Spontaneous remission in adult acute myeloid leukemia in association with systemic bacterial infection—case report and review of the literature

Spontaneous remission of acute myeloid leukemia in the adult is a rare event. We report on a 31-year-old male patient suffering from acute myeloid leukemia (AML) M5a according to the French-American-British (FAB) classification with biphenotypic features in flow cytometric examination and severe bacterial infection with group G streptococci at the time of diagnosis. Because of sepsis and stable clinical conditions, chemotherapy was delayed and antibiotics were administered intravenously. Within 6 weeks a spontaneous remission of AML occurred. Remission lasted for about 2 months. At the time of relapse, a change in phenotype of the leukemic blasts with a loss of B-lymphoid markers could be demonstrated by flow cytometry. The patient was treated with an induction therapy according to the multicentric German AMLCG 2000 schedule. To our knowledge, this is the first report of a spontaneous remission in an AML FAB M5a associated with coexpression of myeloid- and lymphoid-associated antigens on the leukemic blasts. Possible mechanisms of this phenomenon are discussed with a review of the literature.     

Second marrow transplantation following high dose busulfan, etoposide, and Ara-C after testicular relapse in a patient with AML]

Prognosis of second marrow transplantation after leukemia relapse is usually gloomy. We report a patient with AML who was successfully treated by the second marrow transplant following high dose busulfan, etoposide, and Ara-C for the testicular relapse after the first marrow transplantation. A 24-year-old man was diagnosed as having acute myeloid leukemia (AML) in September, 1988. In December of 1989 when he was in early relapse after his 2nd remission, he received the first allogeneic BMT from his HLA identical brother after high dose busulfan and cyclophosphamide conditioning. His posttransplant course was uneventful and graft versus host disease was not observed. Three months after BMT, he noticed swelling on right testicle. Leukemic cell infiltration was confirmed by aspiration cytology. The testicular relapse was followed by marrow relapse. After successful remission induction chemotherapy, he received 17.5 Gy testicular irradiation and second marrow transplantation using high dose busulfan, etoposide, and Ara-C conditioning. Although his posttransplant period was complicated by severe mucositis, high fever and bronchopneumonia, hematologic recovery was obtained by 3 weeks after the second transplant. He is now continuing in complete remission 18 months after the second BMT. This case report suggests that the combination of high dose busulfan, etoposide, and Ara-C could be a choice as a conditioning regimen for resistant AML relapsing after BMT.     

Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission

Ninety-nine consecutive patients with acute leukemia in first complete remission under age 50 (median age 27 years; age range 1 to 47 years) with a histocompatible sibling donor were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation. Sixty-one patients were diagnosed with acute myelogenous leukemia (AML), 34 patients with acute lymphoblastic leukemia (ALL), 3 patients with biphenotypic acute leukemia, and 1 patient with acute undifferentiated leukemia. Thirty of the 34 patients with ALL had at least one of the following high-risk factors: age greater than 30, white blood cell count at presentation > 25,000/microL, extramedullary disease, certain chromosomal translocations, or the need for greater than 4 weeks of induction chemotherapy to achieve first complete remission. Cumulative probabilities of disease-free survival and relapse at 3 years were 61% and 12%, respectively, for the 61 patients with AML and 64% and 12%, respectively, for the 34 patients with ALL. By stepwise Cox regression analysis, significant prognostic variables for patients with acute myelogenous leukemia were the presence of acute graft-versus-host disease and increasing age, whereas for patients with acute lymphoblastic leukemia, significant variables were age and the development of cytomegalovirus-associated interstitial pneumonia. Complications related to graft-versus-host disease and relapse of leukemia were the major causes of death.     

