BL22 and lymphoid malignancies

BL22 is a recombinant immunotoxin containing a truncated form of the bacterial toxin Pseudomonas exotoxin A attached to an Fv fragment of an anti-CD22 monoclonal antibody. Its mechanism of action involves binding to CD22, being internalized into the target cell by endocytosis, being processed to generate a free toxin fragment which is translocated into the cytoplasm, and finally induction of cell death by catalytic inactivation of elongation factor 2. In phase-I testing BL22 was very active in chemoresistant hairy-cell leukemia (HCL), with 19 (61%) of 31 patients achieving complete remission (CR). The low blood counts (cytopenias) which are characteristic of HCL improved in all complete and partial responders. Dose-limiting toxicity in HCL was due to a reversible hemolytic uremic syndrome (HUS), observed only during cycles 2 or 3. Already under way are a phase-II trial in HCL and phase-I trials in chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) administering BL22 in a modified protocol in an effort to prevent HUS.     

Protein C and S levels in acute leukemia.

Patients with acute leukemia undergoing remission induction chemotherapy occasionally develop venous thrombosis despite severe thrombocytopenia and in the absence of disseminated intravascular coagulation. This observation prompted us to study the levels of the naturally occurring anticoagulant proteins C and S prospectively in patients undergoing remission induction chemotherapy for acute leukemia. Plasma samples from 50 adult patients with acute leukemia (34 AML, 16 ALL) were analyzed for protein C antigen, functional protein C, immunologic total and free protein S as well as levels of C4b binding protein (C4bBP). Plasma levels of immunologic protein C were significantly lower in patients with active acute myelocytic leukemia (mean = 77.9) than in controls (mean = 123.6) or patients in remission (mean = 132). Functional protein C levels were also significantly lower in AML patients with active disease (mean = 58.5) than controls (mean = 95.5) or patients in remission (mean = 98.5). Patients with acute lymphocytic leukemia (ALL) had normal levels of immunologic and functional protein C. Although total protein S levels were normal in all patients studied, levels of free protein S were significantly decreased in patients with active AML (mean = 29.3) compared with patients in remission (mean = 42.0) or controls (mean = 42.4). In contrast, patients with ALL, both with active disease and in remission had normal free protein S levels. This decrease in free protein S seen in active AML was not associated with liver disease, white cell count or an increase in C4bBP. These findings provide a possible explanation for the occasional occurrence of venous thrombosis in patients with acute myelocytic leukemia.     

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.     

Hairy cell leukemia: Update on molecular profiling and therapeutic advances

Hairy cell leukemia was initially described as a clinicopathologic entity more than 50 years ago. We have subsequently discovered that HCL is really at least two diseases: classical HCL and the hairy cell leukemia variant. The former is among a small group of cancers exceptional for being (nearly) unified by a single genetic lesion, the BRAF V600E mutation. Over the past three decades, tremendous progress in both diagnostic and prognostic clarification has been accompanied by therapeutic advances in classical HCL. Consequently, this once uniformly fatal disease has been converted in most cases into a chronic illness enabling patients to live long and productive lives. In response to standard therapy, patients have high complete remission rates. Unfortunately, the long-term survival curves have not plateaued, revealing that this disease is controlled but not cured. Though rare and representing only about 10% of an already rare disease, those patients with the variant fare exceptionally poorly with standard therapy: complete response rates to purine nucleoside analogs are reported to be less than 50%, whereas the complete response rates in classical HCL are up to 90%. Novel small molecules targeting BRAF and the B-cell receptor signaling complex, and biologic agents like antibodies and immunotoxin conjugates are being explored for those patients who have relapsed. Substantial opportunities for continued research remain. This complex and multi-faceted disease incorporates challenges from altered immunity associated with the underlying disease and its treatments. Considering the rarity of this malignancy, optimization of patient management requires multi-institutional collaboration. The Hairy Cell Leukemia Foundation (www.hairycellleukemia.org) was formed to coordinate these efforts.     

