A prospective, randomized, double-blind study, comparing unirradiated to irradiated white blood cell transfusions in acute leukemia patients.

A prospective, randomized double-blind study comparing the effects of irradiated and unirradiated white blood cells was conducted in 108 acute leukemia patients with life-threatening infections, refractory to antibiotics. The study demonstrated no significant improvement in 30-day survival or overall survival. Transfusion of unirradiated white cells did not compromise the patient's opportunity to undergo allogeneic stem cell transplant, nor the success rate or overall survival after allogeneic transplant. The important positive finding in this study was that the unirradiated white cells produced a significantly higher increment in circulating granulocytes and in a higher proportion of patients granulocyte count exceeded 1000 per microliter, approaching normal concentrations. The increase in the number and the improved survival of the unirradiated granulocytes suggest that this procedure might potentially be a method to improve the utility of granulocyte transfusions and merits further investigation. The study demonstrated non-inferiority for unirradiated white cells. There were no harmful effects such as graft-versus-host disease, indicating that such studies would be safe to conduct in the future.

Adult acute erythroleukemia: an analysis of 91 patients treated at a single institution.

Acute erythroleukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML); it is considered to have a poor prognosis. From 1 January 1980 to 21 May 2008, 91 patients with newly diagnosed AML-M6 were seen at the University of Texas-M.D. Anderson Cancer Center (UT-MDACC). Forty-five patients (50%) had a history of myelodysplatic syndrome (MDS), compared with 41% in our control group (patients with other AML subtypes) (P=0.08). Poor-risk cytogenetics were more common in patients with AML-M6 (61% versus 38%, P=0.001). Complete remission rates were 62% for patients with AML-M6, comparing with 58% for the control group (P=0.35). Median disease free survival (DFS) for patients with AML-M6 was 32 weeks, versus 49 weeks for the control group (P=0.05). Median overall survival (OS) of patients with AML-M6 was 36 weeks, compared with 43 weeks for the control group (P=0.60). On multivariate analysis for DFS and OS, AML-M6 was not an independent risk factor. AML-M6 is commonly associated with a previous diagnosis of MDS and poor-risk karyotype. The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well known AML prognostic factors.

Leukapheresis reduces early mortality in patients with acute myeloid leukemia with high white cell counts but does not improve long- term survival.

PURPOSE: Current published data on therapeutic leukapheresis in hyperleucocytic AML does not define the impact on survival from this procedure. Between 1992 and 1999 we saw 146 patients with newly-diagnosed AML (APL excluded) and an initial WBC count > 50 x 10(9)/L of whom 71 underwent leukapheresis at the discretion of their treating doctors. We compared outcome (early mortality, CR, and overall survival) rates in the patients who were and were not pheresed. After accounting for covariates relevant to these outcomes, including age, performance status, and cytogenetics, there was evidence (p = .006) that pheresis reduced 2-week mortality rate and a suggestion (p = .06) that this resulted in a higher CR rate. However there was no evidence that pheresis lengthened longer-term or overall survival; if anything the suggestion was the converse (p = .06). These data may reflect the fact that the patients chosen to have pheresis were prognostically unfavorable as defined by variables that were not captured in our data set, since the alternative explanation i.e. that pheresis per se shortens overall survival seems less likely. Whether the above justifies the use of pheresis in the absence of evidence from a randomized trial is doubtful, but it seems likely that any long-term benefit to be derived from this procedure must await further advances in anti-leukemia therapy.

"T-cell-rich B-cell lymphoproliferative disorder" of the bone marrow.

We report four cases of a "T-cell-rich B-cell chronic lymphoproliferative disorder" involving the bone marrow and not extramedullary sites. The neoplastic B-cell proliferation in these cases was composed predominantly of small lymphoid cells with features of both hairy cell leukemia and lymphoplasmacytoid lymphoma. All cases presented with neutropenia and with difficulty in diagnosis. We present the clinical, morphologic, cytochemical, and immunophenotypic findings in these cases and discuss this entity.

Can we conquer cancer in the twenty-first century?

