Correspondence
Treatment of Leukemia in Relapse after Bone Marrow Transplantation
N Engl J Med 1994; 330:645-646March 3, 1994
- Article
To the Editor:
The prognosis of patients with a relapse of leukemia within the first year after allogeneic bone marrow transplantation is dismal. Giralt et al. (Sept. 9 issue)1 described seven patients whose leukemia had relapsed after allogeneic bone marrow transplantation. All were treated with granulocyte colony-stimulating factor (filgrastim) to induce terminal differentiation of the leukemic clone, selectively stimulate donor hematopoietic cells, and enhance the graft-versus-leukemia reaction. Three of the seven patients had a complete response, with reestablishment of hematopoiesis of donor origin. We observed such a trend toward a lower relapse rate in patients treated with recombinant granulocyte-macrophage colony-stimulating factor in a prospective randomized study comparing this factor with placebo in recipients of T-cell-depleted marrow from histocompatible sibling donors2.
There may be an alternative explanation for the remissions observed by Giralt et al. In all seven patients prophylaxis against graft-versus-host disease (GVHD) with cyclosporine and steroids was discontinued 7 to 14 days after filgrastim treatment was started. There have been reports of at least 10 patients with a relapse after allogeneic bone marrow transplantation who had a complete remission after the discontinuation of immunosuppressive therapy without any further specific antileukemic therapy3,4. Most, but not all, patients had clinically evident GVHD3. Interruption of immunosuppression may allow the expansion of donor cells capable of mediating a graft-versus-leukemia effect.
Immunomodulation to treat relapse after allogeneic bone marrow transplantation may be an attractive alternative to conventional chemotherapy or a second transplantation procedure. Several alternatives must be explored further, such as treatment with colony-stimulating factors, withdrawal of immunosuppression, and transfusions of donor lymphocytes5.
5 ReferencesTheo de Witte, M.D., Ph.D.
Ton Schattenberg, M.D., Ph.D.
University Hospital St. Radboud, 6525 GA Nijmegen, the Netherlands1
Giralt S ,Escudier S ,Kantarjian H , et al. Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation. N Engl J Med 1993;329:757-761
Full Text | Web of Science | Medline2
De Witte T ,Gratwohl A ,Van Der Lely N , et al. Recombinant human granulocyte-macrophage colony-stimulating factor accelerates neutrophil and monocyte recovery after allogeneic T-cell-depleted bone marrow transplantation. Blood 1992;79:1359-1365
Web of Science | Medline3
Collins RH Jr ,Rogers ZR ,Bennett M ,Kumar V ,Nikein A ,Fay JW . Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant 1992;10:391-395
Web of Science | Medline4
Alkam M ,Bradstock KF ,Hughes WG ,Watson N ,Bowyer I . Spontaneous complete remission of chronic myeloid leukaemia following haematological relapse after allogeneic bone marrow transplantation. Aust N Z J Med 1990;20:710-712
CrossRef | Medline5
Bar BM ,Schattenberg A ,Mensink EJ , et al. Donor leukocyte infusions for chronic myeloid leukemia relapsed after allogeneic bone marrow transplantation. J Clin Oncol 1993;11:513-519
Web of Science | Medline
To the Editor:
Giralt et al. reported that three of seven patients with a relapse of leukemia or myelodysplasia after allogeneic bone marrow transplantation had complete remissions after treatment with filgrastim. Apparently, four of the patients were receiving immunosuppressive therapy at the time of the relapse; such therapy was discontinued 7 to 14 days after the initiation of filgrastim treatment. The discontinuation of immunosuppressive therapy is known to result in long-term complete remissions,1,2 perhaps by unleashing donor-derived cells with antihost activity. If any of the patients whose immunosuppressive therapy was discontinued were among those who apparently responded to filgrastim, long-term remissions might have been a response to the discontinuation of immunosuppressive therapy rather than to treatment with filgrastim. Remissions that occurred soon after the initiation of filgrastim treatment, at about the time immunosuppressive therapy was discontinued, could simply reflect preferential stimulation of donor cells by filgrastim. If residual host malignant cells were not capable of proliferating in response to filgrastim, they might be expected to be diluted to below the limits of detection by donor cells responding normally to filgrastim; “remission” would not necessarily reflect a reduction in host malignant cells. Early remission could be explained by a dilutional effect, and long-term remission could be due to the discontinuation of immunosuppressive therapy. Since the use of filgrastim in the treatment of relapsed leukemia could result in disease progression, as occurred in one of the patients described by Giralt et al., clarification of these issues would be worthwhile before this approach is used in additional patients.
