A plerixafor-based strategy allows adequate hematopoietic stem cell collection in poor mobilizers: results from the Canadian Special Access Program.

Plerixafor effectively mobilizes hematopoietic stem cells (HSCs). However, most patients' cells are successfully collected using traditional strategies and there is limited cost-effectiveness data. The objectives of this study were to: (1) summarize the published reports of mobilization using a plerixafor-based strategy during compassionate access programs and (2) describe the Canadian experience with plerixafor during its availability by Health Canada's Special Access Program. A literature search identified reports of plerixafor-based mobilization during compassionate access programs. Overall, successful collection of at least 2 × 10(6) CD34+ cells/kg was achieved in ~75% of patients, and about two-thirds of patients went on to HSCT. A greater proportion of patients had successful collections when plerixafor was used in the upfront or preemptive settings. Plerixafor was made available by Health Canada's SAP from September 2008 to December 2010. In 96 of 132 (73%) patients, there was successful collection of at least 2 × 10(6) CD34+ cells/kg. Ninety-nine (75%) patients went on to receive an autologous transplant. Plerixafor-based mobilization is effective in perceived poor mobilizers. The optimal way to incorporate plerixafor into a mobilization strategy, however, remains to be determined. Centre-specific analysis of resource utilization may help to identify the most cost-effective way to implement various plerixafor-based mobilization strategies.

Major ABO-incompatible BMT: isohemagglutinin reduction with plasma exchange is safe and avoids graft manipulation.

The impact of donor-recipient ABO incompatibility on long-term BMT outcomes remains controversial. A common strategy is to deplete the donor marrow of red cells, although this variably reduces the number of CD34+ cells. This 10-year retrospective study assessed the impact of recipient plasma exchange in major ABO-incompatible allogeneic BMT on outcomes and survival. Target Ab titres were ≤ 1:4 for anti-A and ≤ 1:8 for anti-B. Patients with higher titres underwent plasma exchange before marrow infusion. Of 133 patients who underwent allogeneic BMT, 34 had a major ABO-incompatible donor. The median number of exchanges was 2 (range 1-4). There were no acute haemolytic transfusion reactions. Engraftment times, transfusion requirements and acute and chronic GVHD were no different from those of patients with an ABO-identical donor. Treatment-related mortality at 100 days was 21% in the group with a major ABO-incompatible donor and 17% in the group with an identical donor (P=0.8). Plasma exchange of the recipient is a safe method of managing donor-recipient major ABO incompatibility before BMT without the risk of haematopoietic progenitor cell loss associated with red cell depletion of the graft.

Monoclonal B cells detected in autologous PBSC grafts from patients with classical Hodgkin lymphoma: impact on relapse and survival following transplantation.

Autologous peripheral blood stem cell transplantation (PBSCT) for Hodgkin lymphoma (HL) is curative for many patients with relapsed or refractory disease. Relapsing disease, however, remains a major problem. Neoplastic transformation of B-lymphocytes probably underlies the development of classical HL. Whether clonal B cells are critical for disease evolution and response to therapy in HL remains uncertain. We investigated the impact of clonal B cells detected in peripheral blood stem cell (PBSC) collections on the outcome of patients with HL undergoing transplant. Qualitative semi-nested PCR was carried out on genomic DNA from mononuclear cells from PBSCs to determine the presence of clonal immunoglobulin heavy chain (IgH) complementary-determining region 3 (CDR3) gene rearrangements. Clinical factors were assessed for their association with relapse, overall survival (OS) and progression-free survival (PFS). Among 39 patients undergoing PBSCT, 12 grafts (31%) were PCR positive for clonal IgH rearrangements. OS was better in the PCR-negative group (logrank test, P=0.041). The OS at 5 years was 81% in PCR-negative versus 39% in PCR-positive patients; hazard ratio was 3.23 (95% confidence interval: 0.98-10.63). There was a trend towards better PFS (logrank test, P=0.12), estimated as 71% at 5 years in PCR-negative versus 41% in PCR-positive patients. Clonal B-lymphocytes in PBSC collections of patients with HL identify patients at risk of poor outcome. Larger series are needed to confirm our observations. Insight regarding the role of monoclonal B cells may lead to improved therapies.

