Cyclosporin A in myelodysplastic syndrome: a preliminary report

Therapeutic approaches are not well established in patients with myelodysplastic syndrome (MDS). We evaluated response to cyclosporin A (CyA) in 19 cases with MDS who were enrolled for the study [13 refractory anemia (RA), 5 refractory anemia with excess of blasts (RAEB), and 1 refractory anemia with ringed sideroblasts (RARS)]. Bone marrow was normocellular in ten, hypercellular in five, and hypocellular in four cases. Fifteen patients were transfusion dependent and the rest were not transfusion dependent but with a hemoglobin range of 6.4–8.8 g% with a mean of 7.4 g%. CyA was given at a dose of 3–5 mg/kg per day. A major response was observed in seven patients with RA, which was sustained on follow-up. Four cases of RA showed minor response and two cases of RA did not respond to CyA therapy. A minor response was also seen in one RAEB and one RARS case, while one RAEB case that initially showed a major response relapsed on therapy. The first effect of therapy was evident after a mean period of 2.5 months. A rise in platelets and leukocyte count was seen in three and two cases, respectively. One case developed renal failure on therapy and later died of septicemia. Response to CyA was independent of bone marrow cellularity. CyA could be an effective mode of therapy in patients with MDS especially those having RA.     

Cyclosporine-induced graft-versus-host disease after autologous bone marrow transplantation in hematological malignancies

Summary In the attempt to induce graft-vs-host disease (GVHD) in patients undergoing autologous bone marrow transplantation (ABMT) or blood stem cell transplantation (BSCT), 12 consecutive patients received cyclosporin A (CyA) post transplant. CyA was given at a dose of 1.5 mg/kg/day intravenously for 28 days, starting on the day of transplant. Histologically proven acute GVHD of the skin occurred in seven patients 9–14 days after ABMT and lasted 7–11 days. CyA-induced GVHD after ABMT resembles mild GVHD after allogeneic bone marrow transplantation (BMT). Although the preliminary data reported here show that it is possible to induce GVHD in patients undergoing ABMT, it is not yet known whether GVHD after ABMT will have an antitumor activity.     

Response to Cyclosporine Therapy in Patients with Myelodysplastic Syndrome: A Clinical Study of 12 Cases and Literature Review

Cyclosporine (CyA) was administered to 12 patients with myelodysplastic syndrome (MDS), and a response (major erythroid response, according to International Working Group criteria) was observed in 7 patients (58.3%). The median duration of response was 18 months (range, 3-22 months). Two patients are still responding and continuing to take CyA. Three patients stopped because of malignancy complications. To identify variables associated with responsiveness to CyA therapy, we analyzed the treatments of 72 MDS patients, comprising the 12 new patients and 60 patients previously described in the literature. Responses were observed in 44 of the 72 patients (61.1%). Univariate analyses revealed that higher daily dose of CyA (P for trend test, .007) and shorter disease duration (median, 5 months versus 17.5 months, P = .04) were factors significantly associated with response. No significant associations were observed between response and bone marrow features such as erythroid hypoplasia or hypoplastic marrow. Multivariate analysis also demonstrated that high CyA dose (>5 mg/kg per day) was significantly associated with response (P = .02). The present study showed that CyA therapy is useful for MDS patients with any marrow cellularity. Shorter disease duration is a pretreatment variable correlated with response, and a higher CyA dose results in a higher response rate.     

Radiotherapy, concomitant protracted-venous-infusion 5-fluorouracil, and surgery for ultrasound-staged T3 to T4 rectal cancer

