Overcoming Various Comorbidities by G-CSF-Primed Unmanipulated BM SCT in Adult Patients with AML

ORIGINAL ARTICLE Overcoming various comorbidities by G-CSF-primed unmanipulated BM SCT in adult patients with AML

H-J Kim, W-S Min, B-S Cho, K-S Eom, S-Y Kim, Y-J Kim, S Lee, C-K Min, S-G Cho, J-W Lee and C-C Kim

Division of Hematology, Department of Internal Medicine, Catholic Hemopoietic Stem Cell Transplantation Center, St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

We examined whether the use of G-CSF-primed unmani- use of steady-state bone marrow (sBM) stem cells.1,2 In pulated bone marrow (pBM) permits successful transplant- addition, allogeneic G-CSF-primed bone marrow (pBM) ation in patients with adverse comorbid pretransplantation stem cells appear to be similar to PBSCs in terms of conditions. A total of 33 patients at variable risk of AML engraftment potential.3–7 Overall, allogeneic hematopoietic undergoing allogeneic SCT from an HLA-identical sibling SCT using pBM results in more rapid engraftment with a participated. The patients suffered from a variety of lower incidence of chronic GVHD than SCT using treatment-related sequelae before SCT and many cases PBSCs.7–9 However, relatively few studies have reported also featured the presence of major organ dysfunction. The on other important clinical outcomes of SCT using pBM vs median follow-up duration of patients who were among the sBM stem cells, such as acute and chronic GVHD,2 relapse overall survivors was 58 months (range, 11À125 months). rate, overall survival (OS) and disease-free survival, and no The median number of CD34 þ cells infused was 3.5 Â 106 conclusive evidence so far exists that pBM results in per kg (range, 0.8À15.6 Â 106 per kg). The median number improved survival compared to PBSCs or sBM stem cells. of days for recovery of ANC and platelet count without Nevertheless, pBM is advantageous as an allogeneic stem transfusion was 13 (range, 6À22) and 18 (range, 11À29) cell product because of both the rapidity of PB recovery days, respectively. Four patients (12%) died due to and the decreased incidence of chronic GVHD compared to nonrelapse causes and only one patient developed the same SCT using PBSCs. Allogeneic SCT using PBSCs is course of infectious complication as before SCT. No increasing because it permits enhanced engraftment and particular ﬁnding in the context of CMV infection or other the ability to obtain stem cells from donors without the post transplant complication was observed. The estimated need for general anesthesia; however, this technique is 10-year overall survival rate was 68%. Our results suggest associated with the increased incidence of critical forms of that the use of pBM allows successful engraftment without chronic GVHD, without any improvement in speed of increasing complications in patients with various comorbid- engraftment compared to SCT using pBM. To promote ities before transplantation. rapid engraftment while avoiding detrimental chronic Bone Marrow Transplantation (2009) 44, 345–351; GVHD, several previous studies have investigated mega- doi:10.1038/bmt.2009.42; published online 9 March 2009 dose SCT using pBM plus PBSCs10 and high-dose Keywords: G-CSF-primed unmanipulated bone marrow; pBM.5,6,8,11 AML; comorbid conditions; SCT On the basis of these earlier studies, we investigated the use of pBM in allogeneic sibling SCT under less than optimal conditions. More speciﬁcally, we examined the effectiveness of this procedure in cases of inferior donor condition (that is, markedly lower body weight than the recipient) and in recipients exhibiting various clinical comorbidities. We found Introduction that the use of pBM is effective in achieving a good quality of life after allogeneic SCT in patients with AML having Numerous studies have shown that the use of G-CSF- various pretransplant comorbidities. primed PBSCs results in more rapid engraftment than the