The twentieth century recorded the greatest advance in the control of human disease. From the beginning of recorded time, the human life-span changed little until the twentieth century. In the USA, it increased from 47.3 years in 1900 to 76.4 years in 2000. The answer to the question of "Can we cure cancer in the twenty-first century?" requires an appreciation of the contemporary nature of our knowledge. At the beginning of the twentieth century, major problems were nutrition and infection. By 1950, the major causes of mortality and morbidity were still infectious diseases, such as syphilis, tuberculosis, poliomyelitis, and influenza. The 1950s and 1960s were the golden age of control of infectious diseases, while cancer, because of the aging of the population and the strong association between cancer and age, has become the major healthcare problem of the twenty-first century. Until 1960, no one had proposed or demonstrated that a systemic or metastatic form of cancer could be cured. In only 35-40 years not only have techniques for the early detection, prevention, and surgical and radiation therapy treatments improved, but at least 15-20% of patients with systemic/metastatic cancers can be cured with our current primitive systemic treatments. Prior to 1943, there was no chemotherapy. Prior to 1948, no one had described complete regression of a systemic cancer. There were no multi-institution, randomized clinical trials prior to 1949. Additionally, combination chemotherapy, new drugs, bone marrow transplantation, broad-spectrum antibiotics to control infections, and platelets to control hemorrhage have been added in the past 50 years. The pace of progress extrapolates to a prediction of cancer control in the twenty-first century. The human genome has been sequenced, and it will be possible to identify expression profiles not only for malignant cells but for their normal counterparts. It is certain that interventions specific for control of the malignant transformation will be identified. An example of gene-directed therapy is in acute promyelocytic leukemia where trans-retinoic acid is effective and contributes to cure. The signal transduction inhibitors, small molecules bioavailable orally and specific for interfering with signals resulting from ligand-receptor interactions, are a dramatic advance. Because cancer is a genetic disorder, the expanding field of genomics will certainly accelerate our progress toward the control of cancer. Finally, the twenty-first century will be an era of enhanced communication. The computer has given us the internet. Our communication in cyberspace is not only universal but instantaneous. Increases in the speed at which knowledge can be exchanged and the enormous capacity for storing new knowledge in cyberspace ensure that the pace of progress that we saw in the twentieth century will accelerate in the twenty-first. To address the question in the title of this paper, I believe that it is not a question of whether, but only of when.

High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia.

Vascular endothelial growth factor receptor-2 (VEGFR-2), also termed KDR, is a high-affinity vascular endothelial growth factor (VEGF) receptor. VEGFR-2 plays a role in de novo blood vessel formation and hematopoietic cell development. Recently, we found that chronic lymphocytic leukemia (CLL) cells express high levels of VEGF. Therefore, we sought to investigate the role of VEGFR-2 in CLL. Using Western blot analysis, we first determined that VEGFR-2 is present in peripheral blood CLL cells. We then quantified the cellular levels of VEGFR-2 protein using a solid-phase radioimmunoanalysis in peripheral blood cells from 216 patients with CLL. As control, we used peripheral blood mononuclear cells (PBMNCs) from 31 hematologically normal individuals. The median of VEGFR-2 levels detected in the control samples was assigned a value of 1.0, and VEGFR-2 protein levels were normalized to the control median value. The median level of VEGFR-2 in CLL cells was 1.57. Patients with VEGFR-2 levels higher than 1.57 had elevated lymphocyte counts, severe anemia, elevated beta(2)-microglobulin and advanced-stage disease. Elevated VEGFR-2 levels were also associated with statistically significantly shorter survival (35.4 versus 60.1 months; P < 0.01). Our data indicate that cellular VEGFR-2 levels may serve as a prognostic factor in CLL. Further studies should investigate the biological implications of these findings and the effect of the interaction between VEGF and VEGFR-2 on CLL cell proliferation.

Rituximab dose-escalation trial in chronic lymphocytic leukemia.

PURPOSE: To conduct a dose-escalation trial of rituximab in patients with chronic lymphocytic leukemia (CLL) to define the maximum-tolerated dose (MTD), to evaluate first-dose reactions in patients with high circulating lymphocyte counts, and to assess the efficacy at higher versus lower doses. PATIENTS AND METHODS: Fifty patients with CLL (n = 40) or other mature B-cell lymphoid leukemias (n = 10) were treated with four weekly infusions of rituximab. The first dose was 375 mg/m(2) for all patients; dose- escalation began with dose 2 but was held constant for each patient. Escalated doses were from 500 to 2,250 mg/m(2). RESULTS: Toxicity with the first dose (375 mg/m(2)) was noted in 94% of patients but was grade 1 or 2 in most, predominantly fever and chills. Six patients (12%) experienced severe toxicity with the first dose, including fever, chills, dyspnea, and hypoxia in all six patients, hypotension in five, and hypertension in one. Toxicity on subsequent doses was minimal until a dose of 2,250 mg/m(2) was achieved. Eight (67%) of 12 patients had grade 2 toxicity, including fever, chills, nausea, and malaise, although no patient had grade 3 or 4 toxicity. Severe toxicity with the first dose was significantly more common in patients with other B-cell leukemias, occurring in five (50%) of 10 patients versus one (2%) of 40 patients with CLL (P <.001). The overall response rate was 40%; all responses in patients with CLL were partial remissions. Response rates were 36% in CLL and 60% in other B-cell lymphoid leukemias. Response was correlated with dose: 22% for patients treated at 500 to 825 mg/m(2), 43% for those treated at 1,000 to 1,500 mg/m(2), and 75% for those treated at the highest dose of 2,250 mg/m(2) (P =.007). The median time to disease progression was 8 months. Myelosuppression and infections were uncommon. CONCLUSION: Rituximab has significant activity in patients with CLL at the higher dose levels. Severe first-dose reactions were uncommon in patients with CLL, even with high circulating lymphocyte counts, but were frequent in patients with other mature B-cell leukemias in which CD20 surface expression is increased. Efficacy of rituximab was also significant in this group of patients.

