S M Devine

Clinical application of hematopoietic progenitor cell expansion: current status and future prospects

Summary:In the past decade, we have witnessed significant advances in ex vivo hematopoietic stem cell culture expansion, progressing to the point where clinical trials are being designed and conducted. Preclinical milestone investigations provided data to enable expansion of portions of hematopoietic grafts in a clinical setting, indicating safety and feasibility of this approach. Data derived from current clinical trials indicate successful reconstitution of hematopoiesis after myeloablative chemoradiotherapy using infusion of ex vivo-expanded perfusion cultures. Future avenues of exploration will focus upon refining preclinical and clinical studies in which cocktails of available cytokines, novel molecules and sophisticated expansion systems will explore expansion of blood, marrow and umbilical cord blood cells.

Once daily ganciclovir as initial pre-emptive therapy delayed until threshold CMV load |[ges]|10000|[thinsp]|copies|[sol]|ml: a safe and effective strategy for allogeneic stem cell transplant patients

Quantitative polymerase chain reaction (QPCR) for cytomegalovirus (CMV) is emerging as the preferred screening method for detection of CMV viremia in patients following allogeneic bone marrow and peripheral blood stem cell transplant. However, there are currently no universally accepted QPCR treatment thresholds at which to start pre-emptive therapy. We report here results of a pre-emptive therapy strategy using ganciclovir (GCV) 5u2009mg/kg initiated once daily (ODG) delayed till a threshold CMV load of ⩾10u2009000u2009copies/ml whole blood in clinically stable patients. Sixty-nine at risk patients underwent allogeneic stem cell transplant. 48/69 (70%) patients had an initial episode of CMV viremia. 5/48 (10%) cleared viremia without requiring treatment. 28/43 (65%) patients requiring treatment initiated treatment with ODG. 17/28 (61%) patients successfully cleared CMV viremia on ODG, 10/28 (36%) patients required dose escalation to twice daily GCV for increasing viral loads. There were two cases of CMV disease (colitis) and no deaths due to CMV disease in patients initiating treatment with ODG. We conclude delaying pre-emptive therapy with ODG until whole blood QPCR⩾10u2009000u2009copies/ml is a safe and effective strategy for CMV viremia after allogeneic stem cell transplant in clinically stable patients.

Supraventricular tachyarrhythmias after hematopoietic stem cell transplantation: incidence, risk factors and outcomes

Summary:Recent studies suggest that cancer patients may be at increased risk for supraventricular tachyarrhythmias (SVTA). We have observed clinically significant SVTA in patients undergoing hematopoietic stem cell transplantation occurring at a median of 6 days post transplant, manifesting as atrial fibrillation/flutter or regular narrow-complex tachycardia and persisting for a median of 3 days (range, 0–8). All patients received aggressive medical therapy and/or electrical cardioversion to restore sinus rhythm and to re-establish hemodynamic stability. Non-Hodgkins lymphoma (NHL) was the most common diagnosis (53%), and a case control analysis in those patients demonstrated that SVTA occurred in 12% of patients and was associated with older age and pre-existing cardiac conditions. In conclusion, patients undergoing HSCT are at moderate risk for developing SVTA, particularly older patients with a diagnosis of NHL. These arrhythmias are clinically significant, and are a marker for increased mortality and prolonged hospital stay. Additional studies are needed to identify high-risk patients who may benefit from prophylactic anti-arrhythmic therapy.

Reduced risk of acute GVHD following mobilization of HLA-identical sibling donors with GM-CSF alone

Summary:We retrospectively reviewed the results of transplanting peripheral blood progenitor cell (PBPC) allografts from HLA-matched sibling donors mobilized using various hematopoietic cytokines. Patients had received allografts mobilized with Granulocyte colony-stimulating factor (G-CSF) (G, N=65) alone, G plus Granulocyte-macrophage colony stimulating factor (GM-CSF) (G/GM, N=70), or GM-CSF alone at 10 or 15u2009μg/kg/day (GM, N=10 at 10u2009μg/kg/day and 21 at 15u2009μg/kg/day). The CD34+ and CD3+ cell content of grafts were significantly lower following GM alone compared to G alone (P<0.001 and 0.04, respectively). Nonhematopoietic toxicity observed in donors precluded dose escalation of GM-CSF beyond 10u2009μg/kg/day. Hematopoietic recovery was similar among all three groups. Grades II–IV acute graft-versus-host disease (GVHD) was observed in only 13% of patients in the GM alone group compared to 49 and 69% in the G alone or G/GM groups, respectively (P<0.001). In a multivariate analysis, receipt of PBPC mobilized with GM alone was associated with a lower risk of grades II–IV acute GVHD (hazard ratio 0.21; 95% CI 0.073, 0.58) compared to G alone or G/GM. There were no differences in relapse risk or overall survival among the groups. Donor PBPC grafts mobilized with GM-CSF alone result in prompt hematopoietic engraftment despite lower CD34+ cell doses and may reduce the risk of grades II–IV acute GVHD following HLA-matched PBPC transplantation.

