Oncologist. The. ASCO 2001: Critical Commentaries. Hematologic Malignancies. MAGDALENA PETRYK, a MICHAEL L. GROSSBARD a, b ABSTRACT

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1 The Oncologist ASCO 2001: Critical Commentaries Hematologic Malignancies MAGDALENA PETRYK, a MICHAEL L. GROSSBARD a, b Sean P. Murphy a St. Luke s-roosevelt Hospital Center; b Beth Israel Medical Center, New York, New York, USA Key Words. Monoclonal antibody Radioimmunoconjugate Rituximab Tositumomab and 131I tositumomab Ibritumomab tiuxetan ABSTRACT Over the past several years, targeted therapies in hematologic malignancies have progressed rapidly from the laboratory to the bedside. At the 2001 annual meeting of the American Society of Clinical Oncology (ASCO), excitement abounded about the further application of targeted therapies to the treatment of solid tumors. Meanwhile, the 2001 ASCO meeting brought modest, incremental gains in our knowledge of hematologic malignancies and their therapies. While no major new therapeutic modalities were introduced at this meeting, critical abstracts further explore the use of radioimmunoconjugates (RICs) and other monoclonal antibody (mab)-based approaches. Several abstracts concentrated on the search for new therapeutic targets. Importantly, there were also studies exploring strategies for improvement in supportive care and quality of life for patients with 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. The Oncologist 2001;6: LYMPHOMA Response to Zevalin is Superior to Response to Rituximab Regardless of Age and Extent of Disease. TE Witzig, CA White, L Gordon, F Cabanillas, C Emmanoulides, MS Czuczman, R Joyce, B Pohlman, N Bartlett, P Multani, AJ Grillo-Lopez, GA Wiseman (ABSTRACT 1115). Rituximab is a chimeric murine-human anti-cd20 mab, approved by the Food and Drug Administration (FDA) for the treatment of relapsed CD20-positive non- Hodgkin s lymphoma (NHL). Zevalin is an RIC comprised of ibritumomab, the parent murine antibody counterpart to rituximab, and yttrium 90 ( 90 Y). Zevalin is capable of delivering targeted radiation to CD20-positive tumors. In phase I/II studies in relapsed/refractory NHL, Zevalin achieved a Correspondence: Michael L. Grossbard, M.D., St. Luke s-roosevelt Hospital Center, 425 West 9th St., Suite 1A, New York, New York 10019, USA. Telephone: ; Fax: ; mgrossbard@slrhc.org Received June 18, 2001; accepted for publication July 9, AlphaMed Press /2001/$5.00/0 The Oncologist 2001;6:

2 Petryk, Grossbard % response rate (26% complete response [CR]), with an 82% response rate in patients with indolent lymphoma [1]. In the present trial, 143 patients with relapsed/refractory CD20-positive low-grade follicular or transformed B- cell NHL were randomized to Zevalin or rituximab therapy. Patients could not have received prior rituximab, radioimmunotherapy (RIT), or stem cell transplant. More than 50% of patients were resistant to their last chemotherapy, 45% had bulky disease (over 5 cm), and one-third had bone marrow involvement. Patients on the Zevalin arm received rituximab 250 mg/m 2 on day 0 and day 7 followed on day 7 by 0.3 or 0.4 mci/kg 90 Y Zevalin (depending on the platelet count). Control arm patients received rituximab at a standard dose of 375 mg/m 2 weekly times four doses. Overall response rate and CR rate were significantly better in the Zevalin arm compared to the rituximab arm (80% versus 56% and 30% versus 16%, respectively). Median time to progression (TTP) was not reached at months in the Zevalin arm and months in the rituximab arm (Table 1). The duration of CR and time to the next therapy were longer in the Zevalin arm, although the difference was not statistically significant. As expected, the hematologic toxicity of Zevalin was more severe than that of rituximab: 6% of patients had grade 4 thrombocytopenia, 32% experienced grade 4 neutropenia, and 8% were hospitalized for infection. The Zevalin Radioimmunotherapy (RIT) Regimen is Active in Heavily Pretreated, Bulky, Rituximab Refractory NHL. IW Flinn, TE Witzig, CA White, L Gordon, C Emmanoulides, LD Cripe, M Saleh, MS Czuczman, S Spies, DH Silverman, RW Burt (ABSTRACT 1141). Fifty-seven patients with relapsed NHL, rituximabrefractory (no response or TTP less than 6 months) were treated with Zevalin. The median age of patients was 54 years, and the histology predominantly follicular (95%). Patients could not have had prior myeloablative therapy or RIT, external beam radiation to more than 