Unconjugated Antibodies
Unaltered antibodies have been used since the earliest trials of monoclonal antibody therapy in humans.
140, 141 and 142 In early trials, success was limited by the absence of suitable tumor cell surface targets, antigenicity of first-generation (murine) mAbs in humans, modulation of the target structure from the tumor cell surface, and poor recruitment of immune effector mechanisms.
143,144 However, enthusiasm for this approach was rekindled by the enormous success of genetically engineered, chimeric, or fully humanized versions of mAbs, most notably rituximab for lymphoid malignancies and trastuzumab in solid tumors.
144
Rituximab is a chimeric monoclonal antibody with humanized framework and Fc regions. It is directed against the CD20, pan B cell antigen. CD20 is present on pre-B cells and mature B cells, but not on precursor cells or terminally differentiated plasma cells. The function of CD20 remains poorly understood,
145 although it has been implicated in B cell activation, regulation of B cell growth, and regulation of transmembrane calcium flux. The antibody fixes human complement and elicits antibody-dependent cellular cytotoxicity (ADCC). Rituximab was approved for use as monotherapy in patients with low-grade or follicular CD20
+ non-Hodgkin lymphoma (NHL) in 1997. In the pivotal trial involving 166 patients, reported by McLaughlin et al.,
146 patients had relapsed or chemotherapy-resistant disease. Patients received four weekly infusions of rituximab at 375 mg/m
2. Rituximab produced a tumor response in one-half of the patients, with a median duration of response of 11.8 months, comparable to the patients’ response duration on the last chemotherapy treatment. Human antichimeric antibody responses were uncommon. The most common adverse experience associated with rituximab was a constellation of acute infusion-related events, including chills, fever, headache, rhinitis, pruritus, vasodilation, asthenia, and angioedema. This syndrome can progress to hypotension, urticaria, bronchospasm, and, rarely, death. The risk is particularly great in patients with high circulating white cell counts.
147 Other toxicities were, in general, mild and infrequent.
148 Neutropenia and thrombocytopenia were unusual. Circulating B cells were depleted and remained low until recovery at a median of 12 months. Immunoglobulin levels, however, remained normal. No increased incidence of infections was seen. Rituximab was evaluated again in the relapsed, refractory, low-grade, or follicular NHL patient population, using eight weekly infusions rather than four.
149 This extended regimen produced a response rate of 57% and a time to progression (TTP) in responding patients of more than 19.4 months. Adverse event reporting was commensurate with the longer treatment period.
Davis et al.
150 reported a response rate of 43% and a TTP of 8.1 months in the patients with a significant poor prognostic factor, importantly in patients with low-grade or follicular NHL who had bulky disease, using the standard 4-infusion regimen. These investigators also showed an overall response rate (ORR) of 40% in patients who had progressed after an initial response to rituximab, with an estimated median TTP for responding patients of 17.8 months.
151
Rituximab has been used in the first-line treatment of patients with indolent lymphoma, both as monotherapy and in combination with chemotherapy. Hainsworth
150 reported the results of rituximab as monotherapy in 39 previously untreated patients. Patients received rituximab × 4 at the usual dose and schedule, with an ORR of 54%. Patients who had responded or who had stable disease were treated with an additional four weekly treatments of rituximab at 6 months intervals to a maximum of 4 treatment cycles. The ORR rose to 72% after the second course of treatment. Progression-free survival (PFS) at 1 year was 77%. The addition of rituximab to cyclophosphamide, hydroxyldaunomycin, oncovin (vincristine), and prednisone (CHOP) chemotherapy produced impressive results. Patients were treated with six infusions of rituximab, one associated with each of six cycles of CHOP. In 40 patients with newly diagnosed (
n = 31) or relapsed/refractory (
n = 9) low-grade or follicular NHL, rituximab plus CHOP produced an ORR of 95% and complete response (CR) rate of 55%. With a median follow-up of 29 months, median duration of response and median TTP had not been reached. Eight of 18 patients tested for the
BCL-2 [t(14;18)] translocation by PCR testing were positive at initiation of therapy. Seven of these 8 patients, after therapy, became negative for the translocation. The authors concluded that the addition of rituximab to CHOP produced benefits in efficacy parameters without significant additional toxicity. Elimination of PCR positivity for the t(14;18) translocation had not been previously reported with CHOP alone.