Materials and methods Correspondence: Professor W-S Min, Division of Hematology, Department of Internal Medicine, Catholic Hemopoietic Stem Cell Transplantation Patients Center, St Mary’s Hospital, College of Medicine, The Catholic University of A total of 33 consecutive patients treated for AML Korea, 62, Youidodong, Youngdungpoku, Seoul 150-713, Korea. E-mail: [email protected] between January 1998 and December 2007 in the Catholic Received 18 September 2008; revised 5 January 2009; accepted 16 Hemopoietic Stem Cell Transplantation Center were January 2009; published online 9 March 2009 considered eligible for this study if they had an Overcoming various comorbidities pre-SCT H-J Kim et al 346 HLA-identical sibling donor. Our center’s treatment policy Table 1 Clinical characteristics of 33 patients undergoing pBM is to perform myeloablative allogeneic SCT in intermediate- SCT to high-risk adult patients with AML if an HLA-matched Characteristics Number related donor is available. The procedure is performed as soon as possible after the first CR as an intensified post- Median age, years (range) remission therapy. The main clinical characteristics of Patients 37 (19–64) patients at the time of SCT are summarized in Table 1. Donors 36 (16–52) The median follow-up of patients who were among the Sex, male vs female overall survivors after allogeneic SCT was 58 months Patients 20:13 (range, 11–125), and a median period of 5 months (range, Donors 12:21 4–10) had elapsed between diagnosis and transplant. To Sex matching, Donor-Recipient investigate the effectiveness of overcoming various pre- M-M6 transplant comorbidities and to monitor transplantation M-F6 outcomes after SCT using pBM, the same G-CSF-priming F-M14 protocol and a very similar transplant procedure were F-F7 applied in patients with a single-disease entity of AML. The ABO matching most frequent pre-SCT complications were anal or perianal Match 23 infections, followed by lung infections and chemotherapy- Major mismatch 4 related cardiomyopathies. Among 33 patients with AML, Minor mismatch 2 19 showed other comorbidities (Table 2). Separately, a Major/minor mismatch 4 weight disparity of greater than 10 kg between the donor Subtype, FAB classification and the recipient (when the recipient weighed more than the M0 1 donor) was another criterion for enrollment in this study. M1 11 As summarized in Table 1, 30 patients (91%) received M2 14 M4 1 transplants in first CR and 3 patients (9%) in second CR. M5 2 HLA compatibility was determined by serotyping or high- M6 1 resolution genotyping for HLA-A, -B, -C and -DRB1, Secondary from myelodysplastic 3 depending on the method available at the time of SCT. syndrome Before 2005, donor identification was based on HLA Cytogenetics serotyping for class I antigens (HLA-A, -B and -C) and Favorable 5 high-resolution genotyping (PCR with sequence-specific Intermediate 20 primers, SSP) for class II antigens (HLA-DRB1). Since Unfavorable 8 2005, all donor–recipient pairs have been genotyped by Pretransplant status PCR-SSP for class I and II antigens. All 33 patients in this First CR 30 study received pBM transplants from a fully matched Second CR 3 sibling donor. All patients and donors provided written informed consent, and the treatment protocol was ap- Conditioning regimen proved by the institutional review board of the Catholic TBI based 27 Non-TBI based 6 University of Korea. Intensity of conditioning regimen Myeloablative 28 Chemotherapy before SCT Nonmyeloablative 5 Since its introduction in 1996, our center’s chemotherapy GVHD prophylaxis regimen for AML has undergone several modifications that CsA+MTX 28 have been documented in previous publications,12–15 and all Tacrolimus+MTX 5 patients enrolled in this study were treated according to the Median time to ANC 40.5 Â 109 per 13 (6–22) last updated standard protocol. All patients with AML liter, days (range) Median time to platelet 420 Â 109 per 18 (11–29) were subjected to the same induction and consolidation liter, days (range) strategy. Briefly, the treatment regimen consisted of ‘3 Â 7’ idarubicin (IDA) plus N4-behenoyl-1-b-D-arabinofuranosyl Abbreviations: F ¼ female; FAB ¼ French-America-British; M ¼ male. cytosine (BH-AC) induction chemotherapy (IC). IDA was administered i.v. at a daily dose of 12 mg/m2 over a period dose of 400 mg/m2 per day i.v. for 3 additional days (N ¼ 6). of 30 min for 3 consecutive days, and BH-AC was If a patient demonstrated more than 10% leukemic blast administered daily at a dose of 300 mg/m2 over a period levels in D þ 7 marrow, IDA plus BH-AC chemotherapy of 4 h for 7 consecutive days. On the basis of the results of a were administered as follows: IDA at a dose of 8 mg/m2, i.v. BM examination on D þ 7 of chemotherapy (that is, for 2 additional days (D þ 8 and D þ 9) plus BH-AC at a depending on the ratio of the remaining leukemic cells), dose of 300 mg/m2 for 3 additional days (D þ 8, D þ 9 and augmentation treatment was performed if a patient D þ 10; N ¼ 15). No additional treatment was provided if demonstrated more than 5% leukemic blasts. That is, if a the D þ 7 marrow demonstrated leukemic blast levels of patient displayed over 5À10% leukemic blasts in D þ 7 under 5% (N ¼ 12). One course of consolidation marrow following initial IC, BH-AC was administered at a chemotherapy was performed. The first consolidation