25% active bone marrow, or 25% bone marrow involvement with Table 1. Zevalin versus rituximab in relapsed/refractory low-grade non-hodgkin s lymphoma Zevalin Rituximab p value (n = 73) (n = 70) RR 80% 56% p = CR 30% 16% p significant TTP months months Abbreviation: RR = response rate lymphoma. The majority of the patients (82%) were resistant to chemotherapy and had bulky disease ( 5 cm in 74% patients). Zevalin was administered in an outpatient setting at a dose 0.4 mci/kg. The overall response rate was 74% and CR 15% for follicular lymphoma patients. Median duration of response was significantly longer for Zevalin than for prior rituximab (8.4+ months versus 4 months, p = 0.008). The response to Zevalin was better in patients who responded to prior rituximab (TTP < 6 months) than rituximab nonresponders (77% versus 51%, respectively). Among patients who responded to their last chemotherapy, 65% responded to Zevalin as compared with a response rate of 47% among patients resistant to their last chemotherapy regimen. Half of the patients with bulky disease larger than 10 cm responded to Zevalin. The toxicity of Zevalin was mainly hematologic with a 35% incidence of grade 4 neutropenia and a 9% incidence of grade 4 thrombocytopenia. One patient developed human antimouse antibody (HAMA), and one patient was diagnosed with acute myelogenous leukemia (AML) 8 months after treatment. Retreatment with Tositumomab and Iodine I-131 Tositumomab (Bexxar ) for Patients with Low-Grade or Transformed Low-Grade Non-Hodgkin Lymphoma (NHL). M Kaminski, J Estes, D Regan, M Tuck, K Zasadny, P Kison, S Kroll, R Stagg, RL Wahl (ABSTRACT 1139). Bexxar is a conjugate of a murine anti-cd20 antibody (tositumomab) and 131 I. A response rate of 57% (CR 32%) has been reported in the treatment of relapsed/refractory lowgrade or transformed NHL [2]. Due to the reversibility of myelosuppression, the low radiation dose to normal organs, and the infrequent development of HAMA, it is appealing to consider using Bexxar for retreatment in patients who relapse after initial response to this conjugate. In this study, 18 patients with low-grade or transformed low-grade NHL who progressed after responding to Bexxar therapy were retreated with Bexxar. All patients had a PR or CR lasting at least 3 months after initial Bexxar treatment. Patients were required to have adequate marrow function, less than 25% bone marrow involvement with lymphoma and HAMA negativity. The median time from initial Bexxar therapy to retreatment was 20 months. Dosing was based on individual patient dosimetry. Twelve of 18 (67%) patients responded, and 6 patients (33%) achieved CR. The median duration of response was 10.6 months, not statistically different from the median 13 months response following the initial Bexxar treatment. Three patients had a longer duration of response following retreatment, and two of them have ongoing responses of 20 and 48 months. Patients who achieved a CR to initial Bexxar treatment benefited most from retreatment.

3 319 Hematologic Malignancies Hematologic toxicity with Bexxar retreatment was similar to that seen with initial therapy. Three patients developed myelodysplasia 4.5 to 6.1 years after retreatment with Bexxar. None of the patients converted to HAMA positivity. Both Bexxar and Zevalin should soon receive FDA approval for the treatment of relapsed and refractory lowgrade NHL. They are both conjugates of murine anti-cd20 mabs to a radioisotope 131 I (Bexxar) or 90 Y (Zevalin). Their major antilymphoma effect derives from the delivery of targeted radiation to CD20-positive tumors and the induction of lethal damage to CD20-positive as well as nearby CD20-negative tumor cells ( bystander effect ). There are several differences between these two RICs. Although both 131 I and 90 Y are β-emitters, 90 Y has higher β energy, a longer path length, and a shorter half-life. Because 90 Y is not a γ-emitter, imaging or dosimetry with Zevalin requires the use of an indium-111 ( 111 In) conjugate. There are differences in dosing, administration, safety requirements (particular to radioactive iodine), and cost (Table 2). Bexxar and Zevalin have not been compared directly, and it remains to be determined which RIC is best for each of the many possible indications. Clinical studies described in the above Table 2. Comparison of the most widely studied RICs abstracts add to the growing evidence of significant efficacy of RIT in various clinical scenarios. In