Burkitt lymphoma in adolescents and young adults: management challenges

Figures & data

Figure 1 Typical case of endemic BL involving the facial bones in an African child (picture courtesy of RB, taken at Ocean Road Cancer Institute, Dar-es-Salaam, Tanzania, 2007).

Figure 2 Diagnostic pathology of BL: low magnification (×10, ×40) hematoxylin/eosin staining of BL sample involving the gastrointestinal tract, showing monotonous proliferation of medium-sized basophilic lymphoid cells punctuated by lightly colored macrophages (“starry sky” pattern) (A and B); immunohistochemistry, demonstrating staining for B-cell antigens including CD20 and the early CD10 antigen, with concurrent c-MYC and BCL6 expression and high proliferative rate (Ki67) (C–H).

Table 1 Treatment results in BL prior to rituximab (distribution and outcome of different age subsets indicated when available)

Study	Chemotherapy regimen	Patient number	Age (median age range), years	CR rate, n (%)	OS, % (years)	EFS/PFS, % (years)
Fenaux et al^Citation70	ALL-like (4 HCT)	18	26 (16–66)	10 (56)	31 (0.9)	57 (0.6)
Pees et al^Citation71	Pediatric NHL-based	14	39 (16–65)	10 (71)	71 (8)
Soussain et al^Citation72	ALL-like	65	26 (17–65)	58 (89)	74 (3)	71 (3)
Hoelzer et al^Citation73	B-NHL-83	24	33 (15–58) 15–20 (n=3) 20–50 (n=16) 50–65 (n=5)	15 (63)	49 (8)	50 (4)
	B-NHL-86	35	36 (18–65) 15–20 (n=2) 20–50 (n=22) 50–65 (n=11)	26 (74)	51 (4)	71 (4)
Magrath et al^Citation74	89-C-41 CODOX-M/IVAC	41 (20 adults)	25 (18–59)	39 (95)		92 (2)
Thomas et al^Citation75	Hyper-CVAD	26	58 (17–79)	21 (81)	49 (3)	61 (3)
			<60 (n=14)		77 (3)
			>60 (n=12)		17
Rizzieri et al^Citation76	CALGB (GMALL type)	92	47 (17–78)	68 (74)
		52 (cohort 1)	44 (18–72)	41 (79)	54 (3)	52 (3)
		40 (cohort 2)	50 (17–78)	27 (68)	50	45
Lacasce et al^Citation77	Modified CODOX-M/IVAC	14	47 (18–65)	12 (86)	71	64 (2.4)
Smeland et al^Citation78		49	(15–69)	33 (67)
	Arm A: MmCHOP (1982–1987)	13	30 (15–44)	7 (54)	23 (5)	31 (5)
	Arm B: MmCHOP + HCT (1988–1994)	17	31 (15–56)	12 (71)	71 (5)	71 (5)
	Arm C: BFM (1995–2001)	19	36 (17–69)	14 (74)	65 (5)	73 (5)
Di Nicola et al^Citation79	Pediatric NHL-based	22	35 (18–76)	17 (77)	77 (2.5)	68 (2.5)
Tauro et al^Citation80	BFM 90	24	33 (18–48)	39/45 (87)	80 (2)	82 (2)
	NHL 86	22	30 (16–46)			72 (2)

Abbreviations: BL, Burkitt lymphoma; CR, complete response; OS, overall survival; EFS, event-free survival; PFS, progression-free survival.

Table 2 Treatment results in BL with rituximab-based regimens (distribution and outcome of different age subsets indicated when available)