Bone Marrow Transplantation Overcoming various comorbidities pre-SCT H-J Kim et al 347 Table 2 Pretransplant comorbidities and/or weight discrepancies Table 3 Median numbers of cells infused between donor and recipient pBM stem cells, median Range Sequelae Number (%) TNC per kg ( Â 108) 3.7 2.3–6.1 Hemorrhoid with perianal abscess, fissure or fistula 12 (37) MNC per kg ( Â 108) 1.2 0.7–1.6 Pulmonary infectious sequelae 5 (15) CD34+ per kg ( Â 106) 3.5 0.8–15.6 Fungal pneumonia with cavitation 3 CD3+ per kg ( Â 106) 63.7 16.3–73.6 Pneumonectomy due to empyema 1 Pleural effusion 1 Abbreviations: MNC ¼ mononuclear cell; pBM ¼ primed bone marrow; Chemotherapy-induced cardiomyopathy 5 (15) TNC ¼ total nucleated cell. Extramedullary chloroma with poor performance 2 (6) Chronic hepatitis B or C with abnormal liver function 3 (9) Remained abscess pocket(s) formed during chemotherapy 2 (6) 9 Liver 1 0.5 Â 10 per liter and body temperatures exceeding 38.3 1C Spleen 1 were empirically treated with broad-spectrum antibiotics. Weight discrepancy only 2 (6) G-CSF (s.c., 5 mg/kg per day) was initiated on the seventh Poor performance only 2 (6) day post-pBM infusion, and continued until ANC reached 1.0 Â 109 per liter for 3 consecutive days. chemotherapy consisted of a combination of BH-AC (300 mg/m2, i.v. for 5 days) and IDA (12 mg/m2, i.v. for 3 Statistical analysis days). For all analyses, Po0.05 was considered statistically significant. OS was calculated from the time of diagnosis to death. Time to relapse was calculated from the date of Conditioning regimens and pBM transplantation until the date of relapse, and the proba- We performed pBM transplantation using a group of bility of relapse was estimated using the cumulative patients with AML in CR, whose clinical conditions are incidence method. Cumulative incidence of relapse (CIR) summarized in Table 2. The majority of patients (N ¼ 27) was defined based on morphological evidence of leukemia underwent a myeloablative conditioning regimen consisting in BM or extramedullary organs. To evaluate the prob- of CY (60 mg/kg per day for 2 days) and TBI (total ability of relapse, we excluded patients who died from 1320 cGy for 4 days). One patient received BU i.v. (3.2 mg/ either direct procedural toxicity or any other cause not kg per day for 4 days) and CY (60 mg/kg per day for 2 related to leukemia. Event-free survival (EFS) was calcu- days). Uroepithelial prophylaxis was achieved with hyper- lated from the date of stem cell infusion until the date of hydration and mesna. The remaining patients received BU engraftment failure, disease recurrence, secondary malign- i.v. (3.2 mg/kg per day for 2 days) and fludarabine (30 mg/ ancy, death from any cause or the last follow-up contact for 2 m per day for 5 days). pBM stem cells were infused 24 h patients who did not experience any of these events. The after the last CY or fludarabine treatment (day 0). For BM Kaplan–Meier method was used to calculate OS and EFS; expansion with G-CSF priming, the donors received 10 mg/ statistical significance under various clinical conditions was kg per day G-CSF s.c. for 3 days from DÀ3toDÀ1, calculated using the log-rank test. Patients who were still according to our standard protocol. No other treatment, alive in CR were censored at the time of their last follow- such as ex vivo T-cell depletion of the graft, was performed up. Nonrelapse mortality (NRM) was defined as death in any case. occurring in relapse-free patients. Death resulting from any cause after relapse was considered to have been caused by GVHD prophylaxis relapse. Univariate analysis was performed to test for In 28 patients, GVHD prophylaxis was provided by associations between OS/EFS outcomes and the demo- administering a continuous i.v. infusion of 3 mg/kg CsA graphic profiles of recipients and donors, subtypes from day 1. Subsequently, when patients were able to of AML, disease status before transplantation, clinical tolerate oral administration, they received CsA orally at variables including cytogenetics and conditioning regimens, 6 mg/kg per day in two doses until day 120. Tacrolimus was presence or absence of acute and/or chronic GVHD, stem used in the remaining five patients. The dose of CsA or cell source and infused CD34 þ cell dose by using the tacrolimus was then gradually tapered, and in the absence Cochran–Mantel–Haenszel test. Factors associated with of GVHD, discontinued 6 months after SCT. All patients each clinical parameter at Po0.20 in the univariate who received CsA also received a short course of MTX analyses were then used in the multivariate Cox propor- (10 mg/m2) on days 1, 3, 6 and 11; patients who received tional hazards regression analysis, using a forward step- tacrolimus received the same dose of MTX on day 1, and a wise approach. reduced dose (5 mg/m2) on days 3, 6 and 11.