abstract 1115, the randomized comparison of Zevalin and rituximab provides evidence that RICs can achieve higher response rates as compared with an unconjugated antibody. Data regarding the durability of response and survival are not mature yet, although the trend favors the Zevalin arm in TTP and time to next therapy for follicular lymphoma patients. In the absence of evidence of curative potential and survival impact for either Zevalin or Bexxar, one should be careful in choosing RIT early in the course of treatment in low-grade NHL patients. Late effects of RIT, including long-term stem cell toxicity, are still largely unknown. Among 211 patients treated with Zevalin in four phase I/II/III clinical trials, four patients developed myelodysplasia or AML (although all were also pretreated with chemotherapy) [3]. Dr. Witzig, providing updated information, noted at his oral abstract presentation that among 300 patients treated with Zevalin, five patients developed myelodysplastic syndrome (MDS). The safety profile of rituximab suggests that it should be considered prior to administration of RIT in the treatment of relapsed indolent NHL patients. Bexxar Zevalin Generic name Tositumomab/iodine 131 I tositumomab 90 Y ibritumomab tiuxetan, IDEC-Y2B8 mab Murine IgG2a anti-cd20 (tositumomab) Murine IgG1-kappa anti-cd20 (IDEC-2B8; ibritumomab) Radioisotope 131 I 90 Y Energy emitter Beta (0.6 MeV) Beta (2.3 MeV) Gamma (0.36 MeV) Path length χ 90 * 0.7 mm 5.2 mm Half-Life 192 hours 64 hours Urinary excretion Extensive/variable 46%-90% in 2 days Minimal 7% in 7 days Dosimetry Gamma emission by 131 I allows for external imaging Gamma-emitting nuclide ( 111 In) required as a surrogate for imaging Dosing Tracer dose and dosimetry used to customize dose Based on weight and platelet count Treatment schema Day 0: dosimetric dose (450 mg tositumomab followed Day 0: 250 mg/m 2 rituximab by 35 mg tositumomab with 5 mci 131 I ) Day 7: 250 mg/m 2 rituximab followed by 0.4 mci/kg IDEC-Y2B8 Whole body counts 3 Day 7: therapeutic dose (450 mg tositumomab followed by 35 mg tositumomab with mci dose of 131 I to deliver 75 cgy total body dose) Administration Inpatient or restrictions to protect family/environment Outpatient Cost 131 I inexpensive and routinely available 90 Y more expensive Nontarget tissue Rapidly cleared from nontarget tissues. Retained in nontarget organs (eg, liver) [30] distribution Uptake in thyroid gland; SSKI administration prior to 90 Y localizes to bone [31, 32] treatment required for thyroprotection. *χ 90 is the distance within which 90% of the energy is deposited within the radius. Abbreviation: SSKI = saturated solution of potassium iodide

4 Petryk, Grossbard 320 Previous trials have shown that RIT can be administered safely after prior treatment with unconjugated antibodies [4]. Data presented in abstract 1141 provide evidence for significant activity of RIT in rituximab-refractory patients and further support the concept of withholding RIT until after unconjugated antibodies have failed in the palliative treatment of low-grade NHL. When tumors become resistant to rituximab, they usually retain expression of the CD20 antigen, allowing effective delivery of targeted radiation by anti-cd20-based RICs. Abstract 1139 addresses the question of feasibility of retreatment with RIT. The natural history of low-grade NHL is characterized by remissions and relapses after each subsequent treatment. Therapy that can be delivered repeatedly during subsequent relapses is a valuable tool in our armamentarium for the treatment of low-grade NHL. Nevertheless, long-term follow-up data will be required to assess delayed stem cell toxicity from such repetitive therapy. Individualized Patient Dosing Prevents Underdosing and Overdosing of Patients with Non-Hodgkin s Lymphoma (NHL). A Zelenetz, R Wahl, M Kaminski, J Vose, S Kroll, J Leonard (ABSTRACT 1145). Substantial patient-to-patient variability in the rate of Bexxar clearance has been observed, largely due to differences in spleen size, tumor mass, and degree of bone marrow involvement. A Patient Optimized dosing method has been developed to overcome the varieties in individual patient pharmacokinetics and to assure delivery of the prescribed total body radiation (TBI) dose. Patients receive dosimetric doses of Bexxar 7 to 14 days prior to the single therapeutic dose. TBI counts are obtained at three time points, and the total body clearance of radioactive antibody is determined. The