Late marrow recurrences in childhood acute lymphoblastic leukaemia.

Thirty children with acute lymphoblastic leukemia had a recurrence in the bone marrow after treatment was stopped electively. A second haematological remission was achieved in 27 (90%), and the median duration of remission was shortest (six months) in those relapsing within six months of stopping treatment. Four of six children relapsing over one year after stopping treatment remained in second haematological remission. Leukaemic infiltration of the central nervous system developed in four patients remaining in marrow remission. It is concluded that conventional chemotherapy is unlikely to be effective in children with acute lymphoblastic leukaemia who relapse soon after stopping treatment, that "reprophylaxis" of the central nervous system probably with long-term intrathecal chemotherapy is essential, and that some patients relapsing after prolonged unmaintained remission may achieve long-term leukaemia-free survival.     

Poor prognosis of acute lymphoblastic leukemia with translocation (1;19) in childhood: potential interest of allogeneic bone marrow transplantation

We report a new case of childhood acute lymphoblastic leukemia with translocation (1;19). At the time of diagnosis, the only adverse prognosis factor was the existence of this translocation. Under conventional chemotherapy, the girl experienced early marrow relapse (duration of first remission was 2 months). She received allogeneic bone marrow transplantation during the second remission and is alive in continuous complete remission 20 months after transplant. Several earlier reports have suggested that children with the (1;19) have a poor prognosis; If this poor response to conventional therapy is confirmed, an allogeneic bone marrow transplantation should be considered during the first remission.     

In vitro growth of erythropoietic progenitor cells in long-term remission of acute leukemia

In vitro growth of CFU-e and BFU-e in bone marrow and of circulating BFU-e in a group of adult long-term survivors of acute leukemia has been evaluated. Six patients with acute nonlymphoblastic and three patients with acute lymphoblastic leukemia in first continuous remission for more than four years (range 4-12 years) and without maintenance therapy for at least one year were studied. BFU-e and CFU-e growth in patients' bone marrow was not statistically different from a control group of 12 healthy adult volunteers. However, proliferation of BFU-e in peripheral blood of patients was significantly reduced (p less than 0.001). This growth pattern was found in both lymphoblastic and myeloblastic leukemia.     

Fractionated total body irradiation and high dose cyclophosphamide: a preparative regimen for bone marrow transplantation for patients with hematologic malignancies in first complete remission

We treated 73 patients with hematologic malignancies in first complete remission (acute lymphoblastic leukemia = 23 patients; acute non-lymphoblastic leukemia = 25 patients; chronic myelogenous leukemia in first chronic phase = 20 patients, and high grade lymphoma = five patients) with a uniform preparative regimen consisting of fractionated total body irradiation (1,320 cGy) and high dose cyclophosphamide (100 mg/kg), followed by allogeneic bone marrow transplantation. By radiation dosimetry we demonstrated that the calculated doses were delivered accurately and reproducibly. Actuarial survival rates (+/- SEM) in complete remission were as follows: Acute lymphoblastic leukemia = 74 +/- 9%; acute nonlymphoblastic leukemia = 50 +/- 11%; and chronic myelogenous leukemia = 55 +/- 11%. Actuarial relapse rates for these three diagnoses were 19 +/- 9%, 17 +/- 11%, and 0% respectively. Three of the five lymphoma patients are alive in complete remission at 22+, 28+, and 54+ months. Overall probability of survival for the 73 patients was 59 +/- 7%. Interstitial pneumonia, usually associated with cytomegalovirus infection and graft-versus-host disease, and relapse of the underlying malignancy were the major causes of death.     

CFU-gm colony formation of peripheral blood and bone marrow in adult acute leukemia at presentation, during remission, and at relapse

Granulocyte/macrophage colony-forming unit (CFU-gm) formation was studied simultaneously in bone marrow and peripheral blood of 52 previously untreated adult patients with acute non-lymphocytic (ANLL) and 36 with acute lymphoblastic leukemia (ALL). They were followed during induction therapy at monthly intervals while in remission and in 19 ANLL and 22 ALL cases, until relapse. Patients showing a decreased colony number in the marrow but normal or increased colony numbers in the peripheral blood had a high probability of entering remission. Non-responding patients displayed an opposite pattern. The higher the degree of marrow repopulation with granulocytic progenitor cells after induction treatment, the longer remission duration and survival for ANLL patients and the longer survival for ALL patients. CFU-gm formation returned to normal in the early stages of complete remission, but then declined progressively. At ANLL and ALL relapse, colony growth was reduced markedly while cluster formation remained normal. The number of marrow colonies and clusters in ANLL were significantly higher at first and second relapse compared to the growth pattern at first presentation. A similar trend had been observed in ALL, suggesting a selection advantage.     

