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Keywords:

  • Burkitt lymphoma;
  • Magrath regimen;
  • rituximab;
  • CNS prophylaxis;
  • liposomal cytarabine

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Specific trials on adult Burkitt lymphoma (BL) and ‘unclassifiable’ lymphomas with features intermediate between BL and diffuse large B-cell lymphoma (BL/DLBCL) are advocated which include substantial numbers of older patients, to improve treatment feasibility, while countering risks of systemic and central nervous system (CNS) recurrences. We prospectively evaluated a modified CODOX-M/IVAC (CODOX-M: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate; IVAC: ifosfamide, etoposide and high-dose cytarabine) regimen by the addition of rituximab (R) and liposome-encapsulated cytarabine (D) to increase antitumour activity and halve the number of intrathecal treatments. Thirty adults (40% >60 years) with BL (n = 15) and BL/DLBCL (n = 15) were accrued. Primary endpoints were progression-free survival (PFS), CNS recurrence, and liposomal cytarabine-associated toxicity. Eighty percent of patients received the whole treatment programme, the remaining cases received at least three full courses. Application of the RD-CODOX-M/IVAC regimen resulted in remarkable 4-year PFS (78%) and complete remission (CR) rates (93%). However, PFS was significantly lower in patients older than 60 years as compared to younger ones (49%vs 93%, = 0·03; median, 36 months), despite high actual dose-intensity, CR rate and tolerability. Reduced-intensity intratechal prophylaxis through liposomal cytarabine was effective because the CNS failure rate was low (3·4%) and without severe neurological toxicities. The RD-CODOX-M/IVAC strategy is feasible and highly effective, but improving outcomes in elderly patients remains a priority.

Highly aggressive mature B-cell neoplasms in adults encompass classical Burkitt lymphoma (BL) and a number of hybrid malignancies representing a continuum between well-defined clinicopathological extremes, such as BL and diffuse large B-cell lymphoma (DLBCL). Most of these tumours, formerly defined as atypical BL (aBL) or Burkitt-like lymphoma (BLL), are now listed in the updated 2008 World Health Organization (WHO) classification as ‘lymphoma unclassifiable with features intermediate between BL and DLBCL’ (BL/DLBCL) (Jaffe et al, 2001; Leoncini et al, 2005; Swerdlow et al, 2008) and are under active review for underlying genetic and molecular heterogeneity (Salaverria & Siebert, 2011). The current management of such malignancies relies on sparse trial-based evidence, mainly due to the very low incidence of these lymphomas and to the heterogeneous categorizations through subsequent histological classification systems (Perkins & Friedberg, 2008). The outcome of these diseases has been reported to be generally poor after treatment with front-line regimens specifically designed for DLBCL (Dave et al, 2006; Nomura et al, 2008; Smeland et al, 2004), whereas chances of cure up to 70% hinge upon the use of more intense and rapidly recycling multi-agent chemotherapy, coupled with aggressive intrathecal (IT) and systemic prophylaxis for central nervous system (CNS) disease (Blum et al, 2004; Hoelzer, 2009; Kasamon & Swinnen, 2004; Nomura et al, 2008). This strategy, borrowed from paediatric literature, is aimed at countering rapid tumour regrowth/spreading between chemotherapy courses, avoiding early emergence of chemoresistant clones, and preventing the risk, which is expected to be high, for CNS (predominantly leptomeninges) involvement (12–17%) and recurrence (6–11% and 30–50%, with and without IT chemoprophylaxis, respectively) (Bernstein et al, 1986; Hill & Owen, 2006; Magrath et al, 1984; Sariban et al, 1983). Recent studies suggest that this approach can be implemented by targeting the strong expression of the B-cell lineage restricted marker, CD20, on tumour cells of BL and BL/DLBCL, and have reported promising results by the addition of the monoclonal anti-CD20 antibody rituximab to an abbreviated-intensive regimen in human immunodeficiency virus (HIV)-positive adults and patients older than 60 years of age (Oriol et al, 2008; Thomas et al, 2006). If confirmed, this would represent a major advance given that elderly patients, under-represented in most trials despite accounting for about 30% of newly diagnosed cases, have a dismal prognosis and represent an ongoing therapeutic challenge (Kasamon & Swinnen, 2004; Kelly et al, 2009; Perkins & Friedberg, 2008).

One highly effective program, CODOX-M/IVAC [CODOX-M: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (MTX); IVAC: ifosfamide, etoposide and high-dose cytarabine], was pioneered in children and young adult patients with BL and BLL at the National Cancer Institute (Magrath et al, 1996). Modified versions were subsequently developed for older patients to ensure a safer toxicity profile while maintaining the original alternating sequence of CODOX-M and IVAC courses with fractionated schedule of alkylators, high-dose CNS-penetrating agents, and IT cytarabine/MTX injections for CNS prophylaxis (Lacasce et al, 2004; Mead et al, 2008, 2002). This latter CNS-directed programme has been regarded as a critical component of the strategy against these tumours because, when given only as high-dose intravenous (iv) load, cytarabine and MTX were unable to abrogate completely the risk of early leptomeningeal recurrences (Jabbour et al, 2005; Magrath et al, 1984). However, since cytarabine and MTX are cell-cycle S-phase-specific agents with short terminal half-lives (3·4 and 4·5 h, respectively), repeated IT courses are needed, 8–11 for CODOX-M/IVAC (Magrath et al, 1996) and 10–16 for other treatment platforms (Divine et al, 2005; Thomas et al, 1999), to warrant sustained cytotoxic concentrations in the cerebrospinal fluid (CSF) (Fleischhack et al, 2005; Shapiro et al, 1975). A suitable alternative therapy to such a high number of IT injections, which are cumbersome for patients and increase risks of procedural complications (DeAngelis, 1998; Jabbour et al, 2005), can be exemplified by liposome-encapsulated cytarabine. This agent has shown sustained cytotoxic concentrations in the CSF, up to 10–14 d following a single IT injection (Kim et al, 1993; Rueda Dominguez et al, 2005), and more activity than native cytarabine and MTX (Cole et al, 2003; Glantz et al, 1999).

