High Survival Rate in Adult Burkitt’s Lymphoma/Leukemia and Diffuse Large B-Cell Lymphoma with Mediastinal Involvement.

Abstract

With short intensive chemotherapy mainly based on HDMTX, fractionated alkylators and HDAC outcome of Burkitt’s NHL and mature B-ALL (B-ALL) in adults could be improved substantially to CR rates of 80% and overall survival (OS) of 50–70% (Hoelzer et al, Blood, 1996). Further intensification - namely increase of MTX dose - failed to improve these results. Therefore the German Multicenter Study Group for Adult ALL (GMALL) invented in 2002 a new protocol for mature B-ALL/Burkitt and other high-grade NHL, namely primary mediastinal (med) DLBCL, including 6x Rituximab® 375 mg/m2 before each chemo cycle and two R maintenance cycles. In addition 2 cycles based on HDAC 2 g /m2 were included. HDMTX was 1,5 g/m2 in the protocol for younger pts (<55 yrs). Older pts (>55 yrs) received a dose reduced regimen without HDAC and with MTX at 500 mg/m2. 227 pts with Burkitt (27=Burkitt-like), B-ALL or med DLBCL aged between 16 and 78 enrolled between 09/02 and 12/06 were evaluable for response after the first two cycles. The median age was 36 yrs for Burkitt, 46 for B-ALL and 35 for med DLBCL; 18%, 41% and 12% were older than 55 yrs respectively. The subgroups were characterised as follows: 115 Burkitt (stage III–IV 52%, extranodal inv. 78%, aaIPI >1 47%), 70 B-ALL, 42 med DLBCL (stage III–IV 55%, extranodal inv. 71%, aaIPI >1 61%). The CR rate was 90% in Burkitt, 83% in B-ALL and 69% in med DLBCL; death under therapy occurred in 3%, 11% and 0% respectively. The overall survival at 3 yrs was 91% for Burkitt, 79% for B-ALL and 90% for med DLBCL in pts at the age of 15–55 yrs and 84%, 39% and 67% (N=5) respectively in pts >55 yrs. CNS relapses were observed in 3 out of 22 older CR patients with B-ALL whereas in younger pts the CNS relapse rate was 0. CNS relapses are among the reasons for inferior outcome in elderly B-ALL in contrast to elderly pts with Burkitt or med DLBCL. CNS relapse rate may hopefully be reduced by inclusion of an intermediate dose ARAC cycle in the elderly B-ALL. There was no difference in OS between pts with Burkitt (92%) vs Burkitt-like NHL (86%). Since no prognostic factors could be identified in younger pts, there was no need for SCT in CR1. Major grade III/IV toxicity was hematological (28–37%) and mucositis (36%, 37%, 28% in cycles A1, B1, C1 respectively). Compared to the previous GMLL trial B-NHL90 (without Rituximab) with 270 pts the OS of 272 patients (including LBL, LCAL, DLBCL) at 3 yrs improved significantly from 54% to 80% (p<.0001) overall, 56% to 85% (p<.0001) in younger and 39% to 65% (p=.01) in older pts. In this largest prospective study of adult Burkitt’s lymphoma/leukemia and med DLBCL the combination of Rituximab and 6 short intensive chemo cycles was feasible and lead to an OS of 90% in NHL and 79% in mature B-ALL in the younger patient cohort. Even in older pts with Burkitt’s NHL survival was 84%. The further aim is now to reduce toxicity, namely mucositis.

Dose‐intensive chemotherapy including rituximab in Burkitt's leukemia or lymphoma regardless of human immunodeficiency virus infection status

“…In both HIV-positive and HIV-negative patients aged 55 years or older, the frequency of cytopenias was similar but the duration was lower, with fewer infections and mucositis, probably due to reduced intensity of chemotherapy given to these patients. The prognostic factors identified in this study (CNS and BM involvement and poor general status) are consistent with those identified in other trials [15][16][17][18][19][20][21][22][23][24][25][26][27][28] or in population-based studies 30 with the exception of advanced age. We have attributed the lack of poor prognosis in older patients to 2 features.…”

“…15,16 The adaptation of these schedules to adults has led to an increase in the response rate and survival, ranging from 60% to 70% of cases in some series. 17 The addition of rituximab to these specific therapies may represent a step forward in the therapy of BL. Although no randomized trials on the use of rituximab have been published to date, and most of the studies are retrospective and include a limited number of patients, the tolerability and efficacy of specific immunochemotherapy seems to be good, with response rates between 70% and 90% and survival ranging from 70% to 80%.…”

“…Although no randomized trials on the use of rituximab have been published to date, and most of the studies are retrospective and include a limited number of patients, the tolerability and efficacy of specific immunochemotherapy seems to be good, with response rates between 70% and 90% and survival ranging from 70% to 80%. [17][18][19][20][21] The high frequency of virologic and immunologic response to HAART and the improvement in supportive therapy have encouraged some groups to treat patients who have HIV-related BL with the same aggressive schedules as those used in patients without immune suppression, with promising results and acceptable tolerability. [22][23][24][25][26] Several studies have added rituximab to these schedules, with results comparable to those obtained in HIVnegative patients.…”

Optimal management of adults with ALL

“…Monoclonal antibody therapy is an attractive target to study in induction therapy for ALL. CD20 is expressed in 50-70% of pre-B ALL cells and there are preliminary data on the use of rituximab in the treatment of B-cell precursor ALL (Jandula et al, 2001;de Vries et al, 2004;Thomas et al, 2006a;Hoelzer et al, 2007).…”

21.8 Akute lymphatische Leukämie (ALL)

“…In 80-90% der Fälle weisen diese Leukämien/Lymphome eine CD20-Expression auf. Die Gabe von Rituximab vor den Chemotherapiezyklen hat zu einer deutlichen Verbesserung der Therapieergebnisse geführt [15].…”