Performing allogeneic and autologous hematopoietic SCT in the outpatient setting: effects on infectious complications and early transplant outcomes.

This retrospective single-center study compared the incidence, spectrum and effect of infections in 1045 consecutive allogeneic (allo) and autologous (auto) hematopoietic SCT (HSCT) performed between 1995 and 2006 in the inpatient (IP) or outpatient (OP) setting. We analyzed 374 allo-HSCT (196 IP and 178 OP) and 671 auto-HSCT (163 IP and 508 OP). The incidence of infection was lower both in auto-OP (25% OP vs 33% IP, P=0.042) and allo-OP cohorts (42.7% OP vs 55.6% IP, P=0.012). The mean number of infections per transplant was lower in both auto-OP (0.39 OP vs 0.57 IP, P=0.05) and in allo-OP cohorts (0.78 OP vs 1.09 IP, P=0.018). The 100-day non-relapse mortality (NRM) for OP auto-HSCT was 4.72% and for IP 3.95% (P=0.68). The 100-day NRM for OP allo-HSCT was lower at 14.1% than it was for IP at 22.6% (P=0.041). Time to onset of first infection and spectrum of infections was similar in all groups. We conclude that performing allo- and auto-HSCT in the OP setting results in short-term outcomes, including infections complications that are comparable to the standard IP setting.

Contaminating tumour cells in autologous PBSC grafts do not influence survival or relapse following transplant for multiple myeloma or B-cell non-Hodgkin's lymphoma.

Relapsed disease remains a major obstacle following autologous haematopoietic SCT (HSCT) for non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Studies regarding the importance of detectable tumour cells in PBSC collections have been inconclusive. Patients undergoing autologous HSCT for NHL and MM between 2001 and 2006 were enrolled (n=158). PBSC grafts were assessed for clonal IgH CDR3 gene rearrangements using qualitative semi-nested PCR. In comparison to patients with PCR-positive PBSC grafts, patients negative for detectable disease had no improvement in overall survival (OS) or PFS for MM (P=0.91 and 0.91) or NHL (P=0.82 and 0.85). Further, no significant difference in OS was observed between patients with PCR-positive compared with PCR-negative PBSC grafts with aggressive NHL histology (P=0.74) or indolent disease (P=0.29). Patients with contaminating tumour cells in autologous PBSCs do not have worsened OS or PFS in MM or NHL. Tumour cells detected by sensitive molecular methods in PBSC collections may be distinct from cells contaminating marrow and appear to have limited utility in identifying patients with MM and B-cell NHL who would benefit from purging strategies.

Incidence of symptomatic venous thromboembolism following hematopoietic stem cell transplantation.

BACKGROUND: The incidence of symptomatic venous thromboembolism (VTE) following hematopoietic stem cell transplantation (HSCT) is not well described, particularly with increased use of ambulatory care in the transplant setting. METHODS: A retrospective analysis involving 589 patients (382 autologous HSCT, 207 allogeneic HSCT) undergoing transplantation between 2000 and 2005 in a single Canadian institution was undertaken to identify the incidence of proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) in HSCT patients. RESULTS: The total 1-year incidence of symptomatic VTE was 3.7% [95% confidence interval (CI) 2.5-5.6]. Among the HSCT patients, 7/589 (1.2%, 95% CI 0.6-2.4) developed symptomatic non-catheter-related VTE following HSCT (four PE and three DVT). All VTE events occurred after hematopoietic engraftment. Patients undergoing autologous HSCT did not receive thromboprophylaxis, whereas most patients undergoing allogeneic HSCT (79.7%) received enoxaparin 20 mg daily for the prevention of veno-occlusive disease of the liver, starting 6 +/- 3 days before transplantation for a mean of 22 +/- 14 days. CONCLUSION: HSCT patients have a high incidence of VTE. Thromboprophylaxis should potentially be considered in these patients. However, future studies assessing the risk and benefits of thromboprophylaxis are needed in this specific population.

