Patients and methods

Patients

Between May 1992 and April 1996, three phase I clinical trials investigating ¹³¹I-anti-CD33 antibodies in combination with BuCy as a preparative regimen for allogeneic BMT were conducted at the Memorial Sloan-Kettering Cancer Center (MSKCC). All protocols were approved by the Institutional Review Board at MSKCC, and all patients gave informed consent. Patients were eligible if they had relapsed AML, AML refractory to two cycles of induction chemotherapy, AML secondary to MDS, CML in accelerated or myeloblastic phase, or advanced MDS. At least 25% of leukemic cells were required to express CD33. Patients could not receive cytotoxic chemotherapy within 3–4 weeks prior to enrollment, except for hydroxyurea, to control peripheral blood leukocyte counts. Patients were excluded if they had a Karnofsky performance status of 60%, a life expectancy of less than 8 weeks, cardiac dysfunction (left ventricular ejection fraction <50%), renal insufficiency (creatinine >2 times normal), hepatic dysfunction (bilirubin >1.5 mg/dl, aspartate aminotransferase >3 times normal), active CNS leukemia, uncontrolled infection, or pre-existing HAMA.

Radiolabeled antibody preparation and treatment

M195 is an IgG2a anti-CD33 antibody derived from mice immunized with live human leukemic myeloblasts. M195 was produced and purified at the Sloan-Kettering Institute for Cancer Research as previously described.²⁴ HuM195 (Protein Design Labs, Inc., Fremont, CA, USA) is a recombinant IgG1 antibody constructed by combining the complementarity-determining regions of murine M195 with human framework and constant regions as previously described.³⁰ M195 and HuM195 (2–5 mg) were labeled with 100–120 mCi of ¹³¹I (New England Nuclear, Boston, MA, USA) using chloramine-T with an aseptic pyrogen-free technique on the day of treatment. In an attempt to maximize ¹³¹I delivery to the marrow, we adjusted antibody doses for the estimated leukemic burden. For the first injection, unlabeled M195 or HuM195 was added so that the total antibody dose was 3–4 mg/m² plus 100 g for every 10 000 leukemia cells per l of peripheral blood. For subsequent injections, the total antibody dose was 1.5–3 mg/m² plus 100 g for every 10 000 leukemia cells per l of peripheral blood. These dose adjustments were based on theoretical calculations of the number of available antigen sites. The constructs were purified by exclusion chromatography and filtered before administration. Doses for injection contained <2% free ¹³¹I and routinely showed immunoreactivities of >70% in a one-step binding assay with excess antigen.

In the first trial, cohorts of 3–6 patients received ¹³¹I-M195 at doses of 120, 140, and 160 mCi/m². ¹³¹I-M195 was given by 20-min infusion in 2–4 divided doses of 52–133 mCi, each 48–72 h apart, in order to allow for re-expression of CD33 on the cell surface. Fractionated dosing was required since labeling at high specific activities necessarily resulted in decreased immunoreactivity of the immunoconjugate.³¹ In the second trial, individualized patient dosimetry was used to determine the dose of ¹³¹I-M195. Patients initially received a 40-mCi trace-labeled dose of ¹³¹I-M195 followed by biodistribution, pharmacokinetic, and dosimetry studies as described below. Doses of ¹³¹I-M195 calculated to deliver 14 or 16 Gy to the marrow were then administered as in the previous study. The 40-mCi trace dose was included in calculations of total therapeutic dose. In the third trial, cohorts of 3–6 patients were treated with ¹³¹I-HuM195 at doses of 140, 160, and 180 mCi/m². ¹³¹I-HuM195 was given over 20–40 min in 2–4 divided doses of 30–128 mCi, 48–72 h apart. Patients treated with ¹³¹I-HuM195 received diphenhydramine 25–50 mg i.v. and acetaminophen 650 mg orally to avoid infusion-related reactions. Over the treatment course, all patients were confined to single rooms, hydrated, and maintained on allopurinol, Lugol's solution, and potassium perchlorate.

