Accurate Prediction of Initial Busulfan Exposure Using a Test Dose With 2‐ and 6‐Hour Blood Sampling in Adult Patients Receiving a Twice‐Daily Intravenous Busulfan‐Based Conditioning Regimen

Abstract <Introduction> HPS are rare but often-fatal conditions characterized by an inappropriate and sustained activation of the cellular immune system leading to accumulation of activated macrophages and a cytokine storm. HPS consists of primary and secondary Hemophagocytic Lymphohistiocytosis (HLH). Secondary HLH occurs at any age and the genetic contribution remains uncertain. Clinical features in patients with HLH are fever, cytopenias, liver dysfunction, hepato-splenomegaly, and the presence of hemophagocytosis in the bone marrow as well as other reticuloendothelical tissues. We will report on the hematological abnormalities and the clinical course of 20/152 patients who received RI-CBT and developed secondary HLH in adult patients with hematological disease in early phase after RI-CBT. <Object> The 1st purpose was to investigate the incidence of HLH and pattern of chimerism. The 2nd was to identify the risk factors after UCBT. <Patients and Methods> We reviewed medical records of 152 patients with hematological diseases who had received RI-CBT between January 2002 and April 2005 at Toranomon Hospital, Tokyo, Japan. Diagnosis of HLH was made with the followings; high fever, cytopenias, and hemophagocytic findings in bone marrow examination. Time to event curves were plotted by using the actuarial method of Kaplan-Meier, and differences between curves were analyzed by log-rank tests. The following factors were considered potential predictors of outcomes about 2nd purpose: patient’s age, HLA disparity, infused TNC dose/CD34 dose, disease/disease status at transplantation, GVHD prophylaxis and sepsis which coincided with HLH. All factors were tested for the proportional hazards assumption. <Results> Patient’s median age was 55 years (17–79), Primary diseases consisted of standard (n=31) and advanced (n=121). HLA disparities were 4/6 match (n=123), 5/6 (n=22), and others (n=7). Total nucleated cell/CD34 cell dose were 3.46×10E7/kg (1.6–5.2) and 0.78×10E5/kg (0.1–3.3), respectively. Main conditioning regimen was Fludarabine (125mg/m2) +Melphalan (80mg/m2) or Busulfan (8mg/kg) +TBI 4Gy with cyclospoline (n=89) and tacrolimus (n=63) as GVHD prophylaxis and received single cord blood unit. Twenty patients were diagnosis with HLH and the incidence of HLH was 13% (95%CI; 8–18) and median onset day was 18.5 days (range; 10–29). In patients with sepsis (n=46) and without sepsis (n=106), the incidence of HLH was 28% (95%CI; 15–41) and 7% (95%CI; 3–12), respectively (P<0.0002). All patients who were diagnosis with HLH using bone marrow examination achieved 100% of donor chimerism. In multivariate analysis, the most important risk factor of HLH after RI-CBT was sepsis which coincided with HLH at the same times (p<0.05), while other factors did not influence. <Discussion/Conclusion> HLH is fatal complication after allogeneic peripheral stem cell and unrelated bone marrow transplantation. However in RI-CBT, the incidence would be higher and earlier onset than other sources. The most of HLH patients died by multi-organ failure. In this report the most important risk factor was sepsis which coincided with HLH. Figure Figure

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Target Dose Adjustment of Oral Busulfan Using a Test Dose in Japanese Adults Undergoing Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5313.5313 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5313-5313

Author(s):

Yasushi Takamatsu ◽

Kentaro Ogata ◽

Noriaki Sasaki ◽

Shuuji Hara ◽

Tetsuya Eto ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Dose Adjustment ◽

