Allogeneic transplantation remains the only curative treatment modality for certain hemotologic disorders. While allogeneic marrow transplantation is the treatment of choice for chronic myeloid leukemia and aplastic anemia, it has become an increasingly important treatment strategy in the management of various other disorders, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphoid leukemia (CLL), myelodysplasia, sickle cell disease, thalassemia, as well as severe congenital immunodeficiency states [1
]. However the major limiting factor in bone marrow transplantation (BMT) is the availability of an HLA-matched sibling. After an extensive search, only about 30% of the potential recipients will have an HLA-matched sibling donor available [5
]. The presence of a hematologic malignancy in marrow donors leads to their exclusion from the donation process, thus further limiting this valuable donor pool. Here, we report successful marrow transplantations from two donors with hematologic malignancies.
A 56 year old Caucasian male presented in June 1990 with low grade fever, arthralgia and profuse sweating. An extensive work-up for rheumatology and infectious diseases was unrevealing. In August 94, he developed symptomatic anemia, requiring red cell transfusions. In Feb 1995, a bone marrow biopsy revealed hypercellular marrow with increased reticulin fibrosis, and was consistent with myelodysplastic syndrome (MDS). Cytogenetic evaluation of the marrow revealed 46XY/47XY, +marker karyotype, with marker being a derivative of chromosome 3. In April, 95, the patient developed progressive thrombocytopenia, hypercalcemia and atrial fibrillation. A repeat marrow evaluation showed presence of more than 30% blasts, showing cytoplasmic staining for Factor VIII-related antigen and was consistent with M7 variant of acute myeloid leukemia (AML, M7).
The patient underwent induction chemotherapy consisting of cytarabine and idarubicin, followed by an allogeneic BMT from his HLA-matched brother. The 56-year-old male donor, though completely asymptomatic, was found to have peripheral lymphocytosis. Pre-transplant evaluation revealed a white cell count of 17.9x109/L, hemoglobin of 13.7 g/dl, hematocrit 42.1%, platelet count 255x109/L, and absolute lymphocyte count of 7.6x109/L. Peripheral blood smear showed numerous smudge cells. Flow cytometric analysis of the peripheral blood revealed co-expression of CD5/CD20 antigens on 92% of the circulating Blymphocytes. Physical examination was negative for lymphadenopathy or hepatosplenomegaly. The donor was diagnosed to have Stage 0 CLL, based on the clinical and immunophenotypic evaluation outlined above.
After obtaining an informed consent from the recipient, bone marrow transplantation was performed on June 15, 1995 following conditioning with cyclophosphamide (60 mg/kg, days -5, -4), etoposide (30 mg/kg, day -4) and TBI (1200 cGy total). Cyclosporine-A, which was used to prevent both graft rejection and GVHD, was started 1 day before allograft as an intravenous infusion at a dose of 2.5 mg/kg/day and the dose was adjusted according to the serum level of cyclosporine-A (target level: 450-550 ng/ml). Subsequently, patient received oral cyclosporine-A 5 mg/kg per day in 2 divided doses starting on post-transplantation day 50. Methotrexate was administered as a part of GVHD prophylaxis at a dose of 15 mg/m2 intravenously on day 1 and 10 mg/m2 on day 3 after the allograft. Early posttransplant course was complicated by grade IV mucositis and grade I acute graft versus host disease (GVHD). The patient also developed extensive chronic GVHD involving skin, oral mucosa, peripheral nerves and the lungs, which was responsive to a combination of prednisone, cyclosporine and azathioprine. In the setting of a clinical trial, colchicine was added to help control lung GVHD, and was associated with a good clinical response.
The recipient continues to do well with a follow-up of more than 92 months following the transplant procedure. His most current peripheral blood counts showed a white cell count of 7.1x109/L, hemoglobin 12.5 g/dl, hematocrit 38.8, platelet 199x109/L and absolute lymphocyte count of 0.816x109/L, with normal morphology, and without any evidence of CLL by flow-cytometric evaluation.
A 26-year-old Caucasian male was diagnosed in November 1991, with Philadelphia chromosome positive chronic myeloid leukemia (CML). After cytoreduction with hydroxyurea, the patient underwent an allogeneic BMT from his HLA-matched sister on March 26, 1992 following a conditioning regimen consisting of cyclophosphamide and TBI. Post transplantation course was uncomplicated, without any evidence of GVHD. His donor’s history was remarkable for Hodgkin’s disease (HD) diagnosed in 1982. Following a staging laparotomy and splenectomy, she was determined to have Stage IIA disease and was successfully treated with mantle-field radiotherapy.
The patient did well until November 1994, when he relapsed with chronic phase CML, marked by an additional chromosomal abnormality, monosomy 7 at the time of relapse. The patient was treated with donor lymphocyte infusions (DLI), which led to a clinical and molecular remission, as determined by PCR study of peripheral blood for bcr/abl translocation. Subsequently the patient developed severe right hip and ankle pain in October 1995. MRI study showed a mass lesion involving the S1 vertebral body with expansion into the pelvis. Needle biopsy of the mass was consistent with chloroma that was managed with local radiation with resolution of pain.
In January 1996, the patient developed pancytopenia and recurrent bone pains. Bone marrow evaluation revealed 57% blasts, consistent with blastic phase of CML. He underwent induction chemotherapy with cytarabine and idarubicin, followed by a second allogeneic transplantation (April 1996) using peripheral stem cells from the same donor. Conditioning regimen consisted of busulfan (16 mg/kg total), cyclophosphamide (60 mg/kg, days -5, -4) and etoposide (30 mg/kg, day -4). GVHD prophylaxis consisted of cyclosporine-A and short-term methotrexate at the same doses and schedule as the previous patient. Posttransplant course was complicated by grade IV mucositis, grade I acute GVHD, and limited chronic GVHD involving skin and gastrointestinal tract. The patient discontinued cyclosporine in October 96 and was started on interferon with the hope to prevent recurrence.
The donor was in remission from her HD at the time of marrow as well as peripheral stem cell donation, as determined by clinical and radiological criteria. The recipient continues to do well after a follow-up of +80 months following the second transplant. His most current laboratory evaluation showed a white cell count of 4.9x109/L, Hemoglobin of 13.0 g/dl, hematocrit of 39.6%, and platelet count of 160x109/L, with normal morphology, and without any clinical or laboratory evidence of either CML or HD. Repeated studies on peripheral blood for bcr-abl translocation by polymerase chain reaction (PCR) technique have been negative. He has also been followed by chest radiographs at 6-month intervals that have all been normal.