Ferritin heavy/light chain (FTH1/FTL) expression,serum ferritin levels,and their functional as well as prognostic roles in acute myeloid leukemia

Spontaneous remission (SR) of acute myeloid leukemia (AML) represents a rare phenomenon and is usually of short duration although long‐term remissions are reported. Indeed, mechanisms underlying SR remain unclear, but it is suggested that immunactivation, e.g. caused by infections, plays an important role. Here we report on a patient who suffered from pneumonia and simultaneously experienced very late hematologic AML relapse seventeen years after allogeneic blood stem cell transplantation (allo‐BSCT). Surprisingly in parallel to recovery from pneumonia peripheral blood count which previously showed pancytopenia, had normalized and bone marrow (BM) aspiration revealed spontaneous remission of AML. To the best of our knowledge we here report on the latest AML relapse after allo‐BSCT experiencing SR.     

Correlation of occult clonogenic leukemia drug sensitivity with relapse after autologous bone marrow transplantation

Despite initial complete remission rates exceeding 70%, the majority of patients with acute myeloid leukemia (AML) and adults with acute lymphocytic leukemia (ALL) eventually relapse. Improving the therapeutic results in acute leukemia requires detecting, and understanding the biology of, the minimal residual leukemia remaining after therapy and responsible for relapse. To investigate the biologic relevance of an in vitro assay for clonogenic leukemia (leukemia colony-forming units [CFU-L]) as a measure of minimal residual leukemia, we studied 58 consecutive patients with acute leukemia in complete remission undergoing autologous bone marrow transplantation (BMT) with cyclophosphamide-based therapy. CFU-L were cultured from the pretransplant remission marrows in 45 of 58 patients: 35 of 43 patients with AML and 10 of 15 with ALL. Clonal rearrangements, identical to the patients' overt leukemia when available, were detected in the occult CFU-L from four of the eight patients with ALL in whom adequate DNA for analysis could be obtained from the CFU-L. None of the uncultured pretransplant remission marrows from the 15 ALL patients showed clonal gene rearrangements. We also determined the in vitro sensitivity of the occult CFU-L to 4-hydroperoxycyclophosphamide (4HC), and correlated these results with the outcome of the patients. The sensitivity of the occult CFU-L to 4HC was the only factor that predicted relapse following BMT. The actuarial probability of relapse was 18% in the 23 patients whose CFU-L were sensitive to 4HC compared with 77% in the 22 patients whose CFU-L were resistant (P less than .001). The only factor that influenced the CFU-L sensitivity to 4HC was the type of leukemia. The CFU-L from the AML patients were more sensitive to 4HC than the CFU-L from the ALL patients (P = .001). Occult CFU-L genetically and functionally represent occult leukemia. Therefore, the CFU-L assay should provide a means for studying the biology of minimal residual leukemia and improving the therapeutic results in patients with acute leukemia.     

Serial studies of bone marrow-derived fibroblastoid colony-forming cells and granulocyte/macrophage precursor cells in patients with acute leukemia

Bone marrow-derived fibroblastoid colony-forming cells (CFU-F) and granulocyte/macrophage precursor cells (CFU-GM) were studied in patients with acute leukemia. The numbers of CFU-F and CFU-GM were significantly lower in patients with acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) at diagnosis than in normal subjects, although patients with AML had a very wide range of CFU-F colony-forming efficiency. However, a suppressive effect of leukemic cells on normal CFU-F colony formation was not observed. CFU-F and CFU-GM in patients with acute leukemia recovered to normal levels when complete remission (CR) was achieved and decreased again at relapse. Serial studies showed that the increase in CFU-F preceded the recovery of CFU-GM. In AML, furthermore, patients who achieved CR had a higher number of CFU-F than patients without CR, suggesting that the CFU-F level at diagnosis may contribute to the prediction of the likelihood of remission induction in patients with AML.     

Reinduction therapy for adult acute leukemia with adriamycin, vincristine, and prednisone: a Southwest Oncology Group study.