calculated dose is adjusted for obesity and thrombocytopenia. This study is a retrospective analysis of dosimetrybased dosing as compared with a fixed dosing regimen (mci/kg). The target TBI was 75 cgy, and the median mci/kg to deliver that TBI was approximately 1.1 mci/kg. Thus, in a fixed dosing method, all patients should receive 1.1 mci/kg. Six hundred thirty-four patients treated with Bexxar in several clinical studies were included in the analysis. If the fixed mci/kg dosing was used, more than half the patients would have received a dose at least 10% above or below the optimal TBI dose of 75 cgy, and 6% would have been overdosed by at least 25%. In addition, 10% of patients would have been underdosed. Pharmacokinetics of the anti-cd20 radiolabeled antibodies depend on a number of patient-specific and disease-specific factors. Because these lead to high variability in the half-life of the drug, dosimetry may be important to ensure the delivery of a prescribed dose of RIT. However, dosimetry has significant practical shortcomings in that it is cumbersome and adds additional costs to therapy. A fixed dosing regimen is clearly not as accurate but still might result in an acceptable safety and efficacy profile. The experience with Zevalin, another anti-cd20 RIC, indicates that dosimetry can be omitted safely in the majority of patients [5]. Because the 90 Y isotope used in Zevalin is a pure β-emitter, dosimetry with that agent requires the preparation of an alternative RIC between CD20 and 111 In to permit γ-camera imaging. The present clinical development of Bexxar and Zevalin requires dosimetry-based dosing for Bexxar, but accepts fixed dosing (mci/kg) for Zevalin without major differences in their toxicity or efficacy profile. Prospective clinical studies are needed to assess which dosing approach is clinically relevant and should be accepted by practicing physicians. While the present abstract argues that 20% of patients would be either underdosed or overdosed with fixed dosing, this may not be much different than the accuracy of dosing that is already tolerated with chemotherapy administered on the basis of calculated body surface area. High-Dose I-131-Anti CD20 Antibody Therapy (Tositumomab), Etoposide, Cyclophosphamide, and Autologous Stem Cell Transplantation for Patients with Relapsed or Refractory Mantle Cell Lymphoma. AK Gopal, S Petersdorf, D Maloney, J Eary, B Wood, J Rajendran, S Bush, L Durack, T Gooley, P Martin, D Matthews, F Appelbaum, I Bernstein, OW Press (ABSTRACT 1118). Mantle cell lymphoma (MCL) is an incurable malignancy with a median survival of approximately 3 years. CHOP chemotherapy can induce complete remissions in less than 40% of patients and has a median progression-free survival of less than 2 years [6]. Conventional high-dose chemotherapy with autologous stem cell support at relapse rarely results in durable remissions, with studies reporting a 2-4 year diseasefree survival of 30% [7]. Since anti-cd20 RIT can deliver radiation doses 10 times higher to tumor cells than to normal tissue and MCL is a radiosensitive tumor that strongly expresses CD20, there is a rationale in using RIT in an attempt to improve outcome in MCL. Sixteen patients with relapsed or refractory MCL were treated with high-dose chemo-rit using 131 I tositumomab, etoposide, cyclophosphamide, and autologous stem cell transplantation (ASCT). All patients were heavily pretreated (median, three prior regimens) with almost half of the patients resistant to their most recent regimen. The trial excluded patients older than 60 years, those with prior

5 321 Hematologic Malignancies radiation therapy >20 Gy, central nervous system involvement, >500 cc tumor bulk and splenomegaly. Toxicities were comparable to those with standard transplant regimens. There was no treatment-related mortality. Of the 11 patients with evaluable disease at the time of transplant, 8 achieved a CR (73%) at 1 month post-transplant. With a median follow-up of 14 months, all 16 patients are alive, and 12 patients (75%) remain progression free. The estimated 2-year progressionfree survival is 60%. Five of 10 patients with bone marrow involvement assessed by polymerase chain reaction (PCR) analysis for t(11;14), a translocation seen in MCL, converted to PCR negativity 1 month post-treatment. The treatment of mantle cell NHL remains uniquely frustrating when compared with therapy for other histologies of NHL. Results obtained with high-dose 131 