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Biomedical subjects

M J Keating

Publications and source records attributed to M J Keating.

At least 145 records · Page 8Linked to original sources
PubMed1994

Detection of subgroups of chronic B-cell leukemias by FMC7 monoclonal antibody.

Monoclonal antibody FMC7 detects subgroups of B-cell leukemias that have arisen from cells in late stages of B-cell maturation. FMC7 was studied by flow cytometry on cell samples from 192 patients with a diagnosis of chronic lymphocytic leukemia (CLL) or lymphoma. The leukemic cells from 16 patients were reactive with this antibody. These 16 cases were evaluated for other surface markers, morphology of cells, and clinical characteristics. Of the 16 patients, 14 had cells that strongly expressed surface immunoglobulin (SIg). This is atypical of CLL cells, which characteristically show weak expression of SIg. Eleven cases had kappa and five had lambda light chain. All patients' cells had consistently brighter CD20 expression than that of CD19. Fourteen patients had expression of CD5 on their leukemic cells. One patient had more than 55% prolymphocytes, meeting the criteria of prolymphocytic leukemia (PLL), two patients had CLL in prolymphocytic transformation (CLL/PL), and two other patients were classified as having a paraimmunoblastic variant of small lymphocytic lymphoma based on a high number of paraimmunoblasts and on the histologic features. Another nine patients had immature lymphoid cells distinct from prolymphocytes or paraimmunoblasts on morphologic study. The immature cells were variable in size, and the nuclear chromatin was less clumped than that of prolymphocytes. The histologic diagnoses in four of these cases were consistent with mantle cell lymphoma. Splenomegaly was observed in 11 patients (69%), and 11 patients had advanced Rai 3 or 4 disease. Among 10 patients treated with fludarabine, five responded to therapy. Monoclonal antibody FMC7 is useful for identifying a group of atypical variants of CLL, PLL, and other B-cell lymphomas in leukemic phase that can be easily confused with CLL. Careful attention to the cell morphology and histologic features is important for the differential diagnosis of FMC7-positive, B-cell lymphoproliferative diseases.

Adult↗
PubMed1994

Cell kinetic analysis of interleukin-2 receptor-tested chronic lymphocytic leukemia using the AgNOR silver stain.

B-cell chronic lymphocytic leukemia (B-CLL) is typically a low-grade neoplasm with a diploid DNA index and low proliferative activity. Interleukin-2 receptor (IL-2R/CD25) positivity often indicates increased proliferative activity and activation in both T and B lymphocytes. The argyrophilic nucleolar organizer regions (AgNORs) are loops of DNA identified by a silver staining technique and have been correlated with ploidy and proliferative activity. Two distinct AgNOR counting methods have been previously shown to correlate with DNA ploidy and proliferative activity, respectively: the mean AgNOR count (mAgNOR) correlates more with ploidy, and the percentage of nuclei with > or = 5 AgNORs/nucleus (pAgNOR) reflects proliferative activity. We studied bone marrow specimens from 32 patients with B-CLL using both anti-IL-2R on the marrow aspirates and the AgNOR silver stain on marrow biopsy specimens, applying both AgNOR counts. All tumors were CD5+, CD19+, and CD19/CD20+. Sixteen tumors were IL-2R- (< 20% IL-2+ B cells), and 16 were IL-2R+ (> or = 20% IL-2R+ B-cells). No significant difference in morphology of bone marrow involvement was noted in the two groups. A male predominance was noted in the IL-2R+ group of patients (3:1). There was also a preponderance of lambda light chain expression in the IL-2R+ tumors (11/16) compared with the IL-2R- cases (5/16). Except for two cases, all tumors had mAgNOR counts within the diploid range (< 2.4). The 16 IL-2R- tumors had pAgNOR in the range of 0% to 7% (mean, 2.31 +/- 2.18 standard deviation), whereas the IL-2R+ tumors had pAgNOR ranging from 6% to 15% (mean, 10.20 +/- 2.70 standard deviation; P < .0001). This finding suggests that IL-2R+ B-CLL might represent a subgroup of tumors with higher proliferative activity.

