Combination of Rituximab, Bendamustine, andCytarabine for Patients With Mantle-Cell Non-HodgkinLymphoma Ineligible for Intensive Regimens orAutologous TransplantationCarlo Visco, Silvia Finotto, Renato Zambello, Rossella Paolini, Andrea Menin, Roberta Zanotti, Francesco Zaja,Gianpietro Semenzato, Giovanni Pizzolo, Emanuele S.G. D’Amore, and Francesco Rodeghiero Carlo Visco, Silvia Finotto, Andrea Menin, Rodeghiero, San Bortolo Hospital, Vicenza; Purpose
The combination of bendamustine (B) and rituximab (R) is efficacious, with favorable toxicity in
zato, Padua University School of Medicine, Padova; Rossella Paolini, Santa Maria della mantle-cell lymphoma (MCL). In this phase II study, we combined cytarabine with R and B (R-BAC) in patients with MCL age Ն 65 years who were previously untreated or relapsed or refractory (R/R) Zanotti and Giovanni Pizzolo, University of after one prior immunochemotherapy treatment.
Patients and Methods
In stage one, we established the maximum-tolerated dose (MTD) of cytarabine in R-BAC. In stagetwo, patients received R (375 mg/m2 intravenously [IV] on day 1), B (70 mg/m2 IV on days 2 and 3), and cytarabine (MTD IV on days 2 to 4) every 28 days for four to six cycles. The primary endpoint (overall response rate [ORR]) was evaluated by positron emission tomography. Secondary Supported in part by grants from the Asso- end points included safety, progression-free survival (PFS), response duration, and overall survival.
Linfomi e il Mieloma/Associazione Italiana Forty patients (median age, 70 years; 20 previously untreated patients) were enrolled; 93% had Ann Arbor stage III/IV disease; 49% had high Mantle Cell International Prognostic Index scores, with 15% blastoid histology. All R/R patients (35% refractory) had previously received R-containing regimens. The cytarabine MTD used in stage two was 800 mg/m2, and R-BAC was well tolerated, to partially cover management costs of this with an 85% treatment completion rate. The major toxicity was transient grades 3 to 4 thrombocytopenia (87% of patients); febrile neutropenia occurred in 12%. The ORR was 100% which supported the editorial production of (95% complete response [CR]) for previously untreated and 80% (70% CR) for R/R patients. The this article; and by Zaicom Medical Market- 2-year PFS rate (Ϯ standard deviation) was 95% Ϯ 5% for untreated and 70% Ϯ 10% for ing Communications, which provided edito- Presented in part at the 11th International Conclusion
R-BAC is well tolerated and active against MCL.
Lugano, Switzerland, June 15-18, 2011 and 53rd Annual Meeting of the American Soci- J Clin Oncol 31:1442-1449. 2013 by American Society of Clinical Oncology mide, doxorubicin, vincristine, and prednisone), are INTRODUCTION
Munidpharma International had input in the accepted by many groups as standard treatment for content or interpretation of the study or Mantle-cell lymphoma (MCL) is one of the more elderly patients, and their effectiveness has been saw the final results before submission.
aggressive forms of non-Hodgkin lymphoma, with a recently shown to be improved by rituximab Authors’ disclosures of potential conflicts median survival of 3 to 5 years.1 Intensive regimens maintenance.5-8 Bendamustine is also an active adopted for younger patients with MCL (age Ͻ 65 monotherapy that is well tolerated by older or frail years) have provided encouraging short-term patients.9,10 Improved efficacy was demonstrated Clinical trial information: NCT00992134.
results,2-4 with the incorporation of high-dose cytar- when bendamustine was combined with rituximab abine being widely recognized as highly beneficial.2-7 in comparison with R-CHOP in a randomized trial ogy, San Bortolo Hospital, Via Rodolfi 37, However, two thirds of patients diagnosed with 36100 Vicenza, Italy; e-mail: rodeghiero@ MCL are older than age 60 years, and effective and well-tolerated low-toxic first-line therapeutic op- have demonstrated distinct and synergistic mecha- tions are urgently needed for this large group of nisms of action in preclinical studies. Our group recently reported that bendamustine significantly increased cytarabine cytotoxicity in MCL cell lines, such as R-CHOP (rituximab plus cyclophospha- especially when administered sequentially.12,13 2013 by American Society of Clinical Oncology Information downloaded from and provided by at ULSS N6 Vicenza on April 8, 2013 from Copyright 2013 American Society of Clinical Oncology. All rights reserved.
