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.

More cell death in refractory anemia with excess blasts in transformation than in acute myeloid leukemia.

Refractory anemia with excess blasts in transformation (RAEB-T) is a subgroup of myelodysplastic syndrome (MDS) in which the bone marrow blast count ranges from 20% to 30%. The recently proposed World Health Organization Classification of Hematologic Malignancies eliminated this category from MDS by lowering the blast count cutoff for acute myeloid leukemia (AML) from 30% to 20%. However, MDS is distinguished from AML by a significant increase in apoptosis. To investigate the difference in apoptosis between RAEB-T, AML, and other categories of MDS, we prospectively analyzed fresh bone marrow samples using the Annexin V and mitochondrial potential assays. There was a significantly higher level of apoptosis in RAEB-T than in AML according to both assays, while no significant differences between RAEB-T and other categories of MDS were noted. The data suggest that RAEB-T is more likely to be an advanced stage of MDS and biologically different from AML.

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.

Treatment of newly-diagnosed acute promyelocytic leukemia with liposomal all-trans retinoic acid.

It has been postulated that recurrence of disease in some patients with newly-diagnosed APL induced into CR, and subsequently maintained, with single agent oral ATRA results from the decline in ATRA levels that occurs with repeated dosing. Administration of liposomal ATRA (lipoATRA) circumvents, for perhaps several months, the decrease in ATRA levels and produces CRs in patients with relapsed APL. These findings led us to administer lipoATRA "monotherapy" to patients with newly-diagnosed APL. Patients received lipoATRA (90 mg/m2) for induction and continued to receive the drug, by itself, for 9 months unless 2 PCR tests done within 2-4 weeks of each other at a sensitivity level of 10(-4) were positive at 3 or 6 months from CR date, in which case idarubicin was added to lipoATRA. If the PCR test was negative 9 months from CR date, treatment stopped. 34 patients were enrolled, of whom 79% entered CR. The PCR test at time of CR was positive in 23/24 patients, but was negative in 24/26 (92%) 3 months later. Of most interest 11 of the 26 evaluable responding patients have remained PCR negative (tested Q 3 months) with a median follow-up of 18 months (range up to 34 months). It is generally believed that this type of result would be unlikely with oral ATRA monotherapy. Recurrence of morphologic APL has occurred in 4 patients, at 5, 6, 12, and 12 months, with a median follow-up time of 18 months in the patients remaining alive in CR. Comparison of this lipoATRA +/- idarubicin trial with oral ATRA + idarubicin induction and idarubicin + POMP maintenance, our previous trial, indicates similar survival, CR, and DFS in CR rates, with a suggestion that lipoATRA may produce lower CR rates and hence shorter survival in patients with high-risk disease (wbc count > 10,000/microliter. Nonetheless, the rates and duration of PCR negativity produced by lipoATRA monotherapy suggest that lipoATRA is a superior anti-APL agent than oral ATRA.

"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.

Significance of angiogenin plasma concentrations in patients with acute myeloid leukaemia and advanced myelodysplastic syndrome.

Human angiogenin is a potent inducer of angiogenesis. The association between angiogenin and cancer progression and poor outcome in solid tumours has been documented, but its significance in leukaemias has not been evaluated. We evaluated plasma angiogenin levels in 101 previously untreated patients with acute myeloid leukaemia (AML) (59 patients) and advanced myelodysplastic syndrome (MDS) (42 patients). Angiogenin levels were significantly higher in AML and advanced MDS patients than in healthy individuals (P < 0.00001). Angiogenin levels were also significantly higher in advanced MDS than in AML (P = 0.001). Higher levels of angiogenin correlated with prolonged survival periods in both AML and advanced MDS patients (P = 0.02 and 0.01 respectively). We found no correlation between angiogenin plasma level and various patient characteristics, including age, performance status, antecedent haematological disorder, haemoglobin, white blood cell and platelet counts, and poor prognosis cytogenetics. There was no significant correlation between angiogenin level and complete remission rate and duration in AML or advanced MDS patients. In multivariate analysis, angiogenin concentration retained its significance as a prognostic factor in AML (P = 0.03), together with age (P = 0.00007) and haemoglobin (P = 0.03).

Plasma hepatocyte growth factor is a prognostic factor in patients with acute myeloid leukemia but not in patients with myelodysplastic syndrome.

Hepatocyte growth factor (HGF) is a potent angiogenic factor. The aim of our study was to evaluate plasma HGF levels and their prognostic significance in patients with newly diagnosed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The sandwich enzyme immunoassay technique was used to quantify HGF in stored samples obtained before treatment from patients with AML (59 patients) and MDS (42 patients) treated at The University of Texas MD Anderson Cancer Center. HGF levels were significantly higher in patients with AML or MDS than in healthy individuals (P < 0.0001). Higher HGF levels in both AML and MDS correlated significantly with white blood cell (P = 0.000001 for both groups) and monocyte counts (P = 0.0004 and 0.003, respectively), and with poor performance status (P = 0.03 and 0.001, respectively). Using Cox proportional hazard model and HGF levels as a continuous variable, plasma levels of HGF correlated with shorter survival of AML (P = 0.001), but not MDS (P = 0.34) patients. No significant correlation was observed between HGF levels and complete remission rate or duration. In the multivariate analysis HGF retained its significance as prognostic factor in AML (P = 0.02), along with age (P = 0.0005).

BCR rearrangement-negative chronic myelogenous leukemia revisited.

PURPOSE: To document the characteristics of patients with major breakpoint cluster region (M-bcr) rearrangement-negative chronic myelogenous leukemia (CML). PATIENTS AND METHODS: The hematopathologist, who was blinded to patients' molecular status, reviewed the referral bone marrows and peripheral-blood smears from 26 patients with Philadelphia (Ph) translocation-negative CML who lacked Bcr rearrangement (and other evidence of a Bcr-Abl anomaly) and 14 patients (controls) with chronic-phase Ph-positive CML. Clinical data was ascertained by chart review. RESULTS: Among the 26 M-bcr rearrangement-negative CML patients, three pathologic subtypes emerged: (1) patients indistinguishable from classic CML (n = 9), (2) patients with atypical CML (n = 8), and (3) patients with chronic neutrophilic leukemia (n = 9). Among the 14 patients with Ph-positive CML who were included in the blinded review, 13 were classified as classic CML, and one was classified as atypical CML. The only statistically significant difference between M-bcr rearrangement-negative subgroups was in the proportion of patients having karyotypic abnormalities, an observation common only in patients with atypical CML (P = 0.008). However, the small number of patients in each subgroup limited our ability to differentiate between them. Interferon alfa induced complete hematologic remission in five of 14 patients; four of these remissions lasted more than 5 years. Only one of 26 patients developed blast crisis. The median survival of the 26 patients was 37 months. CONCLUSION: Patients with M-bcr rearrangement-negative CML fall into three morphologic subgroups. Disease evolution does not generally involve blastic transformation. Instead, patients show progressive organomegaly, leukocytosis, anemia, and thrombocytosis. Some patients in each subgroup can respond to interferon alfa.

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.