Yttrium-90-labeled anti-CD45 antibody followed by a reduced-intensity hematopoietic cell transplantation for patients with relapsed/refractory leukemia or myelodysplasia.

Outcomes of patients with persistent high-risk leukemia or myelodysplasia prior to allogeneic hematopoietic cell transplantation are dismal. We therefore conducted a phase I trial evaluating the use of CD45-targeted radiotherapy preceding hematopoietic cell transplantation with the goal of improving outcomes for this high-risk scenario. Fifteen patients, median age 62 (range 37-76) years, were treated: ten with advanced acute myeloid leukemia, five with high-risk myelodysplastic syndrome. All patients had evidence of disease prior to treatment including nine with marrow blast counts ranging from 7-84% and six with minimal residual disease. Patients received escalating doses of yttrium-90-labeled anti-CD45 antibody followed by fludarabine and 2 Gy total body irradiation prior to human leukocyte antigen-matched, related or unrelated hematopoietic cell transplantation. Although a maximum dose of 30 Gy was delivered to the liver, no dose-limiting toxicity was observed. Therefore, the maximum-tolerated dose could not be estimated. Treatment led to complete remission in 13 patients (87%). All patients engrafted by day 28. Six patients relapsed, median of 59 (range 6-351) days, after transplantation. The 1-year estimate of relapse was 41%. Eight patients (53%) are surviving with median follow up of 1.8 (range 0.9-5.9) years. Estimated overall survival at one and two years was 66% and 46%, respectively, with progression-free survival estimated to be 46% at each time point. In conclusion, the combination of 90Y-DOTA-BC8 with an allogeneic hematopoietic cell transplantation regimen was feasible and tolerable. This approach appears promising in this high-risk leukemia/myelodysplasia patient population with active disease. (Trial registered at clinicaltrials.gov identifier: NCT01300572).

A phase II trial evaluating the efficacy of high-dose Radioiodinated Tositumomab (Anti-CD20) antibody, etoposide and cyclophosphamide followed by autologous transplantation, for high-risk relapsed or refractory non-hodgkin lymphoma.

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.

A Patient with ß-Thalassemia Intermedia Secondary to Homozygosity for a Polyadenylation Signal Mutation (AATAAA > AATAGA) (HBB: C.*112A > G) on the ß-Globin Gene.

We describe the clinical presentation and laboratory findings of a Malay man with ß-thalassemia intermedia (ß-TI), secondary to homozygosity for a polyadenylation (polyA) signal mutation (AATAAA > AATAGA) (HBB: c.*112A > G) on the ß-globin gene, and give a brief review of the literature. This is the first report of a homozygous case of this polyA mutation, and highlights the importance of molecular analysis of the globin genes in the diagnosis of thalassemia.

Long-term outcomes of patients with persistent indolent B cell malignancies undergoing nonmyeloablative allogeneic transplantation.

Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/µL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT.

High-dose CD20-targeted radioimmunotherapy-based autologous transplantation improves outcomes for persistent mantle cell lymphoma.

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high-dose anti-CD20 radioimmunotherapy (RIT)-based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high-dose RIT-based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT-based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT-based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation-based strategies in a risk-adapted approach to ASCT for persistent MCL.

Myeloablative I-131-tositumomab with escalating doses of fludarabine and autologous hematopoietic transplantation for adults age ≥ 60 years with B cell lymphoma.

Myeloablative therapy and autologous stem cell transplantation (ASCT) are underutilized in older patients with B cell non-Hodgkin (B-NHL) lymphoma. We hypothesized that myeloablative doses of (131)I-tositumomab could be augmented by concurrent fludarabine, based on preclinical data indicating synergy. Patients were ≥ 60 years of age and had high-risk, relapsed, or refractory B-NHL. Therapeutic infusions of (131)I-tositumomab were derived from individualized organ-specific absorbed dose estimates delivering ≤ 27 Gy to critical organs. Fludarabine was initiated 72 hours later followed by ASCT to define the maximally tolerated dose. Thirty-six patients with a median age of 65 years (range, 60 to 76), 2 (range, 1 to 9) prior regimens, and 33% with chemoresistant disease were treated on this trial. Dose-limiting organs included lung (30), kidney (4), and liver (2) with a median administered (131)I activity of 471 mCi (range, 260 to 1620). Fludarabine was safely escalated to 30 mg/m(2) × 7 days. Engraftment was prompt, there were no early treatment-related deaths, and 2 patients had ≥ grade 4 nonhematologic toxicities. The estimated 3-year overall survival, progression-free survival, and nonrelapse mortality were 54%, 53%, and 7%, respectively (median follow up of 3.9 years). Fludarabine up to 210 mg/m(2) can be safely delivered with myeloablative (131)I-tositumomab and ASCT in older adults with B-NHL.

Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

We treated patients under age 50 years with iodine-131 ((131)I)-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332 to 1561 mCi of (131)I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however, no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed grade II graft-versus-host disease (GVHD), 1 patient developed grade III GVHD, and no patients developed grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of nonrelapse mortality were observed in the first year after transplantation. However, 2 patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplantation, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using (131)I-anti-CD45 antibody in addition to standard reduced-intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse.

9°Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma.

Nonmyeloablative allogeneic transplantation (NMAT) infrequently cures active chemoresistant, bulky, or aggressive B-cell lymphoma (B-cell non-Hodgkin lymphoma [B-NHL]). We hypothesized that 9°Y-ibritumomab tiuxetan-based NMAT would facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft. Forty high-risk B-NHL patients with persistent disease received 0.4 mCi/kg (maximum, 32 mCi/kg) 9°Y-ibritumomab tiuxetan, fludarabine, and 2 Gy total body irradiation and matched-related (15) or unrelated (25) transplantation. Baseline features included: median age, 58 years (range, 29-69 years); median prior regimens, 6 (range, 3-12); chemosensitive disease, 6 (15%); bulk > 5 cm, 17 (range, 5.2-18.6 cm, 43%); diffuse large B-cell lymphoma, 14 (35%); and comorbidity score > zero, 34 (85%). Early responses were observed in 24 (60%, 14 complete remission/complete remission unconfirmed, 10 partial response) patients, including 17 of 29 (59%) with chemotherapy-resistant disease and 10 (59%) with bulk > 5 cm. The estimated 30-month survival, progression-free survival, and nonrelapse mortality were 54.1%, 31.1%, and 15.9%, respectively. Early response, baseline platelet counts over 25 000/µL, indolent histology, and related donors were associated with improved survival. The addition of 9°Y-ibritumomab tiuxetan to NMAT is safe and yields early responses and prolonged disease control in some of the highest-risk B-NHL patients. This trial was registered at www.clinicaltrials.gov as #NCT00119392.

PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours.

BACKGROUND: The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours. METHODS: PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles. RESULTS: Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G-CSF and ≥770 mg/m2 when combined with docetaxel 75 mg/m2 plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents. CONCLUSIONS: Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m2 combined with docetaxel 60 to 75 mg/m2 both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836).

Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

We conducted a study to estimate the maximum tolerated dose (MTD) of (131)I-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of (131)I-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates.

Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in 19 nonhuman primates (Macaca fascicularis), the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation compared with directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)(4)SA] produced markedly lower concentrations of radiation in nontarget tissues compared with conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung, and liver (10.3:1, 18.9:1, and 9.9:1, respectively) compared with the conventional RIT controls (2.6:1, 6.4:1, and 2.9:1, respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

90Y-labeled anti-CD45 antibody allogeneic hematopoietic cell transplantation for high-risk multiple myeloma.

To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an antibody-radionuclide conjugate targeting CD45 (90Y-DOTA-BC8) as conditioning. 90Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and ≥1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with ≥1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT.

