Reduced Intensity Conditioning Umbilical Cord Blood Research Articles

Prophylactic Foscarnet for Human Herpesvirus 6: Effect on Hematopoietic Engraftment after Reduced-Intensity Conditioning Umbilical Cord Blood Transplantation

The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.

Sirolimus and Mycophenolate Mofetil as Calcineurin Inhibitor–Free Graft-versus-Host Disease Prophylaxis for Reduced-Intensity Conditioning Umbilical Cord Blood Transplantation

The use of calcineurin inhibitors (CNIs) to reduce the risk of graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) requires intensive post-transplantation toxicity monitoring. Sirolimus-based GVHD prophylaxis is associated with a favorable toxicity profile and requires less intensive monitoring. However, the efficacy of sirolimus-based regimen compared with CNI-based regimen has not been evaluated in the setting of reduced-intensity conditioning (RIC) double umbilical cord blood (UCB) HCT. We compared outcomes of patients receiving sirolimus/mycophenolate mofetil (MMF) (n = 37) or cyclosporine (CSA)/MMF (n = 123) in an ongoing phase II study of RIC UCB transplantation. In multiple regression analysis, sirolimus/MMF did not influence the risk of grades II to IV or grades III and IV acute GVHD. In addition, there was no association between type of GVHD prophylaxis and hematopoietic engraftment. Infection density analysis found a significantly lower risk of infections with sirolimus/MMF between days +46 and +180 after HCT compared with CSA/MMF (3.4 versus 6.3 per 1000 patient-days, P = .03); however, no difference was observed before day +45. Sirolimus/MMF use resulted in no thrombotic microangiopathy, fewer instances of elevated serum creatinine >2 mg/dL (14% versus 45%; P < .01), and similar rates of sinusoidal obstruction syndrome (2.7% versus 4%; P = .68), compared with CSA/MMF. Disease-free survival at 1 year was 51% for sirolimus/MMF and 41% for CSA/MMF (P = .41), and sirolimus/MMF use did not influence the risk of nonrelapse mortality or survival. In conclusion, sirolimus/MMF GVHD prophylaxis was better tolerated and resulted in similar rates of GVHD and survival as compared to CSA/MMF after RIC double UCB transplantation.

Charlson Comorbidity Index (CCI) and Hematopoietic Cell Transplantation Specific-Comorbidity Index (HCT-CI) Do Not Predict Transplant Related Mortality (TRM) and Post-Transplant Outcomes In Young Patients Undergoing Reduced Intensity Conditioning (RIC) Umbilical Cord Blood (UCB) Transplantation