Concomitant chronic lymphocytic leukemia and acute myeloid leukemia with an uncommon immunophenotype

We report a case of simultaneous diagnosis of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), in which the use of flow cytometry analysis allowed the demonstration of two different cell populations and the study of both immunophenotyping patterns with a large panel of monoclonal antibodies (MoAbs). CLL cells showed a typical immunophenotype with coexpression of B cell markers with CD5, CD23, CD43, and weak surface immunoglobulin light chain restriction expression, whereas the AML population had a very uncommon phenotype with expression of myeloid markers and CD56 and lack of expression of other natural killer (NK) antigens, CD34 and HLA-DR. After chemotherapeutic treatment of AML with two induction courses, the patient achieved complete remission of the AML with persistence of a CD19/CD5 positive population. After consolidation chemotherapy, this latter population was no longer detectable despite the presence of lymphoid nodules in a bone marrow biopsy. Six months after diagnosis, the patient relapsed with AML and died shortly afterwards. Am. J. Hematol. 56:281–287, 1997. © 1997 Wiley-Liss, Inc.     

Spontaneous remission of acute monocytic leukemia after infection with Clostridium septicum

Spontaneous remissions of acute myeloid leukemia (AML) have been reported in association with infection. Here, we report a case of spontaneous remission of AML in a 47-year-old Saudi Arabian male patient who presented with a few weeks history of recurrent abdominal pain, vomiting and fever. He was diagnosed with acute monocytic leukemia (AML, FAB M5b) and a perforated bowel. He also had Clostridium septicum bacteremia and thus chemotherapy was deferred. He received supportive therapy and intravenous antibiotics. Six weeks later, he achieved spontaneous and complete remission lasting for about 4 months. The remission and relapse were documented by bone marrow examination. Similarly, previous reports of spontaneous remission of AML were short lived and were followed by relapse and progression.     

Biological characteristics of newly diagnosed poor prognosis acute myelogenous leukemia

A pilot study was conducted of the biological characteristics of the leukemia cells of newly diagnosed patients with poor prognosis acute myelogenous leukemia (AML). This study included measurements of the pretherapy proliferative rate of the leukemia cells in vivo, assessment of differentiation in vivo during remission induction therapy, and the level of expression of the fms, myc, and IL1β genes in pretherapy leukemia cells. Short cell cycle times were characteristic of the best prognostic category and were associated with a rapid reduction in marrow leukemia cells in cytosine arabinoside (araC)-sensitive patients. Expression of c-fms was associated with rapid reduction in marrow leukemia cells during araC therapy and with a successful treatment outcome. Expression of the IL1β gene was associated with short remissions. These studies suggest that when compared to newly diagnosed standard prognosis AML, the leukemia of poor prognosis patients is more likely to exhibit long cell cycle times, low levels of fms expression, and is less likely to be associated with myeloid differentiation during remission induction therapy. © 1993 Wiley-Liss, Inc.     

Persistent Remission after Immunosuppressive Therapy of Hairy Cell Leukemia Mimicking Aplastic Anemia: Two Case Reports

Some patients with hairy cell leukemia (HCL) manifest pancytopenia and bone marrow hypoplasia without an apparent increase in atypical cells, so their disease resembles severe aplastic anemia at onset. We treated 2 HCL patients, who were initially diagnosed with aplastic anemia, with antithymocyte globulin (ATG) in combination with cyclosporine or antilymphocyte globulin (ALG). Both patients obtained partial remission in response to the immunosuppressive therapy and did not need transfusion treatment for more than 3 years. Sustained improvement of hematopoiesis in such B-cell malignancies after ATG/ ALG therapy suggests that the mechanisms underlying successful immunosuppressive therapy for aplastic anemia may involve B-cell suppression, inhibiting hematopoietic stem cells.     