I-tositumomab, VP-16, cyclophosphamide, and ASCT in relapsed MCL patients are promising. However, this is a select group of young patients with relatively lower tumor burdens and the absence of splenomegaly (which frequently accompanies MCL). Longer follow-up is needed to assess the durability of responses given the short median follow-up of 14 months. Similarly encouraging data have come with early follow-up of MCL patients receiving high-dose therapy and autologous stem cell infusion, only to see the disease-free survival decline with longer observation periods. Although molecular CR seems to be a prerequisite for cure, PCR negativity in bone marrow may not be a reliable marker for eradication of minimal residual disease (MRD). In a trial of rituximab and CHOP for newly diagnosed MCL patients, PCR negativity did not correlate with overall response to therapy or progression-free survival [8]. Effective induction regimens still are needed to achieve durable complete remissions along with PCR negativity in the bone marrow in the absence of high-dose therapy. Recent experience with the hyper-cvad regimen is encouraging but again derives from the treatment of a relatively limited number of patients [9]. CHRONIC LYMPHOCYTIC LEUKEMIA Rituximab Added to Fludarabine Improves Response in Previously Untreated Chronic Lymphocytic Leukemia: Preliminary Results from CALGB JC Byrd, B Peterson, K Park, V Morrison, JW Vardiman, RJ Jacobson, K Rai, RA Larson (ABSTRACT 1116). Rituximab has shown modest single-agent activity in previously treated chronic lymphocytic leukemia (CLL) patients with response rates of 36%-44% [10, 11]. To investigate potential synergy between rituximab and chemotherapy, the Cancer and Leukemia Group B (CALGB) conducted a randomized phase II trial of fludarabine and rituximab in the primary therapy of CLL. One hundred four patients with untreated CLL were randomized between two treatment programs. In the concurrent group, 51 patients received fludarabine 25 mg/m 2 days 1-5 every month 6 with rituximab 375 mg/m 2 on days 1 and 4 of cycle 1 and day 1 of cycles 2-6. In the sequential group, 53 patients received fludarabine 25 mg/m 2 days 1-5 every month 6 followed 2 months later by rituximab 375 mg/m 2 every week 4. Nine of 44 patients in the concurrent therapy arm developed grade 3/4 dyspnea and hypotension during their first rituximab infusion. Seven subsequent patients received stepped-up rituximab dosing in their first cycles (with more gradual escalation to the full dose), and no further grade 3/4 infusional toxicity was observed. Patients in the concurrent arm had significantly more hematologic toxicity, but the rate of infections was similar in both groups. Response data are presented in Table 3. After a median follow-up of 20 months, the median progression-free survival has not been reached. Current efforts in the therapy for CLL concentrate on improving the rate and quality of CR as a prerequisite for long-term survival and potential cure. Unfortunately, none of the present trials produce compelling evidence that improved CR rates can improve survival. A large, multicenter, randomized trial conducted by the CALGB compared fludarabine with chlorambucil in the primary treatment of CLL. Patients treated with fludarabine had a significantly improved CR rate (20% versus 4%), overall response rate (63% versus 37%), duration of response (25 months versus 14 months) and progression-free survival (20 months versus 14 months). Nevertheless, fludarabine therapy did not Table 3. Phase II randomized study of concurrent versus sequential fludarabine (Flu) and rituximab (Ritux) Treatment n of patients CR (%) PR (%) OR (%) Flu+Ritux (Concurrent) (47%) 22 (43%) 46 (90%) Flu then Ritux (28%) 26 (49%) 41 (77%) Abbreviation: OR = overall response

6 Petryk, Grossbard 322 prolong overall survival, which is unsurprising given the crossover design of the study [12]. In the current report, the addition of an mab to fludarabine in the primary treatment of CLL yielded an impressive CR rate. Although they may seem similar, the two study arms explored two different concepts of combining cytotoxic and biologic therapy. The sequential fludarabine then rituximab arm uses rituximab consolidation in the setting of reduced tumor burden after prior cytotoxic therapy. The concurrent fludarabine + rituxan approach explores potential synergism between those two agents. In vitro studies have shown that rituximab can sensitize lymphoma cells to