Rituximab also has been used with success in patients with more aggressive lymphomas. Vose et al.
151 reported the results of rituximab plus CHOP chemotherapy (again using 6 infusions of rituximab in association with 6 cycles of CHOP) in 33 previously untreated patients with advanced aggressive B cell NHL. The combination produced an ORR of 94% and a CR rate of 61%. With a median observation time of 26 months, 29 of 31 patients achieving a remission were in continuing remission at the time of the report. Thirteen patients were BCL-2 positive at study entry. Eleven of these 13 patients became BCL-2 negative after treatment, and 10 of the 11 remained BCL-2 negative. The authors concluded that the results were achieved without significant added toxicities above those expected with CHOP. The Groupe d’Etude des Lymphomes de l’Adulte undertook a study to compare the utility of CHOP with that of rituximab plus CHOP in elderly patients with diffuse B cell lymphoma.
152 Patients between the ages of 60 and 80 years with untreated, diffuse large B cell lymphoma were eligible for the study. Patients were randomly assigned to receive 8 cycles of CHOP chemotherapy (197 patients) or to receive 8 cycles of CHOP, each given after an infusion of rituximab (202 patients). Rituximab plus CHOP produced a superior rate of remission, 76% versus 63% (
P = 0.005). With
a median follow-up of 2 years, event-free and overall survivals (OSs) were significantly higher in the rituximab plus CHOP group (
P < 0.001 and
P = 0.007, respectively). These results were achieved without a significant incremental increase in toxicity. The addition of rituximab to CHOP reduced the risk of treatment failure (risk ratio, 0.54; 95% confidence interval [CI]: 0.44, 0.77) and the risk of death (risk ratio, 0.64; CI: 0.45, 0.89). The addition of immunotherapy to standard chemotherapy had accomplished what 25 years of chemotherapy manipulation had failed to do (i.e., improve on the results of CHOP chemotherapy).
153,154 Maintenance rituximab has also been found to prolong event-free survival (EFS) and response duration in follicular lymphoma.
155 In subsequent ongoing randomized phase III studies,
156,157 rituximab maintenance regimen provided significant PFS and OS at 3-year
156 and 4-year
157 follow-up assessments in both previously treated
156 and untreated
157 patients with follicular NHL, compared with no further treatment, though no difference in OS has been reported by other investigators.
158
The mechanism by which rituximab produces these impressive results is less clear. A number of possible mechanisms have been considered: initiation of complement-mediated cell lysis, induction of ADCC, and signaling via CD20 leading to programmed cell death and/or sensitization to cytotoxic drugs. Pretreatment lymphoma cells from 29 patients were examined by flow cytometry for expression of complement inhibitors CD46, CD55, and CD59.
159 Expression of these cell surface inhibitors of complement activation was not predictive of outcome to rituximab therapy. Considerable evidence suggests that induction of ADCC plays an important role in rituximab’s antilymphoma effects. A rituximab-like antibody for which an IgG4
γ framework was substituted for the IgG1 framework of rituximab was incapable of producing B cell depletion in primates.
160 Rituximab was relatively ineffective in eliminating Raji B cell implants in FcR
γ-/-/nu/nu knockout mice compared to nu/nu mice.
161 These mice lack the activating receptor for Fc portions of antibodies, a critical component of the antibody-dependent cell-mediated cytotoxicity mechanism. In patients, response to rituximab has been shown to be associated with homozygosity for the high-affinity allotype of the Fc
γRIIIa receptor.
162 Evidence also exists that rituximab signaling or interference with normal signaling via CD20 may directly induce apoptosis or sensitize cells to the deleterious effects of chemotherapeutic agents.
