Annals of Oncology Advance Access originally published online on October 30, 2006
Annals of Oncology 2007 18(2):370-375; doi:10.1093/annonc/mdl395
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 European Society for Medical Oncology
hematologic malignancies |
Phase II study of gemcitabine–dexamethasone with or without cisplatin in relapsed or refractory mantle cell lymphoma
1 Service des Maladies du Sang, Lille, France
2 Service d'Hématologie, Nîmes, France
3 Service d'Hématologie, Dunkerque, France
4 Service d'Hématologie, Marseille, France
5 Service des Maladies du Sang, Bordeaux, France
6 Service Oncologie-Maladies du Sang, Le Mans, France
7 Centre Léon Bérard, Lyon, France
8 Service d'Hématologie, Pierre Bénite, France
9 Eli Lilly, Paris, France
* Correspondence to: Prof C. Dumontet, Service d'Hématologie, Centre Hospitalier Lyon Sud, 69310 Pierre Bénite Cedex, France. Tel: +33-4-78-86-64-30; Fax: +33-4-78-86-21-35; E-mail: charles.dumontet{at}chu-lyon.fr.
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Single-agent gemcitabine has shown encouraging results in patients with mantle cell lymphoma (MCL). This phase II study further explored the potential of a gemcitabine-based regimen in patients with relapsed or refractory MCL. Patients <70 years old received the PDG regimen: gemcitabine (1000 mg/m2, days 1 and 8), dexamethasone (40 mg/m2, days 1–4), and cisplatin (100 mg/m2, day 1). Patients
70 years of age received dexamethasone and gemcitabine only (DG regimen). Thirty patients (12 in the DG group, 18 in the PDG group) with a median age 66.5 years (range, 47–81) received a median of six cycles in both groups. The overall response rate was 36.4% [95% confidence interval (CI), 15.2% to 64.6%] with the DG regimen and 44.4% (95% CI 24.6% to 66.3%) with the PDG regimen. The median progression-free survival was 3 months (95% CI 0.0–7.9) in the DG group and 8.5 months (95% CI 4.8–12.2) in the PDG group. With a median follow-up of 38.8 months, 13 patients (including 11 given PDG) are still alive. DG was well tolerated, and thrombocytopenia was the most prevalent toxicity in patients receiving PDG. Both regimens deserve to be further investigated as a backbone for combination chemotherapy in patients with MCL. Key words: cisplatin, dexamethasone, gemcitabine, mantle cell lymphoma
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Mantle cell lymphoma (MCL) has one of the poorest prognoses among all non-Hodgkin's lymphoma (NHL) subtypes, with a median overall survival (OS) of
3–4 years [1, 2]. Different strategies have been developed to improve the outcome in MCL, including high-dose therapy with autologous stem cell transplantation (ASCT), combination therapy with rituximab, and the addition of high-dose cytarabine (HD Ara-C) to first-line therapy [3–6]. Even with the best first-line treatments, however, relapse occurs, emphasizing the need for novel drug combinations for relapsed/refractory patients [5]. Nucleoside analogue-based regimens are attractive salvage options in patients with NHL [7–9]. Gemcitabine (2',2'-difluorodeoxycytidine) is one of the best established nucleoside analogues in patients with neoplasia [10]. Among the characteristics of gemcitabine, two are of particular interest with regard to its potential in hematologic malignancies: (i) gemcitabine phosphate derivatives have a greater intracellular retention time than cytarabine derivatives [10] and (ii) gemcitabine displays synergism with cisplatin in vitro [11]. Gemcitabine is effective in heavily pretreated patients with Hodgkin's disease [12, 13], peripheral T-cell lymphoma [14], and diffuse large B-cell lymphoma [15], but was reported to have minimal activity in relapsed/refractory low-grade NHL [16].
Exploratory phase II studies of single-agent gemcitabine in small numbers of patients with relapsed/refractory MCL reported encouraging results [17, 18]. Since a significant number of patients with MCL may receive HD Ara-C as part of their first-line therapy in the future, we hypothesized that gemcitabine might be a potential candidate for salvage combinations in patients with relapsed/refractory MCL.