2 ReferencesRobert H. Collins, Jr., M.D.
Joseph W. Fay, M.D.
Baylor University Medical Center, Dallas, TX 752461
Higano CS ,Brixey M ,Bryant EM , et al. Durable complete remission of acute nonlymphocytic leukemia associated with discontinuation of immunosuppression following relapse after allogeneic bone marrow transplantation: a case report of a probable graft-versus-leukemia effect. Transplantation 1990;50:175-177
CrossRef | Web of Science | Medline2
Collins RH Jr ,Rogers ZR ,Bennett M ,Kumar V ,Nikein A ,Fay JW . Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant 1992;10:391-395
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drs. Collins and Fay as well as Drs. de Witte and Schattenberg correctly point out that withdrawal of immunosuppressive therapy occasionally reinduces remissions in patients who relapse after allogeneic bone marrow transplantation1-3. This is, however, a rare event. Two of the three patients who responded to filgrastim therapy in our series either were not receiving immunosuppressive therapy or were receiving a highly tapered dose at the time of relapse; therefore, it is unlikely that this mechanism had any effect on the subsequent response to filgrastim therapy. The third patient, who relapsed on day 120, was receiving cyclosporine, which was withdrawn abruptly during the two weeks before filgrastim therapy was begun; there was no improvement in her peripheral-blood counts, and leukopenia and thrombocytopenia progressed until the filgrastim therapy was begun, suggesting that if cyclosporine withdrawal had a role, it was a minor one at most.
We agree with Drs. Collins and Fay that disease progression is a potential complication of filgrastim therapy in this setting and have cautioned against its uncontrolled use. We have limited filgrastim therapy to patients with indolent relapses without peripheral-blood blasts or extramedullary disease. We believe that filgrastim is an investigational drug that should only be given in a setting with close patient follow-up.
The mechanism by which this therapy produced complete remissions in these patients is unknown and may reflect direct effects on the leukemia cells, stimulation of normal donor-derived hematopoietic cells, induction of secondary cytokines inhibiting the growth of leukemia cells, or modulation of the graft-versus-leukemia effect.
3 ReferencesRichard Champlin, M.D.
Sergio Giralt, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 770301
Giralt S ,Escudier S ,Kantarjian H , et al. Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation. N Engl J Med 1993;329:757-761
Full Text | Web of Science | Medline2
Higano CS ,Brixey M ,Bryant EM , et al. Durable complete remission of acute nonlymphocytic leukemia associated with discontinuation of immunosuppression following relapse after allogeneic bone marrow transplantation: a case report of a probable graft-versus-leukemia effect. Transplantation 1990;50:175-177
CrossRef | Web of Science | Medline3
Collins RH Jr ,Rogers ZR ,Bennett M ,Kumar V ,Nikein A ,Fay JW . Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant 1992;10:391-395
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
J.-M. Boiren, P. Cony-Makhoul, A. Pigneux, M. Puntous, J. Reiffers, J.-M. Boiron, F.-X. Mahon, A. Pigneux, J. Reiffer. (1994) Treatment of hematological malignancies relapsing after allogeneic bone marrow transplantation. Blood Reviews 8:4, 234-240
CrossRef
