Appropriate Use of Bendamustine in First-Line Therapy of Chronic - DocsLib

sign in sign up

<<

Home , Fludarabine

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

Leukemia Research xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Leukemia Research

journa l homepage: www.elsevier.com/locate/leukres

Appropriate use of bendamustine in ﬁrst-line therapy of chronic

lymphocytic leukemia. Recommendations from SIE, SIES, GITMO Group

a,∗ b c d e

Antonio Cuneo , Monia Marchetti , Giovanni Barosi , Atto Billio , Maura Brugiatelli ,

f g h i

Stefania Ciolli , Luca Laurenti , Francesca Romana Mauro , Stefano Molica ,

j k l

Marco Montillo , Pierluigi Zinzani , Sante Tura

a

Section of Hematology, Department of Medical Sciences, University of Ferrara, Via Savonarola, 9, 44121 Ferrara, Italy

b

Unit of Hematology, Hospital “C. Massaia”, Asti, Italy

c

Unit of Clinical Epidemiology/Centro per lo Studio della Mieloﬁbrosi, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

d

Department of Hematology and TMO, Ospedale Centrale, Bolzano, Italy

e

Divisione di Ematologia, Azienda Ospedaliera Papardo, Messina, Italy

f

Division of Hematology, University of Florence, Florence, Italy

g

Department of Hematology, Catholic University of Rome, “A. Gemelli” Hospital, Rome, Italy

h

Dipartimento di Biotecnologie Cellulari ed Ematologia, Università degli Studi “La Sapienza”, Roma, Italy

i

Oncologia Medica, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy

j

Department of Oncology/Haematology, Division of Haematology, Niguarda Ca’Granda Hospital, Milan, Italy

k

Institute of Hematology and Medical Oncology “Seragnoli”, University of Bologna, Bologna, Italy

l

University of Bologna, Bologna, Italy

a r t i c l e i n f o a b s t r a c t

Article history: By using the GRADE system we produced the following recommendations for the use of bendamus-

Received 20 March 2014

tine in the ﬁrst-line treatment of CLL: (1) bendamustine with rituximab is recommended in elderly ﬁt

Received in revised form 8 June 2014

patients potentially eligible to FCR; (2) Bendamustine alone is recommended in patients who are can-

Accepted 28 June 2014

didate to chlorambucil alone; (3) Rituximab–bendamustine is recommended in patients not eligible to

Available online xxx

FCR, but suitable to receive rituximab. Consensus-based recommendations addressed evidence-orphan

issues concerning the use of bendamustine in genetically-deﬁned high-risk patients and the appropriate

Keywords:

dose of bendamustine as single agent or in association with rituximab.

Chronic lymphocytic leukemia

© 2014 Published by Elsevier Ltd.

First line treatment Bendamustine

Guidelines

1. Introduction increase in progression-free survival (PFS) over ﬂudarabine, that

did not translate into survival advantage.

Considerable progress has been made in the treatment of The adjunct of Rituximab to chemotherapy improved overall

chronic lymphocytic leukemia (CLL) over the last decade [1]. The survival in patients reported by SEER [5]. Importantly, the adjunct

alkylating agent chlorambucil has been the mainstay treatment for of Rituximab to ﬂudarabine achieved a signiﬁcant reduction in

B-CLL for over 50 years; however ﬂudarabine was shown to sig- mortality (HR = 0.58) [5], and this advantage was maintained irre-

niﬁcantly improve PFS in a Cochrane meta-analysis of randomized spective of age in a retrospective analysis of 4 successive frontline

trials [2] and to prolong survival in a long-term observational study CALGB trials [6].

of a randomized trial [3], a finding not confirmed in another trial The combination of rituximab fludarabine and cyclophos-

[4]. Further improvement was achieved by the combination ﬂu- phamide (FCR) was shown to be superior to FC for all clinical

darabine and cyclophosphamide [4] which attained a 20-month endpoints including overall survival in young and/or ﬁt patients and

this chemoimmunotherapy regimen became the standard ﬁrst-line

therapy for CLL without comorbidities [1]. However, this frequent

lymphoid clonal disease occurs at a median age over 70 years

∗ [7,8], and coexisting medical conditions make treatment tolera-

Corresponding author. Tel.: +39 532 236977; fax: +39 532 236654.

E-mail address: [email protected] (A. Cuneo). bility a major issue in a substantial fraction of elderly patients

http://dx.doi.org/10.1016/j.leukres.2014.06.017

0145-2126/© 2014 Published by Elsevier Ltd.

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

2 A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx

[9,10]. In these patients the efﬁcacy of chlorambucil is signiﬁcantly European Hematology Association and the International Conference on Malignant

Lymphoma meetings. Even though the recommendations were issued on the basis

improved by the adjunct of rituximab, obinutuzumab and ofatu-

of systematic review of literature published up to September 2013, analysis of data

mumab [11–13].

published since that date up to January 2014 was performed before publication

Bendamustine hydrochloride is a bifunctional alkylating agent

of the present paper. According to GRADE methodology [20], the AC prepared “evi-

incorporating a central ring system that is similar to that in purine dence tables” and “quality of evidence tables” (available by the corresponding author

analogs. Unlike alkylators, bendamustine primarily targets base on request) for each critical appraisal. The EP received the critical appraisals and

was asked to draft recommendations based on the beneﬁt to risk proﬁle of each

excision repair and activates DNA-damage stress responses and

compared intervention. Deﬁnite agreement of the recommendations and of their

apoptosis. Therefore, it is only partially cross-resistant with other

strength (weak or strong) was made through subsequent face-to-face meetings.

alkylators. Due to its favorable toxicity proﬁle, it has been tested

alone and in combination with rituximab in refractory/relapsed

2.3. Producing consensus-based recommendations

indolent lymphoma, including CLL and, more recently, in treatment

naïve patients [14–18]. The consensus methodology was applied for all the issues worth to be discussed

The Guideline Committee of the Italian Society of Hematology but not addressable by a critical appraisal of evidence. During three consecutive

consensus conferences, the issues were analyzed and discussed according to the

reckoned that an unmet need for CLL was reached and deserved

nominal group technique [21].

a prescriptive position for the community practice for the use of

bendamustine in the ﬁrst-line setting.

3. Results

2. Methods

The following questions were raised by the panel as clinically

2.1. Guidelines development process

relevant (Table 1):

The Advisory Council (AC), composed of three members with expertise in clinical

epidemiology, hematology and critical appraisal, oversaw the process. An Expert

Panel (EP) was selected according to the conceptual framework elements of the NIH 1. Is bendamustine alone appropriate in patients candidate to ﬁrst-

Consensus Development Program [19]. During a ﬁrst meeting, the EP decided which line FCR? (Consensus based)

clinical issues needed recommendations, and the AC checked which clinical queries

might be addressed by a critical appraisal of evidence.