Leading change: Retrospective evaluation of a nurse-led initiative in vascular access options for autologous stem cell transplant recipients ranging from Hickman catheters to peripherally inserted central catheters.

Central venous access is essential for patients undergoing autologous hematopoietic stem cell transplantation (ASCT). Traditionally, tunneled silastic catheters have been inserted in these patients. However, changes in resource allocation, resulting in reduced surgery and surgeon time and decreasing toxicity associated with ASCT, have caused changes in venous access needs and options. This led the advanced practice nurse in the transplant program to evaluate other central access devices, which resulted in the introduction of peripherally inserted central catheters (PICCs) for this patient population. This study reports the results of a retrospective analysis comparing efficacy and complication profiles between 50 patients with the traditional Hickman catheter and 70 patients with PICCs.

Outpatient total body irradiation as a component of a comprehensive outpatient transplant program.

Outpatient total body irradiation (TBI) as part of a comprehensive outpatient transplant program was delivered to 142 of 167 (85%) consecutive patients receiving TBI-based conditioning therapy. Outpatients received either a single fraction of 500 cGy (110 patients) or 1200 cGy in six fractions over 3 days (32 patients). Patients were assessed daily and were administered oral ondansetron and dexamethasone for prophylaxis of nausea and vomiting as well as i.v. hydration. Accommodation during outpatient TBI-based conditioning was either the patient's home if within 30 min of the hospital, a hotel on the hospital grounds or on a closed hospital ward. None of the 142 patients required admission to the inpatient program during their TBI. There was no difference in 100-day mortality between those receiving TBI as an outpatient (9%) vs as an inpatient (16%). Of four deaths occurring within the first 14 days post transplant, none could be attributed to receiving TBI as an outpatient. Two hundred and six inpatient days were saved through the delivery of outpatient TBI. A comprehensive outpatient program, appropriate patient selection, daily hydration, the use of prophylactic 5HT3 antagonist anti-emetic therapy all contribute to the safe delivery of outpatient TBI.

Allogeneic or autologous bone marrow transplantation (BMT) for non-Hodgkin's lymphoma (NHL): results of a provincial strategy. Ontario BMT Network, Canada.

In 1986, the bone marrow transplant centers in Ontario agreed to a strategy for the treatment of patients with NHL. Suitable patients would undergo autotransplant but be referred for allotransplant if they had persistent marrow involvement or an inadequate marrow/stem cell harvest. Data of all patients were recorded in a database. We reviewed this database to compare these transplant modalities with respect to overall survival, rate of relapse and treatment-related mortality. Between January 1986 and August 1997, 429 patients underwent BMT for NHL - 385 autotransplants and 44 allotransplants. Sixty-eight percent of patients received their transplant for aggressive NHL, while the others had indolent lymphoma. Three-year actuarial survival did not differ between allogeneic and autologous BMT: 71% vs 62%, respectively (P = 0.5330 by log-rank testing). Three-year actuarial rate of relapse was lower after allotransplant than autotransplant: 6% vs 41%, respectively (P = 0.0006 by log-rank testing). Treatment-related mortality was higher after allotransplant than autotransplant: 23% vs 6%, respectively (P = 0.001 by chi2 analysis). For further comparison, autotransplant patients were randomly matched 2:1 with the allotransplant patients for age +/- 5 years, disease status at BMT, disease histology, and year of BMT. In the matched comparison, survival did not differ (relative risk of death after allotransplant: 0.711 (95% CI: 0.309-1.637)). Relapse rate was significantly lower in the allotransplant group (relative risk of relapse for allotransplant: 0.190 (95% CI: 0.043-0.834)) and treatment-related mortality was not significantly different (relative risk for allotransplant: 1.425 (95% CI: 0.527-3.851)). In conclusion, a review of a provincial strategy for treatment of NHL, shows that survival is not different after allogeneic or autologous BMT, but the rate of relapse is lower after allotransplant. These data support continuing the current provincial strategy.

