Refractory Burkitt Lymphoma: Diagnosis and Interventional Strategies

Figures & data

Table 1 Relapsed/Refractory BLL: Results with Current Salvage Therapies in Children and Adults

Author	Years	Histology	Total	Age (years)	Refr/Rel	Salvage	Rituximab	ORR/CR	HSCT (Auto/Allo)	Survival
Atra et al 2001^Citation46	1990–1996	BL/B-AL	26	<18	8/18	CHOP-like=3; CYVE=12; palliative care=8	No	NA	Auto=4; allo=3	3y-OS 11%
Griffin et al 2009^Citation44	2008	BL/LBCL	14/6	5–20	20/0	R-ICE	Yes	64%/28%	Auto=4; allo=2	3y-OS 37%
Anoop et al 2012^Citation47	2000–2009	BL/LBCL	12/33	Median 9.3	7/26	UKCCSG2003=13; ICE=8; ESHAP=2; FAB/LMB96=1; palliative care=6	17 pts	42%/33%	Auto=12; allo=4	4y-OS 33% (patients treated with curative intent)
Maramattom et al 2013^Citation48	1985–2007	BL	241	3–76	41/97	Various	29 pts	NA	Auto=57; allo=80;	Auto=5-y OS 31%; 5-y PFS 27%; allo=5-y OS 20%; 5-y PFS 19%
Kim et al 2014^Citation37	1990–2009	BL/L3 B-AL	19	2–13	3/16	Various	4 pts	36.8%	Auto=3; allo=1	OS 31%
Satwani et al 2014^Citation49	2001–2011	BL/HL/NHL	30	1–33	7/23	Various	Yes	CR 23%	Tandem MAC AutoHSCT + rituximab + IFRT + RIC alloHSCT	NHL 10y-EFS 70%
Jourdain et al 2015^Citation38	1989–2007	BL/LBCL	57/10	1–19.6	mTTR=4.8 months	Various	16 pts	47.7%	Auto=33; allo=8	5y-OS 29.9%
Short et al 2017^Citation50	1992–2015	BL	35	18–76	3/32	Various	NA	39%/22.8%	Auto=3; allo=3	1-y OS 11%
Cairo et al 2018^Citation39	1996–2001	BL/LBCL	104	2.5–20.5	28/76	Various	NA	NA	NA	2-y OS 23.3%
Rigaud et al 2019^Citation40	2001–2011	BL/LBCL	33	1.9–17.9	mTTR=4.5 months	Salvage immuno-CHT + HDT and autoHSCT	27 pts	72%/56%	Auto=13; allo=8	5y-OS 36.4%
Woessmann et al 2020^Citation41	1986–2016	BL/B-AL	157	2.9–19.6	mTTR=4 months	Various	55 pts	CR 19%	Auto=20; allo=26	Before 2000: 3y-OS 18.5%; after 2000: 3y-OS 27%
Burkhardt et al 2021^Citation51	2000–2018	BL/LBCL/PTCL/T-LBL	639	0.3–17.9	mTTR=5 months	NHL-BFM or FAB=94; R-ICE=89; R-VICI=33; daEPOCH-R=4	Yes	CR 41%	Auto=64; allo=87	Without HSCT: OS 3%; with autoHSCT: OS 44%; with alloHSCT: OS 46%
Manji et al 2022^Citation52	2003–2018	BL	74	32–61	57/17	Salvage immuno-CHT=43; Palliative care=28	23 pts	NA	Auto=9; allo=1	2y-OS 17.2%
Gardenswartz et al 2022^Citation53	2011–2018	B-NHL	13	Mean 15 years	NA	Various	No	CR 85%	Yttrium90-ibritumomab tiuxetan in 6 + Tandem MAC autoHSCT + RIC alloHSCT	EFS 91%

Abbreviations: BLL, Burkitt lymphoma/leukemia; Refr/Rel, refractory/relapsed; ORR/CR, overall response rate/complete remission; HSCT, hematopoietic stem cell transplant; BL, Burkitt lymphoma; B-AL, Burkitt leukemia; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; NA, not applicable; OS, overall survival; LBCL, large B-cell lymphoma; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; UKCCSG, UK Children’s Cancer And Leukemia Study Group; ESHAP, etoposide, methylprednisolone, high-dose cytarabine, cisplatin; FAB/LMB, French American British/Lymphomes malins B group; pts, patients; PFS, progression-free survival; L3 B-AL, B-cell acute lymphoblastic leukemia with FAB L3 morphology; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; IFRT, involved field radiation therapy; EFS, event-free survival; mTTR, median time-to-relapse; HDT, high-dose therapy; PTCL, peripheral T-cell lymphoma; T-LBL, T lymphoblastic lymphoma; BFM, Berlin–Frankfurt–Münster study group; R-VICI, rituximab, vincristine idarubicin, ifosfamide, carboplatin and dexamethasone; da-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab.

