The role of bone-seeking radionuclides in the palliative treatment of patients with painful osteoblastic skeletal metastases.

BACKGROUND: Pain from skeletal metastases represents a major burden of advanced disease from solid tumors. Analgesic medications, bisphosphonates, hormonal agents, cytotoxic chemotherapy, and external beam radiotherapy are all effective treatments. However, patients often suffer from diffuse painful metastases and respond poorly to these standard therapies. Bone-seeking radionuclides can specifically target osteoblastic lesions to offer palliation of pain. METHODS: This article offers a narrative review of bone-seeking radionuclides, examines the evidence of safety and efficacy for the treatment of painful skeletal metastases, and presents guidelines for their appropriate use in this patient population. RESULTS: Seven bone-seeking radionuclides have shown evidence of both safety and efficacy in reducing pain from diffuse skeletal metastases. 153Sm-EDTMP and 89Sr are most commonly used in the United States and have been safely utilized for both repeat dosing as well as concurrent dosing with cytotoxic chemotherapy. CONCLUSIONS: Targeted bone-seeking radionuclides are underutilized in the treatment of painful diffuse osteoblastic metastases. Several new agents are in active clinical investigation, and the pending approval of the first alpha-emitting radionuclide (223Ra) may offer a new class of agents that provide greater efficacy and less toxicity than those currently available for routine clinical use.

No increased mortality from donor or recipient hepatitis B- and/or hepatitis C-positive serostatus after related-donor allogeneic hematopoietic cell transplantation.

Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C virus (HCV) infection (seropositive donors), or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers, who received a human leukocyte antigen-identical related-donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow-up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment-related mortality, survival, graft-versus-host disease, and hepatic toxicity, appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant.

Difficult stem cell mobilization despite adequate CD34+ cell dose predicts shortened progression free and overall survival after autologous HSCT for lymphoma.

Hematopoietic growth factors alone or in combination with myelosuppressive chemotherapy are used to mobilize peripheral blood stem cells for autologous transplantation. To identify characteristics of successful mobilization with granulocyte colony-stimulating factor (G-CSF) alone and to study the impact of immediate chemotherapy mobilization following G-CSF mobilization, we treated 175 chemotherapy sensitive lymphoma patients with G-CSF (G) mobilization and leukapheresis followed by chemotherapy plus G-CSF (CG) mobilization and leukapheresis and then autologous transplantation. Patients with stage I/II disease at diagnosis and < or =5 years from diagnosis were more likely to mobilize successfully with G-CSF alone (G). CG mobilization led to superior stem cell yields compared to the preceding mobilization with G (median 2.37 vs 1.37 ( x 10(6)CD34+ cells/kg); P<0.0001). Patients (n=58, 33%) with successful G-CSF mobilization (> or =2 x 10(6) CD34+ cells/kg) had quicker platelet recovery and improved progression free and overall survival compared to patients who had adequate collection only after chemotherapy mobilization or to those who failed to collect an adequate graft with either type of mobilization. The poor clinical outcome of patients with difficult mobilization using either method identifies them as a high-risk group who might benefit from alternative therapies.

Use of total leukocyte and platelet counts to guide stem cell apheresis in healthy allogeneic donors treated with G-CSF.

Healthy stem cell donors start leukapheresis 4-5 days after starting G-CSF based on the peripheral blood CD34+ cell count (PBCD34). Data from 137 harvests (68 donors) were analyzed to determine correlation between pre-apheresis leukocytes (11.0-94.8x10(9)/l; median 38.8) and platelets (49-374x10(9)/l; median 180), and PBCD34 (3-276/microl; median 40). PBCD34 correlated positively with leukocytes (r=0.48; P<0.0001) and platelets (r=0.40; P<0.0001). When pre-apheresis leukocytes were >or=25 and platelets were >or=100, PBCD34 and CD34+ collection were 5-276/microl (median 57) and 0.5-27.6x10(6)/kg (median 4.7), respectively; significantly higher than PBCD34 of 3-74/microl (median 17) and CD34+ collection of 0.2-8.9 x 10(6)/kg (median 2.2) when leukocytes were <25 and/or platelets were <100. With leukocytes >or=25 and platelets >or=100, PBCD34 was low (<20/microl) 8% of the time, compared to 57% of the time with leukocytes <25 and/or platelets <100 (P<0.0001). Our data suggest that it is not always necessary to measure PBCD34 to guide leukapheresis in healthy donors because pre-apheresis leukocytes and platelets >or=25 and >or=100, respectively, are associated with excellent mobilization. When blood counts do not meet these criteria, PBCD34 should be determined prior to initiation of apheresis.

Rarity of toxigenic Clostridium difficile infections after hematopoietic stem cell transplantation: implications for symptomatic management of diarrhea.

