Poor Outcomes with Hyper CVAD Induction for T-Cell Lymphoblastic Leukemia/Lymphoma

Background:

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in adults is an aggressive bone marrow malignancy that historically has a poor prognosis.  Hyper-CVAD/methotrexate-cytarabine (hyper CVAD) regimen is a commonly used induction regimen following the protocol developed at MD Anderson Cancer center.  Recent reports from Swedish Cancer Registry showed that relapse rates were much higher than expected with this regimen. We report our retrospective experiences across three different centers, Winship Cancer Institute of Emory University(Atlanta), University of Alabama Cancer Center (Birmingham) and Moffitt Cancer Center,(Tampa), with the use of this regimen for management of T-ALL/LBL.

Methods:

We conducted a retrospective chart review of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician’s discretion. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Since hyper CVAD is a commonly used regimen outside of clinical trials, we focused our analysis on outcomes with this regimen. This regimen consisted of 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8). CNS prophylaxis was given to all patients as per standard of care recommendations. All patients eligible for maintenance received 2 years of POMP (6 mercaptopurine, methotrexate, vincristine and prednisone) maintenance.  Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability.

Results:  

The final analysis included 95 adult patients with 64/95 (67%) patients receiving hyper-CVAD induction. Among the hyper-CVAD patients the median age at diagnosis was 30 (range 17-74). 71% of patients were male. Median white cell count (WBC) was 13.6/mm³ (1.7-500). Cytogenetic analysis revealed diploid in 36, complex ( 1 or more abnormalities in 16) and was not available in 12. WBC count was > 100,000/mm³ in 9 patients.  14 patients had mediastinal disease while 7 had CNS disease at diagnosis.  Hyper-CVAD was the primary induction regimen in 56/64. Other patients either started on non-hyper CVAD induction prior to switching (n=3) or had asparaginase added to induction (n=5).  The median number of cycles given as 7 (range 2-10) with 27(45%) patients receiving the planned 8 cycles. 37 patients did not complete 8 cycles due to stem cell transplant in remission (n=12), progressive disease (n=10) and unclear reasons (n=15). After induction therapy, remission status was unknown in 3 patients while 43/61 patients (70%) achieved remission. Maintenance with POMP was started in 21 patients that were in remission while 12 patients were taken to transplant without starting on maintenance.

At the time of analysis, 23/64(35%) patients are alive. The median relapse free survival was 387 days(12.9 months) and the median overall survival was 536 days (17.6 months). Excluding one patient lost to follow up, 44/63 (69.8%) relapsed. There was no difference in relapse versus non relapse patients in terms of median age (30 vs 33 years), median WBC at diagnosis (13.2 vs 13.6 mm³). Relapse rate was lower in patients with diploid karyotype(22/36, 61%) as compared to those with complex karyotype (14/16). Median survival in patients post relapse was 150 days. Only 9 patients were able to go for transplant after relapse with post transplant survival also being low (6 deaths). For the entire group, the two year survival was 35%.

Conclusion:  Our multi-institutional retrospective review shows that outcomes are poor across various centers in patients outside of clinical trials. This is the largest reported series of patients with adult T-ALL/T-LBL  treated with hyper-CVAD outside of clinical trials. This data warrants investigation with newer agents to improve outcomes in this disease.

Figure 1: Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64)