Oncologist. The. ASCO 2000: Critical Commentaries. Hematologic Malignancies: Selected Abstracts and Commentary MICHAEL L.

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1 The Oncologist ASCO 2000: Critical Commentaries Hematologic Malignancies: Selected Abstracts and MICHAEL L. GROSSBARD Division of Hematology/Oncology, St. Luke s-roosevelt Hospital Center, New York, New York, USA Key Words. Hematologic malignancies Positron emission tomography non-hodgkin s lymphoma Follicular lymphoma I-131 tositumomab ABSTRACT 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 LYMPHOMA Iodine I 131 Tositumomab Therapy for Previously Untreated Follicular Lymphoma (FL). MS Kaminski, J Estes, M Tuck, J Mann, S Fisher, P Kison, D Regan, R Stagg, S Kroll, DE Agnuson, RL Wahl (ABSTRACT 11). Interim Results from a Prospective Randomized Controlled Trial Comparing Zevalin Radioimmunotherapy to Rituximab Immunotherapy for B-cell non- Hodgkin s Lymphoma (NHL): Resistance to Prior Chemotherapy Versus Response Rate. TE Witzig, BR Leigh, LI Gordon, JL Murray, GA Wiseman, MS Czuczman, BL Pohlman, AJ Grillo-Lopez, CA White (ABSTRACT 105). : Abstract 11 In this phase II clinical trial, 76 patients with previously untreated advanced stage follicular lymphoma received 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. The Oncologist 2000;5: therapy with I-131 tositumomab. This agent represents a conjugate of an anti-cd20 antibody and I-131 in an effort to deliver targeted radiation therapy to patients with B-NHL. All patients were required to have CD20 +, the antigen targeted by the B1 antibody (tositumomab). In addition, all patients had less than 25% bone marrow involvement to prevent undue myelosuppression after therapy. Seventy-five percent of patients had stage IV disease. Patients were given a dosimetric dose of unconjugated antibody followed by a therapeutic dose of the conjugate. At a median follow-up of 16.2 months, responses occurred in 97% of patients. Fifty-eight patients achieved a complete remission (CR) and 16 patients achieved a partial remission. The three-year progression-free survival was 57%. Polymerase chain reaction (PCR) analysis was used to determine the presence of cells containing t(14;18) which is seen in more than 70% of cases of follicular lymphoma. Thirty-four of the 37 patients who were PCR-positive in the bone marrow at baseline Correspondence: Michael L. Grossbard, M.D., Division of Hematology/Oncology, St. Luke s-roosevelt Hospital Center, 425 West 59th Street, Suite 1A, New York, New York 10019, USA. Telephone: ; Fax: ; mgrossbard@slrhc.org Received June 29, 2000; accepted for publication June 29, AlphaMed Press /2000/$5.00/0 The Oncologist 2000;5:

2 Grossbard 281 converted to PCR negativity. The toxicity of the therapy was tolerable with cytopenias representing the major side effect. Sixty-two percent of patients developed human anti-mouse antibodies (HAMA) post-therapy. : Abstract 105 Zevalin is a conjugate between the anti-cd20 antibody Y2B8 and the isotope Y90. Previous studies have demonstrated that Zevalin can deliver targeted toxicity to patients with B-cell lymphoma. In this prospective, randomized trial, 143 patients with relapsed or refractory, low-grade, follicular, or transformed CD20 + B-cell NHL were randomized to receive therapy with either Rituximab or Zevalin. Those patients receiving therapy with Zevalin received an initial treatment of Rituximab 250 mg/m 2 on day 0 followed by indium-labeled Zevalin for imaging and dosimetry. On day 7, patients received Rituximab 250 mg/m 2 followed by 0.4 mci/kg 90Y-Zevalin for therapy. Patients randomized to the Rituximab arm of the trial received a standard dose of 375 mg/m 2 weekly for four weeks. In the first 90 patients, the overall response rate was 80% for those patients receiving Zevalin (n = 44) and 44% for those patients receiving Rituximab (n = 46). The response rate to Zevalin was 77% for those patients considered refractory to chemotherapy and 81% for patients who were considered chemotherapy-sensitive. I-131 tositumomab soon should receive FDA approval for the treatment of relapsed and refractory follicular NHL. Previous reports have demonstrated the efficacy of this therapy in patients with relapsed disease, with an overall response rate of 81% (a few patients having had previously untreated disease), and a median duration of response of 11 months [1]. The