Transformed B-cell non-Hodgkin's Lymphoma Research Articles

Theranostics in Hematooncology.

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

Phase I Study Combining Ibrutinib with Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE) in Patients with Relapsed or Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL): NCI-Cancer Therapeutics Evaluation Program (CTEP) #9588

Background: In the post-rituximab era, half the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response with standard salvage therapy, and are thus ineligible to proceed to consolidative autologous stem cell transplantation (ASCT) with curative intent. The Bruton's tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, predominately of the non-germinal center B-cell (non-GCB) phenotype, with minimal toxicity. This single center, NCI-CTEP sponsored phase I study is the first to evaluate the combination of ibrutinib with standard salvage therapy of rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in transplant-eligible rel/ref DLBCL patients.Methods: Patients with rel/ref DLBCL, including transformed B-cell non-Hodgkin lymphoma, are eligible for study. The phase I study design is a standard 3 x 3 dose escalation of ibrutinib at 420 mg (dose level [DL] #1), 560 mg (DL #2) and 840 mg (DL #3) on days 1-21 with standard dosing of R-ICE for 3 cycles, every 21 days. The primary objective is to determine safety and the maximum tolerated dose (MTD) of ibrutinib in combination with R-ICE. Secondary objectives include response rate according to computed tomography (CT) and functional imaging (FDG-PET) per Deauville criteria.Results: To date, 16 patients are evaluable for toxicity, and 15 are evaluable for response. The median age of the 16 evaluable patients is 51 years (range 19-75 years). Histologies of the patients evaluable for response are: GCB DLBCL n=3, non-GCB DLBCL n=4, primary mediastinal large B-cell lymphoma n=4, and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (tCLL/SLL) n=4. There were no dose-limiting toxicities (DLTs) seen at DL #1 (n=3), 2 (n=3), or 3 (n=10, currently in expansion). Of the 16 patients evaluable for toxicity, 15 experienced expected and transient grade 3 or 4 hematologic toxicities with hematopoietic recovery prior to each cycle. The median number of cumulative platelet transfusions per patient for 3 cycles was 2 (range 0-11). Eleven of the 15 patients evaluable for response underwent chemotherapy-primed CD34+ hematopoietic progenitor cells (HPCs) apheresis procedures on study; 10 of the 11 patients successfully collected HPCs with a median of 5.6 x 106CD34+/kg (range 1.7-8.6). The only patient that failed to collect HPCs was an HIV-positive patient at DL #3 in the setting of febrile illness. One patient experienced grade 3 atrial fibrillation/flutter and was subsequently removed from study per treating physician's decision. Per CT criteria, five patients achieved complete remission (CR), eight patients achieved partial remission (PR), and two patients had stable disease for an overall response rate of 87%. All eight patients with non-GCB DLBCL and tCLL/SLL that were evaluable for response achieved chemosensitive remission per CT criteria (CR=4, PR=4). Seven of the 15 total patients (47%) evaluable for response achieved a complete metabolic remission (Deauville 1-3) per FDG-PET, including all 4 patients of non-GCB phenotype.Conclusions: Currently, no DLTs have been observed with ibrutinib at dosing up to 840 mg daily in combination with R-ICE. We are currently expanding DL #3. Manageable and expected hematologic toxicities have been observed. Importantly, hematologic toxicity has not resulted in failure to complete protocol therapy on-schedule or mobilize HPCs. Encouragingly, 87% of patients achieved a CT response (CR/PR) and 47% of patients achieved a complete metabolic remission per FDG-PET, including 100% of patients with non-GCB phenotype. These results compare favorably to historic cohorts. Given the safety and efficacy observed in this phase I, later phase studies for this treatment program are warranted. DisclosuresNo relevant conflicts of interest to declare.

Current concepts of radioimmonotherapy for lymphoma.