Non-cytotoxic asialo-GM1-positive cells exert antimetastatic activity

Summary We examined the results of discontinuing therapy in Japanese children with acute lymphoblastic leukemia. Of the 209 patients in the chemoimmunotherapy study, 120 (57.4%) had all chemotherapy stopped after 3 years of complete remission, and 72 (34.4%) reached the point of discontinuing immunotherapy after 5 years of complete remission. Of the 120 children removed from chemotherapy, 14 (11.7%) have relapsed, mainly in the extramedullary sites (5: testis, 5: bone marrow, 3: central nervous system, 1: bone); relapses occurred 1–23 months after cessation of chemotherapy (median 11 months). Boys had higher post-chemotherapy relapse rate than girls (0.21 versus 0.08, P<0.05). None of the 72 children removed from immunotherapy have yet relapsed. Long-term remission and possibly cure can be expected in approximately one-half of newly diagnosed Japanese patients. Although the active immunotherapy had no beneficial effect on the overall outcome for leukemic children, it could be of benefit to the elimination of bone marrow relapses after cessation of chemotherapy.     

Scene segmentation techniques for the analysis of routine bone marrow smears from acute lymphoblastic leukemia patients.

Automated analysis of lymphoblast cell morphology is being evaluated as a basis for predicting the response to therapy of patients with acute lymphoblastic leukemia. A new technique of scene segmentation particularly applicable to the "cluttered" images of cells in routine bone marrow smears is described. Morphologic characteristics of lymphoblasts found in bone marrow smears made at time of diagnosis were measured by an automated, interactive image-processing system using the new scene segmentation technique. These characteristics, on a patient by patient basis, are being compared to remission length and survival data to develop and test new prognostic methods.     

Acute leukemia in adults: assessment of remission induction with combination chemotherapy by clinical and cell-culture criteria.

Remission induction was assessed by clinical and cell-culture criteria for 65 patients with acute myelogenous leukemia (AML), 11 patients with chronic myelogenous leukemia (CML) in blast crisis and 19 patients with acute lymphoblastic leukemia (ALL). Cyclophosphamide, cytosine arabinoside and vincristine (CAV) therapy resulted in complete remission in 23 of 50 previously untreated patients with AML and in 3 of the 11 patients with CML. Fourteen patients with ALL responded to vincristine-prednisone induction therapy and two to induction therapy with CAV. The median duration of survival of the responding patients was 2.2 years, compared with 4 months for the patients who did not respond to treatment. Granulopoietic colony formation, assessed by assay of colony-forming units dependent on colony-stimulating activity in culture (CFU-C), was abnormal in 37 of 42 bone marrow aspirates from patients with AML before treatement. CFU-C concentration increased when leukocyte-conditioned medium (LCM) was added to the cultures; 13 cultures had normal or elevated CFU-C concentration with LCM. Marrow cells of patients with ALL or CML in blast crisis demonstrated a similar pattern. Serial studies of marrow CFU-C concentration of 31 patients with AML demonstrated a change to a normal pattern with successful remission induction. Results of this study suggest that administration of purified LCM to leukemic patients might increase granulocyte production from potential but unstimulated granulopoietic precursors. This therapy would lessen the probability of death from infection during remission induction.     

A distinct DNA methylation signature defines pediatric pre-B cell acute lymphoblastic leukemia

Pre-B cell acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy and remains one of the highest causes of childhood mortality. Despite this, the mechanisms leading to disease remain poorly understood. We asked if recurrent aberrant DNA methylation plays a role in childhood ALL and have defined a genome-scale DNA methylation profile associated with the ETV6-RUNX1 subtype of pediatric ALL. Archival bone marrow smears from 19 children collected at diagnosis and remission were used to derive a disease specific DNA methylation profile. The gene signature was confirmed in an independent cohort of 86 patients. A further 163 patients were analyzed for DNA methylation of a three gene signature. We found that the DNA methylation signature at diagnosis was unique from remission. Fifteen loci were sufficient to discriminate leukemia from disease-free samples and purified CD34+ cells. DNA methylation of these loci was recurrent irrespective of cytogenetic subtype of pre-B cell ALL. We show that recurrent aberrant genomic methylation is a common feature of pre-B ALL, suggesting a shared pathway for disease development. By revealing new DNA methylation markers associated with disease, this study has identified putative targets for development of novel epigenetic-based therapies.     

