Senji Kasahara

Unrelated Cord Blood Transplantation after Myeloablative Conditioning in Adults with Acute Myelogenous Leukemia

We analyzed the disease-specific outcomes of adult acute myelogenous leukemia (AML) patients treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and February 2008, 77 adult patients with AML were treated with unrelated CBT. All patients received 4 fractionated 12 Gy total body irradiation (TBI) and chemotherapy as myeloablative conditioning. The median age was 45 years, the median weight was 55 kg, the median number of nucleated cells was 2.44 x 10(7)/kg, and the median number of CD34-positive cells was 1.00 x 10(5)/kg. All patients received a single and HLA mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 50 and platelet recovery at day 200 was 94.8% and 91.7%, respectively. A higher CD34-positive cell dose was associated with faster hematopoietic recovery. The cumulative incidence of grade III to IV acute graft-versus-host disease (aGVHD) and extensive-type chronic GVHD (cGVHD) was 25.1% and 28.6%, respectively. With a median follow-up of 78 months, the probability of event-free survival (EFS) at 5 years was 62.8%. The 5-year cumulative incidence of treatment related-mortality (TRM) and relapse was 9.7%, 25.8%, respectively. In multivariate analyses, the risk factor identified for event free survival (EFS) was disease status and cytogenetics. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with AML.

Unrelated cord blood transplantation after myeloablative conditioning in adults with ALL.

We analyzed the disease-specific outcomes of adult ALL treated with cord blood transplantation (CBT) after myeloablative conditioning. Between October 2000 and November 2007, 27 adult patients with ALL were treated with unrelated CBT. All patients received four fractionated 12 Gy TBI and chemotherapy as myeloablative conditioning. The median age was 36 years, the median weight was 57 kg and the median number of nucleated cells was 2.47 × 107/kg. All patients received a single and HLA-mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 30 and platelet recovery at day 200 was 92.6 and 92.3%, respectively. With a median follow-up of 47 months, the probability of EFS at 5 years was 57.2%. The 5-year cumulative incidence of TRM and relapse was 3.7 and 27.4%, respectively. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with ALL.

Cardiovascular toxicity of cryopreserved cord blood cell infusion.

Although infusion of cryopreserved bone marrow or peripheral blood stem cell is associated with a variety of symptoms, there have been no reports detailing the data of infusion-related toxicities of cryopreserved cord blood (CB) units. We prospectively evaluated the incidence and significance of infusion-related toxicities in 34 adult patients undergoing unrelated CB transplantation. Cryopreserved CB units were thawed and immediately infused, unfiltered, through a central intravenous catheter without further manipulation. Heart rate, blood pressure, oxygen saturation and clinical symptoms were recorded during and after infusion. Twenty-four percent of patients experienced non-cardiovascular toxicities related to infusion. The incidence of systolic and diastolic hypertension and bradycardia was 58, 64 and 32%, respectively. Although three patients (9%) with severe systolic hypertension after the infusion required treatment with antihypertensive agents, no patients experienced life-threatening side effects or needed discontinuation of CB unit infusion. Patient or transplant characteristics had no effect on the hypertension and bradycardia related to the infusion of CB. These data suggest that infusion of cryopreserved CB without further manipulation after thawing is safe and well tolerated. However, cardiovascular toxicities including hypertension and bradycardia were frequently observed.

Impact of cytomegalovirus serostatus on outcome of unrelated cord blood transplantation for adults: a single-institute experience in Japan.

Cytomegalovirus (CMV) disease is one of the major infectious complications after allogeneic hematopoietic stem cell transplantation (SCT). Several studies have shown that CMV‐seropositive patients have a substantial survival disadvantage after bone marrow transplantation (BMT) or peripheral blood SCT (PBSCT). Between August 1998 and February 2006, 101 adult patients underwent myeloablative cord blood transplantation (CBT) from unrelated donors at our institution. Sixteen and 85 patients were CMV‐seronegative and CMV‐seropositive, respectively, prior to CBT. Outcomes of CBT were compared between CMV‐seronegative and CMV‐seropositive patients. The cumulative incidences of neutrophil engraftment at 60 d after CBT did not differ between CMV‐seronegative and CMV‐seropositive patients (100% and 94%, P = 0.09); however, the cumulative incidence of platelet engraftment at 100 d was higher in CMV‐seronegative patients than CMV‐seropositive patients (100% vs. 86%, P < 0.005). The cumulative incidence of CMV antigenemia at 100 d was lower in CMV‐seronegative patients than CMV‐seropositive patients (0% vs. 77%, P < 0.001); however, the cumulative incidences of CMV disease did not differ between CMV‐seronegative and CMV‐seropositive patients (0% vs. 1%, P = 0.84). The probabilities of disease‐free survival at 2 yr also did not differ between CMV‐seronegative and CMV‐seropositive patients (92% vs. 72%, P = 0.16). The outcomes of CBT for CMV‐seropositive patients as well as CMV‐seronegative patients in our series were favorable. This might be due to effective antiviral therapy for CMV infection. Large‐scale studies are needed to determine the impact of recipient CMV serostatus on the outcome of CBT for adults.