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High dose chemotherapy with autologous stem cell transplant for patients with transformed B-cell non-Hodgkin lymphoma in the rituximab era

High dose chemotherapy with autologous stem cell transplant (HD-ASCT) is a recommended procedure for patients with transformed indolent B-cell lymphoma from the pre-rituximab era. In this retrospective single-center study, we present our experience with HD-ASCT in patients with histologically verified transformed indolent B-cell lymphoma in the rituximab era. Forty-two patients were included, of whom 28 with chemosensitive disease proceeded to HD-ASCT. Twenty patients (71%) achieved a complete response (CR) and five (18%) a partial response (PR) after HD-ASCT. With a median observation time of 49 months for the survivors, the median progression-free survival (PFS) and overall survival (OS) for patients with HD-ASCT were 39 months and 57 months, respectively. Patients who were rituximab-naive at transformation had a significantly better OS compared to patients previously treated with rituximab, both in the whole patient cohort and among the HD-ASCT-treated patients (p = 0.036 and p = 0.039, respectively). Furthermore, male sex influenced survival negatively, whereas time from diagnosis to transformation was positively associated with survival, both with borderline significance, in HD-ASCT-treated patients. In conclusion, HD-ASCT remains an effective treatment for transformed indolent lymphomas in the rituximab era.

Phase I, Multicenter, Open Label, Dose Escalation of 90yttrium-Ibritumomab Tiuxetan Radioimmunotherapy Using a Modified Regimen for Relapsed or Refractory Follicular or Transformed CD20+ B-Cell Lymphoma

Abstract 1648 IntroductionRadioimmunotherapy capitalizes on the radiosensitivity of non-Hodgkin lymphoma (NHL) and the targeted nature of monoclonal antibody therapy. In an attempt to reverse bone marrow infiltration with B-cells and, hence, optimize the biodistribution and tumor dosimetry of 90Y-ibritumomab tiuxetan, we conducted a multicenter, dose escalation, open label study to determine maximum tolerated dose (MTD), safety, and efficacy of a single course of 90Y-ibritumomab tiuxetan after four weekly doses of rituximab in relapsed or refractory low-grade or follicular or transformed CD20+ B-cell NHL. MethodsA course of therapy included an initial dose of rituximab 250 mg/m2 plus 5 mCi of 111In- ibritumomab tiuxetan followed by three weekly doses of rituximab at 375 mg/m2 followed two weeks later by rituximab 250 mg/m2 plus 5 mCi of 111In-ibritumomab tiuxetan. Gamma camera imaging for dose estimates was conducted on days 1 and 36 following infusion of 111In- ibritumomab tiuxetan. If dose estimates were in the safe defined limits, and bone marrow on day 29 had less than 25% involvement by NHL, patients received on day 43 250 mg/m2 of rituximab plus a dose of 90Y-ibritumomab tiuxetan. Patients were scheduled to receive 90Y- ibritumomab tiuxetan in one of the dose escalation cohorts (0.4, 0.5, 0.6, 0.7 mCi/kg). Eligible patients were required to have histologically confirmed, relapsed or refractory low-grade or follicular or transformed B-cell NHL with demonstrable monoclonal CD20+ B-cell population in the lymph nodes or bone marrow. Patients with impaired bone marrow reserve, as indicated by prior myeloablative therapies with stem cell rescue, hypocellular marrow, history of failed stem cell collection or external beam radiation therapy to >25% of active bone marrow, and marked reduction in bone marrow precursors of one or more cell lines, were excluded. ResultsCohort 1 (0.4 mCi/kg) enrolled 5 patients. Dose escalation was held after significant hematologic toxicity was observed in those patients (1 patient developed grade 4 and 3 grade 3 reversible thrombocytopenia, 4 patients developed grade 4 reversible leukopenia and neutropenia, and 1 patient developed grade 4 febrile neutropenia). One patient in this cohort did not receive the study drug due to the toxicity observed in the previous patients.The protocol was amended and 6 patients were enrolled at a lower dose cohort (0.3 mCi/kg); 1 patient experienced grade 4 neutropenia, whereas grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 2, 3, and 3 patients respectively. As the 0.3 mCi/kg dose was well tolerated, the 0.4 mCi/kg cohort was expanded to enroll 6 additional patients. In the expansion cohort, Grade 4 leukopenia and neutropenia were seen in 1 and 2 patients respectively; also, grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 3, 4, and 4 patients, respectively.All hematologic toxicities were reversible and no non-hematologic toxicities were seen with the exception of grade 1 fatigue in 2 patients. Among those who developed hematologic toxicities, the median duration of at least grade 3 leukopenia, neutropenia, and thrombocytopenia were 12 (range, 7–37), 10 (7–30), and 12 (3–44) days, respectively. Six patients had bone marrow involvement by NHL at registration ranging from <5% to 20%. Following 4 weekly doses of rituximab, marrow involvement decreased in all patients with complete clearance in 3 of them.In an intention-to-treat analysis, complete remission, partial remission, stable and progressive disease was achieved in 6 (35%), 8 (47%), 2 (12%), and 1(6%) patients, respectively (fig 1). With a median follow up of 31.7 months (range, 4.3 – 92.6 months), the median progression free survival (fig 2) and time to next treatment (fig 3) were 12.3 and 10.9 months, respectively. The median overall survival has not been reached. [Display omitted] [Display omitted] [Display omitted] ConclusionThe MTD of 90Y-ibritumomab tiuxetan administered to patients who have NHL marrow infiltration <25% following 4 weekly doses of rituximab was 0.4 mCi/kg. A 4 weekly course of rituximab decreased NHL marrow infiltration in all patients with marrow involvement and led to complete clearance in 50% of them. Although this regimen was associated with a high response rate, the hematologic toxicity was significant. Disclosures:No relevant conflicts of interest to declare.