This prospective study evaluated the feasibility and efficacy of CODOX-M/IVAC plus rituximab (R) and liposomal cytarabine (D) (RD-CODOX-M/IVAC), a modified version of the Magrath regimen (Magrath et al, 1996), in adult patients with BL and BL/DLBCL. It was designed to increase tolerability in older individuals, contained rituximab (R) to foster antitumour activity and included liposomal cytarabine (D) to halve the load of IT therapy.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Patient selection

This independent Phase II study was approved by local Institutional Treatment Review Boards and conducted according to the Good Clinical Practice guidelines and the Declaration of Helsinki. All patients gave written informed consent to treatment and use of clinical data for research. Consecutive patients referred to our centres between May 2005 and August 2009 after histological diagnosis of classic or borderline/atypical BL, were prospectively accrued. Histological (re)evaluations were conducted by two experienced haematopathologists. Tumours with characteristic morphology and phenotype (CD20+ CD10+, CD43+, IRF4/MUM-1, CD5, TdT-, Bcl-6, Bcl-2−/+), a high Ki-67 proliferation index (PI ≥95% of tumour cells), and MYC translocation involving the immunoglobulin chain loci (IGH@-MYC fusion) were classified as classical BL. In Bcl2+ cases the absence of BCL2 translocation was required. All tumours referred as borderline/atypical BL, having highly proliferative activity (PI ≥95%) with Burkitt-like morphology and deviant immunophenotype, i.e. aBL/BLL according to the 2001 WHO classification (Jaffe et al, 2001), were reappraised according to the revised 2008 WHO classification criteria (Swerdlow et al, 2008) and categorized as BL/DLBCL upon detection of CD20+, CD10+, CD43+/−, IRF4/MUM-1−/+, CD5, Bcl-2+/−, Bcl-6+ in concomitance with BCL6 negativity, with or without BCL2 and/or IGH@-MYC translocation(s) (Leoncini et al, 2005; Swerdlow et al, 2008). Fluorescence in situ hybridization (FISH) was performed through LSI IGH/MYC, CEP 8 Tri-colour fusion probe 14q32/8q24, LSI MYC Dual Colour Break Apart, LSI IGH/BCL2 dual-colour, dual-fusion translocation systems and BCL6 (ABR) Dual Colour Break Apart Rearrangement Probe (Vysis, Abbott Molecular, Rome, Italy), as previously described (Franco et al, 2006). G-banding karyotype analyses were not carried out. Eligible patients were ≥16 years and HIV-negative. There was no restriction by performance status (PS), age, or organ dysfunction.

Pre-treatment investigations

All patients underwent staging (Ann Arbor system), clinical assessment, neurological examinations, complete blood cell counts, biochemical profiling, bone marrow biopsy, chest X-ray, whole body computer assisted tomography and 18F-fluoro-deoxy-glucose positron emission tomography (PET). CNS disease was evaluated concurrently with CNS prophylaxis (Day 1/2 of the first course). The CSF was assessed by cell count and differential cytology. Magnetic resonance imaging of the head and axial skeleton was performed for neurological symptoms and/or a positive CSF cytology. Low-risk patients had: normal lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group PS (ECOG PS) <2, stage I or II disease, <2 extranodal sites, and no bulky tumour mass (≥10 cm). All remaining patients were considered high risk (Mead et al, 2002).

Treatment plan

The RD-CODOX-M/IVAC programme and schedule are detailed in Fig 1. The schedule was devised for adult and elderly patients and differed from the original Magrath regimen (Magrath et al, 1996) by the addition of rituximab, the capping of vincristine at 2 mg total dose on Days 1 and 8 and its omission on Day 15, the decrease of iv methotrexate from 6·7 to 3 g/m2, the increase of doxorubicin to 50 mg/m2, a predefined dose-reduction of iv cytarabine, methotrexate and ifosfamide for patients aged >60 years, and the substitution of the planned eight alternating IT injections of cytarabine and methotrexate with one administration of IT liposomal cytarabine per course of chemotherapy with two additional IT injections in case of CNS involvement. The programme comprised four cycles of alternating courses of RD-CODOX-M (courses 1 and 3) and RD-IVAC (courses 2 and 4), regardless of risk group. All BL/DLBCL patients received two additional R-CODOX courses (5 and 6) without liposomal cytarabine, high-dose MTX and day 8 vincristine. Primary prophylaxis with subcutaneous granulocyte colony-stimulating factor (G-CSF) was mandatory in all patients from day +10 (RD-CODOX-M) and day +6 (RD-IVAC) until the absolute neutrophil count (ANC) was >1 × 109/l. Liposomal cytarabine (Depocyte®) was purchased from Mundipharma s.r.l. (Milan, Italy) and administered via lumbar puncture by first withdrawing 6·0 ml of CSF and then sequentially introducing 5·0 ml of Depocyte solution and 1·0 ml of dexamethasone solution (4·0 mg) prepared in separate syringes; patients were maintained at bed rest for 4–5 h with concurrent iv administration of 500 ml normal saline solution, followed by two further doses (4 mg) of iv dexamethasone at 12-h intervals. The first course was accompanied by iv hydration and alkalinization (dextrose water or half normal saline with 75–100 mmol/l sodium acetate/l at 50–100 ml/h) and rasburicase. Oral sodium bicarbonate supplemented the iv formulation on Days 1–3. From cycle 2 onwards, an ANC >1 × 109/l (after discontinuing G-CSF ≥24 h) and platelet count >75 × 109/l were required to begin the next cycle. Dose reduction guidelines included: (i) a cytarabine decrease to 1 g/m2 for age ≥60 years, creatinine 176·8 μmol/l, or MTX levels >20 × 10−6 M at 0 h, (ii) vincristine reduction to 1 mg for total bilirubin >34·2 μmol/l, or elimination if total bilirubin >51·3 μmol/l, or for Grade 3–4 peripheral neuropathy, or ileus, (iii) decrease doxorubicin 50% for bilirubin 34·2–51·3 μmol/l; by 75% for bilirubin 51·3–85·5 μmol/l; or eliminate doxorubicin if bilirubin >85·5 μmol/l, and (iv) decrease MTX to 1 g/m2 for age ≥60 years; by 25–50% for delayed excretion, nephrotoxicity, or ≥Grade 3 mucositis; or by 50% for creatinine clearance 10–50 ml/min. All patients were provided with trimethoprim-sulfamethoxazole as prophylaxis against Pneumocystis spp. Febrile neutropenia was managed by hospitalization.

image

Figure 1.  Protocol planning and daily RD-CODOX-M/IVACschedule. All patients received alternating courses of RD-CODOX-M and RD-IVAC for four total cycles, irrespective of risk. Patients with BL/DLBCL received two additional courses of R-CODOX, i.e. the same as the RD-CODOX-M cycle deprived of Depocyte (liposomal cytarabine) and Day 8 methotrexate/vincristine.

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Comparison with historical CODOX-M/IVAC cohort

RD-CODOX-M/IVAC was compared with a historical cohort of 20 consecutive patients treated with standard CODOX-M/IVAC (Magrath et al, 1996) and enrolled earlier, between September 1997 and April 2005. As for the study group, no patients in the historical cohort were excluded from analysis because of consent refusal or data unavailability. Diagnostic procedures, response criteria and follow-up modalities were equal to those employed for the study group.