median duration of CR was 57 months. Likewise, Zevalin moves in the direction of FDA approval based on the high response rates observed in this and other trials. The optimal therapy for patients with newly diagnosed follicular lymphoma remains unknown. Despite the fact that high response rates can be achieved with purine analogbased regimens and with high-dose therapy, these treatment approaches have not had a significant impact on overall survival for patients. Thus, therapy with chlorambucil alone or combination therapy with cyclophosphamide, vincristine, and prednisone remains the therapy of choice for many oncologists. The results achieved by Kaminski and colleagues are remarkable not only for the high overall response rates and high CR rates with a single-agent therapy, but also because 57% of patients remain in remission at three years post-therapy. In addition, the high rate of conversion to PCR-negativity for cells containing the bcl-2 translocation has not been achieved with any other single-agent therapy. Nevertheless, the high rate of HAMA formation is disturbing in that this may limit the delivery of other monoclonal antibody-based therapies to these patients in the future. Moreover, we really do not know the long-term toxicity of delivering radioactive iodine or yttrium to the bone marrow of patients with a long natural history of disease, as is the case for patients with newly diagnosed follicular lymphoma who may survive for 8 to 10 years. Whether early radioimmunoconjugate therapy will affect stem cell function over the long-term is a critical issue. In the randomized comparison of Zevalin and Rituximab, further evidence regarding the superior response rates of radioimmunoconjugates compared with unconjugated antibody therapy is provided. Data regarding the durability of these responses are not yet available, but the near doubling of response rates is similar to the result achieved with I-131 tositumomab. The last several years of clinical trials have demonstrated that monoclonal antibody therapy is a practical, safe, and active treatment for NHL [2]. At this time, there are intriguing data to suggest that therapy with antibodies may provide long-term remissions, but there is no evidence that this is a curative approach to management. As such, the use of Rituximab or a radioimmunoconjugate as first-line therapy for follicular lymphoma is undefined, and such treatment should not be offered outside of the clinical trial setting. In addition, the safety profile of Rituximab suggests that this agent should be considered as a therapy prior to the administration of a radioimmunoconjugate, especially in the absence of evidence that either Zevalin or I-131 tositumomab therapy impacts survival. Ongoing clinical trials will define the most appropriate sequencing of these agents. Their introduction to the clinical armamentarium certainly alters the options for treatment of follicular lymphoma. Comparative Evaluation of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and Gallium-67 (GA-67) SPECT in Staging of Patients with Lymphoma. L Kostakoglu, JP Leonard, M Coleman, S Vallabhajosula, T Spangler, SJ Goldsmith (Abstract 31). Can F-18 FDG-PET Replace GA-67 Scanning for Staging Hodgkin s Disease (HD) and non-hodgkin s Lymphoma (NHL)? A Wirth, JF Seymour, R Ware, M Wolf, M Prince, H Januszewicz, G Ryan, MP Macmanus, A Hogg, RJ Hicks (Abstract 32). : Abstract 31 This study evaluated the ability of fluorodeoxyglucose positron emission tomography (FDG-PET) and GA-67

3 282 Hematologic Malignancies SPECT to identify disease sites in patients with NHL and Hodgkin s disease (HD) at the time of diagnosis and/or at relapse. The scans were performed in 45 patients with NHL and 13 patients with HD, and disease sites were correlated on a site-by-site basis. Clinical evaluation and computerized tomography (CT) scans were used to classify discordant disease sites. FDG-PET detected 248 disease sites in 58 patients compared to 169 disease sites in 47 patients with gallium scans. Gallium scans failed to detect some disease sites present at all lymph node regions throughout the body. All PET scan findings were confirmed by CT. Three patients were upstaged by FDG-PET. : Abstract 32 This study compared the sensitivity and clinical impact of PET and gallium scans in the staging of HD and NHL. Sixty-two evaluable patients had PET scans at diagnosis (35 patients) or