TRM, drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition to the risks of HCT, existence of pre-transplant comorbidities can have significant impact on transplant outcomes. A comparison of CCI and the HCT-CI revealed that HCT-CI was prognostic and better at predicting TRM and overall survival (OS). However, the HCT-CI and CCI results have been inconsistent in predicting the TRM and OS in validation studies. In subgroup analyses of a large retrospective trial, HCT-CI did not predict TRM or OS for UCB recipients. Patient heterogeneity in age, disease, disease-risk, comorbidities, and conditioning regimens may have limited validation in these UCB recipients. The design of this research was to explore whether or not the HCT-CI and/or CCI can accurately predict post-transplant outcomes in young patients with high risk hematologic malignancies undergoing uniform RIC UCB transplantation. A retrospective chart review was performed on 52 consecutive young (age &lt; 55) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All patients had received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from the CIBMTR pre-TED form for each patient and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. Between 2005 and 2011, 52 patients age 19 – 54 (median 38) years, 30 males (58%) and 22 females (42%), underwent RIC UCB transplantation with the above regimen. Most patients had advanced stage or high risk hematologic malignancies; 28 patients had MDS/AML (54%), 8 patients had ALL (15%), while 16 patients had other hematologic malignancies. 39 patients had a PS = 0, while 13 had a PS = 1. Half of the patients were in CR &gt; 2, with the same number receiving more than 2 prior therapies. 8 patients had received a prior autologous HCT, 8 a prior allo-HCT, and one patient had failed a previous UCD transplantation. 11 patients did not achieve engraftment. Median time to neutrophil engraftment was 26 days (95% CI: 24 – 28 d) and median time to platelets engraftment was 38 days (95% CI: 31 – 45 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 12 / 52 patients (23%). Chronic GVHD was seen in likewise seen in 12 patients (23%). To date 16 patients (30%) have relapsed. OS was 42% and PS was 37% at one year. Median PFS and median OS were 5 months and 7 months, respectively (PFS 95% CI: 1 – 11 months, OS 95% CI: 1 – 13 months). Neither CCI, nor HCT-CI were significant predictors of OS and PFS, however the ECOG PS was significantly associated with an improved OS and PFS (Table).OSPFSN1 yr2 yrs4 yrsp1 yr2 yrs4 yrspECOG PS03946%36%21%0.02644%36%21%0.0311331%0015%00CCI≤ 23944%26%10%0.2238%26%10%0.2&gt; 21338%31%31%38%31%31%HCT-CI02236%31%5%0.3632%32%5%0.3211443%14%14%29%14%14%≥21643%31%31%44%31%31%TRM occurred in 18 patients (35%). Neither comorbidity indices, nor the performance status were correlated to TRM (p &gt; 0.05). For ECOG PS, OR 1.6 p = 0.49, CI 0.42 - 5.93; CCI OR = 2.4, p = 0.09, CI 0.86 - 6.59, HCT-CI OR = 0.6, p = 0.46, CI 0.19 - 2.08. In a previous presentation our group concluded that CCI performs better than HCT-CI in elderly patients undergoing UCB transplant. When tested in a population younger than 55 years old though, we were unable to validate the generally accepted prognostic indices. It is unclear whether this is due to a selection bias: it appears most of the patients were essentially health from a non-hematological stand-point, and as such the “classic” cardiac or pulmonary risk factors were underrepresented. The excess TRM is likely due to the severity of their underlying disease, and the majority were in CR ≥ 2 and had received multiple previous courses of antineoplastic chemotherapy. As umbilical cord transplants become more utilized, a new prognostic index needs to be developed, more fitting to the patients &lt; 55 years old. Disclosures: No relevant conflicts of interest to declare.

Charlson Comorbidity Index (CCI) Not Hematopoietic Cell Transplantation Specific-Comorbidity Index (HCT-CI) Successfully Predicts Transplant Related Mortality and Post-Transplant Outcomes in Elderly Patients Undergoing Reduced Intensity Conditioning (RIC) Umbilical Cord Blood (UCB) Transplantation