R-BAC for the Treatment of Mantle-Cell Lymphoma
receive four cycles of R-BAC, and each treatment cycle lasted 4 weeks (Fig 1).
Previously untreated patients could receive up to six cycles if they were age Ͻ 80 years, exhibited good treatment tolerance, or developed disease regres-sion from treatment cycles two to four. Patients not responding to the initial At the end of treatment, patients underwent CT, PET, and bone marrow biopsy with flow cytometry. CT scan was repeated 3 months later and then every 6 months. Details on dose reductions, supportive care, premedica-tion, blood count checks, definition of complete response (CR), PET evalua- Fig 1. Rituximab, bendamustine, and cytarabine (Ara-C) scheme. Rituximab was
tion and review, and follow-up are reported in the Appendix (online only).
administered on day 1 of the first cycle and on day 2 from cycle two onward.
Bendamustine was administered intravenously during a 30- to 60-minute infusion Assessment of Stem-Cell Mobilization
on days 2 and 3 of each cycle, and cytarabine was administered during a 2-hour Eight patients (four untreated, four R/R) were monitored for stem-cell infusion, 2 hours after bendamustine administration, on days 2 to 4. Eachtreatment cycle lasted 28 days.
collection on neutrophil recovery after cycle three to assess the potentialmobilizing activity of R-BAC (Table 1).
Study End Points
Rituximab also potentiated the cytotoxicity of bendamustine against The primary end points of stages one and two were to determine the NHL cell lines in a previous study.14 Therefore, we investigated the MTD of cytarabine and overall response rate (ORR), respectively. Secondary efficacy and safety of rituximab, bendamustine, and a relatively low end points included safety, CR, progression-free survival (PFS), and durationof response (DOR). Response, overall survival (OS), PFS, and DOR were dose of cytarabine (R-BAC) in older or relapsed or refractory (R/R) defined according to revised Cheson criteria.16 patients with MCL who were not eligible for intensive regimens.
Statistical Analysis and Study Power
The Kaplan-Meier method was used to estimate median PFS, OS, and DOR, PATIENTS AND METHODS
and survival rates were expressed as percentages (Ϯ 95% CI). We hypothesizedthat R-BAC would produce a minimum ORR Ն 70%, with an optimum level ofactivity of 90%. This assumption was based on prior studies indicating an ORR of Study Design
71% to 94% in previously untreated patients of similar age distribution receiving This open-label, single-arm, phase II clinical trial was conducted in two alternative regimens8,17,18 and an ORR of 58% to 75% in R/R patients treated with stages. The dose-finding stage determined dose-limiting toxicity (DLT) and chemoimmunotherapy combinations.9,19 It was determined that a planned sam- the maximum-tolerated dose (MTD) of intravenous (IV) cytarabine com- ple size of at least 36 patients would yield Ͼ 90% power (using an overall, two- bined with fixed rituximab (375 mg/m2) and bendamustine (70 mg/m2) IV sided, 5% significance level) when detecting an increase of 20% in ORR after doses repeated at 4-week intervals. Stage two evaluated the safety and efficacy treatment with R-BAC. According to the optimal two-stage design,20 an ORR of the R-BAC regimen, incorporating the MTD of cytarabine with these fixed would be considered unacceptable if Ͻ 29 of 36 patients responded to R-BAC.
doses of rituximab and bendamustine (Fig 1) in a larger group of patients.
