Hypocellular acute myeloid leukemia in adults: analysis of the clinical outcome of 123 patients

Background

The hypocellular variant of acute myeloid leukemia accounts for less than 10% of all cases of adult acute myeloid leukemia. It is defined by having less than 20 percent of cellular bone marrow in a biopsy at presentation. It is unclear in the literature whether the outcome of hypocellular acute myeloid leukemia differs from that of non-hypocellular acute myeloid leukemia.

Design and Methods

We retrospectively analyzed all the cases reported to be hypocellular acute myeloid leukemia between 2000 and 2009. A second pathology review was conducted and the diagnosis was confirmed in all cases.

Results

One hundred twenty-three (9%) patients were identified: patients with hypocellular acute myeloid leukemia were older than those with non-hypocellular acute myeloid leukemia (P=0.009) and more frequently presented with cytopenias (P<0.001). Forty-one patients with hypocellular acute myeloid leukemia had an antecedent hematologic disorder and 11 patients had received prior chemo-radiotherapy for non-hematopoietic neoplasms. On multivariate analysis, overall survival, remission duration and event-free survival were comparable to those of other patients with acute myeloid leukemia.

Conclusions

The outcome of hypocellular acute myeloid leukemia does not differ from that of non-hypocellular acute myeloid leukemia.     

Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach

Members of the French-American-British Cooperative Leukemia Working Group met to review cases of aplastic anemia, hypocellular myelodysplastic syndrome and hypocellular acute myeloid leukemia. Criteria were proposed and modified following three workshops. Additional input was obtained from another hematopathologist with a special interest in bone marrow histology and immunohistochemistry. Guidelines were recommended based on the workshop results as well as additional studies including selective immunohistochemistry, flow cytometry and cytogenetics.     

Low-dose cytosine arabinoside for treating hypocellular acute leukemia in the elderly.

Ten previously untreated elderly patients with hypocellular acute leukemia received a low dose of cytosine arabinoside (Ara-C), 10 mg/m2 injected subcutaneously every 12 hours for 14-28 days. Six patients achieved a complete remission (CR) for periods ranging for 6-23 months (median 8.5 months) and the others had a partial remission (PR). Relapse has occurred in three patients to date. The median survival ranged from 10-24 months (median 14.5 months). Only two of the six patients, in whom bone marrow biopsy was performed at CR, had a normal cellularity. This change, however, did not appear to be a significant prognostic factor in those patients. In seven patients who achieved a CR or PR low-dose Ara-C was administrated as maintenance therapy at the same low dose for 10 days each month. Treatment was well tolerated in all patients despite for myelosuppression. There were no drug-related deaths. These observations suggest that low-dose Ara-C is effective in treating elderly patients with hypocellular acute leukemia.     

Remission rate and survival in acute myeloid leukemia: impact of selection and chemotherapy

113 patients with acute myelogenous leukemia (AML), representing 82% of the total cohort of AML patients within the geographical area of northern Sweden, were recorded. The total complete remission (CR) rate was 47.8%, and median survival was 4 months. The probability of long-term survival for all patients without exclusions was only 5%. Thus, the results from this study differ strongly from data on patient outcome in most therapy studies in AML, where the influence of patient selection on the results is larger. The median age in our patients was 63 years, which is also higher than in most other studies. Elderly patients had a low CR rate (24% in patients greater than or equal to 70 yr), but remission duration was similar in the different age groups. Patients treated according to "high-dose" protocols had a CR rate of 64%, while only 14% of less aggressively treated patients achieved remission. A better response rate after more aggressive chemotherapy was evident also in elderly patients. CR rate was 81% in patients below 60 yr of age who had no antecedent blood disorder and who had had symptoms for less than 3 months. Other variables with prognostic implications were: cytogenetic subgroup, antecedent hematological disease, and level of serum ferritin. High serum ferritin was associated with short CR duration. Ferritin is produced by the leukemic cells and could be regarded as a marker for leukemic activity.     

