Bone marrow transplantation in childhood leukemia in West Germany.
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Publications and source records attributed to N Schmitz.
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Within less than 14 months of recruitment 32 centers enrolled 97 patients in a multicenter trial for low-dose treatment of hairy cell leukemia (1.2 X 10(6) IU/m2 X 28 days s.c. with dose reduction according to clinically judged improvement) or ultra-low dose treatment (1.2 X 10(5) IU/m2, s.c. daily increasing to a well-tolerated dose) with Hr IFn-2c (arg). Induction therapy was limited to 84 days. Patients who reached the clinical stage Jansen I or A were then randomized to 2 arms either to receive further IFn (1.2 X 10(6) IU/m2 s.c.) twice a week or to be taken off treatment. For both arms induction therapy was reinstituted whenever a patient lost the criteria of Jansen stage A or I. The study included obligatory central diagnostic procedures and several special investigations. During the first year of the study a special problem evolved in the group of 34 patients with recurrent disease after splenectomy. Ten of them died, 9 of septicemia and 1 of bleeding complications, whereas only 1 death occurred in those patients who received IFn before splenectomy. The risk factors and the response to therapy in the two groups will be analyzed in order to define the criteria that will be needed for the proper choice of primary treatment for HCL. It appears important to us to restrict splenectomy to selected patients.
This report concerns a woman who experienced a relapse of acute lymphoblastic leukemia (ALL) associated with an interstitial deletion of the long arm of chromosome 6 in donor cells more than 4 years after allogeneic bone marrow transplantation (BMT). Direct bone marrow preparations revealed the presence of two leukemic clones 46,XY,del(6)(q23q25) and 45,X,-4,del(6)(q23q25),+8,-15,-21,+i(21q), +mar, the former clearly indicating that male donor cells were involved in the malignant process. Relapse as evidenced by these chromosome anomalies was confined to metaphases from directly prepared marrow cells and phytohemagglutinin (PHA)-stimulated peripheral blood cells. Cytogenetic analyses of T cell colonies gave predominantly normal donor karyotypes (65 of 69 mitoses) along with three host mitoses and a single donor metaphase carrying the 6q- anomaly. The marrow stroma, as represented by first-passage adherent layer cells from long-term marrow cultures, showed 17 of 19 host metaphases. One of two donor cells found within the stromal elements exhibited a 6q- chromosome. In the subsequent remission mitoses derived from myeloid and lymphoid cells were exclusively of donor origin, and chromosomal abnormalities could no longer be detected. Stromal elements remained host-derived (14 of 16 mitoses).
Our multicenter study on the treatment of hairy cell leukemia (HCL) started in December 1984 and the present data cover the time up to June 30, 1986. Ninety-seven patients were enrolled. For induction of response daily doses (6 micrograms) of low dose human recombinant alpha 2c-interferon (arg) was chosen. Further dose reduction (3 micrograms) was possible for patients who improved within the first 3-4 weeks. Patients with known risk factors started at lower doses (0.6 microgram daily). As infections are known to be the main cause of death in HCL, splenectomy was not mandatory before treatment. Thirty-nine patients received treatment with interferon. Nevertheless, infections remained the major cause of death in the study. The protocol did not prevent fatal infections in nine of the 34 splenectomized patients. The regimen proved safe for all but one of the nonsplenectomized patients. According to this experience, new criteria are needed for the choice of primary treatment in HCL. In our opinion splenectomy should become restricted to selected cases.
