Highlights From: 37th Annual American Society of Clinical Oncology Meeting, San Francisco, CA May 12–15, 2001

Meeting Highlights From: 37th Annual American Society of Clinical Oncology Meeting San Francisco, CA May 12-15, 2001 Highlights prepared by Amy I. D’Orazio, PhD Reviewed by Bruce D. Cheson, MD and Vinay K. Jain, MD treated with ABVD plus Table 1 ABVD Plus Subtotal Nodal vs. Involvedinvolved-field radiation Field Irradiation: Efficacy therapy. The use of more STNI IFRT limited fields of radiation Arm Arm was desirable due to the short-term and long-term Complete Response Rate 100% 97% Patients with early-stage (I-IIA) adverse effects associated Hodgkin’s disease can be cured using 10-Year PFS 97% 94% with radiation therapy. The radiation therapy, but for definitive stag10-Year OS 94% 94% results, after a median foling, patients have traditionally needed low-up of 87 months, were Abbreviations: IFRT = involved-field radiation therapy; staging laparotomy with a splenectomy. presented by Dr. Bonfante OS = overall survival; PFS = progression-free survival; For this reason, many physicians choose at the 2001 American STNI = subtotal nodal irradiation to treat these patients with a short Society of Clinical Oncolcourse of chemotherapy followed by with a favorable prognosis, and 27% ogy (ASCO) Meeting in San Francisco.3 radiation therapy, which may obviate were stage II with an unfavorable progThis trial enrolled patients with earlythe need for pathologic staging using nosis. About 20% of the patients in stage Hodgkin’s disease (clinical stages 1,2 laparotomy. This combined apboth arms had bulky disease, and 12% I, IIA, IIA bulky, and IIEA). Patients proach also holds the potential for minand 9% in the STNI and IFRT arms, were randomized to treatment with 4 imizing doses and fields of radiation respectively, had extranodal lesions. cycles of ABVD followed by either therapy and decreases the risk of late Twelve patients in each arm had 4 or subtotal nodal irradiation (STNI) or radiation-related toxicities. more sites involved with tumor. involved-field radiation therapy (IFRT). In 1990, investigators from the The complete response (CR) rate was The total doses of radiation were 36 Gy Istituto Nazionale Tumori in Italy un100% in the STNI arm and 97% in the to the involved site and 30 Gy to undertook a trial to determine whether IFRT arm. The 10-year progressioninvolved sites. The patients were strathe outcome of patients with earlyfree survival (PFS) rate was similar in tified by stage (I vs. IIA) and prognosis stage Hodgkin’s disease with a brief both arms (STNI arm, 97% vs. IFRT (favorable vs. unfavorable) (Figure 1). course of the chemotherapy regimen arm, 94%), and the 2 arms had identiOne hundred thirty-six patients were doxorubicin/bleomycin/vinblastine/dacal 10-year overall survival (OS) rates at enrolled. The 2 treatment arms were carbazine (ABVD) and extensive-field 94% (Table 1). well balanced. The proportion of males radiation therapy was superior to those Cardiotoxicity associated with ABVD was 44% and 43% in the STNI and plus radiation therapy included nonIFRT arms, respectively, specific electrocardiogram changes in Figure 1 ABVD Plus Subtotal Nodal vs. Involved-Field and 20% and 13% of 15 patients (11%) and acute myocarthe patients, respecIrradiation: Treatment Schema dial infarction in 2 patients (1.5%). Statively, were over the age tistically significant declines in mean of 40 years. In the STNI ABVD x 4 cycles followed by values for pulmonary function tests (rearm, 9% of the patients Subtotal nodal irradiation R sidual volume and diffusing capacity of were stage I, 59% were 36 Gy involved site a Stratify by: carbon monoxide [DL ]) n stage II with a favorable CO were seen 30 Gy uninvolved site -Stage (I vs. IIA) d on follow-up as well. Clinical hypothyprognosis, and 32% -Prognosis o roidism was seen in 1.5% of the pawere stage II with an m (favorable i tients in either arm. In addition, 2 paunfavorable prognosis. vs. unfavorable) z ABVD x 4 cycles followed by tients treated with STNI developed In the IFRT arm, 13% e Involved-field irradiation 36 Gy of the patients were stage secondary malignancies (1 solid tumor, n = 136 I, 60% were stage II 1 acute leukemia).