To explore the potential of gemcitabine in different age groups, we conducted a phase II trial to determine the efficacy and safety of gemcitabine combined with cisplatin and dexamethasone (PDG regimen) in patients <70 years old and combined with dexamethasone alone (DG regimen) in patients 70 years old in whom cisplatin might lead to excessive toxicity [19].
The primary end points of the study were overall response rate (ORR) and complete response (CR) rate; secondary end points were progression-free survival (PFS), OS, and safety.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
eligibility criteria
Patients were required to be
18 years, have histologically confirmed MCL (World Health Organization classification), have Ann Arbor stage II–IV, and have failed 1 prior chemotherapy with or without rituximab. Other inclusion criteria included: Eastern Cooperative Oncology Group performance status of two or more, adequate renal (creatinine 
150 µmol/l) and hepatic (bilirubin 1.5 x upper limit of normal [ULN], transaminase <3 x ULN) function, and bidimensionally measurable disease of >1.5 cm by computed tomography (CT) scan. Hemoglobin >10.0 g/dl, absolute neutrophil count (ANC) >1.5 x 109/l, and platelets >100 x 109/l without ongoing transfusional support were required, but patients with lower blood counts were eligible if due to lymphoma infiltration. Patients were excluded if they had received any treatment or major surgery within 4 weeks of study entry, ASCT within 3 months, >300 mg/m2 of cisplatin, any nucleoside analogue-based treatment within 6 months, or had possible intolerance to dexamethasone, presence of symptomatic central nervous system lymphoma, known HIV positivity, other primary malignancy, or if they were pregnant or breastfeeding.
This protocol was approved by the Centre Léon Bérard Ethical Committee, and all patients gave written informed consent.
study design
This was a multicenter, open-label, single-arm, phase II study to evaluate the efficacy and safety of gemcitabine and dexamethasone in patients with refractory/recurrent MCL; cisplatin was added to the regimen for patients <70 years old.
treatment regimens
Patients <70 years old received the PDG regimen consisting of gemcitabine (1000 mg/m2 as a 30-minute infusion) on days 1 and 8, dexamethasone (40 mg/m2 p.o.) from days 1–4, and cisplatin (100 mg/m2) as a 1-hour infusion on day 1, preceding the gemcitabine infusion. Patients 70 years received dexamethasone and gemcitabine only (DG regimen). All treatments were to be administered on an outpatient basis. Both regimens were administered as 21-day cycles up to a maximum of six cycles. A cycle was administered if the ANC was 1 x 109/l and platelets 100 x 109/l. In patients with thrombocytopenia due to lymphoma, a cycle was initiated if values returned to pretherapeutic levels, irrespective of the absolute values. For ANC <1 x 109/l and/or platelets <50 x 109/l, the day 8 gemcitabine dose was omitted. When starting a new cycle, both gemcitabine and cisplatin were reduced to 75% of the starting dose in case of ANC grade 4 toxicity lasting <7 days or platelet grade 3 toxicity during the previous cycle. Doses were reduced by 50% for ANC grade 4 toxicity lasting 7 days, platelet grade 4 toxicity, or if a platelet transfusion had been required during the previous cycle. Treatment was stopped if the delay in administering the following cycle exceeded 2 weeks. For grade 3 renal toxicity or grade 2–3 ototoxicity or neurotoxicity, the cisplatin dose was omitted for the rest of the cycles. Grade 4 ototoxicity, neurotoxicity, or renal toxicity resulted in patient withdrawal. Granulocyte colony-stimulating factor (G-CSF) was allowed at day 9 until ANC recovery or at the discretion of the physician.
baseline and treatment assessments
Baseline assessment was performed within 2 weeks of cycle 1 and included relevant medical history; physical examination; stage and extent of the disease (assessed by CT scan and bone marrow aspirate/biopsy); and laboratory assessments, including complete blood counts (CBC), biochemical tests, echocardiography or isotopic method to determine resting ejection fraction, ECG, and any additional examination if clinically indicated (e.g. gastrointestinal endoscopy, spinal tap, or cerebral CT scan). Evaluation during each cycle included clinical examination, CBC, liver enzymes, and creatinine measurements on days 0, 8, and 15 of the cycle.