General supportive care Results All patients were treated in private rooms with laminar airﬂow and received oral nonabsorbable antibiotics and a Infused cell doses and engraftment low-microbial diet for gut decontamination. Trimethoprim The infused CD34 þ cell doses consisted of a median of 3.5 sulfamethoxazole was administered for Pneumocystis (0.8–15.6) Â 106 per kg CD34 þ cells; the median number of carinii prophylaxis. Patients with an ANC of less than infused CD3 þ cells is shown in Table 3. The median

Bone Marrow Transplantation Overcoming various comorbidities pre-SCT H-J Kim et al 348 100 100

80 75 OS, 68%; N=33 60 50 40 CIR, 26%; N=33 25 20 Probability of survival, %

0 Cumulative incidence of relapse, % 0 0 20 40 60 80 100 120 0 20 40 60 80 100 120 140 Months Months Figure 3 The 10-year cumulative incidence of relapse (CIR) after Figure 1 The 10-year overall survival (OS) rate after allogeneic G-CSF- allogeneic G-CSF-primed bone marrow (pBM) SCT using HLA-matched primed bone marrow (pBM) SCT using HLA-matched sibling donors in sibling donors in patients with AML was 26%, as determined by the patients with AML was 68%, as determined by the Kaplan–Meier method. Kaplan–Meier method.

