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ASCO 1999: Critical Commentaries |
Massachusetts General Hospital, Boston, Massachusetts, USA
Correspondence: Michael L. Grossbard, M.D., Massachusetts General Hospital, Cox 228, 100 Blossom Street, Boston, Massachusetts 02114, USA. Telephone: 617-724-1134; Fax: 617-724-1137; e-mail: Grossbard.Michael{at}MGH.Harvard.edu
The 1999 ASCO meeting brought continued progress in the therapy of hematologic malignancies. Over the past several years, clinical trials have helped to define the role of high-dose therapy in the treatment of lymphoma and leukemia, demonstrated the promise of antibody therapy, and defined new chemotherapy programs for the treatment of these malignancies. Nevertheless, multiple questions remain regarding the appropriate timing of high-dose therapy, the toxicities of newer treatments, and the sequencing of biological therapies with conventional chemotherapy treatments.
Building on earlier clinical studies, reports from this year's meeting further elucidated the role of high-dose therapy and autologous stem cell infusion for the treatment of Hodgkin's disease and non-Hodgkin's lymphoma (NHL). Advances in targeted therapies were reported both in the use of monoclonal antibody-based therapies and therapies designed to target specific proteins that are overexpressed in NHL and chronic myelogenous leukemia (CML). The role of purine analogs in the therapy of low grade B-cell malignancies continues to be defined. The following review will summarize key abstracts presented at the 1999 ASCO meeting and will elaborate on the implications of these findings for disease mangement.
Indolent NHL
SWOG 95-01: A Phase II Trial of a Combination of Fludarabine and Mitoxantrone (FN) in Untreated Advanced Stage Low Grade Lymphoma. An Effective, Well Tolerated Therapy. W Velasquez, D Lew, T Miller, R Fisher. (Abstract 27)
Ninety-two patients (median age 53, range 28-80) with stage III/IV low-grade NHL received therapy with fludarabine 25 mg/m2/day i.v. on days 1 through 3 and mitoxantrone 10 mg/m2 i.v. on day 1 every 28 days. Patients also received prophylactic bactrim. Of 78 evaluable patients, 85% had follicular lymphoma. The overall response rate was 94%, with 44% complete remissions. The estimated two-year progression-free survival (PFS) was 60% and overall survival 94%. The predominant toxicity was hematologic with 27 patients developing grade 3 or 4 neutropenia, and one patient grade 4 thrombocytopenia. As compared with prior Southwestern Oncology Group (SWOG) trials using CHOP and ProMACE-MOPP in similar patients, the two-year PFS was similar.
The optimal first-line therapy for patients with advanced stage low-grade NHL remains to be determined. The combination of fludarabine, mitoxantrone, and decadron was recognized as an extremely active treatment program with a response rate of 94% in relapsed low-grade NHL, but the original report described a high rate of toxicity and opportunistic infections [1]. The contribution of decadron to the efficacy of the program never was established. Similarly, the addition of steroids to fludarabine in the treatment of chronic lymphocytic leukemia (CLL) also has been complicated by the development of opportunistic infections. The present program eliminates the decadron while still preserving bactrim prophylaxis. Response rates remained excellent. Thus, this regimen represents a highly effective regimen that can be delivered with tolerable toxicities.
Two abstracts presented at the American Society of Hematology this year also established the efficacy of fludarabine in the initial therapy of low-grade NHL. A randomized trial of fludarabine versus CVP demonstrated a higher response rate (69% versus 53%) and longer time to disease progression (494 days versus 396 days) with the use of fludarabine [2]. Similarly, when fludarabine/mitoxantrone was compared with a modified CHOP regimen (low-dose anthracycline), a similar advantage in response rate (85% versus 63%) and time to progression were observed.
Based on these studies, fludarabine as a single agent or in combination with mitoxantrone deserves consideration as a treatment regimen for younger patients with low-grade NHL. With higher complete remission rates to conventional dose therapy, one can begin to explore the addition of adjuvant targeted therapies to eradicate minimal residual disease.