Transplant procedure

Beginning at least 4 days after the last dose of radiolabeled antibody, patients received busulfan 4 mg/kg orally in four divided doses daily for 4 days (total dose 16 mg/kg; days –7 to –4). A total of 28 patients received cyclophosphamide 60 mg/kg i.v. daily for 2 days (total dose 120 mg/kg; days –3 and –2). Two patients undergoing a second BMT received cyclophosphamide 45 mg/kg i.v. daily for 2 days (total dose 90 mg/kg; days –3 and –2). Mesna was given to three patients undergoing second BMT. Cyclophosphamide was not given to one patient undergoing a second BMT, since persistent lymphoid engraftment was detected. On day 0, all patients received unmodified bone marrow from related donors. This schedule allowed 4–5 half-lives of the radioimmunoconjugate to elapse from the last treatment to the infusion of marrow, leaving only minimal isotope present at the time of BMT. Donors were HLA-identical siblings in 26 patients, and one-antigen mismatched relatives in five patients. The median nucleated cell dose was 2.55 10⁸/kg (range 0.15 10⁸/kg to 8.3 10⁸/kg). In all, 23 patients received a combination of cyclosporine A (CSA) and methylprednisolone (MP) as prophylaxis against acute graft-versus-host disease (GVHD) as previously described.³² Six patients received CSA and methotrexate (MTX) as described by Storb et al.³³ One patient received CSA and MP plus antithymocyte globulin, and one received CSA, MTX, and MP. All patients received routine post transplant supportive care.

Pharmacokinetics, biodistribution, and dosimetry

Eight patients treated with ¹³¹I-M195, including the five patients with advanced CML on the second trial, underwent detailed pharmacokinetic and dosimetry studies. Heparinized blood samples were obtained 5, 30, 60, 240, 360, and 480 min after injection of ¹³¹I-M195 and then periodically until after the last dose of radioimmunotherapy. Whole blood and plasma were analyzed separately for ¹³¹I, and quantitative radioactive decay curves were generated. The data were corrected for decay and expressed as a percentage of injected activity per liter. Anterior and posterior whole-body gamma camera images were obtained after the first dose of radiolabeled antibody (Technicare Gemini II; General Electric, Madison, WI, USA) in all patients, then daily for 3 days in those undergoing dosimetry studies. Bone marrow aspirates and biopsies were performed 24 h after the first dose of radiolabeled antibody, and ¹³¹I per gram of bone marrow core was measured by gamma counting (Compugamma model 1828; LKB Wallac, Gaithersburg, MD, USA). Additionally, whole-body radioactivity measurements were determined at 3 m. Regions of interest (ROI) were drawn around the liver, spleen, vertebrae, and pelvis and used to determine the number of counts in these areas per minute. The data were corrected for physical decay. Single exponential decay curves were generated and converted to percentage injected dose (%ID) for each region. The %ID for the spine and pelvis was converted to marrow %ID by scaling a nominal estimate of the red marrow mass in these areas according to body weight. Organ volumes were estimated from CT volumetric studies when available or from standard reference organ mass values. Absorbed doses accounting for radiation imparted locally from both and photon emissions were estimated using methods of the Society for Nuclear Medicine's committee on Medical Internal Radiation Dose (MIRD).³⁴

Immunogenicity

In selected patients receiving ¹³¹I-M195, HAMA were measured in serum by an enzyme-linked immunosorbent assay (ELISA) as previously described.³⁵ We used a previously described double-antigen ELISA to detect human anti-human antibodies (HAHA) in patients treated with ¹³¹I-HuM195.²⁷ Samples were tested every 2 weeks for 2 months, then monthly for 4 months.

Statistical methods

Toxicity was graded using the common toxicity criteria of the National Cancer Institute.³⁶ Veno-occlusive disease (VOD) was defined as hyperbilirubinemia 2 mg/dl with at least two of the following findings occurring within 21 days of transplantation: hepatomegaly with right upper quadrant pain, ascites, or weight gain >5% of baseline.³⁷ Overall survival was defined as the time from BMT to death or date of last follow-up. Survival distributions were estimated using the Kaplan–Meier method. To assess for correlations between ¹³¹I dose and grade of liver toxicity and between estimated radiation absorbed dose to the liver and grade of liver toxicity, logistic regression models were fit. Associations between adverse events and type of antibody (M195 vs HuM195) were determined by the ² test.

Results

Patient characteristics

We enrolled 32 patients whose median age was 38 years (range 4–60 years) (Table 1). Two patients were children under age 10 years; the rest were adults over age 20 years. A total of 19 patients were treated with M195, including five who had individualized dosing on the second protocol, and 13 patients received HuM195. Total ¹³¹I doses ranged from 110 to 437 mCi. One patient who developed sepsis syndrome after the first infusion of ¹³¹I-HuM195 was removed from study and considered inevaluable. In all, 17 patients had AML. Six of these had primary refractory disease; five were in first relapse; one was in second relapse; four had disease secondary to MDS that was refractory to one cycle of induction therapy; and one was in relapse after a previous BMT. One patient had refractory anemia with excess blasts (RAEB) that relapsed after 5-azacytidine. Of the 14 patients with CML, five were in accelerated phase without having received prior chemotherapy; six were in or had been in myeloid blast crisis; and three had accelerated phase following relapse after a previous BMT.

