-CSF treatment is used in step f) as in |step b).
According to a further aspect of the invention, no bone marrow is I taken and myeloid recovery is achieved only by re-infusion of leucocytes i from cyclophosphamide/GM-CSF treated peripheral blood.
The above disclosure generally describes the present invention. A 1 more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of i illustration only, and are not intended to limit the scope of the invention.
a a C C f t i t I t I C
CCC
CCt 118-7383 -7- EXAMPLE 1 To demonstrate the effects of cyclophosphamide and GM-CSF on myeloid recovery a comparison was performed between 14 control and 5 test patients. Five male and 9 female patients with an average age of 41.5 (range 22-55), of whom 4 had high grade, poor-prognosis non-Hodgkin's lymphoma, 7 had inflammatory breast cancer and 3 had small cell lung cancer, were used as controls and one 1 male and 4 females with an average age of 45 (range 39-53), of whom 1 had high grade non-Hodgkin's lymphoma and 4 had inflammatory breast cancer, were used as test patients.
All 19 patients were subjected to the same high dose chemotherapy programme, consisting of the sequential administration of: a) cyclophosphamide (7 g/m 2 on day 0 b) vincristine (1.4 mg/m 2 methotrexate (8 g/m 2 plus leucovorin S rescue, cisplatin (120 mg/m 2 on days +21-25; and c) total body irradiation (12.5 Gy total) plus melphalan (120-180 mg/m 2 on days +42-45 or melphalan alone (200 mg/m 2 for inflammatory 6 a breast cancer patients.
S
In the 5 test patients, GM-CSF was given, starting 24 hours after cyclophosphamide infusion, as a continuous infusion via a central Scatheter, at 8 pg/Kg/day for 14 days in 3 patients and for 10 days in 2 patients.
Bone marrow with peripheral blood was returned the day after mel- I phalan infusion.
Bone marrow procurement and leukapheresis are performed by standard techniques and stem cells and bone marrow cells are brought to the temperature of liquid nitrogen using controlled freezing techniques.
A
118-7383 -8- Blood samples were obtained prior to treatment and every 2-3 days following cyclophosphamide infusion. Details of the techniques for determination of CFU-GM are described in Lanfrancone et al, J CELL PHYSIOL 122 (1985) 7.
Haematological toxicity of high dose cyclophosphamide and effect of
GM-CSF
The haematological toxicity results may be seen in Fig 1, wherein signifies the control and signifies the test regime; Control: severe leukopenia 500 neutrophils/pi) occurred by day eight. The recovery of neutrophils to 1000/pl was achieved in 17-24 days (average 18), and to 2500/pl in 19-28 days (average 21.5).
Test: neutrophil count showed a more pronounced initial rise above the starting level, lasting from 2-3 days, with the nadir occurring 1-2 days earlier. The recovery phase was associated with marked leukocytosis (up to 25,000 leukocytes/pl) that gradually resolved over 3-4 days after GM-CSF discontinuation. Recovery of neutrophils to 1000/il was achieved in 11-15 days (average 13), and to 2500/pl in 12-19 days (average 14) (Fig There were no differences documented between controls and GM-CSF treated patients in platelet counts or haemoglobin levels.
'it' Effect of GM-CSF on circulating haemopoietic progenitor cells following therapy with cyclophosphamide Sit 4 Using the techniques of Lanfrancone et al, supra, the number of circulating colony forming units in unperturbed conditions is approximately 40 CFU-GM/10 6 mononuclear cells and 40-60 CFU-GM/nml of peripheral Sblood. Following cyclophosphamide treatment, ther2 was observed an approximately 100-fold higher peak value in both the proportion (CFU-GM- 44f
A
118-7383 -9- /mononuclear cells) and the absolute number (CFU-GM/ml of peripheral blood) of colony forming units (Fig Upon addition of GM-CSF (8 pg/Kg/day from day 1 to day 10 following cyclophosphamide), CFU-GM rose i by a further 3 times (peak concentration) and 5 times (peak absolute number), respectively. Of note, these high peak values were maintained Ifor several days both in the control and in the GM-CSF treated patient.
Thus, as compared with normal subjects, the total number of CFU-GM circulating in the peripheral blood during the days of stem cell expansion (area under the curve) was approximatley 30-fold higher following cyclophosphamide plus GM-CSF. A further increase can be anticipated following optimal length of GM-CSF infusion.