Adult↗
PubMed1994

Fludarabine--present status and future developments in chronic lymphocytic leukemia and lymphoma.

BACKGROUND: Fludarabine monophosphate (fludarabine) is an adenine nucleoside analogue active in indolent lymphoproliferative diseases which has an increasing role in studies incorporating combinations of agents which exploit biochemical modulation, inhibition of DNA repair, and radiosensitizing effects. PATIENTS AND METHODS: Patients with lymphoma and chronic lymphocytic leukemia (CLL) treated at the M. D. Anderson Cancer Center (MDACC) and reports in the literature form the basis of this report. RESULTS: CLL has traditionally been treated with alkylating agents and corticosteroids. In this study, fludarabine has shown marked cytoreductive ability in both previously treated patients and untreated patients. In the former group, there has been a 55% response rate in 374 patients, and 79% in the untreated CLL group. Fludarabine has also been very active in the management of low-grade lymphomas, with two-thirds of patients with follicular lymphoma and half of those with other indolent lymphomas responding. Waldenstrom's macroglobulinemia is also sensitive to the effects of fludarabine. Combination regimens were developed incorporating the substantial effectiveness of fludarabine and mitoxantrone where in the previously treated low-grade lymphoma group 25 of 28 patients (89%) responded. Fludarabine has the effect of increasing the triphosphate form of cytosine arabinoside in acute and chronic leukemic cells. This modulation has now been translated into therapy for acute leukemia and combined with cisplatinum in refractory CLL. Fludarabine inhibits DNA repair and enhances cross-linking of DNA by cisplatinum. The combination of fludarabine, ara-C, and cis-platinum is now being used in refractory CLL. Fludarabine is a radiation sensitizer, inhibiting repair of DNA damage. Studies are ongoing with this combination. CONCLUSIONS: Fludarabine is a potent molecule with a wide range of biochemical effects. Optimal use of this drug alone and in combination is continuing to be explored.

Adrenal Cortex Hormones↗
PubMed1994

Acute lymphocytic leukaemia in the elderly: characteristics and outcome with the vincristine-adriamycin-dexamethasone (VAD) regimen.

To analyse the pretreatment characteristics, response to therapy, and overall prognosis of elderly patients with acute lymphocytic leukaemia (ALL), 268 consecutive adults with newly-diagnosed ALL who received the vincristine-adriamycin-dexamethasone (VAD) regimens were reviewed. Pretreatment characteristics, response to VAD therapy, and overall outcome were analysed in patients 60 years or older, and compared to younger patients. Fifty-two patients (19%) were 60 years or older. Compared with younger patients, elderly patients with ALL had a significantly worse performance status at presentation (P < 0.001); higher incidences of FAB L2 morphology (P = 0.03), thrombocytopenia (P < 0.01), hypoalbuminaemia (P < 0.001) and renal dysfunction (P = 0.03); and trends for worse anaemia (P = 0.06) and a higher rate of myeloid markers positivity (P = 0.06). With VAD induction therapy, elderly patients had a lower CR rate than younger patients following two induction courses (CR rate 58% v 82%; P < 0.01), and overall (CR rates 65% v 90%; P < 0.01). The response rate to VAD chemotherapy, however, appeared superior to the 30-35% CR rates reported from other series in elderly ALL patients. The lower CR rate was due to both higher induction mortality (P = 0.02) and more resistant disease (P < 0.01). The long-term CR rate was 20% in elderly patients achieving CR, but the overall survival was poor (< 10% at 3 years). There were strong associations between older age and other poor prognostic features. However, multivariate analyses identified older age to be an independent poor prognostic factor for response to chemotherapy. In summary, elderly patients with ALL have an appreciable CR rate with the VAD regimens. Patients achieving CR may have durable remissions. The myelosuppression-associated mortality in both remission induction and maintenance may be reduced with the addition of growth factors in both treatment phases, and by using standard maintenance therapy without consolidation-intensification phases.

