Localization of eosinophil granule major basic protein in human basophils.

In experiments using an immunofluorescent method to localize human eosinophil granule major basic protein (MBP) in cells and tissues, a small number of cells stained for MBP that subsequently could not be identified as eosinophils. Because the Charcot-Leyden crystal protein, another eosinophil protein, was recently identified in basophils, we tested whether MBP might also be a constituent of blood basophils. Highly purified, eosinophil-free basophil suspensions were prepared using the fluorescence-activated cell sorter (FACS) to sort basophil-containing mononuclear cell preparations stained with fluorescein-conjugated sheep IgG anti-human IgE antibody. Using these FACS-purified basophils, we found that: (a) enrichment for surface IgE-positive cells (greater than 95% basophils) by FACS also enriched for cells staining for MBP by immunofluorescence; (b) MBP appeared to be localized in the histamine-, heparin-containing granules; (c) significant quantities of MBP were measurable by radioimmunoassay (RIA) in freeze-thaw detergent extracts of purified basophils; and (d) RIA dose-response curves for extracts of purified eosinophils and basophils had identical slopes. The MBP content of basophils from normal individuals averaged 140 ng/10(6) cells, whereas purified eosinophils from normal donors and patients with the hyper-eosinophilic syndrome averaged 4,979 and 824 ng/10(6) cells, respectively. MBP was also detected by immunofluorescence and RIA in cells obtained from a patient with basophil leukemia, although the MBP content for basophil leukemia cells was lower than that for normal basophils. We conclude that basophils contain a protein that is immunochemically indistinguishable from eosinophil granule MBP.

Preferential linkage of bcl-2 to immunoglobulin light chain gene in chronic lymphocytic leukemia.

Most of human follicular lymphomas possess the t(14;18) chromosome translocation that juxtaposes the IgH gene to the 3' region of bcl-2 in a head-to-tail configuration. Here we show that the rearrangement of the bcl-2 gene occurs in a significant fraction (approximately of 10%) of B cell CLL. In all cases analyzed, breakpoints on chromosome 18 clustered at the 5' flanking region of the bcl-2 gene, and no rearrangements were found at the major or minor breakpoint clustering region (3' region of bcl-2 gene) typical of the t(14;18) chromosome translocation. All of the rearranged bcl-2 genes were juxtaposed with the Ig lambda or K genes in a head-to-head configuration. These results imply that the bcl-2 gene is preferentially linked to the IgL genes in CLL and could function in leukemogenesis.

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.

ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells.

Disruption of pathways leading to programmed cell death plays a major role in most malignancies, including multiple myeloma (MM). ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 and Bcl-xL, preventing the sequestration of proapoptotic molecules and shifting the cell survival/apoptosis balance toward apoptosis induction. In this study, we show that ABT-737 is cytotoxic to MM cell lines, including those resistant to conventional therapies, and primary tumor cells. Flow cytometric analysis of intracellular levels of Bcl-2 family proteins demonstrates a clear inversion of the Bax/Bcl-2 ratio leading to induction of apoptosis. Activation of the mitochondrial apoptosis pathway was indicated by mitochondrial membrane depolarization and caspase cleavage. Additionally, several signaling pathways known to be important for MM cell survival are disrupted following treatment with ABT-737. The impact of ABT-737 on survival could not be overcome by the addition of interleukin-6, vascular endothelial growth factor or insulin-like growth factor, suggesting that ABT-737 may be effective in preventing the growth and survival signals provided by the microenvironment. These data indicate that therapies targeting apoptotic pathways may be effective in MM treatment and warrant clinical evaluation of ABT-737 and similar drugs alone or in combination with other agents in the setting of MM.

A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy.

Clinical outcomes for multiple myeloma (MM) are highly heterogeneous and it is now clear that pivotal genetic events are the primary harbingers of such variation. These findings have broad implications for counseling, choice of therapy and the design and interpretation of clinical investigation. Indeed, as in acute leukemias and non-hodgkins lymphoma, we believe it is no longer acceptable to consider MM a single disease entity. As such, the accurate diagnosis of MM subtypes and the adoption of common criteria for the identification and stratification of MM patients has become critical. Herein, we provide a consensus high-risk definition and offer practical guidelines for the adoption of routine diagnostic testing. Although acknowledging that more refined classifications will continue to be developed, we propose that the definition of high-risk disease (any of the t(4;14), t(14;16), t(14;20), deletion 17q13, aneuploidy or deletion chromosome 13 by metaphase cytogenetics, or plasma cell labeling index >3.0) be adopted. This classification will identify most of the 25% of MM patients for whom current therapies are inadequate and for whom investigational regimens should be vigorously pursued. Conversely, the 75% of patients remaining have more favorable outcomes using existing - albeit non-curative - therapeutic options.

