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Targeting the Bone Marrow: Applications in Stem Cell Transplantation

Posted on: Sunday, 17 April 2005, 03:00 CDT

Therapeutic doses of radiation can be selectively directed to the bone marrow either directly using vectors that bind to myeloid and/ or lymphoid specific antigens or indirectly by targeting bone matrix. The combination of an accessible target tissue and relatively radiation sensitive malignant cells favours the use of targeted radiotherapy in the treatment of haematopoietic malignancies. Dose escalation of targeted radiation can increase tumour cell destruction and has led to the use of myelosuppressive and possibly myeloablative doses of targeted radiation. A natural development has been the use of targeted radiation in conditioning prior to haematopoietic stem cell transplantation (HSCT). Several groups are actively exploring the use of targeted radiotherapy in the context of HSCT as treatment for haematological malignancies. Although no randomised trials using targeted radiotherapy in HSCT have been published, phase I and II trials have shown very encouraging results stimulating further clinical research in this field. After more than a decade of translational research the optimal combination of therapeutic radioisotope and vector has not been determined. This review summarises the clinical experience of targeted radiotherapy in HSCT and discusses the problems that still need to be solved to maximise the potential of this new treatment modality in HSCT.

Key words: Haematopoietic stem cell transplantation * High close therapy * Acute myeloid leukaemia * Acute lymphoblastic leukaemia * Chronic myeloid leukaemia * Myeloma * Lymphoma * Radionuclide imaging * Dosimetry * Targeted radiotherapy.

Haematopoietic stem cell transplantation (HSCT) has developed as a means of allowing the escalation of therapy beyond the limits of otherwise lethal myeloablation. In autologous HSCT the patient's own cells are re-infused after high dose therapy with cytotoxic drugs and possibly external beam total body irradiation (TBI). Autologous HSCT has become established as the treatment of choice for myeloma and relapsed Hodgkin's and non-Hodgkin's lymphoma.i4 Although response rates and disease free survivals are improved, few patients are truly cured and in the majority their disease will recur. Relapse may result from a failure to eradicate disease or re- infusion of tumour cells that contaminate the stem cells.

Allogeneic HSCT has the advantage of using donor stem cells that are free of disease; in addition, a potent graft-versus-tumour response may be responsible for the significant proportion of patients that remain in remission beyond 5 years. However, despite the highly toxic doses of chemo-radiation used in conditioning regimens, relapse of the underlying disease still occurs and remains a significant reason for treatment failure. The risk of relapse is also a function of the dis ease ranging from 20% for acute myeloid leukaemia (AMD in first remission (CRl) to 90% for patients transplanted for chronic myeloid leukaemia (CML) following blast transformation.5-8Established transplant conditioning regimens use combinations of cytotoxic drugs with or without TBI. These agents cause considerable damage to haematopoietic tissues, killing malignant and normal cells, but also damage non-haematopoietic tissues such as the gut epithelium, liver, lungs and kidneys. The toxicity of these schedules has restricted the application of allogeneic transplantation to younger patients and would rarely be contemplated for those over 50 years of age. In recent years less intensive transplant schedules have been devised, the so-called low- intensity or non-myeloablative regimens. These regimens, although employing lower doses of cytotoxic drugs or very low doses of THI, do not seem to be detrimental to outcome in some types of haematopoietic malignancies although for others significant disease relapse does occur.9-n

Figure 1.-Therapy/toxicity/tumour kill curve.

Despite advances in the care of patients receiving HSCT, immediate and delayed toxicity to nonhaematopoietic tissues contribute to transplant mortality and limit further escalation of therapy. Any attempt to dose escalate conditioning therapy results in a rapid rise in toxicity to non-haematopoietic tissues, as illustrated in Figure 1; dose reduction allows more tumour cells to survive which increases the risk of disease recurrence after transplantation. Targeted radiotherapy may allow the escalation of therapy to specific disease sites such as the bone marrow (BM), spleen and lymph nodes while sparing nonhaematopoietic tissues, by shifting the toxicity-response curve to the right (Figure 1). This review will discuss the theoretical advantages of using targeted radiotherapy in HSCT and the properties of bone marrow that make dosimetry of BM complex. The choice of the components of targeted radiotherapy, the vector and isotope, will be discussed with reference to clinical trials. Finally the results using targeted radiotherapy in HSCT will be summarised.