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Allogeneic bone marrow transplantations were carried out between March 1983 and July 1985 in 31 patients aged 7 to 45 years (median 18 years). Acute lymphoblastic leukaemia in 1st to 5th remission was present in 8 patients, acute myeloblastic leukaemia in 1st and 2nd remission in 4 patients, chronic myeloid leukaemia, with various remission status, in 6 patients, 3 patients had severe aplastic anaemia and there were single cases of myelodysplasia and immature cell megakaryocytic myelosis. Transplantation was carried out during relapse in 8 patients with either acute myeloid or lymphoblastic leukaemia. Phenotypic HLA-identical mothers (n = 2) as well as genotypic HLA-identical siblings (n = 27), and in two cases HLA-non-identical mothers, served as bone marrow donors. In leukaemia patients the conditioning treatment consisted of fractionated total body irradiation and high dose cyclophosphamide or etoposide. Patients with severe aplastic anaemia received cyclophosphamide (4 X 50 mg/kg) and fractionated total nodal irradiation (total dose 8 Gy). 19 patients (61%) survived 14 to 605 days after bone marrow transplantation. 15 patients (48%) continue to remain in complete remission with Karnofsky indices of greater than or equal to 90%. Causes for death were infection (n = 3), interstitial pneumonia (n = 3), relapse (n = 3) as well as single cases involving acute graft-versus-host-disease, non-engraftment of donor marrow and veno-occlusive disease of the liver.
A pericentric inversion of chromosome 16 and acute myelomonocytic leukemia [AMMoL, M4 French-American-British (FAB)] with abnormal bone marrow eosinophils has recently been shown to form a new cytogenetic-clinicopathological entity. A patient otherwise undistinguishable from the more typical cases but lacking the FAB criteria for AMMoL is described. In such a situation, in vitro colony formation closely resembling that of acute myoblastic leukemia together with the clinical, morphological, cytochemical, and cytogenetic characteristics reported might serve as an indicator that these patients run an acute course justifying a diagnosis of acute eosinophilic leukemia and immediate institution of aggressive chemotherapy. The importance of the in vitro growth pattern regarding the differential diagnosis of disorders associated with predominant proliferation of eosinophils is discussed.
This article documents the cytogenetic findings in 79 patients with typical Ph-positive chronic myelocytic leukemia (CML). Direct preparations of bone marrow and/or peripheral blood of 46 males and 33 females were studied with different banding techniques. Seventy patients were studied during chronic phase. Three (4.3%) had unusual or complex translocations: t(6;22)(p21;q11), t(8;12;9;22)(p21;q21;q34;q11), and t(9;11;22)(q34;q13;q11). One (1.4%) had a +Ph, 1 (1.4%) had a +8, 1 (1.4%) had a del(3)(p13,p23), and 4 of 30 males (13.3%) showed loss of Y chromosome. Five of 8 cases studied during blast crisis had additional abnormalities. The +8 occurred in 4 cases, +10 and +19 each in 3 cases, +6, + 9q+, and +13 each in 2 cases, and +5, +11, +14, +21, +Ph, i(17q), dic(1;9), and structural abnormalities of chromosomes #1, #5, #12, and #13 each in 1 case. Two cases studied in blast crisis alone had complex translocations leading to the Ph. Because it cannot be ruled out that these translocations are secondary, they were not included in the calculation of the frequency of atypical translocations.
Acquired amegakaryocytic thrombocytopenic purpura is a rare disease. Most reported patients did not respond to any therapeutical approach. Recently we observed a striking improvement of this disorder in a female patient shortly after therapy with danazol had been initiated. This observation and its possible implication for the treatment of amegakaryocytic thrombocytopenia are reported herein.
Indications, results, techniques, laboratory monitoring and complications of therapeutic plasmapheresis in patients with symptomatic paraproteinemia are reviewed. In paraproteinemia associated with severe complications plasma-pheresis has been used successfully as an emergency treatment, as a treatment that reduces temporarily the paraprotein level until reduction of resynthesis is reached by cytotoxic therapy, or as a longterm adjuvant therapy in cases of slowly proliferating plasmacytoma or lymphoma. Plasmapheresis has not been shown to influence the underlying malignant process. Paraprotein-related complications that can be reduced by plasmapheresis are hyperviscosity, hypervolemia, haemorrhagic diathesis, cryoglobulinemic symptoms, rapidly deteriorating renal insufficiency, visual impairment, and neurologic disturbances. Technically, large-pored plasma filters have some advantage as compared to centrifugation techniques. Paraprotein-specific complications of therapeutic plasmapheresis are rare. As an ancillary treatment, therapeutic plasmapheresis has expanded the therapeutic tools in the management of paraproteinemia.
