WO1991016075A1

WO1991016075A1 - Bone marrow treatments

Info

Publication number: WO1991016075A1
Application number: PCT/AU1991/000155
Authority: WO
Inventors: Harvey J. Turner; Phillip G. Claringbold
Original assignee: Australian Nuclear Science & Technology Organisation
Priority date: 1990-04-20
Filing date: 1991-04-19
Publication date: 1991-10-31

Abstract

Haemotological malignancy in an animal is treated by using a polyvalent particle-emitting radionuclide to label a bone-localising chelating agent and administering this agent to affect bone marrow of the animal, but in a dosage close to but less than a level which will cause complete bone marrow ablation, and administering a cytotoxic pharmaceutical in a dose sufficient to affect bone marrow of the animal, but also in a dose close to but less than a level which will cause complete bone marrow ablation. Examples include the use of samarium-153 as the radionuclide and a radio pharmaceutical selected from EDTMP, DTPMP, HEEDTMP, NTMP, TTHMP, HEDP and physiologically acceptable salts thereof. The cytotoxic drug can be melphalan or a derivative or analogue thereof.

Description

BONE MARROW TREATMENTS

The present invention relates to bone marrow treatments, and more particularly, is concerned with a treatment in which ablation of bone marrow is achieved followed by bone marrow transplantation. Such treatment is possible and can be a cure for many patients with haematological malignancy such as acute leukaemia and l ^pl m^vs!o_ns. It has been found' nsceεεar""- to kill all bone marrow cells. This would be fatal to the patient but for subsequent bone marrow transplantation with healthy bone marrow. If less than all the bone marrow cells are ablated, then natural recovery mechanisms operate through cell regeneration and recurrence of malignancy is likely. Thus, the patient will only enjoy a period of remission. One established technique is to achieve bone marrow ablation with total body irradiation (T.B.I.) . Bone marrow transplantation with healthy bone marrow can then take place almost immediately.

It has also been proposed to use chemoradiotherapy techniques to eradicate the haematological malignancy and this treatment immunosuppresses the patient to prevent rejection of the transplanted marrow. However, a significant proportion of patients experience life threatening or fatal non-haematopoietic toxicity, and furthermore, it appears that the procedures are not sufficiently tumoricidal to ensure ablation of a haematological malignancy and neither are the regimens sufficiently immunosuppressive to ensure marrow graft acceptance.

It is also known to use chemotherapy treatment without radiotherapy generally using a combination of drugs with non-additive toxicities except on bone marrow. Common combination regimens usually include non-cross resistant agents with different spectra of antitumour activity, such as nitrosoureas (BCNU) , epipodophylotoxins (VP-16) and alkylating agents (thiotepa, cyclophosphamide or melphalan) . Melphalan is a drug which has been used alone for attempts at bone marrow ablation. However, for multiple myeloma the success rate is very low for achieving complete clearance of the myeloma and there is significant morbidity and mortality.

Accordingly, it would be desirable to provide a regimen which involves less risk to the patient of life-threatening or fatal conditions and to develop a regimen which would have a high probability of achieving successful cure and not merely a remission.

The present invention is based on the concept of using a radiopharmaceutical comprising a polyvalent particle-emitting radionuclide and a chelating agent which has strong localisation on bone, the irradiation being less than the level which would be fatal in the absence of further treatment steps; administering a cytotoxic compound which affects bone marrow but at a dosage less than that would be fatal in the absence of other treatment; and after allowing for the effects of the radionuclide and cytotoxic compound to dissipate, effecting a bone marrow transplantation. In one aspect, the invention manifests itself in a method of treatment of an animal such as a human being, and in another aspect, manifests itself in a treatment kit for the procedure.

Preferably, the radiation emits principally beta radiation which is short range but highly effective for cell ablation.