Abstract 3006▪FN2▪This icon denotes a clinically relevant abstractTransplant related mortality (TRM), drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition, pre-transplant comorbidities can have significant impact on the transplant outcomes of elderly patients (pts). Two comorbidity measurement tools, the CCI and the HCT-CI have been inconsistent in predicting TRM and overall survival (OS) after conventional HCT. The HCT-CI and CCI scores have correlated less well with TRM and OS in UCB transplantation. These results may have been limited by the heterogeneity of the UCB transplantation study population in age, disease, disease-risk, comorbidities, and conditioning regimens used. This study was performed to explore the accuracy of the HCT-CI and CCI in predicting post-transplant outcomes in elderly pts with high risk hematologic malignancies undergoing uniform RIC UCB transplantation.A retrospective chart review was performed on 35 consecutive elderly (age ≥ 55 years (yrs)) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All pts received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from each pt’s CIBMTR pre-TED form and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. HCT-CI and CCI scores were distributed in the following comorbidity risk groups 0, 1, > 1.Between 2002 and 2011, 35 pts underwent UCB transplantation with the above regimen. Median age was 65 yrs (range 55–71), 21 were male (60%) and 14 female (40%). Most pts had advanced stage or high risk hematologic malignancies; 28 had MDS/AML (80%) and 7 had other hematologic malignancies. All pts had a PS ≤ 2. Twenty-seven pts were in CR ≤ 2, with 31 pts having received ≤ 2 prior therapies. Eight pts had received prior transplants, including 2 pts with prior UCB transplantations and 6 pts with prior autografts. UCB cell dose was calculated on actual body weight (median 84 kg, range 56.1–135.1 kg). A total of 66 UCB grafts matched at a minimum 3/6 (3/6 = 4, 4/6 = 34, 5/6 = 22, 6/6 = 6) were infused. Pts received a range of 1 to 5 UCB units (1 unit = 12 pts, 2 units = 19 pts, 3 units = 2 pts, 5 units = 2 pts). VNTR/FISH analyses confirmed engraftment with median time of 21 days (d) (95% CI: 14–40 d) to achieve > 60% chimerism. Nine pts failed to achieve chimerism > 60%, and 3 had secondary engraftment failure. Median time to ANC > 500/μL for 3 consecutive values was 27 d (95% CI: 21–32 d) and median time to platelets > 20, 000/μL on the first day of 7 consecutive days without a platelet infusion was 40 d (95% CI: 35–71 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 3/35 pts (9%) and chronic GVHD was seen in 6/27 pts (22%). To date 31% (n = 11) of pts have relapsed. Pre-transplant cardiac comorbidities, A-fib/flutter and coronary artery disease, were the most common. Six pts had prior solid tumor malignancies, not active at the time of HCT, including breast (n=2), prostate (n=2), bladder (n=1), and kidney (n=1). After a median follow up of 13 months (range 1–70), 1 yr OS and progression free survival (PFS) were 61% and 55%, respectively. Median PFS and OS were both 16 months (mos) (PFS 95% CI: 8–70 mos, OS 95% CI: 9–70 mos). CCI but not PS or HCT-CI was a significant predictor of OS and PFS (Table and Figure).OS (%)PFS (%)FactorN1 yr2 yr4 yrp-value1 yr2 yr4 yrp-valuePS0175750330.885252350.811-218654534584538CCI01680582267593214100500.04100500.04>115333333333333HCT-CI0125443145644151108069690.296969690.25>113533535453636 [Display omitted] TRM occurred in 8 pts (23%). CCI was associated with TRM (p=0.05): pts with CCI ≥ 2 had a 40% (6/15) TRM vs 10% (2/20) with CCI 0–1. PS (p=0.69) and HCT-CI (p=0.47) did not correlate to TRM.In conclusion, elderly pts undergoing RIC UCB transplantation for high risk hematologic malignancies, the CCI was a statistically significant predictor of TRM, PFS, and OS. This index and not HCT-CI or PS identified elderly pts undergoing RIC UCB transplantation at higher risk of TRM and poor post-transplant outcomes. Larger validation studies of the predictive capacity of these comorbidity indexes need to be performed in the multi-institutional setting. Disclosures:Cooke:Amgen:.

Reduced intensity allogeneic haematopoietic cell transplantation for chronic lymphocytic leukaemia: related donor and umbilical cord allografting

Reduced intensity allogeneic haematopoietic cell transplantation for chronic lymphocytic leukaemia: related donor and umbilical cord allografting

Reduced-intensity conditioning and umbilical cord blood transplantation in adults

Reduced-intensity conditioning (RIC) preparative regimens are now widely used in umbilical cord blood (UCB) transplantation. Developed to reduce the rate of transplant-related morbidity and mortality as in adult stem cell donor transplantation, they are becoming more widely accepted. Results from RIC UCB series show a shortened time to engraftment, ranging from 12 to 24 days, with rates of TRM that generally do not exceed the rates seen with myeloablative UCB transplantation. There does not seem to be a convincing trend toward an increase in the rate of malignant relapse after RIC UCB transplantation, despite the lower intensity of the conditioning regimen. In this review, the results from several RIC UCB series are reviewed, comparisons with myeloablative UCB experiences are made and hypotheses regarding the engraftment potential of UCB after RIC regimens are discussed. In addition, a strategy for the optimal use of RIC regimens and UCB transplantation is presented.

