Vol. 27 No. 1 THE January 2004 CLINICAL CANCER LETTER Cancer research news for clinicians

© Copyright 2004 American Society of Hematology: The Cancer Letter Inc. New Treatment Approaches For A Variety All rights reserved. Of Leukemias Described At ASH Meeting By Lawrence M. Prescott SAN DIEGO—A number of new treatment approaches appear to ASH Annual Meeting: be of real value in patients with a variety of leukemias including acute Trisenox In Children promyelocytic leukemia, chronic lymphocytic leukemia, acute myeloid With APML leukemia, and chronic myeloid leukemia, according to investigators . . . Page 2 presenting their findings at the 45th annual meeting of the American Society of Hematology last month. (Continued to page 2) Campath In CLL . . . Page 2

ASH Highlights: Improved Treatments For NHL, Genasense In AML Poor Prognostic Factors For B-Cell In Children . . . Page 3 By Lawrence M. Prescott SAN DIEGO—New therapeutic modalities for the treatment of Gleevec For CML adults with relapsed and aggressive non-Hodgkin’s lymphoma, as well as . . . Page 4 the identification of poor prognostic factors in children with advanced B- cell NHL and ways to combat this problem are proving to be of particular Zevalin In Mantle Cell benefit in developing effective therapeutic modalities for patients with . . . Page 4 forms of difficult-to-treat NHL, said investigators at the 45th annual meeting of the American Society of Hematology. Rituxan In NHL . . . Page 6 Pixantrone in Relapsed Aggressive NHL A variant of the CHOP (cyclophosphamide, vincristine, prednisone, Sphingosomal Vincristine and doxorubicin) regimen, which substitutes the new anthracycline-derived drug pixantrone for doxorubicin in elderly patients with aggressive NHL Tested in Relapsed NHL who had failed prior doxorubicin-containing CHOP, proved to be a feasible . . . Page 6 and safe approach for the treatment of multiple relapsed aggressive NHL in these difficult-to-treat patients, said Peter Borchmann, hematologist/ Poor Prognostic Factors oncologist, Klinik fur Innere Medizin, University of Cologne, Germany. In Children With B-NHL “This new agent, as a replacement for doxorubicin, in combination . . . Page 7 with the CHOP-like regimen is highly active and well tolerated and appears to be very promising in this setting,” Borchmann said. Arixtra Prevents VTE The CHOP chemotherapy regimen is the standard-of-care treatment . . . Page 8 for newly diagnosed aggressive NHL, said Borchmann.While 70 percent of the patients respond to the CHOP therapy, and the regimen is curative in up to 35 percent to 40 percent of patients, the prognosis is poor for PO Box 9905 individuals who have a recurrence of the disease. Furthermore, despite Washington DC 20016 (Continued to page 5) Telephone 202-362-1809 Study Tests Trisenox with a median age of 12 years, were enrolled in this study from 1998 to 2003. All patients had the In Children With APML hypergranular variety of APML with an average (Continued from page 1) white blood cell count at presentation of 3380/mm3. Highlights of research presentations follow. Induction therapy consisted of intravenous arsenic trioxide 0.15 mg/kg daily until hematologic Arsenic Trioxide for APML remission, or a maximum of 60 days. This was In a study of the role of arsenic trioxide followed by a single course of consolidation therapy (Trisenox, Cti) in the primary treatment of pediatric lasting 28 days, one month after induction therapy. patients with acute promyelocytic leukemia, positive Monthly cycles of maintenance therapy, each lasting data was provided regarding the value of arsenic for 10 days, were administered for six months. trioxide in a pediatric setting, said Mammen Chandy, Nine of the 10 patients achieved hematologic a hematologist/oncologist at Christian Medical remission, Chandy said. One patient died on day 5 of College, Vallore, TN, India. therapy due to an intracranial hemorrhage. Median “Arsenic trioxide can achieve hematologic and time to hematologic remission was 49 days, ranging molecular remission in newly diagnosed children with from 41 to 60 days. Seven patients completed therapy; APML with no significant short-term toxicity,” said two are still on treatment. All patients continue in Chandy. “Long-term followup in a larger number of hematologic remission with a median followup of 24 patients is needed to evaluate late effects