100 marginal significance, as shown in Table 4. By contrast, patient sex, infused CD34 þ cell dose, platelet recovery and 75 the development of chronic GVHD were all marginally EFS, 62%; N=33 significant predictors of EFS by multivariate analysis. Furthermore, the presence of the weight disparity between 50 the donor and recipient was not significantly associated with OS or EFS by multivariate analysis. Therefore, neither the presence of pre-SCT comorbidities nor weight disparity 25 was closely related to inferior survival rates in this study. These findings suggest that we can possibly overcome Probability of survival, % various pre-SCT comorbidities by pBM SCT in adult 0 patients with AML. 0 20 40 60 80 100 120 Months Development of acute and chronic GVHD Figure 2 The 10-year event-free survival (EFS) after allogeneic G-CSF- Of the 33 patients at risk, 14 patients (42%) developed primed bone marrow (pBM) SCT using HLA-matched sibling donors in acute GVHD, with 5 patients (15%) exceeding grade I patients with AML was 62%, as determined by the Kaplan–Meier method. (Table 5). However, only one patient demonstrated steroid- resistant grade III acute GVHD. The incidence of chronic GVHD was 50% (16) of the 32 patients evaluated, which number of days for the recovery of the ANC to over 500 included 5 limited and 11 extensive cases. Notably, 10 cases per ml and platelet count to over 20 000 per ml without evolved from acute GVHD (progressive type). Fortunately, transfusion was 13 (6À22) and 18 (11À29) days, respec- we have not experienced any fatal case of chronic GVHD tively. All patients showed successful engraftment. to date. Upon multivariate analysis, the development of acute GVHD was the only statistically significant factor associated with chronic GVHD. Our analysis did not Survival rate and relapse identify any risk factors for the development of acute The overall 10-year Kaplan–Meier estimated OS and EFS GVHD or the severity of acute or chronic GVHD (data not rates were 68 and 62%, respectively (Figures 1 and 2). Of 23 shown), which may have been the result of a relatively small patients (70%) who survived, 21 (64%) remained in sample size. Furthermore, one relapse developed among continuous CR. Among the 10 patients who died, 4 those who developed a progressive type of chronic GVHD. (40%) died of causes other than leukemic relapse. The 10-year CIR was 26% for all patients (Figure 3). In the univariate analysis, patient age, patient or donor sex, use of NRM heparin for veno-occlusive disease prophylaxis, infused The estimated cumulative incidence of NRM was 15% (4 of CD34 þ cell dose, platelet recovery and presence of anal/ 33; Figure 4; Table 6). Three of these four patients died perianal or pulmonary infectious sequelae before SCT from pneumonia, two of whom also developed acute correlated with OS to the extent of the statistical power, respiratory distress syndrome (ARDS). As mentioned Po0.2 (Table 4). In the multivariate analysis, however, above, one patient developed steroid-resistant grade III only the infused CD34 þ cell dose influenced survival acute GVHD, which resulted in the patient’s death. (P ¼ 0.0274). Both patient and donor sex showed a trend of Furthermore, among 22 cases who had precipitating

Bone Marrow Transplantation Overcoming various comorbidities pre-SCT H-J Kim et al 349 Table 4 Statistical results of univariate and multivariate analyses to test for associations between the clinical variable of AML and OS/EFS after HLA-identical sibling SCT

Patient characteristic OS EFS Univariate Multivariate Univariate Multivariate

PPRR 95% CI PPRR 95% CI

Patient age, p38 vs 438 0.1083 NS — — NS — — — Patient sex, female vs male 0.0906 0.0581 0.03 0.001–1.13 0.0498 0.0785 0.05 0.002–1.39 Donor sex, female vs male 0.1748 0.0529 14.5 0.97–217.73 NS NS — — Prophylaxis of veno-occlusive disease 0.0565 NS — — 0.1441 NS — — with heparin Infused cell dose (CD34+ cells, Â 106 0.066 0.0274 19.5 1.39–272.75 0.1441 0.0649 5.67 0.89–35.81 cells per kg), p3.5 vs 43.5 Platelet recovery to over 20 000 per ml 0.1847 NS — — 0.086 0.0649 5.67 0.89–35.81 without transfusion, p18 vs 418 days Chronic GVHD, yes vs no NS — — — 0.1603 0.0841 5.42 0.79–36.83 Chronic GVHD grade, limited type vs NS — — — 0.1441 NS — — extensive type Weight disparity between the donor and NS — — — NS — — — recipient Infectious conditions of anus or 0.0668 NS — — 0.1306 NS — — perianus Infectious conditions of lung 0.115 NS — — 0.091 NS — —

Abbreviations: CI ¼ conﬁdence interval; EFS ¼ event-free survival; NS ¼ nonspeciﬁc; OS ¼ overall survival; RR ¼ relative risk.