Results of a Phase I Clinical Trial of BCL-2 Antisense Molecule G3139 (GENTA) in Patients with Non-Hodgkin's Lymphoma. JS Waters, A Webb, D Cunningham, PA Clarke, F di Stefano, F Raynaud, BD Brown, FE Cotter. (Abstract 11)
G3139 is an oligonucleotide complementary to the first six codons of the bcl-2 mRNA. Because bcl-2 is overexpressed in most patients with low-grade NHL, conferring resistance to apoptosis, it represents a logical therapeutic target. In vitro, G3139 reduces bcl-2 mRNA and protein expression. Twenty-one patients with NHL (eight small lymphocytic, nine follicular) received therapy with a 14-day subcutaneous infusion of G3139 at doses between 4.6 and 195.8 mg/m2/day. Fever and asthenia were dose limiting in six patients. Local skin inflammation at the infusion site occurred in all patients. Ten patients developed grade 3 or 4 lymphopenia, but this was not dose limiting. The maximum tolerated dose was 147.2 mg/m2/day. One complete remission, lasting 34+ months was observed and 7 of 12 patients had a decrease in circulating lymphoma cells. Bcl-2 protein was reduced in 5 of 13 evaluable patients.
This clinical study confirms that bcl-2 antisense therapy is feasible and biologically active in patients with NHL. Indeed, this represents one of the first cancer therapies to be directed at a molecular target. Since induction of apoptosis appears to play a significant role in the cytotoxicity of radiation, chemotherapy, and monoclonal antibody therapy (rituximab), a decrease in bcl-2 protein production may well sensitize follicular lymphoma cells to the effects of chemotherapy. The fact that this agent has any single agent activity is striking given that its major potential utility may reside in its effect on sensitivity to other therapies.
The precise mechanism of cytotoxicity of this antisense oligonucleotide therapy remains unclear, but at least some patients demonstrate a reduction in bcl-2 protein with therapy. Further trials will need to address potential benefits of this agent as a chemotherapy sensitizer, its role as an agent in purging of harvested autologous marrow, and to determine whether synergistic toxicity exists between this agent and conventional chemotherapy.
Rituximab in Patients (Pts) with Relapsed Low-Grade or Follicular Non-Hodgkin's Lymphoma (LG/F NHL): Response Rate and Duration with a Weekly Times 8 Dosing Regimen. L Piro, CA White, AJ Grillo-Lopez, N Jankiraman, TM Beck, A Saven, S Shuey, M Czuczman, JW Lynch, JE Kolitz, V Jain. (Abstract 49)
This phase II trial was designed to determine whether higher cumulative doses and a more prolonged course of rituximab could increase clinical efficacy as compared with the standard dose of 375 mg/m2 weekly times four. Thirty-seven patients were treated with rituximab 375 mg/m2 weekly times eight. Of the 37 patients, 19% had small lymphocytic lymphoma and the remainder had follicular lymphoma. The overall response rate was 57% with 14% complete remission (CR) and 43% partial remission (PR). Adverse events consisted primarily of infusion-related toxicities including fever, chills, sensation of tongue or throat swelling, and mild hypotension. As compared with the pivotal weekly times four study, the response rate was higher (57% versus 48%) and the median duration response appears longer (13.4+ months versus 11.6 months). These differences did not reach statistical significance.
Despite the wide acceptance of rituximab in clinical practice, little still is known about the optimal treatment schedule or dosage. In the original phase II trial, four weekly doses were delivered with good response rates (48%) of clinically meaningful duration [3]. Because of the excellent response to this regimen and the lack of toxicity, no maximum tolerated dose of this agent ever was defined in clinical trial. Pharmacology studies also indicated that the half-life of this agent increased with successive administration of the antibody. Preclinical studies indicate that antibody-based cytotoxicity is dependent not only on the concentration of the antibody but also the duration of contact with the target cell. Hence, there is a sound clinical rationale to extend the infusion duration and escalate doses of Rituxan, although the feasibility of this approach in practice may be limited by the cost of the antibody.
This is one of a series of trials designed to learn about the clinical activity of Rituxan as we attempt to define its role in the therapy of low-grade NHL. Whether the drug is best administered as a single agent or in combination with chemotherapy remains unclear. Preclinical and clinical studies suggest that Rituxan exerts synergistic cytotoxicity with a number of chemotherapy agents. Likewise, the role of Rituxan as a consolidative and adjuvant therapy will be defined through several ongoing United States cooperative group clinical trials in both indolent and aggressive NHL.
