Emmanuel C. Besa

Analysis of the androgen response of 23 patients with agnogenic myeloid metaplasia: The value of chromosomal studies in predicting response and survival

The responses of 23 patients with agnogenic myeloid metaplasia (AMM) to androgen therapy were studied. Various clinical and laboratory parameters were analyzed for their value in determining response to therapy and length of survival. Fifty‐seven percent of patients responded, as determined by a sustained increase in hematocrit within three months of therapy which thus eliminated the need for transfusions. Chromosome study of the abnormal hemic population was the best predictor of response: 92% of patients with normal chromosomes responded, while 78% of patients with chromosomal abnormalities did not. Responders had a mean survival time of five and a half years from the time of diagnosis as compared with two years for the nonresponders. The degree of thrombocytopenia, suppression of the ferrokinetic, and lack of activity in axial skeleton on bone marrow scans indicated severely compromised hemopoiesis in the nonresponders. The results suggest that in some patients with AMM, more extensive cytogenetic alterations in the abnormal hematopoietic cells result in an inability to respond to androgen therapy and that the chromosome study is the test most accurate for predicting the outcome of therapy.

Treatment with 13-cis-Retinoic Acid in Transfusion- Dependent Patients with Myelodysplastic Syndrome and Decreased Toxicity with Addition of Alpha-Tocopherol

PURPOSE The purpose of this study was to determine the response and tolerance to long-term treatment using 13-cis-retinoic acid (13-CRA) in transfusion-dependent patients with the myelodysplastic syndrome (MDS) and to determine the effects of therapy on the natural history of the disease. PATIENTS AND METHODS Sixty-six consecutive patients with transfusion-dependent MDS seen in a medical school hospital and outpatient clinic from 1981 to 1988 were studied. The first 21 patients were treated with 13-CRA alone and the next 45 patients with 13-CRA plus alpha-tocopherol (AT). We compared responses to and toxicities of therapy, rates of transformation, and survival from onset of therapy in 20 evaluable patients treated with 13-CRA alone and 43 patients treated with 13-CRA plus AT. RESULTS Four patients responded (20%) at 4 to 8 months to 13-CRA alone, but this response was associated with considerable toxicity and resulted in cessation of therapy. Among the responders, only one continued therapy and is currently in remission, whereas three discontinued therapy because of toxicity and have had a relapse and died. In the 13-CRA plus AT group, we observed one prolonged complete remission and 10 partial remissions (26%), with a decrease in skin and constitutional toxicities by the addition of AT, which enabled the continuation of 13-CRA indefinitely. Although the response rates were similar in both groups, fewer patients (28% versus 60%) experienced progression to acute leukemia in the 13-CRA plus AT group than in the group receiving 13-CRA alone, who terminated treatment (p = 0.018). A twofold increase in median survival of the RA/RARS and RAEB/CMML patient groups was observed with 13-CRA plus AT but was not significant (p greater than 0.5). CONCLUSION This study shows a 20% to 26% response rate to 13-CRA and suggests that 13-CRA, if given continuously, decreases the rate of progression or transformation to acute leukemia in patients with MDS. The addition of AT ameliorates the toxicity of 13-CRA and allows for long-term treatment with 13-CRA. Since the standard treatment for MDS is currently unsatisfactory, these findings indicate that longer treatment with a non-marrow-suppressive agent such as 13-CRA is important, and further trials to determine the role of 13-CRA plus AT in combination with new recombinant growth factors in the therapy for transfusion-dependent MDS should offer a new approach to a disease common in the elderly population.

The most common chromosome change in 86 chronic B cell or T cell tumors: a 14q32 translocation.

Among 46 patients with chronic lymphocytic leukemia (CLL) (40 B cell, 6 T cell) and 40 patients with cutaneous T cell lymphoma (CTCL), a chromosomally abnormal neoplastic clone was identified in 43 cases. A translocation involving 14q32 was present in nine cases (five B-CLL, two T-CLL, two CTCL). The donor chromosomal site was 11q13 in four patients and 1q12, 4q25-27, 17q21-22, 18q21, and 22q11 in one case each. The next most frequent abnormalities were rearrangements involving 6q21-23 (four cases), and trisomy 12 (four cases, all B-CLL). In one CTCL patient, the t(11;14) translocation was present in one of three apparently unrelated T cell clones. Recent studies indicate that the selective advantage conferred by the 14q+ chromosome in B cell neoplasms appears to result from an oncogene being brought adjacent to a rearranged and transcriptionally active immunoglobulin heavy chain locus. The present findings suggest that similar mechanisms may operate in certain T cell neoplasms, although the activating gene is not necessarily the same.

Use of intravenous immunoglobulin in chronic lymphocytic leukemia

Five patients with clinical stage III and IV chronic lymphocytic leukemia were treated with a five-day infusion of high-dose intravenous immunoglobulin for either autoimmune hemolytic anemia or immune thrombocytopenic purpura or by a dose of intravenous immunoglobulin G every three to four weeks for prevention and control of infections associated with hypogammaglobulinemia. The hematocrit level stabilized with a decrease in red blood cell destruction by intravenous immunoglobulin G in chronic lymphocytic leukemia patients with AIHA without altering red blood cell autoantibody titers, but severe hemolysis recurred after 21 days. A long-term remission was observed when intravenous immunoglobulin G was combined with steroids, chemotherapy, plasmapheresis, and splenectomy. The platelet count increased and platelet transfusion requirement was eliminated in a chronic lymphocytic leukemia patient with immune thrombocytopenic purpura by the intravenous immunoglobulin G, and chemotherapy was administered and a complete remission resulted. An interesting observation was the lymphocytopenic effects observed in the five patients during a daily infusion of intravenous immunoglobulin for five days. Furthermore, the maintenance intravenous immunoglobulin G given every three weeks controlled both infections and lymphocyte counts with the chemotherapy. Changing the schedule to every four weeks resulted in poor control of the lymphocyte counts with chemotherapy. These observations indicate a direct macrophage blocking effect in autoimmune hemolytic anemia and immune thrombocytopenic purpura, but the lymphocytopenic effect suggests immunomodulating effects of intravenous immunoglobulin G, which may alter the response of chronic lymphocytic leukemia cells to chemotherapy.

Chromosome Studies in Preleukemic States V. Prognostic Significance of Single versus Multiple Abnormalities

The prognostic value of marrow chromosome findings was examined in 242 patients with preleukemic myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD), with emphasis on the significance of single versus multiple karyotypic changes. In both groups, the results showed that patients with multiple chromosome abnormalities in a marrow clone had a very high probability of early death, from progression to leukemia or from other complications of hematopoietic dysfunction. Conversely, in patients with a hemic clone having only one karyotypic alteration (involving a single chromosome or single translocation), survival over 2 years was only slightly reduced as compared to those without chromosome abnormality. The only single karyotypic alteration perhaps associated with a markedly shortened survival was monosomy 7. These findings suggest that the conclusions of previous studies concerning the grave consequences of chromosome alterations in preleukemia largely reflect the clinical significance of clones with multiple cytogenetic changes. Prior knowledge of the karyotypic status of preleukemic patients should be helpful in evaluating current attempts to find effective treatment for these difficult disorders.

Karyotypic stability in chronic B-cell leukemia

Twenty-one patients with B-cell chronic lymphocytic leukemia (B-CLL) have been followed for more than 2 years with serial cytogenetic studies, including 11 cases for more than 5 years and three others for more than 10 years. A chromosomally abnormal clone was present at the time of initial study in 10 of these patients, and neither these nor the 11 individuals with a normal karyotype had any cytogenetic evolution during the follow-up period, although clinical progression, requiring therapy, was observed in 13 cases. In an additional 12 B-CLL patients who had repeat chromosome studies but were followed for less than 2 years, two patients with advanced disease and multiple cytogenetic abnormalities developed minor additional karyotypic changes and died within 18 months, and two patients with a normal karyotype developed rapidly progressive disease associated with an emerging chromosomally abnormal clone and survived only 1 year. These results demonstrate that karyotypic evolution is rare in B-CLL. Its occurrence indicates a poor prognosis, but its rarity suggests that clinical progression in this disease is usually more dependent on other factors.

