Transcutaneous ultrasound-mediated gene delivery into canine livers achieves therapeutic levels of factor VIII expression.

A safe, effective, and inclusive gene therapy will significantly benefit a large population of patients with hemophilia. We used a minimally invasive transcutaneous ultrasound-mediated gene delivery (UMGD) strategy combined with microbubbles (MBs) to enhance gene transfer into 4 canine livers. A mixture of high-expressing, liver-specific human factor VIII (hFVIII) plasmid and MBs was injected into the hepatic vein via balloon catheter under fluoroscopy guidance with simultaneous transcutaneous UMGD treatment targeting a specific liver lobe. Therapeutic levels of hFVIII expression were achieved in all 4 dogs, and hFVIII levels were maintained at a detectable level in 3 dogs throughout the 60-day experimental period. Plasmid copy numbers correlated with hFVIII antigen levels, and plasmid-derived messenger RNA (mRNA) was detected in treated livers. Liver transaminase levels and histology analysis indicated minimal liver damage and a rapid recovery after treatment. These results indicate that liver-targeted transcutaneous UMGD is promising as a clinically feasible therapy for hemophilia A and other diseases.

Long-Term Follow-Up of 90Y-Ibritumomab Tiuxetan, Fludarabine, and Total Body Irradiation-Based Nonmyeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B Cell Lymphoma.

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) can provide prolonged remissions in patients with advanced B cell lymphoma (B-NHL) via the graft-versus-lymphoma effect, although inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy can safely induce responses in B-NHL with minimal nonhematologic toxicity. Initial results of 90Y-ibritumomab tiuxetan-based allografting demonstrated early safety and disease control in nonremission patients but with short follow-up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions. Eleven of 40 patients were alive at a median follow-up of 9 years (range, 5.3 to 10.2). Fourteen (35%) deaths were due to disease progression and 14 (35%) deaths to complications from HCT. One patient died of a Merkel cell carcinoma. The 5-year overall and progression-free survival for patients with indolent B-NHL was 40% and 27.5%, respectively. None of the patients with diffuse large B cell lymphoma was a long-term disease-free survivor regardless of early remission status. 90Y-ibritumomab tiuxetan-based allografting represents a viable option in patients with indolent histologies. Improved strategies are needed for aggressive B-NHL. The original trial was registered at www.clinicaltrials.gov as NCT00119392.

Evaluation of allogeneic transplantation in first or later minimal residual disease - negative remission following adult-inspired therapy for acute lymphoblastic leukemia.

Comparisons without hematopoietic cell transplantation (HCT) to myeloablative (MAC) or reduced-intensity HCT (RIC) for adults with acute lymphoblastic leukemia (ALL) in first minimal-residual-disease negative remission (MRD(Neg) CR1) are limited. Further, the importance of MRD(Neg) following salvage therapy (MRD(Neg) CR2+) is unknown. We evaluated 89 patients in MRD(Neg) CR1 after adult-inspired treatment: 33 received MAC (12 Philadelphia chromosome [Ph]+), 17 received RIC (13 Ph+), and 39 Deferred HCT (3 Ph+). Three-year overall survival (OS) estimates for MAC, RIC, and Deferred HCT were 71%, 69%, and 68%, while 3-year event-free survival (EFS) estimates were 65%, 54%, and 28%, respectively. Further, HCT in MRD(Neg) CR1 performed similarly to MRD(Neg) CR2+: 3-year OS estimates were 70% and 69%, and 3-year EFS estimates were 62% and 62%, respectively. In conclusion, adults with ALL in MRD(Neg) CR1 following adult-inspired therapy had similar OS with or without HCT, and HCT in MRD(Neg) CR2 + can yield long-term survival.

Long-term outcomes of patients with persistent indolent B cell malignancies undergoing nonmyeloablative allogeneic transplantation.

Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/µL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT.

Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation.