No occurrence of Pneumocystis jiroveci (carinii) pneumonia in 120 adults undergoing myeloablative unrelated cord blood transplantation.

Abstract: The incidence of pneumonia caused by Pneumocystis carinii (PCP) (organism now renamed Pneumocystis jiroveci) during the early period after cord blood transplantation (CBT) was studied in 120 adults. Initially 89 patients (74%) received oral administration of 2 single‐strength trimethoprim‐sulfamethoxazole (TMP‐SMZ) tablets twice daily from day −21. In 45 of 89 patients (51%), TMP‐SMZ administration for a scheduled duration was completed. In the remaining 44 patients (49%), however, TMP‐SMZ administration was discontinued prior to day −3 because of toxicity. Among these patients, 42 subsequently received aerosolized pentamidine (AP) on a median of day −13 (range, −20 to −6). Thirty‐one patients (26%) received AP without TMP‐SMZ administration on a median of day −14 (range, −21 to −9). None of the 120 patients were diagnosed with PCP within 100 days or 2 years after CBT; however, one patient who received AP before CBT but no prophylaxis after CBT developed cerebral toxoplasmosis on day +91. Pre‐transplant prophylaxis against PCP did not significantly affect transplantation‐related mortality or disease‐free survival at 2 years after CBT. The results suggest that PCP during the early period after CBT can be effectively prevented by any pre‐transplant prophylactic method.

Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT

There are many reports of second allogeneic stem cell transplantation (allo-SCT) using cord blood (CB) for graft failure after initial allo-SCT. However, the efficacy of second allo-SCT using CB for patients with leukemia relapsed after initial allo-SCT is unknown. We report the results of second allo-SCT using CB in seven adult patients with leukemia relapsed after initial allo-SCT. All patients received a myeloablative conditioning regimen including oral busulfan 16 mg/kg, intravenously fludarabine 100mg/m(2) and cyclophosphamide 120 mg/kg. All but one patient had myeloid reconstitution and four patients remain alive at between 4 and 40 months after second SCT. We conclude that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT.

Early renal injury after myeloablative cord blood transplantation in adults

We report a retrospective analysis of acute renal failure (ARF) in a group of 54 adult patients with hematological malignancies treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. ARF was defined as the doubling serum creatinine occurring within the first 100 days after CBT. A statistically significant decrement of renal function from baseline was observed in days between 11 and 20. ARF occurred in 27.8% of patients. Although no difference was seen in maximum cyclosporine trough levels, the maximum of vancomycin (VCM) trough levels were significantly higher in patients with ARF (p = 0.01). Our result suggests that it is important to monitor VCM dosing more strictly with pharmacokinetic assessment, especially in days 11 – 20, when the most frequently observed declining renal function.

Myeloablative unrelated cord blood transplantation for adult acute myeloid leukemia patients with 11q23 abnormalities