The study was conducted in accordance with the principles of the Dec- laration of Helsinki, Good Clinical Practice, and current national rules. The study, approved by the ethics committee of San Bortolo Hospital (Vicenza,Italy), was registered with the European Medicines Agency (EUDRA-CT2009-009912-34).
Patient Characteristics
The study enrolled 40 patients from June 2009 to October 2011 of Patients and Eligibility
Eligible patients had confirmed bidimensionally measurable MCL, median age 70 years. None presented with non-nodal leukemic pic- WHO performance status of 0 to 2, and adequate renal and hepatic functions ture. All R/R patients had been treated with rituximab-containing and were either previously untreated (age Ն 65 years) or R/R after one previ- regimens (Table 1). Two patients had undergone first-line autologous ous immunochemotherapy treatment (Ϯ autologous marrow transplanta- transplantation, and two others had undergone therapeutic splenec- tion; age Ն 18 years). Patients were recruited from four major hematology units in northeast Italy and were referred to San Bortolo Hospital for screening,treatment, and follow-up. Additional eligibility details are provided in the Stage One: Dose Finding
A diagnosis of MCL was confirmed by WHO classification criteria, Six patients (three previously untreated who received six cy- including lymphoma-cell positivity for cyclin D1, SOX11 positivity in cyclin cles and three R/R receiving four cycles) were independently eval- D1–negative or t(11;14)-negative cells, and expression of CD20 and CD5. All uated after completing 30 cycles of R-BAC at the cytarabine 800 specimens were reviewed by two expert hematopathologists (A.M, E.S.G.D.).
mg/m2 IV starting dose. This dose was considered to be the MTD Stage One: Dose-Finding Treatment Plan and DLTs
because one patient in each cohort experienced a DLT (grade 4 To our knowledge, this is the first clinical study exploring the association thrombocytopenia). Following criteria specified in the Appendix of bendamustine and cytarabine in patients with lymphoma. An initial cytar- (online only), no dose modifications were planned, and stage two abine dose of 800 mg/m2 was adopted because of its good toxicity profile in evaluated the R-BAC treatment scheme shown in Figure 1.
older patients.15 Stage one of the study was designed according to the modifiedFibonacci increment rule, starting with the lowest dose of cytarabine (800 Stage Two: Safety
mg/m2) and adopting the traditional escalation rule, as specified in the Appen-dix (online only).
Thirty-four patients (85%) completed the planned Ն four treat- ment cycles. Six patients (one untreated, five R/R) discontinued af- Stage Two: Baseline Evaluation, Treatment, Response
ter Ͻ four R-BAC cycles because of adverse events (n ϭ 3), progressive Assessment, and Supportive Care
Baseline evaluation included bone marrow biopsy and flow cytometry as disease (PD)/no response (n ϭ 2), or patient decision (n ϭ 1). Of the well as tumor staging using contrast-enhanced computed tomography (CT) 182 treatment cycles administered, 15 (8%) were delayed. However, scan and positron emission tomography (PET). All patients were meant to each delay lasted Ͻ 14 days. Nine previously untreated patients (45%) 2013 by American Society of Clinical Oncology Information downloaded from and provided by at ULSS N6 Vicenza on April 8, 2013 from Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Visco et al
Table 1. Patient Demographics and Clinical Characteristics
Abbreviations: AAS, Ann Arbor stage; CR, complete response; IPI, International Prognostic Index; MCL, mantle-cell lymphoma; MIPI, Mantle-Cell Lymphoma International Prognostic Index; NA, not applicable; NR, no response; OR, overall response; PD, progressive disease; PR, partial response; RB, rituximab combinedwith bendamustine; R-CHOP, rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CVP, rituximab combined with cyclophos-phamide, vincristine, and prednisone; R-FCM, rituximab combined with fludarabine, cyclophosphamide, and mitoxantrone; R-HyperCVAD, rituximab combined withhyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine; R/R, relapsed/refractory.
ءFollowed by autologous transplantation in two patients.
