Long-term update of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma.

The present study aimed to determine the long-term safety and efficacy of chimeric anti-CD 20 antibody rituxan (rituximab, Biogen IDEC, San Diego, CA, USA; Genentech, South San Francisco, CA, USA) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in previously untreated patients with aggressive non-Hodgkin's lymphoma (NHL). Thirty-three patients with previously untreated aggressive B-cell NHL received six infusions of rituximab (375 mg/m(2) per dose) on day 1 of each cycle of CHOP chemotherapy, given on day 3 of each cycle of therapy. Currently, the patients now have a median follow-up of 63 months (range 34 - 82 months). The overall response (OR) rate was 94% and the complete response (CR) rate was 61% at the end of therapy. Of the 33 patients, 2 patients experienced disease progression and subsequently died of their disease, 2 patients experienced disease progression but were alive at last follow-up following additional therapy, and 2 patients died without experiencing disease progression: one due to a cerebral vascular accident at 9 months after therapy and a second patient due to small cell lung carcinoma at 55 months. The 5-year survival rate was 88% (95% confidence interval (CI) 72 - 97) and the 5-year progression-free survival was 82% (95% CI 64 - 93). There were no long-term adverse events noted directly related to the rituximab. The long-term follow-up of patients in this phase II trial of rituximab with CHOP chemotherapy for previously untreated aggressive NHL demonstrates a high response rate, which remains very durable with high 5-year overall and progression-free survivals.

Pancreatic carcinoma with brain metastases: case report and literature review.

The case of a patient developing multiple brain metastases from carcinoma of the exocrine pancreas has been described. A 56-year-old man with stage IV pancreatic cancer attained a clinical and radiographic response while receiving the G-FLIP chemotherapy regimen (biweekly gemcitabine, irinotecan, 5-fluorouracil, leucovorin and cisplatin). After 4 months of therapy, he developed gait imbalance and weakness in the right hand. An MRI of the brain showed multiple 1-2 mm enhancing nodules in the cerebral hemispheres and pons. A subsequent biopsy confirmed that these were pancreatic carcinoma metastases. The patient experienced a rapid deterioration in his neurological status and died 3 days after brain biopsy. Previously reported cases of brain metastases from pancreatic cancer are reviewed.

Phase I dose-finding study of biweekly irinotecan in combination with fixed doses of 5-fluorouracil/leucovorin, gemcitabine and cisplatin (G-FLIP) in patients with advanced pancreatic cancer or other solid tumors.

This phase I trial was initiated based on encouraging clinical data with 5-fluorouracil (5-FU)/leucovorin (LV), gemcitabine and cisplatin (G-FLIP) in the therapy of solid tumors. In this trial, G-FLIP has been modified to facilitate outpatient administration and to optimize sequence-dependent synergistic activity. Treatment consisted of biweekly (once every 14 days) cycles of sequential gemcitabine 500 mg/m, irinotecan per dose escalation schedule, bolus 5-FU 400 mg/m and LV 300 mg on day 1 followed by a 24-h 5-FU infusion 1500 mg/m, followed by cisplatin 35 mg/m on day 2. The irinotecan starting dose was 80 mg/m and escalated by 20 mg/m in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Twenty-three patients were enrolled (13 men/10 women) with the following cancers: 11 pancreatic, five gallbladder, three squamous cell carcinoma of the head and neck, one hepatocellular carcinoma, one melanoma, one gastric, and one breast cancer. Median patient age was 63 years (range 44-78) and median Karnofsky performance status (KPS) was 80. Patients received a median of 8 cycles (range 1-16) over five irinotecan dose levels (80, 100, 120, 140 and 160 mg/m). Dose-limiting toxicity consisting of grade 3 nausea/vomiting despite aggressive anti-emetic therapy occurred in one patient at dose level 1 and three patients at dose level 3. Grade 3-4 hematological toxicities per patient consisted of thrombocytopenia (3%), anemia (6%), thrombosis (23%), neutropenia (16%) and neutropenic fever (10%). Of 18 patients evaluable for response, one complete response (pancreatic) and eight partial responses (three gallbladder, two pancreatic, two head and neck, and one breast) were attained. Seven patients had disease stabilization (five pancreatic, one hepatocellular and one gastric) for a median of 16 weeks (range 10-22). Median time to disease progression among all 23 patients enrolled to the phase I portion of the trial was 20.5 weeks (range 4-37). We conclude that G-FLIP is a novel outpatient chemotherapy regimen with acceptable toxicity at the maximum tolerated irinotecan dose of 120 mg/m. The phase II trial of G-FLIP using an irinotecan dose of 120 mg/m for patients with metastatic pancreatic cancer is ongoing.

