Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy

In current medical practice, patients with refractory anemia with excess blasts in transformation (RAEB-t), and especially patients with RAEB, receive chemotherapy regimens (AML Rx) administered to patients with acute myeloid leukemia (AML) less often than do patients with AML. These entities are distinguished primarily by marrow blast percentage (5% to 19% RAEB, 20% to 29% RAEB-t, and > or = 30% AML). The poor prognosis of many RAEB or RAEB-t patients, if untreated, led us to give them AML Rx using the same plan as for AML. The purpose of this analysis was to see if diagnosis (RAEB, RAEB-t, or AML) affected outcome. We treated 372 patients with AML (acute promyelocytic leukemia [APL] excluded), 106 with RAEB-t, and 52 with RAEB. AML Rx produced a 62% complete remission (CR) rate in RAEB, essentially identical to the rates in RAEB-t and AML, but event-free survival (EFS) from CR and from start of treatment (start of Rx), as well as overall survival, were poorer in RAEB than in AML or RAEB-t, with AML and RAEB-t being identical. However, patients with RAEB or RAEB-t were more likely to have poor prognostic characteristics, in particular complex abnormalities involving chromosomes 5 and/or 7. Multivariate analyses indicated that, when considered together with cytogenetics and other patient characteristics, a diagnosis of RAEB rather than AML or RAEB-t had no effect on EFS from start of Rx, EFS from CR, survival, or achievement of CR. These analyses suggested a trend for patients with RAEB-t to have better EFS from start of Rx than patients with AML or RAEB (P = .08; relative risk, 0.80; 95% confidence interval, 0.62 to 1.03), but there were no differences with respect to the other outcomes. Our data suggest that the propriety of administering AML Rx to patients with RAEB or RAEB-t who have poor prognosis without treatment is identical to the propriety of treating AML in this fashion. Deterrents to standard AML Rx in these patients could justifiably include cytogenetics, age, etc, but not a diagnosis of RAEB or RAEB-t per se.     

Anti-GM-CSF monoclonal antibody therapy for refractory acute leukemia

Several phase I trials and pilot studies using Monoclonal Antibody (MoAb) have been performed in B-cell neoplasms, but this approach has not until now been extensively tested in myeloid leukemias. Recently, we evaluated the use of anti-Granulocyte-Macrophage Colony-Stimulating Factor MoAb (Anti-GM-CSF MoAb) in acute myeloid leukemia (AML). Eight patients fulfilled inclusion criteria and received a single course of Anti-GM-CSF MoAb infusion during 5 to 15 days. Anti-GM-CSF MoAb was well tolerated and was detectable in pharmacokinetics studies. Using Human Anti-Rat Antibodies (HARA), we also observed an immunological response to the MoAb. Despite sufficient levels detected in the serum and biological activity of Anti-GM-CSF MoAb in vivo, no anti-leukemic effect was noted, except for one patient who had a decrease of 50% in the marrow blast cell mass. These observations indicate that leukemic proliferation in vivo involves a complex network spanning many mechanisms, and inhibition of leukemia is not effective if only one of these key targets is attacked. The development of these new approaches may be more effective in the future.     

Continuous infusion etoposide/carboplatin for treatment of refractory acute leukemia

Etoposide (125 mg/m2/d) and carboplatin (200 mg/m2/d) were administered by continuous 5-day intravenous infusion to 10 patients with relapsed or refractory acute leukemia (7 ANLL, 1 ALL, 2 blast crisis of CGL). No complete or partial response was observed despite dose-limiting toxicity characterized by severe diarrhea in four patients and neutropenic colitis in two additional cases. We cannot recommend the present schedule of drug administration for the treatment of acute leukemia.     

Evaluation of CI-973, a platinum analogue, in refractory or relapsed acute leukemia

Uranium isotopes were given via single intravenous injection into 22 young adult beagle dogs of both sexes to determine the metabolism of this element. Animals were given either 232U, 233U, 238U, or a combination of 232 (+) 233U. Calculations to assign a value of skeletal dose for each dog were performed using published radioactive properties of each uranium isotope and the metabolic data (including measured retention and skeletal distribution) derived from this study during a period of up to 2 y after injection. We believe that the procedures illustrated in this communication can serve as a useful pattern for estimating skeletal radiation doses to humans contaminated with 232U, 233U, or 238U.     

Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia

The improved outcome of acquired aplastic anemia (AA) has revealed later complications, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). We retrospectively analyzed 167 children with severe acquired AA. Eleven of 50 children treated with cyclosporin (CSA) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) developed MDS/AML; 8 of these were within 36 months of the diagnosis of AA, much earlier than previous reports. Six of the 11 children received rhG-CSF exceeding 10 microg/kg/d, and 9 received rhG-CSF therapy for over 1 year. Ten children showed monosomy 7 at diagnosis of MDS. All of the 11 children were administered both CSA and rhG-CSF. There was no development of MDS/AML among 41 children treated with either CSA or rhG-CSF or among 48 children who underwent bone marrow transplantation. A well-controlled clinical trial is warranted to determine whether therapeutic modalities affect the development of MDS/AML in children with severe acquired AA.     

Refractory anemia with severe dysplasia: clinical significance of morphological features in refractory anemia

Refractory anemia (RA) in myelodysplastic syndromes (MDS) are very heterogeneous diseases regarding their morphology, clinical features and survival. We proposed the new designations 'RA with severe dysplasia (RASD)' and 'RA with minimal dysplasia (RAminiD)'. In our criteria, RASD is considered present if a bone marrow (BM) examination shows Pseudo-Pelger-Huet anomalies of mature neutrophils > or =3% and/or micromegakaryocytes (mMgk) of megakaryocytes > or =10% in RA patients. RAminiD is defined as RA cases other than RASD. After the reclassification of 58 primary RA patients, the group was composed of 45 RAminiD and 13 RASD patients. The blast percentage in the BM and the frequency of cytogenetic abnormalities observed in the RASD patients were intermediate between those in the RAminiD and RAEB patients. The analysis of survival curves revealed differences among the three groups; the RASD patients had lower survival probabilities than those of the RAminiD group, and significantly higher probabilities than those of the RAEB group. (RAminiD vs RASD, P=0.06; RASD vs RAEB, P=0.004.) Our data indicate that in RA patients, RASD is a distinct subset of RA with an unfavorable clinical outcome.     

A phase II study of interleukin-2 in 49 patients with relapsed or refractory acute leukemia

Two monoclonal antibodies (mAb) within cluster M4 of the myeloid section of the Second International Swine CD Workshop, C4 (No. 144) and PM18-7 (No. 192), showed reactivity with thymocytes and among cells of myelomonocytic origin with mature macrophages but not with monocytes and granulocytes. Both mAb recognize a protein showing two bands of 205 kDa and 130 kDa under both reducing and non-reducing conditions. Although epitope mapping with these mAb could not be performed, this cluster received the SWC9 designation.     

Enterolithiasis, refractory anemia, and strictures of Crohn''s disease

It has been recently shown that NGF is not only involved in the survival and development of sympathetic and neural crest-derived sensory neurons, but also in some mechanisms of the immune system. For this reason, we studied the content of NGF in CSF samples from patients with diseases in which neuroimmunological mechanisms seem to be involved (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer disease, chronic relapsing polyradiculoneuritis, Guillain-Barré syndrome, and tumors of the nervous system), as well as from a number of normal control subjects. We setup an ELISA aimed at the beta subunit of NGF, obtaining good validation tests and a detection limit of 28 pg beta NGF per ml. None of the samples was found to contain detectable levels of NGF and, when a concentration method for sample enrichment was used, only one patient was NGF-positive. This suggests that NGF is probably not involved in the neuroimmunological mechanisms underlying some inflammatory and degenerative diseases of the nervous system.     