Study	Chemotherapy regimen	Patient number	Age (median age range), years	CR rate, n (%)	OS,^Citation2 % (years)	EFS/PFS,^Citation3 % (years)
Thomas et al^Citation84	R-Hyper-CVAD	31	46 (17–77)	24/28 (86)	89 (3)	80 (3)
			<60 (n=22)		90 (3)	76 (3)
			>60 (n=9)		89	89
Kujawski et al^Citation85	Short duration/dose intensive	11	51 (35–71)	10 (91)	72 (3)	64 (3)
Mead et al^Citation86	Dose-modified CODOX-M/IVAC	53	37 (17–76)	34 (64)	67 (2)	64 (2)
Choi et al^Citation87	French pediatric LMB	38	47 (18–70)	28 (74)	68 (5)	75 (5)
Barnes et al^Citation88	R-CODOX-M/IVAC	40	46 (17–78)	36 (90)	77 (3)	74 (3)
Corazzelli et al^Citation89	RD-CODOX-M/IVAC	30	52	93	82 (4)	78 (4)
			<60 (n=18)			93 (3)
			>60 (n=12)			49 (3)
Kasamon et al^Citation90	Various treatments	21	53 (34–75) 30–40 (n=5) 41–50 (n=5) 51–60 (n=5) >60 (n=6)	8/17 (47)	57 (3)	52 (3)
Ribera et al^Citation91	Burkimab (GMALL type)	80	47 (15–83)	70 (87)	78 (4)	80 (5)
Dunleavy et al^Citation92	DA-EPOCH-R	19	25 (15–88)		100 (7.1)	95 (7.1)
Intermesoli et al^Citation93	GMALL B-NHL 2002	105	47 (17–78)	83 (79)	67 (3)	75 (3)
			<60 (n=79)	64 (81)	75 (3)	82 (3)
			>60 (n=26)	19 (73)	45	55
Jain et al^Citation94	R-Hyper-CVAD	52	41 (17–77)	42/44 (95)	70 (5)	70 (5)
Rizzieri et al^Citation95	CALBG 10002 (GMALL type)	105	44 (19–79)	77 (73)	79 (2)	74 (2)
			<60 (n=77)	62 (80)	84 (4)	82 (4)
			>60 (n=28)	15 (54)	61	54
Hong et al^Citation96	R-Hyper-CVAD	43	51 20–40 (n=14) 41–60 (n=17) >60 (n=12)	24 (56)	81 (2)	71 (2)

Abbreviations: BL, Burkitt lymphoma; CR, complete response; OS, overall survival; EFS, event-free survival; PFS, progression-free survival.

Table 3 Comparative features of highly effective, modern treatment regimens for BL (all with rituximab)

Regimens	Main characteristics	Number of cycles	“Surplus”	Main limits
R-CODOX-M/IVAC^Citation86,Citation88,Citation89	First intensive regimen developed for BL, high-dose MTX-based	4 (2 alternating cycles of each regimen)	Reference regimen; including etoposide and ifosfamide	Myelosuppression, mucositis, infections; 20% unable to complete therapy with high-dose MTX
R-Hyper-CVAD^Citation84,Citation94,Citation96	Hyperfractionated cyclophosphamide, high-dose cytarabine/MTX	8, alternating schedule A (cycles 1, 3, 5, 7) and schedule B (cycles 2, 4, 6, 8)	Smaller MTX dose to minimize side effects (1 g/m^2)	Myelosuppression, mucositis, infections related to high-dose cytarabine (3 g/m^2)
R-NHL 2002^Citation78,Citation80	Multidrug regimen, BFM-based	4–6 (A1–B1–C1–A2; B2–C2)	Introduced by BFM and GMALL, used by CALGB, NILG, and PETHEMA	Derived from BFM pediatric protocol; toxicity >55 years (drug reduction)
R-LMB^Citation87,Citation98,Citation100	Dose dense, with high-dose MTX	3–8	Escalating treatment intensity (MTX) according to early response	Myelosuppression, mucositis, infections
DA-EPOCH-R/SC-EPOCH-RR^Citation92	Dose-adjusted chemotherapy, continuous 24-hour infusion (vincristine, doxorubicin, etoposide), no MTX	4–6	More tolerable by older/HIV+/frail patients; no MTX-related toxicity; outpatient administration feasible (after CR)	Few patients treated, mostly used at NCI/NIH

Note: In some regimens, number of cycles may vary depending on disease stage and/or early treatment response.

Abbreviations: BL, Burkitt lymphoma; MTX, methotrexate; BFM, Berlin-Frankfurt-Muenster; GMALL, German Multicenter Study Group for Adult ALL; NCI/NIH, National Cancer Institute/National Institutes of Health; CALGB, Cancer and Leukemia Group B; NILG, Northern Italy Leukemia Group; PETHEMA, Programa Español de Tratamientos en Hematologia.

Table 4 Age-related treatment results in BL with or without rituximab-based regimens

Study	Chemotherapy regimen	Patient number	Age (median age range), years	CR rate, n (%)	OS, % (years)	EFS/PFS, % (years)
Mead et al^Citation99	CODOX-M/IVAC	52	35 (15–60)	39 (75)	73 (2)	65 (2)
			<21 (n=9)			<30: 73 (1)
			21–30 (n=10)			30–49: 71
			31–40 (n=11) 41–50 (n=8) >50 (n=14)			>50: 50
Diviné et al^Citation100	French pediatric	72	33 (18–76)	53 (74)	70 (2)	65 (2)
	LMB		<33 (n=37)		84 (2)
			>33 (n=35)		60
Todeschini et al^Citation101	POG 8617	71		56 (79)		79 (8)
			<15 (n=25)	23 (92)		92
			15–40 (n=24)	18 (75)		75
			>40 (n=22)	15 (68)		68
Hoelzer et al^Citation83	GMALL-B ALL/NHL 2002	363	42 (16–85)	319 (88)	80 (5)	71 (5)
			15–25 (n=69)	15–55: 237/265 (89)	15–25: 90 (5)	<55: 82 (5)
			26–55 (n=196)	>55: 82/98 (84)	26–55: 84	>55: 60
			>55 (n=98)		>55: 62
Ribrag et al^Citation98	R-LMB protocol (±rituximab; phase III)	260	47
		Rituximab: 128			88 (3)	75 (3)
		No rituximab: 129			70	62
			<40 (n=101)		78 (3)	86 (3)
			40–60 (n=98)		69	77
			>60 (n=58)		52	61