PURPOSE: Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown. PATIENTS AND METHODS: Data from 3,033 consecutive recipients of HLA-matched grafts from five institutions contributed to this analysis. Patients were randomly divided into a training set to develop weights for age intervals and a validation set to assess the performance of prognostic models. RESULTS: In the training set, patients age 20 to 39 years, 40 to 49 years, 50 to 59 years, and ≥ 60 years had hazard ratios for nonrelapse mortality (NRM) of 1.21 (P = .29), 1.48 (P = .04), 1.75 (P = .004), and 1.84 (P = .005), respectively, compared with those age younger than 20 years. Consequently, age ≥ 40 years was assigned a weight of 1 to be added to the HCT-CI to constitute a composite comorbidity/age index. In the validation set, the composite comorbidity/age score had statistically significantly higher c-statistic estimates for prediction of NRM (0.664 v 0.556; P < .001) and survival (0.682 v 0.560; P < .001) compared with age, respectively. Patients with comorbidity/age scores of 0 to 2 had comparable mortality risks regardless of conditioning regimens. Patients with scores of 3 to 4 and ≥ 5 had statistically significant higher mortality risks after high-dose versus nonmyeloablative regimens. CONCLUSION: Age is a poor prognostic factor. The proposed composite measure allows integration of both comorbidities and age into clinical decision making and comparative-effectiveness research of HCT.

90Y-ibritumomab tiuxetan therapy in allogeneic transplantation in B-cell lymphoma with extensive marrow involvement and chronic lymphocytic leukemia: utility of pretransplantation biodistribution.

BACKGROUND: Biodistribution data to date using In-ibritumomab tiuxetan have been initially obtained in patients with less than 25% lymphomatous bone marrow involvement and adequate hematopoietic synthetic function. In this article we present the results of an analysis of the biodistribution data obtained from a cohort of patients with extensive bone marrow involvement, baseline cytopenias, and chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: Thirty-nine patients with a diagnosis of B-cell lymphoma or CLL expressing the CD20 antigen, who had failed at least one prior regimen, and had evidence of persistent disease were included in this analysis; however, only 38 of them completed the treatment. Semiquantitative analysis of the biodistribution was performed using regions of interest over the liver, lungs, kidneys, spleen, and sacrum. The observed interpatient variability including higher liver uptake in four patients is discussed. RESULTS: No severe solid organ toxicity was observed at the maximum administered activity of 1184 MBq (32 mCi) Y-ibritumomab tiuxetan. After accounting for differences in marrow involvement, patients with CLL exhibit comparable biodistributions to those with B-NHL. We found that the estimated sacral marrow uptake on 48 h images in patients with bone marrow involvement may be an indicator of bone marrow involvement. There was no correlation between tumor visualization and response to treatment. CONCLUSION: These data suggest that the imaging step is not critical when the administered activity is below 1184 MBq (32 mCi). However, our analysis confirms that the semiquantitative imaging data can be used to identify patients at risk for liver toxicity when higher doses of Y-ibritumomab tiuxetan are used. Patients with CLL can have excellent targeting of disease by In-ibritumomab tiuxetan, indicating potential efficacy in this patient population.

Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality.

Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of ≥3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials.

Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease.

We evaluated short-term response endpoints for acute graft-versus-host disease treatment trials. We postulated that response endpoints should correlate with reduced symptom burden and decreased subsequent treatment failure, defined as non-relapse mortality, recurrent malignancy, or additional systemic treatment. The cohort included 303 consecutive patients who received initial systemic steroid treatment for acute graft-versus-host disease. Response was evaluated at day 28 after initial treatment, which in all cases preceded the onset of chronic graft-versus-host disease. At day 28, 36% of patients had a complete response, 26% had a very good partial response, 10% had another degree of partial response (other partial response) and 28% had no response. As expected, the symptom burden was lower in patients with very good partial response compared to those with other partial response. The frequencies of subsequent treatment failure were similar in patients with complete and very good partial responses, but lower than in patients with other partial response or no response at day 28. The frequency of second-line treatment was lower in patients with very good partial response than in those with other partial response. Risk factors associated with a lower probability of complete or very good partial response at day 28 were unrelated or human leukocyte antigen-mismatched related donor grafts and liver or gastrointestinal involvement at onset of initial treatment. Taken together, these results suggest that endpoints in acute graft-versus-host disease treatment trials should distinguish between very good partial response and other partial response. Our results support the use of complete or very good partial response at day 28 as an appropriate short-term primary endpoint.

Ultrasound-targeted microbubble destruction-mediated gene delivery into canine livers.