Autologous blood and marrow transplantation in patients 60 years and older.

Although many hematologic malignancies are more common in older patients, autologous blood and marrow transplantation (ABMT) has traditionally been restricted to patients younger than 60 years because of concerns that older patients would be either unable to provide a graft or unable to tolerate the therapy. From June 1995 to May 1998, 30 patients > or = 60 years underwent ABMT at our institution for low-grade lymphoma (4 patients), relapsed intermediate-grade lymphoma (17 patients), or multiple myeloma (9 patients). The median patient age was 62.5 years (range 60-73). Pretransplantation conditioning regimens were CBV (cyclophosphamide, BCNU [carmustine], etoposide) or BEAM (carmustine, etoposide, cytarabine, melphalan) for intermediate-grade lymphoma patients and melphalan 140 mg/m2 + etoposide 60 mg/kg + total body irradiation 500 cGy for the others. The rescue product was bone marrow (BM; 4 patients), peripheral blood stem cells (PBSC; 23 patients), or BM+PBSC (3 patients). The median number of CD34+ cells/kg infused was 3.60 x 10(6) (range 0.53-31.0), by the International Society for Hematotherapy and Graft Engineering method. The treatment-related mortality at day 100 and at 6 months was 10% and 16.7%, respectively. The median days to neutrophil > 0.5 x 10(9)/L was 11 (range 9-25) and platelets > 20 x 10(9)/L was 16 (range 6-70). Three patients died of infection (days 26, 27, and 38), and 1 died of an intracranial hemorrhage related to persistent thrombocytopenia (day 130). Bearman regimen-related toxicity was moderate, with most toxicities < or = grade 2. Seven patients developed significant gut toxicity: 4 patients with Clostridium difficile colitis and 3 patients with neutropenic enterocolitis. Depressive symptoms and signs were noted in 4 patients. Three male patients developed decreased gonadal function after transplantation. These transplantations accounted for 997 patient days, of which 266 days (27%) were in the outpatient BMT program--a smaller percentage than in patients < 60 years (56%, P = .002). Twenty patients are alive 153 to > or = 1224 days after transplantation. ABMT in patients > or = 60 years of age is feasible. Further studies addressing supportive care particular to older patients and comparisons of ABMT with traditional approaches to multiple myeloma and relapsed non-Hodgkin's lymphoma in older patients are needed. Further work to identify elderly patients most likely to benefit from this approach is also required.

Selection of appropriate venous access for the collection of peripheral blood progenitor cells by experienced apheresis nurses.

Peripheral blood progenitor cells (PBPC) have been extensively used to restore hematopoiesis after myeloablative chemotherapy. While collection regimens designed for optimal mobilization of PBPC are becoming standardized, the ideal venous access option for collection remains unresolved. The purpose of this study was to determine if the venous access of patients could be accurately assessed and appropriate intervention, if necessary, electively undertaken prior to PBPC collection. In this prospective study, 95 consecutive patients about to undergo PBPC collection were evaluated at time of referral to determine the type of venous access necessary for adequate PBPC collection. There were three possible interventions: 1. No access device for patients determined to have an adequate antecubital vein for apheresis access. 2. Insertion of a double lumen Quinton PermCath for those patients with poor antecubital veins. 3. Insertion of a double lumen Hickman catheter for patients with adequate antecubital veins for apheresis but poor peripheral veins for chemotherapy administration. The blood and marrow transplant nurse coordinator evaluated the patients' veins. Of the 95 patients having 192 PBPC collections, 65 were collected using antecubital veins, 21 were collected from PermCaths, and 9 from Hickman catheters. All patients predicted to collect peripherally did so and achieved flow rates equivalent to the PermCath. No patient required urgent line placement at time of PBPC collection. There was no difference in the number of cells collected between the three groups. The result of this study strongly supports a policy of appropriate venous access based on patient vein assessment by experienced nurses.

