Rituximab-based combination therapy in patients with Waldenström macroglobulinemia: a systematic review and meta-analysis

Figures & data

Table 1 PRISMA checklist

Section/topic	Number	Checklist item	Reported on page number
Title
Title	1	Identify the report as a systematic review, a meta-analysis, or both.	1
Abstract
Structured summary	2	Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.	2
Introduction
Rationale	3	Describe the rationale for the review in the context of what is already known.	3–4
Objectives	4	Provide an explicit statement of questions being addressed with reference to PICOS.	3–4
Methods
Protocol and registration	5	Indicate if a review protocol exists, if and where it can be accessed (eg, web address), and, if available, provide registration information including registration number.	No registration
Eligibility criteria	6	Specify study characteristics (eg, PICOS, length of follow-up) and report characteristics (eg, years considered, language, publication status) used as criteria for eligibility, giving rationale.	4–5
Information sources	7	Describe all information sources (eg, databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.	4–5
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.	4
Study selection	9	State the process for selecting studies (ie, screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).	4–5
Data collection process	10	Describe method of data extraction from reports (eg, piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.	5
Data items	11	List and define all variables for which data were sought (eg, PICOS, funding sources) and any assumptions and simplifications made.	5
Risk of bias in individual studies	12	Describe methods used for assessing the risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.	5–6
Summary measures	13	State the principal summary measures (eg, risk ratio, difference in means).	5–6
Synthesis of results	14	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (eg, I^2) for each meta-analysis.	5–6
Risk of bias across studies	15	Specify any assessment of risk of bias that may affect the cumulative evidence (eg, publication bias, selective reporting within studies).	5–6
Additional analyses	16	Describe methods of additional analyses (eg, sensitivity or subgroup analyses, meta-regression), if done, indicating which were prespecified.	5–6
Results
Study selection	17	Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.	6–7, Figure 1
Study characteristics	18	For each study, present characteristics for which data were extracted (eg, study size, PICOS, follow-up period) and provide the citations.	6–7, Table 1
Risk of bias within studies	19	Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).	7–8
Results of individual studies	20	For all outcomes considered (benefits or harms), present, for each study: 1) simple summary data for each intervention group and 2) effect estimates and CIs, ideally with a forest plot.	7–8, Table 2, Figures 2–6
Synthesis of results	21	Present results of each meta-analysis done, including CIs and measures of consistency.	7–8
Risk of bias across studies	22	Present results of any assessment of risk of bias across studies (see item 15).	8–9, Table 3
Additional analysis	23	Give results of additional analyses, if done (eg, sensitivity or subgroup analyses, meta-regression [see item 16]).	7–8
Discussion
Summary of evidence	24	Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (eg, health care providers, users, and policy-makers).	9–11
Limitations	25	Discuss limitations at study and outcome level (eg, risk of bias), and at review level (eg, incomplete retrieval of identified research, reporting bias).	12–13
Conclusions	26	Provide a general interpretation of the results in the context of other evidence and implications for future research.	13
Funding
Funding	27	Describe sources of funding for the systematic review and other support (eg, supply of data); role of funders for the systematic review.	14

Notes: Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed1000097.⁶⁵

Abbreviation: PICOS, participants, interventions, comparisons, outcomes, and study design.

Figure 1 Selection of studies. Flow diagram demonstrating the identification and selection process of articles included in the meta-analysis.

