Identification of early relapsing patients with adult acute nonlymphocytic leukemia by bone marrow biopsy after initial induction chemotherapy

Bone marrow biopsies obtained from 69 adult patients with acute nonlymphocytic leukemia (ANLL) six to 10 days after initial induction chemotherapy were reviewed blindly to detect the presence of residual leukemia. Discrimination between the presence or absence of leukemic cells was provided by assessment of the numbers, clustering, and nuclear morphology of blasts and promyelocytes. Twenty-six patients had frank leukemia, 25 had no apparent leukemic cells, and 18 had focal residual leukemia. Of 25 patients whose bone marrow contained no detectable residual leukemic cells, 21 gained complete remission without further chemotherapy. These patients had a median duration of remission of 278 days, with five patients still remaining in remission for 578-882 days. Similarly, all of the 18 patients who had focal residual leukemia achieved complete remission without additional chemotherapy; however, all have relapsed with a median duration of remission of 163 days. This study indicates that patients with foci of residual leukemia in their one-week posttreatment bone marrow samples readily achieve remission, but carry a substantial leukemic burden that increases the likelihood of early relapse.     

Prognostic value of clonogenic assay for induction and duration of complete remission in acute myelogenous leukemia

The validity of an in vitro clonogenic drug sensitivity assay to predict the induction and the duration of complete remission was evaluated in a group of 81 patients with acute myelogenous leukemia treated with chemotherapy including an anthracycline drug (daunorubicin or adriamycin) and cytosine arabinoside (Ara-C). The inhibition of bone marrow clonogenic leukemic cells by in vitro exposure to anthracyclines 10(-5) and 10(-6) M, Ara-C 10(-5) M, and daunorubicin 10(-6) M + Ara-C 10(-7) M was significantly correlated with the achievement of a complete remission, but not with the duration of remission. A high second plating efficiency was correlated with short duration of complete remission, reflecting the poor prognosis of a high self-renewal capacity.     

强力化疗加自体骨髓移植术治疗中,晚期实体瘤9例报告

本文报告用强力化疗加自体骨髓移植治疗中、晚期恶性肿瘤9例。其中骨肉瘤3例,恶性淋巴瘤3例,肾胚瘤、脑胶质细胞瘤、骨转移癌各1例。结果2例淋巴瘤、1例肾胚瘤1～2个月内完全缓解,其它5例恶性肿瘤均有效,1例脑胶质瘤无效。结果还表明自体骨髓移植治疗恶性实体瘤,4℃保存骨髓较深低温保存更为实用有效;较少量骨髓有核细胞输入也有利于强化治疗后血象的恢复,且无移植物被排斥的后顾之忧。     

Preventive central nervous system irradiation in children with acute nonlymphocytic leukemia.

In this study of children with acute nonlymphocytic leukemia an attempt was made to prevent central nervous system relapse and to determine whether this therapy, coupled with multiagent chemotherapy, would be successful in prolonging durations of complete remission. Central nervous system relapses were prevented by irradiation, although patients who received this therapy did no better than those who did not receive irradiation. A small group of patients received irradiation to the liver and spleen, but this modality also failed to improve the duration of remission. Control of extramedullary leukemia, in this study, failed to improve remission duration because bone marrow relapse was not prevented or delayed. It is unlikely that focal therapy will have a significant impact in acute nonlymphocytic leukemia until longer marrow remissions are achieved.     

Intensive chemotherapy for acute non-lymphoblastic leukemia after primary myelodysplastic syndrome

Twenty-five patients with a primary myelodysplastic syndrome (MDS) transformed into acute non-lymphoblastic leukaemia (ANL) were treated with intensive chemotherapy. A complete remission (CR) was obtained in six patients (24 per cent). In five of these six patients two courses of chemotherapy were needed to achieve CR. In eight patients chemotherapy cleared the bone marrow of blasts, but the aplasia was fatal. A partial effect on bone marrow blasts was seen in four patients and no effect in another six. Eleven patients (44 per cent) died from the consequences of chemotherapy-induced cytopenia. A short interval between MDS and transformation into ANL was associated with a better chance of achieving complete remission. Age, karyotype, type of MDS, peripheral blood or bone marrow findings had no influence on the result of chemotherapy. The median survival from start of treatment was 5 months (range 0.5-24 months). In the patients who achieved a CR, the median duration of the remission was 7 months (range 3-12 months). The poor response rate, the short duration of the remissions and the high treatment-related mortality suggest that current intensive anti-leukemic chemotherapy in ANL after primary MDS is of limited benefit.     