Diarrhea is a common complication of high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). The frequent and prolonged use of multiple antibiotics in this setting can predispose to infection with toxigenic Clostridium difficile and the development of pseudomembranous colitis. Anti-motility agents are usually not administered in this setting until C. difficile infection has been excluded. The objective of this study was to determine the incidence of C. difficile toxin (CDT) positivity at the time of initial diarrhea in HSCT recipients, and to see if the practice of ensuring negative CDT assays prior to initiating symptomatic management of diarrhea needs modification. One hundred and nineteen patients with malignant diseases undergoing autologous or allogeneic HSCT were studied to determine the incidence of diarrhea and CDT positivity with initial diarrhea. One hundred and nine (91%) had diarrhea. Of these, only seven (6%) were CDT+ at the time of initial diarrhea. The median interval between onset of diarrhea and starting symptomatic anti-diarrheal therapy was 1 day. There were no significant differences between the patients with CDT+ diarrhea and the others in terms of timing or severity of diarrhea, number or duration of antibiotic usage, or leukocyte count. The infection resolved in all patients with metronidazole therapy. Our data suggest that the incidence of CDT+ diarrhea is low in HSCT recipients. Concern about C. difficile infection should not delay symptomatic therapy of initial diarrhea in HSCT recipients.

Comparison of 1-day vs 2-day dosing of high-dose melphalan followed by autologous hematopoietic cell transplantation in patients with multiple myeloma.

High-dose melphalan at 200 mg/m(2) can be administered in 1 day or over 2 consecutive days before autologous hematopoietic cell transplantation (HCT) for multiple myeloma (MM). Limited data exist on the comparison of the two dosing schedules. A retrospective study of 278 consecutive MM patients receiving high-dose melphalan from January 2010 to December 2012 was conducted. Objectives were to compare the length of hospitalization, toxicity profile, response rates, PFS and OS. One hundred and eighty five patients received 2-day dosing and 93 received 1-day dosing. The two end points of the 95% confidence interval (CI) for the difference did not exceed the preselected margin, therefore the length of hospitalization was considered equivalent. No significant differences were found for response rates, PFS and OS.  The toxicity profile was similar with the exception of more frequent ⩾grade 3 oral mucositis in the 2-day group (13.5% vs 5.4%; odds ratio 3.07 (95% CI:1.11-8.48); P=0.03). High-dose melphalan, given either in 1 day or over 2 days, produced comparable treatment outcomes except for increased grade 3/4 mucositis in the 2-day regimen. One-day dosing could shorten the hospital stay by 1 day and may allow better resource utilization.

Pharmacokinetically-targeted BU and fludarabine as conditioning before allogeneic hematopoietic cell transplantation for adults with ALL in first remission.

Allogeneic hematopoietic cell transplantation offers improved survival in patients with ALL, but with regimens containing TBI, the nonrelapse mortality is 20-40%. Efforts to lessen transplant toxicities by reducing conditioning regimen intensity have led to increased relapse risk. Therefore, there is a need for less toxic regimens that maintain an anti-leukemia effect. We report here a retrospective review of 65 patients with ALL in first remission receiving grafts from allogeneic donors after fludarabine 40 mg/m(2)/day for 4 days and i.v. BU targeted to a median daily area under the concentration-time curve below 6000 µmoles min/L. At 2 years after transplantation, OS was 65% (95% confidence interval (CI): 52-77%), relapse-free survival was 61% (95% CI: 48-73%), cumulative incidence of relapse was 26% (95% CI: 17-39%) and cumulative incidence of nonrelapse mortality was 14% (95% CI: 8-26%). Age over 35 years, Ph chromosome positivity and minimal residual disease at transplant did not adversely affect outcomes. Pharmacokinetically targeted BU and fludarabine can provide intensive pre-transplant conditioning for adults with ALL in first remission, with promising relapse-free and OS rates.

Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization.

Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches (n=531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race (P<0.0001) were more likely to find a donor. Younger age (P=0.01), Caucasian race (P=0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk (P=0.005), and 8/8 HLA matching (P=0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63-1.2), P=0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90-100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38-0.90, P=0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups.

Apheresis and transplant of hematopoietic progenitor cells (HPC) from allogeneic donors of age above 60 years.

