Biomedical subjects

M A Gertz

Publications and source records attributed to M A Gertz.

At least 19 recordsLinked to original sources

PubMed2000

Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: a status report.

Stem cell transplantation has been incorporated in the treatment of primary systemic amyloidosis for 5 years. Results reported to date suggest that the response rates are substantially better than those for patients treated with low-dose traditional melphalan and prednisone chemotherapy. Unexpectedly high mortality rates have, however, been reported with stem cell transplantation, reaching 40% in some series. This unexpectedly high mortality appears to be related to multiorgan failure of tissues infiltrated with amyloid deposits. Deaths have been reported from gastrointestinal tract hemorrhage, gastrointestinal tract perforation, sudden cardiac death, and renal failure. The best patient for transplantation appears to have single organ involvement, an age <55 years, the absence of renal insufficiency, and no symptomatic cardiac dysfunction. Patients eligible to receive stem cell transplant represent a highly selected population, and before conclusions about the efficacy of transplantation are drawn, comparison with a matched control group is necessary. Amyloidosis should be considered an indication for stem cell transplantation in the context of a clinical trial so that results can be compiled and reported for an accurate assessment of response rate, survival, relapse rates and treatment-related toxicities. Bone Marrow Transplantation (2000) 25, 465-470.

Age Factors↗

PubMed2000

Delayed stem cell transplantation for the management of relapsed or refractory multiple myeloma.

The optimal timing of stem cell transplantation for multiple myeloma is controversial. Late stem cell collection is undesirable because of the inability to mobilize stem cells. We report on 64 recipients of stem cells collected within 1 year after diagnosis, none of whom had transplantation in plateau phase of their disease. Patients seen within 12 months after diagnosis received four cycles of standard vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy and then had stem cells mobilized. Patients were then placed on maintenance vincristine, BCNU, melphalan, cyclophosphamide, and prednisone or melphalan and prednisone chemotherapy for 12 cycles. At the sign of first progression, transplantation occurred. Fourteen patients were refractory to VAD chemotherapy, 20 relapsed on maintenance chemotherapy, and 30 relapsed off chemotherapy. The time to platelet engraftment was not affected by the duration of stem cell cryopreservation or extent of chemotherapy exposure after mobilization. The complete response rate was 34%. The actuarial median survival from initial diagnosis, from transplant day 0, and post-transplant progression-free survival was 51, 20 and 11.4 months, respectively. The patient status at transplantation and percentage of plasma cells circulating in the blood at apheresis influenced post-transplant survival; circulating plasma cells, status at transplantation and plasma cell labeling index influenced progression-free survival. Response duration was shorter in patients relapsing on chemotherapy.

Adult↗

PubMed2000

Waldenström's macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil.

This prospective study compared continuous and intermittent chlorambucil therapy of untreated Waldenström's macroglobulinaemia. The diagnosis was established by the presence of an IgM monoclonal (M-) protein in the serum, an infiltrate of lymphocytes and plasma cells in the bone marrow, anaemia or other laboratory abnormalities, physical findings or constitutional symptoms. Patients were randomized to receive chlorambucil 0.1 mg/kg/d or chlorambucil 0.3 mg/kg/d orally for 7 d, repeated every 6 weeks. Criteria for response included 50% or more reduction of serum M-protein, increase in haemoglobin level of 2 g/dl without transfusion, >/= 50% decrease of urine M-protein, or a reduction of 2 cm in the size of the liver, spleen or lymph nodes. Forty-six patients were randomized to continuous chlorambucil (n = 24) or to intermittent chlorambucil (n = 22). Nineteen (79%) (95% CI = 58-93) of the 24 patients given continuous therapy had an objective improvement by either reduction of serum M-protein or increase in haemoglobin. Fifteen (68%) (95% CI = 45-86) of the 22 patients given chlorambucil intermittently had an objective response. The size of the liver decreased by >/= 2 cm in 55% of patients, and the size of the spleen decreased >/= 2 cm in 67%. Lymphadenopathy decreased in 71%. Acute leukaemia or refractory anaemia developed in four patients. The median duration of survival was 5.4 years, and there was no difference between the regimens. Chlorambucil is effective for the treatment of Waldenström's macroglobulinaemia. Patients must be treated for at least 6 months before therapy is abandoned because response is slow. Chlorambucil is an effective agent and should be compared with purine analogues or rituxan (Rituximab) in a prospective study.