Preliminary considerations:

2.2. Producing and grading evidence-based recommendations Phase II studies [22] and randomized trials [23] reported that

FCR ﬁrst-line treatment in CLL patients induced complete response

The EP chose the critical outcomes for each clinical query deserving evidence-

(CR) rates ranging from 44% to 70% and a median PFS ranging from

based recommendations. Literature search was performed in February 2013 and

52 to 80 months (Table 2). Grade 3-4 neutropenia usually occured

limited to English-language publications edited after 2005. The search included

proceedings 2011 through 2013 of the American Society of Hematology, the in more than half of the patients and major infections in 2.6% of the

Table 1

Key questions and recommendations for the use of bendamustine in previously untreated CLL.

a

Questions GRADE (critical outcomes) Recommendation

1 Is bendamustine alone appropriate in patients No In patients who are eligible to FCR, bendamustine alone is not

candidate to ﬁrst-line FCR? recommended

2 Is bendamustine alone appropriate in patients No In patients who are candidates to FCR but with contraindications or

potentially candidate to FCR but with intolerance to rituximab, bendamustine alone is a reasonable

contraindications or intolerant to Rituximab? treatment

3 Should R-bendamustine be preferred to FCR in Yes (PFS, severe AE) Based on its efﬁcacy/safety proﬁle R-bendamustine might be

patients candidate to ﬁrst-line FCR? considered as an alternative to FCR in young and ﬁt patients (level of

evidence: low; strength of recommendation: do, weak) and should be

recommended in the elderly (≥65) ﬁt patient (level of evidence: low;

strength of recommendation: do, strong)

4 Should bendamustine alone be preferred to Yes (PFS, severe AE) In patients who are conventionally candidate to chlorambucil alone,

chlorambucil in patients candidate to ﬁrst-line bendamustine alone is recommended.(level of evidence: low; strength

chlorambucil alone? of recommendation: strong)

5 Is R-bendamustine appropriate in patients not Yes (PFS, severe AE) Bendamustine plus rituximab is beneﬁcial in CLL patients non eligible

eligible to FCR? to FCR, but suitable to receive rituximab. (level of evidence: very low;

strength of recommendation: strong)

6 Are bendamustine-containing regimens No Bendamustine with or without rituximab or bendamustine containing

appropriate in patients with 17p- and/or p53 regimens might not be useful options in patients with del 17p and or

mutations? p53 mutation

7 Are bendamustine-containing regimens No Bendamustine and rituximab is recommended in patients with 11q- or

appropriate in patients with 11q- or IGHV IGHV unmutated who are not candidate to FCR

unmutated?

8 Which are the appropriate schedule and No The recommended dose of bendamustine alone in untreated CLL

duration of bendamustine-based regimens patients less than 75 years old is 100 mg/sqm. The recommended dose

of bendamustine in association with rituximab is 90 mg/sqm. The dose

of bendamustine may be reduced in patients older than 75 years

according to ﬁtness and comorbidities

9 Howe should infections and autoimmune No Antibiotic prophylaxis and the prophylactic use of IVIG can be

cytopenia be managed and prevented during considered on an individual basis. Occult HBV infection and HBV

bendamustine therapy? carriers should be given antiviral prophylaxis if bendamustine is

associated with Rituximab. Bendamustine, alone or with rituximab,

may be initiated in patients with AIHA or ITP unresponsive to steroids

10 Should bendamustine therapy be modiﬁed in No In patients with moderately impaired renal function, bendamustine

B-CLL patients with renal or hepatic alone or associated with rituximab can be administered. Since the use

comorbidities? of bendamustine in patients with impaired renal function increases

the risk of cytopenias, in this circumstance the dose should be reduced

a

See text for details.

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx 3

Table 2

Efﬁcacy and safety of bendamustine plus rituximab, FCR, chlorambucil and anti CD20 monoclonal antibodies in previously untreated CLL.

Regimen and reference N. pts Speciﬁc inclusion criteria Age CR rate PFS* % Patients with % Patients with

(median) grade 3–4 grade 3–4 neutropenia infections

R-bendamustine

Fisher et al. [18] 117 WHO PS 0-2; CrCl > 30 ml/min 64 23.1% 33.8 19.7 7.7

Eichhorst et al. [27] 279 CIRS ≤ 6; CrCl > 70 ml/min; No 62 38.1% 78.2%** 56.8 25.4 del(17p) FCR

◦ ◦◦ ◦◦

Keating et al. [22] 224 CLL requiring therapy; 58 70% 80 52 2.6

Cr < 2 mg/dL; Bil < 2 mg/dL

Eichhorst et al. [27] 284 CIRS ≤ 6; CrCl > 70 ml/min; No 62 47.4% 85.0%** 81.7 39.0

del(17p)

Hallek et al. [23] 408 ECOG PS 0–1; CIRS ≤ 6; 61 44% 51.8 34 25

CrCl ≥ 70 ml/min

Chlorambucil and anti CD20

Foà et al.*** [11] 85 >65 or ineligible to ﬂudarabine; 70 16.5% 34.7 19.6% 1%

CrCl ≥ 50 ml/min

Hillmen et al.*** [36] 100 inelegible to ﬂudarabine 70 10% 23.5 41% 7%

Goede et al.*** [12] 330 CIRS > 6, CrCl 30–69 ml/min 73 7% 15.2 28% 6%

Goede et al.**** [12] 333 CIRS > 6, CrCl 30–69 ml/min 74 20.7% 26.7 33% 6%

Hillmen et al.***** [13] 447 Ineligible to ﬂudarabine 69 12% 22.4 26% 15%

◦ ◦◦

*Median (months) unless otherwise speciﬁed; ** at 2 years; *** rituximab; **** obinutuzumab; ***** Ofatumumab; time to progression; % of cycles; Abbreviations: Cr:

serum creatinine; CrCl: Creatinine clearance; DAT: direct antiglobulin test.

courses and in up to 39% of the patients. Reported treatment-related Recommendations:

death in the CLL8 trial was 2%. In patients who are eligible to FCR ﬁrst-line therapy, bendamustine

Bendamustine alone was never tested in a head-to-head study alone is not recommended.

vs FCR, however, the Panel deemed that ﬁrst-line studies of ben-

damustine alone might be the evidence base for a consensus-based

2. Is bendamustine alone appropriate as ﬁrst-line therapy in

recommendation.

patients potentially candidate to FCR but with contraindications

The efﬁcacy of bendamustine alone (Table 3) was tested in

or intolerant to Rituximab? (Consensus-based)

a head to head comparison with chlorambucil in a randomized

study of 319 patients [15,16] with median age 63 years, creati-

Preliminary considerations:

nine clearance ≥ 30 ml/min and advanced stage disease in 28% of

Despite desensitization protocols, severe infusion reactions to

the cases. Bendamustine (100 mg/sqm days 1 and 2, without rit-

Rituximab may occur, preventing its use in a minority of patients

uximab) attained a 31% CR rate the ﬁrst-line setting and prolonged

[24]. Furthermore rituximab cannot be administerd safely in

PFS (median 21.6 months) as compared with chlorambucil (median

rare cases with hypersensitivity and anaphylactic reaction to

8,3 months). Grade 3/4 neutropenia occurred in 23% of the patients

humanized monoclonal antibodies or with coexisting medical

and severe infection in 8% of the patients treated by bendamustine.

conditions. The alternative treatments for the above patients are

The Panel reckoned that the lower median age and better ﬁtness

FC and bendamustine. Salient efﬁcacy and tolerability data in trials

of patients assigned to FCR might partially impair the indirect com-

using bendamustine and FC are shown in Table 3. No study directly

parison with bendamustine, however, the inferior PFS reported by

compared bendamustine with FC, therefore the Panel indirectly

bendamustine was more relevant than the higher toxicity reported

compared bendamustine and FC single arms from randomized

by FCR, therefore the Panel deemed that Bendamustine alone was

trials of bendamustine against chlorambucil [16,17] or FC against

not a favorable alternative to FCR.

other regimens [4,23,25,26], as reported in Table 3. Bendamustine

Table 3

Efﬁcacy and safety of bendamustine, chlorambucil and ﬂudarabine plus cyclophosphamide in previously untreated CLL.