At the time of data collection nine of these cases were classified as having classical BL based on the typical monomorphic morphology, immunophenotypic and genetic profile (Jaffe et al, 2001). An additional 11 cases were diagnosed as BLL due to a more pleomorphic morphology, a BL-concordant immunophenotype (CD20+, CD10+, Bcl-2, CD5, TdT) and a PI ≥95% (Jaffe et al, 2001). Material for molecular revision was available in five of these latter cases and an IGH@-MYC translocation was disclosed in three of them. ‘Low-risk’ patients received 3 CODOX-M cycles; ‘high-risk’ patients received four alternating cycles of CODOX-M and IVAC. The control cohort received higher systemic iv MTX doses (6720 vs. 3000 mg/m2) and lower adriamycin doses (40 vs. 50 mg/m2) than the study group. All patients >60 years received MTX and cytarabine at 1 g/m2, and ≤2 mg vincristine. Urate oxidase was used in the first cycle. G-CSF was available in each cycle.

Study endpoints and statistics

Primary study endpoints were progression-free survival (PFS), CNS failure rate and liposomal cytarabine toxicity. PFS was defined as the interval from starting chemotherapy to first appearance of progressive disease, treatment discontinuation/death from any cause, or to last follow-up date without any event. CNS failure was defined as any relapse/progression with CNS, leptomeningeal and/or parenchymal involvement and evaluated using cumulative incidence curve. Toxicity was evaluated by National Cancer Institute Expanded Common Toxicity Criteria, v3·0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3). Secondary endpoints were complete response (CR), overall (OS) and disease-free survival (DFS). A CR was defined as the complete disappearance of all known disease, clinically and at both radiological and functional PET imaging. OS was calculated from the first day of chemotherapy to death due to any cause, or to date of last follow-up contact for patients who were alive. DFS was calculated for patients having achieved CR, from the day of documented CR to death due to any cause, recurrence, or to date of last follow-up. All enrolled patients were evaluable and results were analysed on an intention-to-treat-basis. Outcomes were compared at 4 years (control patients censored at 60-month follow-up). Plotted actuarial Kaplan–Meier curves were evaluated by Mantel-Haenszel log-rank test. Categorical variables were compared by two-sided Fisher exact test. All P-values were two-sided and statistics were analysed by SPSS v14·0 software (Chicago, IL, USA).

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Patient characteristics

Thirty patients (BL, n = 15; BL/DLBCL, n = 15), of median age 52 years, received RD-CODOX-M/IVAC. An IGH@-MYC rearrangement was found in 13 of 15 (87%) BL cases and in 9 of 15 (60%) BL/DLBCL cases, while an additional patient in this latter group bore concurrent MYC and BCL2 rearrangements. Clinical characteristics at presentation showed no significant differences between the study group and the historical control cohort (Table I), with the only exception of more bulky disease in the control cohort (80 vs. 40%). Two patients (7%; 1 with BL and 1 with BL/DLBCL) receiving RD-CODOX-M/IVAC had cytologically documented CNS involvement (limited to CSF: 130 and 280 lymphoma cells/μl). In the control group, initial CNS involvement was present in two patients as spinal cord compression.

Table I.   Patient characteristics for study and historical groups.
CharacteristicsRD-CODOX-M/IVACCODOX-M/IVAC
N%N%
  1. BL, Burkitt lymphoma; BL/DLBCL, lymphoma unclassifiable with features intermediate between BL and diffuse large B-cell lymphoma; ECOG PS, Eastern cooperative Oncology Group performance status; ULN, upper limit of normal range.

  2. *Low risk (LR) if all of the following features were present: normal lactate dehydrogenase, ECOG PS <2, stage I or II, extranodal sites <2, no bulky tumour mass (≥10 cm); all remaining patients were considered to be high risk.

Total3010020100
Age, median (range), years52 (25–77) 50 (20–83) 
≥60 years1240945
Male gender21701155
Histology
 BL1550945
 BL/DLBCL15 11 
ECOG PS
 0–112 7 
 214 8 
 34 5 
Stage
 III–IV21701680
Lactate dehydrogenase >ULN17571575
No of extranodal sites
 08 4 
 110 9 
 ≥21240735
Bulky tumour (>10 cm)12401680
Bone marrow involvement620420
CNS involvement27210
Low risk*620525

Treatment delivery

Twelve of 15 BL patients (80%) received 4 cycles of RD-CODOX-M/IVAC. Due to initial diagnostic uncertainty, three patients initially received one course of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone)-like regimen, before 3 cycles of RD-IVAC, RD-CODOX-M, RD-IVAC. Similarly, 12 of 15 (80%) BL/DLBCL patients received four courses of RD-CODOX-M/IVAC; of the remaining three patients, 2 (13·3%) skipped the last RD-IVAC course due to persisting severe haematological toxicity, one received 4 R-CODOX courses, with high-dose MTX given only in the first two cycles. Five RD-CODOX-M/IVAC patients had a 50–75% MTX dose reduction due to reduced creatinine clearance.

According to protocol plan, 11 (73%) BL/DLBCL patients had two extra R-CODOX courses. For patients who received the complete alternating RD-CODOX-M/IVAC four course sequence, the median interval was 22·5 d between cycles 1 and 2 (range 15–39 d), and 25 d between cycles 3 and 4 (range 13–33 d). Overall, 117 IT liposomal cytarabine (50 mg) injections were administered during 143 cycles of chemotherapy (median: 4 IT injections/patient). Both patients with CNS involvement received 6 IT injections, according to protocol. IT injections were delivered during the first 4 cycles at a median day of 0 (range –1 to +2) for R-CODOX-M1 (cycle 1), 4·0 (range –2 to +17) for RD-IVAC1 (cycle 2), 1 (range –4 to +6) for R-CODOX-M2 (cycle 3) and 5·0 (range –3 to +14) for RD-IVAC2 (cycle 4).

Efficacy: primary endpoints

More patients were progression-free at 4 years in the RD-CODOX-M/IVAC group than in the control cohort (78 vs. 55%, = 0·036) (Table II; Fig 2A). In each group of treatment, PFS outcomes showed no significant differences between BL and BL/DLBCL. However, BL/DLBCL patients treated with RD-CODOX-M/IVAC had a better PFS outcome than controls (65 vs. 37%; = 0·05; Table II; Fig 2A). Study patients ≥60 years had a significantly worse PFS outcome than those <60 years (49 vs. 93%; = 0·03; Table II; Fig 3B). The PFS outcomes of patients ≥60 years were not significantly different for control and study groups (50 vs. 49%; median 33 vs. 36 months). Four-year PFS outcomes showed no significant difference for high- and low-risk study patients. All low-risk patients had CRs and were alive at 37 months follow-up. The presence of bulky disease did not affect PFS outcome in each treatment group according to univariate analysis (= 0·44).

