Characteristics of the 19 trials included in the final pooled analysis13,18,23-25,27,29-42
| Trial . | Design . | Setting . | Type of lymphoma . | Number of patients . | Accrual period . | Median follow-up (years) . | Median age (years) . | Interventions . | Supportive care . | End points . | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Concurrent CART . | G-CSF . | OI ppx . | CNS ppx . | ||||||||||
| Ribera/Wyen29,42 | Ph II | German HIV Lymphoma Cohort | BL/L3ALL | 38 | ‘05-’09 | 2.28 (0.07-5.17) | 44 (27-69) | GMALL +R | PD | If ANC <500 or FN | PJP, AB-r, AF-r | Universal (MTX, Ara-C, Dex) | 1°: Tox 2°: OS |
| Dunleavy30 | Ph II | NCI | BL & DLBCL | 43 | ‘01-’09 | 4.49 (0.19-10.13) | 43 (24-61) | SC EPOCH-RR | No | Universal | PJP, MAI if CD4 <100 | Universal (MTX) | 1°: PFS 2°: RR, OS, Tox |
| AMC03431 | Ph II | AMC | Aggressive CD20+ B-cell NHL | 106 | ‘01-’06 | 2.53 (0.03-5.62) | 44 (22-76) | R-EPOCH + EPOCH-R | PD | Universal | PJP, AB, AF | PD | 1°: CRR 2°: PFS, TTP, OS |
| Oriol13 | Ph II | PETHEMA | BL/L3ALL | 40 | ‘04-’10 | 1.87 (0.02-5.21) | 42 (20-59) | GMALL + R | Universal | If ANC <500 or FN | PJP-r; AB and AF as per PD | Universal (MTX, Ara-C, Dex) | 1°: Tox 2°: CRR, DFS, & OS |
| Ribera32 | Ph II | PETHEMA, GELTAMO, GELCAB, GESIDA | DLBCL | 81 | ‘01-’06 | 4.65 (0.03-9.52) | 44 (21-74) | R-CHOP | Universal | If ANC <500 or FN | PJP | Universal: (MTX, Ara-C, HC) | 1°: RR 2°: DFS, OS, Tox |
| Galicier23 | Ph II | Single Institution (Paris) | BL | 63 | ‘92-’06 | 1.58 (0.03-16.40) | 40 (20-63) | LMB86 | Universal | Universal | PJP | Universal: (MTX, Ara-C, Dex) | RR, PFS, DFS, OS |
| Boue33 | Ph II | Multicenter France | BL & DLBCL | 61 | ‘99-’01 | 2.82 (0.02-4.96) | 41 (20-59) | R-CHOP | Recommended | PD | PJP-r | PD | 1°: RR 2°: PFS, OS |
| Weiss34 | Ph II | German AIDS-Related Lymphoma Study Group | Aggressive B-cell NHL | 72 | ‘97-’01 | 2.15 (0.07-5.78) | 41 (26-65) | CHOP | Universal (except 6 patients) | If ANC <500 or FN | PJP | IT MTX ×1; more, if risk factors* | 1°: OS 2°: PFS, RR |
| Mounier27 | Ph II | GELA, GICAT | Aggressive NHL | 467 | ‘93-’99 | 0.75 (0-8.16) | 38 (18-67) | Risk group†: good: ACVBP vs CHOP; intermediate: CHOP vs Ld-CHOP; poor: Ld-CHOP vs VS | All patients after June 1996 | ACVBP & CHOP: Universal; Ld-CHOP & VS: only if FN | PJP | Universal | 1°: OS 2°: PFS, OS |
| Navarro35 | Ph II | Single institution, Spain | DLBCL | 49 | ‘89-’06 | 1.02 (0.04-15.22) | 38 (19-62) | CHOP | Universal | Universal | PJP | Universal (MTX) | RR, OS, DFS |
| AMC01018 | Ph III | AMC | CD20+ B-cell NHL | 150 | ‘98-’02 | 0.61 (0.01-5.27) | 41 (26-73) | R-CHOP vs CHOP | Universal | Universal | PJP | Recommended if “high risk”‡ | 1°: CRR 2°: TTP, PFS, OS |
| Spina36 | Ph II | GICAT, University of Vienna, AECC, NY | CD20+ B-cell NHL | 74 | ’98-’03 | 6.55 (0.02-12.13) | 38 (29-65) | R-CDE | Strongly recommended | Universal | PJP, AF | Universal (either MTX or Ara-C) | 1°: CRR |
