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S V Rajkumar

Publications and source records attributed to S V Rajkumar.

At least 37 records · Page 2Linked to original sources
PubMed2001

Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis.

Primary systemic amyloidosis (AL) is a plasma cell (PC) dyscrasia with clinical similarities to multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), but its molecular basis is poorly understood. Translocations at the immunoglobulin heavy-chain (IgH) locus, 14q32, are likely early genetic events in both MM and MGUS and involve several nonrandom, recurrent, partner chromosomes such as 11q13, 16q23, and 4p16.3. Given the similarities between MM, MGUS, and AL, bone marrow clonal PCs were evaluated in 29 patients with AL using interphase fluorescence in situ hybridization (FISH) combined with immunofluorescence detection of the cytoplasmic light-chain (cIg-FISH) for the presence of 14q32 translocations and the t(11;14)(q13;q32). Of 29 patients studied, 21 (72.4%) showed results compatible with the presence of a 14q32 translocation, and 16 (76.2%) of those had translocation (11;14)(q13;q32) for an overall prevalence of the abnormality of 55%. IgH translocations are common in AL, especially the t(11;14)(q13;q32).

Adult↗
PubMed2001

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.

Adult↗
PubMed2001

Methods for estimation of bone marrow plasma cell involvement in myeloma: predictive value for response and survival in patients undergoing autologous stem cell transplantation.

In myeloma, the bone marrow plasma cell percentage (BMPC%) is usually estimated independently on the aspirate, core biopsy, and plasma cell labeling index (PCLI) samples. This study was done to determine which of the 3 individual estimates correlates best with complete response (CR) and survival. Seventy-five consecutive patients who underwent SCT for relapsed myeloma were studied. The median BMPC% on the marrow aspirate, core biopsy, and PCLI studies were 20, 25, and 20, respectively. There was a significant correlation between the three methods, rho > 0.65, P < 0.001. However, in 8% of patients the BMPC% was different by an absolute value of 50% between methods. No individual method was predictive for CR. However, the highest estimate of the BMPC% among the three methods was a significant predictor of CR (P = 0.02). Survival following SCT was longer among patients with a low BMPC% (< or =60) by the PCLI method compared to those with higher values, median survival 23 versus 7 months, respectively, P = 0.02. PFS was also different, with survival times of 11 and 5 months, respectively, P = 0.003. Similar results were obtained when the highest estimate of the BMPC% was used in survival analysis (P = 0.02 and 0.004, respectively). Statistical significance was lower when the BMPC% on the aspirate or biopsy used in survival analysis. Compared to any individual method of estimating BMPC%, the highest estimate of the BMPC% is the best predictor of CR in myeloma. It is also prognostic for poor survival and PFS following SCT for myeloma. We recommend that all three methods of estimating BMPC% be routinely performed and that the highest value be used for prognostic purposes.

Adult↗
PubMed2001

Angiogenesis in multiple myeloma.

Angiogenesis is the process of new blood vessel formation, and normally occurs during embryonal growth, wound healing, and the menstrual cycle. It is essential for the proliferation and metastases of most malignant neoplasms. There is now growing evidence that angiogenesis is increased and is likely important in multiple myeloma. Recent evidence suggests that angiogenesis is greater in multiple myeloma compared to monoclonal gammopathy of undetermined significance (MGUS). Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are expressed by neoplastic plasma cells, and may play a role in the increased angiogenesis seen in myeloma. In a study of 400 patients with plasma cell disorders, microvascular density (MVD) was significantly higher in smoldering myeloma, newly diagnosed myeloma, and relapsed myeloma compared to controls, MGUS, and primary amyloidosis. In another study involving 74 newly diagnosed patients with myeloma treated at the Mayo Clinic, overall survival was significantly longer in patients with low-grade angiogenesis compared to those with high-grade or intermediate-grade angiogenesis. The finding of increased angiogenesis in myeloma provides the rationale for the study of antiangiogenic therapy in this disease.

Angiogenesis Inhibitors↗
PubMed2001

Therapeutic application of thalidomide in multiple myeloma.