Regimen and reference N. pts Speciﬁc inclusion criteria Age CR rate PFS* % Patients with % Patients with

(median) grade 3–4 grade 3–4 neutropenia infections

Bendamustine

Knauf et al. [16] 162 Age ≤ 75 yrs; WHO PS 0–2; 63 31% 21.6 23 8

CrCl ≥ 30 ml/min

Chlorambucil

Knauf et al. [16] 157 Age ≤ 75 yrs; WHO PS 0–2; 63.6 2% 8.3 10.6 3

CrCl ≥ 30 ml/min

Catovsky et al. [4] 387 All ages; Stage A-progressive, B, C 65 7% 20 28 25 (febrile

episodes)

Goede et al. [12] 118 CIRS > 6; CrCl 30–69 ml/min 72 0% 11.1 mo 16 14

FC

Eichhorst et al. [25] 180 Age 18–65; ECOG 0–2 58 23.8% 48 mo 55.5 8.7

(leukopenia)

Flinn et al. [26] 141 Age ≥ 18 yrs; PS 0–2; 61 23.4% 31.6 69 25%**

CrCl ≥ 40 ml/min

Catovsky et al. [4] 196 All ages 65 38% 43 56 35 (febrile

episodes)

Hallek et al. [23] 409 Age 30–81 yrs; ECOG PS 0–1; 61 22% 32.8 21 21

CIRS ≤ 6; CrCl ≥ 70 ml/min

*Median(months) unless otherwise speciﬁed; **5% febrile neutropenia, 8% infection with neutropenia, 9% infection without neutropenia, 3% pneumonitis.

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

4 A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx

was administered to patients with decresed renal function [16]; the receiving R-bendamustine achieved similar CR rates and survival

trials testing FC enrolled different proportions of elderly patients, as FCR-treated ones despite their worse clinical conditions [28].

up to 30% in the UK trial [4] and different proportions of patients The Panel was aware of the limitations imposed by interim anal-

with renal failure, since creatinine clearance was allowed to be a ysis and subgroup analysis of the GCLLSG trial, however, safety

low as 40 ml/min in the US Intergroup study [26], while it was over was judged to be much more relevant than efﬁcacy in the set-

70 ml/min in the other 3 studies. Nevertheless, the above studies ting of elderly patients, therefore the large safety advantage of

reported similar 31% and 22–38% CR rates with bendamustine R-bendamustine in this setting was judged to overcome the pos-

and FC, respectively, and a longer PFS (31.6–48 months) with FC sible efﬁcacy advantage of FCR. On converse, data from longer

than with bendamustine (21.6 months). Despite lower median age follow-up and conﬁrmatory studies are awaited before a deﬁnite

and better renal function in some of the FC trials compared to the evidence-based recommendation can be made for young patients,

bendamustine trial, infections were signiﬁcantly more frequent since long-term PFS was judged to be the master outcome in this

in patients treated with FC (8–21%) than with bendamustine (8%). setting.

Also, febrile episodes and grade 3–4 neutropenia occurred at a Recommendations:

higher rate with FC. Transient autoimmune hemolytic anemia Available data do not prompt a change in the current standard of

occurred in 1,5% of the patients treated by bendamustine [16] care, i.e.FCR in the ﬁrst-line therapy for ﬁt, younger patients. Based

and in 5% and 11% of the patients treated by fludarabine alone on its efficacy/safety profile R-bendamustine might be considered as

or FC in the UK trial [4]. Considering this indirect comparison of an alternative to FCR in young and ﬁt patients (level of evidence: low;

efﬁcacy and safety, the Panel deemed that bendamustine could be strength of recommendation: do, weak) and should be a recommended

considered a treatment option in this setting. option in the elderly (≥65) ﬁt patient (level of evidence: low; strength

Recommendations: of recommendation: do, strong)

In patients who are candidates to FCR but with contraindications

or intolerance to rituximab, bendamustine alone is a reasonable treat- 4. Should bendamustine alone be preferred to chlorambucil

ment. inpatients candidate to ﬁrst-line chlorambucil alone? (Evidence-

based. Critical outcomes: PFS, severe AE)

3. Should R-bendamustine be preferred to FCR in patients candi-

date to ﬁrst-line FCR? (Evidence-based. Critical outcome: PFS, Comorbidity is the major driver of therapeutic decisions in a

severe AE) substantial fraction of patients with hematologic malignancies,

including lymphoid malignancies [29] and single agent chloram-

Preliminary considerations: bucil [30] is an option in unﬁt CLL patients unsuitable to receive

The Panel initially discussed this issue based uniquely on indi- rituximab. Direct randomized comparisons between bendamus-

rect comparisons between data from a phase II prospective study tine (100 mg/mq days 1 and 2 every 4 weeks) and chlorambucil

[18] and those from the randomized GCLLSG trial [23], bearing in (0.8 mg/kg days 1 and 15 every 4 weeks; a dosage corresponding to

2

mind that in the former study patients with higher median age (64 the 10 mg/m day 1–7 used in the UK trial [4]), highlighted a better

vs 61 years) were included and that creatinine levels <70mL/min efficacy profile of the former, including a significant PFS prolonga-

were not an exclusion criterion (Table 2). CR rate in 117 previously tion by more than 12 months, with increased though manageable

untreated CLL using with bendamustine and rituximab was 23.1%, toxicity [16,17]. Time to next treatment, was over 20 months longer

with 33.8 months median PFS after a median observation time of in the bendamustine arm. The incidence of grade 3–4 neutropenia

27 months. Severe hematological toxicity was observed in 52.1% of (23% vs 11%), infections (8% vs 3%), skin reactions and the need

the patients, neutropenia in 19.7% and severe infections in 7.7% of for antiemetics (36% vs 4%)was higher in bendamustine treated

the patients, with 3.4% treatment-related mortality. patients than in the chlorambucil arm. Even though more patients

The GCLLSG CLL10 phase III trial (Eichhorst 2013 ASH) [27] in the bendamustine arm (11% vs 3.2%) stopped treatment due to

recently reported the outcome of 564 patients without severe severe AE, no signiﬁcant effect on the overall quality of life was

comorbidities or del(17p) and with a normal creatinine clearance reported [16]. In the long-term follow-up no statistically signiﬁcant

randomly assigned to FCR or R-bendamustine (90 mg/sqm days 1 OS prolongation was observed in bendamustine-treated patients

and 2) (Table 3). Thirty percent of those assigned to FCR failed to [17]. In a multiple-treatment meta-analysis bendamustine and R-

receive the full 6 cycle program vs 20% of those assigned to R- ﬂudarabine-based regimens [31] were found to achieve a similar

bendamustine: this was in part due to the higher rate of severe PFS advantage (HR = 0.23) over chlorambucil.

