Efficacy of Adoptive Immunotherapy with Donor Lymphocyte Infusion in Relapsed Lymphoid Malignancies

DLIs are frequently used following haematopoietic SCT (HSCT) in patients with risk of relapse but data on GVHD following DLI are scarce. We report on 68 patients who received DLI following HSCT. Most patients developed GVHD following DLI (71%), which was acute in 22 patients (32%) almost half of whom had grade III-IV acute GVHD (aGVHD). Thirty patients (44%) developed cGVHD which followed aGVHD in four patients and was graded severe in nine patients. Corticosteroids were the most common first-line therapy for both acute and chronic GVHD. A wide range of second/third-line agents included cyclosporin, mycophenolate, tacrolimus, imatinib, infliximab and ECP. Relapse of initial malignancy occurred in 37%. Relapse was significantly less frequent in those receiving pre-emptive DLI. Relapse rates were also lower in those with GVHD (31%) than those without GVHD (50%), but this did not reach statistical significance. At 55 months post DLI, 34% of patients had died most commonly from relapse and 22% had on-going GVHD. Although GVHD was an important cause of morbidity post DLI (71%), only 6% died from GVHD. Although most patients develop GVHD post DLI and may require consecutive therapies, mortality from GVHD is infrequent. DLI remains an important option for relapse post transplant and manipulation of the GVT effect needs to be optimised to induce remission without morbidity from GVHD.Bone Marrow Transplantation (2015) 50, 62-67; doi:10.1038/bmt.2014.227; published online 13 October 2014 INTRODUCTION DLI is the only form of adoptive immunotherapy that is in widespread use following haematopoietic SCT (HSCT) in patients with either mixed donor chimerism (pre-emptive) or relapse (therapeutic) to harness the graft-versus-tumour (GVT) effect. The first report of DLI leading to remission of disease following relapse after HSCT was in a patient with CML in 1990.1 Prior to DLI, patients relapsing post HSCT would likely succumb to their disease and a few would receive a second transplant. Following success in CML, DLI was then utilised for other haematological malignancies such as acute leukaemia and myeloma. [2][3][4][5][6] The GVT effect, which is responsible for enabling sustained remission, is also responsible for the most frequent toxicity, GVHD. For this reason, significant pre-existing GVHD is considered a relative contraindication to DLI. There are limited data on the characteristics of GVHD post DLI or response to therapy. The aim of this study was to perform a multicentre study to investigate the type, severity, treatment and response rates of GVHD and DLI schedule.

Section: Discussionmentioning

confidence: 55%

A multicentre UK study of GVHD following DLI: Rates of GVHD are high but mortality from GVHD is infrequent

Scarisbrick¹,

Dignan

Tulpule

et al. 2014

“…As a prophylactic or therapeutic regimen, DLI has been widely employed to boost the graft-vs-tumor (GVT) or GVL effects. 3,6,7 Clinical data have shown that DLI is most effective for CML [7][8][9][10] and the response rate is 70-80% for hematological or cytogenetic relapse, 9 whereas the benefit of DLI for relapsed acute leukemia is often limited, 11 mainly because of the rapid growth of leukemic cell burden, poor response to the GVL reaction 9 and the development of GVHD 12 and aplasia. 8 To overcome these limitations, researchers have attempted to modify the DLI strategies depending on different clinical settings.…”

Section: Introductionmentioning

confidence: 99%

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT

Chang

Zang

Xia

2015

DLI is an effective strategy for patients with recurrent hematological malignancies after allogeneic hematopoietic SCT (allo-HSCT). DLI has been widely applied to boost the graft vs tumor (GVT) or GVL effects. However, given the potentially severe complications associated with conventional DLI and transient GVL effect, new strategies for DLI are emerging. In this review, we have discussed the recent important studies on DLI as a prophylactic or therapeutic modality for relapsed hematological disorders after allo-HSCT. The strategies to separate GVL from GVHD have also been discussed. Leukemia-targeting therapy and lymphodepletion combined with DLI, and prophylactic DLI after allo-HSCT are often employed for patients with high risk of relapse, which has been reviewed as well. In addition, we have also discussed the issues on DLI to be further addressed, such as the doses, timing and frequency of DLI in different clinical settings, leukemic antigen-specific DLI as well as how to augment GVL effect while attenuating GVHD.

“…65 Administration of DLI for relapsed after a T-cell replete allo-HCT is more challenging; but yet capable of inducing responses in over one-third of cases provided that active GVHD is absent. 78,79 FUTURE DIRECTIONS Earlier application of auto-HCT in high-risk HL, destined to do poorly with standard chemotherapies and before emergence of chemoresistance warrants prospective investigation. This strategy could potentially be explored with either high CD68 þ tumor infiltrating macrophages or positive mid-or end-front-line therapy PET scans.…”

Section: Discussionmentioning

confidence: 99%

“…78 A recent meta-analysis showed a pooled proportion of CR of 37% after DLI in T-depleted or T-replete allo-HCT. 79 Brentuximab vedotin combined with DLI for early relapse after allo-HCT induces tumor-specific immunity and sustained clinical remission. 80 This approach is interesting to explore in a prospective clinical trial.…”

Section: Managing Relapse After An Allo-hct Donor Lymphocyte Infusionmentioning

confidence: 99%

Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good cancer after all!

Kharfan‐Dabaja

Hamadani

Sibai

et al. 2014

Hodgkin lymphoma (HL) relapsing after an autologous hematopoietic cell transplant (HCT) poses a therapeutic challenge. In this setting, salvage chemotherapy (for example, gemcitabine-based, ifosfamide-containing and others) or immunotherapy (for example, brentuximab vedotin) is essential as a bridging-cytoreduction strategy to an allogeneic HCT. Myeloablative allogeneic hematopoietic cell transplantation in relapsed HL is associated with high rates of non-relapse mortality. In carefully selected patients with chemosensitive disease, allografting following lower-intensity conditioning regimens can provide durable disease control rates of about 25-35%. Promising early results with haploidentical and umbilical cord transplantation are noteworthy and are expanding this procedure to patients for whom HLA-matched related or unrelated donors are not available. Unfortunately, a significant number of HL patients relapsing after an autologous HCT are not candidates for allografting because of the presence of resistant disease, donor unavailability or comorbidities. Brentuximab vedotin is approved for HL relapsing after a prior autograft. Rituximab and bendamustine are also active in this setting, albeit with short durations of remission. Histone deacetylase inhibitors (for example, panobinostat, mocetinostat), mTOR inhibitors (for example, everolimus) and immunomodulatory agents (lenalidomide) have shown activity in phase II trials, but currently are not approved for this indication. Second autologous HCT are rarely performed but this approach should not be considered standard practice at this time. The need for effective agents for post autograft failures of HL largely remains unmet. Continuous efforts to ensure early referral of such patients for allogeneic HCT or investigational therapies are the key to improving outcomes of this not-so-good lymphoma.