Table 2 Patient characteristics and treatment outcomes of the included studies

References	Study design	Total patients	Previous treatment	Median age (years)	Gender (male/female)	Treatment regimen	CR	VGPR	PR	Minor response	Major response	Overall response	Anemia (grade ≥3)	Neutropenia (grade ≥3)	Thrombocytopenia (grade ≥3)
Treon et al (2005/03)^Citation14	Clinical trial, Phase II; single-arm	13	Both (three previously untreated)	54	NA	Rituximab + CHOP	3	NA	8	1	11	12	NA	NA	NA
Dimopoulos et al (2007/08)^Citation15	Clinical trial, Phase II; single-arm	72	Previously untreated	69	45/27	Rituximab + cyclophosphamide + dexamethasone	5	NA	48	7	53	60	NA	9	0
Treon et al (2008/12)^Citation16	Clinical trial, Phase II; single-arm	25	Both (20 previously untreated)	62	NA	Rituximab + thalidomide	1	NA	15	2	16	18	NA	NA	NA
Buske et al (2009/01)^Citation17	Clinical trial, Phase III; RCT	23	Previously untreated	58	15/8	Rituximab + CHOP	2	NA	19	NA	21	21	NA	NA	NA
Treon et al (2009/01)^Citation18	Clinical trial, Phase II; single-arm	16	Both (12 previously untreated)	65	12/4	Rituximab + lenalidomide	0	NA	NA	4	4	8	1	5	1
Ioakimidis et al (2009/03)^Citation19	Retrospective study	23	Both (13 previously untreated)	54	NA	Rituximab + CHOP	4	2	10	6	16	22	NA	NA	NA
		16	Both (five previously untreated)	60	NA	Rituximab + cyclophosphamide + vincristine + prednisone	2	1	7	4	10	14	NA	NA	NA
		19	Both (12 previously untreated)	65	NA	Rituximab + cyclophosphamide + prednisone	0	0	14	4	14	18	NA	NA	NA
Treon et al (2009/04)^Citation20	Clinical trial, Phase II; single-arm	43	Both (27 previously untreated)	61	NA	Rituximab + fludarabine	2	14	21	4	37	41	1	27	7
Treon et al (2009/08)^Citation21	Clinical trial, Phase II; single-arm	23	Previously untreated	66	NA	Rituximab + bortezomib + dexamethasone	5	3	11	3	19	22	1	7	2
Ghobrial et al (2010/03)^Citation22	Clinical trial, Phase II; single-arm	37	Relapsed or refractory	64	26/11	Rituximab + bortezomib	2	NA	17	11	19	30	4	6	5
Rabascio et al (2010/04)^Citation23	Retrospective study	21	Both	NA	NA	Rituximab + cladribine (2-CdA)	1	NA	10	5	11	16	NA	NA	NA
Ghobrial et al (2010/09)^Citation24	Clinical trial, Phase II; single-arm	26	Previously untreated	62.5	15/11	Rituximab + bortezomib	1	1	15	6	17	23	2	3	2
Agathocleous et al (2010/11)^Citation25	Clinical trial, Phase II; single-arm	10	Relapsed or refractory	NA	NA	Rituximab + bortezomib	0	NA	9	NA	9	9	NA	NA	NA
Peinert et al (2010/12)^Citation26	Retrospective study	19	Both	NA	NA	Rituximab + fludarabine ± cyclophosphamide	1	NA	14	2	15	17	NA	NA	NA
Laszlo et al (2011/02)^Citation27	Clinical trial, Phase II; single-arm	29	Both (16 previously untreated)	64	19/10	Rituximab + cladribine (2-CdA)	7	NA	16	3	23	26	NA	NA	NA
Tedeschi et al (2012/01)^Citation28	Clinical trial, Phase II; single-arm	43	Both	65	25/18	Rituximab + fludarabine + cyclophosphamide	5	9	18	2	32	34	1	38	2
Tedeschi et al (2013/04)^Citation29	Retrospective study	40	Relapsed or refractory	67	28/12	Rituximab + fludarabine + cyclophosphamide	4	9	19	0	32	32	NA	35	NA
Dimopoulos et al (2013/11)^Citation30	Clinical trial, Phase II; single-arm	59	Previously untreated	70	38/21	Rituximab + bortezomib + dexamethasone	2	4	34	10	40	50	0	9	3
Treon et al (2014/07)^Citation31	Clinical trial, Phase II; single-arm	31	Both (28 previously untreated)	61	19/12	Rituximab + carfilzomib + dexamethasone	1	10	10	6	21	27	1	3	0
Tedeschi et al (2015/06)^Citation32	Retrospective study	71	Relapsed or refractory	72	46/25	Rituximab + bendamustine	5	11	37	4	53	57	NA	4	2
Souchet et al (2016/08)^Citation33	Retrospective study	82	Both (25 previously untreated)	NA	NA	Rituximab + fludarabine + cyclophosphamide	1	14	38	17	53	70	7	35	11
Rosenthal et al (2017/05)^Citation34	Clinical trial, Phase II; single-arm	15	Previously untreated	NA	NA	Rituximab + lenalidomide + cyclophosphamide + dexamethasone	1	NA	11	NA	12	12	NA	NA	NA
Paludo et al (2017/10)^Citation35	Clinical trial, Phase II; single-arm	50	Relapsed or refractory	68	NA	Rituximab + cyclophosphamide + dexamethasone	0	2	32	9	34	43	NA	NA	NA

Notes: The references of the included studies were presented in chronological order according to their published date. The term “both” indicates that the study enrolled both patients who had previous therapy and previously untreated patients.