neutropenia and severe infections, especially in the elderly (i.e. 65 The Panel judged that, among critical outcomes, safety has a

years or more). Severe AE were more frequent in the FCR arm (91% priority over PFS in the setting of elderly patients. However, the

vs 78%, p < 0.001) as were neutropenia (81.7% vs 56.8%, p < 0.001) signiﬁcant PFS advantage of bendamustine vs chlorambucil, consis-

and infections, especially in the elderly (FCR: 47.4% vs BR: 26.5%; tent with the very long time to next treatment, was considered to

p = 0.002). Treatment related death were 3.9% vs 2.1% in the FCR provide also an amelioration of patient quality of life. Therefore, the

arm and in the BR arm, respectively. At intention-to-treat analysis Panel judged that the beneﬁt deriving from more prolonged disease

of efﬁcacy, however, the balance between the two treatments was control attained by bendamustine was superior to the disadvantage

reversed: overall response rate was 98% in both arms, but CR rate of in terms of toxicity.

was signiﬁcantly higher in patients treated with FCR (47% vs 38%, Recommendations:

p = 0.031), as was the case with two-year PFS (85% vs 78%, p = 0.041) In patients who are conventionally candidate to chlorambucil

and EFS (83% vs 76%, p = 0.037). These efﬁcacy measures favoring alone, bendamustine alone is recommended (level of evidence: low;

FCR were enhanced in patients younger than 65 years (median PFS strength of recommendation: do, strong).

for R-bendamustine 36.5 months vs not reached for FCR; p = 0.016),

whereas the advantage disappeared in the elderly subgroup where 5. Is R-bendamustine appropriate in patients not eligible to FCR?

the median PFS at 2 years in the R-bendamustine arm was not (Evidence-based. Critical outcomes: PFS, severe AE)

reached as compared with 45.6 months in the FCR arm; p = 0.757).

In an unselected population prospectively enrolled in a Ger- Patients with comorbidities, poor performance status or with

man registry and assigned to one of the two above treatments impaired renal function were excluded from ﬂudarabine-based

according to the physician and patient judgment, those patients clinical trials or featured poor tolerance to FCR [22,23], whereas

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx 5

they made up to 40% of those treated by bendamustine with or 18.3 months and an OS of 38.9 months in previously untreated

without rituximab [18,32]. A retrospective analysis of two elec- patients [37]. Grade 3–4 infections occurred in 35% of previ-

tronic medical databases in the US analysed bendamustine safety ously untreated patients; grade 3–4 hematologic toxicity and

in 379 B-CLL patients, half of which with a creatinine clearance glucocorticoid-associated toxicity occurred in 67%, and 23% of

lower than 60 ml/min, and found no increased toxicity for those patients respectively in the overall cohort, which included 56%

without a severe renal impairment, i.e. creatinine clearance over previously treated patients.

40 ml/min [33]. Subgroup analysis of the phase II R-Bendamustine Bendamustine might potentially be efﬁcacious in these set-

trial, reported a higher rate of hematologic and non-hematologic ting since its cytotoxic effect is related to both p53-dependent

toxicity in patients with impaired renal function, i.e. creatinine and p53-independent mechanisms [38]. However, when combined

clearance between 40 and 70 ml/min, however the observed dif- with rituximab, response in del(17p) patients was unsatisfac-

ferences did not reach statistical signiﬁcance, with the exception tory: none of 8 del(17p) patients treated with bendamustine

of anemia [18]. plus Rituximab achieved a CR, and only 3 achieved PR, with

Fludarabine exposes patients to the risk of developing autoim- a 7.9 months median PFS [18]. The GCLLSG trial comparing R-

mune hemolytic anemia (AIHA), the absolute risk being up to 8% bendamustine with FCR excluded from enrollment patients with

and relative risk higher than 20% [34]. Contraindication to ﬂu- del17(p) therefore no comparative results from this subgroup can

darabine was extended from those patients who developed AIHA be expected from such a study [27]. The synergic in-vitro activ-

after ﬂudarabine exposure to ﬁt patients with ongoing autoimmune ity of bendamustine and cytarabine onto primary tumor cells from

hemolysis before exposure to ﬂudarabine-based therapies [23]. To patients with del(17p) or p53 mutated [39] prompted testing

the contrary, some patients with active hemolysis were enrolled rituximab–bendamustine–cytarabine regimens in the second-line

into trials using bendamustine with rituximab [18] and only occa- setting: favorable response and PFS data were reported also in

sional cases of autoimmune hemolytic anemia were reported using unfavorable cytogenetic risk patients, but multivariate analysis on

bendamustine as single agent [16]. a large set of patients showed that this could not be applied to

R-bendamustine might compete with R-chlorambucil in the patients with del(17p) [40,41]. Ongoing trials are testing this regi-

above reported setting and preliminary data from an ongoing men in the ﬁrst-line setting.

randomized trial are available. The trial enrolled 85 untreated Recommendations:

B-CLL patients not candidate to ﬂudarabine-based treatments as Bendamustine with or without rituximab or bendamustine con-

a result of age or comorbidities and assigned them to either taining regimens might not be useful options in patients with del 17p

R-bendamustine (90 mg/sqm up to 6 cycles) or R-Chlorambucil and or p53 mutation.

(10 mg/sqm days 1–7, up to 12 cycles): CR rates were 30% vs 13%,

respectively, despite similar overall response rates and severe AE

7. Is bendamustine and rituximab appropriate in patients with

rates [35]. Since the above randomized trial included only a small

11q- or with IGHV unmutated? (Consensus-based)

subgroup of untreated patients and no PFS data have yet been

reported, the Panel judged direct evidence insufﬁcient to support

Preliminary considerations:

an evidence-based recommendation.

No study was devoted to speciﬁc cytogenetic subsets of CLL,

Data from two trials testing chlorambucil and rituximab in the

therefore, evidence was based on indirect comparisons between

elderly patients unﬁt for ﬂudarabine-based treatment (Table 2)

patients’ subgroups within clinical trials. Data on bendamus-

showed a 10–16% CR rate with 24–34.7 months PFS [11,36].

tine were reported in the bendamustine plus rituximab trial

The adjunct of rituximab or obinutuzumab to chlorambucil in

[18]. Twenty patients with del(11q) were reported by the R-

patients with comorbidities precluding ﬂudarabine-based treat-

bendamustine phase II trial [17] and 80 in the FCR arm of Hallek

ment attained a 7% and 22% CR rate, respectively, with a 16.3

trial [23]: 40% and 51%, respectively, achieved CR; median PFS was

and 26.7 months median PFS. Notably, obinutuzumab in asso-

shorter than 3 years in the bendamustine trial, while 64% of the

ciation with chlorambucil prolonged survival as compared with

patients were progression free at 3 years in the FCR trial. The Panel

chlorambucil alone [12]. The adjunct of ofatumumab to chloram-

judged that the difference in outcomes might have been inﬂuenced

bucil attained a 12% CR rate with a 22.4 months median PFS

by different selection criteria in these studies, with more patients

(Table 3), these outcome measure being signiﬁcantly better that

with unfavorable features having been included in the trial test-

those attained by chlorambucil alone [13].