Avascular necrosis of the femoral head in chronic myeloid leukemia patients treated with interferon-alpha: a synergistic correlation?

BACKGROUND: The objectives of this study were to describe cases of avascular necrosis of the femoral head (ANFH) observed in chronic myeloid leukemia (CML) patients who were treated with interferon-alpha and to review the literature. METHODS: The authors undertook a case review of the M. D. Anderson experience with ANFH occurring in CML patients who were managed with interferon-alpha-based therapy. MEDLINE (from 1966 to November 1999) and CancerLit (from 1983 to November 1999) searches were conducted to identify cases of avascular necrosis (AVN) associated with either CML or interferon-alpha. RESULTS: Three patients with ANFH were identified from the authors' experience. No common features related to the disease or therapy were seen among them, except for the presence of thrombocytosis and loss of response. A literature review revealed seven cases of ANFH associated with CML with or without interferon-alpha-based therapy. ANFH was not reported in association with interferon-alpha use for indications other than the treatment of patients with CML. CONCLUSIONS: ANFH may be the result of an interaction between CML and interferon-alpha therapy. ANFH that occurs in patients with CML who are treated with interferon-alpha should be recognized for treatment implications. Thrombocytosis with consequent microvascular thrombi and avascular necrosis manifesting in susceptible vascular or weight-bearing areas (e.g., the femoral head) may be an associated finding along with loss of response to interferon-alpha therapy.

Susceptibility gene for familial acute myeloid leukemia associated with loss of 5q and/or 7q is not localized on the commonly deleted portion of 5q.

The molecular mechanism for the occurrence of leukemia in multiple members of a family has not been fully elucidated but data support the contribution of highly penetrant mutations in leukemia susceptibility genes. We have investigated the genetic etiology of an unusual three-generation family with apparent autosomal dominant transmission of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) accompanied by somatic loss of the long arm of chromosome 5 and/or loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) of leukemia cells have been performed, confirming acquired hemi- and homozygous deletion of the long arm of chromosome 5. However, the chromosome lost in the observed LOH event is from the affected parent, in contradiction to the expectation for a two-hit hypothesis involving a tumor suppressor gene. Furthermore, genetic linkage has been performed at 5q31-33 as well as other loci (21q22 and 16q21-23.2) previously implicated in familial leukemia. In this family, linkage analysis excludes loci at 5q31-33 and 21q22, but localization to 16q21-23.2 cannot be excluded. We observed a maximum multipoint LOD score of 1.19 between marker D16S265 and D16S503 at 16q22 (P = 0.03), suggesting possible linkage to this locus. Considering this family and the previous 16q-linked family together, the linkage of a leukemia susceptibility gene to 16q22 achieved an LOD score of 3.63 at D16S265 with theta = 0. Thus, somatic deletion of the long arm of chromosome 5 appears as a necessary but surprisingly noncausative event for onset of AML and MDS in this family, thereby confirming a multistep etiology in which chromosome 5 plays an important secondary role.

Terminal deoxynucleotidyl transferase expression in acute myelogenous leukemia and myelodysplasia as determined by flow cytometry.

The significance of terminal deoxynucleotidyl transferase (TdT) expression in acute myelogenous leukemia (AML) remains controversial. Therefore, we studied TdT expression by flow cytometry in 120 previously untreated patients with AML or myelodysplastic syndrome (MDS) to determine the distribution of TdT-positive blasts and the intensity of TdT expression and to seek clinically significant associations. TdT expression measured by flow cytometry (flow TdT%) was heterogeneous, ranging from 0.1% to 87% (median, 8.5%), and 74 patients (62%) had at least 5% TdT-positive blasts. TdT positivity was associated with the M0 or M1 subtype and with expression of CD34 and CD7. No significant correlation was found between TdT expression and type of cytogenetic abnormality or rearrangement of immunoglobulin or T-cell receptor genes. Remission lasted longer in patients with a flow TdT% < 5 than in patients with a flow TdT% > 5 (median, 95 weeks vs 55 weeks, p = 0.02); however, complete remission rates did not differ when patients were classified by initial flow TdT%. Survival was slightly better for patients with flow TdT% less than 5%. Among patients with a flow TdT% > 5%, those with a higher TdT intensity survived longer than those with a lower intensity. These data suggest that quantitative TdT measurement may contribute to prognostic estimate in AML patients.