163 A direct, growth inhibitory effect of rituximab, with accompanying apoptosis, on cell lines cultured in the absence of complement was demonstrated.
164 Anti-CD20-associated apoptosis has been associated with upregulation of the proapoptotic protein, Bax
165 and downregulation of antiapoptotic protein BCL-2 through inactivation of STAT3.
166 Downregulation of STAT3 appears to be a result of downregulation of an IL-10 autocrine pathway.
167 These changes and/or others may be responsible for increased sensitivity to chemotherapeutic agents.
168
In the wake of the success of rituximab, a number of other antilymphoma mAbs have entered the clinic.
169 Alemtuzumab is a humanized IgG1
κ monoclonal antibody directed against the CD52 cell surface antigen.
144 CD52 is expressed on normal and malignant lymphocytes of B- and T cell lineage, as well as NK cells, monocytes, and macrophages. Alemtuzumab is indicated for the treatment of B cell chronic lymphocytic leukemia (CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. The pivotal clinical trial was carried out in 93 patients with fludarabine-refractory CLL .
170 Alemtuzumab produced a response rate of 33%. Virtually all of the responders were partial responders; the CR rate was 2%. Median duration of response was 7 months. Median TTP was 4.7 months for the group as a whole; 9.5 months for responders. The most common adverse events were infusion related—most were grade 1 or 2 in severity, including rigors in 90% of patients (grade 3 in 14%), fever in 85% of patients (grade 3 or 4 in 20%), nausea in 53% of patients, and vomiting in 38% of patients. Infusion-associated side effects declined with subsequent infusions. During the study, 28% of patients experienced dyspnea, 17% experienced hypotension, and 3% experienced hypoxia. Overall, 55% of patients developed an infection during the study. Approximately one-half of these infections were considered serious (grade 3 or 4). Septicemia occurred in 15% of patients, and two deaths resulted. Opportunistic infections occurred in 12% of patients. Ten percent of patients died during or within 30 days of treatment—one-third of these were attributed to progressive disease. Twenty-four percent of patients discontinued treatment because of a drug-related side effect. Most patients who discontinued had not responded to therapy. Serious infusion-related events associated with alemtuzumab appear to result from ligation of CD16 on NK cells resulting in what has been termed
cytokine storm—release of IL-6, TNF-
α, and interferon
γ.
171 Prolonged immunosuppression after use of alemtuzumab can result in opportunistic infections.
172 Treatment schemas now include the routine use of prophylaxis with both antibiotics and antivirals.
To improve on the immunogenicity and efficacy of rituximab, the last few years have seen the development of new generations of anti-CD20 monoclonal antibodies (mAbs) with enhanced antitumor activity resulting from increased complement-dependent cytotoxicity (CDC) and/or ADCC and increased Fc binding affinity for the low-affinity variants of the Fc
γRIIIa receptor (CD16) on immune effector cells. These second-generation mAbs, such as ofatumumab, veltuzumab, and ocrelizumab, are in clinical development. They are humanized or fully human to reduce immunogenicity, but with an unmodified Fc region. Ofatumumab is a fully human anti-CD20 IgG1 mAb in clinical development for hematologic malignancies and autoimmune diseases. Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of the CD20 molecule, and is more effective than rituximab at CDC induction and killing target cells. Veltuzumab (IMMU-106, hA20) is a humanized anti-CD20 mAb with complementarity-determining regions similar to rituximab. This antibody has enhanced binding avidities and a stronger effect on CDC compared to rituximab. Ocrelizumab is a humanized mAb with the potential for enhanced efficacy in lymphoid malignancies compared to rituximab because of increased binding affinity for the low-affinity variants of the Fc
γRIIIa receptor. Third-generation mAbs are also in clinical development. They are also humanized mAbs, but in addition they have an engineered Fc to increase their binding affinity for the Fc
γRIIIa receptor. Third-generation mAbs also in clinical development include AME-133v, PRO131921, and GA-101 (
Table 70.2), with enhanced affinity for the Fc
γRIIIa receptor and an enhanced ADCC activity compared to rituximab.
