Efficacy of Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Phase Chronic Myelogenous Leukemia (CP-CML) Resistant to or Intolerant of Imatinib: Updated Results of the CA180013 ‘START-C’ Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 164-164 ◽  
Author(s):  
Michele Baccarani ◽  
H.M. Kantarjian ◽  
J.F. Apperley ◽  
J.H. Lipton ◽  
B. Druker ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Myelogenous Leukemia ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Prior Therapy ◽  
Grade 3 ◽  
Dose Reductions

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is an oral, multi-targeted, kinase inhibitor of BCR-ABL and SRC kinases, approved by the US FDA for the treatment of chronic myelogenous leukemia, including chronic phase, with resistance to or intolerance of prior therapy, including imatinib (im). ‘START-C’ is an open-label phase-II study of dasatinib in imatinib-resistant (im-r) or -intolerant (im-i) pts with CP-CML. Preliminary data previously presented on 186 pts treated showed a complete hematologic response (CHR) rate of 90%, and a major cytogenetic response (MCyR) rate of 45%. With additional recruitment, between February and July 2005, a total of 387 pts (191 male, median age 58 yrs [range 21–85]) were enrolled and treated in 75 centers worldwide. The definition of im-r required progressive disease at a maximal dose of im or the occurrence of BCR-ABL mutations associated with insensitivity to im. Of the 387 pts, 288 were im-r and 99 were im-i. Dasatinib was given at 70 mg twice daily (BID) with dose escalation to 90 mg BID in pts lacking response, and dose reductions to 50 and 40 mg BID for toxicity or intolerance. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months, and molecular monitoring of BCR-ABL transcript levels by real-time qPCR every 4 weeks for the first 12 weeks, then every 12 weeks. The primary endpoint was MCyR rate. Median time from diagnosis of CML was 61 months (range 3–250). Prior therapy included interferon-alpha in 65% and stem cell transplantation in 10% of pts. Fifty five percent of pts had >600 mg of prior im. Fifty three percent of pts received im for >3 yrs. Best response to prior im therapy was a CHR in 82%, and complete (CCyR) and partial (PCyR) cytogenetic responses in 19% and 18% of pts, respectively. Updated analyses with a median follow-up of 13 months (0.1–17 months) show 351 (91%) pts had a CHR, and 225 (58%) a MCyR: 79 (80%) im-i pts, and 146 (51%) im-r pts. CCyR rates were 74% (im-i) and 38% (im-r) giving a total CCyR rate of 47%. Sixty three (41%) pts who never achieved a CyR on im achieved a MCyR with dasatinib. The rate of MCyR was 59% among the 160 (44%) pts with BCR-ABL baseline mutations, and was seen across all mutations with the exception of T315I. Grade 3/4 neutropenia or thrombocytopenia was reported in 49% and 48% of pts, respectively. Dose interruptions occurred in 331 (86%) pts, and dose reductions in 269 (70%) pts, with an average daily dose of 103 mg/day (range 11–169 mg). Non-hematologic toxicity consisted mainly of grade 1/2 diarrhea, headache, rash, and pleural effusion, with 6% grade 3/4 pleural effusion. Dasatinib demonstrated substantial hematologic and cytogenetic activity in im-r and im-i pts with CP-CML. Importantly, the responses rates continue to improve with further follow-up, and 221 of the 225 pts who achieved a MCyR have not progressed or died while on study. The 12 month progression-free survival of all patients is 90%. Updated analyses with at least 15 months of follow-up, in addition to the molecular response data and mutational analysis at time of progression, will be presented.