One convenient beta-emitting radionuclide is samarium-153 bμt there are many other possible radionuclides such as strontium-89, yttrium-90, ruthenium-103, indium-115, cerium-144, gadolinium-159, holmium-166, ytterbium-175, lutecium-177, and rhenium-186.

The selection of chelating agent referably involves a selection of one which can be labelled with strong attachment by the radionuclide, and the resulting complex should be highly specific to bone. For example, polyaminepolyalkylphosphonic acids and derivatives including physiological salts thereof can be selected with advantage. An important example of such a compound is ethylenediaminetetramethylene phosphonate (EDTMP) which is a known chelating agent and is readily labelled with samarium-153 and has been found to localise on the surface of cortical and trabecular bone. Other chelating agents in this class are: diεthylenetria inεpentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenepnosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP) ,

HEDP, or physiologically acceptable salts of any one of these compounds.

The choice of cytotoxic compound includes melphalan (described in U.S. patent Nos. 3,032,584 and 3,032,585) and related compounds including equivalent chemotherapeutic agent with a predominantly myelotoxic action.

A preferred embodiment of the invention comprises the use of EDTMP labelled with samarium-153 administered at a high but sub-lethal level. However, it is thought that although samarium-153 labelled EDTMP is myelosuppressive, complete marrow ablation is not achieved even with very high dosage levels. Attempts to produce complete marrow ablation in dogs and rabbits have been reported as not successful, and further studies by the present inventor indicate that in rats samarium-153 EDTMP alone is unlikely to completely ablate red marrow.

Another embodiment consists in the use of rhenium-186 labelled HEDP.

Preferably, the treatment comprises delaying administration of the cytotoxic drug for several days to allow substantial radioactive decay of the radiopharmaceutical.

For illustration purposes only, reference will be now made to the accompanying drawings which illustrate trials in rats.

Referring first to Figure 1, the graph illustrates platelet concentration in the blood with time following a lethal total body irradiation in rats. The irradiation caused marrow ablation and the non-irradiated control example of rats (7 in number) maintained a substantially constant platelet concentration in blood. The irradiated sample of 5 rats showed a decline in platelet concentration in accordance with the normal decline of platelet concentation in the absence of fresh platelet generation by marrow. This model established the validity of monitoring platelet concentration as an indicator of bone marrow ablation.

Figure 2 demonstrates the viability of marrow transplantation after total body irradiation, i.e. marrow ablation. The control sample with no marrow transplantation showed all rats died within about 10 days but a very high survival rate was achieved with those that received marrow transplantation.

Figure 3 is a graph of platelet concentration with time. A lethal total body irradiation is given to the sample and marrow transplantation effected. By day 10, platelet concentration had dropped to a potentially fatal level. However, the increase in platelet concentration demonstrated that the transplantation had been effective and bone marrow cell reproduction had occurred to rescue the animals and a normal platelet concentration was achieved by day 15.

Figure 4 demonstrates the use of samarium-153 EDTMP at a rate of 3.5 GBq instead of total body irradiation. Samarium-153 EDTMP was prepared according to published methods (Turner et al 1989 Eur.J.Nucl.Med.15: 784-795) . Briefly, Samarium-153 was prepared by neutron irradiation of Sπ O- (enriched to 98% Samarium-152) in the HIFAR Research Reactor, Australian Nuclear Science and

Technology Organisation, using a thermal flux of 5 x 10 13ncm—2s—1. Samarium-153 was supplied as a sterile solution of 153 Sm Cl, in physiological saline and was added to a lyophyllized EDTMP kit immediately prior to use. Again the control sample had a steady platelet concentration but the irradiated sample showed that although the platelet concentration had dropped close to the level at which the animal's life is threatened, spontaneous recovery occurred and this is thought to be due to the fact that the samarium-153 EDTMP may not cause complete marrow ablation. Referring now to Figure 5, the effect on rats of melphalan at varying dose rates is indicated. It is only when dosages of around 9 mg/kg are given that survival is threatened, but then a precipitous result is observed. On this basis, in rats, a dose of about 9.5 mg/kg would be close to the fatal dose for most individuals.

