Original Article
Preliminary Results of Treatment with Filgrastim for Relapse of Leukemia and Myelodysplasia after Allogeneic Bone Marrow Transplantation
N Engl J Med 1993; 329:757-761September 9, 1993
- Abstract
Background
Patients whose leukemia relapses after allogeneic bone marrow transplantation have a poor prognosis; few respond to further chemotherapy, and almost none survive over the long term. We present preliminary observations on the use of filgrastim (granulocyte colony-stimulating factor) for relapse after transplantation.
Methods
Seven female patients with leukemia (one with chronic myelogenous leukemia, five with acute myelogenous leukemia, and one with a myelodysplastic syndrome that transformed into acute myelogenous leukemia) whose disease relapsed within 360 days after allogeneic bone marrow transplantation received filgrastim (5 μg per kilogram of body weight per day by subcutaneous injection) to reinduce remission by stimulating residual donor marrow cells. Cytogenetic analysis of bone marrow, fluorescence in situ hybridization, and determination of restriction-fragment-length polymorphisms were used to assess response and chimerism.
Results
Three of the seven patients had a complete hematologic and cytogenetic remission, with reestablishment of hematopoiesis of donor origin. Mild chronic graft-versus-host disease developed in one patient, and acute graft-versus-host disease in none. One patient had a relapse 12 months after treatment, and two others remained in remission after 10 and 11 months. In two of the patients with a response, fluorescence in situ hybridization demonstrated stimulation of donor cells without differentiation of the leukemic clone.
Conclusions
Filgrastim may be effective in selected cases of leukemic relapse after allogeneic bone marrow transplantation.
Media in This Article
Figure 1
RFLP Analysis (Southern Blotting) of Donor Cells and Cells from Patient 1 before (Day 250, Panel A) and after (Day 343, Panel B) Treatment with Filgrastim.Table 1
Characteristics of Seven Patients with Relapse of Leukemia after Allogeneic Bone Marrow Transplantation.Article Activity
- Article
In many patients with leukemia or myelodysplastic syndromes, the underlying disease recurs after allogeneic bone marrow transplantation1. Attempts to reinduce durable remissions with chemotherapeutic agents or a second bone marrow transplant are usually unsuccessful2-5. The chimeric state that follows transplantation provides an opportunity for novel therapeutic approaches, such as selective stimulation of hematopoiesis of donor origin or augmentation of the graft-versus-leukemia (GVL) reaction6-9.
We observed one patient in whom pancytopenia associated with relapse of Philadelphia chromosome-negative chronic myelogenous leukemia developed after allogeneic bone marrow transplantation. Complete hematologic recovery and cytogenetic remission occurred on treatment with filgrastim (granulocyte colony-stimulating factor) without cytotoxic treatment10. Six other patients who had recurrent disease after allogeneic bone marrow transplantation were treated with filgrastim and are described in this report.
Methods
Transplantation Procedures
Seven patients received allogeneic bone marrow from an HLA-identical sibling. The patients' characteristics are summarized in Table 1Table 1
Characteristics of Seven Patients with Relapse of Leukemia after Allogeneic Bone Marrow Transplantation.. All were female, with a median age of 27 years (range, 16 to 50). Five patients had acute myelogenous leukemia (one of whom had previously had myelodysplastic syndrome), one had refractory anemia with an excess of blast cells, and one had Philadelphia chromosome-negative chronic myelogenous leukemia. None of the patients received a T-cell-depleted transplant, and all received cyclosporine after transplantation to prevent graft-versus-host disease (GVHD). Serial cytogenetic and chimerism studies were performed on bone marrow aspirates. Restriction-fragment-length polymorphisms (RFLPs) were determined to assess chimerism, according to established techniques17,18 (Collaborative Research, Waltham, Mass.).Characteristics at Relapse
Relapse was indicated by the presence of more than 5 percent blast cells in a bone marrow aspirate or the presence of an abnormal clone detected by standard cytogenetic techniques. Six patients had a relapse between 40 and 360 days after transplantation. One patient with refractory leukemia did not enter remission after the conditioning regimen. Four patients were receiving cyclosporine to prevent GVHD at the time of relapse. Only one patient had grade 2 GVHD before relapse. One patient had a new chromosomal abnormality, 46,XX,t(1;6)(p34;q27). All other patients had relapses in host-derived cells with characteristics of their original disease.