交叉表达淋系和髓系相关抗原的急性白血病的生物学及临床特征研究

目的：探讨交叉表达淋系和髓系相关抗原的急性白血病患者的生物学与临床特征及预后。方法：用流式细胞术检测白血病细胞的免疫表型，根据FAB亚型和免疫标记将病例分为6组；CD7表达阳性的急性髓细胞性白血病（CD7^ AML）、CD7表达阴性的伴淋系相关抗原的急性髓细胞性白血病（CD7^-Ly^ AML）、不伴淋系相关抗原的急性髓细胞性白血病（Ly^-AML）、伴髓系相关抗原的急性淋巴细胞性白血病（My^ ALL）、不伴髓系相关抗原的急性淋巴细胞性白血病（My^-ALL）和急性杂翕生白血病（HAL）。结果：CD7^ AML组的白细胞数高于Ly^-AML组及CD7^-Ly^ AML组，诱导缓解率（16.7％）低于Ly^-AML组（71.4％），有显著差异；CD7^-Ly^ AML组与Ly^-AML组分别比较，发病年龄较高，白细胞数较高，贫血较明显，平均缓解期及平均生存期较短。结论：CD7^ AML及CD7^-Ly^ AML具有不同的临床特征，预后较差，可以看作一个独特的临床亚型。HAL与My^ ALL相比较，具有不同的临床特征，应该区别对待。     

Ida-FLAG plus imatinib mesylate-induced molecular remission in a patient with chemoresistant Ph1+ acute myeloid leukemia

Imatinib mesylate is a potent, selective inhibitor of the tyrosine kinase activity of bcr-abl,which is now established as the state-of-the-art treatment for chronic, accelerated or even blastic phase of Philadelphia-positive [Ph(1)(+)] chronic myelogenous leukemia. It is also active in Ph(1)(+) acute lymphoblastic leukemia, but its role in Ph(1)(+) acute myeloid leukemia (AML) is less well investigated. We report here a patient with chemoresistant Ph(1)(+) AML, who responded promptly to one cycle of Ida-FLAG second-line chemotherapy by achieving complete morphologic, immunophenotypic, and cytogenetic remission but not a molecular one. The addition of imatinib mesylate led to a molecular remission, which is sustained for 10 months so far.     

Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2)

We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline, etoposide, and behenoyl cytarabine chemotherapy for AML (French-American-British classification, M2; World Health Organization classification, AML with maturation) and achieved complete remission. At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML.     

Features and clinical outcomes in 40 patients with mixed-lineage acute leukemia in a single center

Abstract

Mixed-lineage acute leukemia (MAL) is characterized as acute leukemia involving acute myeloid cells and lymphoid cells at the same time. It is easily misdiagnosed because of the dual characteristics involving both lymphoid and myeloid cells and has a poor prognosis. We retrospectively analyzed the features and treatment effectiveness in a single center in 40 patients with MAL. The morphology was consistent with acute lymphoblastic leukemia (ALL) (47.5%) or acute myeloid leukemia (AML) (20%) or was inconclusive (32.5%). Twenty-two patients were characterized as B/myeloid, and 18 patients as T/myeloid. Cytogenetics showed t(9;22)/(Ph⁺) (12.5%) and 11q23/MLL rearrangements (6.25%). The rate of first complete remission for patients undergoing chemotherapy based on the features of both ALL and AML and of either ALL or AML was 71.4 and 42.9%, respectively. The 1-year overall survival rates were 37.5 and 60.0% for chemotherapy and chemotherapy followed by haploidentical hematopoietic stem cell transplantation (HSCT), respectively. The 1-year disease-free survival rates were 25.0 and 50.0% for chemotherapy and chemotherapy followed by HSCT, respectively. These results showed that MAL is confirmed to be a poor-risk disease. The chemotherapy for remission induction should be based on both myeloid cells and lymphoid cells. Transplantation should be performed after the first remission.     