Diagnostic and therapeutic thoracic surgery in leukemia and severe aplastic anemia

We examined the hypothesis that peak magnitude strain gradients are spatially correlated with sites of bone formation. Ten adult male turkeys underwent functional isolation of the right radius and a subsequent 4-week exogenous loading regimen. Full field solutions of the engendered strains were obtained for each animal using animal-specific, orthotropic finite element models. Circumferential, radial, and longitudinal gradients of normal strain were calculated from these solutions. Site-specific bone formation within 24 equal angle pie sectors was determined by automated image analysis of microradiographs taken from the mid-diaphysis of the experimental radii. The loading regimen increased mean cortical area (+/-SE) by 32.3 +/- 10.5% (p = 0.01). Across animals, some periosteal bone formation was observed in every sector. The amount of periosteal new bone area contained within each sector was not uniform. Circumferential strain gradients (r2 = 0.36) were most strongly correlated with the observed periosteal bone formation. SED (a scalar measure of stress/strain magnitude with minimal relation to fluid flow) was poorly correlated with periosteal bone formation (r2 = 0.01). The combination of circumferential, radial, and longitudinal strain gradients accounted for over 60% of the periosteal new bone area (r2 = 0.63). These data indicate that strain gradients, which are readily determined given a knowledge of the bone's strain environment and geometry, may be used to predict specific locations of new bone formation stimulated by mechanical loading.     

A phase II study with high-dose cytarabine (NS-075) in adult patients with relapsed and refractory acute leukemia

A multi-center phase II clinical study with high dose cytarabine (NS-075) was conducted in adult patients with relapsed and/or refractory acute leukemia. 2 g/m2 cytarabine was given 12 times by 3-hour intravenous infusion every 12 hrs. 46 patients were registered, and 44 were evaluable: 35 with acute myeloid leukemia (AML) and 9 with acute lymphoblastic leukemia (ALL). There were 28 males and 16 females, with a median age of 37.5 years (range 15-68), including 6 of more than 60 years. Among 35 patients with AML, there were 16 (45.7%) complete and 2 (5.7%) partial remissions. Among 9 patients with ALL, there were 2 (22.2%) complete and 1 (11.1%) partial remissions. The major non-hematologic toxicities were gastrointestinal symptoms such as nausea/vomiting, anorexia and diarrhea, as well as fever, infection, conjunctivitis, alopecia, hepatic and renal dysfunctions. Central nervous system (CNS) toxicity was mild and reversible. Therapy-related death occurred in 5 patients resulting from prolonged pancytopenia, which suggests the necessity of strict countermeasures for infections as well as good patient care. These results indicate that high-dose cytarabine is a promising therapy for treatment of relapsed and/or refractory acute leukemia.     

Hypocellular acute leukemia

To establish diagnostic criteria for hypocellular acute leukemia (HL) 32 cases (mean age 67) with 40% or less bone marrow cellularity were analysed and compared with 40 cases of MDS, 27 cases of AML in the elderly (60 > or = ) and 39 cases of AML in the young (60 <). The mean bone marrow cellularity was 30% in HL, 85% in MDS, 87% in elderly AML and 95% in young AML, respectively. Thus hypocellularity was evident in HL. Blast % in bone marrow of HL patients was 17-70% in all nucleated cells including lymphocytes (ANC), 36-93% in non-lymphocytic cells (NLC) and 50% or more in all cases in non-erythroid/non-lymphocytic cells (NENLC). Thus maturation arrest of blast cells was evident in HL, which corresponds to that of overt AML. Out of 20 cases treated with low-dose ara-C 13 cases (65%) achieved complete remission, but most of them relapsed early by manifesting hypocellular bone marrow again. In conclusion HL is a distinct clinical subtype of AML in the elderly, which can be clearly defined by 40% or less cellularity and 30% or more blasts in bone marrow.     