Irinotecan combined with gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (G-FLIP) is an effective and noncrossresistant treatment for chemotherapy refractory metastatic pancreatic cancer.

BACKGROUND: Single agents have only modest activity as treatment for metastatic pancreatic cancer with response rates of less than 10% and median survivals of less than 6 months. Evaluations of single-agent gemcitabine and rubitecan as second-line treatment for relapsed pancreatic cancer have reported good patient tolerability and median survivals of 3.85 months and 4.7 months, respectively. Regimens incorporating two drugs have demonstrated encouraging activity and clinical impact compared with single-agent therapy. G-FLIP is a regimen designed to incorporate four active single agents into a tolerable and active combination. This analysis is a retrospective evaluation of the efficacy and safety of the G-FLIP regimen as second-line chemotherapy in a series of consecutively treated patients with metastatic pancreatic cancer. METHODS: G-FLIP was administered over 48 hours and repeated every 2 weeks. Day 1 treatment consisted of sequentially administered gemcitabine 500 mg/m(2), irinotecan 80 mg/m(2), leucovorin 300 mg, 5-fluorouracil (5-FU) 400 mg/m(2) bolus followed by infusional 5-FU 600 mg/m(2) over 8 hours. Day 2 treatment consisted of leucovorin 300 mg and 5-FU 400 mg/m(2) bolus, followed by cisplatin 50 to 75 mg/m(2), and then infusional 5-FU 600 mg/m(2) over 8 hours. RESULTS: Thirty-four patients with histologically confirmed metastatic pancreatic cancer were consecutively treated. The median patient age was 64.5 years (range 41-82 years) and all patients had objective disease progression on prior therapy: 32 patients had disease progression with gemcitabine and 31 had disease progression with a gemcitabine/5-fluorouracil/cisplatin combination. Grade 3-4 hematological toxicities included anemia (23%), thrombocytopenia (53%), and neutropenia (38%). There were no grade 3-4 neutropenic fevers, treatment-related mortalities, or withdrawals. Nonhematological grade 3-4 toxicities were rare: nausea/vomiting (3%), neurotoxicity (3%), nephrotoxicity (6%), and diarrhea (3%). Based on RECIST criteria a partial response (PR) was attained in eight patients (24%) and seven patients had stable disease (SD). Seven and six patients who attained a PR or SD, respectively, had disease progression with prior gemcitabine-based therapy. The median time to disease progression for all 34 patients was 3.9 months and 5.9 months for the eight patients who attained a PR. Median overall survival for all 34 patients was 10.3 months. CONCLUSION: Adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative to switching to different drug classes for treatment of relapsed/resistant cancer. The promising clinical outcomes and moderate toxicity associated with G-FLIP in this heavily pretreated group warrant development of this novel regimen including tests as first-line therapy in patients with diseases likely to be responsive to the drugs contained in this combination.

Hematologic malignancies.

This article reviews highlights in the field of hematologic malignancies presented at the 2001 annual meeting of the American Society of Clinical Oncology. Targeted therapies continue to proceed from the laboratory to the clinic. Monoclonal antibody-based therapies predominate, and further data on radioimmunoconjugates (RICs) (tositumomab and Iodine 131 tositumomab [Bexxar] and ibritumomab tiuxetan [Zevalin]) are presented. Both agents have high response rates in relapsed B-cell non-Hodgkin's lymphoma (NHL). Results from the first trial directly comparing an RIC (Zevalin) to an unconjugated antibody (rituximab) are presented. A novel application of RIC therapy as part of high-dose therapy for mantle cell NHL is described. A new fusion toxin, BL22, targets the CD22 antigen and shows marked activity in the treatment of hairy cell leukemia. Similarly, the Hu1D10 monoclonal antibody has activity in B-cell NHL and might have a relatively unique mechanism of action. Finally, advances in the treatment of mucositis are described. These abstracts all describe therapies derived from our enhanced understanding of tumor immunology and molecular biology.