173
Two other mAbs with potential utility in the treatment of lymphoma are in early clinical development.
169,174 Epratuzumab is a humanized IgG1 monoclonal antibody directed against the CD22 antigen. CD22 is a pan-B cell antigen with distribution similar to that of CD20. Epratuzumab has a favorable safety profile in early trials. Approximately 50% of follicular lymphoma patients and 25% of diffuse large-cell lymphoma patients responded in a small phase II trial. Some of the responses have been long-lived. A recent phase II trial testing the safety and efficacy of combining epratuzumab with R-CHOP (ER-CHOP) in untreated DLBCL showed that the addition to standard R-CHOP, E 360 mg/m
2 intravenously, administered for 6 cycles in 107 patients, showed similar toxicity to standard R-CHOP. ORR in the 81 eligible patients was 96% (74% CR/CR unconfirmed [Cru]) by computed tomography scan and 88% by positron emission tomography. By intention to treat analysis, at a median follow-up of 43 months, the EFS and OS at 3 years in all 107 patients were 70% and 80%, respectively. Comparison with a cohort of 215 patients who were treated with R-CHOP showed improved EFS in the ER-CHOP
patients. ER-CHOP was well tolerated and results appear promising as a combination therapy.
175
Apolizumab is a humanized IgG1 monoclonal antibody that binds to a variant of the HLA-DR
β-chain. The antibody induces complement-mediated lysis, ADCC, and tyrosine phosphorylation signaling events in cell lines in vitro. The antibody binds to approximately 70% of lymphoma specimens. Administration of the antibody to patients results in typical infusion-related side effects. Four of 8 patients with follicular lymphoma responded to apolizumab. A phase I/II dose-escalation study of thrice-weekly apolizumab (1.5, 3.0, 5.0 mg/kg/dose) for 4 weeks in relapsed CLL resulted in significant toxicity and lack of efficacy; thus, further clinical trials of apolizumab were discontinued, as were other trials in lymphoma and solid tumors.
176 Milatuzumab (hLL1, IMMU-115; Immunomedics) is a fully humanized mAb specific for CD74, a cell surface-expressed epitope of the HLA class II-associated invariant chain. CD74 plays an important role as an accessory signaling molecule and survival receptor in the maturation and proliferation of B cells by activating the PI3K/Akt and the NF-
κB pathways.
177 Milatuzumab demonstrated antiproliferative activity in transformed B cell lines, improved survival in preclinical models, and is presently being evaluated for the treatment of several hematologic malignancies.
Inroads are being made in other hematologic cancers. In multiple myeloma, it was recently reported that the cell surface glycoprotein CS1 (CD2 subset 1, CRACC, SLAMF7, CD319) was highly and universally expressed on myeloma cells while having restricted expression in normal tissues. Preclinical studies showed that elotuzumab (formerly known as HuLuc63), a humanized mAb targeting CS1, could induce patient-derived myeloma cell killing within the bone marrow microenvironment using a SCID-hu mouse model and that the CS1 gene and cell surface protein expression persisted on myeloma patient-derived plasma cells collected after bortezomib administration. In vitro bortezomib pretreatment of myeloma targets significantly enhanced elotuzumab-mediated ADCC, both for OPM2 myeloma cells using NK cells or peripheral blood mononuclear cells from healthy donors and for primary myeloma cells using autologous NK effector cells. In an OPM2 myeloma xenograft model, elotuzumab in combination with bortezomib exhibited significantly enhanced in vivo antitumor activity. Elotuzumab is currently in a phase I clinical trial in relapsed/refractory myeloma.
178 In AML, one strategy for the development of mAbs targeting human AML stem cells involves first identifying cell surface antigens preferentially expressed on AML LSC (leukemia stem cell) compared with normal hematopoietic stem cells. In recent years, a number of such antigens have been identified, including CD123, CD44, CLL-1, CD96, CD47, CD32, and CD25. Moreover, mAbs targeting CD44, CD123, and CD47 have demonstrated efficacy against AML LSC in xenotransplantation models. Hopefully, these antibodies will ultimately prove to be effective in the treatment of human AML.