Remission from central nervous system involvement in adults with acute leukemia. Effect of intensive therapy and prognostic factors

Eighty-seven adult patients who had achieved bone marrow remission of leukemia developed one or more episodes of meningeal leukemia. Multiple patient characteristics were examined for their effect on probability of achieving complete remission from meningeal disease and for their effect on duration of meningeal remission. Presence of obtundation (P less than 0.01) or other symptoms of meningeal disease (P = 0.02) were associated with a low remission induction rate. Other factors which tended (P = 0.06-0.20) to be associated with low remission induction rates included high cerebrospinal fluid (CSF) opening pressure, absence of splenomegaly at initial diagnosis, high peripheral blood leukocyte count (WBC) at the episode of marrow disease most recently preceding the meningeal disease, and use of only one as opposed to two or more intrathecal drugs as treatment. Factors associated with long duration of meningeal remissions included diagnosis (AML greater than acute undifferentiated leukemia greater than ALL, P = 0.05), absence of symptoms (P = 0.04), low CSF WBC (P = 0.01), rapid attainment of meningeal remission (P = 0.01), rapid attainment of initial bone marrow remission (P = 0.02), and long duration of initial bone marrow remission (P less than 0.01). Absence of cranial or peripheral neuropathies, low CSF protein and opening pressure, and short time interval between diagnosis of marrow and meningeal disease also tended (P = 0.06-0.20) to be associated with long meningeal remissions. Patients treated according to an intensive protocol utilizing cranial irradiation and triple drug treatment via an Ommaya reservoir had substantially longer meningeal remissions than did patients treated with less intensive therapy (P = 0.01). Relapse-free survival curves suggest that some patients are cured of their meningeal disease.     

Phase-I–II study of high-dose melphalan and autologous marrow transplantation in adult patients with poor-risk non-Hodgkin's lymphomas

Summary Eleven adult patients with poor-risk non-Hodgkin's lymphoma were treated with high-dose melphalan (140 mg/m²) or high-dose combination chemotherapy (BCNU, Ara-C, vindesine and melphalan) followed by autologous bone marrow transplantation. Six of the eight patients evaluable for response achieved complete remission and one achieved partial remission. Response duration ranged from 1.5 to 12 months (median 2 months). Prompt hematological recovery occurred in all patients. The duration of aplasia and the extrahematological toxicity were similar in both groups. High-dose melphalan alone or associated with other drugs followed by marrow infusion appears to produce a high response rate and demonstrates the potential for salvaging patients with refractory lymphoma.     

Utilization of a human tumor cloning system to monitor for bone marrow involvement in children with non-hodgkin's lymphoma

The objective of this study was to evaluate the sensitivity of two methods for determining bone marrow involvement with non-Hodgkin's lymphoma. These methods were histologic review of bone marrow aspirates, and clot sections versus in vitro growth of lymphoma colonies on soft agar. Forty-two bone marrow aspirates were studied from 14 children who were without bone marrow involvement at diagnosis. There were seven bone marrow aspirates (from five patients) that had histologic evidence of metastatic lymphoma. Six of these seven specimens formed colonies in vitro. Twenty-nine of 35 histologically negative specimens showed no lymphoma colony growth. However, six histologically negative specimens (from three patients) formed lymphoma colonies. Both the Fisher's exact test and the K statistic were significant, indicating not only an association between histology and in vitro culture results, but also a close agreement. In addition, growth of lymphoma colonies in vitro was associated statistically with both a short duration of complete remission and a short duration of survival.     

The Münster study of intensive induction and consolidation therapy without maintenance therapy of acute myeloid leukemia. Results of 93 patients--cellular determinants for response and length of remission

A 9-day high-dose 3-drug induction regimen including ARA-C, DNR, and TG at special time sequencing was given to 93 patients with AML, 15-74 (median 52) years old. After 1-2 courses for remission induction and, if possible, 2 identical courses of consolidation, no further therapy was applied during remission. Complete remission (CR) was achieved in 71% of all patients and in 74% of responders by 1 course only. Median remission duration is at 1 year with 13 patients in continuous CR for 13-38 (median 24) months. Patients completing consolidation reached a median remission duration of 22 months and those with rapid response to 1 induction course and with complete consolidation 38+ months. Patients monitoring included bone marrow DNA-histograms by flow cytometry, blood counts, percentage, and absolute number of blasts in bone marrow and LDH in serum. Among pretherapeutic parameters only LDH (inversely) correlated with CR duration. In contrast during early therapy rapid blast reduction, decrease of S-phase-index and of LDH as well as short recovery time of platelets and neutrophils predicted for low risk (when high risk included non-response and early relapse). Thus, monitoring of early cellular response parameters reflecting cellularity and proliferation seems to provide important individual determinants of therapeutic outcome.     