Aged↗

PubMed2000

The effect of respiration on left ventricular diastolic filling as assessed by radionuclide ventriculography.

Left ventricular function is modified by respiration and pericardial constraint. The aim of this study was to compare left ventricular systolic and diastolic function during inspiration and expiration in four patient groups: patients (1) without cardiac disease, (2) with severe pulmonary disease, (3) with cardiac amyloid and (4) with pericardial constriction (before and after pericardiectomy). Using blood-pool left ventriculography with modified gating, we obtained time-activity curves at the onset of inspiration and expiration. On inspiration and expiration, patients with pericardial constriction and patients with cardiac amyloid were significantly different from those without cardiac disease and those with severe pulmonary disease, in that left ventricular ejection fraction (LVEF) was less, peak filling rate was greater, time to peak filling rate was shorter, and rapid filling fraction was increased. When inspiration and expiration were compared, time to left ventricular peak filling rate was shorter (P = 0.05) on inspiration (118 +/- 48 ms) than on expiration (168 +/- 35 ms) in patients with pericardial constriction. No other measures differed between inspiration and expiration in pericardial constriction, and left ventricular function was unaffected by respiration in the other groups. Time to left ventricular peak filling rate was 49 +/- 69 ms less on inspiration than on expiration in pericardial constriction and this difference was significantly different (P = 0.04) from that in patients with cardiac amyloid (34 +/- 58 ms greater), patients without cardiac disease (2 +/- 69 ms greater) and patients with severe pulmonary disease (19 +/- 63 ms less). In pericardial constriction, pericardial resection caused an increase in LVEF without a change in left ventricular diastolic filling but abolished the differences present between inspiration and expiration in time to left ventricular peak filling rate. This respiratory response in time to left ventricular peak filling rate may be valuable in the diagnosis of pericardial constriction.

Aged↗

PubMed2000

Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma. It has an overall incidence of 2.5/million/year. The median age at diagnosis is 63 years. The clinical manifestations are hepatomegaly (20%), splenomegaly (15%), and lymphadenopathy (15%). The most common symptom is fatigue related to a normochromic, normocytic anemia, and the median hemoglobin value at diagnosis is 10 gm/dl. All patients with Waldenström's macroglobulinemia have a circulating tumor marker, the monoclonal IgM protein. Occasionally high levels of the IgM monoclonal protein can produce a hyperviscosity syndrome manifested by oronasal bleeding. Occasionally retinal hemorrhage or serious neurologic complications, such as somnolence or coma, may occur. The most important prognostic factors are hemoglobin, age, weight loss, and a cryoglobulin. Therapy has included alkylating agents, particularly chlorambucil, purine nucleoside analogs such as fludarabine or cladribine, and most recently the use of rituximab. The median survival of symptomatic patients is 65 months. Patients without symptoms should not be treated.

Age of Onset↗

PubMed1999

Systemic amyloidosis presenting with angina pectoris.

BACKGROUND: Manifestations of cardiac amyloidosis may include congestive heart failure and sudden cardiac death. Although vascular involvement in patients with amyloidosis is common, systemic amyloidosis presenting with angina is rare. OBJECTIVES: To report on patients with systemic amyloidosis presenting with angina pectoris. DESIGN: Case series. SETTING: Academic medical center. PATIENTS: Five patients who presented with angina pectoris and normal coronary angiogram as the initial manifestation of systemic amyloidosis. MEASUREMENTS: Endothelial-dependent and endothelial-independent coronary flow reserve. RESULTS: All patients had coronary flow reserve abnormalities and subsequently developed congestive heart failure and systemic manifestations of amyloidosis. Histologic evaluation revealed amyloid deposition in the intramyocardial coronary vessels. CONCLUSIONS: Cardiac amyloidosis can present as angina pectoris associated with coronary flow reserve abnormalities despite normal coronary angiograms. This finding may have major therapeutic and prognostic implications in this patient population.

Aged↗

PubMed1999

Long-term survival (10 years or more) in 30 patients with primary amyloidosis.