Table II.   Outcome by histology and age for study and historical groups.
OutcomeOverallHistologyAge
N (%)N (%)P-valueN (%)P-value
BLBL/DLBCL<60 years≥ 60 years
  1. BL, Burkitt lymphoma; BL/DLBCL, lymphoma unclassifiable with features intermediate between BL and diffuse large B-cell lymphoma; CR, complete remission; PD, progression of disease; ED, early death; PFS, progression-free survival; CI, confidence interval.

RD-CODOX-M/IVAC
 Total301515 1812 
 CR28 (93)15 (100)13 (87)0·4818 (100)10 (83)0·15
 PD2 2  2 
 ED       
 Relapse312 12 
 4-year PFS, % (95% CI)/median78% (60–96)92% (77–100)65% (33–97)0·1693% (86–100)49% (median PFS, 36)0·03
CODOX-M/IVAC
 Total20911 119 
 CR14 (70)8 (89)6 (55)0·159 (82)5 (56)0·34
 PD4 (20)13 22 
 ED2 (10) 2  2 
 Relapse312 3  
 4-year PFS, % (95% CI)/median55% (34–77)78% (56–100)37% (9–66)0·0960% (20–90)50% (median PFS, 33)0·46
image

Figure 2.  Kaplan-Meier Curves. (A) Overall progression-free survival in RD-CODOX-M/IVAC group and CODOX-M/IVAC historical control cohort (= 0·036); (B) Cumulative risk of central nervous system (CNS) recurrence in the RD-CODOX-M/IVAC group and the CODOX-M/IVAC historical control cohort (= 0·29).

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image

Figure 3.  Progression-free survival in the RD-CODOX-M/IVAC group according to (A) Histology (BL vs BL/DLBCL) and (B) Age (<60 vs. ≥60 years).

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The CNS recurrence rate was not significantly different in the RD-CODOX-M/IVAC study group and control cohort (3·4 vs. 11·1%; = 0·29; Fig 2B). None of patients with a CR in the RD-CODOX-M/IVAC group had an isolated leptomeningeal or parenchymal CNS relapse. The two initial cases of CSF involvement resolved after 2 cycles of RD-CODOX-M/IVAC without leptomeningeal and/or parenchymal recurrence at the longest follow up (>41 months). One case of parenchymal CNS progression (corpus callosum) occurred in a 61-year old high-risk male with primary chemorefractory BL/DLBCL who did not have a CR. He missed the first IT application of liposomal cytarabine due to poor PS and missed the first course of systemic high-dose MTX due to early myelotoxicity.

Efficacy: secondary endpoints

The CR rate was higher in the RD-CODOX-M/IVAC group than in the control cohort (93 vs.70%, = 0·047). Three patients with a CR in the RD-CODOX-M/IVAC group had a systemic relapse at 10, 17 and 36 months. Lymphoma histology (BL vs. intermediate BL/DLBCL) and age had no significant effect on the CR rate in each group (Table II). Induction mortality was higher in the control cohort, where two elderly BL/DLBCL patients (aged: 70, 71 years) died in the 4th and 12th weeks of treatment, due to acute renal failure (tumour lysis syndrome) and acute respiratory failure (agranulocytosis), respectively. Actuarial OS was 82% (95% confidence interval [CI]: 65–99) and DFS 84% (95% CI: 69–99) in the RD-CODOX-M/IVAC group, with 25 patients alive and disease-free at 36 months follow-up. Four patients died of lymphoma at 3, 10, 12 and 40 months. An intermediate BL/DLBCL patient, relapsing at 17 months was rescued with R-GIFOX (gemcitabine, ifosfamide, oxaliplatin, rituximab) and autologous stem cell transplant. He was still alive at the last follow up (41 months) (Corazzelli et al, 2006).

Toxicity: primary endpoint

All liposomal cytarabine-associated adverse events occurred in the same group of 13 patients (43%) in the RD-CODOX-M/IVAC group (Fig 4A). There were no severe and/or life-threatening/invalidating neurotoxicities. Headache (n = 7 Grade 1/2; n = 1, Grade 3; 26%), fatigue (n = 9 Grade 1/2; 30%) and lumbar pain (n = 5; 17%; Fig 4B) were common. Three patients (30%) had moderate fever. The single recorded case of Grade 3 headache lasted 36 h, was exacerbated by movement, accompanied by transient (24 h) blurred vision, and was responsive only to morphine chloridrate.

image

Figure 4.  Liposomal cytarabine-associated toxicity: distribution by (A) patient and (B) adverse event.

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Toxicity associated with chemotherapy

The RD-CODOX-M/IVAC group received 143 courses of chemotherapy. As expected, Grade 3–4 myelosuppression was universal; and febrile neutropenia was common (45%), with a 23% incidence of infection. There was one case of Clostridium difficile-associated enteritis. Four patients developed Herpes zoster virus infection 3–10 months after completing RD-CODOX-M/IVAC (n = 1 severe, disseminated). There were no invasive fungal infections and no cases of induction mortality.

Sixteen (53%; 95% CI: 35·5–71·2) patients had severe (Grade 3–4) gastrointestinal toxicities. One developed cholestatic hepatitis, which resolved upon withdrawal of antibiotics/chemotherapy. Transient transaminitis was frequent, but only three patients had Grade 4 events. No tumour lysis occurred in the first course of treatment, but 5 patients had creatinine increases >2 times upper limit of normal after MTX. Neurotoxicity was mainly Grade 1–2 vincristine-related paraesthesia. However, one elderly patient had transient hallucinations and disorientation during the seconds RD-IVAC cycle. One patient had Grade 3 sensory-motor neuropathy. Cardiac toxicity was acceptable with two episodes of atrial arrhythmia (acute illness), and one patient suffered syncopal episodes due to supraventricular tachyarrhythmia.

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References

In this prospective study, RD-CODOX-M/IVAC showed higher CR and 4-year PFS rates in BL and BL/DLBCL patients as compared with standard CODOX-M/IVAC (Magrath protocol, Magrath et al, 1996). Also, a less demanding injection schedule with liposomal cytarabine safely replaced the traditional ‘double agent’ cytarabine/MTX IT prophylaxis. Comparison with the historical group was limited by small patient numbers and by the lack of an appropriate summary score estimation to simultaneously control for multiple confounders. It is of note, however, that the two groups showed a substantial overlap due to consecutive accrual, no patients were excluded from evaluation, identical eligibility criteria, comparable distribution of the principal ‘observed’ variables, uniform modalities for diagnosis, response assessment and follow up as well as analogous supportive care.

Despite the study group having over one-third of patients older than age 60 years and median age two-fold higher than Magrath’s original study population (Magrath et al, 1996), 80% of patients completed the full four cycles of RD-CODOX-M/IVAC, without unacceptable toxicity or treatment-related deaths. These results compared favourably with the two baseline prospective, international multicentre Phase II trials, UK Lymphoma Group trial LY06 and Medical Research Council/National Cancer Research Institute trial LY10, which were conducted in a much younger patient population and wherein adapted-CODOX-M/IVAC programmes were completed by 43% and 73% of patients, respectively (Mead et al, 2008, 2002).