ABVD Plus Involved-Field Radiation Produces Excellent Long-Term Results in Localized Hodgkin's Disease

June 2001 • 11

Meeting Highlights in Nashville, Tennessee, thus Table 2 Rituximab in Previously Untreated NHL: undertook a phase II trial of Efficacy rituximab as first-line therInitial Response Best Response apy for previously untreated (n = 60) (n = 60) patients with low-grade Complete Response 4 (7%) 18 (30%) NHL. Because retreatment 23 (38%) 22 (37%) of patients with progressive Partial Response disease using rituximab Response Rate 27 (45%) 40 (67%) has proven to be effective,5 Stable Disease 28 (47%) 15 (25%) maintenance courses of ri1-Year PFS 69% tuximab were scheduled as 64% well. The results of this trial 2-Year PFS were updated at the 2001 Abbreviations: NHL = non-Hodgkin’s lymphoma; PFS = ASCO Meeting held in San progression-free survival Rituximab Is Active in Francisco.6 Patients with Previously encing B symptoms at the time of enThe eligibility criteria for this study Untreated Low-Grade Nonrollment. were low-grade NHL (follicular or Hodgkin’s Lymphoma Sixty patients were evaluable for resmall lymphocytic lymphoma [SLL]), sponse at week 6. Twenty-seven pameasurable or evaluable disease, an Low-grade non-Hodgkin’s lymphtients (45%) had an objective response Eastern Cooperative Oncology Group oma (NHL) is a highly chemosensitive (4 CR [7%]). An additional 28 patients (ECOG) performance status (PS) of malignancy, but the cure rate is very (47%) had stable disease. The objective 0-2, stage II-IV disease, and no prior low due to a pattern of continuous reresponse rate (ORR) was similar in pachemotherapy or immunotherapy. lapses, which require ongoing treattients with follicular lymphoma and Treatment consisted of rituximab 375 ment for these patients. Rituximab has 2 SLL at 63% and 66%, respectively. mg/m /week for 4 weeks, administered shown efficacy and is approved for use Following maintenance courses of riintravenously. Patients with an objecin relapsed NHL patients; however, tuximab, 18 patients achieved a CR tive response or stable disease after the limited experience exists with rituxi(30%) and the ORR had improved to first treatment cycle received additional mab in previously untreated patients. 67%. Twenty-five percent had stable maintenance 4-week courses of rituxiSubset analysis of the 166 patients disease as their best response. The 1mab every 6 months up to a maximum enrolled in the pivotal trial of rituximab year PFS rate was 69%, with an actuof 4 treatment cycles (2 years). Patients in NHL, however, revealed that rituxiarial 2-year survival predicted to be with an initial response who experimab had a higher response rate (57%) 64% (Table 2). enced disease progression prior to 6 in patients who had received only 1 The toxicities of this regimen were months could receive maintenance prior chemotherapy regimen as commild and largely infusion related. One courses of rituximab as early as 4 months pared to those who had received 2 or patient had to be withdrawn from the from the previous course of rituximab more previous chemotherapy regimens study due to grade 3/4 infusion-related (Figure 2). (response rate of 38%).4 This suggests events, which occurred with the first Sixty-two patients, having a median that rituximab may be more efficacious rituximab infusion. age of 65 years (range, 27-89 years), in patients who had received little or no were enrolled. Sixty-one percent had prior chemotherapy prior to rituximab Clinical Relevance: follicular histology and 39% had SLL. therapy. Dr. Hainsworth and colleagues Rituximab appears to be active as Fourteen patients (23%) were experifrom the Sarah Cannon Cancer Center first-line therapy for NHL. Additional improvements in response and proFigure 2 First-Line Rituximab in NHL: Treatment Schema longed remissions can be achieved with maintenance courses of rituximab. In Maintenance addition, in contrast to several other Rituximab Objective studies, this trial suggests that SLL may Rituximab 375 mg/m2 I.V., slow infusion 2/week 375 mg/m Response or be as responsive to rituximab as follicux 4 weeks Stable Disease lar lymphomas. Ongoing studies will Reevaluate q 6 months x 2 years define the optimal schedule of rituximab in this setting and the role of 1 2 3 4 5 6 maintenance therapy in prolonging reWeeks Progressive mission in previously untreated NHL Off study Disease patients. Clinical Relevance: At a 10-year follow-up, it appears that ABVD plus IFRT is as effective as ABVD plus STNI for patients with early-stage Hodgkin’s disease. More conservative, IFRT following ABVD is recommended as the therapy of choice for early-stage Hodgkin’s disease patients. This approach requires only clinical staging and obviates the need for staging laparotomy. __________________________________________________