In an attempt to improve remissions and survivals in previously treated patients with adult acute leukemia, we gave Adriamycin, vincristine, and prednisone for induction therapy, followed by 6-mercaptopurine and methotrexate for maintenance therapy to patients attaining complete remission (CR). The study group consisted of 18 patients with acute myeloblastic leukemia (AML), ten with acute lymphoblastic leukemia, and one with acute undifferentiated leukemia. Only one patient had previously received Adriamycin. Overall, there were ten CRs and two partial remissions. The five CRs and one partial remission in patients with AML occurred among those with one prior induction attempt; none of the eight AML patients with more than one prior induction attempt responded. The actuarial median duration of CR was 15 weeks and was similar for AML and acute lymphoblastic leukemia patients. Responders had a longer median survival (30 weeks) than nonresponders (9 weeks). Thus, although a reasonable number of responses in previously treated patients were obtained with this program, improvements in maintenance therapy are clearly needed.     

Second complete remission in an elderly patient with acute myeloid leukemia retreated with decitabine

A 67-year-old man with acute myeloid leukemia (AML) was treated with low-dose decitabine. He achieved a complete remission (CR) after two cycles of therapy, and he remained in remission during 1 year of treatment. He developed recurrent AML after discontinuation of decitabine. He was retreated with decitabine and again achieved a CR, which has been maintained for 6 months. This case demonstrates that durable responses can occur upon retreatment with decitabine.     

Acute myelocytic leukemia with ins(21;8)(q22;q13q22) presenting with AML1/MTG8 chimeric mRNA

We report a case of acute myelocytic leukemia (AML) showing a chromosomal abnormality, ins(21;8), with AML1/MTG8 chimeric mRNA. The patient, a 73-year-old woman, was admitted to our hospital because of AML relapse. Bone marrow aspiration showed 44% blasts and ins(21;8)(q12;q13q22) by cytogenetic study. Moreover, the size of chimeric AML1/MTG8 mRNA detected by RT-PCR in this case was shorter than that of previously reported. The patient was diagnosed as having relapse of AML (M2), but achieved complete remission with DCP therapy. Four months later, extramedullary relapse occurred, and this was followed five months later by bone marrow relapse. However, the patient again achieved complete remission. Most cases of AML1/MTG8 fusion gene are caused by t(8;21), and only very rarely by ins(21;8). In this case, the AML1/MTG8 fusion gene is thought to have been involved in the onset of leukemia.     

The immunologic detection of minimal residual disease in acute leukemia

Certain combinations of differentiation antigens are expressed on leukemia blasts and are absent or extremely rare among normal progenitors in the fetal liver and fetal and regenerating bone marrow. These combinations include cCD3/TdT, a thymic feature retained on thymic-acute lymphoblastic leukemia (T-ALL) blasts outside the thymus, and the coexpression of TdT and myeloid markers (CD13, CD33) on a proportion of ALL and acute myeloid leukemia (AML). Thus, double marker immunofluorescence assays are operationally leukemia-specific and can be applied in 35% of acute leukemias for detecting minimal disease at a less than 10(-4) level; only rare cases, 2 of 35 in our study, switch these relevant features during relapse. The sensitivity and specificity of these assays was tested as follows. First, bone marrow samples taken from patients who had originally presented with blasts expressing the leukemia-associated combinations but were in full morphologic remission were studied, and varying numbers (less than 0.01% to 10% of the mononuclear fraction) of cells with aberrant features were identified in 11.6% of the cases. Second, the outcome of 19 patients with minimal disease identified immunologically while in complete morphologic remission was investigated: all 19 patients have developed systemic relapse within 4 to 25 (median 14.5) weeks. In contrast, 17 of 25 patients also morphologically in complete remission and without residual disease identifiable immunologically after repeated testing are still in morphologic and immunologic remission (follow-up 17 to 114 weeks, median 28 weeks). Only eight patients in this group have relapsed so far: in two patients the relapse was localized in the cerebrospinal fluid, while in six patients a systemic relapse was observed 6 to 51 (median 21.5) weeks after the last negative immunologic bone marrow examination. In conclusion, no false-positive results were detected with these sensitive assays, and the introduction of appropriately planned prospective studies, including the immunologic detection of residual leukemia, is justified on the basis of these observations.     