BACKGROUND: A prospective study was undertaken to evaluate the response and toxicity of neoadjuvant chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. PATIENTS AND METHODS: Since 1995, 30 patients (18 males; median age, 56 (range, 25–83) years) have received preoperative chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. All patients underwent an endorectal ultrasound, CT scan, and review in our multidisciplinary Gastrointestinal Tumor Board before treatment. All patients had pathology-demonstrated invasive adenocarcinoma of the rectum. Eleven patients were Stage T3N0, 14 were T3N1, and five were T4N1. Patients received radiotherapy to the primary tumor and draining lymph nodes (45 Gy) followed by a tumor boost (50.4–54 Gy). Protracted-venous-infusion 5-fluorouracil (225 mg/m² per day, seven days per week) was administered throughout treatment. Surgical resection was performed six to ten weeks after completing chemoradiotherapy. Using endorectal ultrasound measurements, the primary tumor was a median of 4 (range, 0–12) cm from the anal verge, encompassed 50 (range, 20–90) percent of the rectal circumference, and was 6 (range, 3–12) cm in diameter. RESULTS: No Grade 4 toxicity was observed during chemoradiotherapy. Three patients experienced Grade 3 toxicity (diarrhea), and four patients required a treatment interruption of greater than three days. All patients completed at least 90 percent of the prescribed radiotherapy dose. All patients underwent surgical resection. Ninety-four percent had clear surgical margins. All pathologic specimens had significant evidence of necrosis, hyalinization, and fibrosis. Thirty-three percent of the specimens had a complete pathologic response (defined as no evidence of viable tumor cells). Of the 19 patients with ultrasound-staged N1 disease, only five had pathologic evidence of nodal involvement after chemoradiotherapy. Of the 25 patients with ultrasound-staged T3 disease, pathologic staging revealed eight with T0, two with T1, five with T2, and ten with T3 disease. Of the five patients with ultrasound-staged T4 disease, pathologic staging revealed two with T0, one with T2, and two with T3 disease. No patient developed progressive disease while on treatment. Two patients have experienced local failure at 6 and 20 months, and one patient failed in the liver at seven months. Twenty-seven patients remain free of disease with a median follow-up of 20 (range, 3–53) months. CONCLUSION: Our experience suggests that preoperative chemoradiotherapy is well tolerated, down-stages tumors, and sterilizes regional lymph nodes.Presented in part at the meeting of the American Society of Clinical Oncologists, New Orleans, Louisiana, May 20 to 23, 2000.     

Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow

We report 17 cytopenic patients with myelodysplastic syndrome (MDS) of refractory anaemia (RA) subtype with hyper-, normo- or hypo-cellular bone marrow (BM), who were treated with cyclosporin A (CyA). Substantial haematological response was observed in 14 patients (82%): their anaemia improved and all transfusion-dependent patients achieved transfusion independence. Complete trilineage recovery was observed in four patients (23%). The CyA therapy has not yet failed in any of the 14 successfully treated patients during follow-up times ranging from 5 to 30 months. CyA was well tolerated in 14 patients; serious side-effects required termination of the therapy in three patients in whom the blood count rapidly deteriorated to former levels upon cessation of therapy. Two patients benefited from a combination therapy of CyA and erythropoietin. Six patients experienced various autoimmune phenomena. CyA could thus offer an alternative treatment for certain MDS patients with RA regardless of hyper-, normo- or hypo-cellularity of bone marrow (BM). The mechanism of the beneficial effect of CyA is discussed and remains the subject of an ongoing study.     

Relative erythroid hyperplasia in the bone marrow at diagnosis of aplastic anaemia: a predictive marker for a favourable response to cyclosporine therapy

Predicting the treatment response of aplastic anaemia (AA) is essential when considering cyclosporine (CyA) therapy among several treatment options, because it requires at least 2 months to determine whether the therapy is beneficial to a patient with AA. To identify the characteristics of patients with AA who are likely to respond to CyA therapy we retrospectively reviewed the clinical records and bone marrow smears of patients treated with CyA. Among 30 patients who received the therapy for at least 3 months within 1 year after diagnosis of AA, and who had not been exposed to antilymphocyte or antithymocyte globulin, 16 (53%) responded with disease remission. CyA-responsive patients had a significantly higher ratio of erythroblasts to granulocytes (E/G ratio) in the bone marrow at the time of diagnosis as compared with patients refractory to therapy ( P  = 0.004). Multivariate analysis revealed that a high E/G ratio (>0.6) was significantly associated with a good response to CyA ( P  = 0.03): 15 (83%) of the 18 patients with an E/G ratio >0.6 responded, but only one (8%) of the 12 with an E/G ratio ≥0.6 did. Although the presence of subclinical paroxysmal nocturnal haemoglobinuria was suspected from the relative erythroblastosis observed in the bone marrow of these patients, flow cytometric analysis of neutrophils in the peripheral blood failed to reveal neutrophils deficient for glycosyl-phosphatidylinositol (GPI) anchored membrane proteins in all but one case. Identification of the presence of relative erythroid hyperplasia in the bone marrow when AA is diagnosed may help to predict a favourable response to CyA therapy, and therefore facilitate the selection of optimal therapy for AA.     