RD-CODOX-M/IVAC yielded a 4-year OS rate of 82%, which is superior to the survival rates (67–73% at 2 years) reported for modified-Magrath protocols, not including rituximab (Lacasce et al, 2004; Mead et al, 2008, 2002), as well as to OS rates observed for other well-known short, multiagent, cyclical intensive regimens at 2 years (70%)(Divine et al, 2005) and at 3–4 years (49–54%) (Hoelzer et al, 1996; Rizzieri et al, 2004; Thomas et al, 1999).

This is the first prospective study exploring the activity of CODOX-M/IVAC plus rituximab, but some retrospective data on this combination are available from two small and inhomogeneous series of patients, though not so large nor homogeneous, from Japan (15 patients, nine receiving rituximab: 3 BL and 6 BL/DLBCL) (Maruyama et al, 2010) and the UK (23 patients: 14 BL, 5 BL/DLBCL, 4 DLBCL) (Mohamedbhai et al, 2011). A further retrospective analysis was recently reported by US investigators (Barnes et al, 2011). The addition of rituximab to implement abbreviated intensive regimens for BL and BL/DLBCL has been explored in few other prospective trials, mostly published only in abstract form. Results from these studies are depicted in Table III: CR rates of 80–90% seem regularly attainable as well as survivals approaching 80% in the absence of late relapses beyond 2 years. RD-CODOX-M/IVAC is aligned to these performances, for example those achieved in a comparable series of 31 adult patients, one third of whom were older than 60 years, treated at M.D. Anderson Cancer Center with Rituximab plus Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) alternating with methotrexate and cytarabine (Thomas et al, 2006). The proportions of CR rate and 3-years OS and DFS were comparable between RD-CODOX-M/IVAC (CR 93%, OS 82%, DFS 84%) and R-Hyper-CVAD (CR 86%, OS 89%, DFS 88%) (Thomas et al, 2006). Nevertheless, differently from R-Hyper-CVAD (Thomas et al, 2006), but similarly to the Cancer and Leukemia Group B (CALGB) 10002 study (Rizzieri et al, 2010) and to preliminary data from the Massachusetts General Hospital Cancer Center and Dana Farber Institute (Barnes et al, 2009), RD-CODOX-M/IVAC regimen did not specifically improve outcome in patients ≥60 years given that PFS and median survival overlapped with controls. These evidences are consistent with previous reports suggesting that highly aggressive mature B-cell malignancies may have a worse prognosis in the elderly despite adequate actual dose-intensity of treatment (Divine et al, 2005; Mead et al, 2008), with the majority of failures (73%) occurring due to inadequate disease control (i.e. progression within 6 months) rather than toxicity (Mead et al, 2008).

Table III.   Prospective studies of Rituximab plus intensive multiagent chemotherapy in adult patients with Burkitt or Burkitt-like lymphoma/leukaemia.
Study group (reference)ProtocolNo. PtsMedian age, years (range)CR, %TD, %DFS, %EFS, %OS, %
  1. CR, complete remission; TD, toxic death during induction; DFS, disease-free survival; EFS, event-free survival; OS, overall survival; MDACC, M.D. Anderson Cancer Center; R-Hyper-CVAD, rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate and cytarabine; PETHEMA, Programa para el Estudio de la Terapeutica en Hemopatıas Malignas; GMALL, German Multicentre Study Group for Adult ALL; B-ALL, mature B-cell ALL; NHL, non-Hodgkin lymphoma; HIV, human immunodeficiency virus; CALGB, Cancer and Leukemia Group B; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, rituximab; NCI, National Cancer Institute; RD-CODOX-M/IVAC, rituximab, liposomal cytarabine, cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate alternating with ifosfamide, etoposide, high-dose cytarabine.

  2. *Presented in abstract form only; –, not available or not reported.

MDACC (Thomas et al, 2006)R-Hyper-CVAD3146 (27–77)86088 at 3 years80 at 3 years89 at 3 years
Age < 60 years22   88 at 3 years76 at 3 years90 at 3 years
Age ≥ 60 years9   100 at 3 years89 at 3 years89 at 3 years
PETHEMA (Oriol et al, 2008)GMALL B-ALL/NHL 2002 (adapted)3636 (15–55)861390 at 2 years77 at 2 years
HIV negative17 88 93 at 2 years 82 at 2 years
HIV positive19 84 87 at 2 years 73 at 2 years
GMALL (Hoelzer, 2008)*GMALL B-ALL/NHL 200214636903 
Age < 55 years120     91 at 3 years
Age ≥ 55 years26     84 at 3 years
CALGB (Rizzieri et al, 2010)*CALGB 10002105−(19–79)828777 at 2 years79 at 2 years
Age < 60 years77    87 at 2 years 
Age ≥ 60 years28    67 at 2 years 
NCI (Dunleavy et al, 2011)*DA-EPOCH-R2935 (16–88)100097 at 4 years100 at 4 years
HIV negative19      
HIV positive10      
Present studyRD-CODOX-M/IVAC3052 (25–77)93084 at 4 years78 at 4 years82 at 4 years
Age < 60 years18    93 at 4 years 
Age ≥ 60 years12    49 at 4 years 

Albeit results from rituximab-containing regimens appear better than the former protocols without rituximab (Hoelzer et al, 1996; Rizzieri et al, 2004; Thomas et al, 1999), we believe that these nonrandomized and generally small-sized trials are difficult to interpret as they seem also to examine different patient populations. Some series include very large proportion of leukaemia patients (R-Hyper-CVAD) while others are devoid of patients with marrow involvement (DA-EPOCH-R), some included concomitantly HIV-infected patients (GMALL B-ALL/NHL 2002, DA-EPOCH-R) while others excluded them upfront (CALG 10002) or at analysis (R-Hyper-CVAD), some comprised only young patients (GMALL B-ALL/NHL 2002) others presented large proportions of elderly (CALGB 10002, R-Hyper-CVAD) (Table III). In such a context, evidentiary support for the addition of rituximab to current regimens does not seem plausible, as also suggested by a recent population-based study (Wasterlid et al, 2011). Determinants of improved results other than rituximab should be considered, such as enhanced supportive care and adaptation of historical treatment schedules to elderly or HIV-infected patients. Accordingly, the improved survival outcomes achieved, especially in the elderly, by R-Hyper-CVAD in comparison with Hyper-CVAD alone may have benefitted from protective environment and laminar air-flow room predisposed ‘per protocol’ for patients older than 60 years in case of grade 4 neutropenia after the first R-Hyper-CVAD course. This may have favoured R-Hyper-CVAD by zeroing the 33% infection-related induction mortality rate observed among elderly patients treated with Hyper-CVAD alone (Thomas et al, 1999, 2006). A further potential bias in the survival analysis favouring R-Hyper-CVAD may be claimed due to the high prevalence (85 vs. 45%) of patients with leukaemia (i.e., at worse prognosis) in the group treated without rituximab (Thomas et al, 2006). Likewise, in the case of RD-CODOX-M/IVAC, two factors other than rituximab may have contributed to the overall effectiveness of the strategy.