The median survival in primary systemic (AL) amyloidosis is less than 18 months. No published series of patients with AL amyloidosis have reported survival of more than 10 years. The records of all Mayo Clinic patients with a diagnosis of AL amyloidosis between January 1, 1966 and March 1, 1987 were reviewed. Patients with secondary amyloidosis, familial amyloidosis, senile systemic amyloidosis, and localized amyloidosis were excluded. During the 21 years of the study, 841 patients with AL amyloidosis were seen. Of these, 29 were excluded because the diagnosis was made at autopsy, and 2 others were excluded because no follow-up data were available. Actuarial survival for the 810 patients was 51% at 1 year, 16% at 5 years, and 4.7% at 10 years. Thirty patients survived for 10 years or more after the histologic diagnosis of AL amyloidosis; all received alkylating-agent therapy. In 14 patients, the monoclonal protein disappeared from the serum or urine. Of 10 patients with nephrotic syndrome, 4 had an objective response. Congestive heart failure, older age, creatinine value of 2 mg/dL or more, bone marrow plasma cell value of 20% or more, platelet count of 500 x 10(9)/L or less, and the presence of peripheral neuropathy were underrepresented in the 10-year survivors and are unfavorable prognostic features. Five percent of patients with AL amyloidosis survived for 10 years or more.

Adult↗

PubMed1999

Phase II trial of high-dose dexamethasone for previously treated immunoglobulin light-chain amyloidosis.

Immunoglobulin light-chain amyloidosis (AL) is a rare disorder characterized by production of a monoclonal light chain. This insoluble light chain, or a fragment thereof, deposits in tissues as amyloid and results in disruption of organ function and, ultimately, in death. Although melphalan and prednisone are beneficial in approximately 30% of patients with the disease, many patients fail to respond, and the median survival with this disease remains < 2 years. There is a need for new agents for those patients who fail to respond to melphalan-based chemotherapy. A study was undertaken of high-dose dexamethasone in the treatment of 19 patients with AL because of reports of its benefits in previously untreated patients with amyloidosis and its known activity in the management of multiple myeloma, which has many characteristics in common with AL. In this cohort, 3 of 19 patients showed an objective organ response of the disease. The median survival of the entire group was 11.2 months. We conclude that high-dose dexamethasone therapy is of occasional benefit in patients previously treated for amyloidosis. Combining dexamethasone with other therapies may increase the response rate.

Aged↗

PubMed1999

Phase II trial of high-dose dexamethasone for untreated patients with primary systemic amyloidosis.

Primary systemic amyloidosis is the disorder that results from the deposition of insoluble immunoglobulin light chain fragments. Patients seen within 30 days of diagnosis have a median survival of 13 months. Patients treated with melphalan and prednisone have a median survival of 17 months. There is a need for new therapies. A prospective study was undertaken of high-dose dexamethasone in the treatment of 25 patients with previously untreated primary systemic amyloidosis. Treatment was similar to that given to patients with multiple myeloma. In this cohort, three patients showed objective regression with organ-specific improvement of the disease. The median survival of the entire group was 13.8 months. High-dose dexamethasone is of occasional benefit in patients with amyloidosis but does not appear to be superior to melphalan and prednisone chemotherapy.

Adult↗

PubMed1999

Cytogenetic abnormalities correlate with the plasma cell labeling index and extent of bone marrow involvement in myeloma.

Chromosomal abnormalities have biologic and prognostic significance in multiple myeloma, especially among patients with relapsed disease. We report the relationship between chromosomal abnormalities and known prognostic factors such as plasma cell labeling index (PCLI) and bone marrow plasma cell involvement in 75 consecutive patients undergoing autologous stem cell transplantation for relapsed or refractory myeloma. Thirty of 70 patients (43%) had a chromosomally abnormal clone in their bone marrow, and in most cases the karyotype was complex (> 3 abnormalities). Patients with an abnormal clone on cytogenetic analysis had a higher PCLI (median, 1.4) than patients with a normal karyotype (0.2) (P < 0.001). Bone marrow plasma cell percentage also differed: median 48% versus 20%, respectively (P < 0.001). The PCLI and bone marrow plasma cell percentage correlated positively with the percentage of abnormal metaphases on conventional cytogenetic analysis: rho 0.60 (P < 0.001) and 0.46 (P < 0.001), respectively. We categorized patients into those with 20% or more abnormal metaphases, less than 20% abnormal metaphases, and only normal metaphases. The median PCLI values were 3.3, 1.1, and 0.3, respectively (P < 0.001). The bone marrow plasma cell percentage median values were 62%, 40%, and 25%, respectively (P = 0.003). Chromosomal abnormalities may offer a proliferative advantage to the neoplastic plasma cell, thereby leading to an unfavorable outcome.