Cytogenetic Analysis
Chromosome studies were carried out in all seven patients before filgrastim treatment and periodically thereafter, according to standard techniques19. A minimum of 25 metaphases were analyzed, if possible, and characterized according to standard nomenclature20.
Fluorescence in Situ Hybridization
Fluorescence in situ hybridization was performed on marrow samples from two patients with responses (Patients 2 and 3). Patient 2 had a karyotype of 47,XX,+8 and received bone marrow from her brother. A biotinylated centromeric probe specific for chromosome 8 (Oncor, Gaithersburg, Md.) and a digoxigenin-labeled centromeric probe for the Y chromosome were used for hybridization according to a modification of a previously reported technique21. The probes were detected with avidin-Texas red and anti-digoxigenin fluorescein isothiocyanate. The nuclei were counterstained with 4'6-diaminidino-2-phenyl-indole. Hybridization signals were counted in 200 to 500 cells with a fluorescence microscope.
Patient 3 had a karyotype of 46,XX, del(16) (q12),del(19) (p13.3),del(20) (q11) and received bone marrow from her brother. Directly labeled X and Y chromosome probes were used for hybridization (Imagenetics, Naperville, Ill.). The cells were denatured, hybridized, washed, and counted as described above.
Filgrastim Therapy
During relapse after allogeneic bone marrow transplantation, the patients were treated with a daily subcutaneous injection of 5 μg of filgrastim (Neupogen, Amgen, Thousand Oaks, Calif.) per kilogram of body weight. Patient 1 was treated for 21 days, and the other two patients who responded were still receiving filgrastim at the most recent follow-up.
Treatment with cyclosporine and steroids was discontinued 7 to 14 days after filgrastim treatment was started.
Definition of Response
A complete hematologic response was indicated by a granulocyte count above 1500 per cubic millimeter, a platelet count above 100,000 per cubic millimeter, and the absence of a need for red-cell transfusions, with normal bone marrow (i.e., marrow with less than 5 percent blast cells, no leukemic cells, and all cell lines present and maturing) for at least four weeks. A complete cytogenetic response was indicated by the presence of 100 percent normal donor cells on cytogenetic examination. Patients who had more than 20,000 peripheral-blood blast cells per cubic millimeter or who had no response after four weeks of therapy were withdrawn from the study.
Results
Response to Filgrastim
Complete hematologic and cytogenetic remission with reestablishment of donor hematopoiesis occurred in three of the seven patients within 10 to 21 days after treatment began. Data on chimerism in all the patients are summarized in Table 2Table 2
Outcome of Filgrastim Therapy.; chimerism in Patient 1 is shown in Figure 1Figure 1RFLP Analysis (Southern Blotting) of Donor Cells and Cells from Patient 1 before (Day 250, Panel A) and after (Day 343, Panel B) Treatment with Filgrastim..All patients responded with an increase in their granulocyte count after seven days of therapy. None of the three patients who had complete responses had blast cells in their peripheral blood. All four patients without responses had an increase in their peripheral-blood blast-cell count; in one patient the increase appeared to be accelerated by the use of filgrastim. Only the three patients with complete responses had increases in their platelet counts; in these patients, the rate of marrow-cell maturation and differential cell counts became normal after 7 to 14 days of filgrastim treatment. In the patients who had no response, myeloid hyperplasia with increased blast-cell counts and maturation arrest was commonly observed (Table 3Table 3
Effect of Filgrastim on Peripheral-Blood and Bone Marrow Cells.).In response to filgrastim treatment, Patient 1 remained in remission one year. After her second relapse she again received filgrastim, with no response. The two other patients who had responses continued to receive therapy and were in remission 10 and 11 months after treatment was initiated. None of the other patients responded to salvage chemotherapy, and all died of their disease.
Toxicity
The toxic effects of the filgrastim therapy were minimal: only one patient required a reduction of her dose, because of bone pain. The therapy did not exacerbate acute GVHD. In one patient who responded, the alkaline phosphatase and bilirubin levels increased during filgrastim therapy, and the results of a liver biopsy were compatible with chronic GVHD. After she was treated with systemic corticosteroids, her liver function became normal.