Efficacy of Dasatinib in Patients with Chronic-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-C (CA180-013).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 734-734 ◽  
Author(s):  
Richard M. Stone ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Jeffrey H. Lipton ◽  
Timothy Hughes ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Dasatinib (SPRYCEL®) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for patients with imatinib-resistant or -intolerant chronic-phase chronic myelogenous leukemia (CP-CML). Here we report the extended follow-up of START-C, a 75-center, international study of dasatinib in 387 patients with CP-CML with resistance (n=288) or intolerance (n=99) to imatinib. Recruitment took place from February to July 2005. Dasatinib was administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) were allowed for lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 mo (range 32–50). Prior therapy included interferon-α in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses >600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%, respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87–93%), major cytogenetic response (MCyR) in 59% (95% CI 54–64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in 49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a MCyR with dasatinib. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who had achieved a MCyR with dasatinib losing this response. Major molecular response rate (ie, a BCR-ABL/ABL ratio of <0.1% according to the international scale by RQ-PCR) at 12 mo was 25%. Progression-free survival at 15 mo was 90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%; the average daily dose administered was 101 mg (range 11–171). Reports of grade 3–4 thrombocytopenia and neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), and dyspnea (30%). Pleural effusion was experienced by 27% of patients; this was categorised as grade 1–2 in 21% and grade 3–4 in 6%. Dasatinib-induced cytogenetic responses remain durable in patients with CP-CML resistant or intolerant to imatinib. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Treatment of Philadelphia Chromosome-Positive Early Chronic Phase Chronic Myelogenous Leukemia With Daily Doses of Interferon Alpha and Low-Dose Cytarabine

1999 ◽  
Vol 17 (1) ◽  
pp. 284-284 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Terry L. Smith ◽  
Mary Beth Rios ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Interferon Alpha ◽  
Low Dose ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Grade 3 ◽  
Low Dose Cytarabine

PURPOSE: To evaluate the efficacy of the combination of interferon alpha (IFN-α) and daily low-dose cytarabine (ara-C) in the treatment of patients with early chronic-phase chronic myelogenous leukemia (CML) (within 1 year of diagnosis). Improving the degree of hematologic and cytogenetic response in patients with Philadelphia chromosome (Ph)-positive CML may improve prognosis. Both IFN-α and ara-C induce cytogenetic responses as single-agent therapy in CML. PATIENTS AND METHODS: One hundred forty patients with Ph-positive early chronic-phase CML received subcutaneous injections of IFN-α 5 megaunits/m2 daily and ara-C 10 mg daily. Their median age was 46 years; 53% had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Their results were compared with those of patients receiving IFN-α with or without intermittent ara-C (7 days/mo). RESULTS: A complete hematologic response (CHR) was achieved in 92% of patients. A cytogenetic response was seen in 74%: it was major in 50% (Ph-positive < 35%) and complete in 31% (Ph-positive 0%). With a median follow-up of 42 months, the 4-year estimated survival rate was 70% (95% confidence interval, 61% to 79%). Significant side effects included fatigue (43%; grade 3/4, 11%), weight loss (19%; grade 3/4, 11%), muscle and bone aches (20%; grade 3/4, 7%), oral ulcers (4%), diarrhea (6%), and neurologic changes (27%, grade 3/4, 6%). The median dose of IFN-α was 3.7 megaunits/m2 daily, mainly because of reductions for myelosuppression (70% of cases); the median ara-C dose was 7.5 mg daily. Prognostic risk groups were predictive for response to the IFN-α plus ara-C combination. The incidence of CHR was higher with IFN-α plus daily ara-C compared with IFN-α plus intermittent ara-C and IFN-α alone (no ara-C) (92% v 84% v 80%, P = .01), as were the incidences of cytogenetic response (74% v 73% v 58%; P = .003) and major cytogenetic response (50% v 38% v 38%; P = .06). The median time to achievement of major cytogenetic response was significantly shorter than that for previous IFN-α regimens (7 v 10 v 12 months; P < .01). However, with the present follow-up, the survival and time to blastic transformation were similar. CONCLUSION: The combination of IFN-α plus daily low-dose ara-C seems to be promising for the treatment of CML. High rates of CHR and cytogenetic response were observed with acceptable toxicity and a lower daily dose of IFN-α compared with our previous studies.

