Autologous Stem Cell Transplantation for Treatment with Curative Intent in Adult Patients with Acute Lymphoblastic Lymphoma

Introduction

Lymphoblastic lymphoma (LBL) is a rare, aggressive lymphoma that is often classified as a subtype of acute lymphoblastic leukemia (ALL). There is no consensus on the best treatment approach. It is often treated on ALL-type protocols involving prolonged courses of multiagent chemotherapy regimens; the reported long-term disease-free survival is 45-65%. In British Columbia, we take an alternative approach of consolidating initial response to induction chemotherapy with autologous stem cell transplantation (AutoSCT). We present our experience with this treatment pathway.

Methods

We identified 35 patients who received treatment with curative intent for LBL at our centre over the 15-year-period between January 2007 and January 2022 from our database. We excluded one patient who declined AutoSCT, one who received ALL-type chemotherapy and one who had upfront allogeneic stem cell transplantation (AlloSCT) due to complex karyotype. We collected data pertaining to demographics, disease characteristics, treatment course and outcome on the remaining 32 patients by review of clinical documents and laboratory and radiology reports. The primary outcome was event-free survival (EFS), defined as time from diagnosis to disease progression, relapse or death. Surviving patients were censored at the last follow up. We used Kaplan-Meier method to estimate survival and log-rank test and cox-hazard model for comparison of survival. Statistical analysis was performed using STATA® version 16.1 (Texas, USA).

Results

The median age was 35 years (range 18-64). 27/32 (84%) had T-LBL. Bone marrow, CSF and extranodal involvement was seen in 7 (22%), 3 (9%) and 24 (75%) patients respectively.

The majority of patients (30/32, 94%) received induction chemotherapy on the NHL 98-01 protocol (consisting of doxorubicin, cyclophosphamide, vincristine, prednisone, and asparaginase). 16/32 (50%) achieved complete remission and 15/32 (47%) partial response post-induction. 28/32 (88%) proceeded to AutoSCT; four patients had early disease progression, preventing AutoSCT. 21/28 (75%) required bridging chemotherapy - most commonly high dose cytarabine (3000 mg/m2 on days 1-6).

Nearly all patients (26/28, 93%) received conditioning with VP16-CyTBI (etoposide 1800/m2 on day -7, cyclophosphamide 50mg/kg on days -6 to -4 and TBI 200cGy BID on days -3 to -1) pre-AutoSCT. Two received BEAM (carmustine, etoposide, cytarabine, melphalan); both died from disease relapse post-AutoSCT. The stem cell source was bone marrow in 54% and peripheral blood in 46%.

During treatment, all but one had febrile neutropenia and 12/21 (63%) had positive microbiology. Three patients were treated for invasive fungal infection, although only one had a confirmed diagnosis. 5/32 (16%) developed C. difficile infection. 14/32 (44%) patients had unplanned hospital admissions with an average length of stay of 21 days. 5/32 (16%) required ICU admission, two at initial presentation and two post-AlloSCT. Significant viral infections were seen only in the AlloSCT setting.

After a median follow-up of 43 months (range 3-166), 16/32 (50%) patients remained alive, all but one in remission. The estimated 5-year EFS was 46% (95% CI 27-63). 13/28 (46%) patients relapsed post-AutoSCT; the median time to relapse was 10 months (range 3-57). At relapse, eight patients presented with ALL (one with concomitant CSF involvement, one with testicular involvement); three had mediastinal disease; one transformed to mixed phenotype leukemia, myeloid/lymphoid; and one had isolated CSF involvement. 3/13 (23%) who relapsed post-AutoSCT went on to receive AlloSCT following salvage chemotherapy; all died in remission from an infection at 1, 3, and 22 months post-AlloSCT respectively. All other deaths were with relapsed disease. There was no statistically significant difference in EFS by stem cell source (p=0.25). EFS was significantly longer in patients with T-LBL compared to those with B-LBL (HR 0.23, 95% CI 0.08-0.74, p=0.007; graph 2).

Discussion

Autologous stem cell transplantation with TBI-based conditioning for treatment of T-LBL is a viable treatment approach with acceptable tolerability and survival outcome. It also offers the advantage of a shorter treatment course compared to ALL-type chemotherapy. Further research is required to make direct comparison between these two distinct therapeutic approaches and provide guidance on the best practice.

Hay:Janssen: Research Funding; Bristol-Myers-Squibb: Honoraria; Kite/Gilead: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Nevill:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Sanford:Abbvie: Other: Advisory Board ; Astellas: Other: Advisory Board ; Pfizer: Research Funding. Song:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Sutherland:Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Sanofi: Consultancy. White:Novartis: Honoraria. Chung:Astellas: Honoraria, Other: Advisory Board ; Takeda: Consultancy, Honoraria.