†Median No. of harvested CD34ϩ, 11.2 and 12.7 ϫ 106/kg after first and second lines, respectively.
received six cycles because of good tolerance (n ϭ 7) or a continued Overall, R-BAC was well tolerated (Tables 2 and 3). The primary response between cycles two and four (n ϭ 2). Median numbers of toxicity was reversible myelosuppression. Thrombocytopenia re- administered cycles were 4.6 and 4.0 for untreated and R/R patients, quired transfusions in 65% of cycles, and 44% of patients received erythropoietin. Thrombocytopenia and leukopenia were significantly 2013 by American Society of Clinical Oncology Information downloaded from and provided by at ULSS N6 Vicenza on April 8, 2013 from Copyright 2013 American Society of Clinical Oncology. All rights reserved.
R-BAC for the Treatment of Mantle-Cell Lymphoma
Table 2. Hematologic Toxicity According to Patient Status
NOTE. Data refer to cycles with at least 1 day of a grade 3 or 4 event.
Abbreviations: R/R, relapsed or refractory to one prior rituximab-containing immunochemotherapy regimen; NS, not statistically significant.
ءP value refers to the comparison between No. of cycles with grade 3 or 4 event in previously untreated versus R/R patients.
more common in R/R than untreated patients (Table 2). Severe neu- and the patient completed six cycles without additional events, the tropenia (median duration, 2 days; range, 0 to 5 days) was also more patient with pulmonary edema was withdrawn. Four patients (10%) frequent in R/R than untreated patients (49% v 17%; P Ͻ .001).
had glutamic-pyruvic transaminase/glutamic-oxaloacetic transami- Febrile neutropenia was quite uncommon (4% of cycles; 12% of nase increases, and one patient discontinued after three R-BAC cycles patients). Only one patient discontinued treatment after three cycles because of a grade 3 flare. All gamma-glutamyl transferase and because of prolonged grade 3 cytopenia, which slowly resolved 4 glutamic-pyruvic transaminase/glutamic-oxaloacetic transaminase months after the last R-BAC dose. Two patients had grade 2 leukope- increases returned to pretreatment levels within 2 months of com- nia and thrombocytopenia for 6 months after stopping R-BAC, which pleting treatment. Skin rash, sometimes accompanied by localized then resolved spontaneously. There was no clear trend toward an itchy areas of cutaneous desquamation, did not progress to epider- increase in cytopenia severity or transfusion requirements with subse- mal complications and spontaneously regressed. Skin rash was considered possibly related to R-BAC, although other medications Most nonhematologic adverse events were grades 1 to 2, and could have contributed. There was no evidence of renal toxicity or common events attributed to R-BAC included fatigue (35%), cutane- ous rash/desquamation (15%), and isolated gamma-glutamyl trans- Of the eight deaths reported during the study, seven were attrib- ferase elevation (40%; Table 3). Five patients reported grade 3 or 4 uted to PD (all in R/R group), and one was attributed to cerebral infections (respiratory tract infection, n ϭ 1; Herpes zoster, n ϭ 1; stroke. One patient developed a squamous cell carcinoma of the lung Escherichia coli sepsis, n ϭ 1; febrile neutropenia of unknown origin, n ϭ 2). Other grades 3 to 4 nonhematologic toxicities included onegrade 4 myocardial infarction after one cycle and one grade 3 severe Stage Two: Efficacy and Stem-Cell Mobilization
fluid retention with pulmonary edema after two cycles. Although the ORRs were 90% (83% CR; 7% partial response [PR]) for all myocardial infarction was considered unrelated to study treatment, patients, 100% (95% CR; 5% PR) for untreated patients, and 80%(70% CR; 10% PR) for R/R patients. Three R/R patients had noresponse (7%), and another had PD (3%; Table 1). This patient was an Table 3. Nonhematologic Toxicities Occurring in Ն One Patient
81-year-old man with blastoid MCL who previously experienced PD after transiently responding to rituximab and bendamustine. TheORR for seven patients who received first-line R-HyperCVAD (ritux- imab combined with hyperfractionated cyclophosphamide, vincris- tine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine; two had undergone autologous transplantation) was 86% (all CR). ORRs were 67% (50% CR) for six patients with blastoid MCL (all R/R) and 84% (67% CR) for six patients who were refractory After a median follow-up of 26 months (range, 11 to 38 months), 31 patients (78%) were alive and disease free, and median PFS/DOR had not been reached. The 2-year PFS and DOR rates were 95% (Ϯ 95% CI, 5%) and 100% for untreated patients and 70% (Ϯ 95% CI,10%) and 87% ( Abbreviations: Gamma-GT, gamma-glutamyl transferase; GOT/GPT glutamic- Ϯ 95% CI, 8%) for R/R patients, respectively (Fig 2).