Recommendations: ing bendamustine and rituximab. In retrospective analyses and

registries, the efﬁcacy of bendamustine appeared to be indepen-

Bendamustine plus rituximab is beneﬁcial in CLL patients non eli-

dent of cytogenetic risk factors, with the exception of del(17p)

gible to FCR, but suitable to receive rituximab (level of evidence: very

[41]. Finally, the recent interim analysis of the GCLLSG CLL10 trial

low; strength of recommendation: do, strong) The panel also rec-

reported that del(11q) and IGVH status, as well as treatment (FCR

ognized that there are at the present time insufﬁcient data to make a

vs R-bendamustine) were independent prognostic factors for PFS

recommendation in favour either of bendamustine and rituximab or

[27]. Three trials using FC reported a 15–38% CR rate in patients with

chlorambucil plus anti CD20 monoclonal antibodies in patients non

11q- [23,42,43] with a median PFS of 25,2 months [43] and a 32%

eligible to FCR.

PFS at 3 years [23]. In a trial using pentostatine and rituximab a 7.9

months median treatment free survival was reported [44], whereas

6. Are bendamustine-containing regimens an appropriate ﬁrst-line

no data for 11q-patients were provided in trials using ﬂudarabine

therapy in high-risk patients (del 17p and/or p53 mutations)?

(Consensus-based) ad rituximab.

In 66 patients with unmutated IGHV gene bendamustine and

rituximab attained a 27% CR rate, with 33.9 months median PFS

Preliminary considerations:

[18]; in the CLL8 trial a 40% CR rate was reported in 196 unmutated

In B-CLL patients del 17p and/or p53 mutations are

IGHV patients, with 55% PFS at 3 years in the chemoimmunother-

strongly associated with adverse outcomes and resistance to

apy arm. In trials using FC those patients with unmutated IGHV

chemotherapy-based treatment: less than 10% achieve CR and

gene attained a 19% CR rate with 35% PFS at 3 years in the

PFS is shorter than 12 months [23]. Better results were obtained

CLL8 trial [23], and a 31.4 months median PFS in the U.S. trial

in this subset of high risk patients with Alemtuzumab plus high

[43].

dose methylprednisone, which achieved a 65% CR rate, a PFS of

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

6 A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx

Recommendations: Autoimmune complications, mainly autoimmune hemolytic

Bendamustine and rituximab is recommended in patients with 11q- anemia (AIHA) or immune thrombocytopenic purpura (ITP), occur

or IGHV unmutated who are not candidate to FCR. in approximately 4–10% and 2–5% during the course of the disease,

respectively [51]. Data on the incidence of AIHA or ITP following

bendamustine with or without rituximab are limited, however the

8. Which is the appropriate schedule and duration of

risk appears low [16,18]. Autoimmune complications were not con-

bendamustine-based regimens for ﬁrst-line CLL therapy?

(Consensus-based) sidered as contraindications to the use of bendamustine upfront

in those patients with progressive CLL or with active hemolysis

uncontrolled by steroids [51].

Preliminary considerations:

Recommendations:

Bendamustine as single agent was administered at a dose of

In patients candidate to bendamustine as ﬁrst line therapy of CLL

100 mg/mq on days 1–2 in a trial enrolling patients < 75 years

antibiotic prophylaxis and the prophylactic use of IVIG can be consid-

[16,17], 34% of whom required at least one 25% dose reduction. In

ered on an individual basis.

a retrospective study analyzing real-world data on patients treated

Patients with occult HBV infection and HBV carriers should be given

by bendamustine in ﬁrst line dose reductions were reported in 67%

antiviral prophylaxis if bendamustine is associated with Rituximab.

of the patients >70 years [45]. R-bendamustine schedule included

Patients with HCV infection should be treated jointly with a specialist.

the administration of bendamustine at a dose of 90 mg/mq [18,27].

Treatment with bendamustine, alone or with rituximab, may be

Dose reduction was necessary in about half of the patients, but

initiated in CLL patients with an associated AIHA or ITP unresponsive

over 90% of the planned dose was eventually administered [16–18].

to steroids.

Extra-hematologic toxicity was reported to be higher in patients

over 70 years [18]. Doses as low as 75 mg/sqm proved still effective

10. Should bendamustine therapy be modiﬁed in B-CLL patients

and lower doses (50 mg/sqm) were also used [15].

with renal of hepatic comorbidities? (Consensus-based)

Recommendations:

The recommended dose of bendamustine alone in untreated CLL

Preliminary considerations:

patients less than 75 years old is 100 mg/mq iv on days 1–2, every

Bendamustine undergoes extensive primary metabolism in the

4 weeks for 6 cycles. Increasing the dose of bendamustine alone in

liver by the action of cytochrome p450 enzyme complex. How-

unresponsive patients is not recommended.

ever unmetabolized bendamustine accounts for about 45% of the

The recommended dose of bendamustine in association with ritux-

total drug recovered in the urine [52]. Prospective studies excluded

imab as front-line therapy in CLL patients is 90 mg/mqiv on days 1–2

patients with severe renal impairment or high liver enzimes, there-

every 4 weeks for 6 cycles. Increasing the dose of bendamustine alone

fore no prospective evidence is available for such patients. In

in unresponsive patients is not recommended.

clinical trials renal toxicity, including tumor lysis syndrome, was

For patients aged older than 75 years, the dose of bendamustine

observed in less than 1.5% of the patients, and liver toxicity was

alone or when associated with rituximab may be reduced according to

only rarely reported [16,18,19,53,54].

the patient ﬁtness and comorbidities.

Patients treated by bendamustine and rituximab [18] with a

Maintenance with bendamustine is not recommended after

moderate renal impairment experienced a higher rate of anemia

induction therapy with bendamustine alone or bendamustine plus

(p = .033), leucopenia (p = .057) non hematologic toxicity (p = .08)

rituximab.

and infections (p = .097) than patients with a creatinine clearance

Empirical combination of bendamustine with other myelosuppres-

greater than 70 ml/min [18].

sive agents are strongly discouraged outside of clinical trial.

Indeed, at a starting dose of 70 mg/sqm/day, 7 patients with

CLL and a chronic kidney disease (CLL related in 2) received ben-

9. How should infections and autoimmune cytopenias be managed

damustine monotherapy with no worsening of the renal function

and prevented during bendamustine therapy? [54].

Recommendations:

Preliminary considerations: Bendamustine should not be used in patients in whom renal and

Infections remain a major cause of morbidity in CLL and account hepatic functions are severely compromised.

for up to 50% of CLL-related deaths [46]. Risk factors include In patients with moderately impaired renal function, and there-

age, advanced clinical stage, burden of comorbidities, hypogam- fore not eligible for ﬂudarabine containing regimens, bendamustine

maglobulinemia and previous infection history. No mandatory alone or associated with rituximab can be administered with adequate

infection prophylaxis, polyvalent IV immunoglobulin replacement, hydration, tumour lysis syndrome prophylaxis and careful monitoring

or hemopoietic growth factor administration was prescribed in of hematologic toxicity and renal and liver functions.

patients enrolled in bendamustine clinical trials [16,18]. In selected Because of an increased risk of cytopenias the dose of bendamustine

patients with grade 3–4 neutropenia, bacterial respiratory infec- should be reduced in patients with impaired renal function.

tions prophylaxis was suggested [18] and G-CSF prophylaxis

recommended according to ASCO guidelines [47]. Hypogamma- 11. Which are the unmet clinical needs for the appropriate use of

globulinemia occurs in substantial fraction of CLL patients. A bendamustine in ﬁrst-line therapy of CLL?

systematic review and meta-analysis of randomized-controlled

trials comparing prophylaxis with polyvalent IVIG in CLL was The results of the CLL10 trial [27] comparing bendamustine and

performed, showing a signiﬁcant decrease in the occurrence of rituximab with the FCR combination showed greater efﬁcacy and

major infections, without survival advantage [48,49]. Based on toxicity of the FCR combination. However the efﬁcacy advantage

these ﬁnding IVIG replacement therapy was only recommended on was not maintained in elderly ﬁt patients and, since the study was

individual basis for selected CLL patients with hypogammaglobu- not powered to detect difference according to age the identiﬁcation

linemia and/or recurrent infections [49]. of the best regimen in elderly patients requires further study.

