Optimal use of bendamustine in hematologic disorders: Treatment recommendations from an international consensus panel – an update

Figures & data

Table I. Grade 3/4 toxicities associated with bendamustine by disease area.

Disease area	Toxicity category	Reference	Toxicity	% patients with toxicities	p value
CLL	Non-hematological	Fischer et al. [17]	Severe infections	7.7	—
		Eichhorst et al. [14]	Severe infectionsSevere infections (> 65 years)	BR: 26.8/FCR: 39.1BR: 20.6/FCR: 47.7	< 0.001< 0.001
				Fischer et al. [24]	Severe infections	12.8	—
iNHL	Hematological	Flinn et al. [25]	Lymphocytopenia	BR: 61/R-CHOP;R-CVP: 33;28	< 0.05
			Weide et al. [33]	LeukocytopeniaThrombocytopenia	2413	—
	Non-hematological	Rummel et al. [23]	AlopeciaPeripheral neuropathyInfectionsSkin reactions/rashes	BR: 0/R-CHOP: 100BR: 7/R-CHOP: 29BR: 37/R-CHOP: 50BR: 16/R-CHOP: 9	< 0.0001< 0.00010.00250.024
		Brown et al. [22]	Severe infections	BO: 5/FCO: 19	—
				Flinn et al. [25]	AlopeciaPeripheral neuropathyInfectionsSkin rashesNauseaVomitingConstipation	BR: 4/R-CHOP;R-CVP: 51;21BR: 9/R-CHOP;R-CVP: 44;47BR: 55/R-CHOP;R-CVP: 57;50BR: 20/R-CHOP;R-CVP: 12;16BR: 63/R-CHOP;R-CVP: 58;39BR: 29/R-CHOP;R-CVP: 13;13BR: 32/R-CHOP;R-CVP: 40;44	All < 0.05
Other indolent lymphomas	Hematological	Salar et al. [26]	Neutropenia	5.35% of cycles	—
		Non-hematological	Salar et al. [26]	Infections	1.9% of cycles	—
Aggressive NHL	Hematological	Weidmann et al. [27]	Neutropenia	23% of cycles	—
		Weidmann et al. [28]	NeutropeniaThrombocytopenia	6.78.3	—
		Ohmachi et al. [29]	LymphocytopeniaNeutropeniaLeukopeniaCD4 lymphocytopeniaThrombocytopenia	78.076.372.966.122.0	—
			Vacirca et al. [30]	NeutropeniaLeukopeniaThrombocytopeniaAnemia	36292212	—
	Non-hematological	Weidmann et al. [27]	InfectionsNauseaRenal impairmentFatigueDiarrhea	10% of cycles6% of cycles4% of cycles6% of cycles4% of cycles	—
		Weidmann et al. [28]	AlopeciaInfectionsNauseaFever	6.73.31.71.7	—
				Ohmachi et al. [29]	Increased ALTIncreased γ-GTPAnorexiaMaculopapular rashIncreased ASTConstipation	8.56.86.85.13.43.4	—
T-cell lymphoma	Hematological	Damaj et al. [31]	NeutropeniaThrombocytopenia	3024	—
			Zaja et al. [32]	NeutropeniaThrombocytopenia	4425	—
		Non-hematological	Damaj et al. [31]	Infections	20	—
MCL [see Table II]

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BO, bendamustine plus obinutuzumab; FCO, fludarabine plus cyclophosphamide plus obinutuzumab; γ-GTP, gamma-glutamyl transferase.

Table II. Bendamustine-rituximab combinations in Mantle cell lymphoma.

Reference	Regimen	Study type	Line of therapy	Patient no.	ORR (%)	CR (%)	Leukocytopenia grade 3/4	Thrombocytopenia grade 3/4
Rummel et al. [23]	6 × BR, no maintenance	Phase III	First line	46	93	40	37%*	5%*
Flinn et al. [25]	6 × BR	Phase III	First line	36	94	50	33%*	10%*
Rummel et al. [37]	4 × BR	Phase II	Relapse	16	75	25	35%*	7%*
Robinson et al. [43]	6 × BR	Phase II	Relapse	12	92	42	30%*	3%*
Weide et al. [44]	4 × BMR	Phase II	Relapse	18	78	33	78%	10%
Visco et al. [45]	6 × R-BAC	Phase II	First line	20	100	95	32%	70%
			Relapse	20	80	70	67%	83%
Friedberg et al. [46]	6 × BR + Bortezomib	Phase II	Relapse	7	71	N/A	17%*	17%*
Jerkeman et al. [47]	6 × BR + Lenalidomide	Phase II	First line	51	97	79	32%	6%
Zaja et al. [48]	6 × BR + Lenalidomide	Phase II	Relapse	42	90	71	69%	14%
Hess et al. [49]	4 × BR + Temsirolimus	Phase II	Relapse	11	91	45	40%*	13%*

*Includes also follicular lymphoma.