at first progression of disease (24 patients); 43 patients had concurrent gallium scans. Of patients with clinically evident disease, PET scans were positive in 45/47 (96%) and gallium scans were positive in 29/32 (91%). PET scans identified 22 additional disease sites compared to gallium. Twelve of the sites were confirmed as true positives. At diagnosis, two of 32 patients were upstaged by PET scans and two of 23 patients were upstaged by gallium scans. Treatment was altered by PET in three patients and by gallium in two patients. PET scans now are approved in the US for the staging of NHL. As described in the abstracts presented at the 2000 ASCO meeting, PET scans appear more sensitive than gallium scans in the detection of NHL and HD. However, because the gold standard of measurement remains the CT scan, it is not clear that all sites of disease detected on either PET scan or gallium scan represent true active disease sites. In fact, in the second abstract, only 12 of the additional 22 disease sites that were detected could be confirmed as true positives. Thus, there is need for caution before major therapy changes are made based on PET scan findings. Although the authors of both abstracts suggest that therapy was altered for patients based on the detection of additional disease sites, it is impossible to know whether such change in therapy was a correct decision or whether it had any impact on patient outcome. Perhaps the greatest utility of PET scans (or gallium scans) is in the detection of residual viable tumor following therapy and distinguishing this from a post-therapy fibrotic mass. If a positive PET scan post-therapy truly correlates with the risk of recurrence, this could have a profound impact on patient management. In another abstract presented at this meeting, Spaepen et al. described the prognostic value of PET scans following first-line chemotherapy for patients with NHL [3]. They examined 96 patients who underwent a PET scan after completion of first-line chemotherapy for their disease and had a follow-up of at least one year. Of 69 patients who had a normal PET scan after therapy, 55 remained in CR. Persistent abnormal uptake on PET scan was seen in 27 patients following therapy and all of these patients relapsed. In 14 of these patients, no other scans suggested residual disease. Thus, PET scan did have a significant impact on management for these patients. Again, it is impossible to discern whether the long-term outcome for these patients would have been identical if their disease had been detected later by conventional staging tests. The abstracts presented at ASCO provide convincing evidence that PET scans provide superb imaging for all disease sites in patients with NHL and HD, and that the scans may be superior to PET scans for imaging of lymphoid malignancies. The next critical step will be to prospectively evaluate the predictive value of these scans within the context of well-designed clinical trials where patients receive uniform therapy and outcome can be correlated with PET scan findings. ACUTE AND CHRONIC LEUKEMIA Activity of an ABL Specific Tyrosine Kinase Inhibitor in Patients with BCR-ABL Positive Acute Leukemias, Including Chronic Myelogenous Leukemia in Blast Crisis. M Talpaz, CL Sawyers, H Kantarjain, D Resta, S Fernandes Rees, J Ford, BJ Druker (ABSTRACT 6). STI 571 is a rationally designed inhibitor of abl tyrosine kinase. This constitutively activated protein is present in nearly all patients with chronic myelogenous leukemia (CML) in blast crisis and in approximately 20% of patients with acute lymphoblastic leukemia (ALL). Patients with CML in blast crisis, Philadelphia chromosome-positive ALL, or Philadelphia chromosome-positive acute myelogenous leukemia (AML) were treated with STI 571 at doses of 300 mg to 800 mg per day. At the time of this report, 51 patients had been treated and 48 were evaluable. In 33 patients with myeloid blast crisis, 9 CRs and 15 partial remissions were obtained, with responses occurring at all dose levels. In 15 patients with lymphoid blast crisis, nine achieved CR and two achieved partial remission, with one patient achieving a complete cytogenetic remission. While seven of the patients with myeloid blast crisis remained in CR, only one patient with lymphoid blast crisis remained in remission. The side effects of therapy included nausea, vomiting, and periorbital edema.