12 • June 2001

Meeting Highlights Retreatment with 131ITositumomab Is Efficacious and Safe for Patients with Low-Grade or Transformed Low-Grade NHL 131I-tositumomab

(Bexxar®)

is a radiolabeled murine monoclonal antibody that has shown activity in patients with relapsed or transformed low-grade NHL. In a multicenter phase II trial of tositumomab in patients with relapsed or transformed NHL, the ORR was 57%, with 32% of the patients achieving a CR. The 3-year PFS rate was 68%.7 Patients who relapse following 131I-tositumomab may be candidates for retreatment with 131I-tositumomab, as this drug induces only transient myelosuppression, and low doses of radiation are delivered to organs not involved with tumor. Also, a significant proportion of patients treated with 131I-tositumomab do not develop human antimouse antibody (HAMA).8 Dr. Kaminski and colleagues at the University of Michigan undertook a study of retreatment with 131I-tositumomab in patients with NHL who had relapsed following an initial response to 131I-tositumomab in a phase I/II trial9 or the aforementioned phase II trial.7 The results were presented at the 2001 ASCO Meeting held in San Francisco.10 This study included patients with low-grade or transformed NHL who had relapsed after a previous complete or partial response to 131I-tositumomab that has lasted for at least 3 months. Other inclusion criteria were

Table 4

Retreatment with 131I-Tositumomab: Toxicity Initial Therapy (n = 18)

Retreatment (n = 18)

Grade 3/4 neutropenia

8 (44%)

9 (50%)

Time to ANC recovery

7 days

9 days

Hematologic

Neutropenic infection Grade 3/4 thrombocytopenia Median time to platelet recovery

NR

1 (6%)*

4 (22%)

6 (33%)

7 days

7 days

Myelodysplasia (time since retreatment)

3 (17%) (4.5-6.1 years)

Nonhematologic TSH elevation Pruritus

1 (6%)

1 (6%)

NR

1 (6%)†

* This patient died from sepsis. † Ameliorated with an infusion

rate adjustment Abbreviations: ANC = absolute neutrophil count; NR = not reported; TSH = thyroid-stimulating hormone

ANC ≥ 1500/μL, platelets ≥ 100,000/ μL, bone marrow involvement with lymphoma < 25%, and no demonstrable HAMA. Patients who had received another salvage treatment after relapsing from their initial response to treatment with 131I-tositumomab prior to enrollment in this study were eligible. Patients were treated with varying doses of 131 I-tositumomab. Most (67%) received a therapeutic dose of 131 I-tositumomab to deliver a total radiation dose of 65-75 cGy, with the remainder receiving 25-55 cGy. Patients who received the lower doses had initially been a part of the phase I/II dose escalation study9 or had a prior bone marrow transplant. Eighteen patients were enrolled. Most patients (89%) were under the age of Table 3 Retreatment with 131I-Tositumomab: Efficacy 60 years. Thir teen (72%) had low-grade Initial Therapy Retreatment (n = 18) (n = 18) NHL and 5 (28%) had transformed low-grade Complete Remission 12 (67%)* 6 (33%) NHL. Two thirds had Complete Remission not yet reached no bone marrow in12 months Duration (> 12 months) volvement with lymphResponse Rate 18 (100%)* 12 (67%) oma. Fifty-six percent had elevated lactate deResponse Duration† 13 months 10.6 months hydrogenase (LDH) * Includes patients from more than 1 clinical trial and may and 28% had bulky not reflect reported data based on selective nature of patient disease (total tumor population † P = 0.957 bulk estimated to be >

500 g). Twelve patients (67%) had a response (6 CR, 33%) to retreatment with 131I-tositumomab, with a median duration of response of 10.6 months. The response duration was similar to that achieved with the initial treatment with 131I-tositumomab (13 months). The median duration of complete remission has not yet been reached but exceeds that seen in patients who achieved a CR to initial 131I-tositumomab treatment (median CR duration, 12 months) (Table 3). Grade 3/4 hematologic toxicities consisted of neutropenia in 50% and thrombocytopenia in 33% of the patients. The median times to absolute neutrophil count (ANC) and platelet recovery (to grade 2) were 9 days and 7 days, respectively. One patient died from neutropenic sepsis. These toxicities were similar to those experienced by these patients with their initial 131Itositumomab treatment. Nonhematologic toxicity consisted of elevation of thyroid-stimulating hormone in 1 patient. One patient required an infusion rate reduction due to pruritus. In addition, 3 patients developed myelodysplasia at 4.5-6.1 years postretreatment. Of note, none of the patients became HAMA positive after 131I-tositumomab retreatment (Table 4).