Before starting chemoimmunotherapy patients should be The results of two studies incorporating new anti CD20 mono-

screened for hepatitis B and C infections as well as for HIV infection clonal antibodies were recently reported. Obinutuzumab and

and preemptive antiviral treatment was recommended in patients chlorambucil achieved higher response rate and MRD negativity

positive for HBsAg or HBcAb [50]. with statistically signiﬁcant prolongation of PFS compared with

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx 7

rituximab and chlorambucil in patients with comorbidities [12], (ii) that in the elderly ﬁt patient as well as in real-world patients

while ofatumumab plus chlorambucil signiﬁcantly prolonged PFS R-bendamustine was better tolerated and as effective as FCR, the

compared to chlorambucil alone in patients with CLL considered panel judged that R-bendamustine can be a recommended option

inappropriate for ﬂudarabine-based therapy [55]. Inclusion crite- in the elderly ﬁt patient.

ria in trials assessing bendamustine and rituximab were partially We also produced consensus based recommendations on other

overlapping with those adopted in these chlorambucil-based com- queries concerning the use of bendamustine containing regimens in

binations and a direct comparison between these regimens is high risk genetic categories as well as on the role of bendamustine,

lacking. The efﬁcacy of bendamustine should be tested in combi- its optimal dosage, the management of the most relevant frequent

nation with these new CD20 monoclonal antibodies in the front side effects. Even though no study directly assessed the key points

line setting. Results recently reported on the combination of ben- raised by the panel, a careful analysis of data scattered in the lit-

damustine and ofatumumab in previously treated CLL patients are erature allowed the panel to formulate recommendations for each

encouraging [56]. relevant issue.

Ibrutinib, an inhibitor of BTK achieved a high overall response The therapeutic scenario in CLL is being rapidly modiﬁed

rate with impressive PFS in heavily pre-treated high-risk CLL [57] by the introduction of effective BCR-targeted treatment which

and proved to be well tolerated and effective in untreated patients showed durable efﬁcacy in the relapsed/refractory setting [57,59].

as well [58]. Other key components of the BCR pathway, namely Their introduction in the front-line setting appeared to produce

␦

PI3K- , are also being targeted with novel therapies with promising durable responses [58] and their possible combination with several

results [59]. Bendamustine could represent an effective chemother- monoclonal antibodies and chemotherapeutic agents, including

apeutic partner for these new drugs and indeed trials are ongoing bendamustine [60] may change treatment paradigm in the next

that incorporated this agent are ongoing [60]. years.

The recent application of whole genome sequencing identiﬁed

clinically signiﬁcant mutations in NOTCH1, SF3B1 and BIRC3 genes Conﬂict of interest statement

which represent adverse prognostic factors. NOTCH1 mutations

None.

were associated with a shorter time to ﬁrst treatment and, inter-

estingly they identiﬁed a subset of patients that may not beneﬁt

from adjunct of rituximab to FC [61] as well as from the adjunct of Acknowledgements

ofatumumab to chlorambucil [55]. These data suggest that gene

mutations represent novel independent prognostic factors that GB, AB and M Marchetti performed the systematic review of the

may inﬂuence clinical practice and the efﬁcacy of bendamustine- literature, graded the evidence and prepared the summary tables

containing regimens in these genetic subsets of CLL is worth of evidence. AC, AIL-FE, MB, SC, LL, FRM, SM, M Montillo, PZ and ST

exploring. formed the panel of experts who discussed the summaries of evi-

dence and produced recommendations. AC and M Marchetti wrote

the paper. All authors revised the manuscript.

4. Discussion Funding of the project was provided by SIE, SIES, and GITMO

societies.The SIE administered all aspects of the meetings. The fund-

In thIs analysis we adopted the GRADE system to assess the qual- ing sources had no role in identifying statements, abstracting data,

ity of evidence, followed by an analysis of the beneﬁt-risk balance synthesizing results, or preparing the manuscript or in the decision

and by a ﬁnal judgment about the strength of recommendations on to submit the manuscript for publication.Work in the Authors Units

3 key clinical queries, i.e. (i) the role of bendamustine and ritux- was supported by MOH RF-2011-02349712, MIUR, PRIN 2008-2010

imab in patients eligible to FCR, (ii) the role of bendamustine and to AC.

rituximab in those patients not eligible to FCR and, (iii) the role of

bendamustine in patients eligible to chlorambucil alone. References

Even though using the GRADE method the overall the quality

[1] Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk strat-

of available clinical trials was low, mainly due to selection criteria

iﬁcation and treatment. Am J Hematol 2013;88:803–16.

(i.e. limitations in directness of evidence), methodological limita-

[2] Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R. Single-agent purine

tions (i.e. lack of blinding) and imprecision of results (i.e. interim analogues for the treatment of chronic lymphocytic leukaemia: a systematic

review and meta-analysis. Cancer Treat Rev 2006;32:377–89.

analyses, unplanned subgroup analyses), a GRADE-based discus-

[3] Rai KR, Hollweg A. Fludarabine versus chlorambucil: is the debate over? Clin

sion based on the two previously speciﬁed critical outcomes, i.e.

Lymphoma Myeloma Leuk 2011;11(Suppl 1):S7–9.

severe adverse events and PFS, allowed us to produce “strong” rec- [4] Catovsky D, Richards S, Matutes E, et al. Assessment of ﬂudarabine plus

ommendations for 2 out of 3 key queries. We could thus deﬁne an cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF

CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230–9.

appropriate use of bendamustine in those patents not candidate to

[5] Danese MD, Grifﬁths RI, Gleeson M, et al. An observational study of outcomes

receive FCR and in those patients candidate to chlorambucil alone:

after initial infused therapy in Medicare patients diagnosed with chronic lym-

these patients may beneﬁt from bendamustine which proved cost- phocytic leukemia. Blood 2011;117:3505–13.