179
Radioimmunotherapy
The use of immunoglobulin-radionuclide conjugates in cancer treatment represents appropriation of a classic guided-missile strategy. In theory, the antibody homes to its antigenic target and delivers a cytotoxic assault on the cell to which it attaches. Radionuclides offer certain advantages over other cytotoxic agents. They do not have to be internalized. Radioactive particles can deliver their effects over distances of 1 to 5 mm, thus limiting collateral damage to normal tissues while still potentially providing antitumor effects against antigen-negative variants in the vicinity in what has been termed a
cross-fire effect. The principles of radiation physics underlying radioimmunotherapy (RIT) have been reviewed by Press and Rasey.
192 Radiolabeled antibodies deliver continuous, exponentially decreasing, low-dose-rate radiation. Traditional external beam radiotherapy delivers intermittent, fractionated radiation at higher dose rates. The most commonly used isotopes for RIT have been iodine 131 (I-131) and yttrium 90 (Y-90). These radionuclides kill cells primarily through emission of
β particles, resulting in DNA strand breaks. The
β particles of Y-90 are more energetic than those of I-131. They affect cells in a radius of approximately 5 mm compared to approximately 1 mm for those of I-131. I-131 also emits
γ rays. This allows direct imaging of the distribution of the radioconjugate but raises issues regarding shielding and health care worker and family member safety.
Several recent reviews attest to the evolution of this field.
193,194 A number of theoretical and experimentally generated concerns with RIT appear to have been overcome in the successful clinical studies described below. There had been concern that effective delivery of radioimmunoconjugates would be impeded by heterogeneous tumor vasculature, slow diffusion of these large molecules in interstitial spaces, heterogeneous biodistribution in tumor nodules, and high intratumoral pressures.
The two products in clinical use presently, Y-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar), are both directed against the anti-CD20 antigen of B lymphocytes, the same structure targeted by rituximab. Both products are based on murine mAbs. Both are administered after infusion of unconjugated anti-CD20 antibodies—rituximab in the case of Zevalin and tositumomab in the case of Bexxar. Both have used nuclear medicine imaging as a preparatory step to administration, but it is no longer required for Y-90 ibritumomab. Simple dosimetry is accomplished for I-131 tositumomab by capturing whole-body gamma counts after infusion of a 5 mCi “dosimetric dose” of the agent. Imaging was carried out in Y-90 ibritumomab tiuxetan-treated patients to assure normal biodistribution. Whole-body dosimetry is carried out in I-131 tositumomab-treated patients to allow calculation of a patient-specific activity (mCi) to deliver a desired total-body dose of radiation (cGy). Both have been studied most extensively in indolent lymphoma and have been approved for treatment of patients with relapsed or refractory follicular, including rituximab refractory, or transformed B (CD20+) NHL.
The approval for ibritumomab tiuxetan rested primarily on two clinical studies. The first was a randomized controlled comparison of the effectiveness of Y-90 ibritumomab tiuxetan to that of rituximab in patients with relapsed or refractory, follicular, or transformed B cell NHL.
195 The study involved 143 patients; 73 randomized to Y-90 ibritumomab tiuxetan (single administration), and 70 randomized to rituximab (weekly × 4). The median number of prior therapies was 2. Approximately one-half of the patients failed to respond to or had a TTP of less than 6 months to their last chemotherapy regimen. Y-90 ibritumomab tiuxetan produced a statistically superior response rate (using the response definitions of the International Workshop), 80% versus 56% (
P = 0.002). The number of durable responders at 6 months favored Y-90 ibritumomab tiuxetan-treated patients, but the significance of the observation was lost at 9 months and 12 months. Median TTP (estimated by Kaplan-Meier methods) was 11.2 months for patients treated with Y-90 ibritumomab tiuxetan and 10.1 months for patients treated with rituximab (
P = 0.173). Grade 3 and 4 nonhematologic adverse events were unusual in both groups. Y-90 ibritumomab tiuxetan produced grade 3 or 4 neutropenia in 57% of patients, grade 3 or 4 thrombocytopenia in 60% of patients, and grade 3 or 4 anemia in 2% of patients. One patient in the Y-90 ibritumomab tiuxetan-treated group developed myelodysplasia. One patient in the rituximab-treated group developed pancreatic carcinoma. The second trial was a phase II experience in 57 patients who had failed to respond to rituximab or had a TTP of ≤6 months.