June 2001 • 13

Meeting Highlights Clinical Relevance: Retreatment of patients who have previously had an objective response with 131 I-tositumomab is safe and efficacious. Both the response rate achieved and the duration of response appear similar to that achieved with initial 131 I-tositumomab therapy. The toxicity profile is also similar to that seen with initial 131I-tositumomab treatment. __________________________________________________

High-Dose Tositumomab Plus Etoposide/Cyclophosphamide and Autologous Stem Cell Transplantation Shows Encouraging Efficacy in Patients with Relapsed Mantle Cell Lymphoma Non-Hodgkin’s lymphoma is both chemotherapy and radiation therapy sensitive. Regimens consisting of highdose chemotherapy combined with total-body irradiation and autologous stem cell transplantation (ASCT) have proven efficacious in patients with NHL. However, the dose of radiation delivered is limited by the tolerance of normal tissues. For this reason, radiolabeled antibodies such as 131I-tositumomab have been developed with the goal of delivering higher doses of radiation therapy targeted to the tumor cell while minimizing radiation of normal tissues. In a previous phase I trial, myeloablative doses of 131 I-tositumomab achieved a 79% CR rate in patients with relapsed B-cell NHL.11 However, because more than half of the patients on this trial had relapsed within 5 years, Dr. Press sought to improve the regimen using a combination of myeloablative doses of 131I-tositumomab with etoposide/cyclophosphamide (EC) followed by ASCT.9 This strategy led to encouraging 2-year PFS rates of 68% in patients with relapsed B-cell lymphoma and appeared to be superior to total-body irradiation combined with EC, although this comparison was not a randomized controlled comparison.

14 • June 2001

Table 5

High-Dose Tositumomab with High-Dose Etoposide/Cyclophosphamide and ASCT in Patients with Relapsed MCL: Treatment Schema

Day of Administration

Treatment

-14 (therapeutic)

131I-Tositumomab

Total Body Radiation Dose 25 cGy (n = 14) 23 cGy (n = 1) 20 cGy (n = 1) 60 mg/kg (n = 12)

-4

High-dose etoposide

-2

High-dose cyclophosphamide

30 mg/kg (n = 4) 100 mg/kg (n = 12)

0

60 mg/kg (n = 4)

Autologous stem cell reinfusion

Abbreviations: ASCT = autologous stem cell transplantation; MCL = mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive lymphoma that has a median PFS of 12 months and OS of 36 months. 12 Conventional high-dose chemotherapy and ASCT generally fail to produce durable remissions in these patients, and new means of eradicating tumor cells from these patients are currently being sought. Dr. Gopal and colleagues at Fred Hutchison Cancer Research Center and the University of Washington in Seattle undertook a trial using chemoradiotherapy with 131Itositumomab along with high doses of EC followed by ASCT in patients with relapsed MCL.13 The results were presented at the 2001 ASCO Meeting held in San Francisco. This study included patients under the age of 60 years who had CD20positive, relapsed or refractory MCL. Patients who had received previous radiation therapy to a total dose of > 20 cGy, had central nervous system lymphoma, had > 500 cc tumor bulk, or had splenomegaly were excluded. Treatment consisted of 131I-tositumomab on day -14 followed by etoposide on day -4 and cyclophosphamide on day -2. Fourteen patients were given 131I-tositumomab to deliver a total body radiation dose of 25 cGy, and 1 patient each received 131I-tositumomab to deliver total body radiation doses of 23 and 20 cGy. Etoposide was given at a dose of 60 mg/kg to 12 patients and 30 mg/kg