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma.

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m2 per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle. RESULTS: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score > or = 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score > or = 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. CONCLUSION: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score > or = 2 warrants further investigation with a randomized study.

Hematologic malignancies: selected abstracts and commentary.

ASCO 2000 did not offer revolutionary new advances in the treatment of hematologic malignancies. However, reports at the meeting built incrementally on gains established over the past several years. The meeting continued to highlight advances in the targeted therapy of hematologic malignancies. Excitement abounds regarding the clinical development of STI 571, a rationally designed tyrosine kinase inhibitor, for the treatment of chronic myelogenous leukemia. Studies further defined the role monoclonal antibody treatment for non-Hodgkin's lymphoma and more mature data were presented on both unconjugated antibody therapy and radioimmunoconjugates. In disease detection, important data were presented to clarify the role of positron emission tomography scans in the staging and follow-up of lymphoid malignancies. The following review summarizes key abstracts presented at the 2000 ASCO meeting and will elaborate on the implications of these findings for disease management.

Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor.

PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk of recurrence. PATIENTS AND METHODS: Forty-eight assessable patients with stage III or IV melanoma were treated in a phase II trial with long-term, chronic, intermittent GM-CSF after surgical resection of disease. Patients with stage III disease were required to have more than four positive nodes or a more than 3-cm mass. All patients were rendered clinically disease-free by surgery before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 microg/m(2) was delivered daily for 14 days followed by 14 days of rest. Treatment cycles continued for 1 year or until disease recurrence. Patients were evaluated for toxicity and disease-free and overall survival. RESULTS: Overall and disease-free survival were significantly prolonged in patients who received GM-CSF compared with matched historical controls. The median survival duration was 37.5 months in the study patients versus 12.2 months in the matched controls (P <.001). GM-CSF was well tolerated; only one subject discontinued drug due to an adverse event (grade 2 injection site reaction). CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and disease-free survival in patients with stage III and IV melanoma who are clinically disease-free. These results support institution of a prospective, randomized clinical trial to definitively determine the value of surgical adjuvant therapy with GM-CSF in such patients.

Paclitaxel/ifosfamide or navelbine/ifosfamide chemotherapy for advanced non-small cell lung cancer: CALGB 9532.

In order to explore non-cisplatin containing regimens for advanced non-small cell lung cancer, Cancer and Leukemia Group B conducted a randomized Phase-II study of two novel combinations, paclitaxel/ifosfamide and vinorelbine/ifosfamide. Both regimens were active with a 38% response rate (95% CI: 24%, 53%) and 31% (95% CI: 18%, 47%), respectively. Median survivals were 8.5 and 7.4 months. Toxicity, mostly neutropenia, was acceptable. These two combinations establish a 'proof of principle' that non-cisplatin containing regimens also have activity in this setting.

Treatment of multiple myeloma by antibody mediated immunotherapy and induction of myeloma selective antigens.

BACKGROUND: In view of the successful use of serotherapy in many B-cell malignancies, we and others have sought to identify tumor selective antigens for the serotherapy of plasma cell dyscrasias (PCD) including multiple myeloma (MM), and Waldenstrom's macroglobulinemia (WM). We recently identified Muc-1 core protein as a MM selective antigen. Though Muc-1 core protein is abundantly expressed on most MM plasma cells, expression of this antigen can be absent, or weak on some plasma cells which could potentially result in the selection of Muc-1 core protein negative clones following serotherapy of PCD. In addition to Muc-1 core protein, we have also been examining the use of CD20 directed serotherapy for PCD. DESIGN: As part of these efforts, we recently initiated a phase II clinical trial examining the use of Rituximab (Rituxan, MabThera) as a single agent in MM patients; as well several WM patients have been treated with Rituximab at our Institutions. RESULTS: In previous studies, we have shown that CD20 is abundantly expressed on the plasma cells of most WM patients; in contrast, CD20 is expressed on plasma cells from a minority of MM patients, and in these patients expression of CD20 can be weak or heterogeneous with both CD20+ and CD20- plasma cells present. As such, we have sought out clinically useful inducers of Muc-1 core protein, and of CD20 on malignant plasma cells. CONCLUSIONS: These efforts resulted in the identification of dexamethasone (Dex) as a potent inducer of Muc-1 core protein on MM plasma cells, and interferon-gamma (IFN-gamma) as a potent inducer of CD20 on MM plasma cells and B-cells. Importantly, these agents induced their respective antigens at pharmacologically achievable doses.