Treatment with thalidomide and dexamethasone was given to 26 patients with active, previously untreated multiple myeloma (MM). Thalidomide was administered in an initial dosage of 200 mg/d for 2 weeks and then increased as tolerated (in 200-mg increments at 2-week intervals) to a maximum daily dose of 800 mg. Dexamethasone was given orally in a dosage of 40 mg/d on days 1 through 4, 9 through 12, and 17 through 20 in odd cycles and 40 mg/d on days 1 through 4 in even cycles at monthly intervals. Response was defined as a decrease in serum and urine monoclonal (M)-protein by 50% or greater. Twenty (77%) of 26 patients with active MM exhibited a therapeutic response. Among the first seven patients treated with a thalidomide dose of 400 mg, grade III to IV skin toxicity developed in two. Drug titration was then stopped and the thalidomide dose maintained at 200 mg/d. Six (86%) of seven patients showed a response after thalidomide dose escalation, whereas 14 (74%) of 19 patients demonstrated a response with a constant thalidomide dose of 200 mg/d. Thalidomide alone produced a response in six (38%) of 16 patients with smoldering or indolent myeloma. The angiogenesis grade was elevated in only 8% of these patients. Thirty-two patients with relapsed myeloma were treated with thalidomide dosed at 200 mg/d, with 200-mg escalations every 2 weeks to a maximum daily dose of 800 mg. Prior chemotherapy had failed and five (16%) patients had experienced relapse following stem cell transplantation. Ten (38%) of the 26 patients who had received at least two cycles of therapy obtained a response.

Angiogenesis Inhibitors↗
PubMed2001

Thalidomide for previously untreated indolent or smoldering multiple myeloma.

We conducted a clinical trial of thalidomide as initial therapy for asymptomatic smoldering (SMM) or indolent multiple myeloma (IMM). Sixteen patients were studied. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, and then increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. Bone marrow microvessel density (MVD) and angiogenesis grading were estimated using CD34 immunostaining. Six patients had a confirmed response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49%) decrease in M protein concentration) were included, 11 of 16 patients (69%) responded to therapy. Major grade 3-4 toxicities included two patients with somnolence, and one patient each with syncope and neutropenia. Pre-treatment MVD was not a significant predictor of response to therapy, median MVD 4 and 12 in responders and non-responders respectively, P = 0.09. We conclude that thalidomide has significant activity in the treatment of newly diagnosed SMM/IMM. However, we do not recommend treatment with thalidomide at this stage since some patients with SMM/IMM can be stable for several months or years without any therapy. Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma.

Administration, Oral↗
PubMed2001

Thalidomide in the treatment of multiple myeloma.

Thalidomide--banned from clinical use in the 1960s because of severe teratogenicity--is now back in clinical practice as an effective agent in the treatment of relapsed and refractory multiple myeloma. Several clinical trials have determined that thalidomide is active in 25-35% of patients with relapsed myeloma. The role of thalidomide in early-stage myeloma is being actively investigated. Thalidomide has antiangiogenic and immunomodulatory properties and is an effective inhibitor of TNF-alpha. However, the mechanism of its action in myeloma remains unclear. Major toxicities of thalidomide include constipation, sedation, skin rash, fatigue and peripheral neuropathy. This paper summarizes the current status of thalidomide in multiple myeloma.

Angiogenesis Inhibitors↗
PubMed2001

Current status of thalidomide in the treatment of cancer.

Tumor angiogenesis is a critical factor in the growth and metastasis of most malignant neoplasms. Thalidomide (Thalomid), banned from clinical use in the 1960s because of severe teratogenicity, has been shown to possess antiangiogenic properties. A recent clinical trial of antiangiogenic therapy with thalidomide demonstrated significant activity in a group of patients with relapsed refractory myeloma. Although its mechanism of action remains unclear, several trials have since confirmed that thalidomide is active in 25% to 35% of patients with relapsed myeloma. As a result, thalidomide has reemerged in clinical practice and is now actively being studied in the treatment of several cancers. Major toxicities associated with the use of thalidomide include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. This article summarizes the current status of thalidomide therapy in cancer.

Angiogenesis Inhibitors↗
PubMed2000

Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia.

Recent observations have underscored the biologic relevance of intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety of hematologic disorders, including multiple myeloma. The extent and prognostic significance of bone marrow angiogenesis in 114 patients with myelofibrosis with myeloid metaplasia (MMM) was investigated. A control group of 44 patients without bone marrow disease, 15 patients with polycythemia vera, and 17 patients with essential thrombocythemia was also studied. Bone marrow microvessel density was assessed by a semiquantitative method, visual microvessel grading, and 2 separate quantitative methods, visual count and computerized image analysis. Angiogenesis estimation by all 3 methods was highly comparable. On visual microvessel grading, a grade 3 or 4 increase in bone marrow angiogenesis was demonstrated in 70% of patients with MMM, 33% of patients with polycythemia vera, 12% of patients with essential thrombocythemia, and 0% of normal controls. In a multivariate analysis, increased angiogenesis in MMM correlated significantly with increased spleen size and was found to be a significant and independent risk factor for overall survival. Increases in marrow angiogenesis correlated with hypercellularity and megakaryocyte clumping. In contrast, these 2 features were inversely proportional to reticulin fibrosis, whereas increases in marrow angiogenesis were independent of reticulin fibrosis. These preliminary findings suggest that neo-angiogenesis is an integral component of the bone marrow stromal reaction in MMM and may provide useful prognostic information and a rationale for the therapeutic investigation of anti-angiogenic agents.