Targeted radiotherapy in HSCT

Normal haematopoietic tissue and the malignant cells arising from it are relatively radiosensitive and demonstrate a steep dose- response to radiation with no threshold for cell injury.12 Theoretically, intensification of conditioning therapy, particularly total body irradiation (TBI), prior to transplantation could increase tumour reduction leading to improved disease free survival rates for patients with poor risk disease. The assumption that leukaemic cells display a radiationdose response in vivo is supported by the results of 2 clinical trials in which escalating doses of fractionated TBI of 12 or 15.75 cGy were given as part of the chemo-radiotherapy conditioning prior to BMT for AML and CML. Significantly lower relapse rates were achieved for those patients who received the higher dose of TBI; 12% vs 35% for AML and 0% vs 25% for CML. However, treatment intensification was associated with a parallel increase in non-relapse mortality effectively cancelling any improvement in the overall disease free survival results.13,14 Potentially targeted radiotherapy allows treatment intensification without toxicity to non-haematological tissues. In addition, the continuous, low dose rate delivered by the natural decay of a targeted radionuclide may have a greater destructive effect upon tumour cells than single dose or fractionated external beam radiation by preventing DNA repair. 15,17 Resistance to cytotoxic agents is a major cause of treatment failure in patients with haematological malignancies, often by the expression of cellular mechanisms that inactivate or increase the excretion of drugs from the cell.18,19 Malignant cells retain sensitivity to radiation induced damage even after the acquisition of drug resistance mechanisms. In addition, radiation induced cell death does not depend upon effector mechanisms such as complement activation or antibody dependent cellular cytotoxicity. There is some evidence from animal models of lymphoma that radiation may synergise with other mechanisms to increase cell death.20

TABLK I.-Potential target antigens on haematopoietic cells.

Bone marrow as the target

Bone marrow involved in the formation of blood cells, the red marrow, is a complex tissue consisting of haematopoietic cells, stromal cells, adipocytes, mineralised bone trabeculae and blood vessels. In adults, red marrow is located in die axial skeleton, skull, proximally in the long hones (humcrii. femora) and ribs. Red marrow weight for individual subjects will vary greatly, with 2 important variables; the distribution of red marrow and percentage cellularity per unit volume. Patients with haematological malignancies have even greater variation in red marrow distribution and cellularity according to the underlying disease and treatment. These factors will clearly impact on dosimetry and contribute to the problems in estimating radiation dose delivered by targeted radiotherapy.21,22 The red marrow is highly vascular, an estimated 5- 7% of the circulating blood volume passing through at any moment in time. The most prominent feature of the vascular system are venous sinusoids lined by a single layer of endothelial cells.

Haematological malignancies such as leukaemia and myeloma arise from cells that normally reside in the BM. The uncontrolled proliferation of the malignant cell population replaces normal haematopoietic tissue; in leukaemia this is usually by diffuse infiltration while in myeloma and lymphoma diffuse and focal patterns of infiltration occur. Normal red marrow is very radiation sensitive and myelosuppression is the dose limiting toxicity for targeted radiation used in the treatment of solid tumours and lymphoma. When malignant cells within the marrow are the target, myelosuppression is an inevitable consequence. In practice, the antigen targets used to treat haematological malignancies are not only expressed by the malignant cells but are also present on normal cells. Table I lists the antigens present on haematopoietic cells that have been used to deliver radiotherapy to the bone marrow. The cellular component of marrow can be indirectly targeted by using agents that preferentially accumulate within the bone itself, usually at sites of re-mineralisation.23,24 In animal models large doses of radiation have been delivered to the marrow by this indirect targeting.25,27

TABLE II- Therapeutic raclioisotopes used in HSCT.

