"No wash" albumin-dextran dilution for double-unit cord blood transplantation is safe with high rates of sustained donor engraftment.

Washing cord blood (CB) grafts involves product manipulation and may result in cell loss. We investigated double-unit CB transplantation (CBT) using red blood cell (RBC)-depleted units diluted with albumin-dextran in patients with hematologic malignancies. One-hundred thirty-six patients (median age, 43 years; range, 4 to 71; median weight, 69 kilograms (kg); range, 24 to 111) underwent transplantation with a 4/6 to 6/6 HLA-matched graft. Patients ≤ 20 kg were excluded, as they only received washed units. Units were diluted a median of 8 fold to a median volume of 200 mL/unit. The median infused total nucleated cell doses were 2.7 (larger unit) and 2.0 (smaller unit) x 10(7)/kg, respectively, and the median post-thaw recovery was 86%. Units were infused consecutively (median, 45 minutes/unit). While only 17 patients (13%) had no infusion reactions, reactions in the remaining 119 patients were almost exclusively mild-moderate (by CTCAE v4 criteria 12 grade 1, 43 grade 2, 63 grade 3) with only 1 patient (< 1%) having a severe (grade 4) reaction. Moreover, most were easily treated. Grade 2 to 3 hypertension was the most common in 101 (74%) patients. The cumulative incidence of sustained donor-derived neutrophil engraftment was high: 95% in myeloablative and 94% in nonmyeloablative CBT recipients. With appropriate supportive care, double-unit CBT with RBC-depleted grafts infused after albumin-dextran dilution is safe with high rates of engraftment in patients > 20 kg.

Frequent human herpesvirus-6 viremia but low incidence of encephalitis in double-unit cord blood recipients transplanted without antithymocyte globulin.

Cord blood transplantation (CBT) is a known risk factor for human herpesvirus-6 (HHV-6) infection. We analyzed the nature of HHV-6 infections in 125 double-unit CBT recipients (median age, 42 years) transplanted for hematologic malignancies with calcineurin inhibitor/mycophenolate mofetil prophylaxis and no antithymocyte globulin. One hundred seventeen patients (94%) reactivated HHV-6 by quantitative plasma PCR (median peak, 7600 copies/mL; range, 100 to 160,000) at a median of 20 days (range, 10 to 59) after transplantation. HHV-6 encephalitis occurred in 2 patients (1.6%), of whom 1 died and 1 recovered with therapy. No association was found between high-level HHV-6 viremia (≥10,000 or ≥25,000 copies/mL) and age, diagnosis, conditioning intensity, or dominant unit characteristics or between high-level viremia and transplant outcomes (engraftment, cytomegalovirus reactivation, day 100 grades II to IV acute graft-versus-host disease, day 100 transplant-related mortality, or 1-year disease-free survival). HHV-6 therapy delayed the onset of cytomegalovirus reactivation. Interestingly, HHV-6 resolution was observed in untreated patients, and resolution of viremia correlated with absolute lymphocyte count recovery. We observed a low incidence of encephalitis and no association with CBT outcomes. Our data suggest therapy in uncomplicated viremia may not be warranted. However, further investigation of the risk-to-benefit of HHV-6 viremia treatment and standardization of PCR testing is required.

A novel reduced-intensity conditioning regimen induces a high incidence of sustained donor-derived neutrophil and platelet engraftment after double-unit cord blood transplantation.