Comparison of cyclosporin A and azathioprine in the treatment of rheumatoid arthritis — Results of a double-blind multicentre study

Summary In a prospective randomized double-blind multicentre study cyclosporin A (CyA) and azathioprine (AZA) were compared in 117 patients with rheumatoid arthritis (starting dose CyA 5 mg/kg, AZA 1.5–2 mg/kg). The six-month treatment period was similarly completed in 92 patients with good clinical results in both groups (mean improvement rate CyA vs. AZA: Ritchie-Index 8.2 vs. 7.7, morning stiffness 41.6 vs. 28.4 min., grip strength 10.9 vs. 15.2 mmHg, swollen joint count 28.9 vs. 27.9%). Treatment was discontinued prematurely in 12 patients in each group (CyA: 2 deaths not related to drug, 1 lack of effect, 9 adverse reactions — AZA: 2 drop-outs, 1 lack of effect, 9 adverse reactions). Altogether effectivity and tolerability were equal in both treatment groups with the exception of an increase in blood pressure and serum creatinine which occurred only in the CyA group.     

Cell cycle kinetics of hematopoiesis before and after in vivo administration of GM-CSF in refractory anemia: Evidence for a shortening of the granulocyte release time

Summary GM-CSF administration to patients with refractory anemia (RA) induces an increase in neutrophils and eosinophils. We studied cell kinetic mechanisms underlying this observation using clonogenic assays and in vivo iododeoxyuridine labeling of bone marrow cells. Cell cycle kinetics were studied in three patients before and during GM-CSF administration (two daily subcutaneous injections of 54 or 108 g). No consistent effect on the relative number of bone marrow CFU-GM was noticed. The DNA synthesis time and potential doubling time of low-density bone marrow cells remained essentially the same. A slight decrease (1.5–3.7%) in labeling index was found, originating from the myelo(-mono)cytic lineage. In all three patients the release time of labeled granulocytes from the bone marrow into the peripheral blood was shortened (before GM-CSF treatment 5–7 days and during GM-CSF 3–4 days). Cell cycle kinetics of CD34⁺ cells were studied in order to obtain kinetic information on immature precursor and progenitor cells. The DNA synthesis time of the CD34⁺ cells was shortened during GM-CSF therapy, resulting in a shorter potential doubling time. GM-CSF administration to patients with RA results in a rise in granulocytes that might be due partly to an accelerated release of granulocytes from the bone marrow compartment into the circulating blood and partly to an increased proliferative activity of the immature precursor and progenitor cells.     

Cyclosporin-A therapy of pure red cell aplasia in a patient with B-cell chronic lymphocytic leukemia

A 65-year-old woman with B-cell chronic lymphocytic leukemia (CLL) and pure red cell aplasia (PRCA) is described. After initial chemotherapy with three different regimens over 3 months (prednisone, chlorambucil/vincristine, cyclophosphamide, bleomycin/cyclophosphamide, etoposide, prednisone), normalization of the blood lymphocyte count was observed, but lymphocyte infiltration of the bone marrow persisted and erythropoiesis remained virtually absent. Monotherapy with cyclosporin-A (CyA) was begun. After 35 days, a marked increase in the reticulocyte count was observed, and with continuing therapy, there was a rapid increase in the hemoglobin level. Follow-up after 13 months of uninterrupted treatment with CyA revealed remission of both CLL and PRCA. CyA should be investigated further as a therapeutic modality for PRCA in patients with CLL, and such trials might provide further clues to the pathogenesis of this peculiar association.     