Yttrium-90 Anti-CD45 Immunotherapy Followed by Autologous Hematopoietic Cell Transplantation for Relapsed or Refractory Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is a standard of care for several subtypes of high-risk lymphoma, but durable remissions are not achieved in the majority of patients. Intensified conditioning using CD45-targeted antibody-radionuclide conjugate (ARC) preceding AHCT may improve outcomes in lymphoma by permitting the delivery of curative doses of radiation to disease sites while minimizing toxicity. We performed sequential phase I trials of escalating doses of yttrium-90 (90Y)-labeled anti-CD45 antibody with or without BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy followed by AHCT in adults with relapsed/refractory or high-risk B cell non-Hodgkin lymphoma (NHL), T cell NHL (T-NHL), or Hodgkin lymphoma (HL). Twenty-one patients were enrolled (16 NHL, 4 HL, 1 T-NHL). Nineteen patients received BEAM concurrently. No dose-limiting toxicities were observed; therefore, the maximum tolerated dose is estimated to be ≥34 Gy to the liver. Nonhematologic toxicities and engraftment kinetics were similar to standard myeloablative AHCT. Late myeloid malignancies and 100-day nonrelapse deaths were not observed. At a median follow-up of 5 years, the estimates of progression-free and overall survival of 19 patients were 37% and 68%, respectively. Two patients did not receive BEAM; one had stable disease and the other progressive disease post-transplant. The combination of 90Y-anti-CD45 with BEAM and AHCT was feasible and tolerable in patients with relapsed and refractory lymphoma. The use of anti-CD45 ARC as an adjunct to hematopoietic cell transplantation regimens or in combination with novel therapies/immunotherapies should be further explored based on these and other data.

Bilateral massive pulmonary thromboembolism in a young patient treated with supportive measures and an inferior vena cava filter with excellent outcome.

Acute pulmonary embolism (PE) is a common and often fatal disease with a mortality rate of more than 30% in untreated patients. There is a twofold increase in mortality in patients with massive PEs who do not receive treatment. Recurrent embolism is the most common cause of death. A 48-year-old woman presented to Tan Tock Seng Hospital, Singapore, on December 16, 2009, with a massive pulmonary thromboembolism. She was admitted to the intensive care unit and treated with supportive measures, ventilatory support, antibiotics and ionotropes. The patient was diagnosed with urosepsis with septicemic shock, disseminated intravascular coagulation, acute renal failure, high anion gap metabolic acidosis, iron-deficiency anemia secondary to menorrhagia, and a uterine mass with high cancer antigen 125, although malignancy was ruled out. Anticoagulation or thrombolysis could not be provided in view of coagulopathy. The patient subsequently underwent inferior vena cava filter insertion on December 31, 2009. The patient showed clinical improvement over the next two weeks with antibiotics and supportive measures. If there is a contraindication to anticoagulation or thrombolysis, massive pulmonary thromboembolism should be treated aggressively with supportive measures. Inferior vena cava filter insertion should be instituted early to prevent recurrent PE, which can be fatal. It may take weeks before the patient displays clinical improvement.

Biokinetics of Radiolabeled Monoclonal Antibody BC8: Differences in Biodistribution and Dosimetry Among Hematologic Malignancies.

We reviewed 111In-DOTA-anti-CD45 antibody (BC8) imaging and bone marrow biopsy measurements to ascertain the biodistribution and biokinetics of the radiolabeled antibody and to investigate differences based on type of hematologic malignancy. Methods: Serial whole-body scintigraphic images (4 time points) were obtained after infusion of the 111In-DOTA-BC8 (176-406 MBq) into 52 adult patients with hematologic malignancies (lymphoma, multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome). Counts were obtained for the regions of interest for spleen, liver, kidneys, testicles (in men), and 2 marrow sites (acetabulum and sacrum), and correction for attenuation and background was made. Bone marrow biopsies were obtained 14-24 h after infusion, and the percentage of administered activity was determined. Absorbed radiation doses were calculated. Results: Initial uptake in liver averaged 32% ± 8.4% (SD) of administered activity (52 patients), which cleared monoexponentially with a biologic half-time of 293 ± 157 h (33 patients) or did not clear (19 patients). Initial uptake in spleen averaged 22% ± 12% and cleared with a biologic half-time of 271 ± 185 h (36 patients) or longer (6 patients). Initial uptake in kidney averaged 2.4% ± 2.0% and cleared with a biologic half-time of 243 ± 144 h (27 patients) or longer (9 patients). Initial uptake in red marrow averaged 23% ± 11% and cleared with a biologic half-time of 215 ± 107 h (43 patients) or longer (5 patients). Whole-body retention half-time averaged 198 ± 75 h. Splenic uptake was higher in the AML/MDS group than in the lymphoma group (P ≤ 0.05) or the multiple myeloma group (P ≤ 0.10). Liver represented the dose-limiting organ. For liver uptake, no significant differences were observed among the 3 malignancy groups. Average calculated radiation absorbed doses per unit of administered activity for a therapy infusion of 90Y-DOTA-BC8 were 0.35 ± 0.20 cGy/MBq for red marrow, 0.80 ± 0.24 cGy/MBq for liver, 3.0 ± 1.4 cGy/MBq for spleen, 0.055 ± 0.014 cGy/MBq for total body, 0.21 ± 0.15 cGy/MBq for osteogenic cells, and 0.17 ± 0.15 cGy/MBq for kidneys. Conclusion:111In-DOTA-BC8 had a long retention time in liver, spleen, kidneys, and red marrow, and the highest absorbed doses were in spleen and liver. Few differences were observed by malignancy type. The exception was greater splenic uptake in the leukemia/MDS group than in the lymphoma or multiple myeloma group.

Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival.

PURPOSE: Hypoxia is associated with resistance to radiotherapy and chemotherapy and activates transcription factors that support cell survival and migration. We measured the volume of hypoxic tumor and the maximum level of hypoxia in glioblastoma multiforme before radiotherapy with [(18)F]fluoromisonidazole positron emission tomography to assess their impact on time to progression (TTP) or survival. EXPERIMENTAL DESIGN: Twenty-two patients were studied before biopsy or between resection and starting radiotherapy. Each had a 20-minute emission scan 2 hours after i.v. injection of 7 mCi of [(18)F]fluoromisonidazole. Venous blood samples taken during imaging were used to create tissue to blood concentration (T/B) ratios. The volume of tumor with T/B values above 1.2 defined the hypoxic volume (HV). Maximum T/B values (T/B(max)) were determined from the pixel with the highest uptake. RESULTS: Kaplan-Meier plots showed shorter TTP and survival in patients whose tumors contained HVs or tumor T/B(max) ratios greater than the median (P < or = 0.001). In univariate analyses, greater HV or tumor T/B(max) were associated with shorter TTP or survival (P < 0.002). Multivariate analyses for survival and TTP against the covariates HV (or T/B(max)), magnetic resonance imaging (MRI) T1Gd volume, age, and Karnovsky performance score reached significance only for HV (or T/B(max); P < 0.03). CONCLUSIONS: The volume and intensity of hypoxia in glioblastoma multiforme before radiotherapy are strongly associated with poorer TTP and survival. This type of imaging could be integrated into new treatment strategies to target hypoxia more aggressively in glioblastoma multiforme and could be applied to assess the treatment outcomes.

Venous Thrombosis in Acquired Hemophilia: The Complex Management of Competing Pathologies.

Introduction Venous thrombosis is rare in the setting of factor VIII (FVIII) deficiency. Cases of deep vein thrombosis (DVT) have been described in hemophiliacs after recent major surgery, or in association with the administration of FVIII concentrate and activated prothrombin complex concentrates, but occurrence of spontaneous DVT is even more uncommon. Aim We describe the challenging management of extensive DVT in a patient with acquired hemophilia A with concurrent hemorrhagic manifestations and review similar published cases. Methods We summarize a series of 10 cases with the following demographics: 6 males and 4 females; median age at presentation of 65 (21-80); mean inhibitor titer of 68.5 Bethesda Units (BU 1.9 to BU 350). Results Four cases were idiopathic and six had associated conditions (cancer [two cases], recent pregnancy [two cases], and recent surgery [two cases]). Three cases had an inferior vena cava filter inserted for acute lower limb DVT/pulmonary embolism. Inhibitor eradication was achieved with high-dose steroids with or without cyclophosphamide, and adjunct Rituximab administration was used in three cases. One patient received concurrent therapeutic plasma exchange (TPE). Inhibitor eradication was fastest with concurrent TPE at 6 days (range: 6-733 days). The 30-day survival was 90%. Conclusions There was adequate response of inhibitors to immunosuppression with steroids and cyclophosphamide therapy. For more refractory disease, Rituximab is emerging as a beneficial and cost-effective adjunct with better rates of complete remission, and the threshold for its use may be lowered in this complex cohort with dual competing pathologies.