Figure 6 demonstrates survival rate after chemo- and/or radiotherapy treatment comprising 9.5 mg/kg Melphalan and samarium-153 EDTMP administered at 555mBq. A control with melphalan alone indicated 100% survival. A sample comprising the samarium and melphalan but without marrow transplantation produced a low survival rate of about 20%. The third line demonstrates a sample of 13 individuals treated with samarium-153, melphalan, and given a marrow transplant at day 3, and again a survival rate of about 20% only was achieved. This result indicates that the transplantation was not successful due to the half-life of the radionuclide, and marrow transplantation needs to be delayed until the effects of the internal endoradiotherapy have diminished.

Figure 7 indicates the result of delaying marrow transplant until six days after the commencement of the procedure. In this case, the procedure commenced with samarium endoradiotherapy, and five days later the cytotoxic compound melphalan was administered. On day six, marrow transplantation occurred, and in the control sample which did not receive the transplantation, the survival rate was approximately 20% whereas for those individuals receiving the transplant the survival rate exceeded 90%.

Claims

1. A pharmaceutical comprising a supply of bone-localising chelating agent, a supply of polyvalent particle-emitting radionuclide for labelling the chelating agent, and a cytotoxic drug, the radionuclide and cytotoxic drug being in a dosage which when administered in combination will cause bone marrow ablation in animals, each dosage being close to but less than a level which will cause complete bone marrow ablation.

2. A pharmaceutical as claimed in claim 1, wherein the radionuclide is selected from the group consisting of

Samoj.iuiu-_.jo , _>t_.uιiL_.uuι-oj , _^■ ι_. —_. —um—_7u , J.Utiiciiiuin—xu , indium-115, cerium-144, gadolinium-159, holmium-166, ytterbium-175, lutecium-177, and rhenium-186.

3. A pharmaceutical as claimed in claim*1 or claim

2 wherein the radiopharmaceutical is selected from EDTMP, DTPMP, HEEDTMP, NTMP, TTHMP, HEDP and physiologically acceptable salts thereof.

4. A pharmaceutical as claimed in any one claims 1 to 3 and wherein the cytotoxic drug is melphalan or a derivative or analogue thereof, or a chemotherapeutic agent with a predominantly myelotoxic action and substantially equivalent to melphalan.

5. A method of treating haematological malignancy in an animal being comprising administering a bone-localising radiopharmaceutical labelled with a polyvalent particle-emitting radionuclide to affect substantially bone marrow of the animal, administering a cytotoxic pharmaceutical in a dose sufficient to affect substantially bone marrow of the animal, the combined doses of the radio pharmaceutical and the cytotoxic pharmaceutical being chosen to cause bone marrow ablation, after a delay sufficient to allow substantial decay of the radiopharmaceutical, effecting a bone marrow transplantation.

6. A method as in claim 5 wherein the radiopharmaceutical is labelled with a radionuclide selected from the group consisting of samarium-153, strontium-89, yttrium-90, ruthenium-103, indium-115, cerium-144, gadolinium-159, holmium-166, ytterbium-175, lutecium-177, and rhenium-186.

7. A method as in claim 5 or claim 6, wherein the radiopharmaceutical is selected from EDTMP, DTPMP, HEEDTMP, NTMP, TTHMP, HEDP and physiologically acceptable salts thereof.

8. A method^' as in any one of the claims 5 to 7 wherein the cytotoxic drug is melphalan or a derivative or * analogue thereof or a chemotherapeutic agent with a predominantly myelotoxic action and substantially equivalent to melphalan.

9. A method as in any one of claims 5 to 8 wherein the cytotoxic drug is administered a few days after the radiopharmaceutical, and the bone marrow transplantation is delayed of the order of a day after administering the cytotoxic drug.