Table 5 Proﬁle of acute and chronic GVHD after transplantation 100

GVHD Number of patients evaluable (%) 80 Acute, grade 33 0 19 (58) I 9 (27) 60 II 4 (12) III–IV 1 (3) 40 Chronic, type 32 0 16 (50) Limited 5 (16) 20 NRM, 15%; N=33 Extensive 11 (34) Cumulative incidence of NRM, % 0 0 20406080100120 infectious comorbidities before SCT (for example, pneu- Months monia, hemorrhoid sequelae, viral hepatitis), 3 patients Figure 4 The 10-year cumulative incidence of nonrelapse mortality showed aggravation of the same organ condition after SCT. (NRM) after G-CSF-primed bone marrow (pBM) SCT using HLA- One patient died of cardiopulmonary dysfunction due to matched sibling donors in patients with AML was 15%, as determined by pneumonia with precedent chemotherapy-induced cardio- the Kaplan–Meier method. myopathy combined with limited chronic GVHD at 19 months post-SCT. Neither CMV antigenemia nor CMV disease was signiﬁcantly correlated with the development of Table 6 Primary causes of NRM GVHD or NRM in this study (data not shown). Cause of death

Pneumonia±ARDS 3 Discussion Acute GVHD, grade III 1

In general, a high BM or PB cell dose has been shown to Abbreviation: ARDS ¼ adult respiratory distress syndrome. enhance engraftment after transplant and reduce TRM in both sibling and alternative donor transplants.12–14 There- fore, many recent clinical studies have relied on PBSCs as a in 2001, PBSCT involves a slightly increased risk of acute cell source in such cases. Some conflicting results have been GVHD.16 More importantly, recent studies have found no reported with respect to chronic GVHD before 2000, when significant difference between PBSCT and SCT using pBM we performed G-CSF-mobilized peripheral blood stem cell in terms of engraftment, although PBSCT involved a transplantation (PBSCT). However, a higher incidence of significantly increased risk of acute and/or chronic chronic GVHD in PBSCT compared to SCT using sBM GVHD.5,6,17 may be more acceptable with current management strate- In this study treating the single-disease entity of AML, gies.1,2,8,9,15 Moreover, based on a meta-analysis performed allogeneic sibling SCT using 3-day pBM showed stable