Aggressive NHL
Consolidation ABMT after Standard Chemotherapy versus CHVmP/BV Alone for Primary Intermediate and High Grade NHL: A Randomized Phase III EORTC Study. JC Kluin-Nelemans, V Zagonel, J Thomas, I Teodorovic, A Anastasopoulou, D Bron, P Carde. (Abstract 6)
Patients with stage II-IV intermediate and high-grade NHL and stage I bulky NHL received three cycles of chemotherapy with cyclophosphamide, adriamycin, VM-26, prednisone, bleomycin, and vincristine. After three cycles of therapy, patients in CR or PR were randomized to receive an additonal five cycles of the same chemotherapy or an additonal three cycles of this regimen followed by high-dose therapy with BEAC (BCNU, etoposide, Ara-C, cyclophosphamide) and stem cell infusion. Three hundred ten patients were registered and 184 patients were randomized. The major reasons patients were not randomized included patient refusal (41%), insufficient response (20%), and positive bone marrow (17%). Sixty-eight percent of patients would be classified as low or low intermediate risk by the international prognostic index. No grade IV nonhematologic toxicity was observed with the high-dose regimen. At a median follow-up of 41 months, there was no difference in time to progression (five-year: 50% control, 62% ABMT) or overall survival (five-year: 75% control, 67% ABMT).
This trial adds additional data to the body of evidence that fails to support the use of consolidative high-dose therapy as a uniform treatment policy for patients with intermediate and high-grade NHL. Haioun et al. reported a randomized trial of consolidative conventional dose sequential dose therapy versus high-dose therapy and autologous stem cell infusion in patients with aggressive NHL in first remission after standard induction therapy [4]. Among 541 randomized patients, disease-free and overall survival did not differ significantly between the two consolidative treatment arms. While there was a significant improvement in disease-free survival for patients with two or more negative prognostic factors receiving high-dose therapy, there was no significant difference in overall survival for these patients. Similarly, Gianni et al. reported a randomized trial of sequential high-dose therapy versus MACOP-B therapy for patients with aggressive disease [5]. Although rates of CR and freedom from progression were higher with the sequential high-dose therapy, there was no significant difference in overall survival. An attempt to repeat this trial in the United States failed due to poor accrual.
Of note, the trials of consolidative high-dose therapy completed to date all began accrual prior to the development of the International Prognostic Index (IPI). Thus, the studies were underpowered to address whether any benefit might exist for the use of high-dose therapy for patients with high-intermediate or high-risk IPI features. In those higher-risk cases, the outcome of conventional anthracycline-based therapy remains suboptimal and the benefits of high-dose therapy may be greater. A current U.S. intergroup study will randomize patients with high-intermediate and high-risk NHL to receive either CHOP chemotherapy alone or CHOP followed by consolidative high-dose therapy and stem cell infusion. Those patients who received conventional dose therapy alone will be eligible to receive high-dose therapy at the time of disease progression. At present, the data fail to support the routine use of consolidative high-dose therapy for patients with aggressive NHL who are responding to front-line chemotherapy.
Acute and Chronic Leukemia
Preliminary Results of the Efficacy and Safety of CMA-676 in Patients with AML in First Relapse. E Sievers, RA Larson, E Estey, EA Stadtmauer, D-C C Roy, R Spielberger, S Tarantolo, MS Berger, C Eten, L Manley, I Bernstein, F Applebaum. (Abstract 21)
CMA-676 is a targeted therapy that combines the specificity of a humanized anti-CD33 antibody and the potent cytotoxicity of calicheamycin. CMA-676 was administered in this phase II trial to 45 patients with relapsed acute myelogenous leukemia (AML) who had a first remission duration of at least six months. Patients with secondary AML or preceding myelodysplastic syndrome (MDS) were excluded. CMA-676 was administered i.v. at a dose of 9 mg/m2 q two weeks for two doses. Toxicity was significant including hypotension, rigors, chills, transient liver function abnormalities, intussuception, diabetes insipidus, seizures, and intracerebral bleeding. Most patients experienced grade 4 granulocytopenia and thrombocytopenia. Seventeen of 45 patients achieved a remission (characterized by 
5% blasts in the marrow, 
1,500 granulocytes, and platelet transfusion independence). Thirteen of the 17 responding patients remain in remission with a median follow-up after remission of 163 days.