Response was evaluated using the International Working Group Recommendations [20] within 30 days of cycles 3 and 6, and assessments were repeated 2 months after the last cycle and then every 3 months until disease progression. PFS was measured from study entry until documented progression, relapse, or death from any cause. (Patients in remission who received further therapy were censored.) Survival was measured from study entry until death from any cause. Toxicity was assessed via National Cancer Institute—Common Toxicity Criteria (NCI-CTC) version 2.
statistical analysis
Curves for OS and PFS were established using the Kaplan–Meier method [21]. All statistical analyses were performed using SPSS software (Chicago, IL).
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
patient characteristics
From December 2000 to November 2002, 30 patients were enrolled in nine centers in France. The baseline characteristics, demographics, and age-adjusted International Prognostic Index of patients are summarized in Table 1. Table 2 lists the patients' disease status and prior therapy.
|
|
dose administration
DG regimen.
Twelve patients received the DG regimen. Forty-seven cycles of DG were given: six patients (50%) received six cycles while the remaining six had premature withdrawal due to disease progression after two to four cycles (five patients) or fatal toxicity (one patient). Four patients (33%) were given prophylactic G-CSF during a median of 7 days (range, 4–7) per cycle. Day 8 gemcitabine was omitted in five cycles, involving four patients. There were no dose reductions or delays in administering the treatment cycles. The relative dose intensity was 94.6% for gemcitabine in this group.
PDG regimen.
Eighteen patients received the PDG regimen. Ninety cycles of PDG were given with a median of six per patient (range, 1–6). Thirteen patients (72.2%) received six cycles, and five patients had premature withdrawal due to disease progression after one (one patient) to three cycles. Ten patients (55%) were given prophylactic G-CSF during a median of 7 days (range, 3–7) per cycle. Gemcitabine dose reductions occurred in nine patients in a total of 23 cycles (25.6%). Gemcitabine was omitted on day 8 in 14 cycles (15.6%) involving 11 patients. Cisplatin dose reductions occurred in nine patients in a total of 14 cycles (15.6%) due to hematologic toxicity. Six patients received 16 cycles (17.7%) without cisplatin after the occurrence of renal impairment (any grade toxicity) or ototoxicity. Dose delays 1 week occurred in seven patients during the course of 10 cycles (11.1%), mostly because of hematologic toxicity. The relative dose intensity was 84% for gemcitabine and 75.7% for cisplatin in this group.
treatment consolidation and subsequent treatment.
Three patients who received PDG received subsequent consolidation treatment by rituximab (2 patients) or allogeneic transplantation. No patients went on to have peripheral stem cell harvested after PDG since half of them already had prior ASCT. Upon relapse after DG/PDG, patients primarily received different combination chemotherapy (predominantly fludarabine containing) regimens in association with rituximab. Two patients responding after subsequent treatment underwent an allogeneic transplantation with reduced intensity conditioning.
efficacy
DG regimen.
Of the 11 assessable patients, two had CR/CRu (CR unconfirmed) and two had partial response (PR) for an ORR of 36.4% [95% confidence interval (CI) 15.2% to 64.6%]. With a median follow-up of 29.6 months (95% CI 28.0 to 31.2), two patients are still alive. The median PFS was 3 months (95% CI 0.0–7.9) (Figure 1). The median OS was 15.6 months (95% CI 4.6–26.5) (Figure 2).
|
|
PDG regimen.
Of the 18 assessable patients, four achieved CR/CRu (22%) and four had PR for an ORR of 44.4% (95% CI 24.6% to 66.3%). With a median follow-up of 38.8 months, 11 patients are still alive. The median PFS was 8.5 months (95% CI 4.8–12.2) (Figure 1). The median OS has not been reached (Figure 2).
treatment-related toxicity
DG regimen.