and to study months, ranging from 3 to 57 months. the minimum dose and duration of therapy with All 9 patients in hematologic remission are also arsenic trioxide required to reach a sustained in molecular remission, using a nested RT-polymerase remission in children with APML.” chain reaction with a sensitivity of 10-4 in peripheral Arsenic trioxide is a pharmaceutical grade blood, with a median followup of 22 months, ranging arsenic compound that is used in the U.S., Europe, from 1 to 57 months. and a number of countries in Asia to treat patients There was no significant short-term toxicity, with relapsed or refractory APML, Chandy said. Chandy said. Also, there is no cardiac or hepatic There is, however, very limited data on the role of toxicity. Minor hyperpigmentation of the skin and arsenic trioxide in the primary treatment of pediatric icthyosis occurred in five patients, but resolved after patients with APML. To assess the value of arsenic treatment was completed. Increased sleep and mild trioxide in this setting, 10 children aged 6 to 14 years, reversible peripheral neuropathy were seen in one patient each. Hyperleukocytosis was reported in 5

Member, patients, but this resolved with treatment. THE CLINICAL Newsletter and Electronic Publishers Association

CANCER LETTER World Wide Web: http:// Alemtuzumab in CLL www.cancerletter.com The administration of alemtuzumab (Campath, Publisher: Kirsten Boyd Goldberg Berlex) for the elimination of minimal residual disease Editorial Assistant: Shelley Whitmore Wolfe after chemotherapy in patients with CLL results in a clearing of residual bone marrow disease in most Editorial: 202-362-1809 Fax: 202-318-4030 patients and a molecular remission in better than a PO Box 9905, Washington DC 20016 third of patients in whom polymerase chain reaction E-mail: [email protected] results were available, reported Susan O’Brien, professor of medicine, University of Texas M.D. Customer Service: 800-513-7042 Anderson Cancer Center. PO Box 40724, Nashville TN 37204-0724 “These and other data being presented at the American Society of Hematology meeting are THE CLINICAL CANCER LETTER (ISSN 164-985X). encouraging because they demonstrate that Campath Published monthly, subscription $99 per year, by The Cancer Letter Inc. All rights reserved. None of the content of this publication is a safe and effective treatment that induces a durable may be reproduced, stored in a retrieval system, or transmitted in response in CLL patients who show evidence of any form (electronic, mechanical, photocopying, facsimile, or residual disease following chemotherapy, improving otherwise) without prior written permission of the publisher. remissions induced by chemotherapy,” O’Brien said. Violators risk criminal penalties and $100,000 damages. “Furthermore, given the extent of treatment in these

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January 2004 patients, the median time to progression of 42 months combined with a daunorubicin and cytarabine was very encouraging.” chemotherapy regimen proved to be a safe, potentially Alemtuzumab targets the CD52 antigen found active approach for the treatment of patients over on the surface of both cancerous and noncancerous the age of 60 with acute myeloid leukemia, according lymphocytes, but not on the surface of cells that have to Guido Marcucci, assistant professor of medicine, the ability to mature and differentiate into new, healthy Ohio State University. lymphocytes, O’Brien said. It is the first and only “Our data suggest that Genasense in humanized monoclonal antibody approved for B-CLL combination with standard 7+3 cytarabine- and has been shown to be of proven efficacy in daunorubicin induction is feasible with no additional patients who have failed both alkylating agents and toxicity, including cardiotoxicity, observed beyond that fludarabine phosphate treatment. commonly seen with daunorubicin and cytarabine The purpose of this trial was to evaluate the therapy,” Marcucci said. “The 10-day infusion of efficacy of alemtuzumab in patients who had partial Genasense at 7 mg/kg daily is well tolerated.” remission (PR) after chemotherapy but had residual Oblimersen sodium works by inhibiting the disease in their bone marrow and/or lymph nodes, production of Bcl-2, a protein made by cancer cells O’Brien said. Fifty-eight patients with a PR, nodular that