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Hematologic Malignancies

^a St. Luke's-Roosevelt Hospital Center; ^b Beth Israel Medical Center, New York, New York, USA

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: 212-523-5419; Fax: 212-523-2004; e-mail: mgrossbard{at}slrhc.org

	ABSTRACT

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
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.

Key Words. Monoclonal antibody • Radioimmunoconjugate • Rituximab • Tositumomab and 131I tositumomab • Ibritumomab tiuxetan

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.

	LYMPHOMA

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
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 Emmanouilides, 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 (⁹⁰Y). Zevalin is capable of delivering targeted radiation to CD20-positive tumors. In phase I/II studies in relapsed/refractory NHL, Zevalin achieved a 67% 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/m² on day 0 and day 7 followed on day 7 by 0.3 or 0.4 mCi/kg ⁹⁰Y Zevalin (depending on the platelet count). Control arm patients received rituximab at a standard dose of 375 mg/m² 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 15.4+ months in the Zevalin arm and 13.8+ 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.

Fifty-seven patients with relapsed NHL, rituximab-refractory (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 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^TM) 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 ¹³¹I. A response rate of 57% (CR 32%) has been reported in the treatment of relapsed/refractory low-grade 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 re-treated 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. 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.

Commentary
Both Bexxar and Zevalin should soon receive FDA approval for the treatment of relapsed and refractory low-grade NHL. They are both conjugates of murine anti-CD20 mAbs to a radioisotope ¹³¹I (Bexxar) or ⁹⁰Y (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 ¹³¹I and ⁹⁰Y are ß-emitters, ⁹⁰Y has higher ß energy, a longer path length, and a shorter half-life. Because ⁹⁰Y is not a -emitter, imaging or dosimetry with Zevalin requires the use of an indium-111 (¹¹¹In) 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 abstracts add to the growing evidence of significant efficacy of RIT in various clinical scenarios.

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.

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^TM 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 dosimetry-based 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.

Commentary
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 ⁹⁰Y isotope used in Zevalin is a pure ß-emitter, dosimetry with that agent requires the preparation of an alternative RIC between CD20 and ¹¹¹In to permit -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 disease-free 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 ¹³¹I 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 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 progression-free 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.

Commentary
The treatment of mantle cell NHL remains uniquely frustrating when compared with therapy for other histologies of NHL. Results obtained with high-dose ¹³¹I-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

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
Rituximab Added to Fludarabine Improves Response in Previously Untreated Chronic Lymphocytic Leukemia: Preliminary Results from CALGB 9712. 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/m² days 1-5 every month x 6 with rituximab 375 mg/m² 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/m² days 1-5 every month x 6 followed 2 months later by rituximab 375 mg/m² every week x 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.

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

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
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 x 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.

Commentary
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

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
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).

166holmium-DOTMP (166Ho-DOTMP) is a high-energy, ß-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 chemotherapy-refractory 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 follow-up 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/m² 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.

Commentary
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

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
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 ß 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.

Commentary
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.

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 SU5416 145 mg/m² 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%.

Commentary
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

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
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.

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. For example, GM-CSF is being assessed in a Radiation Therapy Oncology Group trial to determine whether it can reduce the incidence of mucositis in head and neck cancer patients receiving radiation therapy. KGF also warrants testing in this setting.

Conclusions
At the ASCO meeting this year, there have been continued advances in the development of targeted therapies and supportive care. Many of the agents reported are nearing FDA approval, and others are well along in phase II and III clinical trials. The explosion of knowledge continues in the treatment of hematologic malignancies, and the horizon remains bright for the application of new technologies to these diseases.

© Sean P. Murphy

	ACKNOWLEDGMENTS

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 
Magdalena Petryk is supported by an unrestricted education grant from Immunex, Inc.

M.L.G. has received honoraia from Genentech/IDEC/ Berlex and is a consultant for Coulter Pharmaceuticals.

	References

Top Abstract Lymphoma Chronic Lymphocytic Leukemia Hairy Cell Leukemia Multiple Myeloma New Therapeutic Targets Supportive Care References

 