Adult↗
PubMed2000

A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma.

We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750 mg/m2 IV day 1 every 28 days (Arm A) or DTIC 200 mg/m2 IV days 1-5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27-67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1-2 nausea (33%). lethargy (28%), diarrhea (15%), alopecia (15%), and grade 3 neutropenia (8%). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazenol imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15 mM min, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29 mM min, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetic studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule.

Adult↗
PubMed2000

Effect of complete response on outcome following autologous stem cell transplantation for myeloma.

We studied the effect of complete response (CR) among 126 consecutive patients who underwent stem cell transplantation (SCT) for myeloma. The CR rate with SCT was 33%. Median overall survival (OS) from diagnosis of myeloma was 56 months. OS following SCT was 22 months. Progression-free survival (PFS) was 12 months. OS was not different between patients who achieved CR and those who did not, median survival 25 vs 24 months, P = 0.5. Corresponding median times for PFS were 15 and 11 months, P = 0.2. The plasma cell labeling index (PCLI) was high (> or = 1%) in 36% (high risk group) and was associated with poor OS and PFS (P < 0.001). Achieving CR did not influence OS or PFS in either the high or the low risk group. In contrast, OS and PFS were significantly influenced by high PCLI both in patients who achieved CR and those who did not. OS was poor (< 30 months) in high risk patients regardless of CR status and in low risk patients who did not achieve CR, compared to low risk patients achieving CR (57 months), making them candidates for novel post-transplant treatment options. Outcome following SCT is dependent more on biological variables such as the PCLI than on CR status.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma.

Angiogenesis is the formation of new blood vessels and occurs physiologically during embryonal growth, wound healing and during the menstrual cycle. It is essential for the proliferation and metastases of most malignant neoplasms. Recent evidence suggests that angiogenesis is increased in multiple myeloma and has prognostic value in the disease. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are expressed by myeloma cells and appear to play a role in the increased angiogenesis seen in myeloma. In addition, VEGF may serve as a paracrine growth factor for myeloma cells. Based on the increased angiogenesis observed in myeloma, thalidomide has been studied as antiangiogenic therapy. Although its mechanism of action in myeloma is still unclear, thalidomide appears to be active in 25-30% of patients with refractory myeloma. Major toxicities include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. Studies are ongoing to determine its role as initial treatment for myeloma. This paper reviews the available data on angiogenesis in myeloma, and summarizes the role of thalidomide therapy in this disease. The pharmacology and toxicity of thalidomide are also discussed.

Angiogenesis Inhibitors↗
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↗
PubMed2000

Fish demonstrates treatment-related chromosome damage in myeloid but not plasma cells in primary systemic amyloidosis.

Conventional cytogenetic analysis is limited in the evaluation of plasma cell disorders because, relative to normal hematopoietic elements, plasma cells divide slowly. Moreover, it is difficult to know whether abnormal metaphases originate from malignant plasma cells or myeloid cells harboring other abnormalities. We studied a patient with primary systemic amyloidosis who had previously been treated with an alkylating agent. Bone marrow cells were analyzed by cytoplasmic-immunoglobulin fluorescent staining combined with fluorescent in situ hybridization (cIg-FISH). Both chromosome enumeration probes for chromosome 1 and 7 and loci-specific probes for the short and long arm of chromosome 7 were used. Cytogenetic analysis disclosed the following abnormality: +der(1;7)(q10;p10). On cIg-FISH, the myeloid cells had fusion signals between chromosome enumeration probes for chromosomes 1 and 7, whereas plasma cells had the normal appearance of two pairs of signals. There was a second clone of abnormal myeloid cells with monosomy of chromosome 7. The bone marrow did not show any evidence of myelodysplasia. Interphase cIg-FISH is a useful technique for assigning the lineage of chromosomal abnormalities in plasma cell disorders.

Amyloidosis↗