Indium-111 Ibritumomab Demonstration of Extremity Involvement in Transformed B-Cell Non-Hodgkin Lymphoma

Yttrium-90 ibritumomab is a recent option in the therapeutic armamentarium for follicular, indolent, or transformed malignant non-Hodgkin lymphoma. Its administration depends on the normal biodistribution of indium-111 ibritumomab on whole-body scintigraphy. Although tumor assessment with an indium-111-1a-beled monoclonal antibody is not an absolute necessity, biodistribution imaging may show extranodal soft tissue involvement of non-Hodgkin lymphoma. A case with an upper extremity lesion is presented in correlation with magnetic resonance examination.

Cellular Localization Pattern of Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in a Patient with Low-Grade Non-Hodgkin's Lymphoma (NHL).

Ytrrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) is indicated for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL at relapse or upon confirmation of refractory disease. Long-term responses in excess of 6 years have been observed following ibritumomab tiuxetan administration, underscoring the efficacy of this selective treatment modality. Dosing guidelines for 90Y ibritumomab tiuxetan were established in phase 1/2 trials and are dependent on body mass and platelet count, with the maximum recommended dose being 32 mCi. Biodistribution is evaluated by whole-body imaging prior to the delivery of the therapeutic dose using the gamma emitter indium 111 (111In) as the imaging radioimmunoconjugate. Current imaging methodology for the ibritumomab tiuxetan regimen has several limitations. First, the correlation between 111In ibritumomab tiuxetan dosimetry and either toxicity or tumor response is poor, and clinical parameters such as platelet count, patient weight, and percentage lymphomatous bone marrow involvement have been much more accurate. Further, while gamma (or PET/SPECT) imaging provides a visual evaluation of uptake in the blood pool and relevant organs, it cannot resolve biodistribution to the cellular level. This is particularly relevant for discriminating between radioisotope uptake in malignant and nonmalignant tissues. In order to assess the uniformity of cellular localization of 90Y ibritumomab tiuxetan, we performed autoradiographic analyses of lymph node tissue and bone marrow sampled after ibritumomab tiuxetan therapy. We also proposed to semi-quantify the energy doses delivered to lymphomatous tissue in an effort to better understand mechanisms of cellular sensitivity or resistance to this form of radioimmunotherapy. Following standard delivery of the ibritumomab tiuxetan regimen, bone marrow and lymph node tissues were sampled from a patient who presented with CD20+ NHL, bulky peripheral lymph nodes, and positive bone marrow involvement. Samples were collected 4 days after the administration of 90Y ibritumomab tiuxetan and immediately processed. Prepared sections were stained with hematoxylin and eosin (H&E) for histologic examination and then submitted for autoradiographic preparation with Kodak NBT-3 nuclear emulsion at 42o C, Kodak D-19 developer, and sodium thiosulphate fixative. Within lymph node tissue, radioisotope uptake was preferentially localized to lymphoma cells. An absence of significant localization in the histologically normal sections of bone marrow was also noted. The observed distribution patterns in the lymph node suggested that distribution of 90Y ibritumomab tiuxetan was localized to the cell membrane of lymphoma cells, with limited stromal and intravascular involvement. We are currently quantifying the density of radioisotope aggregation within malignant cells to assess whether a sufficient quantity of nuclide is recruited to achieve a crossfire effect on neighboring, unlabeled cells. Our results confirm that in vivo,90Y ibritumomab tiuxetan selectively targets tumor tissue with little binding to normal bone marrow and lymph node tissue, including stroma and vasculature. Additional patients with CD20+ NHL are being studied to verify the cellular localization pattern of 90Y ibritumomab tiuxetan.

Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Induces Long-Term Responses in Patients with Relapsed or Refractory Follicular Lymphoma (FL).

Background: Radioimmunotherapy (RIT) is an emerging clinical treatment option for patients with non-Hodgkin's lymphoma (NHL). Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) RIT was approved by the FDA in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL. In 4 registrational trials of 90Y ibritumomab tiuxetan conducted between 1996 and 1999, 211 patients with B-cell NHL were treated. Of these 211 patients, 153 patients (73%) had follicular lymphoma (FL). With ongoing follow-up, long-term durable responses have been observed, but until now have not been more fully characterized.Methods: Responding patients with time to progression (TTP) of ≥12 months were identified and characterized as long-term responding (LTR) patients.Results: In the 4 registrational trials, 78 of the 211 patients (37%) were identified as LTR patients. Characteristics of these LTR patients were as follows: median age 58 years (range, 24 to 80), 44% >60 years old, 55% male, 76% with follicular lymphoma, and 41% with lymphomatous marrow involvement. LTR patients had a median of 2 prior regimens (range, 1–9): 59% had ≥2 prior therapies, 33% had ≥3 prior therapies, and 37% had no response to their last prior therapy. Thirty percent of LTR patients had bulky disease (tumor size >5 cm) and 83% had stage III/IV disease. At the time of this analysis, the median duration of response (DR) and TTP for LTR patients were 28 months (range 11–80) and 29 months (range 12–82), respectively, with a median follow-up of 50 months (range 13–82). The median DR to the last prior therapy for LTR patients was 12 months. The complete response rate (confirmed [CR] and unconfirmed [CRu]) among LTR patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu patients. In ongoing responders the median DR is 52 months (range 48–80). Among the 153 patients with FL, 59 (39%) were identified as LTR patients. Compared to the overall LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates.Conclusions: Ongoing follow-up indicates that 90Y ibritumomab tiuxetan frequently produces durable long-term responses (TTP ≥12 months) in patients with relapsed or refractory B-cell NHL. Failure to respond to the therapy immediately prior to treatment with 90Y ibritumomab tiuxetan does not appear to affect the ability to achieve long-term responses with 90Y ibritumomab tiuxetan. Durable long-term responses were achieved in 37% of all patients and 39% of patients with FL treated in 4 registrational trials of 90Y ibritumomab tiuxetan at 30 centers in the US. Of these LTR patients, a high proportion were >60 years old and had received ≥3 prior therapies.

Follow-Up Results of a Phase II Study of Ibritumomab Tiuxetan Radioimmunotherapy in Patients with Relapsed or Refractory Low-Grade, Follicular, or Transformed B-Cell Non-Hodgkin's Lymphoma and Mild Thrombocytopenia

Follow-Up Results of a Phase II Study of Ibritumomab Tiuxetan Radioimmunotherapy in Patients with Relapsed or Refractory Low-Grade, Follicular, or Transformed B-Cell Non-Hodgkin's Lymphoma and Mild Thrombocytopenia

Analysis of relationship between baseline body weight and efficacy/safety of yttrium 90 (90Y) ibritumomab tiuxetan radioimmunotherapy in patients (pts) with non-Hodgkin's lymphoma (NHL)

