Japanese Journal of Clinical Oncology Advance Access originally published online on January 19, 2006
Japanese Journal of Clinical Oncology 2006 36(1):46-49; doi:10.1093/jjco/hyi211
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© 2006 Foundation for Promotion of Cancer Research
Alemtuzumab, Fludarabine and Melphalan as a Conditioning Therapy in Severe Aplastic Anemia and Hypoplastic Myelodysplastic Syndrome—Single Center Experience
Department of Clinical Oncology, BMT Unit, Central Clinical Hospital Ministry of National Defence, Warsaw, Poland
For reprints and all correspondence: Piotr Rzepecki, Department of Clinical Oncology, BMT Unit, Central Clinical Hospital Ministry of National Defence, 128 Szaserow Street, 00-909 Warsaw, Poland. E-mail: piotr_rzepecki1{at}poczta.onet.pl
Received October 5, 2005; accepted November 17, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Allogeneic hematopoietic stem cell transplantation is the treatment of choice in young patients with severe aplastic anemia. The main causes of failure after this procedure are graft versus host disease, infections and graft failure, often exacerbated by large numbers of transfusions and prolonged disease duration before transplant.
Methods: We report the results of allografting following conditioning with fludarabine, alemtuzumab and melphalan in: five patients with severe aplastic anemia and one with hypoplastic myelodysplastic syndrome. All patients had matched sibling donors. Source of hematopoietic stem cell was: bone marrow—2, blood—3, bone marrow and blood—1. The age of recipients was 18–26 years. Four patients received their graft as the first line therapy and two after failure of cyclosporine and antithymocyte globulin treatment. Number of transfused units including red blood cells and platelets before transplantation was 8–100 (median: 22) and 10–32 (median: 11), respectively. All donors and recipients were CMV-seropositive. Conditioning consisted of: alemtuzumab 30 mg/d (day –7 to –5), fludarabine 30 mg/m2 (days –7 to –3) and melphalan 140 mg/m2 at the day –2.
Results: The time to granulocytes and platelets recovery was 15 and 25 days, respectively. All patients achieved full donor chimerism on day +60. Only two patients needed ganciclovir as preemptive therapy. Recurrent parvovirus B19 infection with pure red cell aplasia and acute viral B hepatitis was observed in one case. Pure red cell aplasia was successfully treated with immunoglobulins and cyclosporine discontinuation. With a follow-up of 16–39 (median: 29) months all patients are alive, and neither graft failure nor graft versus host disease, or any no other severe complications, was observed.
Conclusions: Our study suggests that transplantation of hematopoietic stem cell using alemtuzumab, fludarabine and melphalan as a conditioning therapy is safe, inexpensive and effective treatment for patients with severe aplastic anemia, including multi-transfused adults having their disease for a long time.
Key Words: aplastic anemia • hypoplastic myelodysplastic syndrome • alemtuzumab • fludarabine
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Results of hematopoietic stem cell transplantation for patients with acquired severe aplastic anemia (SAA) have improved considerably over the last decades. The long-term survival of SAA with bone marrow transplantation (BMT) using HLA– identical family donors is in the range of 75–90% (1–4). Three major transplant-related problems were found in aplastic anemia: graft rejection, acute graft versus host disease (GVHD) and chronic GVHD. The incidence of graft rejection has decreased in part because of the use of more effective immunosuppressive conditioning regimens and in part because of changes in transfusion practices—the use of irradiated and leukocyte-depleted blood products before transplant. A higher risk of graft rejection was associated with a higher number of prior transfusions (5–6). Intensive immunosuppression is a key factor for the successful outcome of these transplants. The incidence of acute GVHD has also decreased owing to improved GVHD prevention protocols. Chronic GVHD continues to be a major complication of marrow grafting for SAA. The incidence of it may be decreasing, but mortality from it has not changed much despite prompt therapy. Unlike the graft versus leukemia effect associated with chronic GVHD that can improve survival of patients with leukemia, there is no benefit of chronic GVHD in patients transplanted with SAA. In most current series of matched sibling transplants that included adults the incidence of chronic GVHD was