Phase II Study of Low-Dose Decitabine in Patients With Chronic Myelogenous Leukemia Resistant to Imatinib Mesylate

2005 ◽  
Vol 23 (17) ◽  
pp. 3948-3956 ◽  
Author(s):  
Jean-Pierre J. Issa ◽  
Vazganush Gharibyan ◽  
Jorge Cortes ◽  
Jaroslav Jelinek ◽  
Gail Morris ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chronic Myelogenous Leukemia ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Median Response ◽  
Blastic Phase ◽  
Line1 Methylation

Purpose To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. Materials and Methods Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. Results Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% ± 1.4% (mean ± standard error of the mean) to 60.7% ± 1.4% after 1 week, 50.9% ± 2.4% after 2 weeks, and returned to 66.5% ± 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% ± 3.0% versus 26.8% ± 2.7% in responders versus nonresponders (P = .007). Conclusion Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.

Phase II study of irinotecan (cpt-11) and cisplatin (cddp) regimen (IP) with concurrent thoracic radiotherapy (TRT) in limited-stage small cell lung cancer (LS-SCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7084-7084 ◽  
Author(s):  
D. Castellano ◽  
A. Bartolomé ◽  
A. Font ◽  
A. Lopez-Martín ◽  
P. Diz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Median Number ◽  
Prior Therapy ◽  
Concurrent Therapy ◽  
Primary Endpoints ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Ecog Ps

7084 Background: the combination of CPT-11 and CDDP (IP) is an active regimen for SCLC. (Noda et al NEJM ’02, Hanna et al ASCO 2005). We performed a multicenter phase II study to assess the efficacy and toxicity of IP regimen with concurrent TRT in previously untreated LS-SCLC pts. Methods: Eligible pts were required to have histologically confirmed SCLC, measurable disease, no prior therapy, ECOG PS of 0–2, adequate organ functions, and to give informed consent. Treatment consisted of: CDDP 60 mg/m2 D1, I 60mg/m2 IV D1, 8 Q 21D for 4 cycles, and concurrent TRT 2.0 Gy daily to a total of 60.0 Gy, beginning with the 2nd cycle. I was adjusted to 50 mg/m2 at 2nd and 3rd cycles (during TRT). Pts were restaged after 4 cycles. Pts without progression or undue toxicity received 2 additional cycles. PCI (2.0 Gy X 10) was offered to CR pts. The primary endpoints were response rate and OS. Results: Twenty-six pts were included and 25 pts were evaluable for response (median age 62; M/F, 22/4; PS 0/1/2, 9/17; T2–4N0,T2–4N+ 6/20pts). Among 126 cycles administered, the relative dose-intensities of I and CDDP were 80% and 92% respectively. Median number of cycles/pt was 5 (1–6), and 22 pts completed the IP + TRT program. Fifteen pts achieved a CR and 6 pts a PR, for an overall RR of 84%. Median TTP was 12 months. At a median follow-up of 14 months, 19 pts are alive, and estimated median survival is 17 months. Grade 3–4 (NCI-CTC 3.0) toxicity (per cycle) during concurrent therapy included: neutropenia (25%), anemia (3%), thrombocytopenia (3%), diarrhea (10%), vomiting (5%), esophagitis (10%). There were no treatment-related deaths. Two pts required hospitalization during the concurrent therapy due to g3 diarrhea (1 pt) and febrile neutropenia (1 pt). Conclusions: The concurrent regimen of IP + TRT is highly effective in pts with LS-SCLC. The associated toxicity profile is predictable and adequate. Further study is warranted. No significant financial relationships to disclose.

Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure

2007 ◽  
Vol 25 (25) ◽  
pp. 3908-3914 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Gautham Borthakur ◽  
John Bruzzi ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Myelogenous Leukemia ◽  
Systolic Pressure ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Close Monitoring ◽  
Pleural Effusions ◽  
Ventricular Systolic Pressure ◽  
Daily Schedule ◽  
Grade 3