Bone Marrow Transplantation Overcoming various comorbidities pre-SCT H-J Kim et al 350 engraftment and tolerable outcomes, that is, without critical consequences. These findings suggest that we can development of the same course of infectious complications possibly overcome various pre-SCT comorbidities by and aggravation of major organ dysfunction as before higher doses of pBM SCT in adult patients with AML. SCT. Notably, the patients treated here suffered from In conclusion, our results suggest that a 3-day schedule various pre-SCT comorbidities combined with a weight of pBM is a feasible and reliable method of obtaining discrepancy between the donor and recipient. Overall, the sufficient stem cells from allogeneic sibling donors before 10-year Kaplan–Meier estimated OS and EFS rates were 68 BM harvest, even in cases in which the recipient weighs and 62%, respectively. Chronic GVHD developed in 50% more than the donor or suffers from an infectious or of evaluable patients, with a somewhat higher incidence of noninfectious comorbidity. the extensive type (34%); one patient developed severe acute GVHD (grade III). These results suggest that our pBM strategy may increase the likelihood of chronic Acknowledgements GVHD. However, most patients responded well to the conventional management strategy and the overall rate of This study was supported by a grant from the Korea Health 21 acute and chronic GVHD was deemed acceptable. One R&D Project, Ministry of Health & Welfare, Republic of Korea patient, who showed limited chronic GVHD, died of (A05-0223-AA1018-06A2-00010A). delayed pneumonia with ARDS. Therefore, our results suggest that SCT using pBM may be advantageous in terms of overcoming pretransplant comorbidities. Conflict of interest The dose of G-CSF used in this study was 10 mg/kg per day s.c. for 3 consecutive days (that is, D 3, D 2 and À À The authors declare no financial conflict of interest. DÀ1). According to the literature, several G-CSF regimens have been used to stimulate BM, ranging from 2- to 5-day priming periods at doses of 3À10 mg/kg per day.3–6,18 Our modified G-CSF regimen was chosen based on previous References data indicating that two doses (that is, DÀ2 and DÀ1) þ þ 1 Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, produce sufficient CD34 and CD3 cells to allow rapid Negrin R et al. Transplantation of bone marrow as compared engraftment with modest transfusion requirements and a with peripheral-blood cells from HLA-identical relatives in 3 decrease in hospitalization by a mean of 10 days. The patients with hematologic cancers. N Engl J Med 2001; 344: CD34 þ and CD3 þ cell contents per kilogram recipient 175–181. body weight were comparable with values observed in 2 Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, previous studies.5,6 As observed in both animal and human Howson-Jan K et al. A randomized multicenter comparison of studies, G-CSF induces IL-4 and IL-10 production in bone marrow and peripheral blood in recipient of matched peripheral T cells (that is, the TH2 lymphokine profile) sibling allogeneic transplants for myeloid malignancies. Blood instead of TH1-polarized proinflammatory cytokines; in 2002; 100: 1525–1531. addition, G-CSF induces a reduction in the total number of 3 Isola LM, Scigliano E, Skerrett D, Shank B, Ross V, Najfeld V þ þ 18–21 et al. A pilot study of allogeneic bone marrow transplantation BM T cells and reverses the CD4 /CD8 ratio. using related donors stimulated with G-CSF. Bone Marrow Although some conflicting data have been reported, the Transplant 1997; 20: 1033–1037. majority of studies agree that pBM or sBM SCT reduces 4 Isola L, Scigliano E, Fruchtman S. Long-term follow-up after the incidence of chronic GVHD compared to PBSCT.6,7,9 allogeneic granulocyte colony-stimulating factor-primed bone Thus, considering both in vitro and clinical findings marrow transplantation. Biol Blood Marrow Transplant 2000; regarding acute and chronic GVHD, pBM appears to be 6: 428–433. an appropriate stem cell source for use in patients with 5 Serody JS, Spark SD, Lin Y, Capel EJ, Bigelow SH, Kirby SL critical comorbidities because it is less likely to result in et al. Comparison of granulocyte colony-stimulating factor chronic GVHD. However, our data showed that pBM SCT (G-CSF)-mobilized peripheral blood progenitor cells and resulted in a tendency to increased rate of progressive-type G-CSF-stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation. Biol Blood Marrow chronic GVHD, but comparable values for OS and EFS. Transplant 2000; 6: 434–440. Unfortunately, we did not examine T-cell subsets during 6 Morton J, Hutchins C, Durrant S. Granulocyte-colony- this study, so we are unable to determine any differences in stimulating factor (G-CSF)-primed allogeneic bone marrow: cellular immunologic responses according to the duration significantly less graft-versus-host disease and comparable of G-CSF priming. Further studies are required to reveal engraftment to G-CSF-mobilized peripheral blood stem cells. the exact mechanism(s) underlying these unexpected Blood 2001; 98: 3186–3191. clinical outcomes. 7 Elfenbein GJ, Sackstein R, Oblon DJ. Do G-CSF mobilized, We identified a potential predictor of OS—the infused peripheral blood-derived stem cells from healthy, HLA- CD34 þ cell dose. Interestingly, patient sex showed a trend identical donors really engraft more rapidly than do G-CSF Blood Cells Mol of marginal significance to OS/EFS. Of note, neither primed, bone marrow-derived stem cells? No!. Dis 2004; 32: 106–111. presence of pre-SCT comorbidities nor weight disparity 8 Tanimoto TE, Yamaguchi T, Tanaka Y, Saito A, Tajima K, was closely related to inferior survival rates, as shown in Karasuno T et al. Comparative analysis of clinical outcomes Table 4. The estimated cumulative incidence of NRM was after allogeneic bone marrow transplantation versus peripheral 15% in this study, even though two-thirds of all patients blood stem cell transplantation from a related donor in had prior infectious sequelae with the potential of inducing Japanese patients. Br J Haematol 2004; 125: 480–493.