A preparative regimen of reduced intensity that can reliably engraft cord blood (CB) and can be used as an alternative to either high-dose myeloablative or nonmyeloablative conditioning is needed. We evaluated double-unit CB transplantation in 30 patients (median age, 56 years; range, 18 to 69) with acute leukemia or myelodysplasia using a regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m(2), thiotepa 10 mg/kg, and 400 cGy total body irradiation with cyclosporine-A/mycophenolate mofetil immunosuppression. Ninety-seven percent of patients engrafted at a median of 26 days (range, 13 to 43), and 93% of patients had recovered platelets by day 180. Grades II to IV acute graft-versus-host disease (GVHD) incidence was 67% at day 180, and chronic GVHD was 10% at 1 year. Transplant-related mortality was 20% at day 180, and relapse was 11% at 2 years. Overall, 2-year disease-free survival (DFS) was 60% at 2 years. A hierarchy in DFS was seen according to the Sorror comorbidity score: 11 patients (median age, 55 years) with a score of 1 had a 2-year DFS of 82% compared with 62% in 9 patients (median age, 51 years) with a score of 2 to 3 and 40% in 11 patients (median age, 58 years) with a score of 4 to 5 (P = .13). This reduced-intensity regimen combined with double-unit CB transplantation reliably facilitates sustained donor engraftment without antithymocyte globulin. Although other approaches are needed in patients with high comorbidity scores, this regimen is highly effective in patients ≥50 years old who are otherwise reasonably fit. It also represents a promising alternative to high-dose conditioning in younger patients.

Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts.

The influence of cell dose and human leukocyte antigen (HLA) match on double-unit cord blood (CB) engraftment is not established. Therefore, we analyzed the impact of cell dose and high-resolution HLA match on neutrophil engraftment in 84 double-unit CB transplant recipients. The 94% sustained engraftment rate was accounted for by 1 unit in nearly all patients. Higher CD3(+) cell doses (P = .04) and percentage of CD34(+) cell viability (P = .008) were associated with unit dominance. After myeloablative conditioning, higher dominant unit total nucleated cell (TNC), CD34(+) cell, and colony-forming unit doses were associated with higher sustained engraftment and faster neutrophil recovery (P = .07, P = .0008, and P < .0001, respectively). Total infused TNC (P = .0007) and CD3(+) cell doses (P = .001) also significantly influenced engraftment. At high-resolution extensive donor-recipient HLA disparity was frequent, but had no influence on engraftment (P = .66), or unit dominance (P = .13). Although the unit-unit HLA match also did not affect sustained engraftment (P = 1.0), recipients of units closely (7-10 to 10-10) HLA-matched to each other were more likely to demonstrate initial engraftment of both units (P < .0001). Our findings have important implications for unit selection and provide further insight into double-unit biology.

The use of back-up units to enhance the safety of unrelated donor cord blood transplantation.

The inability to obtain additional stem cells is a disadvantage of unrelated donor cord blood transplantation (CBT). Moreover, in the event of problems with unit shipment, compromised unit quality, thaw mishaps, or graft failure, the time to secure a back-up graft could be unacceptable. Emergent shipment of 1 to 2 back-up units that have been previously typed and reserved could overcome this limitation. However, the advantages of this approach are not established. Therefore, we present our use of back-up units over a 5.5-year period. Six of 121 CBT recipients (5%) required back-up unit infusion. Indications included shipment mishaps (n = 2), poor unit viability (n = 2), significant infusion reaction (n = 1), and graft failure (n = 1). Lack of back-up units would have caused transplantation delay or infusion of inferior-quality units. Five of the 6 patients achieved sustained donor engraftment. We demonstrate that back-up units are emergently required in a significant minority of patients, supporting the incorporation of at least 1 back-up unit in cord blood (CB) selection algorithms to enhance CBT safety.

Serious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin.

Factors contributing to infection risk after cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. In the present study, we investigated the potential of double-unit CBT without ATG to reduce the risk of infection and evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients underwent CBT for hematologic malignancies; of these, 52 patients received myeloablative conditioning, and 20 received nonmyeloablative conditioning. The peak incidences of bacterial infections (32%), fungal infections (14%), and bacterial/fungal pneumonias (10%) occurred in the first 30 days posttransplantation. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days posttransplantation, affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections occurring before day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections occurring after day 120 (n = 5), along with all cases of Epstein-Barr virus viremia (n = 5) and adenoviral enteritis (n = 2), occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death, and 3 contributed to death. Patients exhibited steady immune recovery, achieving a median CD3(+)4(+) T cell count >200 cells/µL by day 120 post-CBT, and no infection-related deaths occurred after day 120. Our results suggest that double-unit CBT without ATG is associated with prompt T cell recovery, and, unlike in CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD, and serious infections remain a challenge, especially in the setting of GVHD. New strategies are needed to further reduce infectious complications after CBT; these will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T cell depletion associated with ATG therapy.