6700 Background: 90Y ibritumomab tiuxetan (Zevalin®) has produced high response rates and durable remissions in pts w/relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Increased stability and favorable pharmacokinetic profile (ie, predictable urinary clearance and absence of dehalogenation) associated w/the 2nd-generation chelator tiuxetan enables simple weight-based dosing and obviates need for determining whole body clearance. Standard dose 90Y ibritumomab tiuxetan is 0.4 mCi/kg in pts w/plts ≥ 150,000/μL, to maximum recommended dose (MRD) 32 mCi. Pts >80 kg, therefore, receive a dose/kg that is less than that received by pts ≤ 80 kg. The objective of this analysis was to determine whether this difference in dose impacts efficacy or safety. Method/Results: Analysis of efficacy and safety data of pts (n=170) who received 90Y ibritumomab tiuxetan 0.4 mCi/kg from 3 registrational trials was performed. 103 pts ≤ 80 kg w/median wt 70 kg (range, 45–80 kg) were compared w/67 pts >80 kg w...

Analysis of relationship between baseline body weight and efficacy/safety of yttrium 90 (90Y) ibritumomab tiuxetan radioimmunotherapy in patients (pts) with non-Hodgkin's lymphoma (NHL)

6700 Background: 90Y ibritumomab tiuxetan (Zevalin®) has produced high response rates and durable remissions in pts w/relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Increased stability and favorable pharmacokinetic profile (ie, predictable urinary clearance and absence of dehalogenation) associated w/the 2nd-generation chelator tiuxetan enables simple weight-based dosing and obviates need for determining whole body clearance. Standard dose 90Y ibritumomab tiuxetan is 0.4 mCi/kg in pts w/plts ≥ 150,000/μL, to maximum recommended dose (MRD) 32 mCi. Pts >80 kg, therefore, receive a dose/kg that is less than that received by pts ≤ 80 kg. The objective of this analysis was to determine whether this difference in dose impacts efficacy or safety. Method/Results: Analysis of efficacy and safety data of pts (n=170) who received 90Y ibritumomab tiuxetan 0.4 mCi/kg from 3 registrational trials was performed. 103 pts ≤ 80 kg w/median wt 70 kg (range, 45–80 kg) were compared w/67 pts >80 kg w/median wt 95 kg (range, 81–59 kg). There were no statistical differences in baseline characteristics in the ≤ 80 kg and >80 kg groups w/exception of gender (41% M vs 73% M, respectively; P<.01). Similar efficacy and safety results were achieved in both groups. Conclusion: A solely weight-based dosing regimen (ie, no MRD 32 mCi) would have given 39% of pts doses > 32 mCi. Despite receiving a lower dose/kg, pts > 80kg had similar efficacy and safety results as pts ≤ 80kg. There is no evidence from this analysis that the 32 mCi MRD results in any significant differences in efficacy or safety for pts > 80 kg. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen/IDEC Biogen/IDEC Biogen/IDEC Biogen/IDEC

ABCs of Radioisotopes Used for Radioimmunotherapy: α- and β-Emitters

Although the introduction of the monoclonal antibody rituximab 5 years ago led to a marked improvement in the treatment of non-Hodgkin's lymphoma (NHL), most patients do not experience a complete response to therapy, and many who do respond relapse. One way of improving the efficacy of monoclonal antibodies is to use them to deliver cytotoxic agents, such as radionuclides, to the tumor. Monoclonal antibodies armed with radionuclides provide a means of targeting radiation therapy specifically to tumor cells that express the antigen to which the antibody was originally raised. Subsequently, in 2002, the first radiolabeled monoclonal antibody, 90Y-ibritumomab tiuxetan was approved for the treatment of patients with relapsed or refractory low-grade follicular or transformed B-cell NHL, including patients with follicular lymphoma refractory to rituximab. Attempts to optimize the efficacy of radioimmunotherapy are ongoing, however, and there are three factors that need to be considered: choice of antibody/antigen, choice of delivery of system to be used, and choice of radionuclide. CD25 (IL-2Rα) is an ideal choice for a target antigen as it is over-expressed by a number of tumor cells, including adult T-cell leukemia (ATL); 9 of 16 patients with ATL responded to treatment with anti-Tac (which targets the interleukin-2 receptor-α [IL-2Rα]), conjugated to 90Y. The dose of radionuclide that can be delivered to a tumor can be increased dramatically by using a three-step process in which the antibody and radioactivity are delivered separately to the antigen in order to improve tumor-to-normal tissue ratios. The most commonly used radionuclides in radioimmunotherapy to date are β-emitters. However, the pretargeting process makes the use of short-lived α-emitters more feasible. The results of experiments involving this pretargeting process and α- and β-emitting radionuclides in leukemia and lymphoma models suggest that α-emitters may be more effective in the treatment of small tumors, micrometastases and isolated cells, and that β-emitters may be more suitable for use in large tumor masses, such as lymphomas.