Age Factors↗
PubMed1994

Post-crucial period effects of visual experience and deprivation on the guinea-pig superior collicular map of auditory space.

There were two primary aims of this study. First, to observe if the map of auditory space in the superior colliculus (SC) of the guinea-pig could recover after periods of normal visual experience following visual deprivation during the crucial period. Second, to determine whether any degradation of the space map was observed when the animal was visually deprived for different lengths of time after the crucial period. Animals deprived of visual experience during the crucial period and then allowed normal experience did show a limited ability to construct a SC auditory space map. Whereas visual deprivation following normal auditory and visual experience during the crucial period caused a profound degradation, of both spatial tuning and topography, of auditory receptive fields in the SC. Additional data indicate that the SC auditory space map remains vulnerable to visual deprivation until at least 100 days after birth.

Analysis of Variance↗
PubMed1994

Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results.

PURPOSE: This study was undertaken to evaluate the feasibility and therapeutic effect of high-dose chemoradiotherapy with autologous or allogeneic bone marrow transplantation (BMT) in patients with advanced chronic lymphocytic leukemia (CLL) who relapse after fludarabine treatment. PATIENTS AND METHODS: Twenty-two patients with advanced CLL received high-dose cyclophosphamide, total-body irradiation, and BMT. Eleven patients with relapsed CLL received autologous BMT with marrow collected during a prior fludarabine-induced remission; leukemia cells were depleted from the autologous marrow in seven patients using an anti-CD19 monoclonal antibody and immunomagnetic separation. Eleven patients received allogeneic or syngeneic BMT, seven of whom had refractory Rai stage III or IV disease. RESULTS: Six autologous transplant recipients achieved a complete remission (CR), four a nodular CR (nCR), and one a partial remission (PR). Two recurred with CLL, and three developed Richter's transformation. Two patients had recurrence of immune cytopenias while in morphologic remission; one of these patients died of cytomegalovirus pneumonia. Six of 11 patients survive in remission 2 to 29 months following BMT. Of the 11 patients who received allogeneic or syngeneic BMT, seven achieved a CR, two a nCR, and one a PR; 10 survive 2 to 36 months following BMT. CONCLUSION: These data indicate that high-dose chemotherapy with allogeneic BMT is effective at producing CRs in patients with CLL. Autologous transplantation in CLL is feasible and is capable of producing remissions in patients with advanced CLL. Further studies are warranted to assess the role of BMT in the treatment of CLL.

Adult↗
PubMed1994

Clinical experience with fludarabine in leukaemia.

Fludarabine (Fludara) is a new purine analogue that was first entered into clinical trials in 1982. Results of initial studies with high dosages (> 96 mg/m2/day for 5 to 7 days) of fludarabine in acute leukaemia showed significant cytoreductive activity but a high incidence of severe irreversible neurotoxicity. The results of subsequent studies with lower dosages of 25 to 30 mg/m2/day for 5 days in chronic lymphocytic leukaemia (CLL) and low grade lymphomas have shown this regimen to be effective and safe, with almost no significant neurotoxicity. At present, the major role of fludarabine in leukaemia is in the management of CLL. In previously treated patients with CLL, responses are obtained in more than 50% of patients, with two-thirds of those responses being complete remissions according to the National Cancer Institute Working Group (NCIWG) criteria for complete response and partial response. The major causes of morbidity associated with fludarabine in CLL are infections and febrile episodes. These occur more frequently in previously treated patients and those with advanced stage of disease. Myelosuppression is dose limiting and a small proportion of patients with CLL develop moderate to severe and sometimes protracted myelosuppression. Administration of combined fludarabine and cytarabine (cytosine arabinoside; ara-C) alone (FA regimen) or together with granulocyte colony-stimulating factor (FLAG regimen) produced high response rates in previously treated refractory patients with acute leukaemia and previously untreated patients with acute myelogenous leukaemia or myelodysplastic syndrome. The wide range of biochemical and biological activities of fludarabine suggests that it will have an expanding role in future combinations in the treatment of both acute and chronic leukaemias.