Ultrasound (US) was applied to a targeted canine liver lobe simultaneously with injection of plasmid DNA (pDNA)/microbubble (MB) complexes into a portal vein (PV) segmental branch and occlusion of the inferior vena cava (IVC) to facilitate DNA uptake. By using a 1.1 MHz, 13 mm diameter transducer, a fivefold increase in luciferase activity was obtained at 3.3 MPa peak negative pressure (PNP) in the treated lobe. For more effective treatment of large tissue volumes in canines, a planar unfocused transducer with a large effective beam diameter (52 mm) was specifically constructed. Its apodized dual element configuration greatly reduced the near-field transaxial pressure variations, resulting in a remarkably uniform field of US exposure for the treated tissues. Together with a 15 kW capacity US amplifier, a 692-fold increase of gene expression was achieved at 2.7 MPa. Transaminase and histology analysis indicated minimal tissue damage. These experiments represent an important developmental step toward US-mediated gene delivery in large animals and clinics.

Prevention of graft-vs.-host disease.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for many malignant and non-malignant hematologic disorders. However, graft-vs.-host disease (GVHD) remains a major complication of allogeneic HCT and limits the success of this approach. AREAS COVERED: This paper reviews recent developments in the prevention of acute and chronic GVHD. In the setting of acute GVHD prevention, recent trials of T-cell depletion using Fresenius-ATG are reviewed, as well as studies testing total lymphoid irradiation, mesenchymal stromal cells, rituximab, statins, sirolimus and other investigational agents. In the setting of chronic GVHD, results with Fresenius-ATG are reviewed, as well as B-cell depletion with rituximab, and the potential role of the B-cell regulatory cytokine BAFF in chronic GVHD is also discussed. Finally, the emerging role of resident skin and gut bacterial flora-the so-called microbiome-in the pathogenesis of GVHD is covered. EXPERT OPINION: Current methods of acute GVHD prevention are highly successful, and a number of investigational approaches promise to further reduce the risk of this complication. By contrast, chronic GVHD is more poorly understood and more difficult to prevent. Future studies are required to delineate the roles of these approaches and to abrogate GVHD without sacrificing the beneficial immunologic graft-vs.-tumor effect.

Decreased serum albumin as a biomarker for severe acute graft-versus-host disease after reduced-intensity allogeneic hematopoietic cell transplantation.

Biomarkers capable of predicting the onset and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) would enable preemptive and risk-stratified therapy. Severe aGVHD leads to gastrointestinal protein loss, resulting in hypoalbuminemia. We hypothesized that decreases in serum albumin at onset of aGVHD would predict the risk of progression to severe aGVHD. We identified 401 patients who developed aGVHD grades II-IV after reduced-intensity allogeneic HCT and reviewed all available serum albumin values from 30 days before HCT to 45 days after initiation of treatment for aGVHD. A ≥0.5 g/dL decrease in serum albumin concentration from pretransplantation baseline to the onset of treatment for aGVHD predicted the subsequent development of grade III/IV aGVHD (versus grade II aGVHD) with a sensitivity of 69% and a specificity of 73%. Overall mortality at 6 months after initiation of aGVHD treatment was 36% versus 17% for patients with and without ≥0.5 g/dL decreases in serum albumin, respectively (P = .0009). We conclude that change in serum albumin concentration from baseline to initiation of aGVHD treatment is an inexpensive, readily available, and predictive biomarker of GVHD severity and mortality after reduced-intensity allogeneic HCT.

Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation.

This study was conducted to elucidate the influence of immunosuppressive treatment (IST) and GVHD on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). The study cohort included 2656 patients who received allogeneic HCT after high-intensity conditioning regimens for treatment of hematologic malignancies. Rates and hazard ratios of relapse and mortality were analyzed according to GVHD and IST as time-varying covariates. Adjusted Cox analyses showed that acute and chronic GVHD were both associated with statistically similar reductions in risk of relapse beyond 18 months after HCT but not during the first 18 months. In patients with GVHD, resolution of GVHD followed by withdrawal of IST was not associated with a subsequent increase in risk of relapse. In patients without GVHD, withdrawal of IST was associated with a reduced risk of relapse during the first 18 months, but the risk of subsequent relapse remained considerably higher than in patients with GVHD. In summary, the association of GVHD with risk of relapse changes over time after HCT. In patients without GVHD, early withdrawal of IST might help to prevent relapse during the first 18 months, but other interventions would be needed to prevent relapse at later time points.

Late effects among pediatric patients followed for nearly 4 decades after transplantation for severe aplastic anemia.

