Fludarabine is an effective treatment for chronic lymphocytic leukemia that does not respond to initial treatment with chlorambucil. We compared the efficacy of fludarabine with that of chlorambucil ...in the primary treatment of chronic lymphocytic leukemia.
Between 1990 and 1994, we randomly assigned 509 previously untreated patients with chronic lymphocytic leukemia to one of the following treatments: fludarabine (25 mg per square meter of body-surface area, administered intravenously daily for 5 days every 28 days), chlorambucil (40 mg per square meter, given orally every 28 days), or fludarabine (20 mg per square meter per day for 5 days every 28 days) plus chlorambucil (20 mg per square meter every 28 days). Patients with an additional response at each monthly evaluation continued to receive the assigned treatment for a maximum of 12 cycles.
Assignment of patients to the fludarabine-plus-chlorambucil group was stopped when a planned interim analysis revealed excessive toxicity and a response rate that was not better than the rate with fludarabine alone. Among the other two groups, the response rate was significantly higher for fludarabine alone than for chlorambucil alone. Among 170 patients treated with fludarabine, 20 percent had a complete remission, and 43 percent had a partial remission. The corresponding values for 181 patients treated with chlorambucil were 4 percent and 33 percent (P< 0.001 for both comparisons). The median duration of remission and the median progression-free survival in the fludarabine group were 25 months and 20 months, respectively, whereas both values were 14 months in the chlorambucil group (P<0.001 for both comparisons). The median overall survival among patients treated with fludarabine was 66 months, which was not significantly different from the overall survival in the other two groups (56 months with chlorambucil and 55 months with combined treatment). Severe infections and neutropenia were more frequent with fludarabine than with chlorambucil (P=0.08), although, overall, toxic effects were tolerable with the two single-drug regimens.
When used as the initial treatment for chronic lymphocytic leukemia, fludarabine yields higher response rates and a longer duration of remission and progression-free survival than chlorambucil.
In order to define more clearly the importance of the degree of HLA compatibility in the hematologic support of patients refractory to random-donor platelets, we retrospectively analyzed over 1000 ...platelet transfusions given during stable periods of their disease to 11 thrombocytopenic, severely alloimmunized patients with aplastic anemia: 28% of the donors fully matched with the recipient for HLA A and B loci (A-matched) and 17% of the donors mismatched with the recipient for two or more HLA antigens (D-matched) provided excellent responses, and 18% of A-matched and 46% of D-matched donors provided poor posttransfusion increments. Among all groups analyzed only A-matched donor-recipient pairs had higher increments than predicted by chance (p < 0.04); no such increments were observed for donor-recipient pairs with lower degrees of HLA compatibility. Cross reactivity, ABO compatibility, and/or absence of HLA-A2 antigen in the recipient did not appear to influence the outcome of platelet transfusions. While HLA-matched platelets are of benefit in selected cases, HLA matching does not reliably predict platelet transfusion responses even in stable patients, and other as yet unknown factors appear to play an important role in determining transfusion outcomes.
Graft-vs.-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Intravenous immunoglobulin (IVIg) given at a dose of 500 mg/kg/wk has been shown to ...decrease the risk of acute GVHD, interstitial pneumonia, and infection in adults early after allogeneic transplantation. The current study is a controlled trial to determine whether a lower total dose of IVIg given with pretransplant loading reduces the incidence of transplant-related complications. In a randomized trial of 241 patients > or =20 years of age who were given related donor marrow allografts, 121 individuals receiving Ig prophylaxis (500 mg/kg/d loading from day -6 to -1 and then 100 mg/kg every 3 days from day 3 to 90) were compared with 120 control patients who did not receive IVIg. Randomization was stratified by human leucocyte antigen-matching, remission status of malignancy, GVHD prophylaxis, and cytomegalovirus (CMV) serology. The study was powered to detect a reduction in acute GVHD by 18% and a decrease in transplant-related mortality by 17%. Pretransplant IVIg loading and posttransplant maintenance achieved median serum IgG levels >1350 mg/dL, which were approximately twofold greater than the untreated controls (p<0.01). White blood cell and platelet recoveries were similar for the two groups, although control patients required fewer units of platelets per day (2.5 vs. 3.3, p = 0.008). No significant differences in the incidence of CMV infection, interstitial pneumonia, or bacteremia were observed. The incidence of acute GVHD did not differ between the two groups; however, acute GVHD was less frequent among IVIg recipients achieving maximum serum IgG levels >3000 mg/dL (60 vs. 79%). Neither transplant-related mortality nor disease-free survival was significantly altered by Ig prophylaxis. However, the cumulative incidence of relapse of malignancy was higher in IVIg recipients than in controls (31 vs. 18%, p = 0.03). Multivariable regression analysis demonstrated a 1.89 increased relative risk of relapse for individuals given IVIg (p = 0.021). We conclude that pretransplant loading and a shorter course and lower total dose of IVIg prophylaxis did not appear to decrease the risk of acute GVHD or mortality among adults receiving related donor marrow transplants. Note, IVIg administration may be associated with an increased risk of recurrent malignancy, a finding that warrants further investigation.