A phase I study of gemcitabine and docetaxel in patients with metastatic solid tumors.

BACKGROUND: A Phase I study was initiated to determine the maximum tolerated dose of weekly gemcitabine combined with monthly, fixed-dose docetaxel. METHODS: Patients with metastatic solid tumors were treated with docetaxel, 60 mg/m(2), on Day 1 every 28 days. Gemcitabine was administered on Days 1, 8, and 15 and underwent dose adjustment in cohorts of 3-6 patients. At the maximum tolerated dose, 11 additional patients were enrolled. RESULTS: Twenty-six patients received 85 cycles of therapy. At the first dose level, the planned gemcitabine dose on Days 1, 8, and 15 was 800 mg/m(2). Two of the 6 patients treated at this dose level experienced dose-limiting toxicities (DLTs) requiring the reduction of gemcitabine to 600 mg/m(2) per dose and the administration of ciprofloxacin, 500 mg orally twice daily, on Days 8-18. At the second dose level the first 3 patients experienced no DLTs and the dose of gemcitabine was increased to 700 mg/m(2). Two of the 6 patients treated at the 700 mg/m(2) dose level experienced DLTs. Eleven additional patients were enrolled at the recommended Phase II dose of gemcitabine (600 mg/m(2)). At this dose level, Grade 3/4 (according the National Cancer Institute's common toxicity criteria) neutropenia and thrombocytopenia occurred in 12.5% and 2.1% of cycles, respectively. Grade 3 and 4 nonhematologic toxicities were uncommon. Three of seven evaluable patients with pancreatic carcinoma had evidence of significant antineoplastic activity (three partial responses). In addition, two complete responses (one patient with gastric carcinoma and one patient with ovarian carcinoma) and one partial response (patient with hepatocellular carcinoma) were noted in patients with other solid tumors. CONCLUSIONS: The regimen comprised of docetaxel, 60 mg/m(2), on Day 1 and gemcitabine, 600 mg/m(2), on Days 1, 8, and 15 with ciprofloxacin on Days 8-18 every 28 days is safe, well tolerated, and active.

Rituximab therapy of B-cell neoplasms.

The development of rituximab, an anti-CD20 monoclonal antibody, represents a revolutionary advance in the therapy of hematological malignancies. Rituximab was approved in 1997 by the Food and Drug Administration for the treatment of relapsed or refractory, CD20(+), B-cell, low-grade or follicular non-Hodgkin's lymphoma (NHL). Recent studies have documented activity of rituximab in other CD20-expressing hematological malignancies including mantle cell lymphoma, small lymphocytic lymphoma, aggressive NHL, chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia. When used in combination with cytotoxic chemotherapy, rituximab achieves response rates of 90%-95% in low-grade follicular and aggressive NHL patients. Currently, rituximab is undergoing intensive investigation in several large phase II and III trials, both as a single agent and in combination with chemotherapy. Clinical research will help define the ultimate role of this agent and its potential impact on survival of patients with B-cell neoplasms. This article describes current clinical trials with rituximab and discusses their significance.

Treatment of plasma cell dyscrasias by antibody-mediated immunotherapy.