S\election of vector

Vectors for targeted radiotherapy are usually monoclonal antibodies (mAb), although some early clinical trials in the treatment of relapsed Hodgkin's lymphoma employed a rabbit polyclonal anti-ferritin.28 However any molecule with the property of targeting haematopoietic cells may be used as a vector, such as a myeloid growth factor (G-CSF or GM-CSF), antibody fragments (Fab, F(ab)^sub 2^) or recombinant antibody fragments. Intact antibodies are ideal vectors for targeting the bone marrow: they are stable, can be consistently produced in bulk, they have high specificity and may be radiolabelled with a wide variety of isotopes. The highly vascular nature of bone marrow means that the haematopoietic tissue is readily accessible to injected antibodies. Uptake of radiolabelled mAb is rapid. Within 10 minutes of the start of infusion of radiolabelled anti-CD53 uptake by bone marrow was shown on real time gamma-imaging and maximal within 1 hour.29 This is in contrast to solid tumours where uptake typically occurs over a much longer period. The use of smaller molecules is therefore not necessary and may be disadvantageous due to problems such as rapid renal clearance.

None of the target antigens are aimour specific i.e. they are present on normal cells and may or may not be present on the malignant cell population. Indeed there are essentially no tumour specific antigens on leukaemic blasts, myeloma plasma cells or lymphoma cells that could be exploited. HSCT is usually performed on patients during a period of remission, after courses of chemotherapy designed to reduce tumour cell burden before transplantation. The cell population in the bone marrow of such patients is therefore essentially normal, it is this nomial bone marrow cellular component that can be targeted, residual tumour cells are killed by the crossfire of radiation delivered to marrow tissue. Targeting antigens present on normal cells is of great advantage, as higher doses of radiation can accumulate within the marrow. In patients that fail to achieve remission with initial chemotherapy, the selected target antigen must be present on the malignant cells, if not, insufficient radiation may be delivered to sites of disease. This requires a detailed understanding of the distribution of radiolabelled vector within the bone marrow.

Selection of isotope

The optimal radioisotope for use in treating haematological malignancies has not yet been determined. Any chosen isotope should have the following basic characteristics:

* gamma emission for imaging/dosimetry;

* beta or alpha emission for therapy.

The following additional characteristics are important in determining which radioisotopes can be used in a clinical setting:

TABLE III.-Clinical trials in HSCT.

* physical half-life suitable for clinical context (<3 d to allow transplantation);

* particle energy;

* readily available (preferably of radiopharmaceutical grade);

* consistent specific activity;

* consistent radiolabelling efficiency;

* acceptable radio-protection measures pre- and post- administration ;

* affordable.

Table II summarises the characteristics of some of the radio- isotopes that have been used in clinical trials of targeted radiotherapy in HSCT.

No single isotope has all of the desired properties, those that are in use currently have the best compromise of characteristics. Most therapeutic targeted radiotherapy trials have used isotopes that emit beta-particles alone (^sup 90^Y) or a combination of beta particles and gamma photons (^sup 131^I; ^sup 188^Re, ^sup 186^Re), (Table III)30-41

It has been suggested that radioisotopes emitting beta particles with high energy could he detrimental to the bone marrow microenviroment and compromise subsequent engraftment, however there is no evidence from animal studies or early clinical trials that this is the case. Tissue penetration estimates use the basic assumption that tissue is essentially water. This is not the case in bone marrow; the mineralised bone trabeculae present in red marrow will have a significant dampening effect on the path of beta particles. However, the bone marrow environment does appear to be susceptible to potentially irreversible damage 26,27 but further studies need to be performed to determine the real maximum tolerated radiation dose that can be delivered by targeted radiotherapy. This is important since the intention of targeted radiotherapy is to maximise local therapy with minimal non-specific toxicity.

The selection of optimal isotope has been helped by the published experience of groups active in this field. Four beta-emitting isotopes have been used in clinical studies of HSCT, ^sup 131^I 30, 31, 33, 42 ^sup 90^Y (with ^sup 111^In for dosimetry),34 ^sup 188^Re 36, 37,43 and ^sup 186^Re.44,45

^sup 131^I has a number of favourable properties; it is easily covalently bound to proteins via tyrosine residues using one of several methodologies;46-49 it is readily available and relatively inexpensive. The combination of gamma and beta emission make it suitable for dosimetry and therapy. The gamma component however becomes problematic when the beta dose is escalated creating significant radiation protection problems for relatives and clinical staff and for disposal of waste. A further problem can occur with ^sup 131^I labelled antibodies which bind to surface antigens that internalise such as CD33 or CD22; the radiolabelled antibody is rapidly catabolised and excreted as ioclo-tyrosine, iodinated short pepticles and free radioiocline.50 In vivo this results in short residence time in the bone marrow and hence poor dosimetry and poor disease response.33, 40, 51, 52