oxaloacetic transaminase/glutamic-pyruvic transaminase; NA, not applicable.
These rates were similar in patients receiving four or six R-BAC cycles ءHerpes zoster virus reactivation (n ϭ 1); febrile neutropenia (n ϭ 2).
and between SOX11-positive and SOX11-negative patients. PET pos- †Pneumonitis (n ϭ 1) and Escherichia coli sepsis (n ϭ 1).
‡Myocardial infarction.
itivity at the end of treatment (P Ͻ .001), high Mantle-Cell Interna-tional Prognostic Index (MIPI) score (P ϭ .02), and Ki-67 Ͼ 20% 2013 by American Society of Clinical Oncology Information downloaded from and provided by at ULSS N6 Vicenza on April 8, 2013 from Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Visco et al
Fig 2. In (A, B) previously untreated and (C, D) relapsed or refractory (R/R) patients with mantle-cell lymphoma, Kaplan-Meier survival curves for (A, C) overall survival
and (B, D) progression-free survival.
(P ϭ .03) were significantly associated with inferior survival. Survival median age 61 years8 or age Ͻ 65 years.21 In these cohorts, ORR, CR curves of the patient subgroups are shown in Figure 3. First-line rate, and median time-to-treatment failure (TTF) with R-CHOP were R-BAC was particularly effective in terms of stem-cell harvest, with 94%, 34%, and 21 months8 and 96%, 48%, and 16 months, respec- 100% CD34ϩ cell mobilizing success (Table 1).
tively.21 Our reported 95% CR rate with first-line R-BAC is markedlyhigher than those reported with R-CHOP and was achieved in olderpatients with higher MIPI scores. However, this discrepancy might DISCUSSION
have resulted in part from the differences in criteria used to measureCR between our study16 and previous studies.22 Unlike in previous The sequential R-BAC regimen was active in this series of elderly studies, a post-treatment residual mass of any size was permitted as patients with MCL, inducing high ORR (100% and 80%) and CR long as it was PET negative in our study. Indeed, two patients achiev- (95% and 75%) rates in treatment-naive and R/R patients, respec-tively. Treatment was well tolerated, with 19 of 20 previously un- ing PR according to CT scan alone were converted to CR in our study treated patients (median age, 72 years) completing at least four cycles; because of PET negativity; both are alive and free of disease after 18 the most common toxicity was reversible and manageable grades 3 to and 26 months. Post-treatment PET has never been systematically 4 thrombocytopenia. Strikingly, none of the treatment-naive patients evaluated in prospective cohorts of patients with MCL, and our results relapsed or experienced PD during the median 27 months of follow- substantiate its use in clinical practice (Fig 3), confirming what has up, and only one adverse event was reported (fatal cerebral stroke 6 been suggested in retrospective studies.23,24 These data, together with months after completing therapy in a patient with sustained CR) in the apparently shorter TTF in the two R-CHOP studies, suggest that this group. Patients with relapsed (n ϭ 14) or refractory (n ϭ 6) MCL, R-BAC induces responses of higher quality and longer duration than all previously treated with rituximab-containing regimens, had prom- R-CHOP in previously untreated elderly patients with MCL.
ising 2-year PFS (70%) and DOR (87%) rates.