高白细胞急性髓系白血病的临床分析

目的:探讨高白细胞急性髓系白血病(HAML)患者的临床特征、预后并与同期非高白细胞急性髓系白血病(NHAML)患者进行比较。方法:观察随访66例HAML(WBC≥100×109/L)病例(非M3型),分析并发症、早期死亡(early death,ED)、治疗反应、远期预后等,并与同期随机选择的202例NHAML(WBC<100×109/L)病例(非M3型)进行比较。结果:①HAML病例发生低钾血症、出凝血异常、感染、肺白细胞淤滞、脾脏肿大、淋巴结肿大等并发症的概率高于NHAML病例(P<0.05)。HAML病例FAB分型以M4/M5型为主。②HAML病例ED 4例(6.1%),ED与出凝血异常(P<0.01)、肺白细胞淤滞(P<0.01)、CNS白细胞淤滞症状(P<0.01)相关。③HAML病例CR率66.7%,且M4/M5型CR率低。HAML病例3年DFS率为45.7%,3年OS率为32.5%。完全缓解(CR)率与年龄、是否为M4/M5型相关(P<0.05)。3年无病生存率(DFS)与是否>50岁及染色体分组相关(P<0.01)。3年总生存率(OS)与是否CR相关(P<0.05)。NHAML病例CR率为90...     

Clinical implications of molecular markers in acute myeloid leukemia

The recently updated World Health Organization (WHO) Classification of myeloid neoplasms and leukemia reflects the fact that research in the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Gene mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk‐stratification schemes and have been proven to be clinically relevant, targetable lesions. We here discuss the utility of molecular markers in AML in prognostication and treatment decision making, specifically highlighting the aberrations included in the current WHO classification.     

Efficacy and toxicity of gemtuzumab ozogamicin in patients with acute myeloid leukemia

Gemtuzumab ozogamicin (GO) is a recently developed antibody-targeted chemotherapeutic agent and has been expected to be less toxic than conventional chemotherapy. We retrospectively evaluated the use of GO in 38 patients. Patients with acute myeloid leukemia (AML) at diagnosis and relapsed AML were treated with 6 and 9 mg/m(2) GO. Efficacy and toxicity of GO were analyzed, as well as several prognostic factors. A complete response (CR) was observed in 12 of 38 patients, including five patients with CR plus incomplete regeneration of platelets. In one patient a partial remission was observed. Twenty-five patients showed no change or progressive disease. The overall response (OR) in patients with AML at diagnosis was 47%, with the best response in patients with primary AML (OR 60%, compared with 21% OR in non-primary AML, P = 0.045). The OR in patients with relapsed AML was 22%. Median white blood cell (WBC) before treatment, CD33 expression on leukemic blasts, and kinetics of response were analyzed as prognostic factors. Median WBC was significantly lower in patients who responded to GO, compared with non-responders (2.1 x 10(9)/L vs. 6.8 x 10(9)/L, P = 0.036). CD33 expression and kinetics of response was not correlated to clinical outcome. Median days to reach 500 x 10(6)/L neutrophils and 100 x 10(9)/L platelets were 36 and 39 d, respectively. Infections and bleedings occurred in 45% and 12%, respectively. This report shows that GO has potent clinical activity and that the OR rate was by far the best in untreated primary AML patients.     

急性髓系白血病伴Inv(16)/t(16;16)的临床分析

目的:探讨影响急性髓系白血病(AML)伴Inv(16)/t(16;16)患者临床特征、细胞遗传学特点以及生存、预后的主要因素。方法:对43例AML伴Inv(16)/t(16;16)患者进行总结分析、随访,了解一般情况、免疫分型、染色体核型及治疗、生存情况,对影响总体生存时间、无复发生存时间的因素进行统计学分析。结果:43例AML伴Inv(16)/t(16;16)患者总完全缓解(CR)率97.5%,1疗程CR率92.6%。所有患者的中位总生存时间(OS)未达(0.33～81.9个月),中位无复发生存(RFS)63.4(3.02～81.9)个月。3年OS率69%,5年OS率56%;3年RFS率68%,5年RFS率43%。统计学分析可见:≥45岁的患者与45岁患者相比较OS、RFS期短,预后差。发病时一般特征、染色体核型及巩固治疗过程中采用中剂量Ara-C治疗的疗程数与OS无关。结论:年龄≥45岁是AML伴Inv(16)/t(16;16)的主要预后不良因素。     

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.     

