Advanced Hematologic Diseases Research Articles

Chronic Kidney Disease in Patients After Allogeneic Hematopoietic Cell Transplant

Hematopoietic stem cell transplant (HSCT) is used in advanced hematologic diseases to restart the immune system. Kidney damage remains significant complication of hematopoietic cell transplant (HCT) affecting the mortality of transplant recipients. The aim of the study was to assess the advancement of chronic kidney disease (CKD) in patients after HSCT. We studied 150 patients who underwent allo-HSCT treatment in our center in years 1995 to 2020 because of acute myeloid leukemia in 47% of patients, acute lymphoblastic leukemia in 19%, and lymphoma in 32%. The mean age of patients with acute leukemia is 48 years (including acute myeloid leukemia it is 47 years, and including acute lymphoblastic leukemia it is 32 years). The mean age of lymphoma patients is 34 years. We studied the prevalence and stages of CKD. CKD stage 3a and 3b was found in 24.6%. None of the patients studied had CKD stage 4 or 5. In patients after HSCT because of both acute myeloid leukemia and acute lymphoblastic leukemia, CKD stage 3a was found in 19% and stage 3b in 7.3%. Estimated glomerular filtration rate (eGFR) >90 mL/min/1.73 m2, was found in 36.8% of this population, whereas eGFR between 90 and 60 mL/min/1.73 m2 was observed in 36.8%. In patients with lymphoma who underwent HSCT, CKD stage 3a was found in 18%, while CKD stage 3b was diagnosed in 27% of the patients. An eGFR >90 mL/min/1.73 m2, was found in 27% of this population, whereas eGFR between 90 and 60 mL/min/1.73 m2 was observed in 27% of patients. The categorization of patients according to the underlying disease is important because other drugs are used in therapy of conditioning before HCT. CKD in patients after allogeneic HSCT is common, although advanced stages were not observed, probably because the age of the population studied was not advanced. CKD in these vulnerable patients may be because of prior chemotherapy, conditioning regimen, post-HSCT calcineurin therapy, and other possible nephrotoxic drugs.

Alternative Donor Hematopoietic Cell Transplantation for Pediatric, Adolescent and Young Adult with Hematological Diseases

Hematopoietic cell transplantation (HCT) is the only potential curative option for many advanced hematologic diseases. Pediatrics, adolescent and young adult (PAYA) patients overall have less pre-HCT comorbidity or organ toxicity and lower transplant related morbidity and mortality risk compared to older adults. As such, a higher percentage of patients in this age group tend to receive myeloablative conditioning (MAC) over non-myeloablative regimens. Current alternative donor sources when a matched sibling donor (MSD) is not available include matched unrelated (MUD), umbilical cord blood (UCB), and haploidentical (Haplo) donors. While there are accumulating data comparing the HCT outcomes between MUD vs. Haplo or UCB in adult patients, the data are sparse in PAYA patients. In this retrospective study, we reviewed 314 consecutive patients aged 1-39 years who underwent their first allogeneic HCT using MAC at City of Hope between 1/2005-7/2018. Patients who received HCT from a matched sibling donor were excluded. Patients received HCT from either an 8/8 HLA MUD (n=196 [BM= 27%, PBSC= 73%]), UCB (n=83 [single: n=30, double: n=53]) or Haplo (n=35) donor. The most used MAC regimens were fractionated total body irradiation-based (n=234, 74%). All Haplo recipients got post-HCT cyclophosphamide (PTCy) as GVHD prophylaxis. To adjust for the difference in transplant era between UCB (predominantly performed in earlier years) and Haplo (carried out predominantly in more recent years) the comparative analyses were focused on Haplo or UCB vs. MUD. Univariate and multivariable Cox regression models were used to assess the impact of patient, disease, and treatment factors on overall survival (OS), progression-free survival (PFS), relapse/progression (RP), and non-relapse mortality (NRM). Median age of patients at the time of HCT was 24 years (range: 0.7-39), with 55% of patients being male. KPS was ≥80% in 88% of the patients and 25% had HCT-CI ≥ 2. The most common diagnoses included: ALL (48%), AML (41%), and MDS/CML (11%). DRI was high/very high in 44% of patients. Groups were balanced in general but patients in the Haplo group had higher HCT-CI (median: 2, p<0.01), more frequently had high/very high disease risk (49%, p<0.01) and higher KPS ≥80% (77%, p<0.01). Neutrophil engraftment was achieved at a median of 23 days (range: 10-94) in the UCB, 16 days (range: 12-32) in the Haplo and 15 days (range: 10-33) in the MUD (p<0.01). After a median follow up duration of 36 months (range: 5.9-36), 3-year OS was inferior among recipients of UCB-HCT (53%, 95% CI: 42-63) compared with the MUD (63%, 95% CI: 56-70; p=0.03), while similar between Haplo (62%, 95% CI:41-78) and MUD (p=0.82). The lower OS in UCB group was primarily due to the significantly higher NRM at 3 years (34%, 95% CI: 24-44) compared with the MUD (16%, 95%CI: 11-22, p<0.01); and 3-year NRM was not significantly different between Haplo (18%,95%CI: 6-34) and MUD (p= 0.99). On the contrary, the cumulative incidence of relapse (CIR) at 3 years was significantly lower in the UCB group (14%, 95%CI: 8-24) compared to MUD (29%, 95%CI: 23-36, p=0.01); the difference in CIR was not significant between Haplo (29%, 95% CI: 16-51) and MUD (p=0.81). PFS at 3 years was not significantly different among the three donor groups (p=0.43). Cumulative incidence of day 100 acute GvHD grade 2-4 was 61% (95% CI: 55-66) in the whole cohort, with no significant difference among the three groups (p=0.27). Cumulative incidence of chronic GVHD at 3 years was higher in the MUD group (66%: 95%CI: 59-72) compared to UCB (45%, 95%CI: 34-56, P<0.01) and Haplo (47%, 95% CI: 28-64, P=0.01). By multivariable analysis, patients with high/very high disease risk had worse OS (HR=1.8, 95% CI: 1.2-2.6, p<0.01) and PFS (HR=1.8, 95% CI: 1.3-2.5, p<0.01) and higher R/P (HR=2.3, 95% CI: 1.4-3.6, p<0.01). Neither Cord nor Haplo was significantly associated with OS compared with MUD when adjusted for Age, HCT CI, DRI, KPS, and HCT Era. In conclusion, our results indicated that in PAYA patients without a suitable MSD, outcomes of Haplo HCT are comparable to MUD HCT. By univariate analysis, UCB HCT was associated with a lower relapse rate compared to MUD. However, survival was worse in recipients of UCB HCT due to the higher NRM, possibly resulted from more infections and engraftment delays in these patients. Figure 1 Disclosures Ali: Incyte Corporation: Consultancy. Nakamura:Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation. Al Malki:Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy; Rigel Pharma: Consultancy.