Adult↗

PubMed1999

Amyloidosis.

Amyloidosis is considered rare but has an incidence similar to that of Hodgkin's disease and chronic granulocytic leukemia. The diagnosis should be considered in any patient with unexplained nephrotic-range proteinuria, heart failure, peripheral neuropathy, or hepatomegaly. If a monoclonal protein is found in a patient with any of these clinical presentations, a biopsy should be performed and the specimen stained with Congo red. The simplest source of diagnostic material is subcutaneous fat tissue. Treatment usually consists of chemotherapy, which may be oral and low dose or high dose with stem cell rescue.

Adipose Tissue↗

PubMed1999

Acquired Fanconi's syndrome associated with monoclonal gammopathies.

Franconi's syndrome is a rare complication of the monoclonal gammopathies characterized by diffuse failure in reabsorption at the level of the proximal renal tubule resulting in glycosuria, generalized aminoaciduria, and hypophosphatemia. Current evidence suggests monoclonal light chains that are incompletely digested in renal tubule lysosomes cause renal injury. The light-chain fragments serve as a nidus for crystal formation, and the crystals interfere with a broad range of apical membrane transporters. Franconi's syndrome is predominantly associated with monoclonal kappa in the urine, but rare instances of FS caused by lambda light chains have been described. Overt hematologic malignancies such as multiple myeloma, Waldenström's macroglobulinemia, or other lymphoproliferative disorders occur in one third of patients. Clinical manifestations include slowly progressive renal failure and bone pain caused by osteomalacia. The osteomalacia is caused by chronic hypophosphatemia and may be exacerbated by secondary hyperparathyroidism and renal tubular acidosis. Treatment consists of supplementation with phosphorus, calcium, and vitamin D. The osteomalacia is often completely reversible with mineral supplementation. Patients with an associated symptomatic malignancy or rapidly progressive renal failure may also benefit from chemotherapy. The prognosis is good in the absence of overt malignant disease.

Fanconi Syndrome↗

PubMed1999

Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma.

Transplantation after high-dose chemotherapy prolongs survival in patients with multiple myeloma compared with standard therapy. It is unclear whether the optimal timing of transplantation is immediately after induction chemotherapy or whether stem cells may be cryopreserved for transplantation at subsequent progression or relapse. In this study, stem cells were collected within 6 months of diagnosis, followed by transplantation only at progression of myeloma. One hundred and eighteen patients with multiple myeloma had stem cells collected and cryopreserved. Eleven had transplants early in the disease after they demonstrated failure to respond to primary therapy. The remaining 107 were eligible for transplants when there was evidence of progressive disease. Of the 118 patients, 67 had transplants, nine died of progressive disease before transplantation, and 42 remain alive in plateau phase. The median survival of the group is 58.5 months; 67 are alive. Serum beta2-microglobulin, bone marrow labeling index (S phase), and hemoglobin level predicted overall survival (P < 0.006, P < 0.001, and P < 0.01, respectively). We conclude that early cryopreservation of blood stem cells followed by transplantation at progression is a feasible approach to therapy in patients with myeloma. The underlying biology of the disease has a greater impact on survival than the timing of transplantation. A prospective randomized trial is required to answer definitively the question of the optimal timing of blood cell transplantation.

Adult↗

PubMed1999

Beta2-microglobulin and bone marrow plasma cell involvement predict complete responders among patients undergoing blood cell transplantation for myeloma.