Abbreviations: CHOP, cyclophosphamide + doxorubicin + vincristine + prednisone; CR, complete response; NA, not available; PR, partial response; RCT, randomized controlled trial; VGPR, very good partial response.

Figure 2 Pooled overall response rate (double arcsine form) of rituximab-based combinations in patients with Waldenström macroglobulinemia. The diamond indicates the estimated overall response rate and their corresponding 95% CI (double arcsine form after Freeman–Tukey transformation).

Note: Weights are from random-effects analysis.

Figure 3 Pooled major response rate (double arcsine form) of rituximab-based combinations in patients with Waldenström macroglobulinemia. The diamond indicates the estimated major response rate and their corresponding 95% CI (double arcsine form after Freeman–Tukey transformation).

Note: Weights are from random-effects analysis.

Figure 4 Pooled complete response rate (double arcsine form) of rituximab-based combinations in patients with Waldenström macroglobulinemia. The diamond indicates the estimated complete response rate and their corresponding 95% CI (double arcsine form after Freeman–Tukey transformation).

Note: Weights are from random-effects analysis.

Figure 5 Summary of pooled response rate (original form) of rituximab-based combinations and different subgroups in patients with Waldenström macroglobulinemia. (A) Pooled ORR. (B) Pooled MRR. (C) Pooled CRR. (D) The percentage bar diagram for overall and subgroups A, B, C, and D for ORR, CRR, and MRR. Subgroup A represents rituximab plus conventional alkylating agents–containing chemotherapy group; subgroup B represents rituximab plus purine analog group; subgroup C represents rituximab plus proteasome inhibitor group; and subgroup D represents rituximab plus immunomodulatory drug group. *P<0.007143. The diamond indicates the estimated response rate and their corresponding 95% CI (original form).

Note: Weights are from random-effects analysis.

Abbreviations: CRR, complete response rate; MRR, major response rate; ORR, overall response rate.

Table 3 Comparison between different subgroups of ORR, MRR, and CRR

	ORR	P-value	MRR	P-value	CRR	P-value
Subgroup A vs subgroup B	86% vs 85%	0.770	74% vs 74%	0.875	8% vs 9%	0.905
Subgroup A vs subgroup C	86% vs 86%	0.878	74% vs 68%	0.118	8% vs 7%	0.553
Subgroup A vs subgroup D	86% vs 67%	0.001	74% vs 56%	0.002	8% vs 5%	0.305
Subgroup B vs subgroup C	85% vs 86%	0.681	74% vs 68%	0.158	9% vs 7%	0.488
Subgroup B vs subgroup D	85% vs 67%	0.002	74% vs 56%	0.006	9% vs 5%	0.280
Subgroup C vs subgroup D	86% vs 67%	0.001	68% vs 56%	0.167	7% vs 5%	0.495

Notes: Subgroup A represents rituximab plus conventional alkylating agents–containing chemotherapy group, subgroup B represents rituximab plus purine analog group, subgroup C represents rituximab plus proteasome inhibitor group, and subgroup D represents rituximab plus immunomodulatory drug group. Comparisons between the four different subgroups were performed with partitions of Pearson’s chi-squared test by which a two-tailed P-value of <0.007143 was deemed statistically significant.

Abbreviations: CRR, complete response rate; MRR, major response rate; ORR, overall response rate.

Figure 6 Pooled rates of grade ≥3 hematological adverse events of rituximab-based combinations. Rates (double arcsine form after Freeman–Tukey transformation) of (A) anemia, (B) neutropenia, (C) thrombocytopenia, and (D) summary of grade ≥3 anemia, neutropenia, and thrombocytopenia (original form).

Note: Weights are from random-effects analysis.

Table 4 Publication bias assessment of the pooled results

Pooled results	P-value
	Egger’s test	Begg’s test
Complete response rate	0.122	0.308
Major response rate	0.931	0.602
Overall response rate	0.836	0.502
Grade ≥3 anemia	0.638	0.404
Grade ≥3 neutropenia	0.654	0.492
Grade ≥3 thrombocytopenia	0.595	0.815

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Data availability statement

Our meta-analysis overviewed and extracted data from the previously published articles, all of which are cited in the manuscript and can be found online. The processed data are available from the corresponding author upon request.