Acute myelogenous leukemia and acute leukemic appendicitis： A case report

Acute myelogenous leukemia (AML) can involve the gastrointestinal tract but rarely involves the appendix.We report a male patient who had 1 year partial remission from AML and who presented with apparent acute appendicitis as the initial manifestation of leukemia relapse. Pathological findings of the appendix revealed transmural infiltrates of myeloblasts, whichindicated a diagnosis of leukemia. Unfortunately, the patient died from progression of the disease on the 19th d after admission. Although leukemic cell infiltration of the appendix is uncommon, patients with leukemia relapse can present with symptoms mimicking acute appendicitis.     

Lineage conversion from acute lymphoblastic leukemia to acute myeloid leukemia on rearrangement of the IgH gene in a patient with Down syndrome

A patient with Down syndrome (DS) at the time of diagnosis of acute lymphoblastic leukemia (ALL) had a relapse with acute myeloid leukemia (AML) after 4 years of complete remission. Although the diagnosis was AML, the leukemic blasts at relapse showed an immunoglobulin H rearrangement that turned out to be identical to that of the initial ALL blasts. It is thought that the leukemic precursor cells of this patient had the potential to differentiate into both lymphoid and myeloid lineages. This case is important for investigating target cells for leukemogenesis in DS.     

Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2

One hundred twenty-seven patients with acute myelocytic leukemia (AML) were given busulfan 4 mg/kg on each of 4 days and cyclophosphamide 60 mg/kg on each of 2 days (BuCy2) followed by allogeneic bone marrow transplantation from an HLA-identical or one antigen disparate sibling. For 71 patients in first complete remission, 23 in second complete remission or initial relapse, and 33 patients with primary refractory disease, second or subsequent relapse, or a preceding hematologic disorder, the 3-year leukemia-free survival (LFS) is 63.1%, 32.6%, and 24.2% respectively. The actuarial probability of relapse for each group is 14.1%, 40.6%, and 61.0%. In multivariate analyses, relapse and decreased LFS were associated with advanced disease phase and with M4/M5 French-American-British classification. The LFS of first remission patients was adversely associated with a short time interval from diagnosis to transplantation. This study indicates that BuCy2 is an attractive preparative regimen for marrow transplantation in patients with AML and that prognostic factors for relapse and LFS are similar those described for regimens containing total body irradiation.     

Differential excretion of modified nucleosides in adult acute leukemia

Excretion of modified nucleosides in urine was measured in 23 adults with acute leukemia to determine correlation of nucleoside excretion with disease activity. In addition, differences in excretion between patients with acute lymphoblastic leukemia (ALL) and patients with acute myeloid leukemia (AML) were established. Six modified nucleosides were resolved and quantitated by reversed-phase high-performance liquid chromatography (HPLC). Patients with ALL at initial diagnosis or in relapse had significantly higher concentrations of 1-methylinosine and N2,N2-dimethylguanosine in their urine compared to patients in remission (p less than 0.01, p less than 0.05, respectively). One patient with ALL was followed with serial nucleoside determinations over a period of 18 mo; nucleoside excretion correlated closely with disease activity. Nucleoside excretion in patients with AML did not change significantly with disease activity. Considering only those patients at initial diagnosis or in relapse, excretion of 1- methylinosine and N2,N2-dimethylguanosine was significantly higher in ALL than in AML (p less than 0.01, p less than 0.05, respectively). Thus, urinary excretion of 1-methylinosine and N2,N2-dimethylguanosine by adults with acute leukemia may prove to be valuable clinically in following disease activity in patients with ALL and in distinguishing patients with ALL from those with AML.     

Spontaneous remission in acute myelogenous leukemia in the adult.

A spontaneous complete remission of 17 months duration was observed in a patient with acute myelogenous leukemia. Resolution of all clinical and morphologic abnormalities occurred. The remission was apparently associated with an acute pulmonary infection. At relapse, remission induction was accomplished with cystosine arabinoside and daunorubicin therapy. In vitro granulocyte-macrophage agar culture studies (CFU-c) showed an abnormal growth pattern at presentation, which persisted during the period of spontaneous remission. Reports of spontaneous remissions of acute myelogenous leukemia in adults have become increasingly rare, and the remissions themselves are short-lived. Despite the association between spontaneous remissions and acute infections or febrile episodes, attempts at remission induction with infectious agents have been unsuccessful. Spontaneous remissions are an uncommon variant of the natural course of acute myelogenous leukemia in the adult.     