Table 1 - Patient characteristics.

Full table

Adverse effects

Infusions of ¹³¹I-M195 and ¹³¹I-HuM195 were generally well tolerated. The most common toxicities were fever (grade 1 or 2) in 11 patients and rigors (grade 1 or 2) in nine patients. Other infusion-related side effects included grade 1 nausea (seven patients), grade 1 or 2 vomiting (five patients), grade 2 dyspnea (three patients), grade 2 chest tightness (two patients), throat tightness (one patient), abdominal pain (one patient), flushing (one patient), and urticaria (one patient). Dyspnea occurred more commonly in patients treated with HuM195 than in those treated with M195 (33 vs 0%, respectively, P=0.03). Differences in the rates of the other infusion-related toxicities were not statistically significant (data not shown).

The regimen-related toxicity seen following intensified conditioning with ¹³¹I-M195 and ¹³¹I-HuM195 was similar to that seen with BuCy alone in this patient population. Hepatic toxicity was most common. Among 29 evaluable patients, 20 (69%) developed serum bilirubin levels of 2 mg/dl within the first 28 days after BMT, and 12 patients (41%) had grade 3 or 4 hyperbilirubinemia. There was no significant correlation between the grade of hyperbilirubinemia and the dose of ¹³¹I administered (P=0.21) or between the grade of hyperbilirubinemia and the estimated radiation absorbed dose to the liver (P=0.99), which was calculated in eight patients. The median peak bilirubin concentration was 5.2 mg/dl (range 1.0–59.4 mg/dl). Five patients met criteria for VOD. Over the long term, 18 patients (64%) developed grade 3 or 4 hyperbilirubinemia. Determining the cause of hyperbilirubinemia was often difficult since various factors like VOD, acute graft-versus-host disease, drug-induced cholestasis, and sepsis were present simultaneously.

A total of 12 patients (39%) developed interstitial pneumonia at a median of 56 days after BMT (range 13–314 days). In some patients with interstitial pneumonia, multiple infectious organisms were identified: cytomegalovirus (CMV) in seven patients; respiratory syncytial virus, aspergillus, candida species, and Mycobacterium avium each in two patients; parainfluenza virus in one patient, and other bacteria in three patients. In three patients with interstitial pneumonia, no causative organism was identified. Other serious infections included bacteremia (10 patients), bacterial meningitis (one patient), sepsis syndrome with no causative organism (one patient), cellulitis (four patients), Clostridium difficile colitis (five patients), CMV colitis (two patients), acute pyelonephritis (one patient), and disseminated aspergillosis (one patient). Hemorrhagic cystitis occurred in nine patients (29%) at a median of 37 days after BMT (range 10–55 days). Papovavirus was identified as the causative organism in four patients, and BK virus was identified in one patient.

Engraftment and GVHD

Among 31 patients who underwent transplant, three died before day 14. All 28 evaluable patients achieved stable engraftment of neutrophils. The median time to recovery with an absolute neutrophil count (ANC) >0.5 10⁹/l was 14 days (range 9–27 days). The platelet count rose above 20 10⁹/l without transfusions in 23 of the 28 patients. Of the five patients who did not have platelet engraftment, four died between 24 and 43 days after BMT. The median time to platelet engraftment was 19 days (range 11–84 days).

Four patients (13%) developed grade I acute GVHD, and eight patients (26%) developed grade II–IV acute GVHD. Of the 31 patients, 14 died before day 100 and therefore are not evaluable for the development of chronic GVHD. Of the remaining 17 patients, three developed chronic GVHD, and one patient died from chronic GVHD.

