Search

Aims and background To present the Italian state-of-the-art contribution to radiobiology of external beam radiotherapy, brachytherapy, and radionuclide radiotherapy.Methods and study design A survey of the literature was carried out, using PubMed, by some independent researchers of the Italian group of radiobiology. Each paper was reviewed by researchers of centers not comprising its authors. The survey was limited to papers in English published over the last 20 years, written by Italian investigators or in Italian institutions, excluding review articles.Results A total of 135 papers have been published in journals with an impact factor, with an increase in the number of published papers over time, for external beam radiotherapy rather than radionuclide radiotherapy. The quantity and quality of the papers researched constitutes a proof of the enduring interest in clinical radiobiology among Italian investigators.Conclusions The survey could be useful to individuate expert partners for an Italian network on clinical radiobiology, addressing future collaborative investigations.

Peptide receptor radionuclide therapy (PRRT) consists of the systemic administration of a synthetic peptide, labeled with a suitable β-emitting radionuclide, able to irradiate tumors and their metastases via internalization through a specific receptor (usually somatostatin S2), over-expressed on the cell membrane. After almost 2 decades of experience, PRRT, with either 90Y-octreotide or 177Lu-octreotate, has established itself to be an efficient and effective therapeutic modality. As a treatment, it is relatively safe up to the known thresholds of absorbed and bio-effective isotope dosages and the renal and hematological toxicity profiles are acceptable if adequate protective measures are undertaken.

A newly developed somatostatin radioligand, DOTA-[D-Phe1-Tyr3]-octreotide (DOTATOC), has been synthesised for therapeutic purposes, because of its stable and easy labelling with yttrium-90. The aim of this study was to determine the dosage, safety profile and therapeutic efficacy of 90Y-DOTATOC in patients with cancers expressing somatostatin receptors. We recruited 30 patients with histologically confirmed cancer. The main inclusion criterion was the presence of somatostatin receptors as documented by 111In-DOTATOC scintigraphy. 90Y-DOTATOC was injected intravenously using a horizontal protocol: patients received equivalent-activity doses in each of three cycles over 6 months. The first six patients received 1.11 GBq per cycle and the four successive groups of six patients received doses increasing in 0.37-GBq steps. Toxicity was evaluated according to WHO criteria. No patient had acute or delayed adverse reactions up to 2.59 GBq 90Y-DOTATOC per cycle (total 7.77 GBq). After a total dose of 3.33 GBq, one patient developed grade II renal toxicity 6 months later. The maximum tolerated dose per cycle has not yet been reached, although transient lymphocytopenia has been observed. Total injectable activity is limited by the fact that the maximum dose tolerated by the kidneys has been estimated at 20–25 Gy. Complete or partial tumour mass reduction occurred in 23% of patients; 64% had stable and 13% progressive disease. It is concluded that high activities of 90Y-DOTATOC can be administered with a low risk of myelotoxicity, although the cumulative radiation dose to the kidneys is a limiting factor and requires careful evaluation. Objective therapeutic responses have been observed.

Metabolic rewiring is a hallmark of cancer and a predominant feature of aggressive lymphoproliferative disorders such as diffuse large B-cell lymphomas (DLBCL), which need a reshaped metabolism in order to meet the increased demands related to rapid cell proliferation.

Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD; NANOSTRING: Other: ADVISORY BOARD. Derenzini: TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; TG-THERAPEUTICS: Research Funding; ADC-THERAPEUTICS: Research Funding.