30%. Therefore, better ways of preventing chronic GVHD are necessary (7–9). In a non-randomized trial a combination of cyclophosphamide (CTX) and antithymocyte globulin (ATG) resulted in a lower incidence of chronic GVHD and improved survival compared with historical controls who received cyclophosphamide alone. However, a prospective randomized trial in 131 patients did not detect a significant benefit from the addition of ATG to CTX as a preparative regimen (10–12). Use of alemtuzumab, anti-CD52 monoclonal antibody showed low incidence of GVHD in marrow transplants from HLA– identical siblings donors in patients with SAA (13). Fludarabine may be used to augment a conditioning regimen for multitransfused or alternative donor transplantation for SAA patients (14). We applied a fludarabine, alemtuzumab and melphalan as a conditioning regimen in 6 six patients: five with SAA, one with hypoplastic myelodysplastic syndrome and report our results here.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENTS
From August 2002 to May 2004 six patients: 5 five with SAA, one with hypoplastic myelodysplastic syndrome received fludarabine, alemtuzumab and melphalan as conditioning regimen before allogeneic transplantation (HSCT) (Table 1). Interval from diagnosis to HSCT was 5–24 months (median: 7) and all were transfusion dependent at the time of transplantation. All patients had normal organ functions, absence of active infections or concomitant life-threatening illnesses. All patients received graft from their matched sibling donors. Source of hematopoietic stem cell was: bone marrow in two, peripheral blood in three, combined bone marrow and peripheral blood in one. The age of recipients was 18–26 (median: 22) years. All donors and recipients were CMV-seropositive. Four patients received their graft as the first line of therapy, two after failure of cyclosporine and ATG/ALG treatment. The last 26-year-old patient received unmanipulated bone marrow and stem cells from peripheral blood from his HLA-identical sister in June 2002. Interval from diagnosis to transplant was nearly 2 years. Before transplantation he was treated with two courses of ATG, cyclosporine A, GM-CSF or G-CSF, erythropoietin without any stable improvement. Then oral cyclophosphamide, 150 mg daily was used but liver injury occurred and treatment was interrupted. Before transplantation the number of transfusions including RBCs and platelets was 100 and 20 units, respectively.
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PREPARATIVE REGIMEN AND GVHD PROPHYLAXIS
The conditioning regimen consisted of: alemtuzumab 30 mg daily from day –7 to –5, fludarabine 30 mg/m2/daily from days: –7 to –3 and melphalan 140 mg/m2 on day –2. Unmanipulated hematopoietic stem cells were infused on day 0 in all patients. Cyclosporine was used as a prophylaxis of GVHD and it was discontinued by the end of the sixth month after transplantation.
SUPPORTIVE CARE
All blood products were irradiated and filtered. Red cell and platelet transfusions were given to maintain hemoglobin of >8 g/dl and platelet count >20 K/µl. All patients received G-CSF from day 1 after hematopoietic stem cell infusion. It was continued until the neutrophil count exceeded 1.5 K/µl for 3 days. Infection prophylaxis consisted of: oral amphotericin B, high-dose acyclovir and cotrimoxazole. All patients received broad-spectrum antibiotics for neutropenic fever. When engraftment occurred the patient received twice-weekly trimethoprim-sulfamethoxazole up to 3 months after cyclosporine stopping. All recipients were screened for CMV infection/reactivation at least weekly until immunosuppression was completely withdrawn. CMV monitoring was performed using a fluorescent antigen detection methodology, cytomegalovirus early nuclear fluorescence antigen. Ganciclovir was used as preemptive therapy.
ASSESSMENT OF ENGRAFTMENT AND RESPONSE
Myeloid engraftment was defined as the first of 3 three consecutive days with an absolute neutrophil count >0.5 K/µl and platelet recovery was defined as the day the platelet count was >20 K/µl with no platelet transfusions the following week. Chimerism was assessed by PCR analysis of short tandem repeat (STR) sequences on whole blood.
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RESULTS |
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ENGRAFTMENT AND OUTCOME
3.5 x 108 to 4 x 108 marrow nucleated cell/kg body weight (median: 3.9) or 3.3 x 106 to 5.5 x 106/per kg CD34+ cells (median: 4.2) from peripheral blood were infused. All patients showed complete hematological reconstitution of donor origin. The time to recovery of granulocytes and platelets was 15 and 25 days, respectively. All patients have become transfusion-independent and achieved full donor chimerism on day +60. On 1 October 2005 all patients are alive and doing well 16–39 months (median: 29) after transplant.
