Biomedical subjects
Publications and source records attributed to A Fefer.
Clinical results of marrow transplantation in the treatment of aplastic anemia and acute leukemia are reviewed. The principal problem areas in this field at this time are discussed.
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Dimethylmyleran (DMM) is an antitumor agent that has minimal effects on immunity. In a study of its usefulness in adoptive chemoimmunotherapy, C57BL/6 mice inoculated on day 0 with C57BL/6 Friend virus-induced leukemia (FBL-3) were treated on day 5 with 12 mg DMM/kg [less than LD10 (lethal dose for 10% of mice)] plus C5BL/6 spleen cells. All untreated mice died, with a median survival time (MST) of 17 days. DMM alone or with nonimmune cells prolonged survival to day 20, and 3/53 mice survived beyond day 60. By contrast, 12/25 mice treated with DMM plus cells immune to FBL-3 were cured. Similar results were obtained in C57BL/6 mice with syngeneic Rauscher virus-induced leukemia (RBL-5). Untreated mice died, with an MST of 14 days. DMM alone or with nonimmune cells prolonged the MST to 21 and 26 days, respectively, and 3/26 and 6/28 mice were long-term survivors. However, 13/28 mice were cured by DMM plus cells immune to antigenically related FBL-3. Lethal irradiation of cells immune to FBL-3 abolished their efficacy. Finally, in contrast to the efficacy of sublethal DMM plus immune cells, an LD100 of DMM (20 mg/kg) plus hematopoietic reconstitution with nonimmune syngeneic cells was not effective against FBL-3 OR RBL-5. The results emphasized the critical role of immune cells in chemoimmunotherapy even when the drug used is nonimmunosuppressive.
Thirty-four patients with severe aplastic anemia were treated with cyclophosphamide or total body irradiation and an infusion of marrow from a genotypically HLA-identical sibling donor. Engraftment occurred in all patients but rejection was noted in 12. Mixed leukocyte culture (MLC) tests undertaken before grafting to determine donor-recipient histocompatibility were analyzed retrospectively. The response of patient cells to sibling cells in mixed culture was compared to the response of patient cells to cells of an unrelated individual and expressed as a relative response index (RRI). Of the 12 patients who showed positive RRI to donor leukocytes in pregraft MLCs, 9 rejected their grafts, wheras of 23 patients with negative RRI only three rejected their grafts (P LESS THAN 0.005). The results suggest that the MLC test can detect individuals who are most likely to reject their HLA identical sibling graft.
The aim of our study was to sensitize cells in vitro, follow their proliferative and cytotoxic responses, and determine their ability to cause lethal graft-versus-host disease (GVHD). C57BL/6 (H2b) spleen cells were incubated with irradiated BALB/C (H2d) Moloney lymphoma cells (LSTRA) in mixed leukocyte culture conditions for 2, 4, or 6 days and then tested. The maximal proliferative response occurred after 4 days. In vitro cytotoxic reactivity against 51Cr-labeled LSTRA was generated by 4 days (76.3+/-3.1% 51Cr released) and 6 days (133.0+/-4.8%) of sensitization but not by 2 days (-0.2+/-1.1%). Induction of fatal GVHD was assayed by injecting graded doses of the C57BL/6 spleen cells i.v. into adult BALB/c mice pretreated with cyclophosphamide, 180 mg/kg. Cells sensitized for 2 days were effective but no more so than were (control) cells cultured with irradiated C57BL/6 spleen cells. However, cells sensitized longer were far more active than the control cells. Cells sensitized for 4 days killed 70 of 88 mice (80%), and those sensitized for 6 days killed 37 of 48 mice (77%), whereas control cells killed only 42 of 90 mice (47%) (P less than 0.005). Thus, cells sensitized in vitro exhibited an increased ability to induce GVHD in vivo, which was temporally associated with the development of cytotoxicity in vitro.
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An 18-year-old white Canadian male patient with paroxysmal nocturnal hemoglobinuria and refractory marrow failure received a marrow infusion from his normal identical twin brother without prior ablation of the patient's marrow by drugs or irradiation. After 2 years of follow-up, the patient is well with no evidence of clinical disease or significant hematological abnormality. The results suggest that normal marrow stem cells can have a selective advantage over the abnormal paroxysmall nocturnal hemoglobinuria clone.