Abstract: . A three-step avidin-biotin approach has been applied as a pretargeting system in radioimmunotherapy (RIT) as an alternative to conventional RIT with directly labelled monoclonal antibodies (MoAbs). Although dosimetric and toxicity studies following conventional RIT have been reported, these aspects have not previously been evaluated in a three-step RIT protocol. This report presents the results of pharmacokinetic and dosimetric studies performed in 24 patients with different tumours. Special consideration was given to the dose delivered to the red marrow and to the haematological toxicity. The possible additive dose to red marrow due to the release of unbound yttrium-90 was investigated. The protocol consisted in the injection of biotinylated MoAbs (first step) followed 1 day later by the combined administration of avidin and streptavidin (second step). After 24 h, biotin radiolabelled with 1.85–2.97 GBq/m2 of 90Y was injected (third step). Two different chelating agents, DTPA and DOTA, coupled to biotin, were used in these studies. Indium-111 biotin was used as a tracer of 90Y to follow the biodistribution during therapy. Serial blood samples and complete urine collection were obtained over 3 days. Whole-body and single-photon emission tomography images were acquired at 1, 16, 24 and 40 h after injection. The sequence of images was used to extrapolate 90Y-biotin time-activity curves. Numerical fitting and compartmental modelling were used to calculate the residence time values (τ) for critical organs and tumour, and results were compared; the absorbed doses were estimated using the MIRDOSE3.1 software. The residence times obtained by the numerical and compartmental models showed no relevant differences (<10%); the compartmental model seemed to be more appropriate, giving a more accurate representation of the exchange between organs. The mean value for the τ in blood was 2.0±1.1 h; the mean urinary excretion in the first 24 h was 82.5%±10.8%. Without considering any contribution of free 90Y, kidneys, liver, bladder and red marrow mean absorbed doses were 1.62±1.14, 0.27±0.23, 3.61±0.70 and 0.11±0.05 mGy/MBq, respectively; the effective dose was 0.32±0.06 mSv/MBq, while the dose to the tumour ranged from 0.62 to 15.05 mGy/MBq. The amount of free 90Y released after the injection proved to be negligible in the case of 90Y-DOTA-biotin, but noteworthy in the case of 90Y-DTPA-biotin (mean value: 5.6%±2.5% of injected dose), giving an additive dose to red marrow of 0.18±0.08 mGy per MBq of injected 90Y-DTPA-biotin. Small fractions of free 90Y originating from incomplete radiolabelling can contribute significantly to the red marrow dose (3.26 mGy per MBq of free 90Y) and may explain some of the high levels of haematological toxicity observed. These results indicate that pretargeted three-step RIT allows the administraton of high 90Y activities capable of delivering a high dose to the tumour and sparing red marrow and other normal organs. Although 90Y-biotin clears rapidly from circulation, the use of DOTA-biotin conjugate for a stable chelation of 90Y is strongly recommended, considering that small amounts of free 90Y contribute significantly in increasing the red marrow dose.

Abstract.: While the incidence of brain tumours seems to be increasing, median survival in patients with glioblastoma remains less than 1 year, despite improved diagnostic imaging and neurosurgical techniques, and innovations in treatment. We have developed an avidin-biotin pre-targeting approach for delivering therapeutic radionuclides to gliomas, using anti-tenascin monoclonal antibodies, which seems potentially effective for treating these tumours. We treated 48 eligible patients with histologically confirmed grade III or IV glioma and documented residual disease or recurrence after conventional treatment. Three-step radionuclide therapy was performed by intravenous administration of 35 mg/m2 of biotinylated anti-tenascin monoclonal antibody (1st step), followed 36 h later by 30 mg of avidin and 50 mg of streptavidin (2nd step), and 18–24 h later by 1–2 mg of yttrium-90-labelled biotin (3rd step). 90Y doses of 2.22–2.96 GBq/m2 were administered; maximum tolerated dose (MTD) was determined at 2.96 GBq/m2. Tumour mass reduction (>25%–100%), documented by computed tomography or magnetic resonance imaging, occurred in 12/48 patients (25%), with 8/48 having a duration of response of at least 12 months. At present, 12 patients are still in remission, comprising four with a complete response, two with a parital response, two with a minor response and four with stable disease. Median survival from 90Y treatment is 11 months for grade IV glioblastoma and 19 months for grade III anaplastic gliomas. Avidin-biotin based three-step radionuclide therapy is well tolerated at the dose of 2.2 GBq/m2, allowing the injection of 90Y-biotin without bone marrow transplantation. This new approach interferes with the progression of high-grade glioma and may produce tumour regression in patients no longer responsive to other therapies.