Pharmacokinetics, biodistribution, and dosimetry

We performed detailed pharmacokinetic, biodistribution, and dosimetry studies in three patients with AML and five patients with accelerated or myeloblastic CML treated with 293–437 mCi of ¹³¹I-M195. As in previous studies, two-phase kinetics were seen in six of the eight patients. The mean plasma half-life (t_1/2) s.d. was 0.60.7 h (range 0.1–2 h); the mean t_1/2 was 4010 h (range 28–62 h). As previously observed,²⁸ gamma camera imaging showed targeting of isotope to all expected areas of leukemic involvement, including bone marrow of the vertebrae, pelvis, and long bones, as well as the liver and spleen. Pharmacokinetic and biodistribution results are summarized in Table 2. The mean peak concentration of ¹³¹I-M195 was 0.0110.002% ID/g for bone marrow (range 0.010–0.016%  ID/g). There was no difference between marrow concentrations for patients with AML and CML (P=0.19). The %  ID for the liver ROI was 7.23.5% (range 3.7–8.5%), with no difference between patients with AML and CML (P=0.23). The % ID for the spleen ROI was 3.70.8% (range 2.8–4.6%). The average marrow retention half-time was 5919 h (range 36–95 h), similar to the whole-body half-life of 5613 h (range 38–80 h). The mean estimated radiation absorbed dose per amount of injected activity was 2.41.3 cGy/mCi for red marrow ROI, 1.10.4 cGy/mCi for liver ROI, 4.20.6 cGy/mCi for spleen ROI, 0.60.1 cGy/mCi for the whole body, and 3.32.0 cGy/mCi for blood (Figure 1). The estimated absorbed radiation dose to the regions of marrow, liver, spleen, blood, and whole body ranged 272–1470, 243–651, 1320–1879, 248–2714, and 132–303 cGy, respectively. The limited amount of pharmacokinetic data did not allow for a definitive analysis of the effect of antibody dose adjustment for leukemic burden on delivery of radiation dose to the marrow.

Figure 1.

Mean estimated radiation absorbed doses of ¹³¹I delivered to the organs in eight patients. The mean estimated radiation absorbed doses (cGy per mCi of ¹³¹I administered) were 2.41.3 for red marrow ROI, 1.10.4 for liver ROI, 4.20.6 for spleen ROI, 0.60.1 for the whole body, and 3.32.0 for blood.

Full figure and legend (56K)

Table 2 - Pharmacokinetics and biodistribution of ¹³¹I-M195.

Full table

Immunogenicity

Despite receiving myeloablative treatment with busulfan and cyclophosphamide and further immunosuppression with MP and CSA, six of 16 evaluable patients (38%) treated with ¹³¹I-M195 (murine) developed HAMA within 1–2 months after treatment. Immunogenic responses were not seen in any of the six patients evaluated after treatment with ¹³¹I-HuM195 (humanized) during the first 4 months post transplant.

Antileukemic effects of radiolabeled antibody

Between the first day of radiolabeled antibody infusion and the first day of busulfan administration (median 12 days; range 6–16 days), peripheral blood leukocyte counts decreased by a mean of 76%. A total of 13 patients with elevated bone marrow blast percentages prior to radiolabeled antibody infusion had bone marrow aspirates that were adequate for evaluation repeated prior to receiving busulfan. The percentage of bone marrow blasts decreased in 11 of these 13 patients (85%), and eight patients (62%) had reductions to <5% (Figure 2).

Figure 2.

Marrow leukemic blast percentages in 13 patients before and after treatment with ¹³¹I-anti-CD33. Reductions were seen in 11 patients (85%), and eight of these patients (62%) had reductions to <5%.

Full figure and legend (23K)

Patient outcomes

Six patients who died on or before day 42 did not undergo a follow-up bone marrow examination after BMT and are not evaluable for response. Of the remaining 25 patients, 24 had no evidence of leukemia on at least one follow-up marrow examination. One patient with accelerated phase CML had persistent disease on bone marrow examination 1 month after transplant. Six patients relapsed at a median of 161 days (range 90–479 days) after BMT; all subsequently died.

The median survival of all 31 patients who underwent transplant was 4.9 months (range 0.3–90+ months). The median survival for the 17 patients with AML or RAEB was 5.7 months (range 0.3–90+ months). Three patients with AML are alive and disease-free at 59+, 87+, and 90+ months (Figure 3). Two of the three patients were children (aged 4 and 9 years) at the time of BMT. All 14 patients with CML died at a median of 4.9 months (range 0.4–23.4 months). Seven patients (23%) died of persistent or relapsed leukemia at a median of 9.4 months (range 4.8–17.5 months) after BMT. A total of 20 (65%) patients died of treatment-related causes, including infections, GVHD, interstitial pneumonia, hemorrhage, VOD, and multiple organ failure. The cause of death in one patient, who was lost to follow-up due to psychiatric illness, is unknown.

Figure 3.

Overall survival of patients with AML and CML.