Umbilical Cord Blood Transplantation with Non-TBI Regimens for Advanced Hematological Malignant Diseases

Allogeneic hematopoietic stem cell transplantation (HSCT) for advanced hematological diseases dose not reach a satisfactory result so far. Recently, umbilical cord blood transplantation (UCBT) is widely practiced for advanced hematological diseases by its tolerance of HLA matching. However, high incidence of transplant related complications such as engraftment failure, infections, pre-engraftment immune reaction (PIR) etc. are still issues to resolve. Although non-TBI regimens are easy to prepare, few reports investigated non-TBI regimens for UCBT. With respect to UCBT with non-TBI conditioning regimens, we examined efficacy and feasibility of them for high-risk hematological diseases.Non-CR hematological malignancies, and int-2/high risk MDS categorized by IPSS were defined as advanced hematological disease. From June 2011 to January 2015, 47 patients consecutively underwent UCBT at our center. Thirty-five of 47 patients (23 male, 12 female), who were suffered from advanced hematological diseases were undergone first-time UCBT with non-TBI conditioning regimens. There were five non-TBI regimens such as fludarabine (Flu) 180mg/m2 + intravenous buslufan (Bu) 12.8mg/kg + melpharan (Mel) 80mg/m2 (FB4M) and Flu 125mg/m2 + Mel 200 mg/m2 (FM200) as the myeloablative conditioning regimens (MAC) and Flu 125mg/m2 + Mel 140mg/m2 (FM140), Flu 180mg/m2 + Bu 6.4mg/kg + Mel 140mg/m2 (FB2M140) and Flu125mg/m2 + cyclophosphamide (Cy) 120mg/kg + ATG 2.5mg/m2(FCyATG) as the reduced intensity conditioning regimens (RIC) has been used at our center. We investigated patients' characteristics, engraftment, overall survival (OS), incidence of transplant related mortality (TRM) and disease related death (DRD). OS was calculated with Kaplan-Meier method and the cumulative incidence of neutrophil engraftment, TRM and DRD was calculated with Gray′s method. Statistical significance was regarded as less than 0.05 of p-value. Statistical analyses were carried out using EZR (Kanda Y. BMT 2013).Median age at UCBT was 57 years (21-70). Fourteen patients with myeloid diseases (11 AML, 3 MDS) and 21 lymphoid diseases (17 ATLL, 1 ALL, 3 NHL) were included. 25 patients used MAC, 21 patients received FB4M, 4 FM200 followed by UCBT. On the other hand, 10 patients recieved RIC, 8 patients with FM140 and 1 each FB2M140, and FCyATG. Median time to neutrophil engraftment was 23 days (14-58) and cumulative incidence of neutrophil engraftment at day100 with the competing risk as early death (14.3%; 95%CI: 0.51-28.0) was 82.9% (95%CI: 64.1-92.4). Cumulative incidence of TRM at day 100 after UCBT was 37.4% (95%CI: 21.5-53.3). Also cumulative incidence of DAD at 3 month after UCBT was 14.9% (95%CI: 5.3-29.2). These results suggested that additional use of melpharan will be contributed to high incidence of engraftment and low incidence of relapse. In patients with myeloid diseases, cumulative incidence of DAD at 6 months after UCBT was 7.9% (95%CI: 0.4-31.3). However, in the patients of lymphoid diseases, cumulative incidence of DAD at 6 months was relatively high (37.1%; 95%CI: 12.4-62.5). There was no statistical difference between myeloid diseases and lymphoid disease about the incidence of TRM at day100 after UCBT.Although a lot of problems to solve were still remained in lymphoid diseases (OS at 1 year: 21.4%; 95%CI: 9.3-66.8), UCBT with non-TBI regimens would be feasible in the aspect of neutrophil engraftment and can be a promising treatment strategy for patients who suffered from advanced myeloid diseases (OS at 1 year: 55%; 95%CI: 25.8-76.8). DisclosuresNo relevant conflicts of interest to declare.