Aplastic anemia (AA), a potentially fatal disease, may be cured with marrow transplantation. Survival in pediatric patients has been excellent early after transplantation, but only limited data are available regarding late effects. This study evaluates late effects among 152 patients followed 1-38 years (median, 21.8 years). Transplantation-preparative regimes were mostly cyclophosphamide with or without antithymocyte globulin. Survival at 30 years for the acquired AA patients is 82%, and for the Fanconi anemia patients it is 58% (P = .01). Multivariate analysis demonstrated that chronic GVHD (P = .02) and Fanconi anemia (P = .03) negatively impacted survival. Two Fanconi patients and 18 acquired AA patients developed a malignancy that was fatal for 4. There was an increased incidence of thyroid function test abnormalities among those who received total body irradiation. Cyclophosphamide recipients demonstrated normal growth, basically normal development, and pregnancies with mostly normal offspring. Quality-of-life studies in adult survivors of this pediatric transplantation cohort indicated that patients were comparable with control patients except for difficulty with health and life insurance. These data indicate that the majority of long-term survivors after transplantation for AA during childhood can have a normal productive life.

Histology and time to progression predict survival for lymphoma recurring after reduced-intensity conditioning and allogeneic hematopoietic cell transplantation.

Reduced-intensity conditioning (RIC) before allogeneic hematopoietic cell transplantation (HCT) is increasingly used as a potentially curative option for patients with advanced lymphoma; however, relapse remains a major challenge. Unfortunately, little data are available on outcomes, predictors of survival, and results of specific management strategies in these patients. In the present study, a total of 101 consecutive relapses occurred and were evaluated in 280 patients with lymphoma who underwent RIC HCT. Diseases included aggressive non-Hodgkin lymphoma (NHL) (n = 42), indolent NHL (n = 33), and Hodgkin lymphoma (HL) (n = 26). Median time to relapse was 90 days (range, 3-1275 days), and graft-versus-host disease at relapse was present in 56 patients (55%). Interventions after relapse included no therapy (n = 14), withdrawal of immunosuppression alone (n = 11), chemoradiotherapy (n = 60), and donor lymphocyte infusion/second HCT (n = 16). Overall survival (OS) was 33% (95% confidence interval [CI], 23%-44%) at 3 years after relapse and 23% (95% CI, 13%-34%) at 5 years after relapse. Both aggressive NHL (vs indolent disease; hazard ratio, 2.29; P = .008) and relapse within 1 month post-HCT (vs >6 months; hazard ratio, 3.17; P = .004) were associated with increased mortality. Estimated 3-year OS was 16% (95% CI, 5%-32%) after relapse for aggressive NHL, 40% (95% CI, 19%-61%) after relapse for indolent NHL, and 47% (95% CI, 29%-64%) after relapse for HL. The 1-year survival was 24% for patients relapsing within 1 month post-HCT, compared with 52% for those relapsing at 1-3 months, 74% for those relapsing at 3-6 months, and 77% for those relapsing at more than 6 months. We conclude that despite relapse of lymphoma after RIC HCT, some patients may experience prolonged survival, with better postrelapse outcomes occurring in patients with indolent NHL, HL, or late relapse.

9°Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma.

Nonmyeloablative allogeneic transplantation (NMAT) infrequently cures active chemoresistant, bulky, or aggressive B-cell lymphoma (B-cell non-Hodgkin lymphoma [B-NHL]). We hypothesized that 9°Y-ibritumomab tiuxetan-based NMAT would facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft. Forty high-risk B-NHL patients with persistent disease received 0.4 mCi/kg (maximum, 32 mCi/kg) 9°Y-ibritumomab tiuxetan, fludarabine, and 2 Gy total body irradiation and matched-related (15) or unrelated (25) transplantation. Baseline features included: median age, 58 years (range, 29-69 years); median prior regimens, 6 (range, 3-12); chemosensitive disease, 6 (15%); bulk > 5 cm, 17 (range, 5.2-18.6 cm, 43%); diffuse large B-cell lymphoma, 14 (35%); and comorbidity score > zero, 34 (85%). Early responses were observed in 24 (60%, 14 complete remission/complete remission unconfirmed, 10 partial response) patients, including 17 of 29 (59%) with chemotherapy-resistant disease and 10 (59%) with bulk > 5 cm. The estimated 30-month survival, progression-free survival, and nonrelapse mortality were 54.1%, 31.1%, and 15.9%, respectively. Early response, baseline platelet counts over 25 000/µL, indolent histology, and related donors were associated with improved survival. The addition of 9°Y-ibritumomab tiuxetan to NMAT is safe and yields early responses and prolonged disease control in some of the highest-risk B-NHL patients. This trial was registered at www.clinicaltrials.gov as #NCT00119392.