In 152 patients with multiple myeloma who had been treated with cytostatic agents the prognostic value of seven staging systems was evaluated: Carbone et al (1967); Acute Leukemia Group B (ALGB) and Eastern Cooperative Oncology Group (ECOG) (Costa et al, 1973); Southeastern Cancer Study Group (SECSG) (1975); Durie & Salmon (1975); Alexanian et al (1975); Merlini et al (1980); British Medical Research Council (1980). The staging systems of the ALGB (Costa et al, 1973) and SECSG (1975), both dividing patients into 'good risk' and 'poor risk' groups, showed significantly different survival curves. Nevertheless, despite statistical significance the observed differences were rather small. In the systems of Carbone et al (1967), Merlini et al (1980), Alexanian et al (1975) and Durie & Salmon (1975) some of the differences in the survival curves were statistically significant while others were not. Our data best fitted into the British Medical Research Council (1980) staging system, the survival curves of all three stages showing significant differences, with median survival time dropping from 83 months in stage A to 52 months in stage B and 26 months in stage C. Nevertheless, none of those systems was clearly superior to single risk factors, especially creatinine and haemoglobin.
Cytogenetic findings from the bone marrow (BM) and the peripheral blood (PB) of nine consecutive patients after allogeneic bone marrow transplantation (BMT) for acute or chronic myelogenous leukaemia are reported. After a conditioning regimen consisting of cyclophosphamide and fractionated total body irradiation (TBI) given in five or six fractions of 2 Gy, persistence of host cells was detected in four out of seven cases with permanent engraftment. While one of these patients relapsed 4 months after host cells had been found in BM and PB, the other patients stayed relapse-free 124, 257 and 347 d after grafting. Before transplantation, the leukaemic cells in all three cases carried unique cytogenetic abnormalities giving us the opportunity to distinguish the leukaemic population from chromosomally non-aberrant cells thought to represent residual normal host cells. As the persisting host cells after BMT lacked any cytogenetic abnormalities, it is suggested that they were members of residual normal clones not involved in the leukaemic process.
Of the many high-dose Ara-C regimens that have been proposed, the one published by Herzig [24] has been applied most widely. Every 12 h patients receive 3 g/m2 Ara-C for 75-90 minutes for a total of 12 doses. Using that regimen, 25% of patients with refractory acute myelogenous leukemia (AML) and 60% of patients in untreated relapse achieve a complete remission (CR). With few exceptions, complete remissions are obtained after one cycle, median remission duration is between 4 and 6 months. Consolidation or maintenance therapy was not usually given. Currently, numerous modifications of that regimen are under investigation: combinations with other cytostatic agents like anthracyclins, m-AMSA, vincristine; the Capizzi-regimen and intermediate dose Ara-C. Preliminary results of those trials are promising but need to be confirmed by other groups. This survey does not comment on Ara-C toxicity and on Ara-C treatment of CNS leukemia, which are both reviewed in two further articles of this issue.
The effects of an intravenous hyperimmune cytomegalovirus globulin after bone marrow transplantation are reported. From day -1 22 patients received 2 ml/kg body weight every two weeks during the first four months after BMT. Infusions were tolerated without any side effects. In three patients a CMV-infection could be documented which was symptomatic in two of them. A further patient experienced a CMV infection during the pretransplant phase before hyperimmune globulin had been administered. The most severe case presented as a nonlethal interstitial pneumonia.
In experimental animals, graft-versus-host reactions can be prevented, even in fully MHC-allogeneic bone marrow transplantation (BMT) by in vitro elimination of mature T cells and their committed precursors from donor bone marrow with a selectively lymphocytotoxic heterologous antiserum. Application of this concept to clinical BMT has previously been hampered by the lack of antibodies of appropriately selective specificity. We describe here the production and characterization of highly selective lymphocytotoxic antisera against mature human T cells and lymphoid precursors using cultured cell lines.