is thought to block chemotherapy-induced cell PR (nPR), or complete remission (CR) with evidence death, Marcucci said. Expression of Bcl-2 may render of disease on immunophenotyping were eligible. AML cells resistant to chemotherapy and has been Alemtuzumab was administered at a dose of 10 mg associated with unfavorable outcome. Obimersen intravenously three times a week (TIW) for four sodium is a phosphorothiate 18-mer antisense weeks. This was followed by a four-week rest period. oligonucleotide directed against the first six codons If disease was still present, patients were given of Bcl-2. By reducing the amount of Bcl-2 in cancer another four weeks of alemtuzumab at 30 mg TIW. cells, oblimersen sodium may enhance the All patients received prophylactic trimethoprin-sulfa effectiveness of current anticancer treatments. and valacyclovir. Treatment was revised after the first Previous results of “in vivo” down-regulation of 23 patients entered in the study were assessed, with the Bcl-2 target by oblimersen sodium and a 45% the dose being changed to 30 mg TIW for four weeks response rate in a pilot study of oblimersen sodium with no further therapy for subsequent patients. therapy combined with fludarabine in refractory or In the assessment of efficacy, 56 patients were relapsed acute leukemia prompted this study of evaluable. The overall response rate was 46%, with oblimersen sodium in combination with cytarabine and a response rate of 39% in the initial 23 patients on daunorubicin in high-risk, previously untreated alemtuzumab 20 mg versus 52% in the patients patients with AML, Marcucci said. treated at the higher dose of 30 mg. Oblimersen sodium was given at a dose of 7 At the start of treatment with alemtuzumab, 33 mg/kg over 10 consecutive days—a higher total dose patients were in PR, 18 in nPR, and 5 patients in CR. than had been administered in previous clinical trials. Nine of the 18 patients in nPR achieved CR and 13 Patients over age 60 were eligible for enrollment in of 33 patients in PR improved to nPR or CR. the study but were enrolled in separate cohorts of de Marrow disease was more likely to be cleared novo and secondary AML. Escalating doses of the than residual adenopathy, O’Brien said. Residual bone chemotherapeutic agents daunorubicin and cytarabine marrow disease was cleared in most patients, with were administered for 7 consecutive days beginning 11 of 29 patients achieving a molecular remission. on day 4 of treatment. Median time to progression was 42 months in To date, 29 patients have been treated and are responders. Non-hematologic infusion-related events evaluable for response and safety, Marcucci said. such as fever, chills, and the like were common with Thirteen of these patients were diagnosed with de initial doses of alemtuzumab, but were grade 1 and novo AML and 16 with secondary AML, known to 2. Reactivation of cytomegalovirus was the main be highly resistant to conventional therapy. Sixteen drug-related adverse effect, with all but one patient of the 29 patients responded to therapy, with 13 responding to appropriate treatment. patients achieving complete remission . Of these 13 patients who achieved complete remission, 7 had Oblimersen Sodium plus Chemotherapy in AML secondary AML. Three additional patients showed Oblimersen sodium (Genasense, Genta/Aventis) no evidence of leukemia after treatment, but failed

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Page 3 to achieve a satisfactory recovery of normal white This benefit increased over time. At 24 months blood cell counts of more than 1500/µL and platelets followup, 48% of the evaluable patients on high-dose of more than 100,000 µL for at least four weeks after imatinib had no evidence of disease compared to 17% induction. of those on low-dose imatinib. In the group receiving Patients with CR received consolidation with standard dose imatinib, four patients have progressed oblimersen sodium 7 mg/m2 daily iv on days 1 to 8 to advanced disease, but, to date, no patients using plus high-dose cytarabine 2000 mg/m2 daily iv on days the higher dose have progressed. Now 30 months 4 to 8, Marcucci said. Earlier results in the first 10 into the studies, data are still being accrued. patients with CR showed that 4 patients received one Overall, imatinib was well tolerated at the higher course of consolidation and 6 patients received 2 