A randomized European MCL Network trial compared induc- Response rates from the present study compare favorably with tion with R-FC (rituximab combined with fludarabine plus cyclophos- those reported for established first-line treatments in elderly patients phamide) with R-CHOP in elderly patients with MCL before with MCL. Similar ORRs but relatively low CR rates have been dem- evaluating the role of rituximab maintenance.5,7 Similar to our study, onstrated with first-line R-CHOP in younger cohorts of patients of median patient age was 70 years, and 50% of patients had high MIPI 2013 by American Society of Clinical Oncology Information downloaded from and provided by at ULSS N6 Vicenza on April 8, 2013 from Copyright 2013 American Society of Clinical Oncology. All rights reserved.
R-BAC for the Treatment of Mantle-Cell Lymphoma
End of treatment PET- (n = 33)End of treatment PET+ (n = 7) Intermediate MIPI (n = 10)Low MIPI (n = 11) Fig 3. Kaplan-Meier survival curves for progression-free survival (PFS) and PFS stratification based on (A) relapsed or refractory patients, (B) cytologic subtype of
mantle-cell lymphoma (MCL), (C) type of previous immunochemotherapy, (D) positron emission tomography (PET) scan evaluation after the end of treatment, (E) MantleCell International Prognostic Index (MIPI) score (P value refers to difference between low or intermediate v high), and (F) Ki-67 expression level. The six refractorypatients had previously been treated with R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone; n ϭ 1), R-CHOP (rituximab plus cyclophosphamide,doxorubicin, vincristine, and prednisone; n ϭ 3), rituximab plus bendamustine (n ϭ 1), and R-HyperCVAD (rituximab combined with hyperfractionated cyclophospha-mide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine; n ϭ 1). R chemotherapy, rituximab-containing chemotherapy.
scores. Reported CR/unconfirmed CR rates were similar for R-FC tients with MCL.11 For patients treated with RB, the reported CR was (52%) and R-CHOP (50%), and patients responding to R-CHOP or 42%, and median PFS (34 months) was significantly better than that R-FC who did not receive maintenance therapy had a median DOR of for those treated with R-CHOP. Although our PFS curve (95% 2-year 18 months, similar to the median TTF duration previously reported PFS rate) compares favorably with the RB study (at least for the first 2 years), a longer follow-up is needed to confirm this observation. More A prospective, randomized, phase III study compared RB (ritux- recently, the addition of bortezomib to R-CHOP (36 untreated pa- imab plus bendamustine) with R-CHOP as first-line therapy in pa- tients with MCL; median age, 66 years; 28% with high-risk MIPI 2013 by American Society of Clinical Oncology Information downloaded from and provided by at ULSS N6 Vicenza on April 8, 2013 from Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Visco et al
scores)25 or RiPADϩC (rituximab plus doxorubicin, dexamethasone, in all patients (87% and 57% of patients with grades 3 and 4 throm- and chlorambucil; 39 patients; median age, 72 years; 54% with high- bocytopenia/leukopenia, respectively), requiring transfusion support risk MIPI scores)26 improved response rates but did not significantly in the majority of cycles, and was considerably higher than with RB or prolong PFS (2-year PFS, 44% and median PFS, 26 months, respec- R-CHOP. Because we also used a particularly low dose of bendamus- tively), with responses seemingly less durable than those after treat- tine (Ͻ 70 mg/m2) in our R-BAC regimen, it is reasonable to assume that the hematologic toxicity (myelosuppression) mainly resulted Efficacy outcomes associated with R-BAC in patients with R/R from cytarabine. Finally, it is worth considering that alopecia was disease are good for this relatively poorly responsive population after reported for only two patients in our study (grades 1 to 2), whereas initial relapse. Two studies have investigated the role of RB in the most patients receiving R-CHOP experience grade 3 or 4 alopecia.8 treatment of small series of patients with R/R MCL.9,10 Compared On the basis of these encouraging results with R-BAC, we have with these studies, R-BAC elicited a higher CR rate (70% v 50% and initiated a multicenter trial (FIL-RBAC500) promoted by the Fonda- 59%) and longer PFS (2-year PFS, 70% v median PFS, approximately zione Italiana Linfomi, with a reduced cytarabine dose of 500 mg/m2.