Grade 3/4 toxic effects in patients treated with the DG regimen are presented in Table 3. One patient required a platelet transfusion, two patients required 1 red blood cell transfusions, there was no grade 3/4 neutropenia, and one patient had grade 3 infection with normal ANC. One toxic death occurred after cycle 1 in a patient with a coma, fever, and hyponatremia of unknown origin. Grade 1/2 toxic effects were infrequent (e.g. neuropathy 25%, renal toxicity 16.7%, and ototoxicity 0%).
|
PDG regimen.
In patients treated with the PDG regimen, grade 3/4 thrombocytopenia was the most prevalent hematologic toxicity (Table 3). Among all the patients receiving PDG, 34% received platelet transfusions (including 61% after cycle 1). Most platelet transfusions were given prophylactically (without bleeding/hemorrhage) if platelets were <20,000/mm3. Four patients experienced febrile neutropenia. Twelve patients received red blood cell transfusions. Patients who had prior high-dose therapy followed by ASCT had a similar hematologic toxicity compared to those who had prior conventional chemotherapy. Grade 1/2 toxic effects (i.e. neuropathy 22.2%, renal toxicity 61.1%, and ototoxicity 16.7%) were more frequent in patients receiving PDG than in those receiving DG.
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Here we report the data from a prospective, multicenter study using gemcitabine-based combinations (PDG and DG regimens) as an outpatient treatment of patients with relapsed/refractory MCL. Both regimens yielded significant response rates in patients who had received a median of one prior treatment (range, 1–4) and of whom 13% had refractory disease. The 44% ORR achieved with the PDG regimen is similar to the 46% ORR observed with the fludarabine, cyclophosphamide, and mitoxantrone (FCM) regimen in 24 patients with a similar proportion of relapsed/refractory MCL [8], but PDG appears better in terms of CR rate (22% versus 0% for FCM) with the same response criteria. All other reports of nucleoside analogue-based salvage regimens, including those combining gemcitabine, steroids, and platinum compounds, included patients with heterogeneous histologies and few patients with MCL. Moreover, these other gemcitabine-based combinations differ in the treatment schedule, dosage, and cycle duration, making efficacy and toxicity comparisons difficult [22–24]. Nevertheless, it is interesting to note that the ORR achieved with PDG was consistent with the 49% ORR achieved with a similar regimen containing gemcitabine–dexamethasone–platinum (GDP) (which contained a lower cisplatin dose of 75 mg/m2 on day 1) [22] and the 45% ORR achieved with a regimen combining fixed infusion rate gemcitabine (10 mg/m2/minute) with cisplatin (35 mg/m2 on days 1 and 15 of a 28-day cycle) [23].
Of note, the median PFS of 8.5 months observed in patients who received PDG compares favorably with the median PFS of 4 months in patients treated with FCM and is similar to the median PFS of 8 months observed when rituximab was added to FCM (R-FCM) in the same patient population [8]. Furthermore, PDG yields a median PFS similar to that of the 6.64 months observed with the GEM-P regimen (gemcitabine 1000 mg/m2 on day 1, 8, 15 and cisplatin 100 mg/m2 given on day 15) [24].
After a significant median follow-up of 38.8 months, the median OS was not reached, which again is similar to what is observed with the R-FCM regimen (but not the FCM regimen alone) in MCL patients with a comparable median age close to 65 years [8]. This probably reflects the fact that younger patients relapsing or progressing after PDG could be offered further cytoreductive regimens in combination with rituximab and in some cases allogeneic stem cell transplantation.
