Management of Postransplant Relapse and Persistent Disease in Lymphoid Malignancies: Exploring the Graft versus Lymphoma Effect

Research Article

Ann Hematol Oncol. 2015;2(4): 1034.

Management of Postransplant Relapse and Persistent Disease in Lymphoid Malignancies: Exploring the Graft versus Lymphoma Effect

Cabrero M, López-Godino O, López-Corral L, Martín A, García-Sanz R, Mateos MV, Perez Lopez E, Labrador J, Vázquez L, Sanchez-Guijo F, Del Ca�izo C and Caballero D*

Department of Hematology, Hospital Universitario Salamanca, Spain

*Corresponding author: Dolores Caballero, Department of Hematology, Hospital Universitario Salamanca-IBSAL, Spain

Received: January 26, 2015; Accepted: April 21, 2015; Published: April 27, 2015


Allogenic hematopoietic Stem Cell Transplantation (AlloSCT) is potentially a curative option for relapse or refractory lympho proliferative disorders, based in part on the Graft Versus Lymphoma Effect (GVLE). However, the role of GVLE enhancement and the means of implementing it effectively in relapse or persistent disease after AlloSCT remain unclear. We report the evaluation of 26 patients with post-AlloSCT relapse or persistent disease in a series of 112 AlloSCTs. In 19/26 (73%) patients, GVLE was enhanced by tapering immunosuppressive treatment (IST) and/or Donor Lymphocyte Infusion (DLI), achieving a response in 13 (68%), 11 of which were Complete Remissions (CRs). With respect to histology’s, an immune-mediated response was observed in 6/6 patients with NHL, 5/7 with CLL and 2/6 with HL. Graft Versus Host Disease (GVHD) appeared in 16/19 (84%); only one death was ascribed to GVHD. The remaining 7/26patients, in whom GVLE enhancement was not possible due to GVHD, received conventional chemotherapy with or without radiotherapy; two patients achieved CR and one achieved Partial Remission (PR).

Four-Year Progression-Free Survival (PFS) and Overall Survival (OS) after treatment of relapse/refractory patients were 40% and 45%,respectively (median follow-up, 56 months; range 11-138 months).

Disease response to immune manipulation proves the existence of GVLE, which appears in all histological subtypes, although less frequently in HL. GVLE enhancement enables us to ensure maintained responses, with PFS and OS similar to those in non-relapsing patients. Therefore, the immune approach should always be considered as a treatment for relapse/refractory patients.

Keywords: Chronic lymphocytic leukemia; Non-hodgkin lymphoma; Hodgkin lymphoma


Allogenic hematopoietic stem cell transplantation (AlloSCT) is potentially a curative option for refractory or relapsed lympho proliferative disorders such as Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL) and Chronic Lymphocytic Leukemia (CLL). The Reduced-Intensity Conditioning (RIC) regimen has lowered the high non-relapse mortality rate previously reported with conventional AlloSCT, so this procedure can be offered to patients who are older, with co morbidities or who have received a previous treatment that excludes them from a myeloablative conditioning regimen. The curative effect of AlloSCT is mainly based on the potential occurrence of the immune Graft Versus Lymphoma Effect (GVLE).It can overcome adverse prognostic factors, allowing patients to achieve long-term Disease-Free Survival (DFS) [1] .The existence of GVLE is supported by the lower relapse rate associated with the development of chronic Graft Versus Host Disease (GVHD) as well as the long-term remissions observed after Donor Lymphocyte Infusions (DLIs) in patients with lymphoid malignancies who relapse after AlloSCT [2,3].

The relapse rate after AlloSCT is highly variable in lymph proliferative disorders, ranging between 20 and 70%, depending on histological subtype and clinical status [4-7]; it is clear that, if the GVLE is the main goal of allogenic transplant, it should be enhanced if relapse occurs. However, few reports have focused on GVLE enhancement for treating relapse after AlloSCT [8]. Accordingly, there is no consensus about the best strategy for managing post- AlloSCT relapsed or persistent disease, and the most effective means of fuelling up GVLE remains unclear.