Encouraging Results of Reduced Intensity Conditioning (RIC) Umbilical Cord Blood (UCB) Transplantation for the Treatment of Advanced Lymphoid Malignancies.

We have reported on the safety and efficacy of RIC UCB transplantation for patients with advanced hematologic diseases. Here we report on 65 patients, median age of 46 yrs (range, 6–68), who underwent RIC UCB transplantation for the treatment of advanced lymphoid malignancies between October 2001 and December 2006. Patients received either one (n=9) or two (n=56) UCB unit grafts matched at 4–6/6 HLA loci. Forty were male and 27 CMV seropositive. Diagnoses were follicular lymphoma (FL, n=11), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL, n=9), mantle cell lymphoma (MCL, n=8), large cell lymphoma (LCL, n=14), and Hodgkin's lymphoma (HL, n=23). Conditioning regimen was cyclophosphamide 50 mg/kg (Day-6), fludarabine 40mg/m2 for 5 days (Day-6 to -2), and single fraction total body irradiation of 200cGy (Day -1), plus cyclosporine A and mycophenolate mofetil (to day +30). At transplantation 53 patients (81%) had chemotherapy sensitive disease, 5 (8%) had bulky adenopathy (≥ 5 cm), 27 (42%) had prior radiation therapy, 26 (40%) had prior autologous transplant, 22 (34%) had an elevated LDH, and 10 (15%) had marrow involvement. The median number of prior treatment courses was 4 (range, 1–9). The median follow-up for survivors is 23 mos. (range, 4–62). Patients were analyzed as indolent (IND=FL+ SLL/CLL), aggressive (AGR=LCL+MCL), and HL. Incidence of acute GVHD grades II–IV was 57% (95%CI, 43–70); grades III–IV 25% (95%CI, 14–35); chronic GVHD 23% (95%CI, 11–35), with similar incidence of acute and chronic GVHD between lymphoma subgroups. The 3-year nonrelapse mortality (NRM) was 15% (95%CI, 5–26) with no significant difference among lymphoma subgroups (IND 5% vs. AGR 24% vs. HL 13%, p=.41). Thirty-five patients (53%) had relapsed or progressive disease with a 3-year progression-free survival (PFS) of 31% (95%CI, 19–44); IND 44% (95%CI, 22–66); AGR 20% (95%CI, 2–39); HL 35% (95%CI, 15–54) (p=.30). Fourteen of these 35 patients were treated with tapering of immunosuppression and rituximab and/or chemotherapy or radiation therapy, and 8 achieved a complete remission. Three-year OS was 55% (95%CI, 42–68); IND 69% (95%CI, 48–90); AGR 54% (95%CI, 33–75); HL 43% (95%CI, 18–69) (p=.37). We conclude that RIC UCB is effective alternative for the treatment of patients with advanced lymphoid malignancy resulting in acceptable NRM and encouraging OS and PFS. Patients with advanced lymphoid malignancies should be considered for a RIC UCBT as a promising alternative for those with no available sibling donor.

Autografting followed by a reduced‐intensity conditioning unrelated donor cord blood transplantation for a patient with refractory multiple myeloma: successful engraftment with minimal toxicity

We report on a 59-yr-old man with recurrent multiple myeloma. To reduce treatment-related mortality, while retaining the cytoreductive effects of high-dose chemotherapy, as well as graft vs. myeloma effect, we used a reduced-intensity conditioning umbilical cord blood (CB) transplantation following high-dose chemotherapy with autologous stem cell transplantation support. This patient was engrafted rapidly and extramedullary toxicities were acceptable. Although he had local recurrence in the right calf on day +130 after the CB transplantation, the tumor was successfully treated with radiation therapy, and he is alive and well at present (day +480).