Targeted therapies have been used increasingly in the treatment of lymphoma, but the development of this treatment modality for therapy of leukemia has lagged behind. The identification of leukemia specific antigens that are not expressed on stem cells has been difficult and the presence of a large circulating tumor burden has led to rapid clearance and limited efficacy of most of the administered unconjugated antibodies and immunotoxins. In another abstract presented at this meeting Feldman et al. have described their use of HuM195, another anti-CD33 antibody [6]. Although the toxicity of this agent was substantially lower than that seen with CMA-676, the efficacy also was lower with only two complete remissions seen in the first 35 patients treated.
By contrast, CMA-676 has substantial activity in the treatment of AML, albeit with major toxicity due to nonspecific side effects of therapy. Nevertheless, the potential specificity of lower doses of this agent suggests that it may be useful as a specifically targeted therapy to eradicate residual tumor cells in patients who have achieved a clinical remission in response to standard induction therapy. The next step in the development of this agent will be to clarify its potential synergy with chemotherapy and its use in the minimal residual disease setting.
Phase I Trial of a Specific Abl Tyrosine Kinase Inhibitor, CGP 57148, in Interferon Refractory Chronic Myelogenous Leukemia Patients. BJ Druker, CL Sawyers, M Talpaz, D Resta, B Peng, J Ford. (Abstract 24)
CML is characterized by the presence of the Philadelphia chromosome and a hybrid p210BCr-Abl protein that has elevated tyrosine kinase activity as compared with c-Abl. This tyrosine kinase function is necessary for the transforming function of the Bcr-Abl fusion protein. In addition, upregulation of abl-kinase may alter cellular resistance to apoptotic cell death. CGP 57148 is a potent and specific inhibitor of both the Abl and the Bcr-Abl protein kinases and therefore has the potential to serve as a selective agent for the therapy of CML. Patients were treated at dose levels of 25-300 mg daily. All patients treated at a dose of greater than 140 mg had a hematologic response with a significant decrease in blood counts. At 200 mg per day, three of nine patients had a complete hematologic response characterized by the normalization of white blood cell counts and platelet counts for at least four weeks. At a dose of 300 mg, four of six patients had a complete hematologic response. No serious side effects have been observed.
Again, this abstract demonstrates a move toward rational drug design based on an understanding of the molecular biology of hematologic disease. We now have recognized specific chromosomal translocations that result in the development of aberrant protein expression and are critical in the pathogenesis of a variety of leukemias and lymphomas. In the present trial, inhibition of abl-kinase exerts a direct and specific cytotoxic effect on CML cells. Other investigators are developing Bcr-Abl antisense oligonucleotides that have been used successfully for in vitro purging of harvested autologous marrow from patients with CML. Phase II studies will examine this agent in patients who have not received prior therapy.
Therapeutic options continue to expand for patients with CML. Also presented at this meeting were results from a randomized trial demonstrating a statistically significant improvement in five-year survival when patients with CML are treated with a combination of interferon and Ara-C as compared with Ara-C alone (70% versus 58%, p < 0.02). Investigations with homoharringtonine, a plant alkaloid, have demonstrated cytogenetic remissions in patients with CML. The next generation of studies will need to clarify the appropriate initial therapy for patients with CML, the optimal timing of BMT, and any synergy that may exist between the new biological agents and conventional cytotoxic approaches.
Therapy-Related Myelodysplastic Syndrome (T-MDS) or Acute Myeloid Leukemia (T-AML) in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Chlorambucil (C), Fludarabine (F) or Fludarabine + Chlorambucil (F + C): An Intergroup Study (Cancer and Leukemia Group B 9011. VA Morrison, KR Rai, B Peterson, JE Kolitz, L Elias, JD Hines, L Shepherd, RA Larsen, CA Schiffer. (Abstract 29)
Five hundred forty-four patients with previously untreated CLL were enrolled on an intergroup trial to determine the optimal front-line regimen for patients with CLL. Patients were randomized to therapy with chlorambucil alone, fludarabine alone, or fludarabine plus chlorambucil. Therapy was continue for three months after a clinical CR or for two months after stable best response, with a maximum therapy duration of one year. At a median follow-up of 17.5 months, six patients (1.2%) have developed MDS or AML. This included 5 of 142 patients treated with fludarabine and chlorambucil, 1 of 188 treated with fludarabine, and no patients treated with chlorambucil alone. Marrow cytogenetics obtained in three of the six cases revealed abnormalities of chromosome 5, 7, or both.