Table 2 Selected Actively Recruiting Clinical Trials Employing Novel Agents for Relapsed/Refractory BLL

Target	ClinicalTrials.gov Identifier	Institution, Sponsor	Phase	Age Criteria	Histology	Strategy	Results
BTK	NCT02703272	Janssen Research & Development	3	3–19	BLL/B-NHL	Random R-ICE/R-VICI vs Ibrutinib + R-ICE/R-VICI	Median EFS ibrutinib arm=6 months; median EFS control arm=7 months, 2023^Citation56
CD20	NCT02393157	New York Medical College	2	3–31	BLL/B-NHL	Obinutuzumab-ICE	4 pediatric BLL enrolled: 3 PR, 1 CR, 2018^Citation57
Proteasome	NCT03136146	M.D. Anderson Cancer Center	2	≥15 years	BLL/B-ALL/B-NHL	Bortezomib + clofarabine, etoposide, cyclophosphamide, liposomal vincristine	N
Multiple targets	NCT04739813	National Cancer Institute	1	≥18 years	Aggressive B-NHL	Polatuzumab-venetoclax + ibrutinib-obinutuzumab-lenalidomide (ViPOR-P)	36% CR, 2022^Citation58
Dual target: CD19/CD3	NCT02568553	National Cancer Institute	1	≥18 years	BLL/B-NHL	Blinatumomab + lenalidomide	ORR=83% (CR 50%); mPFS=8.3 months, 2019^Citation59
CD19	NCT03610724	Novartis Pharmaceuticals	2	1–25 years	BLL/B-NHL	Tisagenlecleucel	No grade ≥3 CRS; 2 pts grade 3/4 neurotoxicity, 2020^Citation60
	NCT02625480	Kite	1–2	1–21 years	BLL/B-ALL/B-NHL	Brexucabtagene autoleucel (KTE-X19)	N
	NCT05537766	Kite	2	≥18 years	BLL/Richter syndrome	Brexucabtagene autoleucel (KTE-X19)	N
	NCT03144583	Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain	1	2–80 years	BLL/B-NHL	Varnimcabtagene autoleucel (ARI-0001)	3y-PFS=40%; 3y-OS=52%, 2023^Citation61
Sequential CD19-CD22-CD20	ChiCTR1800014457	Beijing Boren Hospital, Beijing	1	1–18 years	BLL	Sequential 4–1BB CD19-CD22-CD20 CAR-T	78% CR; 18month-PFS=78%, 2022^Citation62
Sequential CD19-CD22	ChiCTR16008526 ChiCTR16009847	Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China	1	≥17 years	BLL	Trial A: sequential CD28-4-1BB CD19/CD22 CAR-T Trial B: sequential CD28-4-1BB CD19/CD22 CAR-T + autoHSCT	ORR Trial A=46.7%; ORR trial B=92.3%, 2022^Citation63
Dual target: HDAC/Aurora A kinase	NCT01897012	National Cancer Institute	1	≥18 years	Aggressive HL/NHL	Alisertib + romidepsin	12% CR; mOS=12 months, 2020^Citation64
PI3K alfa-delta	NCT04933617	National Cancer Institute	1	≥18 years	BLL/B-NHL	Copanlisib + da-EPOCH-R	N
Dual target: CD20/CD3 CD19	NCT05991388	University of Birmingham	2/3	1–25	B-NHL	Arm A: Odronextamab; Arm B: Loncastuximab tesirine + CHT; Arm C: CD19 CAR-T	N

Abbreviations: BLL, Burkitt lymphoma/leukemia; BTK, Bruton tyrosine kinase; BL, Burkitt lymphoma-leukemia; B-NHL, B-cell non-Hodgkin lymphoma; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; R-VICI, rituximab, vincristine idarubicin, ifosfamide, carboplatin and dexamethasone; EFS, event-free survival; CR, complete remission; PR, partial remission; B-ALL, B-cell acute lymphoblastic leukemia; N, none; ORR, overall response rate; mPFS, median progression-free survival; CRS, cytokine release syndrome; OS, overall survival; HDAC, histone deacetylase; PI3K, phosphoinositide-3-kinase; da-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab.

Figure 1 Selected target therapies for the treatment of Burkitt lymphoma/leukemia.

Abbreviations: BCR, B cell receptor; BET, bromodomain and extraterminal motif; BTK, Bruton tyrosine kinase; HDAC, histone deacetylase; PI3K, phosphoinositide-3-kinase.

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