To the Editor: The prognostic impact of cytogenetics in acute myeloid leukemia (AML) at diagnosis has been clearly demonstrated in several clinical trials (1, 2). Chromosomal abnormalities involving 11q23 is occasionally seen in de novo AML, acute lymphoblastic leukemia, and therapyrelated AML and myelodysplastic syndrome. In adult patients, cytogenetic abnormalities involving 11q23 identified in 5–6 percent of de novo AML and several studies have demonstrated that 11q23 abnormalities were associated with adverse outcome in adult AML treated with conventional chemotherapy (3, 4). There is limited information on the clinical efficacy of allogeneic stem cell transplantation (SCT) from related or unrelated donors in AML patients with 11q23 abnormalities (5, 6). Results with unrelated cord blood transplantation (CBT) in series of adult AML patients with 11q23 abnormalities have not been published. In this report, we report our experience with unrelated CBT after myeloablative conditioning in adult de novo AML patients with 11q23 abnormalities. Between March 1999 and March 2007, eight patients with de novo AML with 11q23 abnormalities received an unrelated CBT at our institution. Two patients included in our detailed previous study were also included (case UPN300,314) (7). Cord blood unit was selected, as reported previously (7–9). All cord blood units were obtained from cord blood banks in the Japan Cord Blood Bank Network. Written informed consent for treatment was obtained from all patients. All patients received myeloablative conditioning regimen including four fractionated 12 Gy total body irradiation (TBI), cytosine arabinoside (Ara-C: total dose 12 g ⁄m) combined with G-CSF (lenograstim), and cyclophosphamide (CY: total dose 120 mg ⁄kg), as reported previously (7– 9). Two days or 3 d after the completion of conditioning, patients received a CBT. Seven patients received standard cyclosporine and methotrexate, and one patient (UPN300) received cyclosporine only as a graft-versushost disease (GVHD) prophylaxis. All patients received G-CSF (lenograstim) by intravenous infusion starting on day 1 until durable granulocyte recovery was achieved. The probability of disease-free survival (DFS) was estimated by the Kaplan-Meier method. Analysis of data was performed on 1 October 2007. The characteristics of the eight patients and cord blood units are shown in Table 1. Among the patients the median age was 33 yrs (range, 19–49 yrs), the median weight was 62 kg (range, 36–71 kg) and the median number of cryopreserved nucleated cells was 2.17 · 10 ⁄kg (range, 1.16–5.29 · 10 ⁄kg). Three patients were in first complete remission, four in relapse, and one in primary chemotherapy refractory at the time of CBT. The median time from diagnosis to transplantation was 8.5 months (range, 6–20 months). All but one patient had myeloid reconstitution and median time to more than 0.5 · 10 ⁄L absolute neutrophil count was 22 d (range, 21–41 d). Acute GVHD occurred in all patients who had myeloid reconstitution. The grading of acute GVHD was grade I in one patient, grade II in three, and grade III in three. Chronic GVHD occurred in six of seven evaluable patients. Among six chronic GVHD patients, three patients were extensive type. The transplant-related mortality was seen for one patient on days 49 (graft failure). Three patients experienced relapse on days 249, 420 and 297 and died of relapse on days 260 and 648, remaining one patient is survived at analysis. Four patients remain alive in free of disease at between 182 and 1074 d after transplantation. With a median followup of 425 d, the estimated DFS at 1 yr was 58% (Fig. 1). Several studies have shown that the predictive impact of the cytogenetics at diagnosis is associated not only with responses to chemotherapy, but also with survival outcomes of allogeneic SCT in adults with AML (10–13). However, the role of myeloablative allogeneic SCT for adult acute leukemia patients with 11q23 abormalities is not well defined. Unrelated CBT has been increasingly used to treat adult patients with hematological malignancies who had no related donors (7–9, 14, 15). The rapid availability of the cord blood graft may be one of the most advantages for patients who lack family member donors and require urgent allogeneic SCT (8). In our study, the median time from diagnosis to transplantation was 8.5 months, which was shorter than other previous report (5). The quick availability of the cord blood graft compared to marrow of volunteer donors might contribute to improved prognosis in patients with high-risk acute doi:10.1111/j.1600-0609.2008.01057.x European Journal of Haematology ISSN 0902-4441