The use of serotherapy to treat patients with plasma cell dyscrasias (PCDs) has been sought by us and others. Candidate antigens that have been targeted or proposed for targeting in PCDs include the immunoglobulin idiotype, CD19, CD38, CD54, CD126, HM1.24, and Muc-1 core protein. Unfortunately, many of these antigens are not ideal for use in serotherapy since they are not selectively expressed, are either shed or secreted, or have not been fully characterized. Serotherapy with an anti-CD19 monoclonal antibody (B4) conjugated to a blocked ricin toxin had no significant activity in patients with multiple myeloma (MM). Circulating CD20+ clonotypic B cells have been detected in the circulation of most MM and Waldenstrom's macroglobulinemia (WM) patients. Plasma cells from most WM patients express CD20, but most MM patient plasma cells either lack CD20 or express it weakly. In view of recent successes with anti-CD20-directed serotherapy in other B-cell malignancies, we initiated a phase II trial to study the anti-CD20 monoclonal antibody rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) in patients with MM. We describe two PCD patients (one with WM and one with MM) who responded to therapy. By flow cytometric analysis, CD20+ plasma cells and B cells present in the bone marrow and peripheral blood of a patient with MM disappeared with response to rituximab therapy. However, residual CD20- tumor cells remained in the bone marrow following rituximab therapy, and after 6 months this patient progressed with CD20- myeloma cells. As a potential strategy to overcome this limitation, we demonstrated that interferon-gamma at pharmacologically achievable levels induced CD20 expression on these CD20- plasma cells, consistent with our recent findings that interferon-gamma is a potent inducer of CD20 expression on MM patient plasma cells and B cells. We also characterize a response to rituximab with a decrease in paraprotein and resolution of anemia in a patient with WM whose response to rituximab is ongoing after 19+ months. This preliminary experience supports the potential use of serotherapy targeting CD20 in PCDs. Our studies further suggest that interferon-gamma may enhance CD20 expression on MM plasma cells, thereby increasing their susceptibility to anti-CD20 monoclonal antibody therapies.

A Phase II study of adjuvant therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with relapsed B-cell non-Hodgkin's lymphoma.

This Phase II trial was undertaken to determine the safety, toxicity, and potential efficacy of the B-cell restricted immunotoxin anti-B4-blocked ricin (Anti-B4-bR) when administered as adjuvant therapy to patients in complete remission (CR) after autologous bone marrow transplantation (ABMT) for B-cell non-Hodgkin's lymphoma (NHL). Forty-nine patients with B-cell NHL in CR 46-202 days (median, 112 days) post-ABMT received Anti-B4-bR at a dose of 30 microg/kg lean body weight/day for 7 days by continuous i.v. infusion. Patients were eligible for up to two additional courses of therapy at 14-day intervals. A total of 83 courses of Anti-B4-bR were administered, with 31 patients receiving two or more courses of therapy. The mean serum level on day 7 of the first course was 0.77+/-0.41 nM. Reversible toxicities included hepatic transaminase elevations, thrombocytopenia, myalgias, fatigue, nausea, hypoalbuminemia, and dyspnea. Human antimouse antibody (HAMA) and/or human antiricin antibody (HARA) responses occurred in 23 patients at a median of 22 days from the initiation of Anti-B4-bR therapy (range, 11-100 days). The 4-year disease-free survival and overall survival are estimated at 56 and 72%, respectively. Twenty-six patients remain in CR after a median follow-up of 54.5 months. This study demonstrates that Anti-B4-bR can be administered safely to patients as adjuvant therapy early after ABMT for B-cell NHL. The toxicities are tolerable and reversible. Although the early estimate of disease-free survival was very encouraging in this single-armed trial, the 4-year follow-up data demonstrate continued relapse.

Mucosa-associated lymphoid tissue lymphoma of the stomach: long term outcome after local treatment.