[6] Woyach JA, Ruppert AS, Rai K, Lin TS, Geyer S, Kolitz J, et al. Impact of age

effective [62] and showed a relatively favorable efﬁcacy/toxicity

on outcomes after initial therapy with chemotherapy and different chemoim-

balance. It is worth noting that these patients’ categories are fre-

munotherapy regimens in patients with chronic lymphocytic leukemia: results

quently encountered in clinical practice and are under-represented of sequential cancer and leukemia group B studies. J Clin Oncol 2013;31:

440–7.

in the majority of clinical trials, which usually adopt selective inclu-

[7] Dores GM, Anderson WF, Curtis RE, Landgren O, Ostroumova E, Bluhm EC, et al.

sion criteria. Chlorambucil with anti CD20 monoclonal antibodies

Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview

may represent an alternative therapeutic approach in some of these of the descriptive epidemiology. Br J Haematol 2007;139:809–19.

patients. [8] National Cancer Institute. SEER Cancer Statistics Review; 2010,

http://seer.cancer.gov, [accessed 10.2.2010].

Available data indicated that R-bendamustine in the young

[9] Abrisqueta P, Pereira A, Rozman C, Aymerich M, Gine E, Moreno C, et al. Improv-

and/or ﬁt patient was better tolerated and produced shorter PFS ing survival in patients with chronic lymphocytic leukemia (1980–2008): the

Hospital Clinic of Barcelona experience. Blood 2009;114:2044–50.

as compared with FCR [18,23,27]. The panel judged that these data

[10] Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, et al.

do not prompt a change in the current standard of care, i.e. FCR

First-line therapy with ﬂudarabine compared with chlorambucil does not result

first-line for fit, younger patients. Based on the considerations (i) in a major benefit for elderly patients with advanced chronic lymphocytic

that FCR improved PFS and not survival in patients >65 years and leukemia. Blood 2009;114:3382–91.

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

8 A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx

[11] Foà R, Giudice ID, Cuneo A, Poeta GD, Ciolli S, Raimondo FD, et al. Chlorambucil chronic lymphocytic leukemia: interim results of a phase IIIb study Blood (ASH

plus rituximab with or without maintenance rituximabas ﬁrst-line treatment Annual meeting abstracts). Abstract 2744 2012;120.

for elderly chronic lymphocytic leukemia patients. Am J Hematol 2014;(Jan), [36] Hillmen P, Gribben JG, Milligan D, Sayala HA, Moreton P, et al. Ritux-

http://dx.doi.org/10.1002/ajh.23668 [Epub ahead of print]. imab plus chlorambucil as ﬁrst-time treatment for chronic lymphocytic

leukemia: Final analysis o fan open-label phase II study. J Clin Oncol 2014;32:

[12] Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obin-

1236–41.

utuzumab plus chlorambucil in patients with CLL and coexisting conditions. N

[37] Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, et al. Alemtuzumab

Engl J Med 2014;(Jan) [Epub ahead of print].

in combination with methylprednisolone is a highly effective induction reg-

[13] Hillmen P, Robak T, Janssens A, Govindbabu K, Grosicki S, Mayer J, et al. Ofatu-

imen for patients with chronic lymphocytic leukemia and deletion of TP53:

mumab + chlorambucil versus chlorambucil alone in patients with untreated

ﬁnal results of the national cancer research institute CLL206 trial. J Clin Oncol

chronic lymphocytic leukemia (CLL): results of the phase III study complement

2012;30:1647–55.

1 (OMB110911). Blood (ASH Annual Meeting Abstracts) 2013 [Abstract # 528].

[38] Roué G, López-Guerra M, Milpied P, Pérez-Galán P, Villamor N, Montser-

[14] Vidal L, Gafter-Gvili A, Gurion R, Raanani P, Dreyling M, Shpilberg O. Bendamus-

rat E, et al. Bendamustine is effective in p53-deﬁcient B-cell neoplasms and

tine for patients with indolent B cell lymphoid malignancies including chronic

requires oxidative stress and caspase-independent signaling. Clin Cancer Res

lymphocytic leukaemia. Cochrane Database Syst Rev 2012;9(Sep):CD009045.

2008;14:6907–15.

[15] Cheson BD, Wendtner CM, Pieper A, Dreyling M, Friedberg J, Hoelzer D, et al.

[39] Castegnaro S, Visco C, Chieregato K, Bernardi M, Albiero E, Zanon C, et al.

Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin

Cytosine arabinoside potentiates the apoptotic effect of bendamustine on sev-

lymphomas, and multiple myeloma: treatment recommendations from an

eral B- and T-cell leukemia/lymphoma cells and cell lines. Leuk Lymphoma

international consensus panel. Clin Lymphoma Myeloma Leuk 2010;10:21–7.

2012;53:2262–8.

[16] Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of ben-

[40] Visco C, Finotto S, Pomponi F, Sartori R, Laveder F, Trentin L, et al. The com-

damustine compared with chlorambucil in previously untreated patients with

bination of rituximab, bendamustine, and cytarabine for heavily pretreated

chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378–84.

relapsed/refractory cytogenetically high-risk patients with chronic lympho-

[17] Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, et al.

cytic leukemia. Am J Hematol 2013;88:289–93.

Bendamustine compared with chlorambucil in previously untreated patients

[41] Zaja F, Mian M, Volpetti S, Visco C, Sissa C, Nichele I, et al. Bendamustine in

with chronic lymphocytic leukaemia: updated results of a randomized phase

chronic lymphocytic leukemia: outcome according to different clinical and

III trial. Br J Haematol 2012;159:67–77.

biological prognostic factors in the everyday clinical practice. Am J Hematol

[18] Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, et al. Bendamustine

2013;88:955–60.

in combination with rituximab for previously untreated patients with chronic

[42] Stilgenbauer S, Eichhorst B, Busch R, et al. Biologic andclinical markers for out-

lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lym-

come after ﬂudarabine (F) or F pluscyclophosphamide (FC) – comprehensive

phocytic Leukemia Study Group. J Clin Oncol 2012;30:3209–16.

analysis of the CLL4Trial of the GCLLSG [Abstract]. Blood 2008;112:3322–32.

[19] Ferguson JH, The NIH. Consensus development program. The evolution of

[43] Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S, et al. Com-

guidelines. Int J Technol Assess Health Care 1996;12:460–74.

prehensive assessment of genetic and molecular features predicting outcome

[20] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al.

in patients with chronic lymphocytic leukemia: results from the US Intergroup

GRADE: an emerging consensus on rating quality of evidence and strength of

Phase III Trial E2997. J Clin Oncol 2007;25:799–804.

recommendations. Br J Med 2008;336:924–6.

[44] Kay NE, Wu W, Kabat B, LaPlant B, Lin TS, Byrd JC, et al. Pentostatin and ritux-

[21] Delbecq AL, van de Ven AH, Gustafson DH. Group Techniques for Program Plan-

imab therapy for previously untreated patients with B-cell chronic lymphocytic

ning: A guide to nominal group and Delphi processes. Glenview, IL, USA: Scott,

leukemia. Cancer 2010;116:2180–7.

Foresman and Co.; 1975.

[45] Günther G, Bartels S, Tessen HW, Sterchele JA. Real-world efﬁcacy and safety

[22] Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy

of bendamustine with or without rituximab in treatment-naïve patients with

regimen of ﬂudarabine, cyclophosphamide, and rituximab as initial therapy for

chronic lymphocytic leukemia: retrospective analysis of a German registry.

chronic lymphocytic leukemia. J Clin Oncol 2005;23:4079–88.

Blood (ASH Annual Meeting Abstracts) 2012;120:2905.

[23] Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Bush R, Mayer J, et al.

[46] Molica S, Levato D, Levato L. Infections in chronic lymphocytic leukemia.

