Clinical Leukemia最新文献

Biphenotypic acute leukemia (BAL) is a rare disorder comprising 5% of acute leukemias, most likely arising from a multipotent progenitor cell. Knowledge of this disease is limited. There is no single chromosomal abnormality uniquely associated with BAL; however, the most common chromosomal abnormalities are t(9;22)(q34;q11) and structural abnormalities involving 11q23. Whether patients with BAL should be treated with regimens designed for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or combination of treatment for AML and ALL remain unclear. Because of its poor prognosis, it is likely that it might require more intensive treatment approaches, including allogeneic progenitor cell transplantation to achieve long-term complete remissions. In this review, we discuss insights into the molecular biology, diagnosis, classification, prognosis, and treatment strategy of this disease.

Opportunistic infections are a leading cause of death in patients undergoing induction chemotherapy for acute myelogenous leukemia. Bacterial infections in this population are common, and virulent Gram-negative organisms pose an ever-growing threat because of the use of broad-spectrum antimicrobial agents, prolonged myelosuppression, and protracted hospitalizations. Recently, a characteristic infectious syndrome of fatal hemorrhagic pneumonia attributed to Stenotrophomonas maltophilia was described in cytopenic patients with acute leukemia who received anthracycline-based chemotherapy. We report another fatal case and review the literature on this recently described infectious syndrome.

In the United Kingdom, low-dose cytarabine (Ara-C) is now considered the standard of care for nonintensive therapy of myelodysplastic syndromes (MDS) with > 10% blasts and acute myeloid leukemia (AML). It remains an inexpensive and effective therapy in older patients with AML or MDS who are not fit for intensive chemotherapy. Low-dose Ara-C is ineffective for adverse-risk karyotype, and the early death rate is high (9%). The incidence of grade 3/4 infection and hemorrhage is as high as 17% and 9%, respectively. A more favorable outcome is linked to the administration of ≥ 4 courses and to the achievement of complete remission (CR). The largest published series showed an overall response rate of 44% in 180 patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation and a progression-free survival time of 9 months. Low-dose melphalan cannot be routinely recommended but should be considered in a subgroup of elderly patients with MDS with > 10% blasts or AML, normal karyotype, and hypocellular bone marrow, where durable CR rates of 30% are reported with minimal side effects. Preliminary phase III trial data suggest that demethylating agents produce superior overall survival compared with other low-dose options.

The clinical outcome of acute myeloid leukemia (AML) is extremely variable, ranging from survival of a few days to cure. Different clinical and biologic features at diagnosis have been reported as useful for the prediction of clinical outcome; however, in most AML cases, induction therapy must be initiated as soon as possible. Therefore, the possibility of stratifying patients at diagnosis is generally not taken into account, with the exception of acute promyelocytic leukemia in which morphology, immunophenotype, and molecular biology allow rapid diagnosis and the adoption of a specific therapy. As a consequence, prognostic factors in AML are more useful for the prediction of relapse rather than for the stratification of induction therapy. However, a further exception is represented by a considerable proportion of elderly patients, in whom the potential benefits of an aggressive approach are not commensurate with the risks. Nevertheless, in order to achieve the best therapeutic results and avoid unnecessary toxicity, it would be of major clinical use to determine which patients will do well with some types of treatment and not others. This is particularly relevant in AML of the elderly because the > 15% risk of death in the month after the start of treatment is difficult to justify because of median survivals of < 1 year in the patients who do not die early. Therefore, factors other than age significantly influencing survival would be considered and taken into account as soon as diagnosis in the process of therapeutic decision-making.

Purpose

Patients with myelodysplastic syndrome (MDS) and iron overload (IOL) often receive iron chelation therapy (ICT); however, data on clinical outcomes are limited. We reviewed 178 patients with MDS to determine the effect of ICT on survival.

Patients and Methods

Data were collected by chart review and survival analysis performed. A subgroup analysis compared control patients with clinical features similar to patients who received ICT.

Results

French-American-British MDS subtypes for patients were as follows: refractory anemia (RA), n = 36; RA with ringed sideroblasts, n = 42; RA with excess blasts (RAEB), n = 28; RAEB in transformation or acute myeloid leukemia (AML), n = 16; chronic myelomonocytic leukemia, n = 25; other, n = 31. International Prognostic Scoring System (IPSS) scores were as follows: low risk, n = 44; intermediate-1 risk, n = 55; intermediate-2 risk, n = 17; high risk, n = 17. Eighteen patients received ICT; median duration was 21.6 months (range, 1.3-151 months). In univariate analysis (UVA), factors significant for overall survival (OS) were IPSS score; MDS subtype; number of red blood cell (RBC) units transfused; MDS treatment; elevated ferritin; clinical IOL; receiving ICT (P < .05 for all); and age (P = .01). In multivariate analysis (MVA), significant factors included IPSS score (P = .008; hazard ratio [HR], 2.2 [95% CI, 1.3-3.7]) receiving ICT (P = .02; HR, 0.2 [95% CI, 0.01-1.0]). For low/intermediate-1 risk IPSS score, 4-year OS was 64% for patients receiving ICT and 43% for patients not receiving ICT (P = .003). An MVA was performed, including number of cytopenias; blast count; karyotype; AML transformation; ≥ 1 serious infection (P < .05 in UVA for all) with MDS treatment; number of RBC units transfused; and clinical IO; receipt of iron chelation therapy determined that factors significant for OS were infection (P = .05; HR, 3.2 [95% CI, 0.97-10.4]) and ICT (P = .02). Improved OS was maintained in the subgroup analysis (P = .01; HR, 0.29 [95% CI, 0.1-0.79]).