EXAMPLE 2 Haemotopoietic reconstitution in 2 specific patients from Example 1 Sis illustrated in Figure 4.
4 1 Patient A received high dose melphalan (200 mg/m 2 followed by intfusion of 2 x 10 8 /Kg bone marrow cells and 1.8 x 10 8 /Kg circulating mononuclear cells. On day 6, the granulocyte count fell to less than 500/pl, remaining below this threshold for 5 days only. Platelet count never fell below 30,000/ul and no tranfusions were required. Unsuppor- Sted platelet count rose to 79,000/pl on day 12 and to 120,000/pl on day .4.
Patient B had high grade non-Hodgkin's lymphoma and received 4.7 x i 10 8 /Kg bone marrow cells plus 8.8 x 10 8 /Kg peripheral blood mononuclear S cells, 24 hours after completion of high dose treatment (12.5 Gy fracttionated total body irradiation and 160 mg/m 2 melphalan On day 3 the granulocyte count fell below 500/pl. Starting from day 5, the t ft1 118-7383 patient showed a steady increase in white cell counts, reaching 500 neutrophils/pl on day 8, 1000/pl on day 10 and more than 10,000/pl on day 12. The patient's platelet count fell below 20,000/pl on day 9, requiring transfusion of one unit of platelets. Unsupported platelet count rose to >50,000/pl on day 12 and to 100,00/pl on day 13, respectively.
Claims (1)
118-7383 -12- 100,000/pl. A method according to any one of claims 1 to 4 in which the myelo- ablative regimen involves total body irradiation plus melphalan. 6 A 'method according to claim 5 in which the re-infusion of bone marrow and peripheral blood, or leucocytes obtained therefrom occurs 3-24 hours after the chemo- or radiotherapy. 7 A method according to any one of claims 1 to 6 in which the cyto- toxic, but stem cell sparing, agent is cyclophosphamide. 8 A method according to claim 7 in which the cyclophosphamide is ad- ministered at a dosage of 6-7 g/m 2 9 A method according to any one of claims 1 to 8 in which the GM-CSF o° is administered as a continuous infusion. 4 0 1o 0 A method according to claim 9 in which the dosage of GM-CSF ranges o0 o ,4 11 between 6 and 24 pg/Kg/day. S° 11 A method according to claim 10 in which the dosage of GM-CSF is 8 ug/Kg/day. 12 A method of treatment of a patient requiring high-dose chemo- or 0 0 o o radiotherapy for cancer, with rescue by leucocyte infusion, com- o prising the steps of; 0 a) administering a high dose of a cytotoxic, but stem cell sparing, i agent sec -fra clcopAospa aide onA e~oposide b) over a subsequent period administering GM-CSF o° c) when precursor stem cells are present in the peripheral blood, 0*1 removing a volume of peripheral blood or leucocytes obtained there- o 0 00 A7 Gi i M s 118-7383 -13- from d) administering a fully myeloablative regimen of chemo- or radio- therapy e) shortly therafter, re-infusing peripheral blood, or leucocytes obtained therefrom; and optionally, f) continuing administration of GM-CSF for a period of time until myeloid recovery has occurred. r i I a -14- 13. A method according to claim 1 or claim 12, substantially as hereinbefore described with reference to the Examples. 14. The steps, features, compositions and crnpounds disclosed herein or referred to or indica e specification and/or cla is application, indivi -or collectively, and any and all combinations of any two r more of said csteps or features. DATED this 24th day of November 1988. SANDOZ LTD. and INSTITUiO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI 6.4 6* 6* d 4 t, o o C, C Sa t ro A, 0 44 *6 Cs- J 4 0 o 4 6 96 V- 6 0 wAL> (l yS 4
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| AU23587/88A AU618283B2 (en) | 1988-10-10 | 1988-10-10 | The use of GM-CSF in the treatment of a patient requiring high-dose chemo- or radiotherapy for cancer |
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| AU23587/88A AU618283B2 (en) | 1988-10-10 | 1988-10-10 | The use of GM-CSF in the treatment of a patient requiring high-dose chemo- or radiotherapy for cancer |
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| EP0188479A1 (en) * | 1984-07-06 | 1986-07-30 | Sandoz Ag | Lymphokine production and purification. |
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