Abstract.: Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe1-Tyr3-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with 90Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 µg), labelled with 150–185 MBq of 111In. Blood and urine samples were collected throughout the duration of the study (0–2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3–4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ µmol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for 111In-DOTATOC in blood was 0.9±0.4 h. The injected activity excreted in the urine in the first 24 h was 73%±11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2±1.8 h in spleen, 1.7±1.2 h in kidneys, 2.4±1.9 h in liver, 1.5±0.3 h in urinary bladder and 9.4±5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03–6.50 h). Based on our findings, the predicted absorbed doses for 90Y-DOTATOC would be 7.6±6.3 (spleen), 3.3±2.2 (kidneys), 0.7±0.6 (liver), 2.2±0.3 (bladder), 0.03±0.01 (red marrow) and 10.1 (range: 1.4–31.0) (tumour) mGy/MBq. These results indicate that high activities of 90Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the disired therapeutic response desired would be obtained.

Abstract.: The prognosis of patients with locally advanced head and neck cancer remains grim due to poor locoregional tumour control. In the attempt to eradicate residual disease, various novel modalities have been tested, among which radioimmunotherapy (RIT) has shown some potential. We present a case of locally advanced oropharyngeal carcinoma successfully treated with a combination of various treatments including surgery, radio-chemotherapy and three-step RIT, with the avidin-biotin pretargeting system. A partial tumour response was achieved after surgery and radio-chemotherapy; persistent disease was documented at computed tomography (CT), ultrasound (US) and immunoscintigraphy (ISG) 10 weeks after the end of chemo-radiotherapy. The good correlation between the tracer localization in the scintigraphic images and residual mass visualized at CT suggested the application of three-step RIT using systemic administration of yttrium-90 (py) biotin. At present, 17 months after RIT, the patient is alive with no evidence of disease as documented by magnetic resonance imaging (MRI) and US. This is the first case of complete clinical remission of a head and neck carcinoma induced by combined treatment including pretargeted RIT with 90Y-biotin.

BACKGROUND: Red marrow (RM) is the critical organ in Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan, especially at myeloablative activities. Different methods for the evaluation of the adsorbed dose in RM have been investigated. The blood method relates the blood time-activity curve to RM by a factor that accounts for the activity concentration ratio between RM and blood. Alternative dosimetric approaches including image analysis and marrow aspirations (MA) were introduced for RM dose comparison in order to collect information about the dose delivered and to verify the correct time of Autologous Stem Cells Transplantation (ASCT). PATIENTS AND METHODS: Twenty-six patients affected by resistant/refractory B-cell Non Hodgkin Lymphoma (NHL) were enrolled in a phase I/II study to