4 Grossbard 283 One patient developed thrombocytopenia and one patient developed exfoliative dermatitis, but it is not clear whether the side effects were drug-related. After more than a decade of intensive investigation, advances in our understanding of the molecular basis of cancer are now being translated from the laboratory to the clinic. The development of STI 571 is the first such success story. At the most recent meeting of the American Society of Hematology in 1999, Druker and colleagues presented data on the use of STI 571 for the treatment of 54 patients with CML [4]. Complete hematologic remissions were obtained in 23 of 24 patients who were treated for at least four weeks at doses of 300 mg or greater; major cytogenetic responses also were observed. There were no major side effects other than myelosuppression. The present study explores the use of this agent in blast crisis of CML and provides convincing evidence that the leukemic clone in bcr-abl positive acute leukemias remains at least partially dependent on activity of the kinase for cell proliferation. Also intriguing is the fact that lymphoid blast crisis seems less sensitive to STI 571 than myeloid blast crisis. The mechanisms of resistance to STI 571 are poorly understood. A recent publication indicates that resistant cells may have amplification of the BCR/ABL transgene, with subsequent increases in the level of BCR/ABL protein [5]. Altered drug metabolism and transport also could mediate resistance. While studies continue to define the maximum tolerated dose of this agent and the optimal dose for therapy, future studies will examine how this agent should best be combined with chemotherapy and used in maintenance therapy. The mere fact that this agent has clinically significant biological activity heralds a revolutionary change in our approach to cancer treatment. Comparison of the Efficacy and Safety of Gemtuzumab Ozogamicin (CMA-676) in Patients <60 and >60 Years of Age with AML in First Relapse. EL Sievers, RA Larson, E Estey, EA Stadtmauer, C Karanes, R Spielberger, MS Berger, C Eten, A Stone, M Munteanu, I Bernstein, F Appelbaum (ABSTRACT 23). CMA-676 is a targeted therapy which combines the specificity of a humanized anti-cd33 antibody and the potent cytotoxicity of calicheamycin. The agent was designed to effectively target cytotoxicity to AML cells. CMA-676 was administered to 104 patients with AML in first relapse at a dose of 9 mg/m 2 i.v. every two weeks for two doses. Thirty-two patients (31%) achieved a remission, characterized by <5% blasts in the bone marrow, 1,500 neutrophils, and platelet transfusion independence. Remission was obtained in 34% of patients under age 60 and 28% of patients over age 60. The durability of the responses is difficult to assess since several patients went on to receive additional consolidative therapy including high-dose therapy. Adverse events included fevers, chills, occasional hypotension, and grade IV neutropenia and thrombocytopenia. Importantly, adverse events were not increased in patients over age 60. The incidence of AML increases with age. Unfortunately, patients over age 60 are less able to withstand the toxicity of induction and consolidation chemotherapy. High-dose cytosine arabinoside (Ara-C) is an important component of AML therapy, yet the incidence of cerebellar toxicity increases for patients over age 60. CMA-676 represents a targeted therapy directed at AML cells. As this study demonstrates, substantial adverse effects occur even with this targeted therapy. However, the high rate of remission with only two courses of therapy for patients with relapsed AML is impressive. Most importantly, this therapy appears to be equally well-tolerated by older and younger patients. CMA-676 appears to be one of the more active singleagent therapies for the treatment of relapsed AML. Clinical studies may demonstrate that this represents an appropriate palliative therapy for older patients with AML. The data presented fail to mention any therapy-related deaths, which is remarkable in a multicenter trial in patients with AML. The sequencing of this agent with conventional therapy and its role in marrow purging for autologous bone marrow transplant candidates remain to be explored. HODGKIN S DISEASE Dose Escalation of BEACOPP Chemotherapy for Advanced Hodgkin s Disease in the HD9 Trial of the German Hodgkin s Lymphoma Study Group (GHSG). V Diehl, J Franklin, H Tesch, M Loeffler, D Hasenclever, M Pfreundschuh, H Mueller-Hermelink, R Hermann, J Wolf, C Longin, M Haenel, P Koch (ABSTRACT 7). Patients with unfavorable clinical stage IIB/IIIA and IIIB/IV HD were randomized to receive standard-dose BEACOPP (405 patients), dose-escalated BEACOPP (403 patients), or COPP/ABVD (262 patients). Initial sites of bulky disease and residual disease after chemotherapy were irradiated. The results of the study are presented in Table 1.