N/A, not available.

Table III. Main characteristics of the published studies on Bendamustine in R/R PTCL.

Reference	Study	Patient no.	Histology	% refractory patients	Median age (years)	B. dosage(mg/m^2)	ORR (%)	CR (%)	PFS (months)
Damaj et al. [31]	Phase II	60	AILTPTCL-nossALCL	45	66	120day 1–2/3 w	50	28	3.63
Zaja et al. [32]	Retrospective	20	AILTPTCL-nossALCL, T-PLL, T-LGL, MF, SS	68	73	60-100day 1–2/4 w	55	10	6 PFS44%
Herbaux et al. [58]	Retrospective	15	T-PLL	33	62	70–120day 1–2/3 w	53	20	5

AILT, angioimmunoblastic T-cell lymphoma; PTCL-nos, peripheral T-cell lymphoma-not otherwise specified; sALCL, systemic anaplastic large cell lymphoma; T-PLL, T-cell prolymphocytic leukemia; T-LGL, T-large granular lymphocytosis; MF, mycosis fungoides; SS, Sezary Syndrome.

Table IV. Clinical activity in Hodgkin lymphoma.

Reference	Patient no.	Dose/schedule	ORR %	CR %	Median PFS (months)
Moskowitz et al. [62]	36	120 mg/m^2 on days 1 and 2 every 28 days	53	33	5.2
Corazzelli et al. [60]	41	90–120 mg/m^2 on days 1 and 2 every 28 days	58	31	11
Ghesquieres et al. [61]	28	90–120 mg/m^2 on days 1 and 2 every 28 days	50	29	5.7
Anastasia et al. [60]	67	90–120 mg/m^2 on days 1 and 2 every 28 days	57	25	10

Table V. Bendamustine in relapsed/refractory multiple myeloma.

Author	Regimen	Study type	Median no. (range) of lines of prior therapy	Patient no.	Overall response/remission rate (%)	Median PFS (months)	Median OS (months)
Bendamustine ± steroids
Michael et al. [76]	B (80–150 mg/m^2; days 1, 2 of 28-day cycle): 39% monotherapy; 61% + steroids	Retrospective analysis	2 (1–5)	39	36 (PR and vgPR)	7 (EFS)	17
Damaj et al. [71]	B (120 –150 mg/m^2; days 1, 2 of 28-day cycle) + prednisolone	Compassionate use program	4 (1–9)	110	30 (≥ PR)	9.3	12.4
Bendamustine + steroids + thalidomide/lenalidomide
Pönisch et al. [77]	B (60 mg/m^2; days 1, 8, 15) + escalating doses of thalidomide + prednisolone	Phase I	2 (1–6)	28	86 (≥ PR)	11	19
Grey-Davies et al. [72]	B (60 mg/m^2; days 1, 8 [15*] of 28-day cycle)  + thalidomide + dexamethasone	Compassionate use program	5 (3–7)	23	61 (≥ SD)	3	13
Lau et al. [73]	B (cumulative dose up to 200 mg/m^2§; 28-day cycles) +  thalidomide + dexamethasone	Retrospective analysis	4 (3–6)	30	87 (≥ SD)	4	7.2
Lentzsch et al. [74]	B (MTD 75 mg/m^2; days 1, 2 of 28-day cycle)  + lenalidomide + dexamethasone	Phase I/II	3 (1–6)	29	76 (incl. minimal responses)	6.1	Not reached
Bendamustine + bortezomib ± steroids
Ludwig et al. [74]	B (70 mg/m^2; days 1, 4 of 28-day cycle)  + bortezomib + dexamethasone	Phase II	2 (1–6)	79	60.8 (75.9% incl. minor responses)	9.7	25.6
Berenson et al. [70]	B (MTD 90 mg/m^2; days 1, 4 of 28-day cycle) + bortezomib	Phase I/II	75% received  ≥ 4 prior therapies	31 (at MTD)	52 (incl. minimal responses)	8.4**	13.3**
Pönisch et al. [78]	B (60 [–120] mg/m^2; days 1, 2 of 21-day cycle) + bortezomib + prednisone	Restrospective	2 (1–9)	78	69 (≥PR)(76%†; 61%‡)	11†3‡	50†5‡

*Day 15 administration discontinued for the final 13 patients due to hematologic toxicity.

**Among all 40 patients enrolled.

†Among patients without severe hematologic toxicity due to previous treatments.

‡Among patients with severe hematologic toxicity due to previous treatments.