determine the feasibility and safety of High Activity (HA) of 90Y-ibritumomab tiuxetan followed by ASC support. Three 90Y-ibritumomab tiuxetan activity levels were planned: 30 MBq/kg (4 patients), 45 MBq/kg (4 patients), 56 MBq/kg (18 patients). One week before treatment all patients underwent dosimetry with 111Inibritumomab tiuxetan. The activity concentration was measured in 9 serial blood samples up to 7 days post injection (pi) and planar images in all patients, in MA in 8 out of 18 patients planned at 56 MBq/kg (4 patients at 160 h pi; 4 patients on day planned for ASCT, i.e. day 0). ASC were reinfused 13 days after 90Y-ibritumomab tiuxetan. ASCT was considered at low risk when the adsorbed dose to reinfused stem cells (rSC) (i.e. dose to RM at time of ASCT) was < 50 mGy. Engraftment was considered delayed if on day 28 from reinfusion ANC did not reach 1.0x109/L or PLT were not ≥ 20.0x109/L. RESULTS: A median of 4,25x106/kg (1,45–20x106/kg) CD34+ cells were reinfused for each patient. A delay of engraftment occurred in only 1 patient who received 56 MBq/kg with a baseline ANC count of 0.20x109/L. Bone marrow biopsies were negative for disease localization in all patients at baseline, but 10 out of 26 had shown prior lymphoma infiltration. Considering the blood method the adsorbed dose to rSC resulted < 50 mGy in all patients with a median adsorbed dose of 11 mGy (4 – 28 mGy). ASC would be reinfused earlier in all patients except one. In particular, the 1st day with a dose to rSC < 50 mGy ranged from day -9 to day -5 at 30 MBq/kg; from day -8 to day -4 at 45 MBq/kg; from day -9 to day 0 at 56 MBq/kg, with a median value on day -3. We observed a possible correlation between total activity administered, dose delivered to RM and dose detectable on day of reinfusion, with higher doses to RM and rSC for those patients planned to received the highest activity. We also evaluated the dose to rSC if reinfusion would be performed 7 days after RIT: only 6 out of 26 patients showed a dose to SC < 50 mGy (2 at the 1st activity level, 3 at the 2nd and 1 at the 3rd activity level). Considering the MA method, the median adsorbed dose to the rSC resulted 25 mGy (9 - 69 mGy): in 2 out of 8 patients evaluated the adsorbed dose to the rSC was > 50 mGy on day 0 (69 and 51 mGy respectively). Even if ASC would be reinfused earlier in 5 out of 8 patients, the first day with a dose to rSC < 50 mGy ranged from day -3 to day +1. Despite bone marrow biopsy being negative in all patients at baseline, scintigraphic images (L2–L4 uptake) showed spine marrow uptake in almost all patients. CONCLUSIONS: Although alternative methods investigated - MA and imaging - are affected by uncertain factors (blood contamination of MA, difficult L2-L4 uptake image quantification), both indicate comparable results, about 2.5-folds higher, suggesting that the blood method provides an underestimate of RM dose. ASCT performed 13 days after HA 90Y-ibritumomab tiuxetan is generally safe. We suggest caution in anticipating the timing of ASCT with respect to 90Y-ibritumomab tiuxetan in those patients planned to receive an activity > 45 MBq/kg: alternative dosimetric approaches including image analysis and MA should be considered.