The authors point out the disturbingly high risk of myelodysplasia and AML in patients treated with an alkylating agent together with a purine analog (fludarabine) raising the question of whether such combination therapy places patients at risk of secondary malignancies. Recently, reports of the high response rate to the regimen of fludarabine and cyclophosphamide have led to an increased use in patients with low-grade NHL. Indeed, the current Eastern Cooperative Oncology Group (ECOG) trial for patients with low-grade NHL randomizes patients to treatment with either CVP or fludarabine/cyclophosphamide. Based upon the reported results of the present trial, the risk of MDS and AML should be further clarified before combination regimens of alkylating agents and purine analogs become standard therapy for the treatment of indolent B-cell neoplasms. The low rate of MDS/AML after therapy with fludarabine alone is somewhat reassuring regarding the use of this agent in CLL and indolent NHL in the absence of combination therapy with an alkylating agent.
Hodgkin's Disease
High-Dose Therapy (HDT) Followed by Hematopoietic Stem Cell Transplantation (HSCT) for Relapsed Chemosensitive Hodgkin's Disease (HD): Final Results of a Randomized GHSG and EBMT Trial (HD-R1). N Schmitz, M Sextro, B Pfistner, D Hasenclever, H Tesch, A Carella, M Haenel, F Boissevain, R Zschaber, AH Goldstone, V Diehl. (Abstract 5)
Patients under age 60 with relapsed Hodgkin's disease (HD) were randomized to receive either four courses of dexa-BEAM (dexamethasone 24 mg p.o. days 1 through 10, BCNU 60 mg/m2 i.v. day 2, etoposide 150-250 mg/m2 i.v., Ara-C 100 mg/m2 i.v. days 4 through 7, and melphalan 20 mg/m2 i.v. day 3) or two courses of dexa-BEAM followed by BEAM (high-dose BCNU, etoposide, Ara-C, and melphalan) and HSCT. Of the 162 patients registered to the trial, only patients who achieved a CR or PR after two cycles of therapy were randomized. Twelve patients were excluded and 26 patients did not proceed on after the first two courses of therapy for reasons including toxic death (nine patients), life-threatening toxicity of prior therapy (five patients), and failure to achieve at least a partial response (eight patients). Time to treatment (TTF) failure was significantly longer for all chemotherapy sensitive patients (p = 0.03) and for the subgroups with early or late first relapse (p = 0.04 each). Overall survival (OS) did not significantly differ. If all eligible patients were considered, TTF and OS were not significantly different.
Controversy still exists over the need for and optimal timing of high-dose therapy for patients with relapsed HD. The data in favor of high-dose therapy come from multiple single-institution studies that document extended disease-free survival (DFS) for patients undergoing high-dose therapy for relapsed HD. However, many experts maintain that high-dose therapy is unnecessary for those patients who relapse more than one year out from their original therapy and that the use of high-dose therapy should be reserved for those patients with early relapse.
In support of high-dose therapy, Horning et al. described the results of high-dose therapy in 119 patients with relapsed or refractory HD [8]. At four years after high-dose therapy, the actuarial survival of these patients was 52% with an event-free survival of 48%. Several prognostic factors including pulmonary parenchymal involvement, constitutional symptoms, and the presence of more than minimal residual HD before the bone marrow transplant (BMT) preparatory regimen were noted to predict for outcome post-BMT. Another study provides a comparison between conventional salvage therapy and high-dose therapy for patients with recurrent or refractory HD [9]. Results from 60 patients with HD undergoing high-dose therapy were compared with the results from a matched group of 103 patients undergoing conventional salvage therapy. Overall and event-free survival at four years favored patients undergoing high-dose therapy. Even patients with refractory disease had some prospect for disease-free survival with the use of high-dose therapy.
The present trial is the first randomized trial to address the question of high-dose therapy versus conventional dose therapy for patients with relapsed HD. The small number of patients limits the conclusions that can be drawn, but it appears that high-dose therapy offers an extended TTF for patients with chemotherapy-sensitive disease. The results of this trial provide support for what already has become the standard of care for such patients with early relapse of their disease. Future studies are planned to address the role of dose intensive therapy as early consolidative therapy for patients with poor prognosis HD.
Acknowledgments
We gratefully acknowledge the cooperation of Kirin Pharmaceuticals and Excerpta Medica, Japan.
References
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