Divergent patterns of marrow cell suspension culture growth in the myeloid leukemias: correlation of in vitro findings with clinical features.

Cellular recovery, maturation, and colony-forming cell (CFC) generation patterns of bone marrow cells from 23 patients with acute, subacute, and chronic myeloid leukemia (AML, SML, and CML) were studied using liquid and agar culture techniques. Increased recovery of proliferative myeloid cells from liquid culture was noted in 6 of 8 AML patients at diagnosis or relapse and 5 of 7 untreated SML patients. Patients with either AML or SML with rapid clinical progression exhibited greater recovery of cells in vitro with less maturation than patients with more stable disease. Studies from 3 patients with CML showed normal to increased cellular recovery with normal maturation. Three of 4 studies of AML patients followed sequentially in apparent remission, but with impending relapse, exhibited increased numbers of myeloblasts and promyelocytes, whereas 28 of 32 studies performed during stable remission were normal. The normally observed increase in CFC during liquid culture was absent in most leukemic marrow samples studied (3 of 4 AML, 4 of 6 SML, and 2 of 3 CML). Persistent low recovery of CFC during AML remission was associated in 3 patients with short remission duration. These studies indicated the potential utility of these techniques for the clinical evaluation of patients with myeloid leukemia and for studying factors involved in the progression of these diseases.     

Spontaneous complete remission in a 70 year-old man with acute myeloblastic leukemia with severe pneumonia

A spontaneous complete remission of 5 month's duration was observed in a 70 year-old man with acute myeloblastic leukemia complicated with severe pneumonia. The remission occurred after severe pancytopenia. He was treated only with antibiotics and blood transfusions. On admission, the leukocyte count was 6.4 x 10(3)/microliters with 98% myeloblasts. The hemoglobin level was 9.9 g/dl and platelet count was 1.5 x 10(4)/microliters. Marrow aspirate was hypercellular with 98.5% myeloblasts, which weakly showed Ia like antigen and myeloid related antigen. On relapse after five weeks' complete remission, leukemic cells were more immature, peroxidase negative and showed no surface markers. Chromosomal abnormalities were detected. During remission induction therapy he died of severe bacterial and fungal sepsis. Such cases of spontaneous complete remission have been rarely reported, previous adult cases were summarized and the role of etiologic factors were discussed.     

Expression of Fas receptor and soluble Fas ligand (sFasL) concentration in acute leukemia

Apoptosis mediated by the interaction of cytotoxic T lymphocyte with blast cell via Fas receptor/Fas ligand (FasL) pathway is a one of the mechanisms of immunological leukemia surveillance. There is few data on possible blocking of Fas receptor by soluble form of Fas (sFasL) present in serum and the role of blast cells as the source of this ligand. Forty-eight patients with de novo diagnosis of acute leukemia, 32 with myeloblastic (AML) and 16 with acute lymphoblastic leukemia (ALL) were studied. Fas expression on bone marrow leukemic blasts was determined by flow cytomertic immunofluorescent analysis and serum concentration of sFasL assessed at presentation, in remission and in relapse. Blasts of all patients expressed Fas at variable degree (0.8 to 100%). Fas expression was significantly higher on myelo--than on lymphoblasts. There was no relation between degree of Fas expression at diagnosis and remission rate. Concentration of sFasL in acute leukemia patients at diagnosis was significantly higher than in healthy control group, decreased to normal values in remission and rose again in relapse. There was a negative correlation between Fas expression on blasts and sFasL concentration at the time of diagnosis. Results obtained suggest that blast cells could be the source of soluble FasL in acute leukemia patients and that sFasL serum concentration could be used for monitoring of disease activity.