Abstract C89: The small molecule inhibitor 4SC-202 controls aberrant HH signaling in cancer

Abstract Introduction: 4SC-202, a clinical stage inhibitor of LSD1 and HDAC1, 2 and 3 was investigated to identify its unique mechanism to target cancer cells by controlling aberrant Hedgehog signaling. Experiments: 4SC-202 is an oral available epigenetic modulator exhibiting a combined inhibition of the lysine specific demethylase LSD1 (KDM1A) and histone deacetylases HDAC1, 2 and 3. 4SC-202's impact on Hedgehog signaling activity was tested in a SMO-dependent setting and in a SMO-independent setting. Therefore, Hedgehog signaling in DAOY cells was either activated by addition of sHH or Smoothened agonist or by stable depletion of SUFU for instrinsic, SMO-independent signaling. Pathway activity was determined by the expression of the effector protein GLI and primary target genes. SMO-independent Hedgehog signaling can be driven as well by growth factors like TGF-ß as demonstrated for the pancreatic cancer cell line PANC1. Therefore, 4SC-202's impact on spheroid formation and protein expression was tested in PANC1 cells. Results: Compared to HDAC inhibitors like Vorinostat, LSD1 inhibitors like OGL-002 and Hedgehog inhibitors targeting SMO like Vismodegib, 4SC-202 was able to inhibit canonical as well as non-canonical GLI-driven Hedgehog signaling. Additionally, 4SC-202 was able to prevent spheroid formation of pancreatic cancer cells and inhibit TGF-ß driven signaling in PANC1 cells. Conclusion: Aberrant activity of the Hedgehog signaling pathway has been implicated in the development, progression and relapse of different cancer entities. Especially the interaction of tumor cells and the microenvironment is driven by SMO-independent Hedgehog signals and therefore Hedgehog inhibitors targeting SMO like Vismodegib were not able to demonstrate clinical benefit in SMO-independent Hedgehog driven cancer types like PDAC. The unique feature of 4SC-202 to control both SMO-dependent and SMO-independent HH signaling provides the opportunity to demonstrate activity in Hedgehog driven entities in further clinical investigations. 4SC-202 was safe and well tolerated in a phase I clinical trial (TOPAS) in patients with advanced hematological diseases. With a disease control rate of 83%, one partial responder treated for 8 months and one complete responder treated for 28 months, patients benefited from 4SC-202 treatment and hints of activity could be demonstrated. Citation Format: Hella Kohlhof, Wolfgang Gruber, Daniel Vitt, Fritz Aberger, Tanja Prenzel. The small molecule inhibitor 4SC-202 controls aberrant HH signaling in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C89.

Higher doses of CD34+ progenitors are associated with improved overall survival without increasing GVHD in reduced intensity conditioning allogeneic transplant recipients with clinically advanced disease

The influence of CD34+ cell dose on the outcome of allogeneic peripheral blood stem cell (PBSC) transplantation after reduced intensity conditioning (RIC) remains controversial. The impact of the number of CD34+ hematoprogenitors infused on transplant outcome and on the incidence of graft versus host disease (GVHD) was analyzed. Data of 138 patients with advanced hematological diseases who received an allogeneic PBSC transplant after RIC were analyzed. Donors were mobilized with granulocyte colony-stimulating factor and underwent one to three apheresis procedures. Incidence of acute and chronic GVHD and overall and event-free survival (OS and EFS) was determined. The median number of CD34+ cells infused was 5.57 × 10(6) kg(-1) (range: 1.1-15.6). There was no relationship between CD34+ cell dose and neutrophil or platelet engraftment. Patients receiving ≥5 × 10(6) kg(-1) CD34+ cells had a 63.1% 5-year OS when compared with 48.2% for those receiving a lower number (P = 0.024). At 5-year follow-up, there was no significant difference in EFS between the groups (44% vs. 42.8%, P = 0.426). No relationship between CD34+ cell dose and acute GVHD was found (P = 0.1). Relapse rate was the same in patients with and without acute GVHD (P = 0.117). A nonsignificant improvement on OS and EFS in patients who developed chronic GVHD was found (P = 0.57 and 0.41). A CD34+ cell dose ≥5 × 10(6) kg(-1) was associated with a significantly higher OS, but no improved EFS in high-risk patients. The number of CD34+ progenitors infused had no influence on the incidence of acute or chronic GVHD.

Chronic Graft versus Host Disease but not the Intensity of Conditioning has Impact on Survival after Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Hematological Diseases

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is often performed in cases of advanced hematological diseases, but because of the associated mortality and a high risk of relapse it is life prolonging only in some patients. Patients and Methods: A retrospective multi-center analysis of 401 patients was conducted to analyze the variables associated with outcome after alloHSCT in advanced hematological diseases. The Cox proportional hazards model was used to assess the independence of overall survival (OS) and disease-free survival (DFS) from prognostic factors in a multivariate model. Results: The 5-year OS and DFS were 27.3 and 21.1% respectively. Multivariate analysis showed that the underlying malignancy had a significant influence on OS and DFS (p < 0.001 and p < 0.011, respectively), whereas development of severe acute graft versus host disease (GvHD) had a negative impact on OS (p < 0.001). Development of chronic GvHD showed a trend to a better OS (p = 0.085) and DFS (p = 0.199). No impact was seen for the intensity of conditioning. Conclusion: Development of chronic GvHD but not the conditioning regimen improved the outcome after alloHSCT for advanced malignancies, underlining the importance of immunological rather than cytotoxic effects.