Bone marrow transplantation in Canada.

Bone marrow transplantation is an established form of therapy for aplastic anemia and severe combined immunodeficiency. It is also a therapeutic option for acute leukemia in remission. Unfortunately, compatible donors are not available for most patients who could benefit from it. Further refinement of the techniques involved may make it suitable for more patients. Graft rejection, recurrent leukemia, graft-versus-host disease and interstitial pneumonia continue to be the main unsolved complications of bone marrow transplantation, but recent advances have decreased their frequency and severity. Most of the complications of allogeneic bone marrow transplantation may be eliminated with the use of autologous stem cells. For further refinement bone marrow transplantation should continue to be performed in large centres that combine treatment with research.     

Low IL-23 levels in peripheral blood and bone marrow at diagnosis of acute leukemia in children increased with the elimination of leukemic burden

IL-23 is an IL-12 cytokine family member with pleiotropic functions that regulates tumour growth in various cancer types, exhibiting both anti-tumorigenic and pro-tumorigenic properties. Preclinical studies have shown a potential anti-leukemic action on childhood B-ALL cells. The study involved 65 children with acute leukemia [59 patients with acute lymphoblastic leukemia (ALL) and 6 patients with acute myeloid leukemia (AML)] and 27 healthy controls. Using an enzyme-linked immunosorbent assay, we aimed to determine the IL-23 levels in the peripheral blood (PB) and bone marrow (BM) of patients at diagnosis and at the end of the induction therapy (EIT). PB IL-23 levels were lower in leukemia patients compared to the healthy controls. In all acute leukemia patients, IL-23 levels were significantly lower at diagnosis both in PB (P = .015) and in BM (P = .037) compared to the PB and BM concentrations at the EIT. The same pattern was present in both subgroups of ALL and AML patients. The high leukemic burden at diagnosis was related with lower IL-23 levels, which were increased with the disease remission. Considering the anti-leukemic potential of this cytokine, the elevation of the IL-23 concentration at the disease remission indicates a beneficial role of IL-23 in paediatric acute leukemia.     

Acute lymphoblastic leukemia in adult identical twins

The development of acute lymphoblastic leukemia (c-ALL) in identical twins is reported. The first born had ALL in 1982 and bone marrow transplantation was performed in first complete remission (CR) from his healthy twin-brother the same year. The bone marrow donor developed ALL in 1985; he received an autologous bone marrow transplantation in first CR in 1986. Unfortunately, both patients relapsed in 1986. Cytogenetic studies of the first born revealed multiple chromosomal abnormalities and a marker chromosome whereas the second patient had a Philadelphia chromosome. Genetic reasons or exposure to leukemogenic agents may be responsible for the onset of these leukemias.     

Granulocytopoiesis in children with acute lymphoblastic leukaemia.

Numbers, proliferative potential, and differentiative capacity of bone marrow granulocyte-macrophage precursor cells were studied in 130 children with acute lymphoblastic leukaemia (ALL), including 77 children in an acute phase of the disease and 53 in remission. Bone marrow samples from 65 children without haematopoietic abnormalities were used as controls. The numbers of clonogenic precursors were found to be below normal in all phases of ALL, particularly during the acute period when the bone marrow was heavily infiltrated with leukaemic cells. It is shown that the decreases in the numbers and proliferative potential of the precursor cells during the acute phases was associated with the effects of leukaemic blast cells, but that in remission the observed reduction in the precursor cell pool was due to the cytostatic effect of therapy. The differentiative capacity of clonogenic granulocyte and macrophage precursors was not altered in children with ALL.     

Stimulant of antibody producers isolated from the supernatants of cell cultures of normal human bone marrow and in various diseases

The biological activity of a stimulant of antibody producers (SAP) isolated from normal human bone marrow was studied and compared with that of a stimulant of antibody producers from the bone marrow of patients with acute myeloblastic leukemia, acute lymphoblastic leukemia, lymphosarcoma, and multiple myeloma. The activity of the SAP from human bone marrow in health was similar to that of analogous transmitters from the bone marrow of other species of the mammals and birds. The activity of the SAP in patients with multiple myeloma was elevated, whereas in patients with acute myeloblastic leukemia, it was lowered.     