BACKGROUND: Red marrow (RM) is the critical organ in Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan, especially at myeloablative activities. Different methods for the evaluation of the adsorbed dose in RM have been investigated. The blood method relates the blood time-activity curve to RM by a factor that accounts for the activity concentration ratio between RM and blood. Alternative dosimetric approaches including image analysis and marrow aspirations (MA) were introduced for RM dose comparison in order to collect information about the dose delivered and to verify the correct time of Autologous Stem Cells Transplantation (ASCT).

We present feasibility and toxicity results of a phase I/II study of High Dose (HD) 90Yttrium (90Y) Ibritumomab Tiuxetan with PBSC support in resistant-refractory NHL patients. From 04/04 to 08/07 25 patients were enrolled. Median age was 68ys (21–75). 21/25 patients had advanced stage disease (III/IV) at diagnosis. 14 patients had Diffuse Large B Cell Lymphoma (DLBCL), 7 Mantle Cell Lymphoma (MCL), 2 Follicular Lymphoma (FL) G3, 1 transformed FL, 1 transformed Marginal Zone Lymphoma (MZL). Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three 90Y-Ibritumomab Tiuxetan activity levels were fixed: 30 MBq/kg, 45 MBq/kg and 56 MBq/kg; 4 patients at the 1st, 4 at the 2nd and 17 at the 3rd level. One week before treatment all patients underwent dosimetry with Indium-111 (111In) ibritumomab-tiuxetan in order to assess organ doses and plan the activity level. PBSC were reinfused 13 days after 90Y-Ibritumomab Tiuxetan. On day 28 from reinfusion engraftment was considered to be delayed if ANC<1.0×109/L or PLT<20.0×109/L. RESULTS: Dosimetry showed acceptable radiation-absorbed doses to normal organs in all cases except one: 1 patient showed an abnormal liver uptake still increasing up to 7 days post injection. The estimated absorbed dose to the liver was 11.3 Gy/GBq, meaning 50 Gy if the prescribed activity of 56 MBq/kg would be administered. Therefore, the patient was excluded from the treatment. The median (24 pts) adsorbed doses for 90Y-Ibritumomab Tiuxetan resulted (mGy/MBq): 0.80 (0.40–1.0), red marrow; 2.1 (1.1–5.4), heart wall; 1.7 (0.3–3.5), lungs; 2.8 (1.8–10.6), liver; 1.9 (0.8–5.0), spleen; 1.7 (0.6–3.8), kidneys; 2.8 (1.3–4.7), testes; 0.5 (0.4–0.8), total-body. Median activity of 90Y-Ibritumomab Tiuxetan delivered: 3.7 GBq, range 2.1–5.55 GBq. All patients engrafted promptly after PBSC transplantation. PLT and ANC-count nadirs were reached 8 and 4 days after transplantation, with median values of 11×109/L PLT (4–35) and 0.01×109/L ANC (0.01–1.09). The time of nadir did not change as a function of 90Y-ibritumomab tiuxetan dose. Median time to engraftment was 12 (0–22) and 20 (1–48) for PLT and ANC respectively. When data were analyzed per dose-level, no statistically significant differences in terms of hematological toxicity were observed. A drop in PLT-counts often occurs after engraftment as a sign of possible late toxicity, particularly in those patients who received more than 3 previous CT regimens. One transient acute G3 liver toxicity was observed at the 3rd level; 1pt died 4 months after treatment due to HCV reactivation; another pt died 2 months after 90Y-Ibritumomab Tiuxetan because of cerebral ischemia; finally we observed a myelodysplastic syndrome in 1pt who had received 45 MBq/kg 2 years after treatment. 22/24 patients are now evaluable for response: 9 CR, 4 PR, 1 SD, 8 PD. CONCLUSION: 90Y-Ibritumomab Tiuxetan at myeloablative activity is feasible with PBSC support and it could be safely delivered also in elderly pts. We suggest dosimetry in order to avoid unpredictable toxicity and an activity of 45 MBq/kg in heavily pretreated patients. Clinical efficacy and mild treatment-related toxicities suggest HD-90Y-Ibritumomab Tiuxetan is an interesting modality treatment to be further investigated as an alternative therapeutic option in ABMT setting.

We present feasibility and toxicity results of a phase I/II study of High Dose (HD) 90Yttrium (90Y) Ibritumomab Tiuxetan with PBSC support in resistant-refractory NHL patients. From 04/04 to 08/07 25 patients were enrolled. Median age was 68ys (21–75). 21/25 patients had advanced stage disease (III/IV) at diagnosis. 14 patients had Diffuse Large B Cell Lymphoma (DLBCL), 7 Mantle Cell Lymphoma (MCL), 2 Follicular Lymphoma (FL) G3, 1 transformed FL, 1 transformed Marginal Zone Lymphoma (MZL). Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three 90Y-Ibritumomab Tiuxetan activity levels were fixed: 30 MBq/kg, 45 MBq/kg and 56 MBq/kg; 4 patients at the 1st, 4 at the 2nd and 17 at the 3rd level. One week before treatment all patients underwent dosimetry with Indium-111 (111In) ibritumomab-tiuxetan in order to assess organ doses and plan the activity level. PBSC were reinfused 13 days after 90Y-Ibritumomab Tiuxetan. On day 28 from reinfusion engraftment was considered to be delayed if ANC<1.0×109/L or PLT<20.0×109/L.

Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT. Zevalin has been demonstrated active in elderly pts with resistant-primary refractory DLBCL at injected activity of 0.4 mCi/kg, however response is usually of short duration. Increasing RIT dose-intensity could improve and prolong efficacy. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 05/06, 18 pts were enrolled. Median age was 66.5ys (21–75). 17/18 pts had advanced stage disease (III/IV) at diagnosis. 11 had DLBCL, 4 MCL, 2 FL, 1 transformed MZL. Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three activity-levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4pts received 0.8, 5pts 1.2 and 9pts 1.5 mCi/kg. One week prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts were reinfused with PBSC previously harvested. On d28 from reinfusion engraftment was considered to be delayed if ANC<1.0x109/L or PLT<20.0x109/L. Dosimetry showed acceptable radiation-absorbed doses to normal organs in all cases. Median adsorbed doses (mGy/MBq): 0.8±0.2 (RM), 3.0±1.7 (heart wall), 1.7±0.8 (lungs), 3.9±2.3 (liver), 2.5±1.6 (spleen), 2.2±1.1 (kidneys), 3.0±1.0 (testes), 0.6±0.1 (total-body). Only 1 pt received 30Gy to the liver, without developing toxicity. Median activity of 90Y-Zevalin delivered: 95 mCi (3,5 GBq), range 57–150 mCi (2,1 – 5, 55 GBq); 9pts received more than 100 mCi (3,7 GBq). All pts but 1 engrafted promptly. PLT and ANC nadirs were observed 21 and 17 days after Zevalin (median values: 11x109/L and 0.01x109/L). The time of nadir did not change as a function of 90Y-ibritumomab tiuxetan dose. For all activity levels, the median time for PLTs to reach >20x109/L was + 25 days (0–35) and the median time for ANC>1.0x109/L was + 33 days (14–61). A non statistically significant difference in terms of hematologic toxicity exists in PLT recovering for pts receiving 1.5 mCi/kg, in respect to other levels, but this phenomenon is probably influenced by PLT count at baseline. A drop in PLT count occurs after engraftment in those pts who had received treatment with a PLT count <100x109/L, as a sign of late toxicity. Non-haematologic toxicity: 1febrile neutropenia, 1HZV-infection at 2nd level; 2febrile neutropenia, 1 G3 liver toxicity (quickly recovered), 1bacterial pneumonia, 1HZV-infection, 1HCV reactivation (pt died 4 months after treatment) at the 3rd level. No pulmonary, renal or cardiac toxicity was observed. All pts are evaluable for response: 7CR, 4PR, 1SD, 6PD. Conclusions: Zevalin at myeloablative activity is feasible with PBSC support and it could be safely delivered in elderly and heavily pretreated pts, including those who previously received HDCT. MTD could be defined according to dosimetry and clinical evaluation. We suggest an activity of 1.5 mCi/kg for those pts with normal PLT count, while 1.2 mCi/kg could be considered for pts with a PLT count <150x109. It is not advisable, in our opinion, to administer elevated Zevalin activity to pts having PLT counts <100x109/L and/or affected by chronic diseases of the liver. Clinical efficacy and mild treatment-related toxicities suggest further investigation.

Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT. Zevalin has been demonstrated active in elderly pts with resistant-primary refractory DLBCL at injected activity of 0.4 mCi/kg, however response is usually of short duration. Increasing RIT dose-intensity could improve and prolong efficacy. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 05/06, 18 pts were enrolled. Median age was 66.5ys (21–75). 17/18 pts had advanced stage disease (III/IV) at diagnosis. 11 had DLBCL, 4 MCL, 2 FL, 1 transformed MZL. Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three activity-levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4pts received 0.8, 5pts 1.2 and 9pts 1.5 mCi/kg. One week prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts were reinfused with PBSC previously harvested. On d28 from reinfusion engraftment was considered to be delayed if ANC<1.0x109/L or PLT<20.0x109/L. Dosimetry showed acceptable radiation-absorbed doses to normal organs in all cases. Median adsorbed doses (mGy/MBq): 0.8±0.2 (RM), 3.0±1.7 (heart wall), 1.7±0.8 (lungs), 3.9±2.3 (liver), 2.5±1.6 (spleen), 2.2±1.1 (kidneys), 3.0±1.0 (testes), 0.6±0.1 (total-body). Only 1 pt received 30Gy to the liver, without developing toxicity. Median activity of 90Y-Zevalin delivered: 95 mCi (3,5 GBq), range 57–150 mCi (2,1 – 5, 55 GBq); 9pts received more than 100 mCi (3,7 GBq). All pts but 1 engrafted promptly. PLT and ANC nadirs were observed 21 and 17 days after Zevalin (median values: 11x109/L and 0.01x109/L). The time of nadir did not change as a function of 90Y-ibritumomab tiuxetan dose. For all activity levels, the median time for PLTs to reach >20x109/L was + 25 days (0–35) and the median time for ANC>1.0x109/L was + 33 days (14–61). A non statistically significant difference in terms of hematologic toxicity exists in PLT recovering for pts receiving 1.5 mCi/kg, in respect to other levels, but this phenomenon is probably influenced by PLT count at baseline. A drop in PLT count occurs after engraftment in those pts who had received treatment with a PLT count <100x109/L, as a sign of late toxicity. Non-haematologic toxicity: 1febrile neutropenia, 1HZV-infection at 2ndlevel; 2febrile neutropenia, 1 G3 liver toxicity (quickly recovered), 1bacterial pneumonia, 1HZV-infection, 1HCV reactivation (pt died 4 months after treatment) at the 3rdlevel. No pulmonary, renal or cardiac toxicity was observed. All pts are evaluable for response: 7CR, 4PR, 1SD, 6PD.

Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent dosimetry and if no abnormal uptake was observed they received the planned dose. On Day −7 and 0 imaging and therapeutic doses were preceded by rituximab 250mg/mq. On Day13 pts were reinfused with PBSC previously harvested. On Day28 from reinfusion engraftment was considered to be delayed if WBC/ANC were<1.0x109/L or PLT<20x109/L. All pts engrafted promptly after PBSCT with median time to WBC/ANC>1.0x109/L and PLT>20x109/L of 19 (range 0–23) and 12 days (0–22) from PBSCT. PLT and ANC count nadirs were observed at 21 (0–24) and 25 (0–31) days after Zevalin with median values of 11x109/L(4–35) and 0.24x109/L(0.01–1.09). Median time to recovery from nadir was 16,5 days (4–175) for PLT and 17days (7–175) for ANC. 8pts required PLT transfusions, 4pts RBC transfusions; median number of PLT transfusions:1(1–4). No G-CSF was administered. No significant differences in terms of haematologic toxicity were observed among the 3 levels. No pulmonary, renal or cardiac toxicity was observed. 11/12 pts are now evaluable for response: 5pts experienced a CR (2 at 0.8mCi/kg, 2 at 1.2mCi/kg, 1 at 1.5mCi/kg), 1 pt receiving 1.5 mCi/kg a PR (ORR 50%); to date 4 pts maintain CR at 12, 11, 9 and 8 months after treatment. Conclusion: Zevalin at dosage higher than MTD is feasible with PBSC support. Even at dosage 4 times higher than standard, HD-Zevalin could be safely delivered in elderly and heavily pretreated pts, including those who previously received HD-CT. Clinical activity and mild treatment-related toxicities suggest that HD-Zevalin is an interesting modality treatment to be further investigated as an alternative therapeutic options for resistant-refractory NHL.

Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent dosimetry and if no abnormal uptake was observed they received the planned dose. On Day −7 and 0 imaging and therapeutic doses were preceded by rituximab 250mg/mq. On Day13 pts were reinfused with PBSC previously harvested. On Day28 from reinfusion engraftment was considered to be delayed if WBC/ANC were<1.0x109/L or PLT<20x109/L. All pts engrafted promptly after PBSCT with median time to WBC/ANC>1.0x109/L and PLT>20x109/L of 19 (range 0–23) and 12 days (0–22) from PBSCT. PLT and ANC count nadirs were observed at 21 (0–24) and 25 (0–31) days after Zevalin with median values of 11x109/L(4–35) and 0.24x109/L(0.01–1.09). Median time to recovery from nadir was 16,5 days (4–175) for PLT and 17days (7–175) for ANC. 8pts required PLT transfusions, 4pts RBC transfusions; median number of PLT transfusions:1(1–4). No G-CSF was administered. No significant differences in terms of haematologic toxicity were observed among the 3 levels. No pulmonary, renal or cardiac toxicity was observed. 11/12 pts are now evaluable for response: 5pts experienced a CR (2 at 0.8mCi/kg, 2 at 1.2mCi/kg, 1 at 1.5mCi/kg), 1 pt receiving 1.5 mCi/kg a PR (ORR 50%); to date 4 pts maintain CR at 12, 11, 9 and 8 months after treatment.