to 4 patients. Cyclophosphamide was given at a dose of 100 mg/kg for 12 patients and 60 mg/kg for 4 patients. Autologous stem cell reinfusion was done on day 0. The stem cell graft had been selected for CD34 stem cells alone in 3 patients (19%) or in combination with a B-cell depletion in 8 patients (50%). The treatment is described in Table 5. Sixteen patients were enrolled in this trial. The patients had a median age of 54 years (range, 35-59 years) and all had stage IV disease, with half of the patients having ≥ 2 extranodal sites involved with lymphoma. Fifty percent of the patients had elevated LDH and 50% had a high-intermediate risk score per the International Prognostic Index for lymphoma. The patients were heavily pretreated, having received a median of 3 prior chemotherapy regimens (range, 2-7 regimens). Eighty-eight percent had failed prior chemotherapy with anthracyclines, and 31% had failed a platinum-containing regimen. There was no transplant-related mortality in these patients. The median time to ANC recovery (> 500/μL) and platelet recovery (> 20,000/μL) was 12 days (range, 9-19 days) and 12 days (range, 8-24 days), respectively. Grade 3/4 Bearman toxicity (interstitial pneumonitis) was seen in only 1 patient. The efficacy of this chemoradiotherapy regimen was encouraging, with an

Meeting Highlights ORR of 82% (73% CR). At a median follow-up time of 14 months (range, 457 months) since transplantation, 75% of the patients remain progression free. All of the patients remain alive at the time of last follow-up. Of 10 patients who were positive by polymerase chain reaction (PCR) for bone marrow involvement with lymphoma prior to the transplant, 5 became PCR negative, suggesting a molecular CR. Clinical Relevance: The results of this phase I/II trial demonstrate the feasibility of a myeloablative chemoradiotherapy approach using 131I-tositumomab with EC followed by ASCT to treat patients with MCL. Both the PFS and OS at 14 months posttransplantation are encouraging particularly given the poor prognosis of this patient population. Overall the treatment was well tolerated with no transplant-related mortality. More extensive trials using this combined high-dose chemoradiotherapy approach are suggested. __________________________________________________

Treatment with Anti-CD22 Recombinant Immunotoxin BL22 Leads to High Response Rate and Eradication of Minimal Residual Disease in Patients with Hairy Cell Leukemia Hairy cell leukemia (HCL) is an uncommon B-cell lymphoproliferative disorder that usually presents with pancytopenia and the presence of “hairy” B cells in the blood and bone marrow. Pentostatin and cladribine are highly efficacious in newly diagnosed HCL patients and generally yield protracted periods of remission; however, some patients will eventually relapse. The risk of relapse is closely linked with the presence of minimal residual disease.14 Treatment options for patients refractory to these purine analogues are limited and primarily consist of another purine analogue or splenectomy.14 In 1 trial, rituximab was shown to be effica-

Figure 3 Molecular Structure of Anti-CD22 Recombinant Immunotoxin BL22

VL

VH -S–S-

Binding

Translocation

ADP-Ribosylation

Pseudomonas exotoxin

The variable regions of an anti-CD22 monoclonal antibody (RFB4) are linked using recombinant gene technology to the toxic portion of the Pseudomonas exotoxin. This leads to internalization of the toxin by CD22-positive cells, which causes termination of protein synthesis and cell death.