dose, Cortes said. Initially, some patients on the higher courses. No unexpected or dose-limiting toxicities dose had more myelosuppression than those on the were observed in patients treated in this study. lower dose, with more anemia, neutropenia, and “Based on the results of this study, the thrombocytopenia, but there was no significant daunorubicin-cytarabine chemotherapy regimen will difference in drug tolerance between the two groups be incorporated into a randomized trial with or without long term. At 6 and 12 months, the median actual Genasense in patients with newly diagnosed AML, dose for the group started at 800 mg was still 800 65 years or older,” Marcucci concluded. “The study mg, compared to 400 mg for the group started at 400 will be a phase III trial conducted by the Cancer and mg. Leukemia Group B, with attention given to biologic correlates.” Zevalin Regimen Effective Imatinib for CML In Mantle Cell Lymphoma High-dose imatinib (Gleevec, Novartis) results By Lawrence M. Prescott in higher rates of complete cytogenetic and molecular SAN DIEGO—Results from a phase II clinical remissions in patients with previously untreated trial indicated that 90Yttrium (90Y) ibritumomab chronic myeloid leukemia than low-dose imatinib, with tiuxetan (Zevalin, Biogen Idec) radioimmunotherapy twice the standard daily dose producing significantly is a promising approach for the treatment of patients higher response rates, said Jorgas Cortes, deputy with relapsed or refractory mantle cell lymphoma, chair and professor of medicine, department of according to a presentation at the American Society leukemia, M.D. Anderson Cancer Center. of Hematology annual meeting here last month. “This is a relatively small study, but there is no “Our data demonstrate that Zevalin has clinical question that patients who use higher doses of Gleevec ac-tivity in patients with heavily pretreated relapsed clearly showed improvement compared with patients or refractory mantle cell lymphoma,” said Anas who used a standard dose,” Cortes said. “We feel so Younes, professor of medicine, M.D. Anderson comfortable with what we are finding that patients Cancer Center. “Based on these encouraging results, being treated at M.D. Anderson already are being further studies in mantle cell lymphoma are warranted given the higher dose therapy.” to address the role of this new agent earlier in the To reach these conclusions, the results of two course of the disease.” ongoing consecutive trials being conducted by the The management of relapsed MCL remains M.D. Anderson Cancer Center were compared, one challenging, Younes said. While some patients with using standard dose imatinib 400 mg daily and the sensitive relapsed MCL may benefit from stem cell other testing the higher dose of imatinib 800 mg given transplantation, the majority of patients with relapsed as 400 mg twice daily, in newly diagnosed patients or refractory disease will not be candidates for stem with CML in the early chronic phase. At 18 months cell transplantation because of advanced age, disease followup, there were 164 evaluable patients, 114 refractoriness, or lack of a suitable donor. patients on high-dose imatinib and 50 patients on low- Furthermore, salvage chemotherapy regimens are dose imatinib. rarely helpful in this setting. Novel treatment At this point in the study, 28% of the evaluable strategies are needed. patients treated with 800 mg of imatinib daily had no Recent advances in radioimmunotherapy have molecular evidence of disease, compared to only 7% demonstrated the clinical utility of one such agent, of the evaluable patients on 400 mg of imatinib daily. 90Y ibritumomab tiuxetan, in patients with relapsed

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January 2004 or refractory low-grade follicular or B-cell non- Early Trials: Hodgkin’s lymphoma, Younes said. The activity of Phase I Trial Of Pixantrone 90Y ibritumomab tiuxetan in patients with relapsed or refractory MCL, however, is still unknown. Indicates Potential For NHL Therefore, a phase II clinical trial was conducted (Continued from page 1) to determine the efficacy and safety of 90Y its impressive anti-tumor activity, the CHOP regimen ibritumomab tiuxetan in patients with relapsed or cannot be used to re-treat the 60 percent to 65 percent refractory MCL. of patients who relapse following CHOP because of Patients were included in the study if they had the cumulative cardiotoxicity associated with one of histologically confirmed relapsed or refractory MCL, its constituent agents, doxorubicin, a well-known were over 18 years of age, had an absolute neutrophil anthracycline. count (ANC) of 1500/mm3 or more, a platelet count Pixatrone is an investigational anthracycline- of 100,000/mm3 or more, adequate hepatic and renal derived drug designed to increase anti-tumor activity function, and bone marrow involvement of less than and decrease the possibility for cardiac toxicity seen 25%, Younes said. with the currently marketed anthracycline drugs, Patients with pretreatment platelet counts Borchmann said. When administered as a single agent greater than 150,000/mm3 receive a 90Y ibritumomab in patients with refractory or relapsed NHL, tiuxetan dose of 0.4 mCi/kg while those with platelet pixantrone has demonstrated efficacy with a counts of 100,000/mm3 to 149,000/mm3 received a favorable toxicity profile. In order to further develop dose of 0.3 mCi/kg. The 90Y ibritumomab tiuxetan this new drug, it was necessary to determine the therapeutic regimen is administered in two steps. maximum tolerated dose of pixantrone in a CHOP- The first step includes an imaging dose of an like regimen substituting pixantrone for doxorubicin. infusion of rituximab (RituxanR, Biogen IDEC) 250 A phase I trial, therefore, was designed to mg/m2 followed by 111Indium ibritumomab tiuxetan 5 examine the safety and efficacy of pixantrone when mCi. The second step, which is the therapeutic dose, substituted for doxorubicin in the CHOP regimen follows step one by seven to nine days and consists among patients who had failed prior doxorubicin- of a second infusion of rituximab 250 mg/m2 followed containing CHOP therapy for aggressive NHL. by 90Y ibritumomab tiuxetan at 0.4 mCi or 0.3 mCi, The trial was an open-label, dose ranging study not to exceed 32 mCi. with pixantrone administered on day 1 of a 21-day To date, 13 patients have been enrolled in the cycle, in combination with fixed doses of trial and, of these, 12 are assessable for teratment cyclophosphamide, vincristine, and prednisone, response and toxicity. Three patients were given the Borchmann said. The trial recruited 23 patients across reduced dose of 90Y ibritumomab tiuxetan 0.3 mCi/ four dose levels: 80 mg/m2, 100 mg/m2, 120 mg/m2, kg. The overall response rate in this group of patients and 150 mg/m2. Besides determining the MTD of was 33%, with three patients having complete pixantrone in the patients, efficacy was determined remissions (CR) and one patient having a partial based on the objective response rate. Secondary remission (PR). Duration of response was 6, 9, 5+, objectives included the evaluation of pixantrone’s and 4+ months in the four responders. One patient toxicity profile in the schedule, the dose limiting had a minor response lasting 8+ months and two toxicity, and pharmacokinetics. Patients with patients had stable disease, with durations of response histologically confirmed relapsed aggressive NHL, of 11 months and 6+ months. Responses were defined as diffuse large B-cell NHL, follicular NHL observed in patients who were given either 0.3 or WHO grade III, transformed follicular NHL, and 0.4 mCi/kg. mantle cell lymphoma, were included. With regard to the safety profile of the 90Y Concerning the dose determination and safety ibritumomab tiuxetan regimen, the treatment was well results, pixantrone 150 mg/m2 at day 1 every three tolerated, with the most common toxicity being weeks in combination with the standard fixed doses hematologic. Nadir platelet counts and neutrophil of cyclophosphamide and vincristine on day 1 and counts occurred six to eight weeks after therapy. prednisone from days 1 to 5 was a feasible and well Three patients required one to three platelet tolerated regimen. Dose escalation of pixantrone transfusions and one patient was hospitalized with beyond 150 mg/m2 was not warranted as active neutropenic fever. myelosuppression was observed beyond that level,

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Page 5 Borchmann said. Toxicities were predominantly randomized to receive either six-to-eight standard hematological and the dose limiting toxicity was cycles of CHOP (cyclophosphamide, doxorubicin, neutropenia. No grade IV non-hematological toxicity vincristine, and prednisone) chemotherapy alone or was observed. in combination with four to five doses of rituximab. Also, cardiac side effects were infrequent. Two After completing the induction phase, 352 evaluable patients had an asymptomatic reduction in their patients whose tumors responded to R-CHOP or cardiac ejection fraction to 20 percent below their CHOP alone were re-randomized to receive either baseline value and one patient with a history of rituximab maintenance therapy of four doses of coronary artery disease and diabetes developed Grade rituximab weekly, every six months for two years, or II angina pectoris. The low rate of cardiac events observation with no further therapy. was very encouraging, considering the age of the An analysis of the primary endpoint of the patients in the study and levels of pre-treatment with induction phase of the study—time to treatment traditional anthracyclines. failure—showed that patients who received R-CHOP With regard to efficacy, pixantrone in the CHOP followed by either rituximab maintenance or variant regimen was highly effective against relapsed observation had a trend toward prolongation of TTF aggressive NHL, said Borchmann. compared to those who received CHOP alone Out of 22 evaluable patients, the overall response followed by rituximab maintenance or observation, rate was 77 percent and the disease control rate was said Havermann. The addition of rituximab to CHOP, 95 percent. Thirteen patients (59 percent) however did not influence overall response or overall experienced a complete response or unconfirmed survival in the induction phase, overall response rates complete response, four (18 percent) had a partial being 77 percent in R-CHOP and 76 percent in CHOP response, and four (18 percent) achieved stable with no difference in overall survival. disease. Furthermore, patients responded at every According to the results from the weighted pixantrone dose level and seven of the seven patients analyses, patients who received R-CHOP induction in the 150 mg/m2 dose level all responded. Patients therapy experienced a significant prolongation of TTF, now are being followed for their duration of response. with a 59 percent increase in median failure-free sur- vival, and a 45 percent increase in overall survival Rituximab in NHL compared to patients who received induction therapy In a comparison study of rituximab (Rituxan, with CHOP alone, said Haberman. Genentech/Biogen/Idec) plus CHOP versus CHOP alone in the treatment of elderly patients with Sphingosomal Vincristine for NHL aggressive NHL, rituximab played a significant role Sphingosomal vincristine (Inex Pharmaceuticals, in the induction phase as well as during the Canada) appears to be a valuable addition to the maintenance phase, said Thomas Haberman, of the physician’s arsenal against multiple relapsed diffuse, Mayo Clinic. aggressive NHL, said Jane Winter, medical director “While the addition of rituximab to induction of the hemopoietic stem cell processing laboratory, CHOP did not influence overall response rates or Northwestern University, and spokesman for the early progression, an unplanned weighted analysis, PIVOTAL (SPhIngosomal Vincristine fOr the performed to remove the confounding effect of Treatment of Aggressive Lymphoma) Multicenter maintenance therapy, demonstrated improvement in Study Group. time to treatment failure and overall survival, “Single agent sphingosomal vincristine proved compared to patients who received induction CHOP to be an active and well-tolerated therapy for multiple therapy alone,” said Haberman. “With regard to the relapsed aggressive NHL,” said Winter. “Responses primary endpoint for the maintenance phase of the occurred in patients previously treated with multiple study, rituximab maintenance demonstrated a benefit prior therapies including those relapsing after in both TTF and OS among patients who received autologous stem cell transplant.” CHOP alone during the induction phase.” The prognosis for patients with recurrent or The study was designed with two distinct refractory diffuse aggressive NHL is poor, Winter randomizations, Haberman said. The first said. Typically, the rate and duration of response randomization, called the induction phase, evaluated decrease with each consecutive line of therapy 546 patients aged 60 years or older who were confirming the need for new approaches.

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January 2004 Sphingosomal vincristine is a novel formulation of Poor Prognostic Factors Identified vincristine encapsulated in sphingomyelin liposomes In Children with Advanced B-NHL or sphingosomes. Encapsulating the cell-cycle A poor response to initial reduction therapy and specific vincristine in sphingosomes results in better combined bone marrow and central nervous system cell retention. disease have been identified as poor prognostic In animal studies, this formulation prolongs the factors in children with advanced B-non-Hodgkin’s circulation time of vincristine in plasma, increases the lymphoma, said Mitchell Cairo, of the Children’s accumulation of drug at the tumor site, and improves Oncology Group. the antitumor efficacy of vincristine. An earlier small “Patients with an initial poor response to a low study demonstrated that sphingosomal vincristine was intensity reductive regimen of cyclophosphamide, well tolerated at 2.0 mg/m2 and showed clinically vincristine, and prednisone may require an alternative significant activity in relapsed or refractory NHL. therapy other than the current FAB approach,” said A total of 119 patients with relapsed or Cairo. “Since the initial response to therapy appears refractory, diffuse, aggressive NHL were enrolled in to be critically important in advanced childhood B- the PIVOTAL multicenter study, Winter said. Ten NHL, future strategies should strongly consider percent of the patients had transformed disease. All intensifying the cytoreductive phase of treatment and patients had two or more combination chemotherapy adding recombinant urate oxide (rosburicase) (Elitek, regimens, one of which contained an anthracycline Sanofi Synthelabo) to minimize severe tumor lysis and at least a minor response to first-line syndrome in order to maximize the complete response chemotherapy. Patients had multiple poor prognostic rate following initial therapy and improve the four- characteristics including a median age of 60 years, year event-free survival.” predominantly Ann Arbor stage III-IV, elevated LDH Studies over the past 20 years have in 66 percent of patients, refractory disease with no demonstrated that with intensive, short duration multi- response to last regimen in 46 percent of patients, agent chemotherapy, the prognosis for children with and relapse within six months of last regimen in an advanced bone marrow and/or CNS Burkitt’s or additional 26 percent of patients. Burkitt’s-like lymphoma has improved significantly, Sphingosomal vincristine was administered at Cairo said. The prognostic importance of the 2 mg/m2 without dose capping as a one-hour iv infusion completeness of initial response to reduction therapy every two weeks for up to 12 cycles, said Winter. in children, however, is unknown. The current Dose reductions of 10 percent were allowed for approach to initial treatment for advanced childhood patients with grade 4 neutropenia lasting greater than B-NHL uses a low intensity reductive regimen of 5 days, grade 3-4 thrombocytopenia, and non- cyclophosphamide 300 mg/m2 on day 1, vincristine hematologic grade 3 toxicity. Objective response 1.5 mg/m2 on day 1, and prednisone 60 mg/m2 daily evaluation was performed at six weeks and for 5 days. This is done, in large part, to avoid severe approximately every eight weeks thereafter. The tumor lysis syndrome. median number of sphingosomal vincristine dose was Initially, 1,138 patients were registered into the four, ranging from 1 to 20. International FAB LMB 96 Trial from May 1996 to The overall response rate was 25 percent in June 2001, said Cairo. Of the 698 pediatric patients these heavily pretreated patients, with 8 patients (7 with B-cell NHL evaluable for efficacy, 242 children percent) having a complete response and 22 patients had advanced BM + CNS B-cell NHL. In this group (18 percent) having a partial response, said Winter. of patients, randomization of standard intensity A further 31 patients (26 percent) had stable disease. therapy versus reduced intensity therapy was Response rate did not decline significantly with assessed comparing efficacy in the two groups. In increasing numbers of prior therapies and the overall addition, the question of the value of cranial irradiation response rate was a significantly higher 46 percent in patients with CNS disease also was considered, in patients with sensitive disease. The median time particularly with respect as to whether or not cranial to disease progression was 3 months for all patients. irradiation could be deleted. Neuropathy was the most common toxicity, occurring The patients, with a median age of 8 (range 1 to in 32 percent of patients with 13 percent withdrawing 19 years), 189 of whom were males and 153 of whom from therapy. Hematologic toxicity was seen but was were females, were divided in groups based on manageable. whether they had bone marrow disease (52 percent),

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Page 7 CNS disease (19 percent), or a combination of both medical patients, the ARTEMIS (ARixtra for (29 percent). The response to the initial COP ThromboEmbolism prevention in a Medical Indication reduction phase on day 7 was defined as CR, Study) clinical trial was undertaken. incomplete response, or non-response (less than 20 The multinational, randomized, double-blind trial percent reduction). compared fondaparinux thromboprophylaxis 2.5 mg In a multivariate analysis, with a median subcutaneously once daily to placebo in patients, age followup of 42 months, initial day 7 tumor response 60 or older, hospitalized for a wide range of acute to COP reduction therapy was significantly important medical conditions including cardiac, respiratory, for 4-year event-free survival, Cairo said. Patients infections, and inflammatory disease, and expected having a CR had a 4-year EFS rate of 92 + 4 percent, to remain bedridden for four days or more. those with an IR had a 4-year EFS rate of 78 + 3 In total, 849 patients, 53.4 percent with a history percent, and patients with an NR had a 4-year EFS of cancer, were randomized to fondaparinux (429 pts) rate of 27 + 15 percent. Patients with combined BM or placebo (420 pts), with treatment continued for 6 + CNS disease at diagnosis had a significantly inferior to 14 days. The primary efficacy outcome was 4-year EFS rate of 61 + 6 percent compared to those confirmed, adjudicated VTE up to day 15, based on with BM disease only with an EFS rate of 86 + 3 bilateral venography, performed between days 6 and percent or patients with CNS disease alone with a 4- 15, or confirmed symptomatic events. year ESF rate of 81 + 6 percent. In a comparison of The main safety outcome was major bleeding, patients who underwent cranial irradiation and bleeding requiring surgical intervention, bleeding historical controls without cranial irradiation, it was associated with a greater than 2 g/dL fall in found that cranial irradiation could be eliminated. hemoglobin, and or transfusion of two or more units. “Finally, an overall comparison of the efficacy Assessment of efficacy was based on data from 644 of standard intensity therapy and reduced intensity evaluable patients. The incidence of confirmed VTE therapy pointed out that while reduced intensity with placebo was 10.5 percent (34/323). therapy was associated with less morbidity, the Fondaparinux prophylaxis led to a significant decrease outcome was inferior to that seen with standard in VTE incidence, to 5.6 percent (18/321), intensity therapy,” said Cairo. “Patients with both representing a relative reduction in risk of 49.5 bone marrow and central nervous system involvement percent. No symptomatic VTE occurred up to day had a significantly inferior outcome with reduced 15 in the fondaparinux-treated patients (0/429) vs. a intensity therapy.” 1.2 percent incidence (5/420) of fatal PE in the placebo group. By day 32 followup, 14 patients in the Fondaparinux Prevents DVT fondaparinux group (3.3 percent) had died compared In Acutely Ill Medical Patients to 25 patients in the placebo group (6.6 percent). By Lawrence Prescott SAN DIEGO—Fondaparinux (Arixtra, Sanofi Clinical Trials Approved By NCI Synthelabo) is of considerable value in the prevention The National Cancer Institute’s Cancer Therapy of venous thromboembolism in acutely ill patients, Evaluation Program Approved the following clinical according to a presentation at the American Society research studies last month. For further information of Hematology annual meeting. about a study, contact the principal investigator listed. Alexander Cohen, of the Division of Medicine, Phase II Trial of Triapine in Combination with Guys, Kings, and St. Thomas School of Medicine, Gemcitabine as Second Line Treatment of Non-Small London, UK, said Arixtra significantly reduced the Cell Lung Cancer. Eastern Cooperative Oncology risk of VTE in acutely ill patients by almost 50 percent Group, protocol E1503, Traynor, Anne, phone 608- up to day 15 and, compared with placebo, significantly 262-5092. reduced the incidence of fatal pulmonary embolism. Injection of AJCC Stage IIB, IIC, III and IV Fondaparinux is approved for VTE prevention Melanoma Patients with a Multi-Epitope Peptide in patients undergoing major orthopedic surgery, a Vaccine Using GM-CSF DNA as an Adjuvant: A population in the highest category of VTE risk, Cohen Pilot Trial to Assess Safety and Immunity. Memorial said. To measure the efficacy and safety of Sloan Kettering Cancer Center, protocol Pilot 5906, fondaparinux for the prevention of VTE in acutely ill Wolchok, Jedd phone 212-639-6570.

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January 2004