A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation with mobilized blood cells.

This retrospective study was performed to compare results with tacrolimus versus cyclosporine in combination with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation (HCT) with granulocyte colony-stimulating factor-mobilized blood cells. The cohort included 456 consecutive patients who received first allogeneic T cell-replete HCT with mobilized blood cells from related or unrelated donors after high-intensity conditioning for treatment of hematologic malignancies. Study endpoints included grades II-IV acute graft-versus-host disease (aGVHD), grades III-IV aGVHD, chronic GVHD (cGVHD), end of treatment for cGVHD, overall mortality, disease-free survival (DFS), recurrent malignancy, and nonrelapse mortality (NRM). Adjusted multivariate Cox regression analysis showed no statistically significant differences between tacrolimus and cyclosporine for any of the endpoints tested. Although the size of the cohort is not sufficient to exclude clinically meaningful differences in outcomes, these results support the continued use of cyclosporine at centers that have not adopted tacrolimus as the standard of care after HCT with mobilized blood cells after high-intensity conditioning regimens. A larger registry study should be performed to provide more definitive information comparing outcomes with the 2 calcineurin inhibitors.

Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria.

Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

A phase I/II study of chemotherapy followed by donor lymphocyte infusion plus interleukin-2 for relapsed acute leukemia after allogeneic hematopoietic cell transplantation.

The efficacy of donor lymphocyte infusion (DLI) for treatment of relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1 × 10(8) CD3/kg for patients with related donors, and 0.1 × 10(8) CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0 × 10(6) IU/m(2)/day representing levels I [n = 7], Ia [n = 9], and II [n = 1]) for 5 days followed by maintenance (1.0 × 10(6) IU/m(2)/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2-related toxicities developed in 1 patient at level I, 2 at level Ia, and 1 at level II. Grades III-IV acute graft-versus-host disease (aGVHD) developed in 5 patients, and extensive chronic GVHD (cGVHD) developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0 × 10(6) IU/m(2)/day. IL-2 administration after DLI might increase the incidence of cGVHD.

Role of comorbidities in optimizing decision-making for allogeneic hematopoietic cell transplantation.

Allogeneic conventional hematopoietic cell transplantation (HCT) following high-dose, myeloablative conditioning regimens has been used since the 1970's as potentially curative treatment for patients with malignant, hematological disorders. The toxicities of conditioning regimens have limited conventional HCT to relatively young patients in otherwise good medical condition. With the development of less toxic nonmyeloablative regimens and improvements in supportive care, increasing numbers of older and medically infirm patients have been treated by allogeneic HCT. Until recently, there has been almost no effort to evaluate the prevalence of comorbidities among HCT recipients and their impact on outcomes. We first evaluated the Charlson Comorbidity Index (CCI) developed for patients with solid malignancies, for this purpose. While useful, it lacked sensitivity and specificity for the HCT setting. We next introduced the HCT-specific comorbidity index (HCT-CI) which was based on objective laboratory data to better define comorbidities. Here, we describe this development and illustrate the usefulness of the HCT-CI in predicting HCT outcomes in patients with myeloid and lymphoid malignancies undergoing allogeneic transplantation.

Allogeneic hematopoietic cell transplantation: the state of the art.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. The field has evolved substantially over the past decade, with advances in patient and donor selection, stem cell sources, supportive care, prevention of complications and reduced-toxicity preparative regimens. As a result, the indications for HCT and the pool of eligible patients have expanded significantly. In this article, we provide an overview of the major aspects of allogeneic HCT, and focus specifically on areas of active research and on novel approaches to challenges in the field. Specifically, we will discuss approaches to reduce the toxicity of the preparative regimen, with the goal of increasing the safety and applicability of HCT. The availability of suitable donors may be an obstacle to wider application of HCT. We review three major approaches to broadening the donor pool: the use of HLA-mismatched unrelated donors, umbilical cord blood and HLA-haploidentical family donors. Graft-versus-host disease remains a major cause of morbidity and mortality after HCT. We review recent advances in the understanding of this phenomenon, and novel prophylactic and therapeutic approaches that hold the promise of further improving the safety of the procedure. We conclude with a speculative outline of the next 5 years of research in the field of HCT.