We studied the prognostic value of clinical and laboratory variables, measured before blood cell transplantation, in predicting complete response among patients undergoing autologous blood cell transplantation for relapsed or primary refractory myeloma. Sixty-seven patients who underwent transplantation for relapsed or primary refractory myeloma were studied. The overall response rate was 90%, and the complete response rate was 33%. Low beta2-microglobulin (< or =2.7 mg/l) was associated with a significantly better complete response rate compared with high levels (54 vs 19%, P = 0.002). Similarly, the complete response rate was 39% when the bone marrow plasma cell percentage was low (<40%) and 21% with greater involvement (P = 0.04). Complete response rate was 50% when beta2-microglobulin and bone marrow plasma cell percentage were low, 36% if either was high, and 12% when both were high (P = 0.01). Median survival measured from initial diagnosis of myeloma was 51 months. Overall survival after transplantation was better among responders who achieved complete response than those who did not: median survival, 24 vs 11 months, P = 0.04 (log-rank) and 0.009 (Gehan-Wilcoxon). Attainment of a complete response independently predicted better survival in a multivariate analysis. beta2-Microglobulin and bone marrow plasma cell percentage predict complete responders among patients undergoing transplantation for myeloma.

Adult↗

PubMed1999

Autologous stem cell transplantation for relapsed and primary refractory myeloma.

The aim of this study was to evaluate the effectiveness of autologous stem cell transplantation for patients with relapsed or primary chemotherapy-refractory myeloma. Seventy-five patients, 50 men and 25 women, ages 33-68 years (median, 53 years), who underwent transplantation for relapsed or primary refractory myeloma were studied. Patients underwent transplantation 5-88 months (median, 23 months) after diagnosis of myeloma. The time to transplantation was significantly shorter in patients with refractory disease than for those with relapsed myeloma (median, 8 and 32 months, respectively; P < 0.001). Patients with primary refractory myeloma had a significantly lower plasma cell labeling index than those with relapsed disease (P = 0.008). There were no differences in overall and complete response rates between patients with primary refractory and relapsed disease. The median survival of the entire cohort from diagnosis was 53 months. Overall survival from transplantation among patients with relapsed myeloma receiving therapy, relapsed myeloma off therapy, and primary refractory myeloma was significantly different (P = 0.04), with median times of 12, 21 and 30 months, respectively. Progression-free survival also was different (P < 0.001), with median times of 7, 13, and 26 months, respectively. We conclude that overall and progression-free survival in patients with primary refractory myeloma appear better than in patients with relapsed disease and need further study.

Adult↗

PubMed1999

Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma.

Although most of the initial studies in angiogenesis were done on solid tumors, there is now data suggesting the importance of angiogenesis in hematologic malignancies. We estimated bone marrow microvessel density before autologous stem cell transplantation and at the time of response in 13 patients with myeloma (seven complete and six partial responders) using an immunohistochemical stain for factor VIII-related antigen (von Willebrand factor). Baseline microvessel density was significantly different between bone marrow samples from patients with myeloma and morphologically normal, staging marrows from patients with limited stage Hodgkin's disease, mean (+/- s.d.) 294 (+/-115)/mm2 vs 93 (+/-26/mm2, respectively, P = 0.001. After transplantation, microvessel density continued to be high in myeloma samples compared to samples from control patients with limited stage Hodgkin's disease, mean (+/- s.d.) 230 (+/-68)/mm2, P = 0.003. There was no difference in microvessel density at the time of complete or partial response compared to values prior to transplantation. This report confirms that increased angiogenesis is found in myeloma bone marrow prior to transplantation, and suggests that increased angiogenesis persists even after complete response.

Adult↗

PubMed1999

Clinical significance of the translocation (11;14)(q13;q32) in multiple myeloma.

The most common chromosomal translocation in multiple myeloma (MM) is t(11;14)(q13;q32). Here, we describe the clinical characteristics of patients with MM who have this translocation. We have identified 24 patients at our institution who had t(11;14)(q13;q32) as determined by standard cytogenetic analysis (CC). Seven patients had the translocation detected at the time of original diagnosis and 17 at the time of relapse. Median survival in all patients after original diagnosis was 43 months; median survival after the translocation was detected was 11.9 months. Four patients had a clinical diagnosis of plasma cell leukemia. Most patients had an elevated beta2-microglobulin (13/20 had >4 microg/ml). The bone marrow (BM) labeling index (LI) of patients, at the time of translocation detection, was elevated in most (median 1.4%, 17/23 patients had BMLI > or = 1%). Of the 24 patients, 19 (79%) died of disease progression and 5 (21%) were alive with disease at last follow-up. Lytic lesions, bone pain, or compression fractures eventually developed in all patients. Patients with MM who have t(11;14)(q13;q32) detected by standard cytogenetics seem to have an aggressive clinical course.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

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.

Adult↗