Antineoplastic Agents↗
PubMed1994

The expanding role of fludarabine in hematologic malignancies.

The major clinical experience with fludarabine has been obtained in patients with chronic lymphocytic leukemia (CLL). In the initial studies in previously treated patients with CLL, the complete and partial response rate (CR + PR) was over 50%, and in previously untreated patients with CLL, a CR + PR rate of 75-80% was noted with or without the addition of prednisone. Subsequent clinical trials have also demonstrated major activity with fludarabine in Waldenstrom's macroglobulinemia. Fludarabine was noted to be an active agent in indolent lymphoma in phase I/II studies. Approximately 60% of patients with follicular lymphoma respond to fludarabine when it is administered as a single agent. Many of these remissions are complete remissions despite patients having received extensive prior therapy. Combination programs are being developed for application in CLL and indolent lymphoma. Because of the activity of fludarabine in inhibiting DNA repair, it has been combined with cisplatinum and cytosine arabinoside and plans are in place to explore the radiation sensitizing effect of fludarabine in clinical trials. A combination of fludarabine plus ara-C is now being used in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) and a combination of fludarabine, ara-C, and G-CSF (FLAG) has been combined with idarubicin for the management of these conditions. Many of these activities of fludarabine are associated with its interaction with many enzymes which are important in DNA and RNA metabolism and in DNA repair. It is anticipated that these actions will be explored in a wider range of studies subsequently.

Antineoplastic Agents↗
PubMed1994

Investigation of karyotypic, morphologic and clinical features in patients with acute myeloid leukemia blast cells expressing the neural cell adhesion molecule (CD56).

The mechanisms of extramedullary leukemic infiltration are not well characterized. The cell-surface glycoprotein CD56, which is identical to the neural cell adhesion molecule, may be involved. Using the Leu-19 antibody and flow cytometric methods, the leukemic blasts of 22% (70 of 314) of patients were CD56 positive. This was most common in acute monocytic leukemia (15 of 18, 83%) and in patients with the cytogenetic abnormalities t(8;21) (seven of 13, 54%) and trisomy 8 (nine of 22, 41%). CD56 expression was not associated with extramedullary leukemic infiltration, but was correlated with positivity for CD11b (p < 0.001), CD14 (p < 0.001) and CD19 (p = 0.018). Although associated with morphologic and cytogenetic features, CD56 expression alone cannot account for most instances of tissue infiltration in acute myeloid leukemia (AML).

Adolescent↗
PubMed1994

Therapy-related leukemia and myelodysplastic syndrome in chronic lymphocytic leukemia.

A retrospective analysis was performed to determine the incidence and clinical features of acute myelogenous leukemia/myelodysplastic syndrome (AML/MDS) developing in chronic lymphocytic leukemia (CLL) patients. AML/MDS occurred in 3/1374 CLL patients seen at a single institution between 1972 and 1992. The median follow-up exceeded 7 years and 72% of these patients had received prior alkylating agent therapy. The expected number of AML/MDS developing in a general population of the same size was 1.2 as calculated from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program data (observed-to-expected ratio = 2.49; 95% confidence interval = 0.9-7.3; p = 0.12). Although, not included in the incidence calculation, four patients with CLL were referred at the time of development of AML/MDS. CLL and AML/MDS were diagnosed concurrently in two patients. Three of the patients had received no prior alkylating agents. The median survival was 17 months in patients who had received no prior treatment, and 5 months in those who had received prior chemotherapy. Our results suggest that patients with CLL in whom AML/MDS develops have similar prognoses to other patients with AML/MDS. Furthermore, this analysis does not provide evidence for a heightened risk of AML/MDS in CLL patients, despite treatment with known leukemogenic agents.