Impaired bone marrow lymphocyte proliferation in acute myelogenous leukemia.

Bone marrow cells were cultured in liquid media with and without phytohemagglutinin (PHA) to test bone marrow lymphocyte response during the remission period of acute myelogenous leukemia (AML). Mitogen-stimulated cultures from nine leukemic patients while in complete remission showed high percentages of morphologically transformed lymphocytes, but proliferation of these cells was significantly decreased (p less than 0.02) in cultures from six patients who subsequently relapsed (mean remission duration 10 months) and died. In contrast, lymphocyte proliferation in cultures from three AML patients with long remission (greater than 30 months) was comparable to controls. Parallel cultures without added PHA showed a progressive decrease in total viable cell number with time, but an increasing percentage of macrophages in both control and AML cultures. These studies suggest that bone marrow lymphocyte proliferation, but not morphologic transformation, is impaired in some patients with AML, and that identification of this defect may be of prognostic value.     

Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse.

For patients with acute myeloid leukemia (AML) relapsed after allogeneic bone marrow transplantation (BMT), donor leukocyte infusion (DLI) as sole therapy has very limited efficacy. We tested the effects of cytoreductive chemotherapy, followed immediately by G-CSF-primed DLI (chemotherapy followed by DLI, Chemo-DLI), in 16 AML patients who relapsed after allogeneic BMT. In all, 10 of these patients achieved complete remission (CR), four of whom remain alive in CR at a median follow-up of 1488 days after DLI. The 2-year overall survival (OS) for the entire cohort was 31%. The 1-year OS for patients with post-BMT remission of 6 months or longer was 55%, compared with 0% for patients with post-BMT remission of less than 6 months, making post-BMT remission duration the only significant prognostic factor for OS (P=0.015). These findings suggest that Chemo-DLI could induce durable remissions in a proportion of relapsed AML patients with relatively long post-BMT remission duration. All five patients who relapsed after achieving CR with Chemo-DLI relapsed at extramedullary sites in the presence of continuous bone marrow remission, suggesting uneven graft-versus-leukemia effects in different parts of the body. Although our data should be interpreted cautiously considering the limited number of patients, isolated extramedullary relapse seems to be common after Chemo-DLI.     

Allogeneic Marrow Transplantation for Myelodysplastic Syndrome Complicating Autologous Bone Marrow Transplantation

A patient with refractory relapsed Hodgkin's disease underwent an autologous bone marrow transplant in July 1987 and achieved remission of Hodgkin's disease. He had complete hematological recovery but developed pancytopenia 3 years post bone marrow transplantation with morphological evidence of myelodysplasia. High-dose cyclophosphamide, 200 mg/kg, chemotherapy followed by an allogeneic bone marrow transplant from a HLA-matched sibling was performed in April 1991 with complete hematological recovery. Allogeneic bone marrow transplantation was thus used successfully to treat a potential complication of autologous bone marrow transplantation.     

High-dose cyclophosphamide with autologous marrow transplantation for small cell carcinoma of the bronchus

Summary Twenty-five patients with previously untreated small cell carcinoma of the bronchus have been treated with cyclophosphamide 160–200 mg/kg and subsequent radiotherapy to the primary site. Eighty-four percent of patients responded to the single cycle of chemotherapy, with 56% attaining a complete response. Median duration of remission was 43 weeks and median survival 69 weeks. 2-Mercaptoethane sulphonate was given to prevent urothelial toxicity. Autologous bone marrow transplantation was used to mitigate bone marrow depression but sequential delay in reinfusing cryopreserved bone marrow did not alter the period of cytopenia. Other toxicities were mild. The procedure proved safe and manageable. High-dose chemotherapy may prove to be useful in the initial management of this tumour.     