Reduced late mortality risk contributes to similar survival after double-unit cord blood transplantation compared with related and unrelated donor hematopoietic stem cell transplantation.

Cord blood transplantation (CB-T) is increasingly used as a treatment alternative for hematologic malignancies. However, how CB-T compares to related (RD-T) and unrelated donor transplantation (URD-T) is not established. We compared survival of 75 double-unit CB-T, 108 RD-T, and 184 URD-T recipients who received transplants over the same period for the treatment of hematologic malignancies. Patients had similar ages and disease risk, and a similar percentage had acute leukemia. The incidence of day 180 transplant-related mortality (TRM) of 21% (95% confidence interval [CI]: 12-31) after CB-T was higher than that of RD-T recipients. However, this was compensated for by a low risk of TRM after day 180, and a relatively low incidence of relapse. Hence, the 2-year progression-free survival (PFS) of 55% (95% CI: 45-68) after CB-T was similar to that after RD-T or URD-T (P = .573). In multivariate analysis, donor source had no influence on PFS, with the only significant factors being recipient age and disease risk. In a subanalysis of 201 patients with acute leukemia, CB-T, RD-T, and URD-T recipients also had similar 2-year disease-free survival (P = .482). These data provide strong support for the further investigation of double-unit CB grafts as an alternative hematopoietic stem cell source.

Incidence, nature and mortality of cytomegalovirus infection after double-unit cord blood transplant.

Cord blood transplant (CBT) extends allograft access but is associated with a significant risk for cytomegalovirus (CMV) infection. We analyzed CMV infection in 157 CBT recipients transplanted for hematological malignancies. As compared with antigenemia testing, routine polymerase chain reaction (PCR) monitoring was associated with increased and earlier CMV infection detection (1-year incidence if seropositive 67% [median onset 41 days] vs. 100% at an earlier 33-day median [p < 0.001]) and decreased gastrointestinal disease. One-year CMV-related transplant-related mortality was 11% in CMV+ patients with 7/9 deaths associated with initial infection. Disease-free survival was lower in seropositive compared with seronegative patients (1-year: 55% vs. 73%, p = 0.02). However, in multivariate analysis adjusting for age, treatment failure risk in CMV+ patients was not significant (hazard ratio 1.52, p = 0.11). CMV infection is a major challenge in seropositive CBT recipients. While PCR surveillance permits early detection of viremia, new prophylaxis and therapeutic strategies are needed.

Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation.

Delayed T cell recovery and restricted T cell receptor (TCR) diversity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and cancer relapse. Technical challenges have limited faithful measurement of TCR diversity after allo-HSCT. Here we combined 5' rapid amplification of complementary DNA ends PCR with deep sequencing to quantify TCR diversity in 28 recipients of allo-HSCT using a single oligonucleotide pair. Analysis of duplicate blood samples confirmed that we accurately determined the frequency of individual TCRs. After 6 months, cord blood-graft recipients approximated the TCR diversity of healthy individuals, whereas recipients of T cell-depleted peripheral-blood stem cell grafts had 28-fold and 14-fold lower CD4(+) and CD8(+) T cell diversities, respectively. After 12 months, these deficiencies had improved for the CD4(+) but not the CD8(+) T cell compartment. Overall, this method provides unprecedented views of T cell repertoire recovery after allo-HSCT and may identify patients at high risk of infection or relapse.

The effect of age in the outcome and treatment of older women with ductal carcinoma in situ.