Aged↗
PubMed1994

Long-term results following treatment of newly-diagnosed acute myelogenous leukemia with continuous-infusion high-dose cytosine arabinoside.

The long-term results in 130 patients with newly diagnosed acute myelogenous leukemia treated with continuous infusion high-dose ara-C (1.5 gm/m2/day x 4 days, CIHDAC) were compared with those in 264 patients treated in previous studies with standard dose ara-C (70-90 mg/m2/d x 7 days) plus either adriamycin (Ad-OAP), or amsacrine (AMSA-OAP). All patients have been followed at least 5 years. Patients in first CR at 5 years (FCR5) treated on protocols prior to CIHDAC had only 5% chance of relapse (median subsequent follow-up of 9 years). Therefore, we considered patients in FCR5 potentially cured. The two groups were similar with respect to known prognostic factors and CR rates. Although remission duration and survival were shorter with CIHDAC than Ad-OAP/AMSA-OAP, the percent of patients potentially cured was similar (10 vs. 15%). Marked differences between regimens were seen in inv(16) and t(15;17) patients. CIHDAC was better for patients with inv(16) with more patients in FCR5 (80 vs. 38%), longer remission duration and survival, and lower incidence of CNS relapse (0 vs. 43%). The Ad-OAP/AMSA-OAP protocols were superior in patients with t(15;17). We also measured steady-state ara-CTP concentrations (ara-CTPss) in 54 CIHDAC-treated patients presenting with high-blast count. While there was no correlation between ara-CTPss and response duration, all five patients in FCR5 in whom ara-CTPss was measured had high concentrations. These data support the concept that patients with AML should be treated differently according to cytogenetics. Inv(16) patients should be treated with high-dose ara-C while t(15;17) should rely more on anthracycline exposure.

Adolescent↗
PubMed1993

Granulocyte colony-stimulating factor supportive treatment following intensive chemotherapy in acute lymphocytic leukemia in first remission.

BACKGROUND: The efficacy of granulocyte colony-stimulating factor (G-CSF) in reducing neutropenia and its associated complications in adults with acute lymphocytic leukemia (ALL) undergoing intensive chemotherapy in first remission was evaluated. METHODS: Fourteen adult patients with ALL in first remission received intensive chemotherapy consisting of mitoxantrone 5 mg/m2 intravenously (IV) over 1 hour daily for 3 days, cytosine arabinoside (ara-C) 3 g/m2 IV over 2 hours every 12 hours x 4 on days 1 and 2, vincristine 2 mg IV on day 1, solumedrol 50 mg IV twice daily for 5 days, and G-CSF 5 micrograms/kg subcutaneously daily starting on day 4 until granulocyte recovery. Their outcome was compared with that of 14 consecutive patients who received the same intensification chemotherapy, but without G-CSF. The latter patients had been entered on the same ALL protocol from April 1990 through June 1991. RESULTS: G-CSF administration was associated with a significant shortening in the duration of neutropenia. The number of days to granulocyte recovery above 0.5 x 10(3)/microliters was 14 in the G-CSF group versus 18 days in the historical group (P < 0.001). Two episodes of documented infections were observed in the G-CSF group compared with four episodes in the historical group. Death during intensification therapy occurred in 2 of 14 patients in the historical group, but in none of the 14 patients receiving G-CSF. CONCLUSIONS: G-CSF as an adjunct to intensive chemotherapy in adults with ALL in first remission yielded positive results. Future studies incorporating growth factors supportive care during remission, induction, and consolidation may reduce treatment-related morbidity and mortality, increase the dose-intensity delivery of therapy, and potentially improve patient outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent.

