Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia

Infusão de linfócitos do doador para o tratamento da doença residual mínima

ARTIGO ARTICLE

Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia

Infusão de linfócitos do doador para o tratamento da doença residual mínima

Andrea Bacigalupo; Alida Dominietto; Sarah Pozzi; Maurizio Miglino; Flavio Albarracin; Giovanna Piaggio; Francesca Bertolotti

Divisione di Ematologia e Trapianto di Midollo Osseo, Ospedale San Martino, Genova, Italy

^{Endereço para correspondência}

ABSTRACT

Minimal residual disease (MRD) was monitored in 80 patients with acute lymphoid (ALL, n=44) or myeloid (AML, n=36) leukemia, undergoing allogeneic haemopoietic stem cell transplantations. MRD markers were IgH-VDJ and TCR gene re-arrangement for ALL, and Wilm's Tumor (WT1) expression for AML. The overall cumulative incidence (CI) of MRD was positive in 45% and the CI of hematologic relapse was 24% (36% in MRD+ vs. 16% in MRD patients, p=0.03). The median interval from transplant to first MRD positivity was 120 days and to hematologic relapse 203 days. Patients were divided in 3 MRD groups: MRD (n=44), MRD+ given donor lymphocyte infusions (DLI) (n=17) and MRD+ not given DLI (n=19): leukemia relapse rates in these 3 groups were 16%, 6% and 63%, respectively (p<0.0001); the actuarial 3-year survival rates were 78%, 80% and 26% (p=0.001). In multivariate COX analysis, the MRD group was predictor of relapse (p<0.0001) and survival (p=0.01), together with disease phase and chronic graft versus host disease. In MRD+ patients, DLI protected against relapse (p=0.003) and improved survival (p=0.01). In conclusion, MRD positivity post-transplant predicts leukemia relapse: however, when MRD+ patients are given DLI, their outcomes are comparable to MRD- patients.

Key words: Minimal residual disease; acute myeloid leukemia; acute lymphoid leukemia; donor lymphocyte infusion; allogeneic hematopoietic stem cell transplantation.

RESUMO

A doença residual mínima (DRM) foi monitorada em 80 pacientes com leucemia linfóide aguda (n=44) e mielóide aguda (n=36) que foram submetidos ao transplante alogênico de célula-tronco. Marcadores da DRM foram a IgH-VDJ e rearranjo do TCR para a LLA e expressão do Tumor de Wills (WT1) para LMA. A incidência acumulada global (IC) para a DRM foi positiva em 45% e a IC para recaída hematológica foi 24% (36% na DRM+ versus 16% na DRM-, p=0.03). O intervalo mediano entre o TMO e a primeira DRM positividade foi dia +120, e para a recaída hematológica, dia +203. Os pacientes puderam ser divididos em três grupos: DRM-(n=44), DRM+ onde foi dada a infusão de linfócitos do doador (ILD) (n=17) e DRM+ não dado ILD (n=19): a recidiva nos três grupos foi de 16%, 6% e 63%, respectivamente (p<0.0001); a sobrevida em três anos foi 78%, 80% e 26% (p=0.001). No modelo de Cox, o grupo de DRM foi preditor de recidiva (p<0.0001) e sobrevida global (p=0.01), juntamente com a fase da doença e a doença do enxerto contra o hospedeiro. Na DRM+, IDL protegeu contra a recidiva (p=0.003) e melhorou a sobrevida (p=0.01). Em conclusão, a positividade para a DRM pós-transplante prediz recidiva da leucemia. Entretanto, quando é dada a ILD ao paciente DRM+, a evolução destes pacientes é comparável aos pacientes DRM-.

Palavras-chave: Doença residual mínima; leucemia mielóide aguda; leucemia linfóide aguda; infusão de linfócitos total; transplante alogênico de células-tronco hematopoéticas.

Hematologic relapse after an allogeneic hemopoietic stem cell transplant (HSCT) in patients with acute leukemia is associated with a poor outcome, despite further cell therapy in the form of donor lymphocyte infusions (DLI).¹ This has been taken as evidence that acute leukemia is less sensitive to the so called graft versus leukemia (GvL) effect, especially if compared with chronic myeloid leukemia (CML), in which DLI alone can induce durable long term molecular remissions.² However, several reports suggest a strong protection exerted by chronic graft versus host disease (GvHD) in acute lymphoid (ALL) and myeloid (AML) leukemia,^3,4 and low dose immunosuppression in the first days after transplant also reduces the risk of relapse.^5,6 Perhaps DLI would be effective in ALL and AML patients, if given when the tumor burden is low. Attempts to monitor minimal residual disease (MRD) in acute leukemia post-HSCT have been reported and seem to predict hematologic relapse.^7,8 Some of these patients were given immune intervention to prevent hematologic relapse.⁹

In this study we wished to assess (a) the predictive value of MRD on hematologic relapse post-transplant in AML/ALL patients and (b) whether cellular therapy with DLI would protect against leukemia relapse. We studied 80 patients with ALL (n=44) or AML (n=36), undergoing an allogeneic hemopoietic stem cell transplant. MRD was evaluated monthly, on bone marrow samples using a qualitative nested polymerase chain reaction (PCR) for IgH VDJ , as previously described,¹⁰ and TCR gene rearrangement for T-ALL. Real time PCR for Wilms Tumour (WT1) expression was used in AML.¹¹ MRD was considered positive in AML when WT1 copy numbers every 104 copies of Abl were superior to 180. Molecular positivity was defined as a positive PCR assay, in the presence of a marrow sample in hematologic remission (blast count < 5%).

The cumulative incidence of MRD positivity was 45%, with a median interval from transplant to first MRD positivity of 120 days, and from transplant to hematologic relapse of 203 days. Hematologic relapse was significantly higher in MRD+ patients (36%) as compared to MRD- patients (16%), p=0.03). Patients were analyzed according to whether they were always MRD- (n=44), MRD+ receiving DLI (MRD+DLI+) (n=17) or MRD+ non receiving DLI (MRD+DLI-) (n=19). Reasons for not giving DLI were presence or development of GvHD after cessation of immunosuppressive therapy (n=7), donor unavailable (n=8), early relapse (n=2), other (n=2). Hematologic relapse was 16% in MRD- patients, 6% in MRD+DLI+ patients and 63% in MRD+DLI- patients (p<0.0001); the actuarial 3 year survival in these three groups was 78%, 80% and 26% (p=0.001) . Mortality due to acute GvHD following DLI was 12%. In multivariate COX analysis, MRD group predicted relapse (p<0.0001) and survival (p=0.01), together with disease phase and chronic graft versus host disease. In MRD+ patients, DLI protected against relapse (p=0.003) and improved survival (p=0.01).

In conclusion, we confirm that minimal residual disease detected post-transplant is a significant predictor of relapse. Treatment of MRD with donor lymphocyte infusions, appears to protect against leukemia relapse, although caution with DLI dosing, needs to be used, because of the potential risk of graft versus host disease.

Recebido: 13/05/2008

Aceito: 13/05/2008

This work was partly supported by Associazione Italiana Ricerca contro il Cancro (A.I.R.C.) Milano, Foundation FA-RITMO and CARIGE Genova.

O tema apresentado constou do programa do Encontro AIBE.

Avaliadores: Professores Ângelo Maiolino, Cármino Antonio de Souza e Marcio Nucci.

Publicado após concordância do editor.

Conflito de interesse: não declarado.

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Publication Dates

• Publication in this collection
  09 Dec 2008
• Date of issue
  June 2008

History

• Accepted
  13 May 2008
• Received
  13 May 2008