Overall the treatment was well tolercious in 8 patients with relapsed HCL.15 ated. The dose-limiting toxicities conBL22 is a recombinant immunosisted of reversible renal failure in 1 toxin targeted to the CD22 molecule patient and hemolytic uremic synfound on the surface of both normal drome (HUS) in 2 patients, which was and malignant B cells (Figure 3). The also reversible. It was established that toxic subunit of BL22, derived from using good hydration prior to administhe Pseudomonas exotoxin, is highly tration of BL22 prevented the renal potent, with the ability to kill cells that toxicity and HUS. A BL22 dose of 40internalize even 1 molecule of the toxin. 50 μg/kg on days 1, 3, and 5 was well Dr. Kreitman and colleagues from the tolerated and recommended for future National Cancer Institute in Bethesda, study. Maryland, undertook a phase I trial Among 16 evaluable patients, there using BL22 in patients with HCL rewere 11 CR, 1 unconfirmed CR, and 1 fractory to pentostatin or cladribine. PR, for an ORR of 81%. The median The results were presented at the 2001 duration of complete remission was ASCO Meeting held in San Francisco.16 12+ months. Of note, 1 CR was in a This trial enrolled patients with hisCLL patient whose response duration tologically confirmed CD22-positive exceeds 21 months. The 3 patients who HCL, chronic lymphocytic leukemia (CLL), or NHL that was refractory or did not respond were either treated at had recurred following purine analogue the lowest dose of BL22 or had pretherapy. Measurable disease was reexisting neutralizing antibodies. Of quired along with a Karnofsky perfornote, 3 patients who had a poor progmance status ≥ 60%. Treatment connosis variant of HCL achieved CR after sisted of escalating doses of BL22 (3-50 a median of 4 cycles (range, 1-9 cycles) μg/kg) given intravenously over 30 (Table 6). minutes on days 1, 3, and 5 of each 21day treatment cycle. Up to 16 courses were Table 6 Efficacy of BL22 in HCL given, with treatment Number of Patients 16 discontinued for dis11 (69%) ease progression or the Complete Remission* presence of neutralizing Median Duration of Complete Remission 12+ months antibodies. Unconfirmed CR/PR 2 (13%) Thirty-one patients were enrolled in this Response Rate 81% trial. Sixteen patients (52%) had HCL, 11 * Includes 3 patients with poor prognosis variant HCL and 1 patient with CLL (36%) had CLL, and 4 Abbreviations: CLL = chronic lymphocytic leukemia; HCL = hairy cell leukemia (13%) had NHL.

June 2001 • 15

Meeting Highlights Clinical Relevance: BL22 represents the first immunotoxin to produce a CR in cladribinerefractory or pentostatin-refractory HCL or a poor prognosis variant of HCL. This agent appears to be active in patients with CLL as well. BL22 at a dose of 40-50 μg/kg on days 1, 3, and 5 every 21 days administered after good hydration is well tolerated. The high response rate and apparent eradication of minimal residual disease by this immunotoxin are encouraging. ________________________________________________________________________________________________________

Thalidomide Shows Promise in Previously Untreated and Refractory Multiple Myeloma Approximately one half of patients with previously untreated multiple myeloma (MM) will not respond to chemotherapy, and nearly all of those who respond will eventually relapse.17 The treatment options for patients with MM are limited, and median survival remains at 3 years for these patients. New treatment options are therefore actively sought for these patients. Recent data suggest that angiogenesis may play a significant role in MM disease progression. Neovascularization, plasma cell angiogenic potential, and the secretion of matrix metalloproteinase-2 have all been associated with disease progression. 18 Thalidomide,

Table 7

which has antiangiogenic properties, has therefore been used to treat MM patients and has shown promising activity as a single agent, with durable responses in 26% of patients. 19 Investigators from the Mayo Clinic in Rochester, Minnesota, undertook a phase II trial of thalidomide in patients with relapsed MM. In addition, based on other data that suggest that thalidomide may have synergy with dexamethasone,20 patients with previously untreated MM were treated with thalidomide/dexamethasone. The preliminary results of this trial were presented by Dr. Rajkumar from the Mayo Clinic at the 2001 ASCO Meeting held in San Francisco.21 This trial enrolled 3 groups of patients. One group consisted of patients with smoldering or indolent MM who would not otherwise require treatment with chemotherapy. The second group consisted of patients with relapsed or refractory MM. Patients in the first and second groups were treated with increasing doses of thalidomide starting at 200 mg/day and increasing by 200 mg/day as tolerated on a biweekly basis to a total dose of 800 mg/day. The third group consisted of patients with newly diagnosed active MM. This group was also required to have ≥ 10% monoclonal plasma cells in the bone marrow, serum monoclonal protein ≥ 2.0 g/dL or ≥ 400 mg/dL monoclonal light

Study Design for Phase II Study of Thalidomide in Multiple Myeloma

Group Number

Eligibility Criteria

1

Smoldering/Indolent MM

Treatment Thalidomide 200-800 mg/day Increasing doses as tolerated on a biweekly basis

2

Relapsed MM

Thalidomide 200-800 mg/day Increasing doses as tolerated on a biweekly basis Thalidomide 200 mg/day* Dexamethasone 40 mg/day

3

Active MM No prior chemotherapy

days 1-4 (all cycles) days 9-12 and 17-20 (odd cycles only)

* The protocol initially called for a dose escalation in this group as well. However, due to toxicity in the first cohort of patients treated, the dose was held at 200 mg/day. Abbreviations: MM = multiple myeloma

