Update of the Modified Hyper-CVAD Regimen with or without Rituximab as Frontline Therapy of Adults with Acute Lymphocytic Leukemia (ALL) or Lymphoblastic Lymphoma (LL).
Deborah A. Thomas, MD1,
Hagop Kantarjian, MD1,
Stefan Faderl, MD1,
Charles Koller, MD1,
Farhad Ravandi-Kashani, MD1,
Miloslav Beran, MD, PhD1 and
Susan OBrien, MD1
1 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
The hyper-CVAD regimen is an effective therapy program for adultALL and LL [Kantarjian, JCO 18:547, 2000[Abstract/Free Full Text]; Kantarjian, Cancer101:2788, 2004[Medline], Thomas, Blood 104:1624, 2004[Abstract/Free Full Text]]. Intensive chemotherapywith hyper-CVAD (fractionated cyclophosphamide, vincristine[VCR], doxorubicin, dexamethasone) alternates with high dosemethotrexate and cytarabine every 21 days for 8 courses, followedby maintenance with POMP (6-mercaptopurine, methotrexate, VCR,prednisone). Historical CR rate was 92% with 3-year disease-freesurvival (DFS) rate of 38%. The regimen was modified in 1999to address the following:
higher induction mortality in patients (pts) aged 60 years orolder (17% vs 3%);
possible benefit of early anthracyclineintensification;
worse survival with CD20 expression; and
late relapses after completion of POMP therapy.
Newly diagnosed or primary refractory (1 course only) ALL orLL pts were treated on two sequential studies. Burkitt leukemia/lymphoma(BLL) and Philadelphia positive ALL pts were treated on separateprotocols. From May 2000 to December 2001, 69 pts were treatedwith the modified regimen as detailed above (9 courses of intensivechemotherapy). Course 2 was eliminated from the second study,with an additional 124 pts were treated (8 courses of intensivechemotherapy). Results were reviewed by lineage (T-cell versusnon T-cell), outcome after therapy with rituximab for CD20 positiveALL, and age. Overall CR rate of the group (n=190) was 91%.Median age of the T-lineage pts was 30 (range, 17–74)versus 43 (range, 15–83) for the non-T lineage pts. Aftera median follow-up of 30 months (range, 6–80), outcomeappeared favorable for the younger group aged 30 years or lesswith 3-year DFS rates of 61% and 66%, and 3-year OS rates of73% and 71% for non-T and T-lineage, respectively. When comparingoutcome of non-T lineage CD20 positive ALL with historical experience,the addition of rituximab appeared to improve DFS rates (56%versus 35%, p=.06) but did not affect survival (62% versus 46%,p=0.23). A subset analysis showed that younger pts aged 30 orless with non T-lineage CD20 positive ALL treated with rituximabhad superior outcomes compared with historical experience (DFSrates 62% versus 28%, p=.005; OS rates 73% versus 50%, p=.07).No such benefit of rituximab was observed for the elderly group,in contrast to data previously reported for BLL. Anthracyclineintensification appeared to worsen outcome, particularly forT-lineage ALL. Rituximab may benefit subsets of CD20 positiveALL; alternative monoclonal antibodies should be explored. Furtherimprovements in outcome may be achieved with incorporation ofnovel agents such as nelarabine for T-lineage ALL and sphingosomalVCR for elderly ALL.
Modifications to Hyper-CVAD
Laminarair flow rooms
For age [ 60yrs or poor PS
C2 Liposomal DNR & cytarabine
Intrathecal CNS prophylaxis
4, 8 (16 BL)
6 or 8(16 BL)
Months 6, 7 & 18, 19
Disclosure:Off Label Use: Use of rituximab for CD20 positiveALL.