Full figure and legend (16K)

Discussion

The optimal transplant preparative regimen in patients with advanced myeloid leukemias remains unknown. Historically, the 'standard' regimen has been TBI/Cy. In the 1980s and early 1990s, reports that busulfan could be substituted for TBI with similar efficacy and perhaps less toxicity emerged.^6,7,8,9,11 Subsequently, four trials were conducted in which patients were randomized to receive either TBI/Cy or BuCy. The French BMT group treated patients with AML in first CR and found higher overall survival and disease-free survival rates in patients treated with TBI/Cy.^12,38 The Seattle group treated patients with CML in chronic phase and found no significant differences in survival and less toxicity with BuCy.^13,39 The Nordic Bone Marrow Transplantation Group treated patients with AML, CML, and ALL and found higher overall survival rates and less toxicity in patients treated with TBI/Cy.^14,40 Finally, the French Society of Bone Marrow Graft treated patients with CML in chronic phase and found similar rates of survival between the two groups.¹⁵ A meta-analysis of all four trials concluded that TBI/Cy and BuCy result in similar outcomes in patients with CML, but that TBI/Cy provides slightly better long-term survival in patients with AML.¹ Regardless of the preparative regimen, results of BMT for patients with relapsed or refractory AML or accelerated and blastic phase CML remain suboptimal, as the majority of patients will die from either relapsed leukemia or complications of BMT.

The antileukemic effect of allogeneic marrow transplantation stems from both the high doses of chemotherapy and radiotherapy in the preparative regimen and the allogeneic graft-versus-leukemia effect.⁴¹ It follows that one possible way to decrease relapse rates after transplantation would be to intensify the preparative regimen by using higher doses of radiation. Clift et al¹⁷ randomized patients with AML in first CR to receive cyclophosphamide plus either 12.0 or 15.75 Gy of TBI. The rate of relapse was lower in the 15.75 Gy group. As transplant-related mortality was higher in that group, however, overall survival was not significantly improved. Similar results were found in a trial in patients with CML.¹⁸ At Memorial Sloan-Kettering Cancer Center, patients with AML in first CR received high-dose TBI (15 Gy) plus thiotepa and cyclophosphamide, followed by a T cell depleted bone marrow transplant.⁴² Disease-free survival at 4 years was 70%, and the relapse rate was only 5%. Higher doses of TBI appear to decrease relapse rates but also to increase the toxicity of the transplant.

Radioimmunotherapy is an alternative method of delivering radiation to the marrow. Owing to its selectivity, it offers the potential to intensify conditioning with less toxicity to normal organs. At the Fred Hutchinson Cancer Research Center, two radioiodinated antibodies have been investigated in the setting of BMT. ¹³¹I-labeled p67, a murine IgG that targets CD33, was studied in nine patients with advanced AML.²⁰ When administered as a single dose with a high specific activity, ¹³¹I-p67 had limited efficacy because of the short marrow residence times of the radiolabel, presumably due to modulation of the antigen–antibody complex with subsequent release of ¹³¹I from the marrow space. In contrast, ¹³¹I-M195 and ¹³¹I-HuM195, when administered at lower specific activities, are retained within the marrow for at least 3 days after infusion.^25,27,28

The second antibody investigated in Seattle was BC8, a murine IgG directed at the pan-leukocyte antigen CD45. Patients with advanced acute leukemia and MDS were treated with ¹³¹I-BC8 plus cyclophosphamide (120 mg/kg) plus TBI (12 Gy) followed by either autologous or allogeneic BMT.^{21 131}I-BC8 was estimated to deliver an additional 24 Gy to the marrow in patients treated at the maximum tolerated dose. In the second trial, ¹³¹I-BC8 was combined with BuCy in patients with AML in first CR. In an encouraging preliminary report, 18 of 24 patients were alive and free of disease at a median of 42 months after transplant.^21,22

In the present study, ¹³¹I-labeled anti-CD33 antibodies were used to intensify the BuCy conditioning regimen. The rationale for using radiolabeled anti-CD33 was based on the results of several prior studies. In the initial phase I trial using M195 trace-labeled with ¹³¹I, dosimetry calculations suggested that M195 could deliver myeloablative doses of radiation to the bone marrow.²⁵ In the subsequent phase I trial of ¹³¹I-M195, prolonged myelosuppression occurred at ¹³¹I doses greater than 135 mCi/m².²⁸ The next logical step was to investigate whether ¹³¹I-M195 could be administered safely together with a standard transplant conditioning regimen such as BuCy. This was the treatment schema for the first two trials reported here. While these trials were ongoing, it became evident that HuM195 offered several advantages compared with M195, including the ability to mediate antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, the lack of immunogenicity, and modest intrinsic antileukemic activity.^27,30 Based on these data, ¹³¹I-HuM195 was used in place of ¹³¹I-M195 in the third trial reported in this paper.