Myelosuppression was the most prevalent toxicity for the PDG regimen. While neutropenia was not an issue, with only four patients hospitalized for neutropenic fever and no death from infection, thrombocytopenia was a significant problem in our population, reaching grade 3/4 in 47.7% of cycles and 86% of patients (grade 4, 33%). This higher incidence of grade 3/4 thrombocytopenia as compared to other published reports with regimens combining gemcitabine and platinum compounds [22–24] primarily seemed related to the 33% patients with baseline platelet counts <100 x 109/l as a consequence of blood (33% of the patients) and/or bone marrow infiltration (72% of the patients). Indeed, the proportion of patients who required platelet transfusions was 61% after the first cycle but clearly lower in the subsequent cycles when patients had responded to therapy and normalized blood counts. Interestingly, the dose intensity of cisplatin was 75.7% in this study, which is comparable to that of the Ng et al. [24] study where cisplatin was also given at 100 mg/m2. Knowing that the dose of cisplatin may also impact platelet toxicity, it may be useful to evaluate a lower cisplatin dose (e.g. 75 mg/m2) to potentially have less platelet toxicity without losing efficacy. With regard to the nonhematologic toxicity, we observed that with our strict guidelines, renal impairment (any grade) was the main reason to discontinue cisplatin. Using a less toxic platinum compound such as oxaliplatin could help improve the toxicity profile of this type of regimen.
In the 11 patients >70 years (median age 76 years) treated with DG, the 36% ORR (including 18% CR) was consistent with the 30% ORR obtained in our previous study with gemcitabine alone in 11 patients with MCL. The median PFS of 3 months was short but similar to the median PFS of 2.4 months reported in 20 patients with predominantly relapsed (only one refractory patient) low-grade NHL who received gemcitabine alone [16] and equivalent to the median time to progression of 3 months in 17 elderly patients with recurrent/refractory aggressive NHL treated with the more toxic GDP regimen [22]. With a median of 15.4 months, the OS was good compared to those reported in other studies [16, 25]. The toxicity associated with the DG regimen in this patient population with a median age of 76 years was predominantly myelosuppression, which was mild and quite manageable. Thus, our results indicate that the DG regimen is reasonably efficient, well tolerated, and nicely tailored to the outpatient setting in patients older than 70 with relapsed MCL.
In conclusion, this 30-patient study shows that gemcitabine-based combinations are effective in relapsed/refractory MCL. The DG regimen seems to be a reliable and minimally toxic option for future combinations in elderly patients with MCL. Our results suggest that adding a platinum compound to gemcitabine probably improves the response rate and response duration compared to gemcitabine alone. However, the short PFS suggests the use of the PDG regimen as a cytoreductive treatment before high-dose therapy or allogeneic stem cell transplantation whenever possible in younger patients. The DG and PDG regimens could serve as backbones for developing more effective treatment regimens for patients with MCL. Most probably, the efficacy of both DG and PDG regimens will be further improved by adding rituximab [8, 25, 26]. The proteasome inhibitor bortezomib, which was shown to have good single-agent activity against MCL [27], would be another interesting agent to test in combination with gemcitabine as suggested by in vitro studies [28].
|
Acknowledgements |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
The authors thank Karim Benhadji, MD, for facilitating this publication. The manuscript preparation and editorial help provided by Donna Miller, Diana Kelley, Lori Anderson, Poonam Neki, Peter Fairfield, and Ghulam Kalimi is gratefully acknowledged. Delphine Combier from Group d'Etude des Lymphomes de l'Adulte Recherche Clinique was a research assistant responsible for this study. This work was supported by Eli Lilly and Company.
Received for publication June 13, 2006. Revision received September 6, 2006. Accepted for publication September 14, 2006.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
1. Samaha H, Dumontet C, Ketterer N, et al. (1998) Mantle cell lymphoma: a retrospective study of 121 cases. Leukemia 12:1281–1287.[CrossRef][Web of Science][Medline]
2. Zucca E, Roggero E, Pinotti G, et al. (1995) Patterns of survival in mantle cell lymphoma. Ann Oncol 6:257–262.
3. Teodorovic I, Pittaluga S, Kluin-Nelemans JC, et al. (1995) Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 13:2819–2826.[Abstract]
4. Bosch F, Lopez-Guillermo A, Campo E, et al. (1998) Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors. Cancer 82:567–575.[CrossRef][Web of Science][Medline]
5. Witzig EW. (2005) Current treatment approaches for mantle-cell lymphoma. J Clin Oncol 23:6409–6414.
6. Romaguera JE, Fayad L, Rodriguez MA, et al. (2005) High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 23:7013–7023.