1. Witzig TE, White CA, Wiseman GA et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol 1999;17:3793–3803.[Abstract/Free Full Text]
2. Vose J, Wahl R, Saleh M et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade non-Hodgkin's lymphomas. J Clin Oncol 2000;18:1316–1323.[Abstract/Free Full Text]
3. Witzig T, Gordon L, Wiseman G et al. Zevalin radioimmunotherapy is safe and well tolerated in patients with relapsed or refractory, B cell non-Hodgkin's lymphoma. Blood 2000;96:731a.
4. Gregory S, Leonard J, Coleman M et al. Bexxar (tositumomab, iodine I 131 tositumomab) can be safely administered to relapsed low-grade or transformed low-grade non-Hodgkin's lymphoma patients after prior treatment with rituximab: initial experience from the expanded access study. Blood 1999;94:91a.
5. Wiseman G, White C, Stabin M et al. Phase I/II ⁹⁰Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory NHL. Eur J Nucl Med 2000;27:766–777.[CrossRef][Medline]
6. Samaha H, Dumontet C, Ketterer N et al. Mantle cell lymphoma: a retrospective study of 121 cases. Leukemia 1998;12:1281–1287.[CrossRef][Medline]
7. Milpied N, Gaillard F, Moreau P et al. High-dose therapy with stem cell transplantation for mantle cell lymphoma: results and prognostic factors, a single center experience. Bone Marrow Transplant 1998;22:645–650.[CrossRef][Medline]
8. Howard O, Gribben J, Neuberg D et al. Rituxan/CHOP induction therapy in newly diagnosed patients with mantle cell lymphoma. Blood 1999;94:631a.
9. Romaguera J, Khouri I, Kantarjian H et al. Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma 2000;39:77–85.[Medline]
10. Emmerich B, Huhn D, Peschel C et al. Treatment of chronic lymphocytic leukemia (CLL) with the anti-CD20 antibody rituximab. Blood 1999;94:309b.
11. O'Brien S, Thomas D, Freireich E. Rituxan has significant activity in patients with CLL. Blood 1999;94:603a.
12. Rai KR, Peterson BL, Appelbaum FR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750–1757.[Abstract/Free Full Text]
13. Demidem A, Lam T, Alas S et al. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 1997;12:177–186.[Medline]
14. Alas S, Bonavida B, Emmanouilides C. Potentiation of fludarabine cytotoxicity on non-Hodgkin's lymphoma by pentoxifylline and rituximab. Anticancer Res 2000;20:2961–2966.[Medline]
15. Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin Cancer Res 2001;7:709–723.[Abstract/Free Full Text]
16. Czuczman MS, Grillo-Lopez AJ, White CA et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268–276.[Abstract/Free Full Text]
17. Vose JM, Link BK, Grossbard ML et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 2001;19:389–397.[Abstract/Free Full Text]
18. Coiffier B, Lepage E, Herbrecht R et al. Mabthera (rituximab) plus CHOP is superior to CHOP alone in elderly patients with diffuse large B-cell lymphoma (DLCL): interim results of a randomized GELA trial. Blood 2000;96:223a.
19. Keating M, O'Brien S, Lerner S et al. Combination chemo-antibody therapy with fludarabine, cyclophosphamide and rituximab achieves a high CR rate in previously untreated chronic lymphocytic leukemia (CLL). Blood 2000;96:514a.
20. Cassileth P, Cheuvart B, Spiers A et al. Pentostatin induces durable remissions in hairy cell leukemia. J Clin Oncol 1991;9:243–246.[Abstract]
21. Catovsky D, Matutes E, Talavera J et al. Long-term results with 2-deoxycoformycin in hairy cell leukemia. Leuk Lymphoma 1994;14:109–113.
22. Piro L, Ellison D, Saven A. The Scripps clinic experience with 2-chlorodeoxyadenosine in the treatment of hairy cell leukemia. Leuk Lymphoma 1994;13:121–125.
23. Cheson B, Sorensen J, Vena D et al. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients. J Clin Oncol 1998;16:3007–3015.[Abstract/Free Full Text]
24. Hakimian D, Tallman MSJ, Kiley C et al. Detection of minimal residual disease by immunostaining of bone marrow biopsies after 2-chlorodeoxyadenosine for hairy cell leukemia. Blood 1993;82:1798–1802.[Abstract/Free Full Text]
25. Ellison DJ, Sharpe RW, Robbins BA et al. Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia. Blood 1994;84:4310–4315.[Abstract/Free Full Text]
26. Tallman MS, Hakimian D, Kopecky KJ et al. Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse. Clin Cancer Res 1999;5:1665–1670.[Abstract/Free Full Text]
27. Leonard J, Coleman M, Chadburn A et al. Epratuzumab (HLL2, anti-CD22 humanized monoclonal antibody) is an active and well-tolerated therapy for refractory/relapsed diffuse large B-cell non-Hodgkin's lymphoma. Blood 2000;96:578a.
28. Kreitman RJ, Margulies I, Stetler-Stevenson M et al. Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) toward fresh malignant cells from patients with B-cell leukemias. Clin Cancer Res 2000;6:1476–1487.[Abstract/Free Full Text]
29. Leonard J, Coleman M, Schuster M et al. Immunotherapy of NHL with epratuzumab (Anti-CD22 monoclonal antibody): excellent tolerability with objective responses. Proc Am Soc Clin Oncol 2000;19:17a.
30. Larson SM, Carrasquillo JA. Advantages of radioiodine over radioindium labeled monoclonal antibodies for imaging solid tumors. Nucl Med Biol 1988;15:231–233.
31. Mausner LF, Srivastava SC. Selection of radionuclides for radioimmunotherapy. Med Phys 1993;20:503–509.[CrossRef][Medline]
32. Deshpande SV, DeNardo SJ, Kukis DL et al. Yttrium-90-labeled monoclonal antibody for therapy: labeling by a new macrocyclic bifunctional chelating agent. J Nucl Med 1990;31:473–479.[Abstract/Free Full Text]

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