The effect of increasing age on outcomes and type of treatment given to older women with ductal carcinoma in situ (DCIS) was assessed. 646 women ≥60 years old (654 cases) receiving surgery for DCIS at Memorial Sloan-Kettering Cancer Center between 2000 and 2007 (8 bilateral) had wide local excision (WLE; 37%), WLE plus radiotherapy (WLE+RT; 41%), or mastectomy (22%). 45%, 38%, and 16% of patients 60-69 years, 70-79 years, and ≥80 years, respectively, received WLE+RT (P<0.001) and 25%, 20%, and 13%, received mastectomy, respectively (P<0.001). Age (P<0.001), grade (P<0.001), and necrosis (P<0.01) were highly associated with treatment. Four-year local recurrence was 3.6%. Overall local recurrence differed by treatment (mastectomy, 0%; WLE, 5%; WLE+RT, 4%; P<0.00001) but not age. It is possible to identify older women with DCIS in whom the risk of recurrence is acceptably low after WLE alone. WLE alone may be a viable treatment option for select older women with DCIS.

[¹8F]FDG-positron emission tomography coregistration with computed tomography scans for radiation treatment planning of lymphoma and hematologic malignancies.

PURPOSE: Positron emission-tomography (PET) using 2-[(18)F]fluoro-2-deoxyglucose (FDG-PET) increases sensitivity and specificity of disease detection in lymphoma and thus is standard in lymphoma management. This study examines the effects of coregistering FDG-PET and computed tomography (CT) (PET/CT) scans on treatment planning for lymphoma patients. METHODS AND MATERIALS: Twenty-nine patients (30 positive PET scans) underwent PET/CT treatment planning from July 2004 to February 2007 and were retrospectively studied. For each patient, gross tumor volume was blindly contoured on the CT-only and PET/CT studies by a radiation oncologist. Treatment plans were generated for both the CT-only and PET/CT planning target volumes (PTVs) for all patients. Normal tissue doses and PTV coverage were evaluated using dose--volume histograms for all sites. RESULTS: Thirty-two treatment sites were evaluated. Twenty-one patients had non-Hodgkin lymphoma, 5 patients had Hodgkin lymphoma, and 3 patients had plasma cell neoplasms. Previously undetected FDG-avid sites were identified in 3 patients during PET/CT simulation, resulting in one additional treatment field. Due to unexpected PET/CT simulation findings, 2 patients did not proceed with radiation treatment. The addition of PET changed the volume of 23 sites (72%). The PTV was increased in 15 sites (47%) by a median of 11% (range, 6-40%) and reduced in 8 sites (25%) by a median of 20% (range, 6%-75%). In six (19%) replanned sites, the CT-based treatment plan would not have adequately covered the PTV defined by PET/CT. CONCLUSIONS: Incorporation of FDG-PET into CT-based treatment planning for lymphoma patients resulted in considerable changes in management, volume definition, and normal tissue dosimetry for a significant number of patients.

Characteristics and outcomes of breast cancer in women with and without a history of radiation for Hodgkin's lymphoma: a multi-institutional, matched cohort study.

PURPOSE: To compare characteristics and outcomes of breast cancer in women with and without a history of radiation therapy (RT) for Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Women with breast cancer diagnosed from 1980 to 2006 after RT for HL were identified from eight North American hospitals and were matched three-to-one with patients with sporadic breast cancer by age, race, and year of breast cancer diagnosis. Information on patient, tumor and treatment characteristics, and clinical outcomes was abstracted from medical records. RESULTS: A total of 253 patients with breast cancer with a history of RT for HL were matched with 741 patients with sporadic breast cancer. Median time from HL to breast cancer diagnosis was 18 years. Median age at breast cancer diagnosis was 42 years. Breast cancer after RT for HL was more likely to be detected by screening, was more likely to be diagnosed at an earlier stage, and was more likely to be bilateral at diagnosis. HL survivors had an increased risk of metachronous contralateral breast cancer (adjusted hazard ratio [HR], 4.3; 95% CI, 1.7 to 11.0) and death as a result of any cause (adjusted HR, 1.9; 95% CI, 1.1 to 3.3). Breast cancer-specific mortality was also elevated, but this difference was not statistically significant (adjusted HR, 1.6; 95% CI, 0.7 to 3.4). CONCLUSION: In women with a history of RT for HL, breast cancer is diagnosed at an earlier stage, but these women are at greater risk for bilateral disease and are more likely to die as a result of causes other than breast cancer. Our findings support close follow-up for contralateral tumors in these patients and ongoing primary care to manage comorbid conditions.