Over the immediate past 4 years, our program has collected hematopoietic progenitor cells by apheresis from 48 individuals aged 61 and over (range 61-71 years of age). We have retrospectively analyzed the collection and transplant results associated with employing these donors, and have compared them with 175 donors aged 60 or less who were collected during the same time period. We have found no significant difference in venous access (P = 0.208), rate of post-transplant engraftment of neutrophils (P = 0.117) and platelets (P = 0.692), or in rate and grade of acute GVHD (P = 0.806). However, we have found that these older donors have a significantly lower mobilization of CD34 + cells as reflected in lower absolute counts of circulating CD34 + cells pre-apheresis (P = 0.016). This, in turn, results in lower CD34 + cell yields in apheresis products (P < 0.001), trending towards requiring more apheresis procedures (22.9 vs 13.7%, P = 0.095) to collect sufficient CD34 + cells for transplantation. We conclude that it is practical when necessary to employ donors aged 60 and above, as well as safe for both donor and intended recipient. However, concern over reduced CD34 + cell mobilization may be sufficient grounds to seek younger donors when possible.

Fewer infections and lower infection-related mortality following non-myeloablative versus myeloablative conditioning for allotransplantation of patients with lymphoma.

Non-myeloablative (NMA) allogeneic donor SCT for patients with relapsed lymphoma is associated with lower treatment-related mortality (TRM). However, the impact of conditioning intensity on post transplant infections remains unclear. We evaluated infections in 141 consecutive patients with lymphoma who were allografted using NMA (n=76) or myeloablative (MA; n=65) conditioning regimens. Using infection incidence density per 1000 patient days, we accounted for all infectious episodes during the first post transplant year. Before neutrophil engraftment, the NMA cohort had a 53% lower rate of bacterial infection (relative risk=0.47; P=0.06), whereas after engraftment the density of bacterial infections was similar in the two groups. In the first month, both invasive fungal infections and viral infections were twofold less frequent (P=0.22; P=0.06) in NMA patients. Late viral and fungal infections as well as CMV reactivation were infrequent after either conditioning intensity. The 1-year infection-related mortality was significantly lower after NMA conditioning (NMA 9% (3-16%) vs MA 22% (11-40%); P=0.03). NMA allogeneic transplantation for lymphoma patients results in substantially fewer early infections and lower infection-related deaths, although the similar frequency of later infections suggests that immune reconstitution is delayed with either conditioning intensity.

Comparison of two mycophenolate mofetil dosing regimens after hematopoietic cell transplantation.

Mycophenolic acid (MPA) is the active component of mycophenolate mofetil (MMF). Low MPA exposure is associated with a higher incidence of acute GVHD and possibly worse engraftment. Therapeutic plasma targets have been proposed in hematopoietic cell transplantation (HCT), however, are difficult to achieve in adult patients with MMF doses of 2 g/day. Mycophenolate pharmacokinetics was prospectively studied in adults undergoing nonmyeloablative HCT who received MMF 3 g/day with CYA. The first 15 individuals received 1.5 g every 12 h and the second 15 received 1 g every 8 h. Sampling was performed in each patient with i.v. and oral administration. There were no differences in total or unbound MPA 24-h cumulative area under the curves (AUCs), concentrations at steady state (Css) or troughs between the two dosing regimens (all P>0.01). The previously proposed total MPA Css target of 3 microg/ml and trough >or=1 micro/ml were achieved in only 13-27% and 20-53% of patients, respectively, on 3 g/day. However, the 3 g/day regimens readily achieved satisfactory unbound 24-h cumulative AUC targets of 0.600 microg(*)h/ml in 87-100% of subjects. There appears to be no significant difference in daily MPA exposure when MMF of 3 g/day is divided into two or three equal doses.

Donor lymphocyte infusions: the long and winding road: how should it be traveled?

Donor lymphocyte infusions (DLI) often are used after allo-SCT to augment the graft-versus-tumor effect. Timing of infusion varies according to indication, for example to treat tumor recurrence, as a planned strategy to prevent disease relapse in the setting of T-cell-depleted grafts or non-myeloablative conditioning regimens, or as a method to convert mixed to full donor chimerism. The optimal strategy of timing, use of cytotoxic conditioning, cell dose and cell product composition, and so on, for DLI administration remains unclear. Despite varied techniques, DLI may lead to 3-year disease-free survivals (DFS) in excess of 60% for all CML patients and approach 90% in patients with only molecular or cytogenetic relapse. Other hematologic malignancies appear much less responsive, as less than 50% of patients respond and provide, at best, 3-year DFS rates of 20-50%. Multiple myeloma patients have overall response rates of 40-45% after DLI, suggesting benefit in relapsed disease, but limited experiences for diseases such as Hodgkin's lymphoma, myelodysplasia and ALL preclude recommendations for use of DLI at this time. Regardless of the indication, treatment-related mortality after DLI is 5-20% and more than one-third of patients will develop acute and/or chronic GVHD after DLI. The risks of these complications appear related, in part, to donor source, cell dose and therapy prior to DLI. Although there are no definitive answers, the information gleaned from published literature suggests that DLI should be administered early after relapse or as a prophylactic strategy in patients receiving T-cell-depleted grafts, and patients with bulky or aggressive disease may benefit from disease reduction prior to DLI.