PurposeWe investigated the risk factors and management of pleural effusion associated with dasatinib therapy for chronic myelogenous leukemia (CML) after failure of imatinib.Patients and MethodsWe analyzed 138 patients with CML treated with dasatinib from November 2003 to January 2006 in one phase I (n = 50) and four phase II (n = 88) studies for the development of pleural effusion.ResultsPleural effusion occurred in 48 patients (35%; grade 3/4 in 23 [17%]), including 29% of those treated in chronic phase (CP), 50% in accelerated phase (AP), and 33% in blast phase (BP). By multivariate analysis, history of cardiac disease, hypertension, and use of a twice-daily schedule (v once daily) were identified as factors associated with development of pleural effusions. Effusions were exudative in 78% of the assessable cases. In some patients, effusions were associated with reversible increments of right ventricular systolic pressure. Management included transient dasatinib interruption in 83%, diuretics in 71%, pulse steroids in 27%, and thoracentesis in 19% of patients.ConclusionPleural effusions occur during dasatinib therapy, particularly among patients in AP or BP. A twice-daily schedule may result in a higher incidence of pleural effusion. Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit.

Treatment of Chronic Myelogenous Leukemia with Interleukin-2: A Phase II Study in 21 Patients

1999 ◽  
Vol 22 (2) ◽  
pp. 175-181 ◽  
Author(s):  
Norbert Vey ◽  
Didier Blaise ◽  
Marina Lafage ◽  
Daniel Olive ◽  
Patrice Viens ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Interleukin 2 ◽  
Myelogenous Leukemia

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

Association of Hydroxyurea to Imatinib Is Effective in Patients with Chronic Myelogenous Leukemia Resistant to Imatinib Alone.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4693-4693 ◽  
Author(s):  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Ida Carmosino ◽  
Chiara Sarlo ◽  
Rosa De Cuia ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Imatinib Treatment ◽  
Duration Of Response ◽  
Wbc Count

Abstract The introduction of Imatinib in the treatment of Chronic Myelogenous Leukemia (CML) leads to the achievement of Complete Cytogenetic Response (CCR) in about 70% of patients: however, in the remaining 30% of patients there is a persistance of Ph+ cells also after standard (400 mg/day) and increased (600 mg/day) dose of Imatinib. These patients are thus cytogenetically resistant to Imatinib alone and their management is at present unclear. From 11/2002 to 11/2003, 10 patients in chronic phase (6 male and 4 female, median age 52.5 years, range 29 – 68 years) with persistance of 100% Ph+ cells (9 patients) or BCR/ABL + cells (1 patient with Ph- BCR/ABL+ CML at onset) after standard (at least 6 months of treatment) followed by increased dose (at least 3 months of treatment) of Imatinib alone, were considered resistant and added Hydroxyurea (HU) to Imatinib. Seven patients have been pretreated with IFN before Imatinib; median times from diagnosis and from Imatinib treatment to HU addition were 51 months (range 23 – 151) and 14 months (range 10 – 31), respectively. HU was given according to WBC count: patients with WBC < 10 x 109/l started HU at the dose of 1 g/day, patients with WBC > 10 x 109/l at the dose of 1.5 g/day. Imatinib was continued at the same previous dosage (600 mg/day in 6 patients and 400 mg/day in 4 patients who did not tolerate increased dosage for hematological toxicity). Three patients achieved a complete response (2 CCR after 3 and 12 months respectively and 1 molecular complete response after 9 months in the patient Ph- BCR/ABL+ at onset) and 1 patient achieved a partial CR (Ph+ < 33%) after 9 months: the remaining 6 patients were resistant with persistance of 100% Ph+ cells. Toxicity was mild and only 1 patient discontinued for 2 weeks the association due to transient thrombocytopenia: no extra-hematological toxicity has been recorded. After a median follow-up of 14 months (range 20 – 10), 2 patients (1 resistant and 1 after 5 months from the achievement of CCR) evolved in Blastic Phase (BP), 5 patients are in stable chronic phase with 100% Ph+ cells and 3 patients are still in response after 4,6 and 7 months respectively. In conclusion, the association of HU with Imatinib seems capable to induce cytogenetic response in at least one third of patients resistant to Imatinib alone, with minimal toxicity: a longer follow-up and a comparison with other associations is needed to evaluate the quality and duration of response in such group of patients.