Clinical and Pharmacokinetic Evaluation of Prophylactic Micafungin 150mg Daily Against Invasive Fungal Infections in Cord Blood Transplant Recipients

Abstract 1961▪▪This icon denotes a clinically relevant abstract Objectives:Invasive fungal infections (IFIs) are considered as important problems especially in the early period after allogeneic cord blood transplantation (CBT), because of the significantly prolonged neutropenia compared to bone marrow or peripheral blood stem cell transplantations. Antifungal prophylaxis should be therefore carefully selected to assure definite effects with less toxicity, without being affected by drug interactions, and patient's compliance and situation. The object of this study was to evaluate antifungal prophylactic efficacy and safety of micafungin (MCFG) at 150mg with monitoring of the plasma concentrations in high-risk CBT recipients.Patients and Methods: The study was a prospective, one-institution, single-arm trial of MCFG administered during neutropenic phase of CBT. Adult patients aged >= 20 years who were scheduled for CBT were eligible for this study, if they had no history of or symptoms consistent with IFIs. Approval for the study protocol was obtained from the ethical committee of Toranomon Hospital, and written informed consent was obtained from each patient. MCFG at a once daily dose of 150 mg as a 1-h infusion was initiated at the beginning of the transplant-related conditioning regimens. Although the study treatment was principally continued beyond 3 days after engraftment up to a maximum of 50 days after transplantation, it was ceased earlier in cases of the followings; development of proven, probable, or suspected IFIs; development of unacceptable drug toxicity; receipt of a re-transplant; death; withdrawal of study participation by patient’ decision; or discontinuation of the study treatment by physician’s decision. Trough and peak plasma concentrations of MCFG were measured on the day of transplantation and a week after by using high-performance liquid chromatography. The primary end point was treatment success, which was defined as the absence of proven, probable, or suspected IFIs through the end of therapy and as the absence of proven and probable IFIs through the end of the 50-day period after treatment. Results:A total of 73 patients with advanced or high-risk hematologic diseases were enrolled for this study between May, 2010 and June, 2011. The median age was 55 (20–73) years old, and 67 patients who received reduced-intensity conditioning were included. Sixty-four patients achieved engraftment at a median of 18.5 (9–36) days during the study period. The median duration of MCFG administration from transplantation was 33 (2–50) days. No patients discontinued use of the study drug because of an adverse event. In 70 patients who received at least 7 doses of study drug, median trough levels were 3.46 (0.63-7.81) μg/mL on the day of transplantation and 2.88 (0.30-8.25) μg/mL a week after, which were not influenced by body weight, creatinine clearance or serum levels of albumin, bilirubin and hepatobiliary enzymes. Median peak levels of MCFG in the first 10 patients were 12.99 (10.27-18.74) μg/mL and 12.40 (9.46-15.64) μg/mL, respectively, which were fairly constant over time in each individual. The treatment success rate at 50 days after transplantation was 76.7% and the Kaplan-Meier estimate of the treatment success was 75.6%. Seven breakthrough infections occurred at a median of 29 (8–38) days, with a cumulative incidence of 10.0%. There were 4 cases of invasive pulmonary aspergillosis (IPA) and three caused by Candida species recovered from the bloodstream. One probable IPA and two candidemia due to Candida parapsilosis and Candida krusei developed during prophylactic treatment, whereas three probable IPA and one candidemia due to Candida parapsilosis developed during the post-treatment follow-up period. There were 10 patients with suspected IFIs on the basis of abnormality in CT scan, in whom MCFG was switched to a different class of mold-active agents (liposomal amphotericin B in 7 and voriconazole in 3). Nine patients died during the study, one of who died of IPA associated with graft failure at 32 days after transplantation. Conclusions:Daily administration of MCFG at 150mg appears to be an effective and generally well-tolerated antifungal prophylaxis during neutropenic phase in high-risk CBT recipients. Prophylactic use of MCFG in the early period after transplantation might also be an appropriate approach to easing concerns about drug interactions and variability of drug concentrations. Disclosures:No relevant conflicts of interest to declare.

Tacrolimus and mycofenolate mofetil as GvHD prophylaxis following nonmyeloablative conditioning and unrelated hematopoietic SCT for adult patients with advanced hematologic diseases

In the current study, we evaluated a combination of tacrolimus and mycophenolate mofetil (MMF) as GvHD prophylaxis in 50 patients undergoing truly nonmyeloablative (NM; 90 mg/m(2) fludarabine, 2 Gy TBI) hematopoietic SCT (HSCT) from unrelated donors. Median patient age was 51 years (range, 25-67 years). After a median follow-up of 1123 days (range, 47-2729 days), 20 patients (40%) are alive and free from disease. The probabilities of 1-, 2- and 3-year survival were 57, 47 and 39%, respectively. Patients who achieved a remission before HSCT had a significantly better OS compared with those who had active disease (P=0.01). The incidences of grade II-IV and III-IV acute GvHD (aGvHD) were 54% (n=27) and 16% (n=8). Remarkably, using tacrolimus and MMF, the median onset of aGvHD occurred distinctly late on day +66 (range, 12-119 days). A total of 46 patients were evaluable for chronic GvHD (cGvHD). Out of these, 26 (56%) patients developed cGvHD, with 16 (34%) of them showing limited and 10 (21%) showing extensive disease. We conclude that the combination of tacrolimus and MMF as post transplant immunosuppression for patients receiving NM unrelated donor HSCT permits stable engraftment and effective prophylaxis for acute and cGvHD. In particular, the occurrence of severe early-onset aGvHD was attenuated.