Biol Blood Marrow Transplant 1999;5(6):369-78.
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules ...governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
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•A scRNA-seq study reveals shared and distinct features of human MMRd and MMRp CRC•Co-variation of single-cell transcriptional programs across specimens predicts immune hubs•A myeloid-rich inflammatory hub is identified below the colonic lumen in human CRC•CXCR3-ligand+ cells form foci with activated T cells in human MMRd CRC
Single-cell transcriptomics-based co-variation analysis of human colorectal cancer identifies a spatially resolved myeloid-rich inflammatory hub that is shared by mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors and CXCR3-ligand+ multicellular foci distinct for MMRd tumors.
An advanced cancer diagnosis can be associated with a significant profile of distress. Psychedelic compounds have shown clinically significant effects in the treatment of psychological distress in ...patients with advanced-stage cancer. Given the challenges of delivering timely and effective intervention in the advanced cancer context, it is possible that an alternative, more pragmatic, approach lies in psychedelic 'microdosing'. Microdosing refers to repeated administration of psychedelics in sub-hallucinogenic doses. The purpose of this study is to evaluate the feasibility of conducting a full-scale randomised controlled trial comparing psychedelic microdose-assisted-meaning-centred psychotherapy (PA-MCP) to standard meaning-centred psychotherapy (MCP) in New Zealand indigenous (Māori) and non-indigenous people with advanced cancer and symptoms of anxiety and/or depression. Although MCP is a well-established psychotherapeutic treatment in advanced cancer populations, the potential efficacy and effectiveness of this therapy when delivered alongside a standardised microdose regimen of a psychedelic compound have not been investigated.
Participants with advanced-stage cancer and symptoms of anxiety and/or depression (N = 40; 20 Māori, 20 non-Māori) will be randomised under double-blind conditions to receive 7 sessions of MCP alongside 13 doses of either an LSD microdose (4-20 µg) (PA-MCP) or inactive placebo (placebo-MCP). The feasibility, acceptability, and safety of this intervention and physiological and psychological measures will be recorded at baseline, at each session of MCP, and at a 1-month and 6-month follow-up.
Our findings will evaluate the feasibility, acceptability, and safety of a larger randomised controlled trial and provide an initial indication of the potential benefits of psychedelic microdosing for psychological distress in advanced-stage indigenous and non-indigenous cancer patients.
NZCTR, ACTRN12623000478617. Registered 11 May 2023. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385810&isReview=true .
The experiences of 69 (38 marrow and 31 peripheral blood stem cell PBSC) donors participating in a randomized trial comparing allogeneic bone marrow with PBSC transplantation were studied. Marrow was ...collected by means of standard harvest techniques and general or regional anesthesia. PBSC donors were treated with 5 to 7 days of filgrastim at a dose of 16 μg/kg/d and underwent 1 to 3 days of apheresis to obtain 5 × 106 CD34+ cells per kilogram recipient weight. Donors completed questionnaires describing their health experiences before, during, and then weekly after donation until return to baseline status. Both marrow and PBSC donors reported minimal fluctuation in symptoms measuring emotional status. In contrast, both groups of donors reported deterioration in physical status starting with administration of filgrastim (PBSC donors) or after the marrow collection procedure. The symptom burden reported was similar, with pain a prominent symptom for both groups. Equivalent mean levels of maximal pain, average pain, and pain duration through the day were reported, although toxicity peaks occurred at different time points during the harvest procedures. All PBSC donors but only 79% of marrow donors reported good physical status by 14 days after the harvest procedures. These data demonstrate similar levels of physical discomfort for hematopoietic stem cell donors regardless of the collection procedure used, but a quicker resolution of symptoms for PBSC donors.
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