Phase I Study of a CD45-Targeted Antibody-Radionuclide Conjugate for High-Risk Lymphoma.

PURPOSE: External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an antibody-radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression. PATIENTS AND METHODS: We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 (131I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), or Hodgkin lymphoma. The primary objective was to estimate the maximum tolerated radiation absorbed dose. RESULTS: Sixteen patients were enrolled: 7 patients had B-NHL, 6 had Hodgkin lymphoma, and 3 had T-NHL. Median number of prior therapies was three (range: 2-12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Nonhematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26-32 Gy) remain in CR without subsequent therapy 35-41 months later. CONCLUSIONS: CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma.

Myeloablative 131I-tositumomab radioimmunotherapy in treating non-Hodgkin's lymphoma: comparison of dosimetry based on whole-body retention and dose to critical organ receiving the highest dose.

UNLABELLED: Myeloablative radioimmunotherapy using (131)I-tositumomab (anti-CD20) monoclonal antibodies is an effective therapy for B-cell non-Hodgkin's lymphoma. The amount of radioactivity for radioimmunotherapy may be determined by several methods, including those based on whole-body retention and on dose to a limiting normal organ. The goal of each approach is to deliver maximal myeloablative amounts of radioactivity within the tolerance of critical normal organs. METHODS: Records of 100 consecutive patients who underwent biodistribution and dosimetry evaluation after tracer infusion of (131)I-tositumomab before radioimmunotherapy were reviewed. We assessed organ and tissue activities over time by serial gamma-camera imaging to calculate radiation-absorbed doses. Organ volumes were determined from CT scans for organ-specific dosimetry. These dose estimates helped us to determine therapy on the basis of projected dose to the critical normal organ receiving a maximum tolerable radiation dose. We compared organ-specific dosimetry for treatment planning with the whole-body dose-assessment method by retrospectively analyzing the differences in projected organ-absorbed doses and their ratios. RESULTS: Mean organ doses per unit of administered activity (mGy/MBq) estimated by both methods were 0.33 for liver and 0.33 for lungs by the whole-body method and 1.52 for liver and 1.74 for lungs by the organ-specific method (P=0.0001). The median differences between methods were 0.92 mGy/MBq (range, 0.36-2.2 mGy/MBq) for lungs, 0.82 mGy/MBq (range, 0.28-1.67 mGy/MBq) for liver, and -0.01 mGy/MBq (range, -0.18-0.16 mGy/MBq) for whole body. The median ratios of the treatment activities based on limiting normal-organ dose were 5.12 (range, 2.33-10.01) for lungs, 4.14 (range, 2.16-6.67) for liver, and 0.94 (range, 0.79-1.22) for whole body. We found substantial differences between the dose estimated by the 2 methods for liver and lungs (P=0.0001). CONCLUSION: Dosimetry based on whole-body retention will underestimate the organ doses, and a preferable approach is to evaluate organ-specific doses by accounting for actual radionuclide biodistribution. Myeloablative treatments based on the latter approach allow administration of the maximum amount of radioactivity while minimizing toxicity.

Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond.

Biochemical and molecular imaging of cancer using positron emission tomography (PET) plays an increasing role in the care of cancer patients. Most clinical work to date uses the glucose analogue [(18)F]fluorodeoxyglucose (FDG) to detect accelerated and aberrant glycolysis present in most tumors. Although clinical FDG PET has been used largely to detect and localize cancer, more detailed studies have yielded biological insights and showed the utility of FDG as a prognostic marker and as a tool for therapeutic response evaluation. As cancer therapy becomes more targeted and individualized, it is likely that PET radiopharmaceuticals other than FDG, aimed at more specific aspects of cancer biology, will also play a role in guiding cancer therapy. Clinical trials designed to test and validate new PET agents will need to incorporate rigorous quantitative image analysis and adapt to the evolving use of imaging as a biomarker and will need to incorporate cancer outcomes, such as survival into study design.