Early plasmacytoid dendritic cell leukemia/lymphoma coexpressing myeloid antigenes

Early plasmacytoid dendritic cell (pDC) leukemia/lymphoma has recently been described as a CD4⁺CD56⁺ lineage negative malignancy with characteristic clinical, morphologic, immunophenotypic, and biological features. We present a case of a 72-year-old man who was diagnosed with isolated skin involvement 30 months ago and received numerous chemotherapy cycles that did not prevent three relapses of the disease, the last two involving the bone marrow. The bone marrow was nearly completely infiltrated with small- to medium-sized blasts displaying a high nuclear to cytoplasmic ratio, a cytoplasm with faint basophilia lacking granulations or Auer rods. Small vacuoles surrounding the nucleus were frequently observed. Flow cytometry showed CD4⁺, CD56⁺, CD45⁺, CD38⁺, HLA-DR⁺, CD33⁺, CD123⁺, CD2^–, cyCD3^–, CD7^–, CD10^–, CD11b^–, CD13^–, CD14^–, CD16^–, CD19^–, cyCD22^–, CD24^–, CD34^–, CD57^–, CD61^–, CD64^–, CD65^–, cyCD79a^–, CD117^–, MPO^–, and TdT^– population. At the second bone marrow relapse, CD117 was also positive. Our patient was initially treated with acute myeloid leukemia-type chemotherapy, later he was given acute lymphoblastic leukemia-type treatment, and at the last relapse he received CHOP chemotherapy. Each treatment led to rapid response of tumor manifestations with disease-free intervals of 7 months, 9 months, and 8 months, respectively. Although patients usually have an ominous prognosis, with only 25% living more than 24 months, our patient is alive after 30+ months and has again achieved complete remission after the last chemotherapy.     

Hematopoietic colony formation after allogeneic bone marrow transplantation: enhancement by cyclosporin A and anti-gamma-(immune) interferon antiserum in vitro

Bone marrow hematopoietic progenitors (CFU-GM, CFU-E, and BFU-E) were found to be markedly decreased in 21 bone marrow transplant recipients studied from one to 51 months after transplantation. In these patients, bone marrow colony formation could be significantly enhanced by in vitro incubation of the bone marrow target with cyclosporin A (CyA; 0.5 microgram/ml) or with a monoclonal anti-gamma-(immune) interferon (IFN-gamma) antibody. Both effects were highly correlated. The data indicate that (a) endogenous elaboration of IFN-gamma may contribute to decreased colony formation in allogeneic bone marrow transplant recipients, and (b) CyA may induce a gradual release of the progenitor cell pool from IFN-gamma-mediated suppression.     

Effect of tacrolimus in a patient with pure red-cell aplasia

A 78-year-old woman has suffered from pure red-cell aplasia (PRCA) associated with generalized myasthenia gravis and thymoma. Cyclosporin A (CyA) with corticosteroid increased numbers of erythroid cells in her bone marrow cells but she required monthly blood transfusions. Administration of tacrolimus as a substitution for CyA inhibited progression of anemia without the need for further blood transfusion. No serious side effects were observed. This case demonstrates that tacrolimus is another option of treatment for PRCA in patients who fail to respond to CyA.     

Palliative hormone therapy, low-dose chemotherapy, and bisphosphonate in breast cancer patients with bone marrow involvement and pancytopenia: report of a pilot experience

Background: The choice between supportive care or specific anticancer treatment for poor performance status (PS) breast cancer patients with multimetastatic disease and pancytopenia due to bone marrow involvement (BMI) often remains a clinical dilemma. Patients and methods: Five consecutive patients with poor PS (WHO 2 or 3) and severe pancytopenia due to BMI received concomitant hormone therapy, weekly low-dose chemotherapy (anthracycline or anthracenedione), and either oral clodronate or intravenous pamidronate. Hormone therapy was adjusted to the patients’ menopausal status and/or previous (adjuvant) therapy and consisted of either tamoxifen±LH-RH agonist or an aromatase inhibitor. Results: In the five treated patients, one treatment-unrelated death was observed in the early phase. Significant PS improvement, pain relief, and rapid normalization of the blood counts were observed in the remaining cases. No major toxic phenomenon was observed. No severe infection occurred, and red cell or platelet transfusions were not required after 1–4 months of treatment. Three patients showed objective tumor response. Overall survival ranged from 12 to 38 months. Conclusion: Due to its low aggressiveness and potentially high activity, this combined treatment should be preferred to supportive care alone. A significant survival gain can be obtained in patients who respond, even with initially poor PS.     