Abbreviations: BL, Burkitt lymphoma; CR, complete response; OS, overall survival; EFS, event-free survival; PFS, progression-free survival.

Table 5 Critical issues and steps to optimize the initial management of BL

Criticisms	Implications	Prevention and/or management
Late diagnosis and referral	Extensive/bulky disease Organ involvement/damage (liver, kidney, CNS, gastrointestinal tract) Poorer performance status Reduced treatment compliance	Avoid any diagnostic delay and referral to qualified treatment center
Tumor lysis syndrome	Phosphate shower with cardiac dysrhythmia Acidosis Acute renal failure/tubular necrosis Risk of hemodialysis Reduced treatment compliance (no MTX), treatment delay	Evaluation of metabolic disturbances and renal function; hydration with adequate urinary output; correction of electrolyte imbalance and acidosis; use of rasburicase and allopurinol to inhibit uric acid synthesis
Infections	Risk of pneumonia, abdominal infections, septic shock if severely neutropenic (Burkitt leukemia)	Antibiotic prophylaxis; G-CSF if neutropenic (neutrophils <0.5×10^9/l)
CNS involvement	CNS symptoms: cranial nerve palsies, mental neuropathy, headache/pain Association with extensive disease Higher risk of relapse if not recognized/treated	Early diagnostic lumbar puncture and repeated intrathecal therapy
Ascites/pleural effusion	Extensive abdominal disease Fluid overload Risk of pulmonary edema and heart failure	More precarious balance between hydration and diuretic therapy (similar as tumor lysis syndrome)
Surgery-related issues	BL not amenable to surgical debulking for organ infiltration/adhesions Gastrointestinal perforation, enterocutaneous fistula, bowel obstruction	Quick start of chemotherapy to reduce BL size and reset organ function; local surgery when indicated/possible after start of treatment
Poor performance/older (>55 years)/frail patients	Comorbidity Inability to engage in intensive chemotherapy Increased risk of kidney/heart damage and infections	Need to reduce chemo intensity; SC-EPOCH-RR may be preferable
HIV+ patients	Higher risk of infections Overall prognosis tendentially worse	SC-EPOCH-RR may be preferable; association with HAART needed

Abbreviations: BL, Burkitt lymphoma; CNS, central nervous system; MTX, methotrexate; G-CSF, granulocyte colony-stimulating factor; HAART, highly active antiretroviral therapy.

FenauxPLaiJLMiauxOZandeckiMJouetJPBautersFBurkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 casesBr J Haematol19897133713762930722

 PubMed Web of Science ®Google Scholar

PeesHWRadtkeHSchwambornJGrafNThe BMF-protocol for HIV-negative Burkitt’s lymphomas and L3 ALL in adult patients: a high chance for cureAnn Hematol19926552012051457577

 PubMed Web of Science ®Google Scholar

SoussainCPatteCOstronoffMSmall noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the LMB pediatric protocolsBlood19958536646747833470

 PubMed Web of Science ®Google Scholar

HoelzerDLudwigWDThielEImproved outcome in adult B-cell acute lymphoblastic leukemiaBlood19968724955088555471

 PubMed Web of Science ®Google Scholar

MagrathIAddeMShadAAdults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimenJ Clin Oncol19961439259348622041

 PubMed Web of Science ®Google Scholar

ThomasDACortesJO’brienSHyper-CVAD program in Burkitt’s-type adult acute lymphoblastic leukemiaJ Clin Oncol19991782461247010561310

 PubMed Web of Science ®Google Scholar

RizzieriDAJohnsonJLNiedzwieckiDIntensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251Cancer200410071438144815042678

 PubMed Web of Science ®Google Scholar

LacasceAHowardOLibSModified Magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicityLeuk Lymphoma200445476176715160953

 PubMed Web of Science ®Google Scholar

SmelandSBlystadAKKvaloySOTreatment of Burkitt’s/Burkitt-like lymphoma in adolescents and adults: a 20-year experience from the Norwegian Radium Hospital with the use of three successive regimensAnn Oncol20041571072107815205201