Reduced-Intensity Unrelated Cord Blood Transplantation in Adult – a Single Center Analysis of 318 Transplants.

Objective: Cord blood is widely used as a third possible stem cell source for allogeneic transplantation following bone marrow and peripheral blood. CBT has unique characteristics such as allowing 2 loci mismatch and emergency use or ready to use transplantation. Reduced-intensity transplantation also has been widely accepted to offer opportunities for allogeneic transplant for older and poor overall status patients. We previously showed the feasibility of reduced-intensity cord blood transplantation (RI-CBT) in 30 patients with advanced hematological diseases. Then performed more than 300 time RI-CBT to those whom needed urgent transplantation without suitable HLA matched donors.Methods: We retrospectively analyzed medical records of 318 times and 287 cases of RI-CBT from 1/1/2004 to 5/7/2008 in Toranomon Hospital. Disease distribution of 287 studied patients was as follows; acute myeloblastic leukemia/myelodysplastic syndrome was 136 cases, malignant lymphoma 58, acute lymphoblastic leukemia 42, adult T cell leukemia/lymphoma 25, severe aplastic anemia 8 and others 18. A mean age was 56 ranging from 19 to 79 years old. The number of high risk and standard status patients were 243 and 44, respectively. High risk disease status is defined as residual uncontrolable tumor cells despite of chemotherapy such as primary refractory and beyond CR1 and standard risk is as in remission in a meaning of tumor control. MDS and SAA patients who need frequent transfusions and intensive care for infection are defined as standard risk. Preparative regimen mainly composed of fludarabine 25 mg/m2 on days -7 to -3, melphalan 80 mg/m2 on day -2, and 4 Gy total body irradiation on day -1. Some patients were contiditioned with iv-busulfan without TBI. Graft-versus- host disease prophylaxis was composed of cyclosporine or tacrolimus alone.Results: We analyzed the association of various factors on engraftment in possible 158 patients. Eighty eight % (95% CI, 83%–93%) of patients were engrafted on a median days of 20 (range, 11–55 days) after transplant. Multivariate analysis revealed 5 to 6 antigen match in GVH direction was a significant independent factor for engraftment as well as CD34 dose, while HLA in HVG direction did not significantly influence on engraftment. Three-year estimated overall survival (OS) in total 287 cases was 39.6% (95% CI: 33.5–45.8%). Standard risk patients (n=44) showed 3-year OS of 53.8% (95% CI: 38.3–69.2%) and high risk (n=243) was 26.3% (95% CI:20.2–32.5%). Tacrolimus GVHD prophylaxis group (n=159) had superior 3y-OS of 33.8%(95% CI: 25.9–41.8) to cyclosporine alone with 3yOS of 22.4 % (95% CI: 14.2–30.7). We previously reported pre-engraftment immune reaction characterized by high-grade fever and weight gain and developed on a median of day 9. More intensive immune suppression after RI-CBT using tacrolimus decreased the incidence and severity of PIR and increased OS.Conclusion: RI-CBT is a feasible approach even for relatively aged patient population (Mean age=56) with advanced hematological malignancies.

Unrelated Cord Blood Transplantation after Nonmyeloablative Conditioning: Single Institutional Retrospective Comparison with Bone Marrow or Peripheral Blood Stem-Cell Transplants.