Firstly, patients with BL/DLBCL received ‘per protocol’ two additional courses of R-CODOX. This may have contributed to achieving outcome similar to BL and a PFS rate significantly higher than the historical cohort. As their disease is deemed biologically intermediate between BL and DLBCL, patients with BL/DLBCL may have benefitted from more protracted treatment and higher load of anthracycline and rituximab.

Secondly, the full planned RD-CODOX-M/IVAC programme was administered to all patients regardless of risk, whether low or high. Modified-Magrath protocols have so far assigned low-risk patients to CODOX-M courses only, and reserved the full CODOX-M/IVAC alternating sequence to high-risk patients (Lacasce et al, 2004; Mead et al, 2008, 2002), as originally designated by Magrath in a population of 21 children (median age,12 years) and 20 adults (median age, 25 years)(Magrath et al, 1996). However, while studies in children/adolescents supported that low-risk patients deserve a shorter and less intensive treatment, there is no evidence that this concept is equally valid as applied to the adult population. We designed this study to deliver the whole RD-CODOX-M/IVAC sequence regardless of risk because (i) in adults with BL and BLL the low-risk profile as defined by Magrath et al (1996) is uncommon, and no alternative clinical and/or biological prognostic system has been validated yet (Perkins & Friedberg, 2008), (ii) CNS recurrence frequently occurs in adults with early stage BL (resected stage I and abdominal stage II) (Divine et al, 2005), and (iii) chemoresistant clones can emerge early also in patients with limited stage disease and salvage strategies have previously proven ineffective (Blum et al, 2004; Hoelzer, 2009; Thomas et al, 1999).

RD-CODOX-M/IVAC yielded a low CNS failure rate (3·4%), comparable with the original Magrath regimen (11·4%) and the modified-Magrath protocols (6–11%) (Magrath et al, 1996; Mead et al, 2008, 2002), with the number of IT prophylactic administrations reduced from 8 to 4. The dual results of a less intensive but equally effective IT program may be related to the favourable pharmacokinetics of liposomal cytarabine over standard cytarabine and MTX. Liposomal cytarabine maintains cytotoxic concentrations in CSF for up to 14 d following a single IT injection (Bleyer, 1999; Glantz et al, 1999; Kim et al, 1993), compared with 24–48 h for standard cytarabine and MTX (Shapiro et al, 1975; Zimm et al, 1984). This may allow improved exposure of lymphoma cells, which have a very slow growth rate in CSF, to the cell-cycle S-phase-specific agent cytarabine gradually released from liposome particles (Kim et al, 1993). Furthermore, liposomal cytarabine distributes more homogeneously than standard MTX and cytarabine within the subarachnoid space, particularly in the cerebral ventricles, where tumour cells often accumulate (Chamberlain & Kormanik, 1996; Kim et al, 1993; Muldoon et al, 2007; Shapiro et al, 1975). Co-administering IT liposomal cytarabine with systemic high-dose cytarabine has been associated with significant neurotoxicity (encephalopathy, cauda equina syndrome, seizure and pseudotumour cerebri) in the Hyper-CVAD regimen (Jabbour et al, 2007). However, no severe neurotoxicity occurred in the present study, possibly because of (i) a reduced pre-exposure of CNS tissues to cytarabine deriving from high-dose systemic treatment (2 g/m2 vs. 3·0 g/m2 of Hyper-CVAD, (ii) a longer time interval between delivery of systemic high-dose cytarabine and IT application of liposomal cytarabine, and (iii) intralumbar and systemic administration of dexamethasone. Liposomal cytarabine-associated adverse neurological events were mild-to-moderate and interestingly affected the same group of 13 patients while all others were completely free from any toxicity. Similar results have been reported in a recent study of HIV-seropositive patients (Spina et al, 2010). It is, therefore, conceivable that neurotoxicity to liposomal cytarabine may occur in an especially predisposed subset of patients.

In conclusion, the RD-CODOX-M/IVAC strategy may represent an effective and tolerable treatment for both BL and BL/DLBCL and, within the limits of a retrospective comparison, improve Magrath protocols in adults. Further progress is needed for elderly patients, whose outcome still remains unsatisfactory despite safe and adequate treatment/dose delivery.

Funding

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Ministero della Salute, Ricerca Finalizzata FSN and Ricerca Corrente IRCCS, Rome, Italy; Associazione Volontari Ematologia Pascale, AVEP Onlus, Naples, Italy.

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References

AP, GC designed the study, analysed data, performed research and wrote the manuscript. UV, FF, FR designed the study, analysed data, performed research and reviewed the manuscript. MA, CF, GE, ADC, EM, GC, CB, FV, GM, RDF performed the research, collected data and reviewed the manuscript. MS collected and analysed data.

We are grateful to Dr Alessandra Trocino, Librarian at the NCI’G Pascale’of Naples, for the excellent bibliographic assistance and to Mrs Rosaria Nota for expert support in data filing.