18 months for RB). However, it is important to note that the patients The FIL trial will include minimal residual disease evaluations in with MCL in these studies were more heavily pretreated than those in parallel with PET scans. The absence of minimal residual disease, our study (30% to 40% patients had Ն one prior treatment [maxi- which is a useful tool in MCL, was a flaw in our present study.35 mum, three]) and that the CR rate might have been underestimated In conclusion, these study results support the use of R-BAC in because it was assessed by CT scan only.9,10 On the other hand, one of elderly patients with MCL who are not candidates for intensive treat- the studies, conducted by Rummel et al,9 did not include rituximab- ment regimens. This combination elicited durable responses with a pretreated patients. Overall, with the limits of the different inclusion low incidence of severe or life-threatening adverse events but with criteria in the R/R setting and of the shorter follow-up of our first-line significant transient myelosuppression. On the basis of its remarkable patients, R-BAC seems to produce more frequent and durable CRs activity as well as stem-cell mobilizing potential in the first-line setting, compared with RB and has a good stem-cell mobilizing capacity.
R-BAC could be a useful option in the preintensification phase for However, remarkably higher myelosuppression was observed. Several younger patients with MCL, in whom achieving CR before transplan- other regimens, including investigational drugs administered alone or tation can elicit long-lasting remissions. Additional studies are awaited in combination, in the relapsed setting have reported median PFS durations ranging from 5 to 12 months.27-34 The R-BAC regimen was well tolerated in first-line and relapsed AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
settings. Nonhematologic toxicity was considered acceptable, with OF INTEREST
febrile neutropenia occurring in 12% of patients (4% of administeredcycles), whereas hematologic toxicity was frequent. Grades 3 to 4 The author(s) indicated no potential conflicts of interest.
thrombocytopenia was observed in 87% of patients but was transient(median duration, 3 days) and mainly asymptomatic, with no AUTHOR CONTRIBUTIONS
significant bleeding signs or symptoms (Table 2). The rate ofleukocytopenia with R-BAC was similar to that reported for other Conception and design: Carlo Visco, Francesco Rodeghiero
rituximab-containing chemotherapy regimens. Regimens such as Provision of study materials or patients: All authors
R-FCM (rituximab plus fludarabine, cyclophosphamide, and mitox- Collection and assembly of data: Carlo Visco, Silvia Finotto, Renato Zambello,
antrone)19 and R-CHOP8 have demonstrated 54% and 69% grade 3 Rossella Paolini, Andrea Menin, Roberta Zanotti, Francesco Zaja, GianpietroSemenzato, Giovanni Pizzolo, Emanuele S.G. D’Amore or 4 leukocytopenia rates and 12% and 5% severe thrombocytopenia Data analysis and interpretation: Carlo Visco, Emanuele S.G. D’Amore,
rates, respectively. In contrast, RB has demonstrated grade 3 or 4 cytopenia rates in the range of 15% to 25%.9,10 Overall, myelosupres- Manuscript writing: All authors
sion was significant in the study despite prophylactic growth factor use Final approval of manuscript: All authors
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Sportsrideklubben Silkeborg Sportsrideklubben Silkeborg, LC Springning Heste Dotering: 300, 250, 200, 175, 150Start: Lørdag Start Stv. Resultat Placering Sportsrideklubben Silkeborg Sportsrideklubben Silkeborg, U-LC Springning Heste Start Stv. Resultat Placering Sportsrideklubben Silkeborg Sportsrideklubben Silkeborg, LB Springning Heste Dotering: 300, 250, 200


Your Bible A Tutorial in Using Key Scriptural Passages when Engaging in Evangelism 1 Supernatural physical body. 44 It is sown a natural body; it is raised a spiri- 2 Mortality cannot inherit God’s Kingdom. tual body. There is a natural body, and there isa spiritual body.… 50 Now this I say, breth- 3 Other New Testament verses. ren, that flesh and blood cannot inherit the king-do

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