The isotopes of rhenium, ^sup 188^Re and ^sup 186^Re appear to have good physical characteristics; both produce gamma and beta radiation allowing preliminary dosimetry, both have relatively short half lives (^sup 188^Re 17 hours; ^sup 186^Re 3.8 days). Radiolabelling proteins with rhenium isotopes requires similar methodologies as used for technetium, however the protein-rhenium complex appears to be less stable in nro which may result in unforeseen toxicities when used at high doses. The release of rhenium from the vector may have been the cause of renal toxicity reported by the group in UIm using ^sup 188^Re-labelled anti-CDoo in HSCT. 37,53 Despite favourable physical characteristics, ^sup 186^Re is not readily available, being generated by neutron irradiation of ^sup 185^Re in a reactor. However. ^sup 186^Re has been used in myeloablative conditioning schedules in allogeneic HSCT for ALL with encouraging results in a small trial45 and for autologous HSCT in NHL.44

The radiometal ^sup 90^Y is a pure beta emitter. This is an advantage for therapeutic doses of radiation, as the radiation exposure of relatives and staff is reduced. If the target antigen is internalised, radiometals such as ^sup 90^Y remain within the cell complexed to proteins. ^sup 90^Y has a short half-life, which allows infusion of stem cells 12-14 days after therapy.

Unlike isotopes of iodine, ^sup 90^Y cannot be directly covalently bound to antibodies, however, the use of bifunctional chelators such as modified DTPA derivatives allows successful radiolabelling. The radiolabelling requires 2 stages: the initial covalent attachment of the bifunctional chelator (conjugation), followed by the relatively simple chelation of the radiometal. The first stage can be performed on a large bulk of antibody which can then be stored frozen in single dose vials for subsequent radiolabelling. This has advantages for quality control and labelling consistency, an important factor when the treatment parameters for targeted radiotherapy are still being developed. The lack of gamma radiation makes dosimetry with ^sup 90^Y difficult, normally tracer doses of the isotope ^sup 111^In have been used as a surrogate which has been shown to give very similar biodistribution m vivo54

Alpha particles have shorter path lengths of 0.04-0.1 mm but much greater linear-energy transfer, up to 500 times greater than beta panicles. In vitro, using the cell line HLoO. 2 alpha particles are sufficient to trigger cell death55 Experimental models using ^sup 213^Bi, ^sup 211^Bi and ^sup 211^At to treat haematopoietic malignancies have demonstrated the ability for these isotopes to efficiently kill malignant cells but without systemic toxicity34,56 Despite technical problems relating to the shoit half-life, supply and radiation protection issues, ^sup 213^Bi has been used clinically in treating myeloid leukaemia with a humanised anti-CD33 mAb as vector.34

Clinical experience

The feasibility of using targeted radiotherapy for the treatment of haematological malignancies as part of preparative regimens prior to HSCT has been explored by several groups using both animal models and in clinical trials with extremely encouraging results. In most reported studies, the bone marrow and spleen have been shown to accumulate radiation, however in the majority of patients significant amounts of activity also accumulated in the liver, which becomes the dose-limiting organ. In most clinical trials liver accumulation of radioactivity is a problem; to avoid serious liver toxicity the administered radiation dose has been set according to initial dosimetry in each patient with a maximum liver dose as the determinant. Criteria for therapy would include a minimum of two- fold higher radiation dose accumulated in the marrow as compared to the liver. Patients with unfavourable dosimetry would not receive the therapeutic dose of radiation. The reasons for the uptake of radiolabelled antibody by the liver are not known but will include specific binding (to cells expressing the target antigen) and non- specific binding (via Fc-receptors, Brambel receptor on endothelium and mechanisms that remove abnormally glycosylatecl or damaged antibody molecules).