Conflict of Interest

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Antonio Pinto and Umberto Vitolo; lecture fees from Roche and Mundipharma. All of the other authors declare no competing financial interests.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Funding
  7. Acknowledgements
  8. Conflict of Interest
  9. References
  • Barnes, J.A., Lacasce, A., Feng, Y., Toomey, C., Neuberg, D., Hochberg, E.P. & Abramson, J.S. (2009) Rituximab added to CODOX-M/IVAC has no clear benefit compared to CODOX-M/IVAC alone in adult patients with Burkitt Lymphoma. Blood, 114, Abstract 1667.
  • Barnes, J.A., Lacasce, A.S., Feng, Y., Toomey, C.E., Neuberg, D., Michaelson, J.S., Hochberg, E.P. & Abramson, J.S. (2011) Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis. Ann Oncol, 22, 18591864.
  • Bernstein, J.I., Coleman, C.N., Strickler, J.G., Dorfman, R.F. & Rosenberg, S.A. (1986) Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt’s and non-Burkitt’s types). Journal of Clinical Oncology, 4, 847858.
  • Bleyer, W.A. (1999) Intrathecal depot cytarabine therapy: a welcome addition to a limited armamentarium. Clinical Cancer Research, 5, 33493351.
  • Blum, K.A., Lozanski, G. & Byrd, J.C. (2004) Adult Burkitt leukemia and lymphoma. Blood, 104, 30093020.
  • Chamberlain, M.C. & Kormanik, P.A. (1996) Prognostic significance of 11-DTPA CSF flow studies in leptomeningeal metastases. Neurology, 46, 16741677.
  • Cole, B.F., Glantz, M.J., Jaeckle, K.A., Chamberlain, M.C. & Mackowiak, J.I. (2003) Quality-of-life-adjusted survival comparison of sustained-release cytosine arabinoside versus intrathecal methotrexate for treatment of solid tumor neoplastic meningitis. Cancer, 97, 30533060.
  • Corazzelli, G., Russo, F., Capobianco, G., Marcacci, G., Della Cioppa, P. & Pinto, A. (2006) Gemcitabine, ifosfamide, oxaliplatin and rituximab (R-GIFOX), a new effective cytoreductive/mobilizing salvage regimen for relapsed and refractory aggressive non-Hodgkin’s lymphoma: results of a pilot study. Annals of Oncology, 17(Suppl 4), iv1824.
  • Dave, S.S., Fu, K., Wright, G.W., Lam, L.T., Kluin, P., Boerma, E.J., Greiner, T.C., Weisenburger, D.D., Rosenwald, A., Ott, G., Muller-Hermelink, H.K., Gascoyne, R.D., Delabie, J., Rimsza, L.M., Braziel, R.M., Grogan, T.M., Campo, E., Jaffe, E.S., Dave, B.J., Sanger, W., Bast, M., Vose, J.M., Armitage, J.O., Connors, J.M., Smeland, E.B., Kvaloy, S., Holte, H., Fisher, R.I., Miller, T.P., Montserrat, E., Wilson, W.H., Bahl, M., Zhao, H., Yang, L., Powell, J., Simon, R., Chan, W.C. & Staudt, L.M. (2006) Molecular diagnosis of Burkitt’s lymphoma. New England Journal of Medicine, 354, 24312442.
  • DeAngelis, L.M. (1998) Current diagnosis and treatment of leptomeningeal metastasis. Journal of Neuro-Oncology, 38, 245252.
  • Divine, M., Casassus, P., Koscielny, S., Bosq, J., Sebban, C., Le Maignan, C., Stamattoulas, A., Dupriez, B., Raphael, M., Pico, J.L. & Ribrag, V. (2005) Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Annals of Oncology, 16, 19281935.
  • Dunleavy, K., Pittaluga, S., Wayne, A.S., Shovlin, J.L., Johnson, J.L., Little, R., Steinberg, S., Cheson, B.D., Hsi, E., Jaffe, E.S. & Wilson, W.H. (2011) Myc+ aggressive B-cell lymphomas: novel therapy of untreated Burkitt Lymphoma and Myc+ Diffuse Large B-cell Lymphoma with DA-EPOCH-R. Annals of Oncology, 22, iv107.
  • Fleischhack, G., Jaehde, U. & Bode, U. (2005) Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clinical Pharmacokinetics, 44, 131.
  • Franco, R., Camacho, F.I., Caleo, A., Staibano, S., Bifano, D., De Renzo, A., Tranfa, F., De Chiara, A., Botti, G., Merola, R., Diez, A., Bonavolonta, G., De Rosa, G. & Piris, M.A. (2006) Nuclear bcl10 expression characterizes a group of ocular adnexa MALT lymphomas with shorter failure-free survival. Modern Pathology, 19, 10551067.
  • Glantz, M.J., LaFollette, S., Jaeckle, K.A., Shapiro, W., Swinnen, L., Rozental, J.R., Phuphanich, S., Rogers, L.R., Gutheil, J.C., Batchelor, T., Lyter, D., Chamberlain, M., Maria, B.L., Schiffer, C., Bashir, R., Thomas, D., Cowens, W. & Howell, S.B. (1999) Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. Journal of Clinical Oncology, 17, 31103116.
  • Hill, Q.A. & Owen, R.G. (2006) CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood Reviews, 20, 319332.
  • Hoelzer, D. (2008) Recent results in the treatment of Burkitt lymphomas [abstract]. Annals of Oncology, 19(Suppl 4), iv83.
  • Hoelzer, D. (2009) Update on burkitt lymphoma and leukemia. Clinical Advances in Hematology and Oncology, 7, 728729.
  • Hoelzer, D., Ludwig, W.D., Thiel, E., Gassmann, W., Loffler, H., Fonatsch, C., Rieder, H., Heil, G., Heinze, B., Arnold, R., Hossfeld, D., Buchner, T., Koch, P., Freund, M., Hiddemann, W., Maschmeyer, G., Heyll, A., Aul, C., Faak, T., Kuse, R., Ittel, T.H., Gramatzki, M., Diedrich, H., Kolbe, K., Fuhr, H.G., Fischer, K., Schadeck-Gressel, C., Weiss, A., Strohscheer, I., Metzner, B., Fabry, U., Gokbuget, N., Volkers, B., Messerer, D. & Uberla, K. (1996) Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood, 87, 495508.
  • Jabbour, E., Thomas, D., Cortes, J., Kantarjian, H.M. & O’Brien, S. (2005) Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies. Cancer, 116, 22902300.
  • Jabbour, E., O’Brien, S., Kantarjian, H., Garcia-Manero, G., Ferrajoli, A., Ravandi, F., Cabanillas, M. & Thomas, D.A. (2007) Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia. Blood, 109, 32143218.
  • Jaffe, E., Harris, N.L., Stein, H. & Vardiman J.W. (Eds) (2001) Burkitt lymphoma. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. pp. 181183. IARC Press, Lyon.
  • Kasamon, Y.L. & Swinnen, L.J. (2004) Treatment advances in adult Burkitt lymphoma and leukemia. Current Opinion in Oncology, 16, 429435.
  • Kelly, J.L., Toothaker, S.R., Ciminello, L., Hoelzer, D., Holte, H., LaCasce, A.S., Mead, G., Thomas, D., Van Imhoff, G.W., Kahl, B.S., Cheson, B.D., Magrath, I.T., Fisher, R.I. & Friedberg, J.W. (2009) Outcomes of patients with Burkitt lymphoma older than age 40 treated with intensive chemotherapeutic regimens. Clinical Lymphoma, Myeloma, 9, 307310.