New Drug Alert

Ibritumomab tiuxetan (Zevalin) is the first radioimmunoconjugate to receive FDA approval for the treatment of cancer. The drug is indicated for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), including patients with follicular NHL refractory to rituximab. Zevalin is a murine monoclonal antibody (the murine parent of rituximab) linked to the radioisotope yttrium-90, targeting the CD20 antigen on the surface of mature B cells and B-cell tumors, inducing cellular damage in both the target and neighboring cells. Zevalin was approved based on two major studies conducted in the United States. The Zevalin regimen includes rituximab given first, followed seven to 10 days later by a second infusion prior to Zevalin. The first study, on which full FDA approval was based, included 54 patients with relapsed follicular lymphoma who no longer had an adequate response to rituximab. Of this group 74 percent of patients responded to treatment with Zevalin as part of the therapeutic regimen, including 15 percent who achieved a complete response. The second study, on which accelerated FDA approval was based, was a Phase III randomized, controlled trial conducted in 143 patients with relapsed or refractory low-grade or follicular NHL or transformed B-cell NHL. Among patients who were randomized to receive Zevalin as part of the therapeutic regimen, the overall response rate was 80 percent versus 56 percent in patients who received rituximab alone. Thirty percent in the Zevalin-treated group achieved a confirmed complete remission versus 16% of rituximab-treated patients. Two experts experienced with ibritumomab were asked what advice they would have for clinicians starting to use the agent. Russell Schilder, MD, is a member of the Department of Medical Oncology at Fox Chase Cancer Center in Philadelphia; and Leo I. Gordon, MD, is the Abby and John Friend Professor of Cancer Research, Professor of Medicine, and Chief of the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine in Chicago.

Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial

Mildly thrombocytopenic patients with relapsed or refractory low-grade non-Hodgkin lymphoma (NHL) have an increased risk of chemotherapy-induced myelosuppression following treatment. The safety and efficacy of radioimmunotherapy with a reduced dose of (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]; maximum 32 mCi [1.2 GBq]) was evaluated in 30 patients with mild thrombocytopenia (100-149 x 10(9) platelets/L) who had advanced, relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. The ibritumomab tiuxetan regimen included an infusion of rituximab (250 mg/m(2)) and injection of (111)In ibritumomab tiuxetan (5 mCi [185 MBq]) for dosimetry evaluation, followed 1 week later with rituximab (250 mg/m(2)) and (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]). Patients (median age, 61 years; 90% stage III/IV at study entry; 83% follicular lymphoma; and 67% with bone marrow involvement) had a median of 2 prior therapy regimens (range, 1-9). Estimated radiation-absorbed doses were well below the study-defined maximum allowable for all 30 patients. With the use of the International Workshop criteria for NHL response assessment, the overall response rate was 83% (37% complete response, 6.7% complete response unconfirmed, and 40% partial response). Kaplan-Meier estimated median time to progression (TTP) was 9.4 months (range, 1.7-24.6). In responders, Kaplan-Meier estimated median TTP was 12.6 months (range, 4.9-24.6), with 35% of data censored. Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively. Reduced-dose ibritumomab tiuxetan is safe and well tolerated and has significant clinical activity in this patient population.