Leukaemia

Initial experimental work was performed at theFred Hutchinson Cancer Research Centre in Seattle, using murine and canine models 30,57 and the Memorial Sloane Kettering Cancer Centre in New York. The first myeloid antigen selected for targeting was CD33, a 67 kD cell surface antigen expressed by normal myeloid cells from early in differentiation and present on blasts from 80% of patients with AML.58 It is an internalising antigen, a member of the sialic acid- binding immunoglobulin-like lectin group (Siglecs) and is involved in cell signalling."59 Antibodies binding to CD33 are rapidly internalised. Initial targeted trials used ^sup 131^I as the therapeutic isotope and used targeted radiotherapy in addition to standard transplant conditioning regimens; in the Seattle series using a murine IgGl (p67), good bone marrow targeting was seen in 4 out of 9 patients with the marrow and spleen accumulating more radiation than the liver, these patients received HSCT after a therapy dose of ^sup 131^I-labelled anti-CD33 of 4.07-12.21 GBq (110- 330 mCi) 14 days before transplantation, then received cyclophosphamide and TBI (12 Gy fractionated). When last reported 3 of 4 patients have relapsed, 1 remained in remission 5 years post- transplant.35 Total radiation doses to the marrow were low, probably due to the short residence time in the marrow because of ^sup 131^I- P67 internalisation, catabolism and excretion of isotope. Similar problems were reported by the MSKCC group who used ^sup 131^I- labelled anti-CD33 (M195, murine IgG2a) alone to treat 22 patients with relapsed or refractory AML or CML in blast transformation. They used escalating doses of radiation in successive cohorts of patients ranging from 1.85-7.77 GBq (50-210 mCi) per m^sup 2^ body surface area. Transplantation was required for patients in whom pancytopenia lasted longer than 12 days. This study was important in 2 respects; firstly, a reduction of more than 99% of leukaemic blasts (in bone marrow) was demonstrated in the majority of patients; as targeted radiotherapy alone was used this was the first demonstration of the ability of targeted radiotherapy to kill malignant leukaemic cells in vivo. secondly, the group were able to demonstrate that the duration and depth of myelosuppression could be correlated to the radiation dose administered. Non-haematological toxicity was low and limited to elevation of liver function tests in 4 patients.4- The same group report the results of using wi-labelled M195 as part of a transplant schedule including cyclophosphamide and busulphan for patients with relapsed or refractory leukaemia. Nineteen patients received radiation doses from 8.88-13.7 GBq (240-370 mCi) total dose 12 days before infusion of stem cells. Overall results were not impressive in this small study with a high treatment related mortality unrelated to targeted radiation (infection and graft- versus-host disease) but the majority of patients achieved a complete remission. No bone marrow dosimetry was reported but all patients demonstrated marrow uptake. Poor bone marrow residence time using ^sup 131^I prompted the MSKCC group to explore alternative isotopes for therapy such as 90Y and ^sup 213^Bi 29 while using a humanised anti-CD33 antibody (HuM195). A study using ^sup 90^Y- labelled HuM195 is still underway, initial results in 19 patients that received ^sup 90^Y doses from 3.7-11.1 MBq per kg indicate that the radiation remained m aiM in the marrow for longer than with ^sup 131^I. Absorbed radiation doses to the marrow of up to 56 Gy have been reported, with 75 Gy to the spleen. Transient abnormalities in liver function tests were the only reported toxicities.34 Importantly they determined the minimum myeloablative dose of radiation delivered to the bone marrow with this combination of vector and isotope as approximately 11 MBq (0.3 mCi) per kg body weight.

The Seattle group decided to continue working with ^sup 131^I but changed the target antigen to CD45, the common leucocyte antigen. CD45 does not modulate following binding of antibody, is abundantly expressed on haematopoietic cells with 200 000 molecules per cell. In a phase I study, escalating doses of ^sup 131^I-labelled anti- CD45 murine monoclonal antibody (BC8, murine IgGl) were combined with standard chemotherapy and TBI as the conditioning therapy prior to bone marrow transplantation for patients with poor risk AML, ALL and transformed myelodysplasia.30,31 The targeted therapy was well tolerated and estimated additional radiation doses of 24 Gy to the marrow and 50 Gy to the spleen were delivered at the highest dose levels. Toxicity to non-haematopoietic organs was not in excess of that associated with standard conditioning regimens. Twelve of 25 (48%) patients remained in complete remission (range 24-60 months), while for a comparable patient group with poor risk leukaemia the disease free survival in published series is in the order of 250 - 30%.60,61 In a phase II study, ^sup 131^I-labelled anti-CD45 targeted radiotherapy was combined with busulphan and cyclophosphamide without TBI as conditioning regimen prior to allogeneic BMT for patients with standard risk acute leukaemia. The infused radiation dose was determined from preliminary dosimetry in each patient, using the liver dose to calculate the total dose for infusion. Although still in progress, 91% of 32 patients had favourable dosimetry and received between 3 74-9.7 GBq (101-203 mCi) of ^sup 131^I-labelled BC8 anti-CD45 mAb. When last reported. 18 of 32 patients (75%) were alive in complete remission 10 to 63 months32