196 These patients had a median of 4 prior therapies, and 74% had bulky tumors (greatest diameter ≥ 5 cm). In this patient population, Y-90 ibritumomab tiuxetan produced a response rate of 74% and CR rate of 15%. The median TTP was estimated at 6.8 months. Grade 4 neutropenia occurred in 35% of patients, grade 4 thrombocytopenia in 9% of patients, and grade 4 anemia in 4% of patients.
The pivotal study for I-131 tositumomab enrolled 60 patients with refractory or transformed low-grade NHL who had been treated with at least two different qualifying chemotherapy regimens.
197 Patients must also have failed to achieve an objective response or relapsed within 6 months after completion of their last qualifying chemotherapy (LQC) regimen. Median age was 60 years, and other poor prognostic features included: median of 4 prior therapies, bulky disease, bone marrow involvement, elevated serum lactate dehydrogenase, advanced stage, and transformation from an initial low-grade histology to a higher-grade histology in 38% of the patients. A statistically significant improvement in the primary endpoint was achieved, with a longer duration of response (>30 days) after I-131 tositumomab therapy (
n = 26) compared to patients after their LQC (
n = 5;
P < 0.001). Improvements in secondary efficacy endpoints after I-131 tositumomab compared to those after LQC were also achieved: overall response (47% vs. 12%;
P < 0.001), duration of response (11.7 vs. 4.1 months;
P < 0.001), and CR (22% vs. 2%;
P = 0.002). Fifteen of 60 patients (25%) were classified as long-term responders (patients with a MIRROR Panel-assessed TTP of a year or more). Nine (15%) of the 60 patients remained in CR, with TTP ranging from 41+ to 57+ months.
A second trial examined the incremental benefit of the radioconjugate (I-131 tositumomab) compared to the nonradioactive antibody (tositumomab).
198 This study was a randomized, twoarm, open-label, multicenter study that enrolled patients with chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL. Patients were randomized to receive either I-131 tositumomab therapy or unlabeled tositumomab alone. The primary endpoint was a comparison of the rates of CR. Secondary endpoints included ORR, duration of responses, and TTP. A total of 78 patients (18% with transformation) participated in the study. Patients had been previously treated with one to three chemotherapy regimens. One or more therapies must have included an anthracycline, anthracenedione, or alkylating agent. A significant difference was observed for the primary efficacy endpoint. The CR rate was 33% (14 of 42 patients) for the patients treated with I-131 tositumomab compared to 8% (3 of 36) for patients treated with unlabeled tositumomab (
P = 0.012). In addition, the ORR was greater after treatment with I-131 tositumomab: 23 of 42 patients (55%) compared to 7 of 36 patients (19%;
P = 0.002). Nineteen patients initially treated with the unlabeled antibody crossed over to receive I-131 tositumomab after disease progression. A CR then was observed in 42% (8 of 19 patients) and an ORR in 68% (13 of 19 patients) in the crossover patient population. A total of 20 patients (33%) from the I-131 tositumomab-treated populations, including patients in the crossover arm, were classified as having a long-term response, including ten patients continuing in CR, with TTP ranging from 23+ to 59+ months.
The efficacy of I-131 tositumomab was also evaluated in patients who had progressed after rituximab.
