Bendamustine treatment of haematological malignancies: significant risks of opportunistic viral, fungal and bacterial infections

Figures & data

Table 1. Demographic and clinicopathologic features of 306 patients receiving bendamustine treatment for lymphoid neoplasms.

Demographic/Clinicopathologic features	Number^a
Sex
Male	179
Female	127
Age, median (range), years	61.5 (20–90)
Status at treatment
Newly-diagnosed	139
Relapsed/refractory	160
Diagnoses
Follicular lymphoma	77
T-cell lymphoma	33
Multiple myeloma	32
Marginal zone lymphoma	30
Chronic lymphocytic leukaemia	29
Mantle cell lymphoma	18
Splenic marginal zone lymphoma	11
Hodgkin lymphoma	7
Others^b	69
Lactate dehydrogenase
Normal	174
Increased	117
Albumin
Normal	186
Decreased	107
ECOG performance score
0	92
1	129
2	44
3	24
4	4
Number of cycles of bendamustine administered
1	48
2	29
3	34
4	16
5	17
6	145 (47%)
>6	7

^a Not all data tally to 306 because of missing data.

^b This category included chronic B-cell lymphoproliferative diseases, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, grey zone lymphoma, and other unclassified low-grade B-cell lymphomas.

Table 2. Demographic and clinicopathologic features of 58 patients with cytomegalovirus virologic reactivation and disease during bendamustine treatment for lymphoid neoplasms.

Demographic/Clinicopathologic features	Number (%)
Sex
Male	32 (55%)
Female	26 (45%)
Age, median (range), years	68 (39–85)
Status at treatment
Newly-diagnosed	29 (50%)
Relapsed/refractory	29 (50%)
Bone marrow infiltrated	35 (60%)
Stage IV disease	36 (62%)
Decreased serum albumin	30 (52%)
Increased lactate dehydrogenase	29 (50%)
Diagnoses
Follicular lymphoma	14 (24%)
T-cell lymphoma	14 (24%)
Multiple myeloma	5 (9%)
Marginal zone lymphoma	3 (5%)
Chronic lymphocytic leukaemia	4 (7%)
Mantle cell lymphoma	6 (10%)
Splenic marginal zone lymphoma	1 (2%)
Hodgkin lymphoma	2 (3%)
Others	9 (16%)
ECOG performance score
0–1	38 (66%)
≥2	20 (34%)
Number of cycles of bendamustine administered
1	8 (14%)
2	8 (14%)
3	8 (14%)
4	4 (7%)
5	2 (3%)
6	26 (49%)
>6	2 (3%)
Drugs used concomitantly with bendamustine
Rituximab	18 (31%)
Obinutuzumab	16 (28%)
Cytarabine	3 (5%)
CMV disease	5 (9%)

Figure 1. Infective complications of bendamustine-treated patients. (A). Patient 4 of the cytomegalovirus (CMV) disease cohort. Magnetic resonance imaging showed periventricular hyperintensities (arrows) indicative of ependymitis/ventriculitis. (B). Patient 5 of the CMV disease cohort. Upper endoscopy showing duodenal inflammation (left panel), and colonoscopy showing colitis (right panel). Histopathology of duodenal biopsy showed intranuclear CMV inclusion bodies, confirming CMV disease. (C). Patient 4 of the invasive fungal disease (IFD) cohort. Chest X ray showing bilateral consolidation. The patient was subsequently found to have cryptococcemia. (D). Patient 1 of the IFD cohort. Computed tomography (CT) scan of chest, showing wedge-shaped segmental lobar involvement (arrow) and consolidation (open arrow). Sputum grew Aspergillus niger. (E). Patient 3 of the IFD cohort. CT scan showed dense, well-circumscribed lesions (arrows). Bronchoalveolar aspirate grew Scedosporium apiospermum.

Table 3. Cytomegalovirus (CMV) disease in five patients treated with bendamustine.