The largest clinical studies have been performed by the group in Dim. using CD66 as the target antigen and ^sup 188^Re for initial dosimetry and for therapy. CDon has several favourable characteristics as the target antigen; it is not shed nor internalised, it is expressed at high density on normal myeloid cells from the promyelocyte onwards. CD66 is a member of the carcino- embryonic antigen (CEA) group of membrane proteins.

TABLE IV.-Indirect targeting.

Bunjes et al.36 reported the results of ^sup 188^Re-labelled anti- CD66 (BW250/183, murine IgGl) in 36 patients with poor risk AML or myelodysplasia. Favourable dosimetry was seen in all patients, the therapeutic dose of radiation was determined by the liver dose. Patients received targeted therapy prior to standard conditioning with cyclophosphamicle, TBI (12 Gy fractionated) or busulphan with or without thiotepa. The mean radiation close administered was 10.22.1 GBq (range 6.9-15.8). A mean BM absorbed radiation dose of 15.3 Gy (range 8.1-28 Gy) was achieved. Of particular note the liver uptake of radiation was low. An unexpected toxicity was a delayed deterioration of renal function in a significant proportion of patients. This may have been related to the use of ^sup 188^Re with release of isotope from the antibody in vivo and renal uptake resulting in high dose exposure of renal tissue, an estimated mean renal dose of 7 Gy (range 2.3-11.6) was reported.53 The group also reported a strong influence of disease status, the overall disease free survival (DFS) was 45%, however for patients in remission at the time of transplant the DFS was 67% while for those in relapse it was only 31%. This large difference may relate to unequal distribution of radiation in patients with foci of blasts that did not express the target antigen.36 The same group more recently reported the results for a larger group of patients with similar results.37

These phase I trials demonstrated that, by choosing an appropriate target antigen, haematopoietic cells can be selectively targeted and radiation delivered to sites of disease involvement with minimal toxicity to non-haematopoietic tissues. Responses were obtained in patients refractory to standard chemotherapy and there appeared to be a decrease in the relapse rate for patients in the Seattle and UIm studies.

Multiple myeloma

External beam radiation therapy is an important adjuvant therapy in myeloma and is largely used in the treatment of localised disease activity. Multiple myeloma would in theory be very amenable to treatment with targeted radiotherapy; the malignant myeloma plasma cells predominantly reside in the marrow and would be readily accessible to radiolabelled antibodies. However to date there have not been published clinical trials using antibodies targeting plasma cells directly. There are a few potential surface antigens targets on plasma cells, such as CD38, CD138 (syndecan-1), PC1 and BIyS receptor.

Malignant plasma cells may also be indirectly irradiated by the cross-fire effect either by targeting normal bone marrow elements or by targeting the bone matrix using bone seeking agents such as the bisphosphonates, 1,4,7,10-tetraazcyclododecane-1,4,7,10-tetra- methylenephosphonate (DOTMP) and ethylenediaminetetramethylene phosphonic acid (EDTMP). These are small molecules that preferentially accumulate at sites of active bone re- mineralisation. They can be readily radiolabelled with a number of radiometals as they also function as chelating agents. Holmium-166 (^sup 166^Ho) and samarium-153 (^sup 153^Sm) have been used to deliver therapy complexed to bisphosphonates (Table IV).62, 63 ^sup 166^H0 emits a high energy beta particle and has a relatively short half-life of 20.8 hours. It has been used complexed to EDTMP in a canine model and caused marrow aplasia that could be reversed by bone marrow transplantation.25 ^sup 153^Sm emits a beta particle of medium energy and a gamma photon allowing dosimetry.