The prognostic significance of myelonecrosis after induction therapy in acute leukemia

Myelonecrosis is a rare antemortem finding in acute leukemia and its clinical significance is uncertain. The clinical events in nine patients with acute leukemia whose bone marrow biopsies after induction therapy revealed myelonecrosis were reviewed. No patient gained a complete remission and four patients achieved a partial remission. The median duration of survival was 2 months (range, less than 1 month to 8.5 months) from the start of therapy. Myelonerosis after induction therapy in acute leukemia indicates a very poor prognosis.     

Remission of acute myelogenous leukemia in elderly patients with prior refractory dysmyelopoietic anemia

Refractory dysmyelopoietic anemia (RDA) is a myeloproliferative disorder usually of elderly patients which often evolves into acute myelogenous leukemia (AML). AML in such patients is usually considered untreatable with standard aggressive chemotherapy in part because these patients are often elderly, but primarily because of the concern that the bone marrow of these patients no longer has a residual stem cell to repopulate the bone marrow following chemotherapy-induced aplasia. The authors treated three patients (ages 72, 69, and 62 years, respectively) with intensive chemotherapy after RDA evolved into AML. Each patient had been pancytopenic for 3 to 15 months prior to their transition to AML. At the onset of therapy for AML, all were severely pancytopenic with greater than 50% myeloblasts in the bone marrow. All patients had bone marrow aplasia by day 14 after chemotherapy with a complete bone marrow remission and normal peripheral counts by day 26. These data suggest that intensive chemotherapy of AML with prior RDA may result in complete bone marrow remission.     

Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients

Introduction The presence of disseminated tumor cells in the bone marrow of breast cancer patients has proven to be an independent prognostic factor. The aim of this study was to investigate the status of tumor cell dissemination after primary systemic therapy in relation to therapy response. Methods Bone marrow aspirates were obtained from 120 patients after completion of primary systemic therapy. Disseminated tumor cells were detected by immunocytochemistry using the APAAP method. Bone marrow status was correlated with clinicopathological factors as well as tumor response to primary systemic therapy. Results Sixty out of 120 patients had disseminated tumor cells in their bone marrow aspirates (50%). Response rates were 18% for pathologic complete remission, 52% for partial remission, 28% for no change and 3% for progression. Despite complete remission, 36% of these patients were bone marrow positive. In the partial remission group, the positivity rate was 48%. About 61% of patients with stable disease had disseminated tumor cells in their bone marrow. A trend to higher positivity rates was observed in the poor responder group compared to responders (61% vs. 38%, P = 0.1). Conclusion Primary systemic therapy does not completely eradicate disseminated tumor cells in the bone marrow of breast cancer patients. The biological role of persistent disseminated tumor cells needs to be further investigated to optimize current and future therapeutic strategies.     

Transplantation of non-purified autologous bone marrow in patients with AML in first remission

Four patients with acute myeloid leukemia (AML) were treated with high-dose cyclophosphamide and total body irradiation followed by reinfusion of a portion of their own bone marrow collected during remission. This procedure was applied when the patients were in complete remission. They did not receive further maintenance chemotherapy after grafting. The use of bone marrow for grafting that had been pre-exposed to high-dose chemotherapy for remission induction did not preclude good hematologic regeneration. All patients showed stable remissions that lasted for 64+, 21, 40+, and 19+ months, respectively. Death in the second patient was due to a medullary relapse of the leukemia. Autologous bone marrow transplantation in patients with AML in remission may permit lasting remissions, even when applied without additional chemotherapy and attempts to purify the marrow of neoplastic cells.     

High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.     

Infusion of Cryopreserved Autologous Marrow in the Treatment of Acute Leukemia: A Preliminary Report

Autologous marrow was collected from patients with acute leukemiaduring their first remission, and cryopreserved. In relapse,four of the patients were treated with remission-induction chemotherapymore intensive than the previous treatment, followed by infusionof the cryopreserved autologous marrow. Autologous marrow infusioncaused relatively rapid hematological recovery from the bonemarrow depression induced by high-dose chemotherapy. All fourpatients achieved a second complete remission, but with no maintenancetherapy leukemic relapses were observed in three of them. Onepatient survived without leukemic relapse for 19 months, 13months longer than the previous remission period. Another effectof autoinfusion was reduction in blood products required duringthe bone marrow depression. These observations suggest thatcryopreserved autologous marrow may retain its hemopoietic activityand autologous marrow infusion may be effective in providingearly recovery or rescue from bone marrow failure.