Thymoglobulin targets multiple plasma cell antigens and has in vitro and in vivo activity in multiple myeloma.

Multiple myeloma is characterized by the proliferation of clonal plasma cells that have a heterogeneous expression of various cell surface markers, precluding successful use of monoclonal antibodies for therapeutic targeting of the tumor cell. Thymoglobulin (rabbit-derived polyclonal anti-thymocyte globulin), by virtue of its method of preparation, contains antibodies against several B-cell and plasma cell antigens and offers an attractive option for immunotherapy of myeloma. Here, we demonstrate potent anti-myeloma activity of the rabbit anti-thymocyte globulin preparation Thymoglobulin in vitro and in vivo in an animal model of myeloma. Thymoglobulin was able to induce dose- and time-dependent apoptosis of several myeloma cell lines, including those resistant to conventional anti-myeloma agents. Importantly, the anti-myeloma activity was preserved even when myeloma cells were grown with different cytokines demonstrating the ability to overcome microenvironment-mediated resistance. Thymoglobulin induced apoptosis of freshly isolated primary myeloma cells from patients. Using a competitive flow cytometric analysis, we were able to identify the potential antigen targets for Thymoglobulin preparation. Finally, in a plasmacytoma mouse model of myeloma, Thymoglobulin delayed the tumor growth in a dose-dependent manner providing convincing evidence for continued evaluation of this agent in the clinic in patients with myeloma, either alone or in combination with other agents.

Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma.

A specific role for increased level of expression of CKS1B, as a consequence of chromosome 1q21 copy number gain, has been postulated as both pathogenic, as well as a powerful clinical prognostic factor in multiple myeloma (MM). The purpose of this study is to determine the clinical associations and prognostic impact of copy number gain at chromosome 1q21 (with a bacteria artificial chromosome clone containing CKS1B) and CKS1B gene level of expression in MM. We studied the chromosome region 1q21 for copy number change in a cohort of myeloma patients treated by high-dose therapy with stem-cell rescue (HDT) (n = 159). A separate cohort of patients, treated by HDT was studied for CKS1B messenger RNA expression by gene expression profiling (n = 67). 1q21 gain was then correlated with clinical parameters and survival. Gain of 1q21 copy number was detected in about a third of MM and was associated with more proliferative disease and poor-risk cytogenetic categories such as t(4;14), and chromosome 13 deletion. Both 1q21 gain and increase gene expression level were significantly associated with reduced survival. However, neither is an independent prognostic marker in MM on multivariate Cox proportional hazard analysis.

Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations.

Chromosomal hyperdiploidy is the defining genetic signature in 40-50% of myeloma (MM) patients. We characterize hyperdiploid-MM (H-MM) in terms of its clinical and prognostic features in a cohort of 220 H-MM patients entered into clinical trials. Hyperdiploid-myeloma is associated with male sex, kappa immunoglobulin subtype, symptomatic bone disease and better survival compared to nonhyperdiploid-MM (median overall survival 48 vs 35 months, log-rank P = 0.023), despite similar response to treatment. Among 108 H-MM cases with FISH studies for common genetic abnormalities, survival is negatively affected by the existence of immunoglobulin heavy chain (IgH) translocations, especially those involving unknown partners, while the presence of chromosome 13 deletion by FISH did not significantly affect survival (median overall survival 50 vs 47 months, log-rank P = 0.47). Hyperdiploid-myeloma is therefore a unique genetic subtype of MM associated with improved outcome with distinct clinical features. The existence of IgH translocations but not chromosome 13 deletion by FISH negatively impacts survival and may allow further risk stratification of this population of MM patients.

Ploidy status rarely changes in myeloma patients at disease progression.

Hyperdiploid and non-hyperdiploid multiple myeloma represents distinct biological entities characterized by different patterns of genetic changes. We sought to determine whether ploidy category (non-hyperdiploid versus hyperdiploid) remains stable over time from diagnosis to progression. Of the 43 patients studied (39 by flow cytometry DNA index and 4 by a FISH-based index), only five (12%) altered their ploidy status at progression. In three of these patients, the change may possibly be attributable to technical artifacts because of the low absolute change in DNA index. For those who retain their ploidy subtypes, the DNA index change minimally (3.75+/-4.87%). It would appear that the initiating genetic events underlying hyperdiploid and non-hyperdiploid MM that marks them out as distinct entities continue to dominate and persist during disease evolution and progression.

CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations.

Multiple myeloma (MM) is characterized by accumulation of clonal plasma cells (PCs). CD45, a key regulator of antigen-mediated signaling and activation in lymphocytes, is present in early stages of PCs development. We studied CD45 expression on MM PCs by flow cytometry, correlating it to important biological disease characteristics. Additionally, we examined the expression of various adhesion molecules on PCs. A total of 75 patients with untreated MM (29), relapsed MM (17), smoldering MM (12), and monoclonal gammopathy of undetermined significance (MGUS) (17) were studied. The proportion of PCs expressing CD45 was higher among those with early disease (MGUS or smoldering MM) compared to those with advanced disease (new or relapsed MM) (43 vs 22%; P=0.005). Among those with advanced disease, patients with bone lesions had a lower percentage of CD45-positive (CD45+) PCs; 14 vs 34% (P=0.02). Patients with high-grade angiogenesis had a lower percentage of CD45+ PCs; 13 vs 31% (P=0.03). The median overall survival for the CD45+ group (>20% PCs positive) was 39 vs 18 months for the CD45-negative (CD45-) group (P=0.07). The expression of CD138, CD56 and CD54 were higher among the CD45- PCs. This study demonstrates important biological correlates of CD45 expression on myeloma cells.

A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.

Elevated glucocorticoid receptor binding in cultured human lymphoblasts following hydroxyurea treatment: lack of effect on steroid responsiveness.

While studying the effects of chemotherapy on glucocorticoid receptor (GR) binding levels in hematological malignancies, we observed a sizable increase in nuclear GR binding of [3H]dexamethasone in peripheral leukocytes from a chronic basophilic leukemia patient following treatment with hydroxyurea plus prednisone, but not after prednisone alone. This apparent clinical effect of hydroxyurea led to an examination of hydroxyurea effects on GR binding and sensitivity in the glucocorticoid-sensitive human lymphoblast cell line GM4672A. GR binding levels in GM4672A cells were measured following a 3-day exposure to 50 microM hydroxyurea, a concentration chosen to have a minimal but measurable effect on cellular growth rates with little or no effect on cellular viability. Under these conditions, nuclear [3H]dexamethasone receptor binding measured by Scatchard analysis using a whole-cell assay was elevated 2.4-fold over control values (P less than 0.05), while cytosolic residual receptor binding (measured at 37 degrees C) remained unchanged. Thus, the total cellular content of measurable GR was increased, and this increase was totally accounted for by GR capable of nuclear binding. Hydroxyurea treatment of GM4672A cells had no effect on the affinity of nuclear or cytosolic GR for [3H]dexamethasone. The increase in measurable nuclear-bound receptors occurred in a time-dependent manner over a period of 3 days and was fully reversible within 3 days following removal of hydroxyurea. The increase in receptor binding could not be explained by the slight alterations in cell cycle kinetics which occur at this low level of hydroxyurea. Despite increased receptor binding, cellular glucocorticoid responsiveness was unaltered as assessed by dexamethasone inhibition of cell growth and dexamethasone inhibition of a urokinase-like plasminogen activator. Thus, increased nuclear and total cellular GR binding levels in hydroxyurea-treated GM4672A cells are not associated with increased glucocorticoid responsiveness.

A variant glucocorticoid receptor messenger RNA is expressed in multiple myeloma patients.

In multiple myeloma cells resistant to glucocorticoids, we have previously identified a variant glucocorticoid receptor (GR) transcript (P. A. Moalli et al., Cancer Res., 53: 3877-3879, 1993). Here, we report a reverse transcription-PCR assay to assess whether this aberrant GR transcript is present in myeloma patients. We detected both the wild-type and variant GR transcripts in the patient isolate that was the source of our myeloma cell lines, in patients refractory to steroid treatment, and in healthy control subjects. Simultaneous amplification of wild-type and variant GR mRNAs indicates that the variant GR is more highly expressed in cells that are resistant to glucocorticoids. We hypothesize that the variant GR is a normal mRNA transcript that acts to modulate glucocorticoid responsiveness, and increased expression contributes to a resistant phenotype.

Coexistence of aneuploid subclones within a myeloma cell line that exhibits clonal immunoglobulin gene rearrangement: clinical implications.