^sup 166^Ho has been used clinically complexed to DOTMP in addition to high dose melphalan with autologous stem cell transplantation in patients with myeloma.62 In a phase I dose escalation study patients received increasing doses of ^sup 166^Ho- DOTMP after initial dosimetry, intended to deliver from 20-40 Gy to the marrow. Patients were randomised to receive in addition either 140 or 200 mg/m^sup 2^ melphalan or 140 mg/m^sup 2^ melphal\an plus 8 Gy TBI. Fifty-four patients received treatment, 43% achieved a complete remission. There were no differences in response rates between the various treatment arms. The most significant problem was of haemorrhagic cystitis due to the high dose of radiation received by the bladder wall. This was a consequence of using an isotope with a short half-life and the high renal excretion rate for the complex. Significant dose in-homogeneity was seen, probably due to the unequal uptake of the bisphosphonate by the skeleton.63,64

A second group has used the same concept but with ^sup 153^Sm complexed to EDTMP. Less toxicity was seen with ^sup 153^Sm-EDTMP, however radiation dose delivered to the limb skeleton was low and external beam limb irradiation was added. Initial results were promising with high CR rate and low toxicity.63

Our own targeted therapy group has used an ^sup 111^In labelled anti-CD 138 antibody for targeting multiple myeloma and has shown good localisation at disease sites/" However, there are no other published studies using radioimmunotherapy to treat multiple myeloma by direct targeting.

Lymphoma

There has been extensive use of targeted radiotherapy for the treatment of non-Hodgkin's lymphomas (NHL), due to the sensitivity of these malignancies to radiation and the large number of well characterised surface antigens that are potential targets. Lymphoic! cell targets include CD20, CD22, CD37, CD25 and HLA class II. Most clinical trials have focussed on the use of sub-myeloablative doses of radiation 66 and are discussed in detail in other articles in this issue. Antibodies targeting B-lymphocyte antigens remain in the blood pool for several days. Bone marrow is therefore irradiated partly by circulating unbound antibody and from antibody binding to tumour cells (or normal B-lymphocytes) present in the marrow. Escalation of the infused radiation dose leads inevitably to progressive myelosuppression and possible myeloablation requiring stem cell rescue. Some investigators have extended the radiation dose to levels that require stem cell rescue, with or without additional chemotherapy conditioning (Table II).67,68

To summarise the clinical results from the few published trials; once the conditions have been optimised (antigen target and vector, isotope, pre-infusion of cold antibody, selecting patients with low tumour bulk and minimal splenomegaly) increasing the activity of labelled antibody resulted in increased complete remission rates and durable responses.38,39,69,70 Radiation close appears to be limited by toxicity to the heart and lungs with a maximum of 27 Gy to these organs. The phase I/II trials published to date indicate that the use of myeloablative doses of targeted radiotherapy in the treatment of NHL and HD with planned stem cell rescue is clearly feasible with minimal additional toxicity. There are also many histological groups of NHL and targeted radiotherapy with HSCT may be appropriate for specific types but not others.

A retrospective analysis of autologous HSCT for relapsed follicular NHL compared outcomes for 98 patients that had received conventional conditioning with 27 that had received "'!-labelled anti-CD20 (Bexxar) in addition to chemotherapy. Superior overall survival and progression free survival was demonstrated in the group that received targeted radiation."!

However the treatment options for NHL are increasing and whether the high radiation dose approach really offers any benefit over less technically demanding treatments can only be determined from carefully constructed randomised trials.

For Hodgkin's disease (HD) the only published clinical trials have been with polyclonal anti-ferritin -" mainly using sub- myeloablative doses of infused radiation. A single report using ^sup 90^Y-labeled anti-ferritin in combination with high dose chemotherapy and autologous stem cell rescue concluded that the approach was feasible with no additional toxicity/' The development of targeted radiotherapy for the treatment of relapsed HD seems to have virtually halted although there is some interest in using anti- CD25 in HD with a phase I trial open in one centre.