  • Kim, S., Chatelut, E., Kim, J.C., Howell, S.B., Cates, C., Kormanik, P.A. & Chamberlain, M.C. (1993) Extended CSF cytarabine exposure following intrathecal administration of DTC 101. Journal of Clinical Oncology, 11, 21862193.
  • Lacasce, A., Howard, O., Lib, S., Fisher, D., Weng, A., Neuberg, D. & Shipp, M. (2004) Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Leukaemia & Lymphoma, 45, 761767.
  • Leoncini, L., Deisol, G., Gascoyne, R.D. & al., E. (2005) Aggressive B-cell lymphomas: a review based on the workshop of the XI Meeting of the European Association for Haemopathology. Histopathology, 46, 241255.
  • Magrath, I.T., Janus, C., Edwards, B.K., Spiegel, R., Jaffe, E.S., Berard, C.W., Miliauskas, J., Morris, K. & Barnwell, R. (1984) An effective therapy for both undifferentiated (including Burkitt’s) lymphomas and lymphoblastic lymphomas in children and young adults. Blood, 63, 11021111.
  • Magrath, I., Adde, M., Shad, A., Venzon, D., Seibel, N., Gootenberg, J., Neely, J., Arndt, C., Nieder, M., Jaffe, E., Wittes, R.A. & Horak, I.D. (1996) Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. Journal of Clinical Oncology, 14, 925934.
  • Maruyama, D., Watanabe, T., Maeshima, A.M., Nomoto, J., Taniguchi, H., Azuma, T., Mori, M., Munakata, W., Kim, S.W., Kobayashi, Y., Matsuno, Y. & Tobinai, K. (2010) Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL. International Journal of Hematology, 92, 732743.
  • Mead, G.M., Sydes, M.R., Walewski, J., Grigg, A., Hatton, C.S., Pescosta, N., Guarnaccia, C., Lewis, M.S., McKendrick, J., Stenning, S.P. & Wright, D. (2002) An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study. Annals of Oncology, 13, 12641274.
  • Mead, G.M., Barrans, S.L., Qian, W., Walewski, J., Radford, J.A., Wolf, M., Clawson, S.M., Stenning, S.P., Yule, C.L. & Jack, A.S. (2008) A 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). Blood, 112, 22482260.
  • Mohamedbhai, S.G., Sibson, K., Marafioti, T., Kayani, I., Lowry, L., Goldstone, A.H., Linch, D.C. & Ardeshna, K.M. (2011) Rituximab in combination with CODOX-M/IVAC: a retrospective analysis of 23 cases of non-HIV related B-cell non-Hodgkin lymphoma with proliferation index >95%. British Journal of Haematology, 152, 175181.
  • Muldoon, L.L., Soussain, C., Jahnke, K., Johanson, C., Siegal, T., Smith, Q.R., Hall, W.A., Hynynen, K., Senter, P.D., Peereboom, D.M. & Neuwelt, E.A. (2007) Chemotherapy delivery issues in central nervous system malignancy: a reality check. Journal of Clinical Oncology, 25, 22952305.
  • Nomura, Y., Karube, K., Suzuki, R., Ying, G., Takeshita, M., Hirose, S., Nakamura, S., Yoshino, T., Kikuchi, M. & Ohshima, K. (2008) High-grade mature B-cell lymphoma with Burkitt-like morphology: results of a clinicopathological study of 72 Japanese patients. Cancer Science, 99, 246252.
  • Oriol, A., Ribera, J.M., Bergua, J., Gimenez Mesa, E., Grande, C., Esteve, J., Brunet, S., Moreno, M.J., Escoda, L., Hernandez-Rivas, J.M. & Hoelzer, D. (2008) High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer, 113, 117125.
  • Perkins, A.S. & Friedberg, J.W. (2008) Burkitt lymphoma in adults. Hematology the Education Program of the American Society of Hematology, 1, 341348.
  • Rizzieri, D.A., Johnson, J.L., Niedzwiecki, D., Lee, E.J., Vardiman, J.W., Powell, B.L., Barcos, M., Bloomfield, C.D., Schiffer, C.A., Peterson, B.A., Canellos, G.P. & Larson, R.A. (2004) Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer, 100, 14381448.
  • Rizzieri, D.A., Johnson, J.L., Byrd, J.C., Lozanski, G., Powell, J., Shea, T.C., Nattom, S., Hoke, E., Chessin, L.N. & Larson, R. (2010) Efficacy and toxicity of Rituximab and brief duration, high intensity chemotherapy with Filgrastim support in Burkitt or Burkitt/like Leukemia/Lymphoma: Cancer and Leukemia Group B (Calgb) Study 10002. Blood, 116, Abstract 858.
  • Rueda Dominguez, A., Olmos Hidalgo, D., Viciana Garrido, R. & Torres Sanchez, E. (2005) Liposomal cytarabine (DepoCyte) for the treatment of neoplastic meningitis. Clinical and Translational Oncology, 7, 232238.
  • Salaverria, I. & Siebert, R. (2011) The gray zone between Burkitt’s lymphoma and diffuse large B-cell lymphoma from a genetics perspective. Journal of Clinical Oncology, 29, 18351843.
  • Sariban, E., Edwards, B., Janus, C. & Magrath, I. (1983) Central nervous system involvement in American Burkitt’s lymphoma. Journal of Clinical Oncology, 1, 677681.
  • Shapiro, W.R., Young, D.F. & Mehta, B.M. (1975) Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. New England Journal of Medicine, 293, 161166.
  • Smeland, S., Blystad, A.K., Kvaloy, S.O., Ikonomou, I.M., Delabie, J., Kvalheim, G., Hammerstrom, J., Lauritzsen, G.F. & Holte, H. (2004) Treatment 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 regimens. Annals of Oncology, 15, 10721078.
  • Spina, M., Chimienti, E., Martellotta, F., Vaccher, E., Berretta, M., Zanet, E., Lleshi, A., Canzonieri, V., Bulian, P. & Tirelli, U. (2010) Phase 2 study of intrathecal, long-acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer, 116, 14951501.
  • Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J & Vardiman JW. (Eds) (2008) Burkitt lymphoma. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. pp. 262263. IARC Press, Lyon.
  • Thomas, D.A., Cortes, J., O’Brien, S., Pierce, S., Faderl, S., Albitar, M., Hagemeister, F.B., Cabanillas, F.F., Murphy, S., Keating, M.J. & Kantarjian, H. (1999) Hyper-CVAD program in Burkitt’s-type adult acute lymphoblastic leukemia. Journal of Clinical Oncology, 17, 24612470.
  • Thomas, D.A., Faderl, S., O’Brien, S., Bueso-Ramos, C., Cortes, J., Garcia-Manero, G., Giles, F.J., Verstovsek, S., Wierda, W.G., Pierce, S.A., Shan, J., Brandt, M., Hagemeister, F.B., Keating, M.J., Cabanillas, F. & Kantarjian, H. (2006) Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer, 106, 15691580.
  • Wasterlid, T., Jonsson, B., Hagberg, H. & Jerkeman, M. (2011) Population based study of prognostic factors and treatment in adult Burkitt lymphoma: a Swedish Lymphoma Registry study. Leukaemia & Lymphoma, 52, 20902096.
  • Zimm, S., Collins, J.M., Miser, J., Chatterji, D. & Poplack, D.G. (1984) Cytosine arabinoside cerebrospinal fluid kinetics. Clinical Pharmacology and Therapeutics, 35, 826830.