Bone Marrow Transplantation Overcoming various comorbidities pre-SCT H-J Kim et al 351 9 Storek J, Gooley T, Siadak M, Bensinger WI, Maloney DG, acute myeloid leukemia in ﬁrst complete remission. Bone Chauncey TR et al. Allogeneic peripheral blood stem cell Marrow Transplant 2004; 34: 215–220. transplantation may be associated with a high risk of chronic 16 Mavroudis D, Read E, Cottler-Fox M, Couriel D, Molldrem J, graft-versus-host disease. Blood 1997; 90: 4705–4709. Carter C et al. CD34+ cell dose predicts survival, posttrans- 10 Langer T, Beck JD, Gravou-Apostulatou C, Lang P, plant morbidity, and rate of hematologic recovery after Handgretinger R, Greil J. Successful treatment of primary allogeneic marrow transplants for hematologic malignancies. refractory acute myeloid leukemia with megadose stem cell Blood 1996; 88: 3223–3229. transplantation, bone marrow boost and reduced intensity 17 Bahceci E, Read EJ, Leitman S, Childs R, Dunbar C, Young conditioning avoiding chronic graft vs. host disease and severe NS et al. CD34+ cell dose predicts relapse and survival after late toxicity. Pediatr Transplant 2003; 7: 494–496. T-cell depleted HLA-identical haematopoietic stem cell trans- 11 Ji SQ, Chen HR, Wang HX, Yan HM, Zhu L, Xue M et al. plantation (HSCT) for haematological malignancies. Br J G-CSF-primed haploidentical marrow transplantation without Haematol 2000; 108: 408–414. ex vivo T cell depletion: an excellent alternative for high-risk 18 Singhal S, Powles R, Treleaven J, Kulkarni S, Sirohi B, Horton leukemia. Bone Marrow Transplant 2002; 30: 861–866. C et al. A low CD34+ cell dose results in higher mortality and 12 Park HS, Kim DW, Kim CC, Kim HK, Kim JS, Hwang TJ poorer survival after blood or marrow stem cell transplanta- et al. Induction chemotherapy with idarubicin plus tion from HLA-identical siblings: should 2 Â 106/kg CD34+ N4-behenoyl-1-b-D-arabinofuranosylcytosine in acute myelo- cells/kg be considered the minimum threshold? Bone Marrow genous leukemia: a newly designed induction regimen-a Transplant 2000; 26: 489–496. prospective, cooperative multicenter study. Semin Hematol 19 Majolino I, Saglio G, Scime R, Serra A, Cavallaro AM, 1996; 33 (Suppl 3): 24–29. Fiandaca T et al. High incidence of chronic GvHD after 13 Min WS, Kim HJ, Choi Y, Jeong HY, Kim CC. Interpretation primary allogeneic peripheral blood stem cell transplantation of interleukin-2 receptor alpha positive cells during induction in patients with hematologic malignancies. Bone Marrow chemotherapy for adult acute myelogenous leukaemia pa- Transplant 1996; 17: 555–560. tients. Hematol Oncol 2007; 25: 76–83. 20 Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, 14 Kim HJ, Min WS, Eom KS, Cho BS, Kim SY, Bok JN et al. Antin JH. Acute and chronic graft-versus-host disease after Anti-leukaemic role of acute GvHD after unrelated haemato- allogeneic peripheral-blood stem-cell and bone marrow trans- poietic stem cell transplantation in intermediate- to high-risk plantation: a meta-analysis. J Clin Oncol 2001; 19: 3685–3691. acute myelogenous leukaemia. Bone Marrow Transplant 2007; 21 Frangoul H, Nemecek ER, Billheimer D, Pulsipher MA, Khan 40: 1069–1074. S, Woolfrey A et al. A prospective study of G-CSF-primed 15 Kim HJ, Min WS, Eom KS, Park SJ, Park YH, Kim DW et al. bone marrow as a stem-cell source for allogeneic bone marrow Autologous stem cell transplantation using modiﬁed TAM or transplantation in children: a Pediatric Blood and Marrow combination of triple-alkylating agents conditioning regimens Transplant Consortium (PBMTC) study. Blood 2007; 110: as one of the post-remission treatments in patients with adult 4584–4587.

Bone Marrow Transplantation