Alpha emitting isotopes in clinical trials of HSCT

Alpha-emitting radionuclides have a number of characteristics that may be of advantage in the treatment of haematopoietic malignancies. Alpha particles have high LET and are highly cytotoxic.55,72 Their short path length could in theory offer greater selectivity, however this is really only an advantage if internalising tumour specific antigens are the target, any target more generally expressed by myeloid cells will inevitably cause myeloablation. The MSKCC group has used ^sup 213^Bi-labelled anti- CD33 (HuM195) in a phase I clinical trial in patients with myeloid leukaemia 34 and actinium-225 (^sup 225^Ac) in xenograft models of disseminated lymphoma.73 In the phase I radiation dose escalation study. IH patients with relapsed or refractory AML or chronic myelomonocytic leukaemia received a total of 10.36-37MBq (0.281 mCi) per kg body weight ^sup 213^Bi-labelled anti-CD33 fractionated in 3- 7 infusions in 5 dose cohorts. HSCT was not scheduled, the targeted radiation was used to induce remission without stem cell support. Treatment was well tolerated with no dose-limiting toxicity reported. Some hepatotoxicity was seen with transient elevation of liver function tests in 6 patients. Localisation of isotope within the BM was apparent and myelosuppression (8-34 days) seen in all patients. Uptake was also seen in the spleen and liver. Disease responses were seen with reduction of BM leukaemic blasts in 14 of 18 patients with a trend for greater response at the higher radiation dose levels. Myeloablation was not a treatment intention, however with higher doses of ^sup 213^Bi. stem cell rescue may be required. Absorbed radiation doses were estimated to be 1 000-fold greater than those possible with beta-particle emitting isotopes,74 however dosimetry with alpha-emitting radio-isotopes is problematic, the radiobiological effect of the 2 types of radiation need to be determined in model systems.

The same group are exploring ^sup 225^Ac as a therapeutic isotope, progressive decay events of daughter radionuclides results in the release of 4 alpha particles with the potential for very potent cell kill. The daughter radionuclides may remain within target cells, however initial toxicity studies in animals indicate the potential for renal toxicity at high doses.75

The Seattle group has used ^sup 213^Bi-labelled anti-CD45 in a canine HSCT model.56 An initial radiation dose escalation allowed treatment parameters to be established and 3 dogs received either 133, 170 or 320 MBq (3.6. 4.6 or 8.8 mCi) per kg of ^sup 213^Bi- labelled anti-CD45 followed by HSCT from a DLA-identical animal. Mixed chimerism of donor/recipient was seen in all 3 animals. The dose estimates to tissues for alpha-emitting isotopes is difficult but the group determined that the radiation dose of 137-218 MBq per kg was equivalent to 200300 cGy external beam TBI for marrow toxicity.

The use of most alpha-emitting radio-isotopes is limited by their short physical half-lives, which necessitates repeated infusions, the high cost and limited availability.

Conclusions

Targeted radiotherapy using vectors that can selectively direct radiation to the sites of involvement of haematological malignancies has already been shown to result in significant disease responses for leukaemia, myeloma and lymphoma. Dose escalation of radiation that targets the bone marrow results in prolonged myelosuppression and probable myeloablation with the need for HSCT. Phase I trials using radiation that targets haematopoietic tissues using a variety of vector and radioisotope combinations have shown that the procedure is possible, does not compromise engraftment and shows a lack of toxicity to non-haematopoietic tissues. There are several important problems still to resolve before the full potential of targeted radiotherapy can be explored in large phase III trials; for example determining the optimal combination of vector/target antigen and radioisotope, the specific transplant protocol (with or without TBI, low intensity conditioning schedules), the diseases most appropriate for treatment. Current methods and models used to determine BM dosimetry are inaccurate and better methodologies such as the use of SPECT and PET imaging should be developed in parallel with measurement of the biological effects of targeted radiation. It is hoped that within the next few years these problems will be solved and the role of targeted radiotherapy in HSCT established by large randomised clinical trials.

References

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K. ORCHARD ', M. COOPER 2

1 Department of Haematology Southampton Uniivrsity Hospitals Trust Southampton. Uniteel Kingdom

2Pharmacy Department St Bartholomew ' 's Hospital London, United Kingdom

Address reprint requests to: Dr K. Orchard, Senior Lecturer and Consultant Haematologist, Department of Haematology, Southampton University Hospitals Trust, Southampton SO16 6YD, United Kingdom. E- mail: kho@soton.ac.uk

Copyright Edizioni Minerva Medica Dec 2004

Source: Quarterly Journal of Nuclear Medicine, The

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