Hyperkalemia in a cyclosporine A-treated allogeneic bone marrow transplant recipient]

A 9-year-old boy was admitted with the diagnosis of myelodysplastic syndrome (FAB RAEB in T). The patient was treated with busulfan and cyclophosphamide and transplanted with bone marrow cells from an HLA identical sister. Cyclosporin A (CyA) and short term methotrexate (MTX) was given for prophylaxis against graft versus host disease (GvHD). The serum potassium value was observed to increase to 6.3 mEq/l during the period of CyA therapy. The serum potassium value returned to 4 mEq/l when CyA treatment was decreased to a serum concentration of less than 50 ng/ml (FPIA). On day 90 post transplantation the patient was diagnosed as relapsed. The patient was preconditioned with cyclophosphamide and total body irradiation and a second bone marrow transplantation was performed using cells from the same donor. He was treated again with CyA and short term MTX for the prevention of GvHD. Once again the patient became hyperkalemic with 6.8 mEq/l. The serum creatinine level was 0.9 mg/dl, the GFR was 52.1 ml/min, FEK was 7.1%. Pseudohypoaldosteronism or hyporeninemic hypoaldosteronism was suspected. To investigate this possibility a renin/aldosterone stimulation test was performed. We speculate that an idiosyncratic response to CyA resulted in pseudohypoaldosteronism and produced a defect in potassium secretion.     

Marked increase in veno-occlusive disease of the liver associated with methotrexate use for graft-versus-host disease prophylaxis in patients receiving busulfan/cyclophosphamide.

The use of cyclosporine-A/methotrexate (CyA/MTX) for graft-versus-host disease (GVHD) prophylaxis is safe and effective for patients undergoing allogeneic bone marrow transplantation after preparation with cyclophosphamide and total body irradiation. We report 87 patients prepared for allogeneic transplant with busulfan 4 mg/kg/d orally for 4 days, followed by cyclophosphamide 60 mg/kg/d intravenously for 2 days (Bu4Cy2). A marked increase in hepatotoxicity was observed in 20 patients administered CyA/MTX, compared with 67 historical control patients who received CyA/methylprednisolone (CyA/MP) for GVHD prophylaxis with all other treatment and support variables remaining constant. The incidence of hyperbilirubinemia (bilirubin greater than or equal to 2 mg/dL) increased from 48% to 80% (P = .02), and the mean maximal bilirubin increased from 4.67 +/- 7.27 to 8.72 +/- 8.73 mg/dL (P = .04), when CyA/MTX was used in place of CyA/MP for GVHD prophylaxis. In addition, the incidence of veno-occlusive disease (VOD) increased from 18% to 70% (P = .0001), and death caused by VOD increased from 4.5% to 25% (P = .02). Survival was not significantly different for the two groups because of a higher non-VOD death rate in patients receiving CyA/MP for GVHD prophylaxis (P = .77). We suggest caution when using Bu4Cy2 in combination with CyA/MTX for GVHD prophylaxis.     

Cyclosporin A (CyA) in primary Sj?gren's syndrome: a double blind study.

The efficacy and toxicity of cyclosporin A (CyA) were studied in a blind fashion in 20 patients with primary Sjögren''s syndrome (pSS). The dose of CyA or placebo was 5 mg/kg of body weight daily. Among the 20 patients, 10 received CyA and 10 placebo. The two groups were matched for age, sex, and disease duration. Patients treated with CyA improved in subjective xerostomia in comparison with patients treated with placebo. Subjective xerophthalmia and recurrent parotid gland enlargement did not differ in the two groups. No change in Schirmer''s test and stimulated parotid flow rate was observed in either group. In contrast, the histopathological lesion of patients treated with CyA remained unchanged in most of the patients, while in the placebo treated group the lesion deteriorated. Laboratory parameters did not change before or after treatment in either group. The only clinical side effect observed in the CyA treated group was hypertrichosis.     