A new human myeloma cell line, ANBL-6, was established and characterized at the genotypic and phenotypic levels. The cells exhibit a clonally rearranged immunoglobulin gene locus and resemble plasma cells morphologically. The ANBL-6 cells also exhibited an absolute dependence on exogenous interleukin 6 for growth. Of interest, DNA ploidy analysis suggested the existence of a near-diploid as well as a near-tetraploid population in this cell line. Cytogenetic studies confirmed the existence of two aneuploid karyotypes and further revealed a clonal relationship between the two karyotypes, as evidenced by numerous shared structural abnormalities. To determine whether the near-diploid cells functioned as stem cells for the near-tetraploid population, the near-diploid population was separated via flow cytometry and recultured prior to ploidy analysis. This population was observed to remain predominantly near-diploid over time, suggesting that these cells did not function as stem cells for the near-tetraploid population. However, the near-tetraploid cells did exhibit a growth advantage in vitro. Moreover, sequential ploidy analysis performed retrospectively on fresh bone marrow cells from the patient also suggested that there was an expansion of the near-tetraploid population during clinical relapse. These results suggest that both populations are self-regenerating and reflect the consequences of clonal evolution in the myeloma tumor. The coexistence of clonally related subclones with shared chromosomal abnormalities, however, suggests that the near-tetraploid subclone was derived from the near-diploid subclone at an unknown time during tumorigenesis.

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan-Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density.

Peripheral blood B cell labeling indices are a measure of disease activity in patients with monoclonal gammopathies.

Labeling indices (LI) provide a rapid measure of the bone marrow (BM) plasma cell proliferation rate and are useful in the diagnosis and prognosis of monoclonal gammopathies. Because circulating B cells may be a part of the neoplastic clone, we examined peripheral blood B cells that were producing the same cytoplasmic light chain isotype as the patient's monoclonal; protein (M-protein) and determined the peripheral blood LI (PBLI) by a two-color immunofluorescence bromodeoxyuridine method. The 105 patients studied were divided into three disease activity groups by standard clinical criteria. Median PBLI was 0.2% for the 29 patients with inactive monoclonal gammopathies (monoclonal gammopathy of undetermined significance [MGUS] and smoldering multiple myeloma [SMM]), 0.8% for the 35 patients with new, untreated multiple myeloma (MM), and 1.7% for the 41 patients with relapsed MM. These differences between groups were statistically significant (P less than .001, Wilcoxon). Four patients had high PBLI but clinically inactive gammopathy at the time of study, and all developed active MM within 6 months that required treatment. In 92 patients a BMLI was performed simultaneously with the PBLI (rank correlation coefficient, 0.69). In patients with new, untreated MM, use of both tests identified 72% of patients (23 of 32) with high LI, rather than 56% (18 of 32) by BMLI alone or 63% (20 of 32) by PBLI alone. These results suggest that PB B cells bearing the same cytoplasmic light chain isotype as the monoclonal protein are part of the malignant clone and can be kinetically active. The LI of these cells can provide a measure of disease activity and may help to differentiate active from inactive disease.

Prospective randomized trial of melphalan and prednisone versus vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of primary systemic amyloidosis.

PURPOSE: Primary systemic amyloidosis is an immunoglobulin deposition disorder in which insoluble light chains cause organ dysfunction and death. The established conventional therapy is treatment with melphalan and prednisone. We investigated whether treatment with multiple alkylating agents improved the response rate or survival time, compared with melphalan and prednisone therapy. PATIENTS AND METHODS: We treated 101 patients with biopsy-proven primary amyloidosis. The patients were randomly assigned to receive melphalan and prednisone (52 patients) or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (49 patients). Patients were stratified according to the presence of cardiac involvement, time from diagnosis to randomization, serum beta2-microglobulin level, and whether peripheral neuropathy was the major manifestation of the disease. RESULTS: The median duration of survival after randomization was 29 months, with no differences in survival time between the two groups. There were 29 patients who fulfilled the response criteria: 15 in the vincristine, carmustine, melphalan, cyclophosphamide, and prednisone arm and 14 in the melphalan and prednisone arm. CONCLUSION: Therapy with multiple alkylating agents did not result in a higher response rate or longer survival time, compared with standard melphalan and prednisone treatment in patients with primary systemic amyloidosis.

Plasmablastic morphology is an independent predictor of poor survival after autologous stem-cell transplantation for multiple myeloma.