Background: Unrelated cord blood transplantation (CBT) has emerged as an effective therapy for treating patients with advanced or high-risk hematologic diseases who have no suitable related or unrelated donor. In older patients or those with extensive prior therapy or other clinical features, nonmyeloablative regimens have been used to reduce the risk of regimen-related toxicity and transplantation-related mortality (TRM). Several studies have been reported on the use of unrelated CBT using various reduced-intensity conditioning regimens.Objectives: This study aimed to evaluate the safety and efficacy of unrelated CBT after nonmyeloablative conditioning using fludarabine, cyclophosphamide and single fraction of total body irradiation of 200 cGy, compared with bone marrow transplantation (BMT) or peripheral blood stem-cell transplantation (PBSCT) for adult Japanese patients with hematologic diseases and relate those to biological and procedural factors.Patients and Methods: Clinical data were collected retrospectively on 70 adults with hematologic disease who received unrelated CBT (n=19) or BMT from unrelated donors (n=27), or PBSCT from related donors (n=24) between August 2000 and June 2008 in our institution. All patients received nonmyeloablative conditioning regimens including fludarabine. The median period of follow-up for survivors was 253 days after CBT, 364 days after BMT and 692 days after PBSCT, respectively. We analyzed the hematopoietic recovery, incidence of graft-versus-host disease (GVHD), risks of TRM and relapse, and disease-free survival (DFS) using Cox proportional hazards models.Results: Comparisons of characteristics in 3 groups showed similar distributions for age, gender ratio, diagnosis, risk of disease at the transplant. Compared with BMT and PBSCT (BMT/PBSCT) recipients, CBT recipients had more previous history of hematopoietic stem cell transplantation (HSCT), less human leukocyte antigen-matched donor and less methotrexate (MTX)-containing GVHD prophylaxis. Multivariate analysis demonstrated slow neutrophil (P<0.01) and platelet (P<0.01) recoveries in CBT compared with BMT/PBSCT. The cumulative incidence of grade II to IV acute GVHD in CBT recipients were significantly higher than those in PBSCT recipients (60% versus 23%, P=0.02), but not significantly different from BMT recipients. The cumulative incidence of extensive-type of chronic GVHD at 1 year in CBT recipients was not significantly different from BMT/PBSCT recipients. No statistically differences were seen in TRM (22% in CBT, 24% in BMT and 9% in PBSCT recipients at 1 years), relapse (38% in CBT, 32% in BMT and 40% in PBSCT recipients at 1 years) and DFS (46% in CBT, 50% in BMT and 46% in PBSCT recipients at 1 years) among 3 groups. Risk of disease at the transplant was the only factor for DFS result (standard versus high, P<0.01).Conclusion: These data suggest that unrelated cord blood (UCB) after this nonmyeloablative conditioning could be a safe and effective stem cell source similar to bone marrow or mobilized peripheral blood for adult Japanese patients, and also support the use of UCB as a strategy for extending the availability of transplantation therapy, particularly for older patients without suitable related or unrelated blood or bone marrow donor.

Umbilical Cord Blood Transplantation after Reduced-Intensity Conditioning for Elderly Patients with Hematologic Diseases

Although allogeneic hematopoietic stem cell transplantation is a potentially curative approach for advanced hematologic diseases, its application to elderly people is limited because of their comorbid physical conditions and lower chance of finding suitable related donors. Umbilical cord blood transplantation with reduced-intensity pretransplant conditioning (RI-UCBT) is 1 way to avoid these obstacles. We analyzed elderly patients aged 55 years and older with hematologic diseases who underwent RI-UCBT at our institute to assess feasibility and effectiveness of this treatment approach. Among the 70 patients included, 50 died, 74% of them from nonrelapse causes. Infection was the primary cause of death. Estimated overall survival and progression-free survival at 2 years were both 23%. In multivariate analyses, standard-risk diseases, age younger than 61 years, grade 0-II acute graft-versus-host disease, and the absence of preengraftment immune reaction were significantly associated with better overall survival. RI-UCBT is a potentially curative and applicable approach for elderly patients. Higher mortality, especially from nonrelapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

334: Non-Myeloablative Transplantation is a Feasible Option in Patients with Advanced Hematological Malignancies: A Single Center Experience

Introduction: There are limited therapeutic options in patients with advanced hematologic diseases. Historically patients with relapsed/refractory disease do not fare well after non-myeloablative allogeneic stem cell transplantation (NST). Methods: In an attempt to examine whether NST provides disease control in patients with high risk hematologic malignancies, we retrospectively evaluated our experience and analyzed the outcomes of NST in patients with high risk hematologic malignancies from 1999 to 2006.

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.

Successful Engraftment of Cord Blood Transplantation Following Reduced-Intensity Conditioning Regimen Using Fludarabine and Busulfan for Advanced Hematologic Malignancies.

Background: The potential role of reduced-intensity cord blood transplantation (RI-CBT) without total body irradiation (TBI) in adults remains unclear. We investigated the feasibility of RI-CBT using non- TBI regimen for the treatment of patients with advanced hematologic malignancies.Methods: Twenty-three patients (median age, 61, range, 38–74) with advanced hematologic malignancies were enrolled in this study (18 patients in refractory or relapsed phase,5 patients in remission or chronic phase). Conditioning regimen comprised of fludarabine 30 mg/m2 on days −8 to −3, busulfan 4 mg/kg p.o. or 3.2 mg/kg i.v. on days −6 to −5. In one cases. we administered busulfan 3.2mg/kg i.v. on days −6 to −3, because of blastic crisis. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus alone. Engraftment was defined as an absolute neutrophil count > 0.5 x 10E9/l. Primary graft failure was defined as the complete loss of donor-type hematopoiesis without engraftment. Secondary graft failure was defined as the loss of donor-type hematopoiesis after primary engraftment. Median follow-up of surviving patients was 1096 days (range, 53–1207). Primary endpoint was engraftment. All patients provided informed consent in accordance with the requirements of Institutional Review Board.Results: All the patients tolerated the conditioning regimen. Median dose of infused nuclear cells was 2.7x10E7 /kg (range, 1.9–4.6). Twelve patients achieved engraftment at a median of day 20.5 (range, 10–36), but two of them developed secondary graft failure. Complete donor-type chimerism was documented within 30 days of transplant in six patients. Primary graft failure was diagnosed in remaining eleven patients. Six of them, underlying disease progressed despite conditioning regimens. As of August 2007, five patients survived (3 patients in complete remission, one patients relapsed after transplantation, the other one not reached remission). Estimated 1-year overall survival rate was 20.7% (95% confidence interval, 3.0–38.4%).Conclusions: Though the pre-transplant condition of patients were not good, engraftment was obtained with approximately the half patients. This study demonstrated the feasibility of RI-CBT using non-TBI regimen for adult patients with advanced hematological diseases; however, high incidences of disease progression before engraftment was significant problem. RI-CBT may become the choice of treatment for patients with advanced hematologic malignancies that are incurable with conventional treatments.