In the present study, we evaluate how GVLE enhancement, through tapering Immune Suppressive Treatment (IST) and/or DLI, is able to control the disease in patients with lymphoid malignancies who relapse after AlloSCT or whose disease persists by day +100.

Patients and Methods

Starting with our AlloSCT database of 112 patients who received an AlloSCT between January 1999 and December 2012, we selected those with NHL, HL or CLL. The current indications for AlloSCT in our center are: 1) patients with aggressive NHL who do not achieve at least a Partial Response (PR) after two lines of chemotherapy or relapse after Autologous Stem Cell Transplant (ASCT); 2) patients within do lent lymphomas and several relapses; 3) patients with HL who relapse after ASCT; 4) poor-risk CLL according to the 2007 EBMT consensus (17p deletion and/or resistance to purine analogues) [9].

From all patients with CLL, NHL or HL who consecutively underwent Reduced Intensity Conditioning (RIC) followed by AlloSCT, we identified those who had not achieved Complete Remission (CR) by day +100 or who had relapsed after AlloSCT, and thereby managed to recruit 26 patients.

We collected data from all 26 patients about the treatment applied and their response. Baseline clinical data were previously reported in the EBMT-group database and additional information from patient medical records was collected. Every patient and donor signed a consent form before AlloSCT.

Our primary objective was to evaluate whether potentiating of GVLE can contribute to control the disease in patients with persistent disease at day +100 or who had relapsed after AlloSCT. A secondary objective was to evaluate progression-free survival and Overall Survival (OS) in the whole series of patients, recalculating the outcome in a second step after GVLE enhancement in those patients who relapsed or progressed after AlloSCT.

Response and Graft Versus Host Disease Assessment

Disease response was assessed by chest-abdomen-pelvis Computerized Tomography (CT) or Positron Emission Tomography (PET), and bone marrow biopsy if necessary, according to standard criteria [10] on day +100, or earlier if progression or relapse was suspected. Thereafter, the disease was evaluated on the basis of clinical criteria according to the standard of care at our center, with radiological evaluations every 3 months during the first year post-AlloSCT. In relapsed/persistent disease, at least one complete evaluation was undertaken after each treatment line had been completed.

GVHD diagnosis was based on clinical and histological criteria. Acute GVHD was classified as grade 0 to IV according to the international standards [11], and chronic GVHD was defined as mild, moderate or severe according to the recommendations of the NIH working group, which includes the category of acute lateonset GVHD (features of acute GVHD appearing after day +100) and overlap syndrome (diagnostic or distinctive features of chronic GVHD and acute GVHD appearing together) [12].

Statistical Analysis

Statistical analyses were done using SPSS version 20.0 (SPSS, Chicago, IL, USA).

Frequencies among the classes of categorical variables were examined with the chi-square test. OS and PFS were estimated by the Kaplan–Meier (KM) method, and KM curves were compared by the log-rank test.

OS was defined as the time from the date of AlloSCT to death from any cause. Progression-free survival 1 (PFS-1) was taken as the time from the date of AlloSCT to death, progression or relapse, considering the first relapse or progression of the disease after AlloSCT as an event. PFS-2 was calculated as the time from AlloSCT to death, relapse or disease progression, but not considering the first relapse or progression as an event if it was controlled by GVLE enhancement.


Between 1999 and 2012, 112 patients with NHL, HL or CLL received a RIC AlloSCT in our Transplant Unit(13 diffuse large B cell lymphomas(11.6%), 22 indolent NHLs(19.6%), 25 CLLs (22.3%), 18 T cell lymphomas (TCLs) (16.1%), 10 mantle cell lymphomas(8.9%) and 24 HLs(21.4%)). The donor was unrelated in 34 patients (30.4% of cases). With a median follow-up of 58 (5-127) months, OS and PFS were 55.4% and 48.2%, respectively. The overall Non-Relapse Mortality (NRM) rate was 21.4%.

From this whole cohort, we recruited 26 patients with persistent disease at day +100 (n=11; 42.3%) or relapsed after AlloSCT (n=15; 57.7%) for the present study. Their baseline characteristics are summarized in Table 1.