199,200 Patients must have had prior treatment with at least four doses of rituximab without an objective response, or to have progressed during or after treatment. Twenty-four patients did not respond to their last treatment with rituximab, and, of the 16 patients who did respond to rituximab, five patients had a duration of response exceeding 6 months. A response occurred in 27 of 40 patients (68%), with a median duration of response of 14.7 months (95% CI; 10.6 months no response). A CR occurred in 12 of 40 patients (30%); the median duration of CR had not been reached (95% CI; 11 months no response). Twenty-four patients had a longer (at least 30 days) duration of response after I-131 tositumomab than after rituximab; 5 patients had a longer duration of response after rituximab than after I-131 tositumomab; 9 patients had equivalent durations of response; and 2 patients were censored (
P < 0.001). A total of 14 patients (35%) had a TTP of 12 months or longer. The median PFS was 10.4 months (95% CI, 5.7 to 8.6) for all patients and 24.5 months for confirmed responders (95% CI, 16.8 to not reached [NR]). PFS for 15 confirmed CR patients was NR with an estimated 3 years PFS of 73%. Prior response to rituximab did not significantly affect the confirmed OR rate, duration of response, or median PFS.
Radioiodinated tositumomab and Y-90 ibritumomab tiuxetan have also been used at myeloablative doses, with stem cell rescue in patients with relapsed B cell lymphomas.
201,202,203,204 Radioiodinated tositumomab was used initially as a single agent.
202 Twenty-five patients were imaged after a tracer dose of radioiodinated tositumomab. Twenty-two of these 25 patients achieved favorable biodistributions (i.e., had tumor doses in excess of doses to normal organs). These 21 patients received therapeutic infusions of radioiodinated tositumomab (345 to 785 mCi) followed by reinfusion of autologous hematopoietic stem cells. All patients achieved bone marrow engraftment (19 with bone marrow stem cells, two with peripheral blood stem cells). However, two patients died before full neutrophil recovery; one of sepsis, one of progressive lymphoma. Nonhematologic toxicities included nausea in most patients, mild mucositis in five patients, and partial alopecia in four patients. One patient experienced reversible cardiomyopathy and interstitial pneumonitis. Eighteen patients responded to this therapy; 16 patients experienced a CR. With a median follow-up of 2 years, 2 years PFS was estimated at 62%, with OS estimated at 93%. Press et al. then combined radioiodinated tositumomab with chemotherapy and autologous stem cell transfusion in a series of patients with relapsed B cell lymphomas.
203 Fifty-two patients received the planned therapy. Patients were again given tracer doses of radioiodinated tositumomab and underwent sequential gamma camera imaging. Absorbed doses of radiation to tumor sites and normal organs were determined. Thereafter, patients received a therapeutic infusion of radioiodinated tositumomab calculated to deliver between 20 and 27 Gy to normal organs (e.g., liver, kidneys, and lungs). Patients then received etoposide, 60 mg/kg, and cyclophosphamide, 100 mg/kg, followed by reinfusion of autologous hematopoietic stem cells. The maximal tolerated dose of radioiodinated tositumomab to be combined with chemotherapy was determined to be that dose that delivered 25 Gy to normal organs. Eight patients experienced 13 grade 3 or 4 toxic events. These included 3 patients with acute respiratory distress syndrome, 3 patients with severe mucositis or gastrointestinal toxicity, 1 patient with venoocclusive disease, and 4 patients with fatal infections. At 2 years, the Kaplan-Meier estimates of OS and PFS for all treated patients were 83% and 68%, respectively. These findings were considered superior to results previously observed in patients who had undergone conventional external beam total-body radiation with etoposide/cyclophosphamide preparation for transplantation in the same institution. Thirty-one patients with CD20
+ NHL were treated with high-dose Y-90 ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide and were followed by autologous hematopoietic cell transplantation (HCT).
204 Treatment also was well tolerated; there were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2 years estimated OS rates are 92% and 78%, respectively. Retreatment with tositumomab and I-131 tositumomab, has also been found possible in patients with progressive disease after treatment with I-131 tositumomab, who were able to receive subsequent therapy, including cytotoxic chemotherapy and stem cell transplantation.
205 In patients with prior response, I-131 tositumomab can produce second responses that can be durable.
206
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