§Starting dose either 60 mg/m² on days 1, 8 and 15 or 100 mg/m² on days 1 and 8. Dose scaled up to 200 mg/m²/cycle based on neutrophil counts.

EFS, event-free survival; MTD, maximum tolerated dose; N/A, not available; OS, overall survival; PFS, progression-free survival; PR, partial response/remission; SD, stable disease; vgPR, very good partial response/remission.

Table VI. Consensus panel dose recommendations and dose reductions with bendamustine therapy.

Dose recommendation	Dose (days 1 and 2)	Cycles	Notes
CLL
Front line, single agent	100 mg/m^2 every 4 weeks	6	Rarely used in this situation
Front line + rituximab	90 mg/m^2 every 4 weeks	6
R/R ± rituximab	70 mg/m^2 every 4 weeks	4
iNHL
Front line + rituximab	90 mg/m^2 every 4 weeks	6	No rituximab maintenance
R/R ± rituximab	70–90 mg/m^2 every 4 weeks	4
Follicular		6
Waldenstroem		4–6
Marginal zone		4–6
Aggressive non-Hodgkin lymphoma
Front line + rituximab	120 mg/m^2 every 3 weeks	6	Reduced as needed
R/R ± rituximab	90–120 mg/m^2 every 3–4 weeks	6	Clinical experience suggests that 120 mg/m^2 is not well tolerated by a significant sub-population of patients
Peripheral T-cell lymphoma (includes angioimmunoblastic and NOS)
R/R	90–120 mg/m^2 every 3 weeks	4–6	Start with 120 mg/m^2; can be reduced to 90 mg/m^2 if needed
Mantle-cell lymphoma
Front line + rituximab	90 mg/m^2 every 4 weeks	6	Patients not considered for high-dose therapy
R/R ± rituximab	90 mg/m^2 every 4 weeks	4–6	Can be reduced to 70 mg/m^2 if needed.
Hodgkin lymphoma
R/R	90 mg/m^2 every 3 weeks	4–6	No difference has been observed at doses 100–120 mg/m^2Number of cycles based on tolerance
Multiple myeloma
Front line single agent	100 mg/m^2 every 4 weeks	6	Label suggests 120–150 mg/m^2, but this is not recommended by the panel
Front line combination therapy	60–90 mg/m^2 every 4 weeks	6	Start at 60 mg/m^2 and escalate to 90 mg/m^2 with tolerability
R/R	60–90 mg/m^2 every 4 weeks	6
Dose reduction
CLL
Front line + rituximab	90 to 70 mg/m^2
R/R + rituximab	70 mg/m^2 to dose delay*
iNHL
Front line or retreatment	60-min infusion of 500 mL		To reduce skin reactions The reconstituted concentrate (50 mL) should be diluted immediately with 0.9% sodium chloride solution, otherwise there is an increased risk of rash Once reconstituted and diluted it is stable for 3–4 h at room temperature or for 48 h in the fridge
Dose reduction	90 to 70 mg/m^2		Discontinue if still problems at 70 mg/m^2
Aggressive non-Hodgkin lymphoma
Front line	120 to 90 mg/m^2
R/R	1^st reduction: 120 to 90 or 90 to 70 mg/m^22^nd reduction: 90 to 70 mg/m^2		In a Japanese/Korean phase II study, the 2^nd dose reduction was from 90 mg/m^2 to 60 mg/m^2
Hodgkin lymphoma
R/R	90 to 70 mg/m^2
Multiple myeloma
Monotherapy	100 to 70 mg/m^2
Combination therapy	90 to 60 mg/m^2

iNHL: in the front-line setting, bendamustine should not be used as a single agent. Consider pre-medicating with dexamethasone (8 mg, IV, in combination with 5-HT3 antagonist) or hydrocortisone (50–100 mg). Normally recommend dose delay before dose reduction. Use dose reduction as a first step in those patients with transient non-hematological toxicity.

Aggressive non-Hodgkin lymphoma: BR can be used in those patients who cannot use R-CHOP or a CHOP-like regimen. Definition includes follicular lymphoma, grade 3b. No recommendations for Burkitt’s lymphoma or lymphoblastic lymphoma.

T-cell lymphoma: bendamustine has no known role in the front-line setting.

Mantle-cell lymphoma: further dose reductions of bendamustine are needed when in combination with potentially myelosuppressive agents (e.g. ibrutinib, bortezomib, lenalidomide).

Multiple myeloma: bendamustine should be dosed on two days (Days 1 + 2, Days 1 + 8 or Days 1 + 4) within a 28 day cycle. Bendamustine would be considered first-line therapy in non-transplant-eligible patients.

*Doses < 60 mg/m² are considered sub-therapeutic and dose delays are preferred.

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