A randomized trial of granulocyte colony-stimulating factor (Neupogen) starting day 1 vs day 7 post-autologous stem cell transplantation.

The purpose of the study was to evaluate the effect of delayed granulocyte colony-stimulating factor (G-CSF) use on hematopoietic recovery post-autologous peripheral blood progenitor cell (PBPC) transplantation. Patients were randomized to begin G-CSF on day +1 or day +7 post transplantation. Thirty-seven patients with lymphoma or myeloma undergoing high-dose therapy and autologous PBPC rescue were randomized to daily subcutaneous G-CSF beginning on day +1 or day +7 post-transplant. Patients < or =70 kg received 300 microg/day and >70 kg 480 microg/day. All patients were reinfused with PBPCs with a CD34+ cell count >2.0 x 10(6)/kg. Baseline characteristics of age, sex and CD34+ cell count were similar between the two arms, the median CD34+ cell count being 5.87 x 10(6)/kg in the day +1 group and 7.70 x 10(6)/kg in the day +7 group (P=0.7). The median time to reach a neutrophil count of >0.5 x 10(9)/l was 9 days in the day +1 arm and 10 days in the day +7 arm, a difference which was not statistically significant (P=0.68). Similarly, there was no difference in median days to platelet recovery >20000 x 10(9)/l, which was 10 days in the day +1 arm and 11 days in the day +7 arm (P=0.83). There was also no significant difference in the median duration of febrile neutropenia (4 vs 6 days; P=0.7), intravenous antibiotic use (7 vs 8 days; P=0.54) or median number of red blood cell transfusions (4 vs 7 units; P=0.82) between the two arms. Median length of hospital stay was 11 days post-PBPC reinfusion in both groups. The median number of G-CSF injections used was 8 in the day +1 group and 3 in the day +7 group (P < 0.0001). There is no significant difference in time to neutrophil or platelet recovery when G-CSF is initiated on day +7 compared to day +1 post-autologous PBPC transplantation. There is also no difference in number of febrile neutropenic or antibiotic days, number of red blood cell transfusions or length of hospital stay. The number of doses of G-CSF used per transplant is significantly reduced with delayed initiation, resulting in a significant reduction in drug costs. For patients with an adequately mobilized PBPC graft, the initiation of G-CSF can be delayed until day +7 post-PBPC reinfusion.

Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis.

BACKGROUND: Acute deep vein thrombosis has traditionally been treated with unfractionated heparin (UFH), administered intravenously, but low-molecular-weight heparins (LMWH), administered subcutaneously, have recently become available. The authors sought to determine which therapy was more cost-effective for inpatient and outpatient treatment of deep vein thrombosis. METHODS: An incremental cost-effectiveness analysis based on a decision tree was performed for 4 treatment strategies for deep vein thrombosis. Rate of major hemorrhage while receiving heparin, rate of recurrence of venous thromboembolism 3 months after treatment and mortality rate 3 months after treatment were determined by meta-analysis. Costs for the UFH therapy were prospectively collected by a case-costing accounting system for 105 patients with deep vein thrombosis treated in fiscal year 1995/96. The costs for LMWH therapy were modelled, and cost-effectiveness was determined by decision analysis. RESULTS: Meta-analysis revealed a mean difference in risk of hemorrhage of -1.1% (95% confidence interval [CI] -2.4% to 0.3%), a mean difference in risk of recurrence of venous thromboembolism of -2.6% (95% CI -4.5% to -0.7%) and a mean difference in risk of death of -1.9% (95% CI -3.6% to -0.4%), all in favour of subcutaneous unmonitored administration of LMWH. The cost to treat one inpatient was $2993 for LMWH and $3048 for UFH. Even more would be saved if LMWH was delivered on an outpatient basis (cost of $1641 per patient). The cost-effectiveness analysis showed that LMWH in any treatment setting is more cost effective than UFH. A sensitivity analysis demonstrated the robustness of this conclusion. INTERPRETATION: Treatment of deep vein thrombosis with LMWH is more cost effective than treatment with UFH in both inpatient and outpatient settings.