PURPOSE: To study the prognostic value of plasmablastic morphology after autologous stem-cell transplantation for relapsed or primary refractory myeloma. PATIENTS AND METHODS: Seventy-five patients were studied. Investigators blinded to the clinical details of the individual cases reviewed bone marrow aspirate slides to determine plasmablastic classification. Plasmablasts were defined using strict, well-described criteria. Plasmablastic morphology was considered to be present (plasmablastic myeloma) when 2% or more plasmablasts were present in the plasma-cell population. RESULTS: Patients underwent transplantation 5 to 88 months (median, 20 months) after the initial diagnosis of myeloma. Twenty-eight percent of patients had plasmablostic morphology. A significantly greater proportion of patients with plasmablastic morphology had abnormal cytogenetics compared with those with nonplasmablastic classification (73% v 31%, respectively; P = .003). The overall survival rate measured from the time of transplantation was significantly worse in patients with plasmablastic morphology compared with those without (median survival time, 5 months v 24 months, respectively; P < .001). Progression-free survival time was shortened also, with a median time of 4 months compared with 12 months, respectively (P < .001). In the multivariate analysis, plasmablastic classification was the most powerful prognostic factor after transplantation for both overall (P = .001) and progression-free survival rates (P < .001). We also identified three risk groups based on plasmablastic morphology: plasma-cell labeling index, lactate dehydrogenase, and cytogenetics. The median overall survival time was 38 months when none of these factors was abnormal, 17 months with one abnormal factor, and 8 months with two or more abnormal factors (P < .001). CONCLUSION: Plasmablastic morphology is a powerful independent predictor of poor survival rate after autologous stem-cell transplantation for relapsed or primary refractory myeloma.

Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.

PURPOSE: Based on the success of hematopoietic stem-cell transplantation (HSCT) for multiple myeloma, HSCT is being used to treat patients with primary systemic amyloidosis (AL). This article addresses the extent to which eligibility to undergo HSCT is a favorable prognostic feature and explores prognostic factors within the subset of eligible patients. PATIENTS AND METHODS: The Mayo Clinic amyloid database was queried for all patients with AL seen at the Mayo Clinic from 1983 through 1997 who would have been eligible for peripheral-blood stem-cell transplantation. Inclusion criteria included biopsy-proven amyloid, symptomatic disease, absence of a clinical diagnosis of multiple myeloma, age < or = 70 years, cardiac interventricular septal thickness < or = 15 mm, cardiac ejection fraction more than 55%, serum creatinine < or = 2 mg/dL, and direct bilirubin < or = 2.0 mg/dL. RESULTS: Median age was 56 years (range, 25 to 70) with 79 (34%) older than 60 years. One hundred patients had early cardiac involvement; 41, hepatic involvement; 167, renal involvement; and 39, nerve involvement. The 229 patients have had a median follow-up of 52 months, and 151 have died. The median survival was 42 months with 5- and 10-year survival rates of 36% and 15%, respectively. Important predictors of survival were size of M-component in 24-hour urine, number of involved organs, alkaline phosphatase, performance score, and weight loss. CONCLUSION: The same patients who are eligible for HSCT are a good-risk population who do relatively well with chemotherapy (median survival, 42 months), substantially better than the expected median survival of 18 months for all patients with AL. A randomized trial is needed to assess the true effect of HSCT.

Echocardiographic findings in systemic amyloidosis: spectrum of cardiac involvement and relation to survival.

One hundred thirty-two patients with biopsy-proven systemic amyloidosis underwent echocardiographic examination to define the spectrum of cardiac involvement. Echocardiographic abnormalities were then correlated with clinical variables and survival at follow-up. Patients were subgrouped by left ventricular wall thickness: Group I, mean wall thickness 12 mm or less; Group II, mean wall thickness greater than 12 mm but less than 15 mm; Group III, mean wall thickness 15 mm or greater; or Group IV, atypical features such as wall motion abnormalities or left ventricular dilation. Patients with greater wall thickness had a higher frequency of associated echocardiographic abnormalities such as left atrial enlargement or granular sparkling appearance on two-dimensional examination and, more commonly, reduced systolic function. The occurrence of clinical congestive heart failure was strongly correlated with greater wall thickness and multiple other echocardiographic abnormalities. Survival was negatively influenced both by greater wall thickness and reduced systolic function. The median survival of the entire group was 1.1 years. Echocardiographic examination is an important tool for establishing the presence of cardiac amyloid involvement and may be useful in estimating prognosis in such patients.