16 • June 2001

Figure 4 Efficacy of Thalidomide in Patients with Multiple Myeloma (MM) Indolent MM Relapsed MM

38%

33%

Active MM

77% 0% 20% 40% 60% 80% 100% Response Rate

chain, an ECOG PS of 0-3, and adequate organ function. The third group of patients was treated with thalidomide 200 mg/day along with dexamethasone 40 mg/day on days 1-4 (all cycles), 9-12 (odd cycles only), and 1720 (odd cycles only). The protocol initially called for a thalidomide dose escalation in these patients with active, previously untreated MM as well as the other 2 groups. However, due to toxicity in the first cohort of patients treated, the dose of thalidomide was held at 200 mg/day (Table 7). Eighty-four patients were enrolled. Sixteen (19%) had smoldering/indolent MM, 42 (50%) had relapsed MM, and 26 (31%) had active MM. Thalidomide was active in subgroups of MM patients, with the highest efficacy among previously untreated patients with active MM. Among the 16 patients with smoldering/indolent MM, 6 had an objective response (38%). Five others (31%) had a minor response. The ORR was 33% among the 42 patients with refractory MM. In the 26 patients with newly diagnosed active MM, the response rate was 77% (Figure 4). Severe toxicities were uncommon in all 3 patient cohorts. In the 16 patients with smoldering/indolent MM, grade 3/4 somnolence was seen in 2 patients (13%) and 1 (6%) patient each experienced syncope and neutropenia. Grade 3/4 sedation and neuropathy were each seen in 4 patients (10%) with refractory MM, and constipation was seen in 2 patients (5%) with refractory MM.

Meeting Highlights Table 8

Grade 3/4 Toxicities Associated with Thalidomide Treatment for Multiple Myeloma (MM) Smoldering/Indolent MM (n = 16)

Relapsed MM (n = 42)

Active MM (n = 26)

Somnolence

2 (13%)

0

0

Syncope

1 (6%)

0

1 (4%)

Sedation

0

4 (10%)

1 (4%)

Neuropathy

0

4 (10%)

0

Constipation

0

2 (5%)

1 (4%)

Rash

0

0

3 (12%)

Arrhythmia

0

0

1 (4%)

Myalgia

0

0

1 (4%)

1 (6%)

0

0

Neutropenia

In the 26 patients with active MM, 3 patients (12%) developed a grade 3/4 rash and 1 patient (4%) each experi-

Clinical Relevance: This trial shows that thalidomide is active in patients with smoldering/ indolent and newly diagnosed/active, as well as relapsed, MM. For patients with smoldering/indolent or relapsed MM, single-agent thalidomide achieved encouraging response rates in approximately 35% of patients. In patients with newly diagnosed, active disease, an ORR of 77% was seen after treatment with thalidomide/dexamethasone. Thalidomide has a number of side effects that are minimized by the administration of lower doses of this drug.

enced syncope, sedation, constipation, arrhythmia, and myalgia (Table 8).

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J Clin Oncol 2000; 18:1316-1323. 08. Kaminski MS, Estes J, Tuck M, et al. Iodine I 131 tositumomab therapy for previously untreated follicular lymphoma (FL). Proc Am Soc Clin Oncol 2000; 19:5a (Abstract #11). 09. Press OW, Eary JF, Gooley T, et al. A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood 2000; 96:2934-2942. 10. Kaminski M, Estes J, Regan D, et al. Retreatment with Bexxar TM (tositumomab and iodine I-131 tositumomab) for patients with low-grade or transformed low-grade non-Hodgkin lymphoma (NHL). Proc Am Soc Clin Oncol 2001; 20:285a (Abstract #1139). 11. Press OW. Emerging immunotherapies for nonHodgkin lymphomas: the tortoise approaches the finish line. Ann Intern Med 2000; 132:916-918. 12. Weisenburger DD, Vose JM, Greiner TC, et al. Mantle cell lymphoma. A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group. Am J Hematol 2000; 64:190-196. 13. Gopal AK, Petersdorf S, Maloney D, et al. High-dose I-131-anti Cd-20 antibody therapy (tositumomab), etoposide, cyclophosphamide and autologous stem cell transplantation for patients with relapsed or refractory mantle cell lymphoma. Proc Am Soc Clin Oncol 2001; 20:280a (Abstract #1118).

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