Fluorescence in Situ Hybridization
Patient 2 had acute myelogenous leukemia and trisomy 8. At relapse, 10 percent of her bone marrow cells lacked a Y chromosome and had trisomy 8, 86 percent were diploid for chromosome 8 and contained a Y chromosome, and less than 1 percent of cells were diploid for chromosome 8 and lacked a Y chromosome. Follow-up studies 7, 8, and 10 weeks later showed that the percentage of host (female) cells indicating trisomy 8 had decreased to less than 2 percent.
Patient 3 had two X chromosomes in 76 percent of cells at the time of relapse. By day 10 of treatment, the percentage of donor-derived XY cells had increased to 83 percent and that of XX cells had decreased to 15 percent. On follow-up studies on day 18, cells with a female karyotype had disappeared. The percentage of host cells, recorded monthly for four months, ranged from 1 percent to 4.5 percent.
The granulocyte and mononuclear-cell counts, recorded separately at selected times, showed percentages of host and donor cells that were similar to those in unseparated blood and bone marrow (Table 4Table 4
Percentage of Host and Donor Cells as Determined by Fluorescence in Situ Hybridization during Filgrastim Therapy.).Discussion
The chimeric state that follows allogeneic bone marrow transplantation allows clinicians to consider innovative approaches in the event of leukemic relapse7. Residual normal hematopoiesis and immunity typically remain of donor origin. Potential therapeutic interventions include selective stimulation of donor hematopoietic cells and enhancement of the GVL reaction.
Filgrastim can induce terminal maturation of myeloid leukemia cell lines and suppress their capacity for self-renewal22. It stimulates the proliferation and maturation of neutrophil precursors in vitro and induces granulocytosis in vivo. Filgrastim therapy increases the number of circulating neutrophils, usually without affecting erythropoiesis and megakaryopoiesis. In patients with myelodysplasia, filgrastim can stimulate both normal cells and the dysplastic clone; in some patients, the number of abnormal cells increases, and in others it decreases23-25.
In this trial, filgrastim treatment reinduced remission in three patients whose disease relapsed early after allogeneic transplantation. Of the patients who did not respond, one had a dramatic increase in the number of peripheral-blood blast cells after four days of treatment, suggesting that in some patients this approach could stimulate leukemic cell growth.
Remission may have been reinduced by filgrastim through several possible mechanisms: preferential stimulation of donor hematopoietic progenitors; induction of differentiation, with loss of the leukemic clone's capacity for self-renewal; or induction of secondary cytokines in filgrastim-responsive cells, suppressing proliferation of the abnormal clone or enhancing a GVL reaction. The fluorescence in situ hybridization studies failed to detect clonal abnormalities in maturing cells, suggesting that the malignant clone did not mature or differentiate.
Of the three responding patients, two had no signs of GVHD during filgrastim treatment; the third had chronic GVHD during therapy after donor hematopoiesis was reconstituted. A reduction of either immunosuppressive therapy or filgrastim therapy could activate the cellular mechanisms responsible for the GVL effect.
We conclude that treatment with filgrastim results in the reestablishment of normal donor hematopoiesis in selected patients with leukemic relapse after allogeneic bone marrow transplantation. This offers a potential new strategy for reinducing remission and, possibly, preventing relapse in this setting. Further study may provide insight into the mechanisms involved in maintaining remission after allogeneic bone marrow transplantation.
We are indebted to the technical personnel at Collaborative Research for the RFLP studies; to Denise Lovshe, C.L.Sp.(C.G.), and Kimberley Hayes, C.L.Sp.(C.G.), for the cytogenetic studies; to Dr. Roger Lyons for assisting in the care of Patient 2; to Dr. Steve Seelig (Imagenetics) for providing the probes for in situ hybridization; to the physicians and nurses at M.D. Anderson Cancer Center who cared for the patients; to Eva Barcelo for assistance in the preparation of the manuscript; and to Katy Hall for editorial advice.
Source Information
From the Departments of Hematology (S.G., S.E., H.K., A.D., E.J.F., B.S.A., S.O., M.A., R.E.C.) and Laboratory Medicine (H.F., A.C., C.H.-G., J.T., S.S.), University of Texas M.D. Anderson Cancer Center, Houston.
Address reprint requests to Dr. Champlin at Bone Marrow Transplantation, Department of Hematology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
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