VNCOP-B (Etoposide, Mitoxantrone, Cyclophosphamide, Vincristine, Prednisolone, Bleomycin) Plus Rituximab Therapy in Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Phase II Study of Efficacy and Safety

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3586-3586
Author(s):  
Kazuyoshi Ishii ◽  
Masahiro Manabe ◽  
Toshiya Yagi ◽  
Hirofumi Teshima ◽  
Yasuaki Nagare ◽  
...  
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
Phase Ii ◽  
Induction Therapy ◽  
Phase Ii Study ◽  
B Cell Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Grade 3

Abstract [Background and Objectives] CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety because of agespecific comorbidity, increased toxicities of chemo-agents, and the more aggressive aspect of the lymphoma itself. Zinzani reported that a combination therapy including etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin (VNCOP-B) was effective in elderly aggressive NHL patients (Blood1999;94:33–38). We conducted a phase II multicenter study in 8 collaborative institutions to determine if VNCOP-B plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. The primary endpoint was to detect overall survival (OS). The second endpoint was to detect the response rate (RR) and progression-free survival (PFS). [Patients and Treatment] Eligible patients were those aged over 60 years, with aggressive B-NHL documented as CD20 surface antigen positive, performance status (PS) 0 to 2, clinical stage over II or I with a bulky disease, measurable lesions, no prior chemotherapy nor radiation, no severe complications, no major organ dysfunction, no other active cancer, not a HBV carrier, no central nervous system involvement with lymphoma, and who gave the required written informed consent. VNCOP-B plus rituximab was administered as an induction therapy. This protocol was completed in 8 weeks and consisted of weekly doses of chemotherapy combined with rituximab every two weeks. During the 8 weeks of therapy, granulocyte colony-stimulating factor (G-CSF) was administered on a prophylactic base. Rituximab was administered weekly four times a month as a sequential therapy, following one month after the end of the induction therapy. [Results] Between September 2004 and December 2007, 23 patients, median age 73 years, 50.0% classified as high-intermediate/high risk on the age-adjusted International Prognostic Index (IPI), entered this trial and 21 were evaluated for feasibility, toxicity, and efficacy. Twenty-two patients (95.2%) were diagnosed with diffuse large B-cell lymphoma and one (4.8%) with mediastinal large B-cell lymphoma. The nineteen patients (90.5%) completed the induction therapy and all these then received a sequential rituximab therapy. Complete remission rate was 90.5%, with a 100% overall RR at the end of induction therapy; OS rate at 3 years was 76.4% (median follow-up 744days); with an 82.6% 3-year PFS rate (median follow-up 744days). Average Relative dose intensity (RDI) in MIT was 0.61, no significant difference in survival was found regarding RDI. Although IgG level decreased during the induction therapy, it recovered to the prior level after sequential rituximab (IgG means±standard error: pre-treatment 1355.2±146.4mg/dl, post-induction therapy 785.3±107.0mg/dl, post-sequential rituximab 1010.4±60.2mg/dl). According to the IPI, there was a trend suggesting a lower probability of OS and PFS in high/high-intermediate risk than in low/low-intermediate risk cases (3-year OS: 67.5% versus 100.0%, P=0.51; 3-year PFS: 66.7% versus 100.0%, P NA). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the 21 patients despite prophylactic administration of G-CSF, febrile neutropenia in 30.0%, and thrombocytopenia in 10.0%, respectively. Regarding non-hematologic grade 3/4 toxicities, hepatitis occurred in one patient (5.0%) from HCV reactivation, intestinal perforation involving the lymphoma in one patient (5.0%). There was no treatment-related mortality. We had conducted a phase II study of VNCOP-B therapy in 16 elderly patients with aggressive B-NHL (Gan To Kagaku Ryoho2005;32:39–44, in Japanese). Against this historical comparison, the present protocol seemed better in PFS than that without rituximab (3-year PFS: 82.6% versus 56.0%, P=0.11), although OS was almost the same (3-year OS: 76.4% versus 73.4%, P=0.22). [Conclusion] Although our enrolled patients were quite elderly with a median age of 73 years, and half of them had a poor prognosis index, VNCOP-B combined with rituximab was well tolerated and showed promise.

Sign in / Sign up

Export Citation Format

Share Document