Conditioning with Fludarabine, BCNU, and Melphalan in Allogeneic Stem Cell Transplantation Results in Reduced Toxixcity and High Activity Against Advanced Hematologic Malignancies.

Conditioning with reduced intensity regimens have been proven problematic for the control of advanced hematologic diseases. Therefore we applied a new protocol (FBM) in a prospective, two-center, phase II trial in 133 patients (median age: 55.6 years, 23–73) undergoing allogeneic cell transplantation (HCT). FBM contains fludarabine (5×30mg/m2), BCNU (2×200mg/m2) and melphalan (140mg/m2). Patients >=55 years received dose reduction in BCNU (2×150mg/m2) and melphalan (110mg/m2). Diagnoses and patients included AML (58), MDS (23), CML (11), MPS (9), ALL (3), myeloma (9), lymphoma (13) and CLL (7). Most patients (n=106) had advanced disease (AD) defined as ≥ CR2/CP2, refractory, relapsed or untreated. Only 27 patients presented with early disease (ED): CR1, CP1 or MDS RA/RARS. The stem cell graft was BM in 15 and PBSCT in 116 patients. Related (SIB) donors were used in 68, unrelated (MUD) donors in 65 cases. GvHD prophylaxis was CsA+MTX (23pts) and CsA+MMF (110pts) with additional ATG in MUD HCT. Median time to leukocyte engraftment (WBC >1×10e9/L) was 12.7 (1–41) days. One primary graft failure occurred. Platelet count >= 20×10e9/L was reached median day 17.4 (5–113). Complete donor chimerism at day 30 was reported in 95.7% of patients. Grade 3 organ toxicity according to Bearman et al. was observed in 21 cases, three patients died due to toxic complications. After a median follow up of 58.5 months, non-relapse mortality (NRM) was 15.8% (95%CI 10.7–23.4) and 27.8% (95%CI 21.2–36.6) at day 100 and 2 years. The relapse rate was 14.3% (95%CI 9.4–21.7) at 2 years. Acute GvHD III-IV developed in 23.3%, extensive chronic GvHD in 32.3% of all evaluable patients. Overall survival (OS) after 3 years was 53.0% (95%CI 44.5–61.6) and 46.1% (95%CI 36.9–55.2) after 5 years. Cases with ED had an OS of 63.0% (95%CI 44.7–81.2) and patients with AD experienced a 50.4% (95%CI 40.8–60.1) OS after 3 years. Event free survival (EFS) after 3 years was 46.4% (95%CI 37.9–54.9) and 41.9% (95%CI 33.1–50.7) after 5 years. EFS for ED patients was 55.6% (95%CI 36.8–74.3), for patients with AD 44.0% (CI 34.5–53.5) after 3 years. Interestingly, patients allografted from female donors showed a significant reduction in EFS with increased incidence of chronic GvHD in uni- and multivariate analyses. No significant differences were observed between patients >= 55 years and < 55 years or MUD/SIB donors. The subgroup of AML/MDS patients (n=81) showed a 5-year OS/EFS of 52.9% (95%CI 29.2–76.7)/47.1% (95%CI 23.3–70.8) for ED and 42.4% (95%CI 29.9–54.9)/38.6% (95%CI 26.5–50.7) for AD patients. There were no relapses in ED patients after HCT. NRM after 100 days was 17.3% (95%CI 10.7–27.8). Patients age and donor choice did not show statistically significance for OS and EFS in AML/MDS cases. Among cases with advanced disease, patients (n=33) with circulating blasts (median 21,1%) at the time of HCT, showed an OS of 44.4% after 5 years. We conclude that FBM conditioning prior to allogeneic HCT is especially effective in cases of advanced myeloid disease and can be safely administered to older or comorbid patients.

Tacrolimus as Prophylaxis for Acute Graft-Versus-Host Disease in Reduced Intensity Cord Blood Transplantation for Adult Patients With Advanced Hematologic Diseases

Myeloablative cord blood transplantation (CBT) for adult patients offers a 90% chance of engraftment with a 50% rate of transplant-related mortality, mostly attributable to infection. We have demonstrated the feasibility of reduced-intensity CBT (RI-CBT) for adult patients, in which cyclosporine was used for acute graft-versus-host disease (GVHD) prophylaxis. Transplantation-related mortality (TRM) was 27% within 100 days. Therefore our objective was to evaluate the feasibility of RI-CBT with tacrolimus as GVHD prophylaxis for adult patients with hematologic malignancies. Thirty-four patients with a median age of 56.5 years (range; 22-68) with hematologic diseases underwent RI-CBT at Toranomon Hospital between November 2003 and September 2004. Preparative regimen comprised fludarabine 25 mg/m2 on days -7 to -3, melphalan 80 mg/m2 on day -2, and 4 Gy total body irradiation on day -1. GVHD prophylaxis was continuous intravenous infusion of tacrolimus 0.03 mg/kg, starting on day -1. Thirty-one patients achieved neutrophil engraftment at a median of day 20. Median infused total cell dose was 2.4 x 10E7/kg (range; 1.6-4.8). Thirty-two patients achieved complete donor chimerism at day 60. Grade II-IV acute GVHD occurred in 45% of patients, with a median onset of day 26. Primary disease recurred in five patients, and TRM within 100 days was 12%. Estimated 1-year overall survival was 70%. This study demonstrated the possible improvement in transplant-related mortality by tacrolimus as GVHD prophylaxis in adult RI-CBT recipients.