Low-dose short-course intravenous ganciclovir as pre-emptive therapy for CMV viremia post allo-PBSC transplantation

Summary:In contrast to allogeneic bone marrow transplantation (allo-BMT), there is a paucity of data on cytomegalovirus (CMV) infection and pre-emptive therapy (PT) strategies following allogeneic peripheral blood stem cell (allo-PBSC) transplantation. We report here on the patterns of CMV infection in a cohort of 225 patients following sibling donor allo-PBSC transplantation. In an attempt to reduce neutropenia, we used intravenous low-dose short-course (LDSC) ganciclovir (GCV) 5u2009mg/kg once daily for 21 days as preemptive therapy. A total of 165 recipient–donor pairs were CMV seropositive. An initial episode of viremia (detected by shell vial/tube culture) occurred in 75/165 (45%) at a median of day +35 (17–445) post allo-PBSC. In all, 58 patients received PT with LDSC GCV. Among 58, 55 (94%) completed the 21-day course of PT. A second episode of viremia occurred in 19/58 (33%) at day+80 (50–174) and a third episode in 5/58 (9%) at day+134 (103–218). Among patients receiving LDSC GCV, 5/58(9%) developed disease (four pneumonia, one colitis) at day+211 (63–487). No patient on LDSC GCV exhibited a decline in their ANC below 500/μl and none required growth factors. LDSC GCV is extremely well tolerated and cost-effective as PT for CMV viremia following allo-PBSC transplantation.

Primary amyloidosis patients with significant organ dysfunction tolerate autologous transplantation after conditioning with single-dose total body irradiation alone: a feasibility study

High-dose melphalan has been commonly used as conditioning for amyloidosis with considerable toxicity. We hypothesized that the novel conditioning regimen of 550 cGy total body irradiation (TBI) alone for autologous peripheral blood stem cell transplantation would have reduced organ toxicity and thus permit safer transplantation of primary amyloidosis patients, even those with poor risk disease. The comprehensive regimen included pretransplantation chemotherapy, single-dose TBI alone (550 cGy at 30 cGy/min) conditioning, and post-transplantation interferon-alpha maintenance. Thirteen patients were enrolled in this feasibility study. Patients with multiorgan involvement were included; 10 patients had poor or intermediate risk disease. Cardiac toxicity was significant. Treatment-related mortality through 100 days post-transplantation was 15% and was caused by cardiac mortality. One patient died from arrhythmia after receiving TBI; 2 patients had grade IV cardiac toxicity (with subsequent complete recovery). One patient died 1 month after mobilization from progressive cardiomyopathy and never received conditioning. However, noncardiac organ toxicity was mild. No patient required parenteral nutrition support; no patient developed mucositis; and no patient experienced gastrointestinal bleeding following transplantation. The complete hematologic remission rate was 45%, with pretransplantation chemotherapy being the most active part of the regimen. Survival estimates from enrollment to 1 and 2 years post-transplantation were 66% and 47%, respectively. Causes of death were disease progression (6), myelodysplasia (1), arrhythmia following TBI (1), and congestive heart failure after mobilization (1). In this cohort of primary amyloidosis patients, the transplantation regimen of 550 cGy TBI was feasible and associated with modest treatment-related mortality. Efficacy with TBI conditioning may be reduced compared with high-dose melphalan, but this should be explored in a future trial with a larger cohort of patients.

West Nile Virus encephalopathy in an allogeneic stem cell transplant recipient: use of quantitative PCR for diagnosis and assessment of viral clearance

West Nile Virus encephalopathy in an allogeneic stem cell transplant recipient: use of quantitative PCR for diagnosis and assessment of viral clearance

Pilot study of 13cis-retinoic acid + dexamethasone + alpha interferon as maintenance therapy following high-dose chemotherapy and autologous stem cell transplant for multiple myeloma

Summary:Interleukin 6 (IL-6) is a major growth factor for myeloma cells and retinoids have been shown to inhibit expression of the interleukin 6 receptor (IL-6R). We performed a pilot study to assess the efficacy and tolerability of 13cis retinoic acid (13cRA) and dexamethasone (Dex), when added to interferon α (IFNα) as maintenance therapy post autologous stem cell transplantation. Between 90 and 120 days post stem cell transplantation, 33 patients were started on 13cRA 1u2009mg/kg p.o. daily for 14 days and Dex 40u2009mg p.o daily for 5 days every month. 13cRA was dose escalated by 0.5u2009mg/kg/month to 2u2009mg/kg. Seventeen patients had a persistent paraprotein post transplant. Overall, a response to therapy was observed in 11/17 (64%), with a complete response in 4/17 (23.5%) and a partial response (⩾50% paraprotein decline) in 7/17 (41%). With a median follow-up of 34.8 months, 22/33 (66%) demonstrated disease progression and 11/33 (33%) died. The median progression-free survival from diagnosis was 34.7 months. Although a decline in paraprotein was frequently observed on triple therapy, many patients discontinued therapy due to the side-effects of the IFNα. Future trials should be designed using 13cRA and Dex alone.