Adult acute leukemia

Untreated acute leukemia is a uniformly fatal disease with a median survival time shorter than 3 months. Current treatment strategies provide a significant increase in survival time for most patients, some of whom may be cured. The majority of patients with acute leukemia, however, ultimately die of the disease or complications of treatment. The effective treatment of acute leukemia requires (1) differentiation of acute myeloid leukemia (AML) from acute lymphoblastic leukemia (ALL) and recognition of clinically relevant subtypes; (2) identification of patients who are more likely or less likely than average to benefit from a conventional treatment; and (3) selection of therapy that provides a reasonable likelihood of response with acceptable risk of toxic effects. The diagnosis of acute leukemia is established in most cases by a bone marrow aspirate that demonstrates at least 30% blast cells. The traditional criteria to distinguish between AML and ALL rely on morphology and cytochemical reactions. Immunologic analysis of antigen expression and analysis for numerical or structural chromosomal abnormalities of leukemia cells are routinely feasible. Karyotypic analysis is of prognostic importance and should be performed on all diagnostic specimens of bone marrow aspirate. Immunophenotypic analysis may be useful to confirm the disease classification in selected cases. The importance of the routine immunophenotypic characterization of acute leukemia, however, is controversial. The subtypes that must be recognized because of the need for specific treatment include (a) acute promyelocytic leukemia (APL), which is the M3 subtype of AML, and (b) the L3 subtype or mature B-cell ALL. Induction therapy for acute leukemia is treatment intended to achieve induction of complete remission (CR). Complete remission is defined as the absence of morphologic evidence of leukemia after recovery of the peripheral blood cell counts. Failure to achieve CR may be attributed to death during chemotherapy-induced bone marrow hypoplasia or to drug resistance manifested either as failure to achieve hypoplasia or as persistent leukemia after recovery from hypoplasia. Postremission therapy is treatment administered in CR to prevent or delay relapse of the leukemia. However, the majority of patients have disease relapse. Intensification of therapy is a treatment strategy designed to overcome resistance to chemotherapy. Recent clinical trials of intensified induction or postremission therapy suggest improved outcome. However, the toxic effects of dose intensification can be substantial, limiting any potential benefit of this approach. Identification of prognostic factors may allow one to estimate the likelihood of an outcome, to determine an optimal treatment strategy. It is well established that age at the time of diagnosis, leukemia cell karyotype, and whether the leukemia is de novo or secondary are factors that influence treatment decisions. Patients with favorable prognostic factors should probably receive conventional therapy. Patients with unfavorable prognostic factors have shown little benefit from conventional therapy. In addition, factors that indicate poor outcome with conventional therapy are also predictive of poor outcome with intensified therapy. Consequently, these patients should be considered for investigational therapeutic strategies. The bias may be to counsel them to accept the potential increased morbidity of such treatment before there is definite evidence of the possibility of improved outcome. Induction chemotherapy for younger patients with AML (less than 55 years of age) in general consists of one or more courses of cytarabine (ara-C) and an anthracycline or an anthracycline derivative. Randomized trials have failed to confirm that treatment with either etoposide or high-dose ara-C induces disease remission. Patients with secondary AML, high levels of CD34 antigen expression, or an unfavorable karyotype, however, may benefit from ind     

Acalculous acute cholecystitis in leukemia

Alcaligenes xylosoxidans is an uncommon but serious cause of nosocomial epidemics. This report describes a cluster of two patients who underwent revision of hip arthroplasties and one patient who had a lumbar puncture. Cultures obtained during all three procedures showed A. xylosoxidans with similar antibiotic sensitivity patterns. An investigation found that saline used to process these specimens was contaminated with this organism.     

High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia

A high frequency (24%) of acute promyelocytic leukemia (APL) was noted among acute myelocytic leukemia (AML) cases at the Los Angeles County-University of Southern California (LAC-USC) Medical Center, in comparison with the expected frequency of 5% to 15%. Because of the high proportion of Latinos in this center, we questioned if APL is more common in this ethnic group. The proportion of APL among the 80 AML patients of Latino origin was significantly higher (30; 37.5%) when compared with the 62 non-Latinos (4; 6.5%) (P = .00001). In an attempt to verify this finding on a larger group of patients, we analyzed 276 pathologically verified cases of AML in patients aged 30 to 69 years from the entire County of Los Angeles, registered on an ongoing population-based epidemiologic study of AML. APL was more frequent among the 47 Latinos (24.3%) than in the 229 non-Latinos (8.3%) (P = .0075). APL is seen in younger patients with AML, but Latino AML patients also had a higher frequency of APL after accounting for their younger age (age-adjusted odds ratio for APL among Latinos in LAC-USC Medical Center, 9.4 [95% confidence interval (CI) 2.9, 30] P = .0002; among Latinos in the population-based study, 3.0 [95% CI 1.3 to 6.9] P = .01). The different ethnic distribution of AML was found to be due to a higher proportion of APL cases per se, and not to a lower proportion of any other French-American-British subtype (P = .0004). These results, from two different populations of AML patients, indicate that Latinos with AML have a higher likelihood of the APL subtype of disease, which may suggest a genetic predisposition to APL and/or exposure to distinct environmental factor(s).