Successful engraftment following reduced-intensity cord blood transplantation with fludarabine and oral busulfan for advanced hematologic diseases

7110 Background: Feasibility of reduced-intensity cord blood transplantation (RI-CBT) has been demonstrated in adult patients. Most researchers use preparative regimens containing total body irradiation (TBI) 2–4 Gy, while TBI causes considerable toxicities in elderly patients. We investigated the feasibility of RI-CBT using non-TBI regimen for the treatment of adult hematologic diseases. Methods: Nineteen patients (median age, 61, range, 38–74) with advanced hematological diseases were enrolled in this study. Fifteen patients had chemorefractory diseases at RI-CBT. Preparative regimen comprised fludarabine 180 mg/m2 and oral busulfan 8 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus. Engraftment was defined as an absolute neutrophil count &gt; 0.5 × 10E9/l. Primary graft failure was defined as the complete loss of donor-type hematopoiesis occurring without engraftment. Secondary graft failure was defined as the loss of donor-type hematopoiesis occurring after primary engraftment. Endpoint of this study was engraftment. Median follow-up of surviving patients was 24.7 months (range, 21.6–25.8). Results: All the patients tolerated the preparative regimen. Median dose of infused nuclear cells was 2.7x10E7/kg (range, 1.9–4.6). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigen (n=3). Eleven patients achieved engraftment at a median of day 18 (range, 9–30). Chimerism analysis was conducted in six of these eleven patients, and complete donor-type chimerism was documented within 30 days of transplant in five patients. Primary graft failure was diagnosed in two patients. The other six patients died without engraftment due to diffuse alveolar hemorrhage(n=1) and disease progression(n=5). No patients developed acute GVHD. Five of the 11 patients who achieved primary engraftment developed secondary graft failure. As of December 2006, four patients survived in complete remission with complete donor-type chimerism. Estimated 1-year overall survival rate was 21.1%. Conclusions: This study demonstrated the feasibility of RI-CBT using non-TBI regimen; however, high incidences of disease progression before engraftment and secondary graft failure were significant problems. No significant financial relationships to disclose.

Antifungal prophylaxis following reduced-intensity stem cell transplantation

Reduced-intensity stem cell transplantation (RIST) has been developed to be a novel curative option for advanced hematologic diseases. Its minimal toxicity allows for transplantation in patients with advanced age or with organ dysfunction. Young patients without comorbidity can undergo RIST as outpatients. However, fungal infection remains an important complication in RIST. Given the poor prognosis of fungal infection, prophylaxis is critical in its management. The prophylactic strategy is recently changing with the development of RIST. Hospital equipment is important for fungal prophylaxis; however, the median day for the development of fungal infection is day 100, when most RIST patients are followed as outpatients. The focus of fungal management after RIST needs to shift from in-hospital equipment to oral antifungals. Various antifungals have recently been developed and introduced for clinical use. A major change in antifungal management will probably occur within several years.

Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases

Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases

Reactivation of Cytomegalovirus Following Reduced-Intensity Cord Blood Transplantation for Adult Patients.

Backgrounds: Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem-cell transplantation. We and other groups recently reported the feasibility of cord blood transplantation using reduced-intensity regimens (RI-CBT) for adult patients with advanced hematologic diseases. We have little information on the clinical features of CMV reactivation after RI-CBT.Patients/methods: We reviewed medical records of 142 patients who received RI-CBT at Toranomon Hospital between January 2002 and March 2005. Median age of the patients was 55 years (range 17–79). Underlying diseases were chemorefractory hematologic diseases (n=136) and severe aplastic anemia (n=6). Conditioning regimens comprised fludarabine 125 mg/m2, melphalan 80 mg/m2 and total body irradiation (TBI) (4–8 Gy). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n=86) or tacrolimus (n=56). Median number of total nucleated cells and CD34+ cells was 2.7×106 cells/kg (0.39–4.8), and 0.73×105 cells/kg (0.03–5.7) respectively. HLA disparity was 6/6 (n=3), 5/6 (n=21), 4/6 (n=116), and 3/6 (n=2). All the patients were monitored CMV-antigenemia weekly and received pre-emptive ganciclovir or foscarnet.Results: CMV antigenemia tested positive in 77 patients on a median of day 36 (range, 4–87) after RI-CBT. Median of maximal CMV antigenemia was 22 per 50,000 leukocytes (range, 1–1806). CMV diseases developed in 18 patients on a median of day 40 (range 15–99); enterocolitis (n=18), and adrenalitis (n=1). CMV-antigenemia remained negative in two patients, when CMV disease was diagnosed. CMV disease was successfully treated using ganciclovir or foscarnet in 17 patients, and the other patient died of septic shock. Multivariate analysis revealed grade II–IV acute GVHD as a risk factor (odds, 95% CI).Discussion: CMV reactivation and diseases develop early after RI-CBT. Optimal strategy for preventing CMV disease should be established in RICBT.