Conclusion

Patients with MDS and IOL receiving ICT had improved survival compared with patients not receiving ICT, suggesting a possible beneficial effect on clinical outcome. Prospective studies of ICT in MDS are warranted.

Background

The treatment of elderly adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of complete responses and long-term overall survival (OS). Therefore, a clinically useful prognostic index would facilitate therapeutic decision-making and evaluation of investigational treatment strategies in this patient population.

Patients and Methods

A prognostic score is presented based on the multivariate analysis of 432 patients with non-M3 AML aged > 60 years, selected on the basis of their initial performance status and the absence of severe comorbid factors for entering into 5 successive clinical trials combining an anthracycline and cytarabine. Four clinically relevant parameters are included in this index: cytogenetics at diagnosis, history of previous hematologic disorder, hematologic features at diagnosis, and lactate dehydrogenase level at diagnosis.

Results

Using this stratification system, 3 risk groups were defined: a favorable-risk group A (OS of 39% at 2 years and 21% at 5 years), an intermediate-risk group B (OS of 19% at 2 years and 8% at 5 years), and a poor-risk group C (OS of 5% at 2 years and 0 at 5 years).

Conclusion

The prognostic index estimates the outcome of elderly patients with AML usually selected for intensive chemotherapy trials using 4 easily determined parameters and might identify patients who are really candidates for this treatment strategy from those for whom investigational therapy or palliation might be most appropriate.

Human nucleophosmin (NPM1), an essential gene, encodes for a ubiquitously expressed protein that plays multiple functions, including stabilization of the Arf tumor suppressor protein, regulation of ribosome biogenesis, and control of centrosome duplication. Although NPM1 constantly shuttles between nucleus and cytoplasm, it resides mainly in the nucleolus. The NPM1 gene is mutated in about one third of adult acute myeloid leukemia (AML) cases. Despite molecular heterogeneity (about 40 variants have been identified to date), all NPM1 mutations determine common alterations at the C-terminus of NPM1 mutant proteins (changes of tryptophans 288 and 290, or 290 alone, and creation of an additional nuclear export signal motif), which cause aberrant NPM1 mutant expression in the cytoplasm of leukemic cells. Acute myeloid leukemia with mutated NPM1 shows distinctive biologic and clinical features, including unique gene expression profile, high frequency of FMS-like tyrosine kinase (FLT3)-internal tandem duplication (ITD), increased incidence in adults and women, wide morphologic spectrum, CD34 negativity, multilineage involvement, and good response to induction therapy. Discovery of mutated NPM1 in AML has already had major diagnostic and clinical implications. Immunohistochemical detection of cytoplasmic nucleophosmin, which is fully predictive of NPM1 mutations, might help rationalize cytogenetic/molecular studies and facilitate genetic classification of AML. Within the heterogeneous category of AML with normal karyotype, NPM1 mutations in the absence of FLT3-ITD identify a subset of patients with favorable prognosis. Because of their stability, NPM1 mutations might become a new tool for monitoring minimal residual disease in about 30% of patients with AML. Understanding how mutations in NPM1 promote leukemia could provide the rationale for the development of targeted therapies.

The 5q– syndrome is the most distinct of all the myelodysplastic syndromes. Importantly, there is a clear genotype- phenotype association in the 5q– syndrome, and it is believed that the deletion of 5q marks the location for ≥ 1 gene, the loss of which might affect important processes such as growth control and normal hematopoiesis. We identified the commonly deleted region (CDR) of the 5q– syndrome at 5q31-32 and suggest that ≥ 1 of the 44 candidate genes mapping within this interval represents the gene or genes critical to the development of the 5q– syndrome. Pinpointing the causative gene(s) has proven challenging; however, new data that support a role for several candidate genes assigned to this interval are now emerging. We have demonstrated haploinsufficiency of the tumor suppressor gene SPARC in the CD34+ cells of patients with the 5q– syndrome and have shown that lenalidomide upregulates this gene in cultured erythroid progenitors from patients with 5q– syndrome. We have also demonstrated haploinsufficiency of RPS14, a component of the 40S ribosomal subunit, in the 5q– syndrome. In Diamond-Blackfan anemia, haploinsufficiency of the ribosomal gene RPS19 is critical, and we have speculated an analogous role for RPS14 in the 5q– syndrome. New data obtained using a functional genomic approach strongly suggests that haploinsufficiency of RPS14 is critical to the development of the 5q– syndrome. We suggest that reduced expression levels (a gene dosage effect) for ≥ 1 of the genes mapping to the CDR is the pathogenetic basis of the 5q– syndrome.