5 284 Hematologic Malignancies Table 1. Results of GHSG HD9 trial 3-yr failure-free survival 3-yr overall survival n cases leukemia/mds BEACOPP 79% 90% 1 Escalated BEACOPP 88% 91% 7 COPP/ABVD 0 Hematologic toxicity was significant in the escalated BEACOPP arm despite the use of G-CSF, but the toxic death rate was no greater than that seen in the conventionaldose groups. No survival advatage was apparent with the dose-escalated BEACOPP. Dr. Diehl and colleague are to be commended for their continuing series of phase III clinical trials in patients with HD. In the United States, ABVD or Stanford V currently remain the regimens of choice for the treatment of advanced stage HD. The long track record with ABVD and its welldefined toxicity profile make it an acceptable treatment regimen for most practicing clinicians. While limited studies of Stanford V suggest that it affords superior remission rates, these high remission rates are achieved with both chemotherapy and involved field radiation therapy. Since only 50%- 60% of patients with stage III/IV HD are cured with ABVD, interest exists in devising alternative therapy regimens. In contrast to Dr. Diehl, I am unenthusiastic about the use of dose-escalated BEACOPP. It is unclear to me that the substantial hematologic toxicity and the high rate of REFERENCES 1 Vose JM, Zelenetz AD, Rohatiner A et al. Iodine I 131 tositumomab for patients with follicular non-hodgkin s lymphoma (NHL): overall clinical trial experience by histology. Blood 1999;94:89a. 2 McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent NHL: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16: Spaepen K, Stroobants S, Dupont P et al. Prognostic value of positron emission tomography with fluorodeoxyglucose secondary leukemias are acceptable side effects of therapy. Although Dr. Diehl suggests that the long-term leukemia risk for patients will be lower with dose-escalated BEA- COPP because the patients will be less likely to receive second-line therapy for management of their disease, this hypothesis is pure speculation. These data do not convince me that dose-escalated BEACOPP is a regimen that should be employed in most HD patients or that it should be used outside of the clinical trial setting. This is a well-performed clinical trial. The enthusiastic data interpretation of Dr. Diehl should be viewed with caution and long-term follow-up of these results will be critical. CONCLUSIONS These abstracts presented important findings that are likely to have relevance for the practicing hematologist and oncologist. As with all early data presentations, final analysis of these new data will have to await the publication of detailed manuscripts. Nevertheless, there are several important new therapies that will soon be available for the treatment of hematologic malignancies, and proper studies are being designed to assess the role of these novel treatment approaches. (FDG-PET) after first line chemotherapy in non-hodgkin s lymphoma (NHL). Proc Am Soc Clin Oncol 2000;19:11a. 4 Druker BJ, Talpaz M, Resta D et al. Clinical efficacy and safety of an ABL specific tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia. Blood 1999;94:368a. 5 Weisberg E, Griffin JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI 571 in BCR/ABL-transformed hematopoietic cell lines. Blood 2000;95: