THE ONCOLOGY REPORT (Fall 2006) :: Leukemia

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THE ONCOLOGY REPORT (Fall 2006) :: Leukemia

  1. 1. HEMATOLOGICMALIGNANCIES:LEUKEMIA Hematologic Malignancies Fall 2006 / THE ONCOLOGY REPORT 69 L ong-term benefits of imatinib (Gleevec) for patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase have been confirmed by data from the 5-year update of the landmark phase III IRIS (Inter- national Randomized Study of In- terferon vs STI571), reportedly the Five-year IRIS data confirm high response rates with imatinib in CML patients Yearly risk of disease progression continues to drop over time as well script levels, compared with 98% (n = 54) for those with a < 3 log reduction and 87% (n = 88) for those without a CCyR (P < 0.001). The overall survival rate at 5 years is 89%, compared with no more than 50% with prior thera- pies. “This represents a complete turnaround in the prognosis for pa- tients with this disease,” Dr. Druker revealed. “Prior to this, we had to project what the 5-year survival data would be and worried that the risk of relapse might increase. With these data, we have increased confidence in this targeted therapy,” he added. O nly 5% of patients dis- continued imatinib be- cause of side effects. Grade 3/4 hematologic/liver tox- icities ranged from 5.3% (elevat- ed liver enzyme levels) to 16.7% (neutropenia), and other drug- related adverse events occurred at a rate of 17%. Importantly, new-onset side effects declined sharply after 2 years and were reduced to 2% after 4 years. The overall risk of disease pro- gression to advanced phase is low and is associated with the degree of response, regardless of when it is achieved. “Our hope is that patients can stay on this drug indefinitely,” he concluded. Druker BJ, Guilhot F, O’Brien S, et al. Long-term benefits of imatinib for patients newly diagnosed with chronic myelogenous leukemia in chronic phase: the 5-year update from the IRIS study. abstract 6506 standard of first-line therapy for all CML patients,” pronounced IRIS lead author Brian J. Druker, MD, from Oregon Health & Sci- ence University Cancer Institute in Portland. That confidence emerged from strong findings among 382 (69%) of the initial 553 patients assigned to imatinib remaining on treatment at 5 years. M ost striking was the con- tinuing improvement in responses over time for those with complete hematologic response (CHR), major cytogenetic response (MCyR), and complete cytogenetic response (CCyR). Par- ticularly impressive was the contin- ued rate of achievement of a CCyR beyond the 1-year time point, Dr. Druker added. CCyR responses achieved late remained durable. In addition, estimated 60-month rates showed only 7% of patients on imatinib progressing to accelerated phase or blast crisis (AP/BC) and 83% remaining event-free. Also, annual event rates declined over time, with risk dropping from 3.3% in the first year to 0.9% in the fifth year. Risk of disease progression to AP/BC declined over the same pe- riod, from 1.5% to 0.6%. Comparing rates of survival without disease progression to AP/ BC among those with a CCyR with those without an MCyR (defined by the presence of > 35% of Phila- delphia chromosome positive), the investigators reported that the dif- ference from 97% to 81% was sig- nificant (P < 0.001). Looking more closely at molecular responses, Dr. Druker noted that survival without AP/BC at 18 months was 100% for individualswithCCyR(n=139)and a ≥ 3 log reduction in Bcr-Abl tran- Cumulative best response with imatinib At 12 At 60 Response months (%) months (%) CHR 96 98 MCyR 85 92 CCyR 69 87 CHR = complete hematologic response; MCyR = major cytogenetic response; CCyR = complete cytogenetic response Hematologic Malignancies Leukemia Commentary by Steven E. Coutré, MD The American Society of Clinical Oncology (ASCO) meeting served as a showcase for ongoing advances in the treatment of chronic myeloid leukemia (CML). Brian Druker, from Oregon Health & Science University Cancer Institute in Portlant, presented the 5-year update of the IRIS study involving newly diag- nosed, imatinib-treated patients. Sixty-nine percent of the original 553 patients remained on imatinib therapy, with 98% of patients maintaining a complete hematologic response (CHR). There was continued improvement in complete cytogenetic response (CCyR) when compared with the 12-month data (87% vs 69%), and overall survival remained high (89%). For the first time, a decline in annual event rates was reported. For instance, only 7% of patients had pro- gressed to accelerated phase (AP) or blast crisis (BC), with the risk declining from 1.5% during the first year to 0.6% in the fifth year. For those who did not achieve at least a major cytogenetic response, the risk of progression to AP or BC was 19%, versus 3% if a major or CCyR was attained. On the molecular level, ≥ 3 log reduction in Bcr-Abl transcript levels at 18 months predicted 100% survival without progression to AP or BC. —Steven E. Coutré, MD Comment INDEX Alemtuzumab (Campath), 73 Chlorambucil (Leukeran), 73 Clinical trials CAM 307, 73 IRIS, 69 START-R, 71 Cyclophosphamide, 74 Dasatinib (Sprycel), 71 Fludarabine, 74 Hematopoietic cell transplantation, 72 Imatinib (Gleevec), 69 Nilotinib (AMN107), 71 Oblimersen (Genasense), 74 Rituximab (Rituxan), 74 Recent survival data represent a complete turnaround in the prognosis for CML. longest ever follow-up study of a targeted cancer therapy. The study, which began in mid-2000, involved 1,106 patients at 117 centers in 16 countries. High overall survival, in- creasing response, and decreasing disease progression validate the use of imatinib in this setting. “Imatinib is confirmed as the For more meeting reports, visit www.OncologyReport.com© 2006 Elsevier Inc. All rights reserved.
  2. 2. HEMATOLOGICMALIGNANCIES:LEUKEMIA 70 THE ONCOLOGY REPORT / Fall 2006 Hematologic Malignancies For more meeting reports, visit www.OncologyReport.com© 2006 Elsevier Inc. All rights reserved.
  3. 3. HEMATOLOGICMALIGNANCIES:LEUKEMIA Hematologic Malignancies Fall 2006 / THE ONCOLOGY REPORT 71 Dasatinib achieves responses in imatinib-resistant CML Accelerated approval recommended for effective alternative to imatinib N ilotinib (AMN107), an investigational, next-gen- eration tyrosine kinase inhibitor, is clinically active with an acceptable safety and toler- ability profile in patients with imatinib (Gleevec)-resistant/intol- erant chronic myelogenous leu- kemia (CML) in various stages of Nilotinib yields promising results in imatinib-refractory CML Novel investigational agent is clinically active and generally well tolerated D asatinib (Sprycel) has produced deep and dur- able responses in imatinib (Gleevec)-resistant/refractory pa- tients with chronic myeloid leu- kemia (CML) in chronic phase as well as blast crisis, according to the preliminary results of three multi- centered trials. In addition, dasat- inib has been found to be active in patients with CML who are resis- tant to nilotinib (AMN107). The US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee recently recommended accelerated approval of dasatinib for adults in all phases of CML with resistance or intolerance to prior therapy. In the START-R trial, dasatinib, a multitargeted kinase inhibitor that is 325-fold more potent than ima- tinib and directed at the Bcr-Abl do- main (particularly 20/21 imatinib- resistant mutations), was superior to high-dose imatinib in producing deep cytogenetic responses. The rate of complete cytogenetic response (CCyR) was 21% in patients treated with dasatinib, compared with only 8% in patients treated with 800 mg of imatinib/d, said Neil P. Shah, MD, PhD, from the University of Califor- nia at San Francisco. The START-R trial included 150 patients with chronic-phase ima- tinib-resistant CML who were fol- lowed for a minimum of 3 months. Patients received either 70 mg bid of dasatinib or 800 mg/d of ima- tinib. Although 800 mg/d is not the maximum tolerated dose of ima- tinib, a substantial proportion of patients have difficulty tolerating it, Dr. Shah added. In the START-C trial, dasatinib elicited durable responses, with dis- ease progression in only 2 of 197 patients who had a MCyR, said Andreas Hochhaus, MD, from the University of Heidelberg, Germany. The START-C open-label phase II trial included 385 patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive the number of patients with major molecular responses starting after 3 months of therapy. A total of 44 different Bcr-Abl mutations were identified in 160 patients. Bcr-Abl mutations were more frequent in patients whose disease was resistant to imatinib (52%) than in patients who were intolerant to imatinib (20%), according to Dr. Hochhaus. In another study of Ph+ CML patients who had failed nilotinib therapy and were hematologically resistant to imatinib, 8 of 12 evalu- able patients (67%) responded to dasatinib, reported Zeev Estrov, MD, from The University of Texas M. D. Anderson Cancer Center in Houston. P atients with imatinib-resis- tant/intolerant CML in my- eloid crisis also responded favorably to dasatinib, according to the findings of the START-B study. Complete major hematologic re- sponse lasting for at least 4 weeks was confirmed in about one-quarter of the 109 patients with currently available data, revealed Jorge E. Cortes, MD, from the M. D. An- derson Cancer Center. Over follow-up of at least 6 months, 53% of patients with no mu- tation showed a hematologic response (29% major hematologic response, 35% MCyR); 27% of patients har- boring P-loop mutations achieved an MCyR, and 32% achieved a major hematologic response. According to Dr. Cortes, dasat- inib has a manageable safety profile, with cytopenia and fluid retention being the most important adverse events noted. However, cytopenia was usually transient and resolved with dose modification and/or in- terruption of treatment. Likewise, fluid retention was manageable in most patients with dose modifica- tion and treatment with diuretics and/or pulse steroids, he added. D r. Hochhaus concluded that dasatinib had sig- nificant hematologic and cytogenetic efficacy in the treat- ment of patients with CML who were resistant to or intolerant of imatinib. The drug also was effec- tive in patients with a variety of Bcr-Abl mutations associated with imatinib resistance and in patients with resistance that was indepen- dent of Bcr-Abl mutations. Shah NP, Rousselot P, Pasquini R, et al. Dasatinib vs high dose imatinib in patients with chronic phase chronic myeloid leukemia resistant to imatinib: results of CA180017 START-R randomized trial. abstract 6507 Hochhaus A, Kantarjian H, Baccarani M, et al. Dasatinib in patients with chronic phase chronic myeloid leukemia who are re- sistant or intolerant to imatinib: results of the CA180013 ‘START-C’ Study. abstract 6508 Cortes JE, King DW, Rosti G, et al. Da- satinib in patients with chronic myelogenous leukemia in myeloid blast crisis who are ima- tinib-resistant or IM-intolerant: results of the CA180006 ‘START-B’ study. abstract 6529 Estrov Z, O’Brien S, Giles F, et al. Da- satinib, a dual Src-Abl inhibitor, is active in Philadelphia chromosome-positive chronic myelogenous leukemia following treat- ment failure with imatinib mesylate and AMN107. abstract 6530 Dasatinib was effective in patients with a variety of Bcr-Abl mutations linked to imatinib resistance. (Ph+) chronic-phase CML. Most of the patients in the study (75%) had disease that was resistant to ima- tinib; the remaining 25% could not tolerate the drug. A total of 51% of patients achieved an MCyR, and 40% achieved a CCyR. Ninety per- cent of patients achieved complete hematologic response over a me- dian follow-up of 7.8 months, Dr. Hochhaus commented. Molecular data on 195 patients from the START-C study showed a steady decline in median Bcr- Abl levels in the first 6 months af- ter treatment and an increase in disease. These are the preliminary findings of a phase II, open-label, multicenter study reported by Drs. Philipp le Coutre, Hagop Kantar- jian, and Frank Giles. Nilotinib, reportedly 30 times more potent than imatinib, has been specifically designed to be the most selective inhibitor of Bcr-Abl, the definitive cause of Philadelphia chromosome-positive (Ph+) CML, and its mutations. According to the manufacturer, nilotinib does not in- hibit 32 of the 33 mutations most commonly associated with ima- tinib-resistant Ph+ CML. In 25 patients with accelerated- phase imatinib-resistant/intolerant CML (median age, 62 years; 12 men, 13 women), 10 patients (40%) achieved a hematologic response to 400 mg of nilotinib given twice dai- ly; four had a complete response, two had a marrow response or no evidence of CML, and four returned to the chronic phase. Seven patients experienced a cytogenetic response For more meeting reports, visit www.OncologyReport.com© 2006 Elsevier Inc. All rights reserved.
  4. 4. HEMATOLOGICMALIGNANCIES:LEUKEMIA 72 THE ONCOLOGY REPORT / Fall 2006 Hematologic Malignancies (four complete, three partial). Eighty-one patients with chron- ic-phase CML (median age, 60 years; 59% men) were enrolled in the study at the same dosage regi- men. At baseline, 25% had a com- plete hematologic response (CHR) and 16% had extramedullary in- volvement. Of the 54 patients with no CHR at baseline, 37 had a major cytogenetic response (CyR; 24 re- sistant, 13 intolerant), 26 of which were complete and 11 were par- tial. The median time to CHR was 1 month, and the median time to CCyR was 3 months. Results from trials involving the second-generation Abl tyrosine kinase inhibitors dasatinib (Sprycel) and nilotinib (AMN107) for CML were high- lighted at the ASCO meeting. The START trials involved dasatinib in pa- tients with all phases of CML or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who were resistant to or intolerant of imatinib. In the randomized START-R trial, dasatinib was superior to high-dose imatinib, with 21% of chronic phase (CP) patients achieving a CCyR versus only 8% with high-dose imatinib after 3 months of therapy. In the START-C trial, a nonrandomized trial for imatinib-resistant chronic phase patients, 90% of patients demonstrated a complete hematologic response, with 40% achieving a CCyR despite short follow-up. Of 19 patients with imatinib-resistant mutations in the Abl kinase domain, 18 responded to dasatinib. Patients with imatinib-resistant/intolerant AP, BC, and Ph+ ALL also responded to dasatinib as reported in three additional trials. This oral drug was well tolerated, although some patients experi- enced pleural effusion. After the ASCO meeting, the US Food and Drug Administration approved dasatinib for use in imatinib-resistant/intolerant patients with CML and in all patients with Ph+ ALL. Several other presentations reported results of phase II trials with nilotinib, also for imatinib-resistant/intolerant CML and Ph+ ALL. Eighty-one patients with CP disease were treated. Of the 54 patients with no CHR at baseline, 26 had a CCyR. Of 25 patients with AP dis- ease, 10 achieved a hematologic response. BC and Ph+ ALL patients also benefited from treatment. These potent Abl inhibitors offer hope to patients with imatinib-resistant/intolerant CML and Ph+ ALL and provide yet another example of the efficacy of oral targeted therapy for patients with cancer. —Steven E. Coutré, MD Comment Furthermore, 24 patients (medi- an age, 52 years) with imatinib-re- sistant/intolerant CML (13 myeloid disease, 6 lymphoid disease, 5 dis- ease status unknown) in blast crisis and 16 patients with Ph+ acute lymphoblastic leukemia (ALL) were treated with the same dosage regi- men; the dose was increased to 600 mg/d if patients failed to achieve a return to chronic phase, lost an achieved hematologic or cytogenet- ic response, or experienced disease progression. Among the patients with my- eloid CML, one had a major he- matologic response, one had a CCyR, one had a partial cytoge- netic response (PCyR), five had stable disease, and three experi- enced disease progression; infor- mation was not available for two patients. Among the six patients with lymphoid disease, one had a complete hematologic response, one returned to chronic phase, two had a CCyR, one had a PCyR, and one had stable disease. Among five patients whose disease status was unknown, two had a CCyR, two had stable disease, and one experi- enced disease progression. I n the patients with chronic- phase CML, the most com- monly observed grade 3/4 non- hematologic toxicities associated with nilotinib included rash (4%), arthralgia (5%), and fatigue (3%). In the patients with accelerated- phase CML, grade 3/4 reactions consisted of neutropenia (36%), thrombocytopenia (28%), anemia (16%), leukopenia (12%), urinary tract infection (8%), and gastroin- testinal effects (4%); similar reac- tions at higher rates were seen in patients with CML in blast crisis. Thrombocytopenia, anemia, and neutropenia, as well as pyrexia, nausea, diarrhea, pruritus, and my- algia, were reported in the patients with Ph+ ALL. The investigators concluded that nilotinib represents a novel treat- ment option for patients with ima- tinib-resistant/intolerant CML and for previously treated patients with Ph+ ALL. The drug was generally well tolerated, as shown by the me- dian dose intensity of nearly 800 mg/d used over the study’s course. However, long-term follow-up to assess for additional responses and durability is needed. le Coutre PD, Ottmann O, Gatterman N, et al. A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia in acceler- ated phase. abstract 6531 Kantarjian HM, Gattermann N, O’Brien SG, et al. A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia in chronic phase. abstract 6534 Giles FJ, Larson R, le Coutre P, et al. A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resis- tant or intolerant patients with Ph+ chronic myelogenous leukemia in blast crisis or re- lapsed/refractory Ph+ acute lymphoblastic leukemia. abstract 6536 Nonmyeloablative HCT prolongs survival in fludarabine-refractory CLL Median survival of > 3 years a “considerable improvement” over past results Disease response 3 years after hematopoietic cell transplantation MRD (n=44) URD (n=20) P value Complete response 44% 80% 0.005 Relapse/disease progression 37% 22% 0.06 MRD = HLA-matched related donor; URD = unrelated donor P atients with fludarabine-re- fractory chronic lymphocytic leukemia (CLL) who under- went nonmyeloablative conditioning and hematopoietic cell transplanta- tion (HCT) experienced an extend- ed median survival of more than 3 years. According to Mohamed L. Sorror, MD, from the Fred Hutchin- son Cancer Research Center in Se- attle, Washington, this result repre- sents a considerable improvement over past research showing a median 12-month survival recorded among patients given no further treatment and a 16-month survival found in a phase II trial of alemtuzumab (Cam- path) in a similar population. In their initial study, Dr. Sorror and colleagues previously report- ed a disease-free survival rate of 52% and a 2-year overall survival rate of 60% for 64 patients with CLL treated with nonmyeloabla- tive HCT from related (44) and unrelated (20) donors (Sorror ML et al. J Clin Oncol 2005;23:3819– 3829). Patients receiving an un- related transplant had a higher complete response rate and lower relapse rate than did those who had a transplant from a relative, suggesting that the technique of- fered more effective graft-versus- leukemia activity. Inthe38-monthfollow-up(range, 10–74 months), Dr. Sorror reported chronic, extensive graft-versus-host disease (GVHD) in 53% of the pa- tients and death not due to relapse in 27%. The majority of surviving patients stopped using immuno- suppressive drugs for their chronic GVHD after this extended follow- up. Of 30 patients who achieved ini- tial responses, 28 continued to thrive and were in remission. Once again, recipients of unrelated transplants had a significantly higher complete response rate than did those who re- ceived a transplant from a relative. Interestingly, all 10 responsive pa- tients tested for molecular eradica- tion of disease had negative results at a median of 52 months. Finally, an estimated 3-year over- For more meeting reports, visit www.OncologyReport.com© 2006 Elsevier Inc. All rights reserved.
  5. 5. HEMATOLOGICMALIGNANCIES:LEUKEMIA Hematologic Malignancies Fall 2006 / THE ONCOLOGY REPORT 73 all survival rate of 54%, a disease- free survival rate of 42%, and a nonrelapse mortality rate of 27% were noted. According to multivari- ate analysis, patients with high pre- transplant comorbidity scores had a greater chance of nonrelapse mor- tality and a lower overall survival rate; patients with bulky lymphade- nopathy had a greater risk of dis- ease progression. Dr. Sorror concluded that non- myeloablative HCT provided a median survival that extended beyond 3 years for CLL patients refractory to fludarabine thera- py. Further, patients with unre- lated grafts had a greater chance of developing chronic, extensive GVHD—but they also tended to have a greater complete response rate, a lower rate of relapse and disease progression, and better disease-free and overall survival A ccording to the first-re- sponse data from the CAM 307 study, a randomized, controlled post-marketing trial re- quired by the US Food and Drug Administration to test the safety and effectiveness of alemtuzumab (Campath) against those of an es- The results of a randomized trial comparing alemtuzumab (Campath) and chlorambucil (Leukeran) for the initial treatment of patients with pro- gressive CLL were reported by Peter Hillmen, from the Leeds General Infirmary in the United Kingdom. The overall (82.6% vs 54.7%) and com- plete (22.1% vs 2.0%) response rates favored alemtuzumab. More pa- tients receiving alemtuzumab experienced a serious adverse event (34.7% vs 19.7%), primarily due to a higher incidence of grade 3/4 neutropenia (42.2% vs 23.1%), infections (excluding cytomegalovirus [CMV]; 14.3% vs 6.8%), and CMV infections (6.8% vs 0%). There was no difference in the rates of febrile neutropenia; all CMV infections were successfully treated, and there were no deaths in alemtuzumab-treated patients. The incidence of neutropenia with alemtuzumab is comparable to that seen with fludara- bine-based combination regimens. The primary endpoint of progression- free survival was not reported. We await more detailed results that provide support for the earlier use of this potent antibody therapy for CLL. —Steven E. Coutré, MD Comment Post-FDA approval study confirms activity of alemtuzumab in B-cell CLL Potent drug will have a “major” role to play, even in poor-prognosis patients Michael J. Keating, MD, professor of medicine from the University of Texas M. D. Anderson Cancer Cen- ter in Houston. The CAM 307 trial included 297 patients with previously un- treated and progressive Rai stages I–IV B-CLL who were treated in 44 centers in the United States and Europe. Patients were ran- domized on a 1:1 basis to receive alemtuzumab (30 mg IV 3 times a week for a maximum of 12 weeks) or chlorambucil (40 mg/m2 orally once every 28 days for a maximum of 12 cycles). When evaluated by investiga- tors, 46 patients (31%) treated with alemtuzumab had a complete re- sponse, compared with 6 patients (4%) treated with chlorambucil (P < 0.0001). Sixty-eight patients (46%) in the alemtuzumab group had a partial response, compared with 51 patients (35%) in the chloram- bucil group. The overall response rate of 77% for the alemtuzumab group was roughly two times higher than the 36% for the chlorambucil group, and the difference was high- ly significant (P < 0.0001). When assessed by an independent panel of researchers, the overall re- sponse rate was 83% among patients who received alemtuzumab and 56% among patients who received chlo- rambucil (with complete response rates of 22% vs 2% [P < 0.0001]), revealed the lead investigator of the study, Peter Hillmen, MB, ChB, from the Leeds General Infirmary in Leeds, United Kingdom. T here was no significant dif- ference in the incidence of infection between the two groups, although there was a higher rate of CMV in patients who re- ceived alemtuzumab. Among these patients, 68 (46%) had an infection, including 11% who had a febrile infection. Among chlorambucil- treated patients, five (3%) had an infection, with no febrile infections. Grade 3 infections occurred in three patients (2%) treated with alemtu- zumab and no patients treated with chlorambucil. The first signs of in- fection typically appeared within 2 months of the start of therapy, and the infections were manageable clinically, Dr. Hillmen reported. Dr. Keating predicts that alemtu- zumab will increasingly be used in combination with other active drugs and perhaps in treatment regimens directed at specific clinical targets. “The drug is so potent, I’m sure it will have a major role to play,” he concluded. Hillmen P, Skotnicki A, Robak T, et al. Preliminary phase III efficacy and safety of alemtuzumab vs chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphocytic leukemia. abstract 6511 Patients with fludarabine-refractory chronic lympho- cytic leukemia (CLL) have a poor prognosis, with median survival of less than 1 year. Alemtuzumab (Campath) can extend survival to 16 months, but all patients will eventu- ally relapse. A consortium of investigators from the Fred Hutchinson Cancer Research Center, Baylor University, University of Leipzig, and Stanford University reported 38-month follow-up results of a trial involving nonmye- loablative hematopoietic cell transplantation for 64 pa- tients with refractory CLL. Overall survival (OS) of 54%, disease-free survival (DFS) of 42%, and a nonrelapse mortality rate of 27% were noted. Extensive chronic graft-versus-host disease (GVHD) was seen in 53% of the patients, with a higher incidence in those receiving matched, unrelated donor (MUD) grafts. However, those receiving MUD grafts had a greater complete response rate, a lower rate of relapse and disease progression, and better DFS and OS than did those receiving grafts from matched siblings, suggesting a graft-versus-leukemia effect. Longer follow-up is needed to determine whether this approach is curative for some patients, and modifica- tions are necessary to decrease the morbidity associated with chronic GVHD. —Steven E. Coutré, MD Comment rates at 3 years than did those re- ceiving grafts from relatives. Sorror M, Sandmaier B, Maris M, et al. Nonmyeloablative hematopoietic cell trans- plantation for treatment of patients with fludarabine-refractory chronic lymphocytic leukemia results in prolonged median sur- vival. abstract 6520 We saw impressive responses in patients with poor prognostic cytogenetic abnormalities when treated with alemtuzumab. tablished agent, the drug elicited significantly greater complete and overall responses than chlorambucil (Leukeran) in patients with B-cell chronic lymphocytic lymphoma (B- CLL). Alemtuzumab also was well tolerated, with rates of cytomegalo- virus (CMV) infections as might be expected. “It is gratifying to see no differ- ence in infection rates with a potent drug and reassuring to see that only 10%–12% of patients probably needed treatment for viremia,” said For more meeting reports, visit www.OncologyReport.com© 2006 Elsevier Inc. All rights reserved.
  6. 6. HEMATOLOGICMALIGNANCIES:LEUKEMIA 74 THE ONCOLOGY REPORT / Fall 2006 Hematologic Malignancies Oblimersen active with other agents against CLL Bcl-2 antisense agent combination well tolerated in several studies W hen added to differ- ent chemotherapy regi- mens, oblimersen (Ge- nasense), an anti-Bcl-2 nucleotide, is active and tolerable in patients with chronic lymphocytic leukemia (CLL), according to the findings of two different studies in patients with advanced disease. The presence of the Bcl-2 anti- apoptotic protein has been associat- ed with resistance to treatment and poor prognosis in CLL. Past studies in patients with advanced, chronic disease have shown that oblimersen enhances apoptosis resulting from treatment with fludarabine given with either rituximab (Rituxan) or cyclophosphamide. B lanche Mavromatis, MD, from the Lombardi Cancer Center at the Georgetown University Medical Center in Washington, DC, and others studied outcomes related to prognostic markers using flow cy- tometry in 24 patients with advanced CLL. In all, 19 of the patients were treated previously, with 14 having re- ceived fludarabine and 13 having re- ceived rituximab. In fact, two of the patients were refractory to combined use of these two drugs, one to fluda- rabine alone, two to rituximab alone, and three to other agents. Common findings were CD38 overexpression, ZAP-70 expression, and abnormal cytogenetics. Overall, all 5 previously untreated patients and 12 of 19 previously treated patients responded; there were 2 molecular complete responses, 1 in a previously untreated patient with CD38 overexpression and a nor- mal karyotype and 1 in a previously treated patient with a 13q deletion who had been refractory to the combination of fludarabine, ritux- imab, and oblimersen. Three nodu- lar partial responses occurred: two in untreated patients who expressed CD38 and ZAP-70 and one in a pre- viously treated patient with a 13q deletion. Partial responses were seen in one patient refractory to fludara- bine, one patient refractory to fluda- rabine/rituximab, and two patients with poor-risk (11q–) cytogenetics. Overall, 8 of 10 patients expressing CD38 and 5 of 11 patients express- ing ZAP-70 responded. Toxicity for the combination of fludarabine, rituximab, and oblimers- en was acceptable and similar to that expected with rituximab and fluda- rabine alone. Furthermore, the com- bination was active even in patients with poor prognostic markers. I n the second study, Benjamin Koziner, MD, from Buenos Ai- res, Argentina, assessed the safe- ty results from two CLL clinical tri- als to determine the relative effect of oblimersen on treatment-emergent adverse events related to its use with fludarabine and cyclophosphamide. to tumor lysis syndrome. Discon- tinuation of treatment related to events occurred in 20% of oblim- ersen-only patients, 35% of those using fludarabine/cyclophospha- mide, and 35% of those using the three-drug combination. Adding oblimersen to fludara- bine/cyclophosphamide was well tolerated and associated with sim- ilar low frequencies of grade 3/4 adverse events related to therapy, primarily with fludarabine plus cytarabine alone. Even though there was a greater incidence of serious adverse events related to therapy observed with the com- bination of oblimersen, fludara- bine, and cyclophosphamide, the percentage of patients discontinu- ing the protocol therapy due to such reactions was the same in each group. Thus, patients must be observed closely during initia- tion of combination therapy for first-cycle reactions. Mavromatis B, Rai K, Wallace PK, et al. Impact of prognostic markers on outcomes in patients with advanced chronic lymphocytic leukemia treated with the regimen of fludara- bine/rituximab plus oblimersen. abstract 6609 Koziner B, O’Brien S, Boyd T, et al. Pooled safety analysis of oblimersen alone or with fludarabine and cyclophosphamide in patients with advanced chronic lympho- cytic leukemia. abstract 6611 The Bcl-2 antiapoptotic protein has been associated with resistance to treatment and poor prognosis in CLL. The most frequent grade 4 treatment-related adverse events were mainly hematologic. Throm- bocytopenic events with the com- bination of oblimersen, fludara- bine, and cyclophosphamide were reversible and not associated with clinically significant bleeding. Events resulting in death occurred in two patients given oblimersen alone, five patients given fluda- rabine/cyclophosphamide, and nine patients given the three-drug combination; one death in the latter group was related to a cy- tokine release reaction and one, For more meeting reports, visit www.OncologyReport.com© 2006 Elsevier Inc. All rights reserved.

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