cytotoxic and apoptotic effects of therapeutic drugs including fludarabine [13-15]. Clinical experience in NHL patients also seems to suggest that synergism [16-18]. In addition, single institution data from M.D. Anderson Cancer Center have reported extraordinary activity for a regimen of fludarabine, cyclophosphamide, and rituxan in patients with CLL [19]. Whether such deeper remissions will translate into improved survival remain unclear. Long-term follow-up will be critical to assess the full clinical value of the regimen described in this trial as well as that of similar therapies. HAIRY CELL LEUKEMIA High Complete Remission Rate Without Minimal Residual Disease in Purine Analog-Resistant Hairy Cell Leukemia Induced by the Anti-CD22 Recombinant Immunotoxin BL22. RJ Kreitman, WH Wilson, M Stetler- Stevenson, L Sorbara, DJ FitzGerald, I Pastan (ABSTRACT 1119). BL22 immunotoxin (RFB4[dsFv]-PE38) consists of the Fv portion of the anti-cd22 mab RFB4 fused to a truncated Pseudomonas exotoxin. The abstract reports the results of a phase I trial of BL22 in 16 patients with CdA-resistant hairy cell leukemia (HCL). The maximal tolerated dose (MTD) was established at 40 µg/kg/d 3. Common toxicities included mild hypoalbuminemia and transient transaminase elevations. The dose-limiting toxicity was reversible renal failure, and two patients had hemolytic uremic syndrome (HUS) documented by renal biopsy. BL22 demonstrated significant activity in this phase I study. Overall, 81% of patients (13/16) responded with 11 CRs, and two partial responses. In six patients, CR was achieved with a single cycle of BL22. After CR was documented, up to two cycles of BL22 were given for consolidation. The only three patients who failed to achieve major responses received low doses of immunotoxin or had pre-existing toxin neutralizing antibodies. All three patients with poor prognosis HCL-variant (HCLv) responded. Pancytopenia resolved in all responders, and splenomegaly improved within a week of starting treatment. At 12-months follow-up, three patients relapsed, and all achieved CR again with additional BL22 treatment. MRD was detected by flow cytometry in the peripheral blood of 1/11 CR patients and in bone marrow aspirates of 7/11 CR patients. HCL is an uncommon B-cell lymphoproliferative disorder, affecting middle-aged men and characterized by splenomegaly, pancytopenia, and infiltration of bone marrow by lymphocytes with hairy-like projections. It is uniquely sensitive to purine analogues. Both 2 -deoxycoformycin (2 -DCF) and 2-chlorodeoxyadenosine (2-CdA) induce durable complete remissions in the overwhelming majority of treated patients [20-23]. Those patients who fail to respond to or relapse after 2-CdA can be treated with interferon or splenectomy, but less toxic therapy would be appealing. The current abstract provides compelling evidence of impressive clinical activity of the recombinant immunotoxin BL22 in HCL including CdA-resistant and poor prognosis HCLv patients. In addition to a high response rate, a significant proportion of patients had no detectable MRD. Experience with purine analogue-treatment of HCL has shown that 13%-50% of patients in apparent CR have evidence of MRD, and its presence is associated with increased risk of relapse [24-26]. Longer follow-up is needed to determine whether the eradication of MRD with BL22 will translate into durable remissions and prolonged survival in resistant HCL. As HCL is a rare disease, the results of the present abstract directly apply to a limited group of patients. It will be interesting to see whether BL22 can be utilized in the treatment of other CD22-expressing neoplasms. The unconjugated anti-cd22 mab epratuzumab has shown promising results in refractory/relapsed B-cell lymphoma [27]. The immunotoxin BL22 demonstrates in vitro activity against a variety of CD22-positive B-cell malignancies including acute lymphocytic leukemias, CLLs, large-cell lymphomas, MCLs, and follicular lymphomas [28]. Clinical testing of BL22 in a spectrum of hematologic malignancies is clearly warranted. MULTIPLE MYELOMA 166holmium-DOTMP Plus Standard High Dose Chemotherapy (HDC) with Autologous Transplant Produce High Rates of Complete Remission (CR) in Multiple Myeloma (MM) Patients: an Updated Report of a Phase I/II Study. B Besinger, S Giralt, J Eary, K Thoelke, JK Bryan, P Williams, L Holmberg, R Alexanian, M Goodman, A Serafini, D Podoloff, R Champlin, L Ishak, D Sackner-Moreland (ABSTRACT 18).