plasma von Willebrand factor antigen (vWF:AG) and thrombomodulin (TM) levels in adult thrombotic thrombocytopenic purpura/hemolytic uremic syndromes (TTP/HUS) and bone marrow transplant-associated thrombotic microangiopathy (BMT-TM)

Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndromes (TTP/HUS). The present studies measured two markers of endothelial cell stimulation and/or activation [von Willebrand Factor (vWF:Ag) and thrombomodulin (TM)] in patients with TTP/HUS disorders and compared them to controls. The patient groups consisted of adults with TTP/HUS, with (n = 13) and without (n = 14) peak Cr levels >2.0 mg/dl. Additionally, 52 patients with Bone Marrow Transplant‐associated Thrombotic Microangiopathy (BMT‐TM) following allogeneic BMT were evaluated. Both vWF:Ag and TM were elevated in all patient groups compared to controls. TTP/HUS patients with peak Cr >2.0 mg/dl had higher TM levels (P <0.001) than did those with peak Cr levels below 2 mg/dl. However, thrombomodulin/creatinine (TM/Cr) ratios did not differ in these two groups nor did they differ from controls. BMT‐TM pts had higher vWF:Ag levels and higher TM/Cr ratios than controls and TTP/HUS, P < 0.001. The median TM/Cr ratio in BMT‐TM was 91 (range = 34–229) compared to 38 (range = 29–50) in controls, P < 0.001 and 38 (range = 6 to 156) in TTP/HUS, P < 0.001. Additionally both TM (P < 0.001) and TM/Cr (P < 0.02) were higher in patients with Grades 3 and 4 BMT‐TM compared to those with Grade 2 BMT‐TM. These results suggest that endothelial cell activation occurs in TTP/HUS and BMT‐TM. Since TM/Cr ratios were higher in BMT‐TM compared to TTP/HUS, these findings suggest that the mechanism of elevated TM in BMT‐TM cannot be explained solely by altered renal excretion. Taken together, these findings strongly indicate a role of endothelial cell damage in BMT‐TM.

Prognostic significance of single chromosome abnormalities in preleukemic states

Clinical outcome was evaluated in 43 patients with a myelodysplastic syndrome or myeloproliferative disorder and a bone marrow clone containing a single chromosome abnormality: monosomy 7/del(7q), trisomy 8, i(17q), del(5q), del(20q), or a t(2;11). Those with one of the first three abnormalities (22 patients) had shorter survival, more frequent progression to leukemia, and less response to treatment with 13-Cis-retinoic acid than did those in the latter three groups (21 patients). Additional data on these subgroups of preleukemic patients may confirm the prognostic value of such karyotypic information.

Rapid stem cell differentiation induced by 19-nortestosterone decanoate.

Summary. Erythropoiesis was suppressed in mice by hyperoxia (HOX) and/or post‐hypoxic plethora (PCT), the cytocidal effects of actinomycin‐D (ACT), or by a combination of these techniques.

Specific immunoadsorption of IgG antibody in a patient with chronic lymphocytic leukemia and autoimmune hemolytic anemia: A new form of therapy for the acute critical stage☆

Progressive and severe autoimmune hemolytic anemia developed in a patient with chronic lymphocytic leukemia (CLL) despite treatment with chlorambucil, high doses of corticosteroids and attempts to transfuse packed red blood cells. Splenectomy was not performed because of severe coronary artery disease. Direct antiglobulin tests revealed a warm red blood cell autoantibody of IgG-type with anti-e specificity. The patient was treated by extracorporeal immunoadsorption of plasma IgG using a cell separator and protein A as the immunoadsorbent. The patient responded by an increase in the hemoglobin levels and platelet counts after two treatments. Specificity of the procedure was shown by a decrease in the serum IgG and by the demonstration of the same reactivity to ficin-treated reagent red blood cell panel of the eluate from the protein A. Antibody titers of the patients red blood cell eluate decreased from 1:128 to 1:64 and eventually the anti-e specificity was lost. This is a report of a novel approach to treatment of the acute phase of an autoimmune hemolytic anemia.