Robert B. Howe

High-Resolution Chromosomes as an Independent Prognostic Indicator in Adult Acute Nonlymphocytic Leukemia

Using high-resolution chromosomes of bone-marrow specimens from 105 consecutive adult patients with de novo acute nonlymphocytic leukemia, we found an unusually high degree of complexity in this disorder, which may explain previous difficulties in identifying useful prognostic indicators. Specimens from 99 of the 105 patients were successfully analyzed, and 92 (93 per cent) had a chromosomal defect. Seventeen categories were identified, 12 representing a specific recurrent defect. Three of them have been found to have independent prognostic importance. Patients with an inversion 16 (9 per cent), diagnosed as having M2, M4, or M5b disease according to the morphologic classification of the French-American-British Acute Leukemia Cooperative Study Group, had a uniform and sustained complete remission and a median survival of 25 months. In contrast, 14 patients (14 per cent) with complex chromosomal abnormalities and a diagnosis of M1, M2, M4, M5a, or M6 disease had a very poor prognosis. In 12 of the 14 patients efforts to achieve induction of remission failed, and the group had a median survival of 2.5 months. A third group with a trisomy 8 as the single defect (11 per cent) had an intermediate prognosis and a median survival of 10 months. With the different types of treatment for acute nonlymphocytic leukemia that are now available, we suggest that high-resolution chromosome analysis will become an important tool in selecting specific types of therapy for groups of patients with differing prognoses.

Recurrent chromosomal defects are found in most patients with non-Hodgkin's-lymphoma

Using methotrexate cell synchronization, we successfully analyzed chromosomal preparations of 40 lymph node biopsies and one bone marrow sample from 44 patients with non-Hodgkins, non-Burkitts lymphoma. All of the 41 patients successfully analyzed showed clonal chromosomal abnormalities. In 25 of the 41 (61%), the defects were found to be consistent with (A) a deletion 6q in five of seven patients with diffuse large cell lymphoma, (B) a t(11;14), a del 11q, or a + 12 in seven of nine patients with small cell lymphocytic lymphoma, and (C) a t(14;18) in 12 of 15 patients with follicular lymphoma (small cleaved and mixed small and large cleaved) and in a single case of diffuse large cell lymphoma. In three patients with small cell lymphocytic lymphoma whose biopsies exhibited a t(11;14), lymphocytes were cultured and chromosomes examined for the presence of fragile sites. In two, frequent breaks at band 11q13.3 were observed. Such findings suggest a possible relationship between a fragile site and a predisposition to a specific chromosomal rearrangement in human neoplasia.

Paraneoplastic autoimmune phenomena in patients with myelodysplastic syndromes: response to immunosuppressive therapy

Summary. We analysed the clinical features, course and response to immunosuppressive therapy in 30 patients with autoimmune disorders associated with myelodysplastic syndromes (MDS). 18 patients with MDS developed acute systemic autoimmune disorders. Common manifestations were skin vasculitis (n=15) and arthritis (n=11). Seven patients had an acute clinical syndrome of vasculitic skin rash, fever and arthritis with peripheral oedema in three and pulmonary infiltrates in five of these seven patients. Other acute manifestations included pericarditis, pleural effusions, skin ulceration, seizures, myositis and peripheral neuropathy. Chronic or isolated autoimmune manifestations (n=11) included glomerulonephritis, polyneuropathy, pyoderma gangrenosum, ulcerative colitis and polyarthritis. Classic connective tissue disorders recognized included relapsing polychondritis, polymyalgia rheumatica, Raynauds syndrome and Sjogrens syndrome. Autoimmune manifestations responded to immunosuppressive therapy (primarily prednisone) in 26/27 patients treated. Furthermore, cytopenias improved substantially in six patients, including complete normalization of peripheral blood counts in two patients with cytogenetic remission in one. Patients with a haematological response to immunosuppressive therapy had improved survival compared with non‐responding patients. The autoimmune syndrome was implicated as a primary cause of death in 8/17 patients who died. Autoimmune manifestations may be more common than previously recognized in patients with MDS. Aggressive therapy with immunosuppressive agents in selected patients often controls autoimmune phenomena associated with MDS and may lead to haematological responses in some patients.

Abnormal Red Cell Metabolism Causing Hemolysis in Uremia: A Defect Potentiated by Tap Water Hemodialysis

Abstract A plasma factor that inhibits red cell hexose monophosphate (HMP) shunt metabolism and thereby shortens red cell survival has been found to accumulate in roughly half of uremic patients. T...

Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption

The objective of this study was to assess the effect of protein A immunoabsorption in terms of response rate and toxicities in patients with classical thrombotic thrombocytopenic purpura (TTP) refractory to therapeutic plasma exchange. The study included nine females and one male with a diagnosis of classical TTP treated at multiple university hospital centers with protein A immunoabsorption (PAI) after having failed plasma exchange. The 10 patients had an age range 17‐62 years. Prior to PAI, the patients had failed to respond to a mean of 15 (range 6‐39) therapeutic plasma exchanges. Three patients had previous episodes of TTP.

Hypocellular acute leukemia

Abstract We examined the clinical features and therapeutic response of a group of patients with acute leukemia and hypocellular bone marrow. Therapists have generally avoided, delayed or modified therapy because of hypocellularity. We demonstrated not only that aggressive therapy is possible, but also that the remission rate is high (complete remission=73 percent) and survival prolonged (x > 40 months).

Antithymocyte globulin treatment of severe aplastic anaemia

Nineteen patients with severe aplastic anaemia were treated with antithymocyte globulin. Ten patients obtained remissions (transfusion independent, at least 45000 platelets and 2000 PMN/mm3) within 2–3 months and continue in remission 5–35 months after antithymocyte globulin. Ages of responders ranged from 17 to 71. Complications of antithymocyte globulin included arthralgias, rash, serum sickness, angioedema and fever. Two patients died during, two shortly after, and one 10 months after therapy. One patient with a previous remission following antithymocyte globulin relapsed and achieved a second remission with retreatment. Previous androgen therapy did not affect outcome since two of four patients with and eight of 15 patients without previous androgen therapy achieved remission with ATG. Treatment with antithymocyte globulin is a promising alternative to bone marrow transplantation in the treatment of severe aplastic anaemia.

Effect of therapy on T cell subpopulations in patients with chronic lymphocytic leukemia

We have previously demonstrated functional and quantitative imbalances in two human thymic (T) cell subpopulations, T gamma and T mu, in chronic lymphocytic leukemia (CLL) patients. Serial evaluations of the numbers of T gamma and T mu subsets in CLL were performed in order to delineate more completely the patterns of T cell abnormalities two groups of CLL patients were studied: (I) previously untreated (n = 3) and (II) stable CLL on chemotherapy (n = 12). In Group I, two of three patients had significantly increased percentages of T gamma cells (mean +/- S.E.M. = 57 +/- 5 vs 18 +/- 2 for controls). There was defective in vitro appearance of T mu cells in both groups. In Group II, repeated studies of T cell subsets revealed persistently elevated T gamma cells despite various modes of oral chemotherapy. In three CLL patients who required splenectomy a dramatic decrease in the percentages of T gamma cells was noted post-splenectomy (51 +/- 3 to 15 +/- 3). In all cases the spleen was diffusely involved with CLL. These findings indicate: (1) abnormalities of T cell subsets are present early in CLL, (2) chemotherapy does not affect the levels of T gamma cells in stable patients and (3) removal of infiltrated CLL spleens results in a dramatic decrease in the proportion of T gamma cells. This latter finding plus the increase in T gamma cells in progressive disease post-splenectomy suggest T gamma cells may be an important determinant of the course of CLL.

Red Cell Hexosemonophosphate Shunt Deficiency in Uremia

Shortened red cell survival commonly occurs in uremia. Although the present studies indicate that hemolysis is by no means universal in patients with renal failure, hemolytic anemia can, in fact, be troublesome, especially in hemodialysis units (Huntley et al., 1971). The pathogenesis of uremic hemolysis is uncertain, but it is clear that it occurs unpredictably with a severity unrelated to the degree of renal failure (Erslev, 1970; Eklund et al., 1971).

Reversible pancytopenia following OKT3: use in the context of multidrug immunosuppression for kidney allografting

We present two instances of pancytopenia in kidney transplant patients associated with a course of OKT3 therapy. In one case, OKT3 was used prophylactically, in the other therapeutically to treat biopsy-proved rejection. They both occurred in the setting of multi-drug immunosuppression, including Minnesota anti-lymphocyte globulin, and recovered with supportive therapy. Previous antihypertensive medication, antibiotics, and azathioprine were restarted without hematologic sequelae. Evidence implicating OKT3, and resultant gamma-interferon-induced marrow suppression is discussed.