Addition of rituximab to ﬂudarabine and cyclophosphamide in patients with

Analysis of incidence as a function of length of follow-up. Haematologica

chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet

2010;76:1164–74. 1993;78:374–7.

[47] Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al.

[24] Hegele V, Stoll P, Wust D, Ehrenbrink G, Grazziottin LR, Caregnato JP, et al.

2006 update of recommendations for the use of white blood cell growth

Pharmaceutical follow-up for patients on rituximab therapy for non-Hodgkin

factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:

lymphoma: what is the evidence? Int J Clin Pharm 2013;35:513–9.

3187–205.

[25] Eichhorst BF, Busch R, Hopﬁnger G, Pasold R, Hensel M, Steinbrecher C,

[48] Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O.

et al. Fludarabine plus cyclophosphamide versus ﬂudarabine alone in ﬁrst-

Cochrane Immunoglobulin prophylaxis in chronic lymphocytic leukemia and

line therapy of younger patients with chronic lymphocytic leukemia. Blood

2006;107:885–91. multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma

2009;50:764–72.

[26] Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, et al.

[49] Brugiatelli M, Bandini G, Barosi G, Lauria F, Liso V, Marchetti M, et al.

Phase III trial of ﬂudarabine plus cyclophosphamide compared with ﬂudara-

Management of chronic lymphocytic leukemia: practice guidelines from the

bine for patients with previously untreated chronic lymphocytic leukemia: US

Italian Society of Hematology, the Italian Society of Experimental Hemato-

Intergroup Trial E2997. J Clin Oncol 2007;25:793–8.

logy and the Italian Group for Bone Marrow Transplantation. Haematologica

[27] Eichhorst B, Fink A-M, Bush R, Lange E, Koppler H, Sokler M,

2006;91:1662–73.

et al.Chemoimmunotherapy with ﬂudarabine (F), cyclophosphamide (C),

[50] European Association of the Study of Liver. EASL clinical practice guidelines:

and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously

management of chronic hepatitis B virus infection. J Hepatol 2012;57:167–85.

untreated and physically ﬁt patients (pts) with advanced chronic lymphocytic

[51] Hodgson K, Ferrer G, Pereira A, Moreno C, Montserrat E. Autoimmune cytope-

leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an

nia in chronic lymphocytic leukaemia: diagnosis and treatment. Br J Haematol

International, Randomized Study of the German CLL Study Group (GCLLSG).

2013. 2011;154:14–22.

[52] Gandhi V, Jan A, Burger. Bendamustine in B-Cell Malignancies: The New 46-

[28] Knauf W, Abernhardt W, Engel E, Grugel R, Harde J, Marschner N.Response

Year-Old Kid on the Block. Clin Cancer Res 2009;15:7456–61.

to ﬁrst line treatment with BR or FCR in patients with chronic lymphocytic

[53] Bergmann MA, Goebeler ME, Herold M, et al. Efﬁcacy of bendamustine in

leukaemia: ﬁrst outcome data from the German prospective TLN registry. 2013.

patients with relapsed or refractory chronic lymphocytic leukemia: results

[29] Najman A, Gorin NC. Inﬂuence of comorbidities on decision caring of malignant

of a phase I/II study of the German CLL Study Group. Haematologica

haematological diseases. Bull Cancer 2009;96:563–70.

2005;90:1357–64.

[30] Mauro FR, Bandini G, Barosi G, Billio A, Brugiatelli M, Cuneo A, et al. SIE, SIES,

[54] Nikitin E, Dzhumabaeva B, Kaplanskaya I, et al.Safety of Bendamustine

GITMO updated clinical recommendations for the management of chronic lym-

Monotherapy in CLL Patients with Concomitant Chronic Renal Failure.

phocytic leukemia. Leuk Res 2012;36:459–66.

2012.

[31] Tersawa T, Trikalinos NA, Djulbegovic B, Trikalinos TA. Comparative efﬁcacy

[55] Tausch E, Beck P, Schlenk RF, et al. NOTCH1 mutation and treatment outcome

of ﬁrst-line therapies for advanced-stage chronic lymphocytic leukemia: a

in CLL patients treated with chlorambucil (Chl) or Ofatumumab-Chl (O-Chl):

multiple-treatment meta-analysis. Cancer Treat Rev 2013;39:340–9.

results from the phase III study complement 1 (OMB110911). Blood (ASH

[32] Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab

Annual Meeting Abstracts) 2013 [Abstract 527].

in patients with relapsed and/or refractory chronic lymphocytic leukemia: a

[56] Cortelezzi A, Sciumè M, Liberati AM, Vincenti D, Cuneo A, Reda G, et al.

multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study

Bendamustine in combination with Ofatumumab in relapsed or refractory

Group. J Clin Oncol 2011;29:3559–66.

chronic Lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial. Leukemia

[33] Nordstrom BL, Knopf KB, Teltsch DY, Engle R, Beygi H, Sterchele JA. The safety of

2014;28:642–8.

bendamustine in patients with chronic lymphocytic leukemia or non-Hodgkin

[57] Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting

lymphoma and concomitant renal impairment: a retrospective electronic med-

BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med

ical record database analysis. Leuk Lymphoma 2013;55(Oct):1266–73.

2013;369:32–42.

[34] Garbe E, Andersohn F, Bronder E, Klimpel A, Thomae M, Schrenmeier H, et al.

[58] O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibruti-

Drug induced immune haemolyticanaemia in the Berlin Case–Control Surveil-

nib as initial therapy for elderly patients with chronic lymphocytic leukaemia

lance Study. Br J Haematol 2011;154:644–53.

or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.

[35] Leblond V, Laribi K, Ilhan O, Aktan M, Unal A, Rassam S, et al. Rituximab in

Lancet Oncol 2014;15:48–58.

combination with bendamustine or chlorambucil for treating patients with

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

G Model

LR-5205; No. of Pages 9 ARTICLE IN PRESS

A. Cuneo et al. / Leukemia Research xxx (2014) xxx–xxx 9

[59] Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Ide- [61] Stilgenbauer S, Busch R, Schnaiter A, et al. Gene mutations and treatment out-

lalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med come in chronic lymphocytic leukemia: results from the CLL8 trial. Blood (ASH

2014;(Jan) [Epub ahead of print]. Annual Meeting Abstracts) 2012;(Nov):433.

[60] Brown JR, Barrientos JC, Barr PM, et al. Ibrutinib in combination with bendamus- [62] Woods B, Hawkins N, Dunlop W, O’Toole A, Braham-Jones S. Bendamus-

tine and rituximab is active and tolerable in patients with relapsed/refractory tine versus chlorambucil for the ﬁrst-line treatment of chronic lymphocytic

CLL/SLL: ﬁnal results of a phase 1b study. Blood (ASH Annual Meeting Abstracts) leukemia in England and Wales: a cost-utility analysis. Value Health

2013;122(Nov):abs N. 525. 2012;15:759–70.

Please cite this article in press as: Cuneo A, et al. Appropriate use of bendamustine in ﬁrst-line therapy of chronic lymphocytic leukemia.

Recommendations from SIE, SIES, GITMO Group. Leuk Res (2014), http://dx.doi.org/10.1016/j.leukres.2014.06.017

Web Analytics