BACKGROUND: Although antibiotic therapy is emerging as effective initial treatment for patients with gastric lymphoma of mucosa-associated lymphoid tissue (MALT), there is a subset of patients for whom antibiotics are ineffective or inappropriate. Surgical resection can be curative, but total gastrectomy may be required for the eradication of all disease. To identify the optimal nonantibiotic therapy for early stage gastric MALT lymphoma, the authors retrospectively evaluated the Massachusetts General Hospital experience with gastric MALT lymphoma. METHODS: Disease patterns and treatment outcomes were retrospectively analyzed in data from 21 consecutive patients with gastric MALT lymphoma who were treated between 1978 and 1995 at the Massachusetts General Hospital. RESULTS: Sixteen patients were Stage IE, and 5 were in higher stages. Treatment consisted of resection with or without radiation or chemotherapy (14 patients), radiation alone (4 patients), or radiation plus chemotherapy (2 patients). Thirteen Stage IE patients received local therapy only. The 10-year actuarial relapse free survival rate for Stage IE patients was 93%, with 1 relapse among 15 treated patients. Because the patient who relapsed was treated successfully with chemotherapy, the 10-year cancer free survival was 100%. Overall survival for Stage IE patients was 93% at 5 years and 58% at 10 years, with no deaths from lymphoma. CONCLUSIONS: These data indicate that a high probability of long term remission can be achieved with only local treatment of patients with Stage I gastric MALT lymphoma. Preliminary results suggest that radiation therapy is well tolerated and effective and may well be the optimal nonantibiotic treatment for patients with localized gastric MALT lymphoma.

Monoclonal antibody-based therapies for hematologic malignancies.

PURPOSE: To review recent advances in the development and clinical roles of monoclonal antibody (MoAb)-based therapies in the treatment of hematologic malignancies. DESIGN: A search of MEDLINE and CANCERLIT was conducted to identify relevant publications. The bibliographies of these references also were used to identify articles and abstracts. These references were then reviewed. RESULTS: In the two decades since the first patient was treated with MoAb therapy, there have been significant advances in the biology, pharmacology, and clinical application of MoAb-based therapies. Three distinct fields of research have emerged: unconjugated MoAbs, immunotoxin-conjugated MoAbs (ITs), and radionuclide-conjugated MoAbs (RICs). The unconjugated MoAbs are less toxic but depend on host mechanisms to mediate cytotoxicity. The ITs carry a potent toxin, although at the cost of a narrow therapeutic index that may limit clinical use. The RICs offer significant potency, even in refractory disease, but their complexity may limit their use to large cancer centers. The current challenges in the development of MoAb-based therapies are to identify the proper target antigens, contend with bulk disease in which penetration may be limited, and choose the optimal clinical settings for their use, such as the minimal residual disease state or in combination with conventional chemotherapy. CONCLUSION: Although significant research is still needed, MoAb-based therapies promise to offer new options for the treatment of patients with hematologic malignancies.

Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin's lymphoma.

Immunotoxins, composed of a monoclonal antibody conjugated to a protein toxin, mediate cell death through novel cytotoxic mechanisms. Anti-B4-blocked ricin (anti-B4-bR) recognizes CD19-positive cells, which includes most B-cell non-Hodgkin's lymphomas (NHLs). Previous Phase I clinical studies of anti-B4-bR, using both bolus and continuous dosing regimens, demonstrated no safety or efficacy advantage to the continuous infusion regimen. This Phase II trial in 16 patients with relapsed CD19-positive NHL was conducted to evaluate the efficacy of anti-B4-bR when administered at the previously established maximum tolerated dose using a daily bolus for a 5 consecutive days schedule. Serum pharmacokinetics were measured in selected patients. Tissue samples of involved lymph nodes and bone marrow were also obtained from a portion of patients for determination of anti-B4-bR penetration into tissues. Toxicity was similar to what has been described previously for anti-B4-bR and consisted mainly of reversible elevations of hepatic transaminases and mild to moderate thrombocytopenia. No sustained clinical responses were documented. Pharmacokinetic measurements demonstrated that serum levels compatible with 3 logs of cell kill in vitro could be sustained for several hours in most patients. Immunohistochemical analysis of tissue samples provided some insight into the low efficacy. The immunotoxin could be detected in three of the four bone marrow aspirate samples but in only two of the seven lymph node specimens. Thus, anti-B4-bR, using a single daily bolus for a 5 consecutive day schedule, is not an active agent in relapsed NHL. Poor penetration into certain sites of disease may be one explanation for its lack of efficacy.