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Forty-nine patients with severe aplastic anemia, 33 due to unknown cause, 11 drug or chemical related, 2 associated with hepatitis, 1 with paroxysmal nocturnal hemoglobinuria, and 2 possibly associated with Fanconi syndrome did not show recovery after 0.5-96 (median 2) mo of conventional therapy. Twenty-two were infected and 21 were refractory to random platelet transfusions at the time of admission. All were given marrow grafts from HLA-identical siblings. Forty-five were conditioned for grafting by cyclophosphamide (CY), 50 mg/kg on each of 4 successive days, and four by 1000 rad total body irradiation. All were given intermittent methotrexate therapy within the first 100 days of grafting to modify graft-versus-host disease (GVHD). Three patients died from infection too early to evaluate (days 1-8). Forty-six had marrow engraftment. Of these, 20 are surviving with good peripheral blood counts between 186 and 999 days, and 18 have returned to normal activities. Chronic GCHD is a problem in five. Twelve patients died of infection following rejection of the marrow graft. Twelve patients died with bacterial or fungal infections or interstitial pneumonia and active GVHD or soon following resolution of GVHD. Two patients died with marrow engraftment and no GVHD, one with an interstitial, and the other with a bacterial pneumonia. Thirty-six patients who had received random donor blood transfusions were randomly assigned to receive either CY or procarbazine-antithymocyte globulin-CY as conditioning regimens to test whether the incidence of graft rejection could be decreased. There was no difference in the incidence of graft rejection between the two regimens. In 13 patients with rejection, second transplants were attempted either with the original marrow donor (9 patients) or another HLA-identical sibling (4 patients). Three of these transplants were not evaluable, seven were unsuccessful and three were successful with only one of the three surviving for more than 468 days. In conclusion, the long-term survival of 41% of the patients in the present study is similar to that achieved in our first 24 patients, and confirms the importance of marrow transplantation for the treatment of severe aplastic anemia. Marrow graft rejection, GVHD, and infections continue to be the major causes of failure.
One-way mixed leukocyte cultures were used to study the ability of cells from 53 patients with aplastic anemia and 65 of their HLA-identical siblings to stimulate and to respond to cells from unrelated individuals. The capacity of leukocytes from 28 of 53 patients to stimulate was diminished or absent, wheras their ability to respond remained comparable to that of cells from their HLA-identical siblings. Leukocytes from the group of patients with the lowest peripheral lymphocyte count were least stimulatory. The results indicate that in acquired aplastic anemia there exists a dissociation between stimulation and response in mixed culture.
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Human marrow transplantation has resulted in observations of fundamental significance in understanding both aplastic anemia and acute leukemia. For example, the observation that transplanted marrow can grow successfully in patients with aplastic anemia indicates that the disease is due to a defect in the marrow precursor cells and not in the marrow microenvironment. Similarly, the observation of recurrent leukemia in donor cells has important implications. Nonetheless, marrow transplantation is sufficiently established therapeutically to be considered the treatment of choice for patients with severe aplastic anemia, and a realistic alternative for patients with recurrent acute leukemia. We suggest that patients be managed with regard to marrow transplantation according to the general approach outlined in Table 3. Marrow transplantation and histocompatibility typing are available at increasing numbers of institutions throughout the world. More and more patients with either severe aplastic anemia or recurrent acute leukemia should have marrow transplantation available to them when it is indicated as part of optimal management of these no longer hopeless diseases.
A 23-year-old man with severe idiopathic aplastic anemia was prepared for marrow transplantation by the administration of cyclophosphamide (CY) 50 mg/kg on each of 4 days. He then received an intravenous infusion of 9.5 x 10(9) marrow cells from an HL-A matched and mixed leukocyte culture non-reactive sister. The graft was successfully established as shown by cytogenetic studies but was rejected after approximately 4 weeks. In preparation for a second transplant he was given procarbazine 12.5 mg/kg and goat antihuman thymocyte globulin (ATG) 7 mg/kg administered on alternate days for a total of 4 doses of each agent. At the end of this therapy his white blood cell count was noted to be going up and the second transplant was not carried out. Complete hematologic recovery of host type marrow ensued and persists now 20 months later. The various pathophysiologic mechanisms that may be involved are discussed.
This report summarizes the experience with 25 patients who received a second marrow transplant. The marrow donor for the first transplant was an identical twin in four cases and a sibling matched at the major histocompatibility complex in 21 instances. The donor for the second transplant was the same as the first except for three patients whose second donor was another matched sibling. Nine patients with aplastic anemia rejected their first graft. Four of these patients were prepared for the second graft with a regimen of procarbazine and antithymocyte globulin (ATG) followed by cyclophosphamide or total body irradiation and were successfully regrafted. One rejected the second graft, two died of septicemia and one is alive and well 10 months after the second graft. Twelve patients with hematologic malignancy had a recurrence of disease after the first transplant. Despite preparation for the second graft with a variety of intensive chemotherapeutic regimens, the five patients who did not succumb to infection showed an early recurrence of disease. Four patients with hematologic malignancy had a failure of the first graft for unknown reasons, possibly related to the administration of ATG or methotrexate. One patient prepared for the second graft with procarbazine and ATG showed evidence of engraftment but died of infection. Two out of three patients given no additional preparation were successfully grafted. One died of recurrent central nervous system leukemia after 18 months and one is alive and well 26 months after the second graft.
Eleven of twenty-four patients with severe aplastic anemia given marrow grafts from HLA-identical siblings between October 1970 and March 1973 are alive with normal marrow function and continued evidence of engraftment 3-5 yr later. Ten have been leading normal lives with no immunosuppressive or other drug therapy since day 100 postgrafting. One has had chronic graft-versus-host disease of the skin which is now slowly improving with no therapy. He returned to full-time employment in the summer of 1975. The long-term well-being of almost half of our initial patients emphasizes the importance of marrow transplantation for the treatment of severe aplastic anemia.