| 2°: FFS, EFS, PFS, OS | |||||||||||||
| PETHEMALAL3/9737 | Ph II | PETHEMA | BL/LAL3 | 14 | ‘97-’01 | 1.15 (0.01-4.48) | 44 (23-65) | LAL3/97 | Strongly recommended | If ANC <500 or FN | PD | Universal (MTX, Ara-C & HC) | CRR, OS, DFS |
| E149438 | Ph II | ECOG | Intermediate or high grade NHL | 117 | ‘95-’99 | 1.23 (0-11.78) | 39 (26-66) | CDE | DDI before 1996, then cART | Universal | PJP,AF; MAI optional | If high risk§ (Ara-C) | 1°: CRR, OS |
| 2°: FFS | |||||||||||||
| Little39 | Ph II | NCI | Aggressive B-cell NHL | 17 | ‘97-’00 | 1.45 (0.06-11.10) | 43 (31-55) | EPOCH | No | Universal | PJP, MAI if CD4 <100 | Only last 17 patients (MTX) | OS, PFS, DFS, CR rate |
| AMC00540 | Ph II | AMC | Intermediate or high grade NHL | 64 | ‘97-‘98 | 0.34 (0.01-1.38) | 41 (28-58) | First 40 patients m-CHOP, next 25 patients CHOP | Universal | CHOP: Universal m-CHOP: only if ANC <1000x2 or FN | PJP; AB, AF, and MAI optional | Recommended for all (Ara-C) | RR, Tox, DFS |
| Remick41 | Ph II | 3 US institutions | NHL | 20 | ‘93 | 0.60 (0.04-1.97) | 40 (24-51) | Remick regimen¶ | PD (PIs not available) | Universal | PJP; AB, AF, and MAI optional | None | RR, OS, PFS, Tox |
| Oksenhendler24 | Ph II | Intermediate or high grade NHL | 52 | ‘91-’96 | 1.49 (0.19-17.34) | 33 (24-59) | LNH84-91 | No | Universal | PJP | Universal (MTX) | RR, OS, PFS, Tox | |
| Remick25 | Ph II | 4 US institutions | NHL | 18 | ‘93 | 0.55 (0.04-1.97) | 36 (23-52) | Remick regimen¶ | No | No | PJP | None | RR, OS, Tox |
| Trial . | Design . | Setting . | Type of lymphoma . | Number of patients . | Accrual period . | Median follow-up (years) . | Median age (years) . | Interventions . | Supportive care . | End points . | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Concurrent CART . | G-CSF . | OI ppx . | CNS ppx . | ||||||||||
| Ribera/Wyen29,42 | Ph II | German HIV Lymphoma Cohort | BL/L3ALL | 38 | ‘05-’09 | 2.28 (0.07-5.17) | 44 (27-69) | GMALL +R | PD | If ANC <500 or FN | PJP, AB-r, AF-r | Universal (MTX, Ara-C, Dex) | 1°: Tox 2°: OS |
| Dunleavy30 | Ph II | NCI | BL & DLBCL | 43 | ‘01-’09 | 4.49 (0.19-10.13) | 43 (24-61) | SC EPOCH-RR | No | Universal | PJP, MAI if CD4 <100 | Universal (MTX) | 1°: PFS 2°: RR, OS, Tox |
| AMC03431 | Ph II | AMC | Aggressive CD20+ B-cell NHL | 106 | ‘01-’06 | 2.53 (0.03-5.62) | 44 (22-76) | R-EPOCH + EPOCH-R | PD | Universal | PJP, AB, AF | PD | 1°: CRR 2°: PFS, TTP, OS |
| Oriol13 | Ph II | PETHEMA | BL/L3ALL | 40 | ‘04-’10 | 1.87 (0.02-5.21) | 42 (20-59) | GMALL + R | Universal | If ANC <500 or FN | PJP-r; AB and AF as per PD | Universal (MTX, Ara-C, Dex) | 1°: Tox 2°: CRR, DFS, & OS |
| Ribera32 | Ph II | PETHEMA, GELTAMO, GELCAB, GESIDA | DLBCL | 81 | ‘01-’06 | 4.65 (0.03-9.52) | 44 (21-74) | R-CHOP | Universal | If ANC <500 or FN | PJP | Universal: (MTX, Ara-C, HC) | 1°: RR 2°: DFS, OS, Tox |
| Galicier23 | Ph II | Single Institution (Paris) | BL | 63 | ‘92-’06 | 1.58 (0.03-16.40) | 40 (20-63) | LMB86 | Universal | Universal | PJP | Universal: (MTX, Ara-C, Dex) | RR, PFS, DFS, OS |