Intensified conditioning with ¹³¹I-M195 or ¹³¹I-HuM195 resulted in few toxicities beyond those expected with BuCy alone. Infusion-related reactions were mild, and delayed engraftment was not seen. The rate of hepatic toxicity (61% incidence of grade 2 or more hyperbilirubinemia in the first 28 days after BMT) was similar to what was reported with BuCy alone^10,13 and with TBI/Cy¹³ in other series. Nevertheless, dosimetry studies showed that ¹³¹I-M195 and ¹³¹I-HuM195 delivered 243–651 cGy to the liver in this study. Furthermore, in an earlier phase I study, four of 24 patients (17%) treated with ¹³¹I-M195 developed hepatic toxicity.²⁸ We suspect that the BuCy preparative regimen was primarily responsible for the hepatic toxicity seen in this study. The absence of significant correlation between ¹³¹I dose and grade of hyperbilirubinemia or between estimated radiation absorbed dose to the liver and grade of hyperbilirubinemia supports this supposition. However, as the number of patients included in these analyses was small, a contribution of radioimmunotherapy to hepatic toxicity cannot be excluded.

The data reported here and in previous work demonstrate several limitations associated with the use of ¹³¹I-labeled anti-CD33 constructs in the setting of BMT. First, radioiodination of M195 and HuM195 at high specific activities decreases the ability of these antibodies to bind to CD33.³¹ This occurs because approximately one-third of the tyrosine residues to which ¹³¹I binds are located in the hypervariable regions.³¹ As a result, multiple antibody infusions are necessary to deliver adequate doses of radiation to the marrow for ablation. Allowing for antigen re-expression, these infusions add up to 16 days to the preparative regimen. Second, the 8-day half-life of ¹³¹I delays the time from treatment to marrow infusion, since retained isotope within the marrow must decay to prevent injury to grafted hematopoietic stem cells. Third, because of the high-energy emissions of ¹³¹I, treatment with high doses requires isolation of the patient to prevent radiation exposure to hospital staff.

Owing to these difficulties, radiometals such as yttrium-90 (⁹⁰Y) and rhenium-188 (¹⁸⁸Re) have been investigated as possible alternatives to ¹³¹I. Radiometals offer several advantages over ¹³¹I, including better retention by target cells after internalization of antigen–antibody complexes.⁴³ Additionally, the higher energy emissions of these isotopes permit a lower effective dose, and the shorter half-lives decrease the time from treatment to stem cell infusion. Finally, because ⁹⁰Y does not emit rays, it can be given safely in the outpatient setting, with minimal exposure to medical personnel or patients' families. We are currently investigating the use of ⁹⁰Y-labeled HuM195 as part of a preparative regimen for nonmyeloablative stem cell transplantation based on promising results in a phase I trial.⁴⁴ Investigators at the Ulm University Hospital have used a ¹⁸⁸Re-labeled anti-CD66 monoclonal antibody in combination with several preparative regimens before BMT in high-risk AML or MDS.^{23 188}Re-anti-CD66 delivered a mean of 15.3 Gy of additional radiation to the marrow. In 21 patients not in remission at the time of BMT (a patient population similar to this study), estimated disease-free survival after a median follow-up of 18 months was 31%, and treatment-related mortality was 22%.

Radioimmunotherapy is a promising strategy to increase the delivery of radiation selectively to the marrow in preparation for BMT, and this study confirms the feasibility of this approach with prototypic agents. While ¹³¹I-M195 and ¹³¹I-HuM195 delivered up to 1470 cGy to the bone marrow, patient outcomes were not significantly different from those expected after standard conditioning with TBI/Cy or BuCy alone. Among the 17 patients with AML or MDS, three (18%) remain in remission at 59+, 87+, and 90+ months post transplant. In contrast, none of the 14 patients with advanced CML achieved long-term remission. Although only seven patients (23%) died from persistent or relapsed leukemia, 20 patients (65%) died from transplant-related causes. Further advances in radioimmunotherapy will require investigation of alternative radioisotopes. Eventually, phase III trials will be required to demonstrate whether conditioning that includes radioimmunotherapy confers a benefit compared with standard preparative regimens.

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