7 323 Hematologic Malignancies 166holmium-DOTMP (166Ho-DOTMP) is a highenergy, β-emitting, phosphonate chelate that localizes to bone and produces aplasia in the marrow. Eighty-three patients with multiple myeloma (MM) were treated with melphalan, escalated doses of 166Ho-DOMPT, and autologous stem cell support. All patients received at least two prior chemotherapy regimens, and none had chemotherapyrefractory disease. The dose of 166Ho-DOTMP for each individual patient was calculated by dosimetry to deliver a target radiation dose to bone marrow. Forty-three percent (32/75) of patients achieved a CR. With a median followup of 12 months, the projected 18-month survival is 75%. Nonhematologic toxicity was mainly related to the presence of radioactive urine in the bladder. Grades 1-3 hemorrhagic cystitis occurred in 24 patients but did not occur in patients who had continuous bladder irrigation (CBI). Seven patients developed HUS (fatal in four patients) at a median of 6-7 months post-treatment. A non-marrow dose of radiation in excess of 1,000 mci/m 2 was associated with increased risk for HUS. The investigators concluded that with CBI, 166Ho-DOTMP doses targeting up to 40 Gy to the marrow can be safely administered, and a high CR rate is achieved. MM is another hematologic malignancy with a high intrinsic rate of tumor cell resistance. Although long-term remissions can be achieved after single or tandem courses of high-dose therapy followed by autologous stem cell infusion, most patients ultimately will develop progression of their disease. A significant proportion of patients who survive the acute toxicity of allogeneic bone marrow transplantation also will eventually relapse. Thus, standard high-dose chemotherapy cannot eradicate MRD in the bone marrow of MM patients. Since myeloma cells are radiosensitive, targeting a radiation dose to the bone marrow several-fold higher than the dose achieved with conventional external beam total body irradiation (TBI) dose may improve the outcome for patients. The high CR rate achieved with 166Ho-DOTMP is promising, but this comes at the cost of serious toxicity. Although dose related, the high frequency of HUS may limit the ultimate use of this therapy. In order to limit serious adverse late effects of exposing the marrow to high doses of radiation, the minimal effective dose, rather than MTD, should be established. NEW THERAPEUTIC TARGETS Phase I Study of Hu1D10 Monoclonal Antibody in Patients with B-cell Lymphoma. BK Link, H Wang, JC Byrd, JP Leonard, TA Davis, I Flinn, WC Hall, JF Turner, D Levitt, GJ Weiner (ABSTRACT 1135). Hu1D10 is a humanized mab directed against a polymorphic determinant (1D10 antigen) on the HLA-DR β chain expressed on normal and malignant B cells. The 1D10 antigen is present in 60% of NHL tissue biopsies. Hu1D10 is capable of mediating antibody-dependent-cellular cytotoxicity, complementing mediated lysis, and inducing apoptosis. In a phase I study, 20 patients with relapsed/refractory 1D10+ NHL were treated with Hu1D10. The antibody was given as 4 weekly intravenous infusions (cohort A) or 5 daily infusions (cohort B). In cohort A, infusion-related events were common, but mild and reversible. In contrast, the daily infusion regimen was tolerated poorly with dose-limiting hypotension, nausea/vomiting, rash, and fatigue. Among the 18 evaluable patients, there were 4 responses and 8 patients with stable disease. All responders had follicular lymphoma, and response rate in this subtype of patients was 50% (4/8). All responses are ongoing with the duration of response between 90 and 548 days. Responses always occurred beyond day 100, which is a longer time than usually observed after treatment with other antibodies. Antilymphoma antibodies were detected in responding patients, and in one patient, those antibodies persisted long after clearance of Hu1D10. The development of rituximab and its striking efficacy in patients with a number of different lymphoma subtypes regenerated interest in the field of mab-based therapy. Over the past 3 years, hundreds of abstracts presented at the ASCO meeting have detailed the development of antibody-based therapies, almost all directed at the CD20 antigen. Last year, exciting evidence emerged about the efficacy of an anti-cd22 antibody (epratuzumab) in patients with B-cell NHL, including some who failed to respond to rituximab [27, 29]. Hu1D10 is yet another antibody with efficacy in NHL. The unusual pattern of delayed and durable responses and presence of antilymphoma antibodies long after clearance of Hu1D10 suggest an alternative mechanism of action with possible induction of an active antilymphoma humoral response. A weekly dosing schedule at dose levels 2 and 3 (0.5 and 1.5 mg/kg) is being further evaluated in a recently opened phase II multicenter, randomized, open-label trial for grades 1-3 follicular NHL patients. Now that we might have multiple antibodies with different targets on B cells, it is intriguing to postulate that cocktails of antibodies might exert synergistic cytotoxicity and enhance response rates. This concept is being explored in clinical trials.