The clinical response and survival of 113 patients with at least 3-year follow-up after treatment with fludarabine as a single agent for chronic lymphocytic leukemia has been evaluated. Seventy-eight patients were previously treated and 35 were untreated. The response to therapy and survival were strongly correlated with the degree of previous therapy, the stage of disease, and whether or not the patients were refractory to alkylating agents. Other characteristics associated with survival were the age of the patient and the serum albumin level at the start of therapy. The median time to progression of responders who had not received prior therapy was 33 months and was 21 months for previously treated patients. Survival after progression of disease was also strongly correlated with the degree of prior therapy. No successful salvage regimen after initial fludarabine therapy was shown for patients refractory to alkylating agents, although fludarabine achieved further remissions in patients who had received fludarabine as their initial treatment or were not refractory to alkylating agents. The morbidity of patients in unmaintained remission on discontinuation of fludarabine was low, with less than one episode of infection per patient-year at risk. The morbidity during this time was correlated with clinical response and whether the patients had received prior therapy. Although fludarabine is a very effective cytoreductive regimen, most patients, including those who achieved true complete remissions, will have recurrent disease. Longer follow-up and comparative trials are required before the effect of fludarabine on survival is shown.

Adult↗
PubMed1993

Fluorescent in situ hybridization and cytogenetic studies of trisomy 12 in chronic lymphocytic leukemia.

Cytogenetic studies (CG) of 475 chronic lymphocytic leukemia (CLL) cases showed trisomy 12 in 6.1% or 26% of patients with abnormal karyotypes. Fluorescence in situ hybridization (FISH) detected trisomy 12 in 35% of 117 CLL patients. Only 34.6% of cases detected by FISH were detected by CG. Twelve patients had low levels of trisomic cells (4% to 11%) relative to clonal B cells (47.5% to 86%), suggestive of clonal evolution. Untreated patients with trisomy 12 were predominantly male (P < .05) and had an increased incidence of splenomegaly (P < .03). Patients with trisomy 12 were more likely to be previously treated and had advanced Binet stage compared with those without trisomy 12. The median survival was shorter in patients with trisomy 12 (7.8 years) and patients with other chromosomal abnormalities without trisomy 12 by FISH (5.5 years) than in patients with diploid karyotypes (14.4 years). The response to fludarabine was similar to that of patients with diploid karyotypes, but there was a trend for earlier disease progression. FISH detected residual disease in all patients with trisomy 12 in complete (n = 6) or partial remission (n = 4). As few as 1 trisomic cell in 5,000 was detected by performing FISH on fluorescence-activated cell sorter-sorted cells. Trisomy 12 was absent in T cells in patients with trisomy 12. We conclude that FISH identifies trisomy 12 approximately 2.6 times more often than CG, readily identifies minimal residual disease, and predicts for a shorter median survival.

Antigens, CD↗
PubMed1993

Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia.

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to-moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Acute Disease↗
PubMed1993

Treatment of Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine.

OBJECTIVE: To evaluate the activity of 2-chlorodeoxyadenosine (2CdA) in the treatment of patients with Waldenstrom macroglobulinemia. DESIGN: Uncontrolled phase II trial. SETTING: Tertiary, referral cancer center. PATIENTS: Twenty-nine consecutive, symptomatic patients with Waldenstrom macroglobulinemia, of whom 9 were previously untreated. INTERVENTION: 2-Chlorodeoxyadenosine was administered as a continuous intravenous infusion at a dose of 0.1 mg/kg body weight per day for 7 days. Only two courses of 2CdA were given and responding patients were then followed without further treatment. MEASUREMENTS AND MAIN RESULTS: A total of 17 (59%) patients responded, including all of those who were newly diagnosed and 40% of those who had failed previous therapies. Treatment was well tolerated except for one death in a patient who had presented with severe pancytopenia. With a median follow-up of 7 months, only one responding patient has relapsed. CONCLUSION: 2-Chlorodeoxyadenosine is a nucleoside analog that was effective in most patients with Waldenstrom macroglobulinemia and was associated with little toxicity.

Adult↗