Concurrent acute myeloid leukemia with inv(16)(p13.1q22) and chronic lymphocytic leukemia: molecular evidence of two separate diseases

Acute myeloid leukemia (AML) occurring concurrently with or after untreated chronic lymphocytic leukemia (CLL) is rare. We report a case of a 59-year-old man who was evaluated for anemia, thrombocytopenia, and leukocytosis with circulating blasts. On the basis of the morphology and immunophenotyping results, a preliminary diagnosis of chronic myelomonocytic leukemia with concurrent CLL was considered. Subsequently, cytogenetic analysis of the leukemic blood specimen revealed inv(16)(p13.1q22) with secondary trisomy 22 in a sideline clone. Fluorescence in situ hybridization confirmed the CBFbeta rearrangement associated with inv(16) in myeloblasts and myelomonocytic cells, but not in CLL cells. Therefore, a final diagnosis of AML with inv(16) with concurrent CLL was made. After standard chemotherapy for AML, the patient achieved complete remission for both his AML and CLL. The unique aspects of this case include concomitant AML and CLL, which do not share clonality, complex cytogenetic abnormalities with trisomy 22 as a secondary abnormality associated with inv(16), and achievement of remission for both AML and CLL by AML chemotherapy regimen. This case also represents one of the rare instances where a diagnosis of AML can be established even when the blast percentage in the marrow and blood is less than 20%.     

High-dose hydroxyurea in the treatment of poor-risk myeloid leukemias

The aim of the study was to evaluate the antileukemic effectiveness and toxicity of high-dose hydroxyurea (HHY) and to assess its acute toxicity. Between August 1997 and October 1998, 12 consecutive adult patients (>18 years) with high-risk acute myeloid leukemia (AML) (four patients in first early relapse, seven patients with secondary AML, and one patient with de novo AML concomitant to a lymphoproliferative disorder) were enrolled to receive a single course of HY (100 mg/kg per day) until bone marrow aplasia or for a maximum of 30 days. Of the 12 patients, 5 (41.6%) achieved complete remission (CR), 1 achieved partial remission (PR), 4 were resistant to treatment, and 2 died during induction from infection. No patient with relapsed AML achieved CR, while it was achieved by five of eight patients with secondary AML at diagnosis; five of six MDR1+ patients achieved CR. As concerns follow-up of the CR patients, one did not receive any further treatment and died in CR from pulmonary aspergillosis, and one with a concomitant chronic lymphocytic leukemia (CLL) received two courses of FLAG (fludarabine, cytarabine, granulocyte colony-stimulating factor) regimen with disappearance of the clonal Ig rearrangement, but relapsed after 11 months and died from pneumonia. The remaining three patients were consolidated with two courses of high-dose cytosine arabinoside (AraC), followed by peripheral blood stem cell transplantation (PBSCT) in one patient. One of them relapsed after 3 months, while the other two are still in continuous complete remission (CCR) after 16 and 28 months, respectively. This study has demonstrated the safety and efficacy of HHY in inducing CR in AML patients with unfavorable prognosis. Despite the small number of patients, these encouraging results warrant further studies.     

Analysis of the cellular DNA and RNA content in acute leukemias by flow cytometry

Summary In the present study bone marrow samples from 573 patients with newly diagnosed acute myeloid (AML) and lymphoblastic or undifferentiated leukemias (ALL/AUL), were analysed for their cellular DNA und DNA/RNA content, respectively, by means of flow cytometry. From 237 patients with AML 35.4% revealed aneuploid DNA stemlines. While no relation of DNA aneuploidy with other pretherapeutic parameters, including FAB subtype, white blood cell count, lactate dehydrogenase, S-phase index and percentage of blasts in the bone marrow, was observed, cases with aneuploid DNA stemlines revealed a tendency towards longer remission duration. In ALL/AUL 21.8% of 280 patients expressed DNA aneuploidies, which were less frequently found in T-cell ALL (11.1%) as compared to common(C)-ALL (21.4%) or null-cell(null)-ALL (23.5%). DNA aneuploidy was not related with other clinically defined risk factors such as age, white blood cell count, and rapid achievement of remission. Patients with DNA indices <1.0, however, tended to have shorter remissions. A significant difference in RNA indices was observed between AML and ALL/AUL with median values of 14.4 and 10.1, respectively (P<0.05). These data indicate the usefulness of flow cytometric analyses of cellular DNA and RNA content for the characterization and classification of acute leukemias, complementing the identification of clinical risk factors, immuno-phenotyping and cytogenetics.Abbreviations AML acute myeloid leukemia - ALL acute lymphoblastic leukemia - AUL acute undifferentiated leukemia - T-ALL, C-ALL and Null-ALL T-cell, common and Null-cell ALL     