Cytogenetics of pediatric acute myeloid leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease accounting for 15–20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. This article focuses on the significance of cytogenetic analysis in pediatric AML supporting the importance of cytogenetic analysis in the pathogenesis, diagnosis, prognosis, follow‐up and treatment selection in childhood AML. It reviews in detail the types and frequencies of most common chromosomal aberrations, their molecular background, their correlation with French American British (FAB) subtypes and age distribution and their prognostic relevance. It also summarizes some less frequent or rare chromosome aberrations in which the prognostic classification has not been determined yet owning to the small number of patients and the variable treatment modalities used in different study groups. Furthermore, it discusses the association of specific chromosome rearrangements with prenatal exposure to carcinogenic agents or therapeutic agents and highlights the ongoing and future research on pediatric AML in the evolving field of Cytogenetics.     

A phase 2 study of vorinostat in acute myeloid leukemia

Background

This two-stage, multi-institutional, randomized phase 2 trial assessed the toxicity and response rate associated with two treatment schedules of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamic acid; SAHA) in patients with relapsed acute myeloid leukemia and in selected untreated patients with high-risk acute myeloid leukemia.

Design and Methods

Patients with relapsed or untreated acute myeloid leukemia who were not candidates for chemotherapy entered one of the two treatment arms. In both arms a total dose of 8400 mg of vorinostat was delivered in each 21-day cycle of treatment: in arm A the dose regimen was 400 mg daily whereas in arm B the dose regimen was 200 mg three times daily for 14 days followed by 1 week rest.

Results

Data from all 37 patients were used for the analyses. In arm A (n=15), the confirmed complete remission rate was 0% (95% CI, 0% to 23%); this arm was closed at the planned interim analysis. In arm B (n=22), the confirmed complete remission rate was 4.5% (1 response; 95% CI, 0.4% to 24%), with a duration of response exceeding 398 days. The median time to treatment failure in arm A was 42 days (95% CI, 26 to 57); although a minimum of four cycles of treatment were planned, 11 patients (79%) received no more than two cycles. The median time to treatment failure in arm B was 46 days (95% CI, 20 to 71); 13 patients (59%) received no more than two cycles of treatment.

Conclusions

Vorinostat monotherapy demonstrated minimal activity in this group of patients with acute myeloid leukemia. Therapy was discontinued in many patients before the planned four cycles had been administered, either because of failure of vorinostat to control the leukocyte count or patients’ and physicians’ preference. Future studies of vorinostat in acute myeloid leukemia should focus on combinations with other drugs with which it might interact pharmacodynamically. ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00305773","term_id":"NCT00305773"}}NCT00305773.     

Therapy for acute myeloid leukemia in 119 adults: A comparison of two treatment protocols

Summary Of 119 patients with acute myeloid leukemia, 69 were treated with Adriamycin, Vincristine and Cytosine Arabinoside (Therapy 1) and 50 with Daunorubicin, Cytosine Arabinoside and 6-Thioguanine (Therapy 2) as well as a consolidation therapy. The maintenance therapy with Cytosine Arabinoside and 6-Thioguanine was the same for both groups. The complete remission rate was 44% for Therapy 1 and 68% for Therapy 2 (p<0.05). — The median values for remission duration were 7 and 13 months respectively (p=0.10); for survival time the median values were 18 and 19 months. These figures show in retrospect that high remission rates can be attained through intensive induction therapy and that longer remission duration is correlated with more aggressive induction therapy. A mild form of maintenance therapy seems to have little effect on the duration of complete remission.     

Anticardiolipin antibodies in acute myeloid leukemia: Prevalence and clinical significance

This prospective study was designed to explore the prevalence and the clinical and prognostic significance of anticardiolipin (ACL) antibodies in patients with acute myeloid leukemia (AML). The study includes 37 consecutive AML patients >15 years old without previous history of thromboembolism, recurrent fetal loss, or autoimmune disease and with no evidence of infection at the time of enrollment. ACL antibodies were found in 25 patients (68%). None of the patients had high positive titers; 8 had moderately positive while 17 had low positive ACL antibody titers. ACL antibody positivity did not predict response to chemotherapy and was not correlated with age, gender, FAB class, platelet and white blood cell counts at presentation, and the risk of thromboembolism. ACL antibody titers did correlate, however, with AML activity in the majority of patients (93%) during 4–19 months of follow up. These results demonstrate a high prevalence of ACL antibodies in AML patients and suggest that serum ACL antibodies may be a useful adjunct in predicting relapse and documenting disease activity and therapy response. Am. J. Hematol. 57:139–143, 1998. © 1998 Wiley-Liss, Inc.     