| Boue33 | Ph II | Multicenter France | BL & DLBCL | 61 | ‘99-’01 | 2.82 (0.02-4.96) | 41 (20-59) | R-CHOP | Recommended | PD | PJP-r | PD | 1°: RR 2°: PFS, OS |
| Weiss34 | Ph II | German AIDS-Related Lymphoma Study Group | Aggressive B-cell NHL | 72 | ‘97-’01 | 2.15 (0.07-5.78) | 41 (26-65) | CHOP | Universal (except 6 patients) | If ANC <500 or FN | PJP | IT MTX ×1; more, if risk factors* | 1°: OS 2°: PFS, RR |
| Mounier27 | Ph II | GELA, GICAT | Aggressive NHL | 467 | ‘93-’99 | 0.75 (0-8.16) | 38 (18-67) | Risk group†: good: ACVBP vs CHOP; intermediate: CHOP vs Ld-CHOP; poor: Ld-CHOP vs VS | All patients after June 1996 | ACVBP & CHOP: Universal; Ld-CHOP & VS: only if FN | PJP | Universal | 1°: OS 2°: PFS, OS |
| Navarro35 | Ph II | Single institution, Spain | DLBCL | 49 | ‘89-’06 | 1.02 (0.04-15.22) | 38 (19-62) | CHOP | Universal | Universal | PJP | Universal (MTX) | RR, OS, DFS |
| AMC01018 | Ph III | AMC | CD20+ B-cell NHL | 150 | ‘98-’02 | 0.61 (0.01-5.27) | 41 (26-73) | R-CHOP vs CHOP | Universal | Universal | PJP | Recommended if “high risk”‡ | 1°: CRR 2°: TTP, PFS, OS |
| Spina36 | Ph II | GICAT, University of Vienna, AECC, NY | CD20+ B-cell NHL | 74 | ’98-’03 | 6.55 (0.02-12.13) | 38 (29-65) | R-CDE | Strongly recommended | Universal | PJP, AF | Universal (either MTX or Ara-C) | 1°: CRR |
| 2°: FFS, EFS, PFS, OS | |||||||||||||
| PETHEMALAL3/9737 | Ph II | PETHEMA | BL/LAL3 | 14 | ‘97-’01 | 1.15 (0.01-4.48) | 44 (23-65) | LAL3/97 | Strongly recommended | If ANC <500 or FN | PD | Universal (MTX, Ara-C & HC) | CRR, OS, DFS |
| E149438 | Ph II | ECOG | Intermediate or high grade NHL | 117 | ‘95-’99 | 1.23 (0-11.78) | 39 (26-66) | CDE | DDI before 1996, then cART | Universal | PJP,AF; MAI optional | If high risk§ (Ara-C) | 1°: CRR, OS |
| 2°: FFS | |||||||||||||
| Little39 | Ph II | NCI | Aggressive B-cell NHL | 17 | ‘97-’00 | 1.45 (0.06-11.10) | 43 (31-55) | EPOCH | No | Universal | PJP, MAI if CD4 <100 | Only last 17 patients (MTX) | OS, PFS, DFS, CR rate |
| AMC00540 | Ph II | AMC | Intermediate or high grade NHL | 64 | ‘97-‘98 | 0.34 (0.01-1.38) | 41 (28-58) | First 40 patients m-CHOP, next 25 patients CHOP | Universal | CHOP: Universal m-CHOP: only if ANC <1000x2 or FN | PJP; AB, AF, and MAI optional | Recommended for all (Ara-C) | RR, Tox, DFS |
| Remick41 | Ph II | 3 US institutions | NHL | 20 | ‘93 | 0.60 (0.04-1.97) | 40 (24-51) | Remick regimen¶ | PD (PIs not available) | Universal | PJP; AB, AF, and MAI optional | None | RR, OS, PFS, Tox |
| Oksenhendler24 | Ph II | Intermediate or high grade NHL | 52 | ‘91-’96 | 1.49 (0.19-17.34) | 33 (24-59) | LNH84-91 | No | Universal | PJP | Universal (MTX) | RR, OS, PFS, Tox | |
| Remick25 | Ph II | 4 US institutions | NHL | 18 | ‘93 | 0.55 (0.04-1.97) | 36 (23-52) | Remick regimen¶ | No | No | PJP | None | RR, OS, Tox |