Itraconazole and multidrug resistance: Possible effects on remission rate and disease-free survival in acute leukemia

Summary Itraconazole, a triazole antifungal agent, has been reported to reverse drug resistance against daunorubicin in acute leukemia. In a subanalysis from a double-blind, placebo-controlled trial examining the effects of itraconazole on the prevention of fungal infections in neutropenic patients, we studied the effects of itraconazole on remission rate and disease-free survival in patients with acute lymphoblastic (ALL) and acute myelogenous leukemia (AML) receiving remission induction treatment schedules containing daunorubicin (DNR). Eleven ALL and 17 AML patients received itraconazole and 12 ALL and 25 AML patients were given placebo. Among AML patients the remission rate was slightly higher in the itraconazole group, whereas the disease-free survival was higher mong ALL patients given itraconazole. In AML patients DFS was comparable in both groups but the number of high-risk patients in the itraconazole group was higher. These preliminary results may suggest a role for itraconazole in reversing multidrug resistance. Larger trials, however, are required to substantiate these findings and to correlate them with its in vitro effects on multidrug resistance.     

老年急性髓系白血病的治疗现状

急性髓系白血病（AML）随着年龄的增长发病率逐渐升高。由于老年AML患者化疗完全缓解率低,治疗相关死亡率高,长期生存率低,预后差,尚缺乏统一有效的治疗策略。本文就目前老年AML治疗现状作简单综述,探讨传统化疗、造血干细胞移植及新的靶向药物在老年AML治疗中的应用。     

Long-Term Survival in Acute Leukemia

ABSTRACT. An intermittent combination chemotherapy program was initiated in 1971–79 in 172 patients, aged 15–59 years, with acute leukemia (131 myelogenous (AML) and 41 lymphoblastic (ALL)). Sixteen patients with AML and 6 with ALL have survived for more than 5 years. These long-term survivors represent 24% of AML and 18% of ALL patients who obtained complete remission. Twelve patients (10 AML and 2 ALL) are in continuous first remission 5.5–13.5 years after diagnosis. Occasional late relapses up to 9 years after diagnosis make it impossible to declare any individual patient cured.     

Clinical aspects of acute myeloid leukemias of the FAB types M3 and M4Eo

Summary Acute promyelocytic leukemia (AML FAB M3, APL) and acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) are considered distinct entities with characteristic clinical, morphological, cytogenetic, and prognostic features. Promyelocytic leukemia is characterized by abnormal promyelocytes replacing normal hematopoiesis associated with a translocation between the long arms of chromosomes 15 and 17 t (15; 17), severe coagulopathy, and responsiveness to all-trans retinoic acid (tretinoin). Characteristic features of AML M4Eo are a myelomonocytic marrow infiltration, eosinophils with abnormal immature granules positive for chloroacetate esterase, an inversion or translocation of chromosome 16, and an increased risk of meningeal relapses. Prognosis of both types of AML has been reported to be better than prognosis of the other entities combined. Since most of the published data were collected from heterogeneous patient populations treated with various chemotherapeutic regimens, we have analyzed treatment outcome of AML M3 and M4Eo in the AMLCG-85 study for patients younger than 60 years. For the total population of 594 patients of this study, CR rate was 68.89%, early death rate 11.60%, and no or partial remission was achieved in 19.51% of the cases. Of 40 patients with AML M3 or M3v complete remission was attained in 62.5%. Nine patients died within 42 days after the start of antileukemic therapy (22.5%). Of these nine, four died because of infection, five because of bleeding. Relapse-free survival rate was 59% after 3 years, significantly better than the respective curve of the other FAB types combined (35% after 3 years). In AML M4Eo, 91.7% of the 24 patients reached complete remission. The early death rate was 8.3%. No case of nonresponse was seen. Relapse-free survival rate was 49% after 3 years compared with 35% for the other types combined.     

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.