Diagnostic and prognostic significance of serum measurements of lactoferrin, lysozyme and myeloperoxidase in acute myeloid leukemia (AML): recognition of a new variant, high-lactoferrin AML

92 patients with acute myeloid leukemia were classified according to the FAB classification (M1 n = 20, M2 n = 43, M3 n = 1, M4 n = 19, M5a n = 2, M5b n = 2, and M6 n = 5 patients). Serum measurements of lactoferrin (LF), myeloperoxidase (MPO) and lysozyme (LYS) were performed before the start of treatment. LF was significantly lower in M1 when compared with M2 but not as compared to M4, MPO was significantly higher in M2 and M4 than in M1, but comparable MPO levels were found in M2 and M4. LYS was significantly elevated in M2 in comparison with M1, and in M4 when compared to both M1 and M2. Polymorphonuclear granulocytes (PMNs) in M1 were significantly reduced when compared with M2 and M4, whereas mononuclear cells were significantly increased in M4 in comparison with both M1 and M2. FAB classification did not generate any prognostic information. When the patients were, instead, subdivided according to LF levels were found prognostically significant differences. Of patients below 100 micrograms/l, 44% went into remission as compared to 77% with LF from 101 to 400 micrograms/l. In patients with LF levels above 400 micrograms/l the remission frequency was only 14%. Multivariate statistical analysis on the data further suggested that lactoferrin may be used as an independent prognostic indicator. We conclude that although determination of the serum-levels of lactoferrin, lysozyme and myeloperoxidase in certain cases may be valuable as a supplement to the morphological examination of acute myeloid leukemia, it is evident that none of the three determinations can be used alone to distinguish between the FAB groups.     

Outcome of acute myeloid leukemia patients with pulmonary nodules of uncertain etiology receiving allogeneic hematopoietic progenitor cell transplant

Pulmonary nodules (PNs) develop frequently in patients with acute myeloid leukemia (AML). They are of infectious or inflammatory origin. They pose potential challenges to successful hematopoietic progenitor cell (HPC) transplant as they may be niches for infection reactivation or sites susceptible to subsequent infections. We retrospectively analyzed the outcome of 20 AML patients with multiple PNs who underwent allogeneic HPC transplants (12 related, 8 unrelated). There were 13 males and seven females (median age 52 yrs). Nine patients were in CR1, seven in CR2, and four with residual disease. The median times from appearance of PNs and from last positive CT scans to transplant were three and two months, respectively. The median time from pretransplant CT scans to transplant was one month. Multiple PNs were still reported in 5/20 of the pretransplant scans. The PNs in all five patients did not worsen after transplant. Four patients (one with positive pretransplant CT scan) died within the first 100 d after transplant, but none from primary pulmonary pathology. The median survival of this group of patients was 350 d. Our results, therefore, suggest that multiple PNs of uncertain etiology in patients with AML do not impact adversely on the outcome of allogeneic HPC transplant.     

Impact of body-mass index on the outcome of adult patients with acute myeloid leukemia

Background Obesity increases the risk of treatment-related complications and reduces survival in children with acute myeloid leukemia. Little is known about the impact of obesity on the outcome of adult patients with acute myeloid leukemia. DESIGN AND METHODS: We compared the baseline characteristics and effect on treatment and survival in 1,974 previously untreated adult patients with acute myeloid leukemia undergoing treatment, according to international classification of body-mass index. RESULTS: The median body-mass index was 26.7 (15.5-61) and 63% of patients were overweight/obese. After adjustment for other confounders, such as age, gender, performance status, karyotype, white blood cell, platelet and peripheral blast counts, obese patients had better complete remission rates (P=0.0046), lower rates of resistant disease (P=0.038) but similar rates of survival and severe adverse events. Conclusions In the treatment of acute myeloid leukemia in adults, obesity was associated with increased response rates and no apparent increase in toxicity. Obesity should not, therefore, be a criterion for excluding patients from aggressive therapy.