 PubMed Web of Science ®Google Scholar

Di NicolaMCarlo-StellaCMariottiJHigh response rate and manageable toxicity with an intensive, short term chemotherapy programme for Burkitt’s lymphoma in adultsBr J Haematol2004126681582015352985

 PubMed Web of Science ®Google Scholar

TauroSCochraneLLauritzsenGFDose-intensified treatment of Burkitt lymphoma and B-cell lymphoma unclassifiable, (with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) in young adults (<50 years): a comparison of two adapted BFM protocolsAm J Hematol201085426126320201088

 PubMed Web of Science ®Google Scholar

BurkittDO’ConorGTMalignant lymphoma in African children. I. A clinical syndromeCancer19611425826914448554

 PubMed Web of Science ®Google Scholar

MagrathIJaffeESBhatiaKBurkitt’s lymphomaKnowlesDMNeoplastic HematopathologyPhiladelphia, PALippincott Williams & Wilkins2001953986

 Google Scholar

ThomasDAFaderlSO’BrienSChemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemiaCancer200610671569158016502413

 PubMed Web of Science ®Google Scholar

KujawskiLALongoWLWilliamsECA 5-drug regimen maxi-mizing the dose of cyclophosphamide is effective therapy for adult Burkitt or Burkitt-like lymphomasCancer Invest2007252879317453819

 PubMed Web of Science ®Google Scholar

MeadGMBarransSLQianWA prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial)Blood200811262248226018612102

 PubMed Web of Science ®Google Scholar

ChoiMKJunHJLeeSYTreatment outcome of adult patients with Burkitt lymphoma: results using the LMB protocol in KoreaAnn Hematol200988111099110619288103

 PubMed Web of Science ®Google Scholar

BarnesJALacasceASFengYEvaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt’s lymphoma: a retrospective analysisAnn Oncol20112281859186421339382

 PubMed Web of Science ®Google Scholar

CorazzelliGFrigeriFRussoFRDCODOX-M/IVAC with rituximab and intrathecal liposomal cytarabine in adult Burkitt lymphoma and ‘unclassifiable’ highly aggressive B-cell lymphomaBr J Haematol2012156223424422098541

 PubMed Web of Science ®Google Scholar

KasamonYLBrodskyRABorowitzMJBrief intensive therapy for older adults with newly diagnosed Burkitt or atypical Burkitt lymphoma/leukemiaLeuk Lymphoma201354348349022835045

 PubMed Web of Science ®Google Scholar

RiberaJMGarcíaOGrandeCDose-intensive chemotherapy including rituximab in Burkitt’s leukemia or lymphoma regardless of human immunodeficiency virus infection status: final results of phase 2 study (Burkimab)Cancer201311991660166823361927

 PubMed Web of Science ®Google Scholar

DunleavyKPittalugaSShovlinMLow-intensity therapy in adults with Burkitt’s lymphomaN Engl J Med2013369201915192524224624

 PubMed Web of Science ®Google Scholar

IntermesoliTRambaldiRRossiGHigh cure rates in Burkitt lymphoma and leukemia: Northern Italy Leukemia Group study of the German short intensive rituximab-chemotherapy programHaematologica201398111718172523753030

 PubMed Web of Science ®Google Scholar

JainPKantarjianHMCortesJELong term follow-up of de novo or minimally treated Burkitt lymphoma/leukemia (BL/B-ALL) after frontline therapy per the hyper-CVAD regimen with or without rituximab: 20-year cumulative experienceBlood20131223917

 Google Scholar

RizzieriDAJohnsonJLByrdJCImproved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia Group B study 10 002Br J Haematol2014165110211124428673

 PubMed Web of Science ®Google Scholar

HongJKimSJAhnJSTreatment outcomes of rituximab plus hyper-CVAD in Korean patients with sporadic Burkitt or Burkitt-like lymphoma: results of a multicenter analysisCancer Res Treat201547217318125544581

 PubMed Web of Science ®Google Scholar

RibragVKoscielnySBosqJRituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: a randomised, controlled, open-label, phase 3 trialLancet2016387100362402241127080498

 PubMed Web of Science ®Google Scholar

DivinéMCasassusPKoscielnySBurkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocolAnn Oncol200516121928193516284057

 PubMed Web of Science ®Google Scholar

MeadGMSydesMRWalewskiJAn international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 studyAnn Oncol20021381264127412181251

 PubMed Web of Science ®Google Scholar

TodeschiniGBonifacioMTecchioCIntensive short-term chemotherapy regimen induces high remission rate (over 90%) and event-free survival both in children and adult patients with advanced sporadic Burkitt lymphoma/leukemiaAm J Hematol2012871222522086870

 PubMed Web of Science ®Google Scholar

HoelzerDWalewskiJDöhnerHImproved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trialBlood2014124263870387925359988

 PubMed Web of Science ®Google Scholar