AB, antibacterial prophylaxis; AB-r, antibacterial prophylaxis recommended; AECC, Albert-Einstein Cancer Center; AF, antifungal prophylaxis; AF-r, antifungal prophylaxis recommended; AMC, AIDS Malignancy Consortium; ANC, absolute neutrophil count; Ara-C, cytarabine; CNS ppx, central nervous system prophylaxis; CRR, complete response rate; DDI, didanosine; Dex, dexamethasone; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; EPOCH-R, EPOCH followed by rituximab (sequential); FFS, failure-free survival; FN, febrile neutropenia; GELA, Groupe d'Etude des Lymphomes de l'Adulte; GELCAB, Grupo d'Estudi dels Limfomes de Catalunya I Balears; GELTAMO, Grupo Español de Linfomas-Trasplante de Medula Ósea; GESIDA, Grupo de Estudio del SIDA de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica; GICAT, Gruppo Italiano Cooperativo AIDS e Tumori; GMALL, German Multicenter Study Group for the Treatment of Adult Acute Lymphoblastic Leukemia protocol as described by Hoelzer et al22 consisting of a prophase using cyclophosphamide and prednisone, followed by cycles A, B, and C using rituximab, iphosphamide, high-dose methotrexate, cytarabine, teniposide, vincristine, daunorubicin, vindesine, and etoposide; HC, hydrocortisone; IT, intrathecal; L3ALL, L3 variant of acute lymphoblastic leukemia; Ld-CHOP, low-dose and/or dose-modified CHOP; LMB86, cytoreductive phase using low dose cyclophosphamide, VS, followed by induction with vincristine, methotrexate, cyclophosphamide, adriamycin and prednisone ×2, followed by consolidation with etoposide and cytarabine ×2 and 4 maintenance courses combining previous drugs with lower dosage; LNH84-91, ACVBF ×3 followed by cyclophosphamide, etoposide, methotrexate (CVM) ×3; MAI, Mycobacterium avium intracellulare; m-CHOP, modified CHOP, dose of cyclophosphamide and doxorubicin reduced by 50% compared with CHOP; MTX, methotrexate; OI ppx, opportunistic infection prophylaxis; PD, physician discretion; PETHEMA, Programa de Estudio y Tratamiento de las Hemopatías Malignas; Ph, phase; PI, protease inhibitor; PJP, Pneumocystis jirovecii pneumonia; PJP-r, PJP prophylaxis recommended; ppx, prophylaxis; R, rituximab; R-CHOP, rituximab plus cyclophosphamide, vincristine, doxocrubicin, and prednisone; R-EPOCH, EPOCH concurrently with rituximab; RR, response rate; SC EPOCH-RR, short course EPOCH 1 cycle beyond CR to a maximum of 6 cycles, each cycle with 2 doses of rituximab; Tox, toxicities; TTP, time-to-progression.
Stage 4 or LDH >800 IU/L.
Risk factors: Eastern Cooperative Oncology Group (ECOG) performance status > 1, prior AIDS, baseline CD4 count < 100 cells/μL. Classification based on number of risk factors present: 0 factors = good risk, 1 factor = intermediate risk, ≥2 factors = poor risk.
Small noncleaved histology; bone marrow, paranasal sinus, or testicular involvement; presence of epidural disease.
small noncleaved histology or bone marrow involvement.
Combination of oral lomustine, etoposide, cyclophosphamide, and procarbazine.