Relations between chromosomal findings and prognosis in acute nonlymphoblastic leukemia (author's transl)]

In 48 patients with acute non-lymphoblastic leukemia, all of whom had been treated according to the protocol 7421 of the "acute leukemia group B", remission rates and survival times were correlated with the chromosome constitution of bone marrow cells at diagnosis. 45.8% of the patients had only normal metaphases (N-patients), 31.3% had normal and abnormal metaphases (AN-patients), and 22.9% had only abnormal metaphases (AA-patients). Chromosomal findings were unrelated to patients' age. The remission rate of the N-patients was 72.7%, of the AN-patients 60%, and of the AA-patients 36.4%. The respective median survival times were 12.5, 8.5 and 4.0 months. The difference in remission rates and survival times between patients with normal and without normal metaphases was significant. Once a remission had been obtained the prognosis was similar among the 3 groups. The better prognosis of the AA-patients in this study as compared to previous reports might be related to a more effective chemotherapy.     

难治性急性白血病研究现状与进展

难治性急性白血病治疗反应差,诱导缓解率低,复发率高,生存期短,因而是白血病治疗中的难题。本文从难治性急性白血病诊断标准与免疫学、细胞遗传学及分子生物学特征,多药耐药与难治性白血病,难治性急性白血病治疗现状以及治疗展望五大方面阐述了难治性急性白血病研究现状与进展。基础与初步临床研究显示中药配合化疗能够提高难治性急性白血病围化疗期临床缓解率。认为中药在提高难治性白血病临床疗效方面具有潜在临床应用前景和开发的商业价值,值得进行深入研究。     

An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T (CAR-T) cells

Anti-CD19 chimeric antigen receptor-modified T (CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune- cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines (mainly interleukin 6 and C-reactive protein) were identified in two patients (Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.     

An abnormal CD34+ myeloid/CD34+ lymphoid ratio at the end of chemotherapy predicts relapse in patients with acute myeloid leukemia.

During conventional follow-up of patients with acute myeloid leukemia (AML), the emergence of cytopenias is considered to be a sign of impending relapse, and it represents an example of how leukemic hematopoiesis affects normal hemopoietic differentiation. In the present study, we have explored the possible value of the analysis of the distribution of CD34+ myeloid and CD34+ lymphoid progenitor cells in follow-up complete remission bone marrow samples from de novo AML patients as a prognostic parameter for predicting relapse. A total of 213 bone marrow samples from 36 AML patients in morphological complete remission, obtained at the end of induction, consolidation, and intensification therapy and every six months thereafter were analyzed. The normal CD34+ myeloid/CD34+ lymphoid ratio ranged between 2.4 and 8.9. In contrast, in most AML cases an abnormally high ratio (> or =10) was observed at the end of induction and consolidation therapy: 96% and 75% of cases, respectively. On the other hand, at the end of intensification, 70% of the patients displayed a normal CD34+ ratio. Patients with a myeloid/lymphoid CD34+ ratio higher than 10 at the end of intensification showed a significantly lower overall survival (median survival of 19 months versus median not reached, P = 0.05), as well as a lower disease-free survival (median of 7 months versus 30 months, P = 0.0001). Regarding sequential studies, 67% of the relapses were preceded by the re-appearance of an abnormal CD34 ratio, whereas relapse was not predicted in four patient with leukemia classified as M3 undergoing maintenance therapy. From the remaining 18 patients who are still in continuous complete remission, all except 3 cases (17%) displayed a normal CD34 myeloid/lymphoid ratio. In summary, the present study shows that the persistence at the end of chemotherapy of an abnormally high (> or =10) ratio between CD34+ myeloid and CD34+ lymphoid progenitors in the bone marrow of AML patients is associated with high risk of relapse and a shorter overall survival.     

Vincristine and Prednisone for the Induction of Remissions in Acute Childhood Leukaemia

A total of 65 children with acute lymphoblastic leukaemia and seven with other types of acute leukaemia received treatment with a combination of vincristine and prednisone. In all 122 courses of treatment were given. Of 22 patients with acute lymphoblastic leukaemia who received this as their first treatment, all achieved complete remission. The complete remission rates were 82% for patients with acute lymphoblastic leukaemia in their first relapse, 63% in the second relapse, and much lower in subsequent relapses and in the patients with other types of acute leukaemia. Alopecia and gastrointestinal and neuromuscular toxicity occurred respectively in 51%, 29%, and 21% of instances, only the last of these side-effects of vincristine being dose-related. Most of the complete remissions were obtained with a total dose of vincristine which carried only a low risk of neurotoxicity.