TOXICITY (ACCORDING TO WHO SCALE) AND GVHD
The preparative regimen was well tolerated. Only oral mucositis (grade II) was observed. Patients did not require hyper-alimentation and intravenous opioids for pain control during hospitalization. No renal or hepatic toxicity was detected. All patients developed fever in the neutropenic phase of transplantation, which responded to appropriate antibiotic therapy. Only two patients had to receive ganciclovir as preemptive therapy. Neither graft failure nor acute GHVD, chronic GHVD, or any other severe complications, was observed.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Allogeneic BMT is the treatment of choice in young patients suffering from SAA. This therapeutic method should be performed immediately after diagnosis. Graft rejection as well as refractoriness to platelet transfusions is associated with large numbers of transfusions and prolonged disease duration before transplantation. Graft rejection and GVHD are the main causes of failure after BMT in patients with SAA. Purine analogs in particular fludarabine possess powerful immunosuppressive potential with mild systemic toxicity. Fludarabine based preparative regimens were sufficient to engraft patients with hematological malignancies using either matched sibling or alternative donors (14–16). Therefore, fludarabine would be an attractive agent to be incorporated into a conditioning regimen for transplantation of SAA patients. However the ability of these patients to reject a transplant remains a concern. First, their immune system may be more intact than that of leukemia or lymphoma patients who have had prior anti-cancer therapy. Furthermore, frequent transfusion of blood products in SAA patients could have enhanced the allogeneic resistance to donor grafts. The number of prior transfusions and the interval between diagnosis and transplantation haves both been shown to adversely affect post-transplant survival (17–19). Alemtuzumab (Campath-1H) is a humanized IgG1 monoclonal antibody directed against the CD52 antigen, which is widely expressed on all human lymphoid cells except terminally differentiated plasma cells. It is also expressed on eosinophils, monocytes, dendritic cells and macrophages. The most commonly used regimen combines alemtuzumab with fludarabine and an alkylating agent, usually melphalan or busulfan. These regimens lead to paresis of donor immunological system and they can be useful for SAA patients. The use of alemtuzumab has been associated with slower immune reconstitution and an increased incidence of viral infections. The use of alemtuzumab was associated with a low incidence of acute and chronic GVHD but a high incidence of CMV infections and prolonged immunodeficiency. There also appears to be an increased incidence of adenovirus, respiratory syncytial virus and parainfluenza virus infections in alemtuzumab treated patients. However, many of these infections are not associated with serious clinical sequel and, at least in the case of CMV, do not adversely affect TRM (15,20,21).
We did not observe any serious viral infections in our patients. Only two of them had to receive ganciclovir as preemptive therapy for CMV reactivation. None of the patients developed symptoms of CMV disease. Recurrent parvovirus B19 infection with profound anemia due to pure red cell aplasia (PRCA) was observed in one case. PRCA was successfully treated with immunoglobulin supplementation and discontinuation of cyclosporine. The same patient suffered from acute viral B hepatitis (before transplantation donor and recipient were HBV antigen and antibody negative), which was diagnosed 6 months after transplantation. After therapy with lamivudine he became HbsAg negative.
In our study alemtuzumab, fludarabine and melphalan as a conditioning therapy was well tolerated. No renal, liver or bowel toxicity was observed. No evidence of severe mucositis or veno-occlusive disease (VOD) was seen in any of the patients and none of them required parenteral nutrition. All patients engrafted and none of them developed late graft failure. Neither graft failure nor acute GHVD, chronic GHVD, or any other severe complications, was observed. With a median follow-up of 26.5 months (range 16–39) all patients are alive, in remission of their disease and have performance status of 100%.
Our study suggests that transplantation of hematopoietic stem cell using alemtuzumab, fludarabine and melphalan as a conditioning therapy is safe, inexpensive ($2900 compared with $7200 for CTX + ATG conditioning regimen) and effective treatment for patients with SAA, including multi-transfused adults having their disease for a long time.
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References |
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