7. Lazzarino M, Orlandi E, Montillo M, et al. (1999) Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma. Ann Oncol 10:59–64.
8. Forstpointner R, Dreyling M, Repp R, et al. (2004) The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:3064–3071.
9. Seymour JF, Grigg AP, Szer J, Fox RM. (2002) Cisplatin, fludarabine, and cytarabine: a novel, pharmacologically designed salvage therapy for patients with refractory, histologically aggressive or mantle cell non-Hodgkin's lymphoma. Cancer 94:585–593.[CrossRef][Web of Science][Medline]
10. Johnson SA. (2001) Nucleoside analogues in the treatment of haematological malignancies. Expert Opin Pharmacother 2:929–943.[CrossRef][Medline]
11. Peters GJ, Ruiz van Haperen VW, Bergman AM, et al. (1996) Preclinical combination therapy with gemcitabine and mechanisms of resistance. Semin Oncol 23:16–24.[Web of Science][Medline]
12. Baetz T, Belch A, Couban S, et al. (2003) Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 14:1762–1767.
13. Santoro A, Bredenfeld H, Devizzi L, et al. (2000) Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study. J Clin Oncol 18:2615–2619.
14. Zinzani PL, Magagnoli M, Bendandi M, et al. (1998) Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 9:1351–1353.
15. Fossa A, Santoro A, Hiddemann W, et al. (1999) Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 17:3786–3792.
16. Larson BJ, Waples JM, Pusateri A, et al. (2005) A phase II study of gemcitabine in patients with relapsed or refractory low-grade non-Hodgkin lymphoma. Am J Clin Oncol 28:165–168.[CrossRef][Web of Science][Medline]
17. Dumontet C, Morschhauser F, Solal-Celigny P, et al. (2001) Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin's lymphoma. Br J Haematol 113:772–778.[CrossRef][Web of Science][Medline]
18. Savage DG, Rule SA, Tighe M, et al. (2000) Gemcitabine for relapsed or resistant lymphoma. Ann Oncol 11:595–597.
19. Bouabdallah R, Delmer A, Xerri L, et al. (2005) ESHAP chemotherapy regimen and 13-CIS-retinoic acid in elderly patients with untreated poor-prognosis peripheral T cell lymphoma: a GELA phase II trial of feasibility and efficacy. Ann Oncol 16:v131.
20. Cheson BD, Horning SJ, Coiffier B, et al. (1999) Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244.
21. Kaplan EL and Meier P. (1958) Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481.[CrossRef][Web of Science]
22. Crump M, Baetz T, Couban S, et al. (2004) Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a phase II study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer 101:1835–1842.[CrossRef][Web of Science][Medline]
23. Emmanouilides C, Colovos C, Pinter-Brown L, et al. (2004) Pilot study of fixed-infusion rate gemcitabine with cisplatin and dexamethasone in patients with relapsed or refractory lymphoma. Clin Lymphoma 5:45–49.[Web of Science][Medline]
24. Ng M, Waters J, Cunningham D, et al. (2005) Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma. Br J Cancer 92:1352–1357.[CrossRef][Web of Science][Medline]
25. Wenger C, Stern M, Herrmann R, et al. (2005) Rituximab plus gemcitabine: a therapeutic option for elderly or frail patients with aggressive non Hodgkin's lymphoma? Leuk Lymphoma 46:71–75.[CrossRef][Web of Science][Medline]
26. Howard OM, Gribben JG, Neuberg DS, et al. (2002) Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20:1288–1294.
27. O'Connor OA, Wright J, Moskowitz C, et al. (2005) Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 23:676–684.
28. Zheng B, Georgakis GV, Li Y, et al. (2004) Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors. Clin Cancer Res 10:3207–3215.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Ghielmini and E. Zucca How I treat mantle cell lymphoma Blood, August 20, 2009; 114(8): 1469 - 1476. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||