Blood eosinophilia after unrelated cord blood transplantation for adults

Blood eosinophilia occurs under various conditions, such as infection, drug administration and autoimmune disease (secondary) or with hematological malignancy (clonal). Eosinophilia also occurs after hematopoietic SCT; however, the majority of patients studied were BMT recipients. Here, we studied on eosinophilia in 101 adults after umbilical cord blood transplantation (CBT). Patient characteristics are listed in Table 1. Transplantation procedures and supportive care were described previously. The degree of eosinophilia was graded according to the reported criteria: mild (an absolute eosinophil count (AEC), 500–1500 10/l), moderate (1500– 5000 10/l) and severe (45000 10/l). Mild-to-severe eosinophilia occurred in 75 (74.3%) patients at a median of 41 days (range 25–99) after CBT (Figure 1). The median duration of eosinophilia was 14 days (range 1–60). The median maximum AEC was 1180 10/l (520–7200 10). The median day at the maximum AEC was 61.5 days (range 28–99) after CBT. Moderate-to-severe eosinophilia occurred in 24 (23.8%) patients at a median of 40 days (range 27–98) after CBT. The median duration was 10 days (range 1–22). Severe eosinophilia occurred in four (4.0%) patients at a median of 48.5 days (range 41–56) after CBT. The median duration was 2.5 days (range 1–4). No study patients were treated for eosinophilia. The association of possible risk factors for developing eosinophilia after CBT was studied using Fisher’s exact test. Age (less than 40 versus 40 years or more), gender (male versus female), disease status (low risk versus high risk), total nucleated cell dose (less than 2.5 10 versus 2.5 10/kg or more), CD34-positive cell dose (less than 1.0 10 versus 1.0 10/kg or more) and HLA-matching (5or 4-match versus 3or 2-match) were not associated with the incidence of mild-to-severe or moderate-to-severe eosinophilia (data not shown). Unexpectedly, pretransplant CMV-seropositivity was associated with a lower incidence of moderate-to-severe eosinophilia after CBT (17.6 versus 56.2%, P1⁄4 0.0004), but not mild-to-severe eosinophilia (72.9 versus 81.2%, P1⁄4 0.10). The main reason for the association between pretransplant CMV seropositivity and less occurrence of moderate-to-severe eosinophilia after CBT is probably the myelotoxic effect of ganciclovir therapy against CMV infection. The association between GVHD and eosinophilia within 100 days after CBT was studied. Grade II–IV acute GVHD occurred in 47 of 75 (62.7%) patients with mild-to-severe eosinophilia and 14 of 26 (53.8%) patients without mildto-severe eosinophilia (P1⁄4 0.44 by Fisher’s exact test). In patients with and without moderate-to-severe eosinophilia, grade II–IV acute GVHD occurred in 17 of 24 (70.8%) and 44 of 77 (56.1%), respectively (P1⁄4 0.13). Within 1 year after CBT, chronic GVHD occurred in 65 of 75 (86.7%) patients with mild-to-severe eosinophilia and 24 of 26 (92.3%) patients without mild-to-severe eosinophilia (P1⁄4 0.52). In patients with and without moderate-to-severe eosinophilia, chronic GVHD occurred in 20 of 24 (83.3%) and 69 of 77 (89.6%), respectively (P1⁄4 0.49). These results indicate no association between eosinophilia and acute or chronic GVHD after CBT. The impact of eosinophilia within 100 days after CBT on disease-free survival (DFS) was studied using the Kaplan– Meier method and the log-rank test. The probabilities of DFS at 3 years after CBT in patients with and without eosinophilia were 81.5 and 82.6%, respectively (P1⁄4 0.96). In patients with and without moderate-to-severe eosinophilia, DFS also did not differ significantly (87.1 versus 80.8%, P1⁄4 0.76). These results indicate no association between eosinophilia and DFS after CBT. This study showed that eosinophilia (AEC 4500 10/l) occurred in 75 of 101 (74.3%) patients within 100 days after CBT. This incidence seems to be higher than the previously reported incidence of eosinophilia ranging from 9.4 to 38.9%. Aisa et al. showed that the incidence of eosinophilia, defined as blood eosinophil percentage of more than 4%, was 57% at 100 days after SCT. When we used this definition to diagnose eosinophilia, the incidence at 100 days after CBT increased to 93.1% in our study patients. Because of differences in various conditions other than the stem cell source, such as the conditioning regimen and GVHD prophylaxis, the precise comparison of the incidence in our report and in others is difficult; however, our study shows that eosinophilia is quite common after CBT. The association between eosinophilia and GVHD remains controversial. In previous studies, some authors suggested that eosinophilia after SCT is clinically correlated with the development of acute or chronic GVHD. In contrast, Aisa et al. recently showed that eosinophilia (blood eosinophil 44%) within 100 days after SCT was associated with lower rates of grade II–IV acute GVHD (43 versus 68%, Po0.001) and chronic GVHD (60 versus 74%, P1⁄4 0.011). As eosinophilia can occur in Th-2-mediated processes, the authors speculate that the association between eosinophilia and the reduced incidence of severe acute GVHD may reflect the immunosuppressive role of Th-2 cytokines. Sato et al. showed that pediatric patients with eosinophilia (AEC 4500 10/l) at any time after SCT had a higher event-free survival rate (81.1 versus 44.6%, P1⁄4 0.0025). As eosinophilia was also associated with a Bone Marrow Transplantation (2008) 42, 63–65 & 2008 Macmillan Publishers Limited All rights reserved 0268-3369/08

Myeloablative unrelated cord blood transplantation for acute leukemia patients between 50 and 55 years of age: single institutional retrospective comparison with patients younger than 50 years of age

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