Effect of tacrolimus in a patient with pure red‐cell aplasia

A 78‐year‐old woman has suffered from pure red‐cell aplasia (PRCA) associated with generalized myasthenia gravis and thymoma. Cyclosporin A (CyA) with corticosteroid increased numbers of erythroid cells in her bone marrow cells but she required monthly blood transfusions. Administration of tacrolimus as a substitution for CyA inhibited progression of anemia without the need for further blood transfusion. No serious side effects were observed. This case demonstrates that tacrolimus is another option of treatment for PRCA in patients who fail to respond to CyA.     

Immunoadsorption for removal of anti-A and anti-B blood group antibodies in ABO-incompatible bone marrow transplantation

Summary About 10–15 percent of all patients undergoing allogeneic bone marrow transplantation have a major ABO-incompatibility with their donors. The risk of acute hemolytic reactions due to the infusion of an incompatible donor marrow into the recipient can basically be prevented by recipient antibody depletion or by donor marrow red cell depletion. Nine patients were treated by immunoadsorption using a cartridge with chemically synthesized human blood group A and B antigen as immunoadsorbent for antibody depletion. Within a four-hour-procedure about 2–4 times the patient plasma volume could be processed, thus lowering the anti-A and -B hemagglutinins by 2 to 3 tubes. There was a tendency of better IgG removal when titers initially were high, showing a high antibody clearing capacity. There was no significant correlation between starting titer or amount of plasma volume processed and titer reduction. No decrease in titers were observed in one case. We propose repeated immunoadsorption procedures over 2–3 consecutive days before BMT. The procedure is largely safe and without serious side effects. A major advantage is the avoidance of nonautologous human blood products compared to the conventional plasma exchange. All 8 patients surviving long enough had prompt and stable engraftment of all three cell lines post BMT. No late serological complications occurred when patients were regularly monitored and in vivo adsorption was used when titers increased.     

Influence of graft-versus-host disease prophylaxis on early T-lymphocyte regeneration following allogeneic bone marrow transplantation

An early decrease in the ratio between T4+ and T8+ T lymphocytes has been shown to correlate with the development of grade II-IV GVHD in allogeneic bone marrow transplant (BMT) recipients receiving methotrexate (MTX) as prophylaxis for acute graft-versus-host disease (GVHD). This study compares the onset of T-cell regeneration in patients receiving cyclosporin A (CyA) with those receiving MTX. Firstly, lymphoid recovery occurred at a significantly faster rate in the patients on CyA. Secondly, in those patients, the repopulation of T4+ and T8+ T cells started simultaneously, whereas in patients on MTX the repopulation of the T8+ subset lagged about a week behind that of the T4+ subset. Thirdly, the decrease in the T4/T8 ratios as a function of the lymphocyte counts occurred at a significantly slower rate in the patients on CyA than in those on MTX. Thus, the differences in the onset of T-cell regeneration in BMT recipients on CyA as compared with those on MTX abolished the correlation of the T4/T8 ratio changes with grades II-IV GVHD as described in patients receiving MTX.     

Extended treatment of primary osteoporosis by sodium fluoride combined with 25 hydroxycholecalciferol

Summary Nineteen patients suffering from primary osteoporosis, all having at least one vertebral collapse, initially received 50 mg of sodium fluoride alone per day for 6–18 months. Subsequently fluoride was associated with 25–50g of 25 OH cholecalciferol (calcifediol) per day for 6–18 months in 12 of these patients and 9 were treated for 31–58 months. As control group, 9 patients were given placebo for 6–18 months. The effect of the treatment was assessed by three methods: 1) the metacarpal index (MI) determined by radiogrammetry, 2) the calcium content of the hand bone (Ca) measured by local neutron activation, 3) the iliac bone histomorphometry. MI and (Ca) did not change significantly at any time in any group. In each group there was a significant increase in trabecular bone volume, osteoid volume, osteoid surfaces and a significant decrease in mineralization fronts. On the other hand, the changes in osteoblastic surfaces, osteoclastic surfaces, number of osteoclasts/mm2 were not significant in any group. No change was observed in the placebo group. These data suggest that the increase in the trabecular volume of fluorided bone is mainly due to the increase in osteoid which itself is due to a bone mineralization defect despite the association of calcifediol. This is probably one of the reasons why (Ca) does not change significantly.