8 Petryk, Grossbard 324 A Phase II Study with SU5416 in Patients with c-kit Positive AML. WM Fiedler, H Tinnefeld, T Mende, U Gehling, G Vohwinkel, S Kelsey, P Scigalla, DK Hossfeld (ABSTRACT 1148). Vascular endothelial growth factor (VEGF) is secreted by AML blasts in the majority of AML patients. Increased microvessel density has been observed in the bone marrow of AML patients. c-kit is a receptor tyrosine kinase structurally similar to the VEGF receptor. VEGF-R and c-kit are expressed by leukemic blasts and involved in antiapoptotic or proliferation pathways. SU5416 is a small molecule inhibitor of phosphorylation of VEGF-R and c-kit. In preclinical studies, SU5416 was capable of inducing apoptosis and inhibiting proliferation in human myeloid leukemia cell lines. This phase II study enrolled 32 patients with refractory c-kit positive AML. Patients received SU mg/m 2 intravenously twice weekly for 4 weeks. Treatment generally was well tolerated. Three patients experienced severe bone pain during treatment. There was one fatal case of acute hepatic failure with gastric hemorrhage and septic shock. Other serious adverse events potentially related to treatment included one case of grade 4 pancreatitis (recurrent on rechallenge) and one case of grade 3 polyneuropathy. Among 19 evaluable patients, one patient achieved morphological response and seven patients had transient (1-5 months) reduction of blasts in the peripheral blood and bone marrow by 50%. SU5416 has biological activity in refractory AML. Numerous groups now have demonstrated that neovascularity is increased in the bone marrow of patients with AML, and that the expression of VEGF is increased on blasts from AML. However, whether this has any role in the progression of AML, or merely represents a reactive process, remains unknown. Clinical trials using antiangiogenic agents are just beginning to assess this relationship. Indeed, another anti-vegf directed therapy, bevacizumab (a recombinant humanized antibody directed against VEGF) is currently being evaluated in a phase II study by the Southwest Oncology Group for treatment of relapsed, aggressive NHL. This abstract is intriguing because of the biological activity of this agent, which was observed in a significant number of patients. With the present generation of antiangiogenic agents, it will be surprising to see major responses in most patients with established tumors. However, the demonstration of clinical activity should lead to their use in more appropriate adjuvant or minimal disease settings after safety has been established. SUPPORTIVE CARE Efficacy of Recombinant Human Keratinocyte Growth Factor (rhukgf) in Reducing Mucositis in Patients with Hematologic Malignancies Undergoing Autologous Peripheral Blood Progenitor Cell Transplantation (auto- PBPCT) After Radiation-Based Conditioning. Results of a Phase II Trial. RT Spielberg, P Stiff, C Emmanouilides, S Yanovich, W Bensinger, E Hedrick, S Noga, T Ziegler, A Keating, S Frankel, T Gentile, R Heard, B Yao, D Elhardt (ABSTRACT 25). Transplant conditioning regimens with TBI and high-dose chemotherapy induce severe grade 3 and 4 mucositis in over 80% of patients. This double-blind, placebo-controlled study enrolled 129 patients undergoing TBI and high-dose chemotherapy with etoposide/cyclophosphamide and an ASCT for various hematological malignancies. Patients were randomized to receive placebo or recombinant human keratinocyte growth factor (KGF) 60 µg/kg/day intravenously for 3 days before TBI and/or 3 days after ASCT. KGF significantly reduced the duration of severe oral mucositis (Table 4). A quality-of-life assessment revealed reduced mouth and throat pain, improved swallowing, drinking, eating, talking, and sleeping in patients receiving KGF. Patients receiving KGF also required less intravenous opioid analgesics and total parenteral nutrition. KGF was well tolerated with transient adverse events of mild/moderate skin and oral erythema and edema. Severe mucositis is a uniform and extremely debilitating complication of many high-dose therapy regimens. The development of grade 3 and 4 mucositis increases infection rates, impairs nutrition and predicts for greater complications Table 4. Effect of recombinant human keratinocyte growth factor on duration of severe mucositis KGF administration Median duration of grade 3/4 mucositis p value (versus placebo) Pre-TBI & post-asct 4 days Pre-TBI 5 days 0.04 Placebo 7.7 days

9 325 Hematologic Malignancies from high-dose therapy. KGF administration produced a nearly 50% reduction in the duration of severe mucositis. In addition to an improvement in quality of life, it can potentially decrease incidence of infections, help to maintain adequate nutritional status and prevent deconditioning of transplant patients. As more attention is paid to supportive care for cancer patients, the development of mucositis also remains a limiting factor in other diseases not treated with high-dose therapy. Most notably, patients receiving radiation therapy for the treatment of head and neck cancer are at high risk of developing this debilitating complication, particularly when radiation is delivered twice daily or in association with radiation sensitizers. While the use of amifostine and ice chips may ameliorate this toxicity, there is an urgent need to assess other agents. 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