Case	Sex/Age	Disease	Previous Rx	Benda (cycles)	Cytomegalovirus disease
					Previous react./pp65	Prophylaxis/Tx	Sites	Type	CMV Tx results	Outcome
1	F/49	FL-DLBCL	R-FND, R-CHOP, Hyper-CVAD, R-DHAP, DIME, R-GEMOX	R-Benda (1)	Yes, 240	Yes	Bilateral retinitis	Proven	Systemic, intravitreal, poor vision persisted	Dead, underlying diseae, 8 m
2	F/69	Myeloma	VTD, VRD, VCMD	Benda (2)	Yes, 243	Yes	Bilateral retinitis	Proven	Systemic, good visual improvement	Dead, acute myocardial infarction, 2 m
3	F/58	AITL	CHOP, FND, SIMPLE	Benda (4)	Yes, 7	Yes	Left retinitis	Proven	Systemic, intravitreal, good visual improvement	Dead, sepsis, 2 m
4	F/70	AITL	SIMPLE, FND	Benda (1)	Yes. > 700	Yes	Ependymitis/ventriculitis	Possible	Systemic, stable neurologic status	Dead, sepsis, 4 m
5	F/49	MCL	–	O-BAC (3)	Yes, 1*	Yes	Duodenitis, colitis, bilateral retinitis	Proven	Systemic, not evaluable	Dead, invasive fungal disease, 2 wks

Rx: Previous treatment regimens for the underlying disease; Pervious react./pp65: virologic CMV reactivation preceding the development of CMV disease, peak CMV pp65 antigenic assay (per 2 × 10⁵ leucocytes); prophylaxis/Tx: either treatment for CMV virologic reactivation, or prophylaxis; CMV Tx results: results of antiviral treatment for CMV disease; F: female; M: male; Age: age in years; FL-LCT: follicular lymphoma with transformation to diffuse large B-cell lymphoma; AITL: angioimmunoblastic T-cell lymphoma; MCL: mantle cell lymphoma; R-FND: rituximab, fludarabine, mitoxantrone, dexamethasone; CHOP: cyclophosphamide, adriamycin, vincristine, prednisolone; Hyper-CVAD: cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine, methylprednisolone; DHAP: dexamethasone, cytarabine. Cisplatinum; DIME: dexamethasone, ifosfamide, methotrexate, etoposide; GEMOX: gemcitabine, methotrexate, oxiplatin; VTD: bortezomib, thalidomide, dexamethasone; VRD: bortezomib, lenalidomide, dexamethasone; VCMD: bortezomib, cyclophosphamide, melphalan, dexamethasone; SIMPLE: dexamethasone, ifosfamide, methotrexate, cisplatin, L-asparaginase, etoposide; Benda: bendamustine; O-BAC: obinutuzumab, bendamustine, cytarabine; m: months; wk: weeks; *: interpretation limited by neutropenia.

Table 4. Invasive fungal diseases (IFD) in five patients treated with bendamustine.

Case	Sex/Age	Disease	Previous Rx	Benda (cycles)	Invasive fungal disease
					Prophylaxis	Organism	Sites, specimen	Type	Tx and results	Outcome (time)
1	M/55	FL-DLBCL	R-CHOP, R-DHAP, allo-HSCT, IMVP16	O-Benda (1)	Micafungin	Aspergillus niger	Lung, sputum	Probable	voriconazole	Dead, underlying disease, 2 m
2	M/63	MZL-DLBCL	Nil	R-Benda (1)	Nil	Candida albicans	Blood	Proven	Fluconazole	Dead, underlying disease, 15 m
3	M/59	FL	Nil	O-Benda (6)	Anidulafungin	Scedosporium apiospermum	Lung, BAL	Probable	Liposomal amphotericin	Dead, sepsis, IFD, 1 m
4	F/78	AITL	Nil	Benda (6)	Nil	Cryptococcus neoformans	Lung, blood	Proven	Fluconazole	Dead, sepsis, IFD, 2 wk
5	F/49	MCL	Nil	O-BAC (3)	Itraconazole	Candida parapsilosis	Blood	Proven	Liposomal amphotericin	Dead, sepsis, IFD, 2 wk

Rx: Previous treatment regimens for the underlying disease; Benda (cycles): cycles of bendamustine administered before invasive fungal disease occurred; Type: type of invasive fungal disease according to EORTC 2020 definitions; Tx results: anti-fungal drug used and outcome of treatment; outcome (time): outcome of patient, and time from diagnosis of invasive fungal disease; F: female; M: male; Age: age in years; FL-DLBCL: follicular lymphoma with transformation to diffuse large B-cell lymphoma; MZL-DLBCL: marginal zone lymphoma in large cell transformation; FL: follicular lymphoma; AITL: angioimmunoblastic T-cell lymphoma; MCL: mantle cell lymphoma; R-CHOP: rituximab, cyclophosphamide, adriamycin, vincristine, prednisolone; DHAP: dexamethasone, cytarabine, cisplatinum; allo-HSCT: allogeneic haematopoietic stem cell transplantation; IMVP16: ifosfamide, methotrexate, etoposide; O: obinutuzumab; BAC: bendamustine, cytarabine; m: months; wk: weeks; IFD: invasive fungal disease.