Dead space ventilation parallels changes in scintigraphic vascular obstruction at recurrence of pulmonary embolism and after thrombolytic therapy: a case report.

Physiological and alveolar dead space ventilation both increase in pulmonary embolism (PE) in proportion to the severity of vascular obstruction. The case of a patient with recurrent PE while on heparin therapy is presented. The recurrence was characterized clinically by severe pulmonary vascular obstruction and right heart dysfunction. The patient was treated with thrombolytic therapy, with excellent clinical and scintigraphic resolution. Dead space ventilation measurements at baseline, at the time of recurrence and after thrombolytic therapy are presented. The potential utility of dead space ventilation measurements for PE diagnosis and management are discussed.

Cost analysis of the introduction of PBPC for autologous transplantation: effect of switching from bone marrow (BM) to peripheral blood progenitor cells (PBPC).

Increasingly, PBPC instead of BM are used for autologous transplantation. Limited data exist on the economic effects of this change. Using a resource-based utilization model we prospectively determined the costs of 48 autologous transplants (eight BM, 17 BM + PBPC, 23 PBPC), isolating the post-reinfusion period (day 0 to discharge) to better determine the effect of the rescue product. Length of stay post-reinfusion was significantly shorter in patients receiving PBPC (median 13 days) or BM + PBPC (median 14 days) vs BM alone (median 20 days) (P < 0.01). Accordingly, transplant admission costs were less in the PBPC groups (PBPC $22089, BM + PBPC $23179) vs the BM alone group ($32289) (P < 0.05). Rescue product acquisition costs were higher for PBPC (range $3439-$5157) vs BM ($2766) but these costs were offset by the more rapid recovery of patients receiving PBPC. Overall transplant costs depend on the conditioning regimen with a 10-fold cost variation among regimens. Modeled costs for autologus transplantation using various approaches to rescue product acquisition are given. The introduction of PBPC for autologus transplantation has resulted in cost savings at our institution. Although the acquisition costs of PBPC rescue product are greater than for BM, this incremental expense is more than offset by a less expensive post-reinfusion period.

Progression of rheumatoid arthritis following bone marrow transplantation. A case report with a 13-year followup.

The progression of rheumatoid arthritis (RA) is documented in a patient receiving a sex-mismatched, allogeneic bone marrow transplant (BMT) for gold-induced marrow aplasia. DNA typing confirmed a high probability of a full donor engraftment (complete chimerism). Although the RA was in complete remission 2 years post-BMT, clinical, laboratory, histologic, and radiologic evidence of the recurrence of synovitis from 3-13 years post-BMT is presented. Implications of these observations for theories of the pathogenesis of RA and the future of immunotherapies are discussed.

Effect of pentoxifylline on regimen related toxicity in patients undergoing allogeneic or autologous bone marrow transplantation.

An unblinded, historical controlled study of 49 bone marrow transplant (BMT) patients was carried out in our institution to assess the effect of oral pentoxifylline (PTX) on BMT regimen related toxicity (RRT). Twenty-eight consecutively treated BMT patients (17 allogeneic, 11 autologous) were entered into the PTX treatment group and treated with oral PTX 400 mg at intervals of 4 h from day -10 until day +35 or discharge, whichever came sooner. These were compared with a control group of 21 BMT patients (14 allogeneic, 7 autologous). Patient groups were very similar with respect to age, sex, conditioning regimen, graft-versus-host disease (GVHD) prophylaxis and baseline liver and renal function. Compliance with the drug was 85%. Despite this, no significant difference in days of mucositis or hyperalimentation, incidence or severity of renal or hepatic dysfunction, hypertension, GVHD, weight gain > 5%, day 100 mortality or length of hospitalization was observed. Median follow-up is > 2 years in both groups and no difference in relapse or survival was observed. We were unable to confirm an effect of oral PTX on BMT related morbidity or mortality.