Prospective Trial ◽

Conditioning Regimen ◽

Test Dose ◽

Hematopoietic Stem

Abstract Oral busulfan (BU) is widely used in patients undergoing hematopoietic stem cell transplantation (HST). Therapeutic effect of BU is related to the area under the plasma concentration-time curve (AUC) or the average plasma concentrations at steady state (Css). It has been shown that BU pharmacokinetics (PK) are highly variable and the dose adjustment according to the BU levels is critical to get the successful results of HST for Caucasians. BU is metabolized mainly in the liver through conjugation with glutathione by glutathione S-transferase (GST). Recent study has shown that the polymorphisms of GST genes are associated with the risk of developing hepatic veno-occlusive disease in patients undergoing HST. Ethnic variation is also demonstrated in relation to a gene deletion polymorphism of GST, suggesting that BU metabolism is influenced by the race. BU PK have been extensively investigated in Caucasians and few studies have focused on Asian people. We therefore underwent a prospective trial of adjusting BU doses depending on the individual BU PK in 36 Japanese patients aged from 16 to 64 years (median; 47 years). All patients received a busulfan-containing conditioning regimen and underwent allogeneic HST. Individual PK were studied following a 0.5 mg/kg test dose of BU administered orally. BU concentrations were measured by a high-performance liquid chromatographic method and individual PK parameters of BU were calculated with a one-compartment model by using Bayesian modeling program. The median clearance (CL/F) was 0.16 L/hr/kg (0.09 to 0.34 L/hr/kg), the median volume of distribution (Vd/F) 0.65 L/kg (range; 0.41 to 0.97 L/kg), the median elimination half-life (t1/2) 2.9 hr (range; 1.9 to 7.0 hr), and the median absorption rate constant (ka) 2.46 /hr (range; 0.53 to 6.03 /hr). BU doses were adjusted to achieve a target BU Css between 800 and 900 ng/mL. Twenty-six (72%) patients were required to reduce BU doses and adjusted BU doses ranged from 0.51 to 1.29 mg/kg/time (median; 0.85 mg/kg/time). After administrating the 6th dose of BU for the conditioning regimen, BU PK were analyzed. Expected Css was significantly correlated with observed Css and predictability of the test dose was 106.4±21.8%. Engraftment was successful in 34 of 36 (94%) patients. Grade 2 to 4 regimen-related toxicity except stomatitis occurred in 4 (11%) patients. These data demonstrate that BU PK vary widely from one patient to another after oral BU in Japanese and individualization of BU doses depending on the BU PK are useful in improving clinical outcome in patients undergoing HST.

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Pre-Transplant Test Dose vs. PK Studies during Conditioning Regimen To Target iv Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.3006.3006 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3006-3006

Author(s):

Sandeep Chunduri ◽

Rakesh Beri ◽

Lisa C. Dobogai ◽

Elizabeth Hurter ◽

Christina Mactal-Haaf ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Conditioning Regimen ◽

Test Dose ◽

Hematopoietic Stem ◽

Blood Samples ◽

The Mean

Abstract In this study we tested the efficacy of a test dose of iv busulfan in targeting blood levels of this drug during the conditioning regimen prior to an allogeneic hematopoietic stem cell transplant. We analyzed blood samples of 22 patients undergoing allogeneic hematopoietic stem cell transplantation with a busulfan-based conditioning regimen. Patients received a test dose of busulfan at 0.8 mg/kg as a 60 minute intravenous infusion. Serial blood samples were drawn at eight time points: 15 minutes before dose, at end of infusion, 15 minutes after completion, 30 minutes after completion, 60 minutes after completion, 2 hours after completion, 4 hours after completion, and 6 hours after completion. Pharmacokinetics (PK) studies were then performed at the Seattle Cancer Care pharmacokinetics laboratory. The AUC was determined using WinNonlin Professional software. The conditioning dose of busulfan was calculated by multiplying the test dose in mg/AUC × 4800. After the first dose of busulfan was administered, the same protocol was used to test busulfan PK. If the Busulfan AUC was therapeutic (between 4800 μM*min and 5200 μM*min) then the same dose was continued. If the Busulfan AUC was low or high then the third and fourth doses of busulfan were adjusted. The test dose of 0.8 mg/kg intravenous did not have any hematological side effects. The mean historic dose (solely based on weight) was 3.2 ± 0.1 mg/kg and the mean dose based on the test dose was 3.5 ± 0.5 mg/kg (p=0.02). In 12 patients where we also analyzed PK after the first day of conditioning regimen, AUC values of busulfan obtained during test dose and after day 1 dose were not different (p=0.7). The mean dose of busulfan based on test dose was 3.5 ± 0.6 mg/kg while the final dose based on day 1 busulfan PK was 3.6 ± 0.7 mg/kg (p=0.9). Nevertheless, in 2 CML patients who were on treatment with dasatinib or nilotinib at the time of the test dose, a higher AUC was observed (AUC 6065 and 6200, respectively). A pre-transplant busulfan test dose can be safely performed anytime prior to transplant and allows targeting the dose of busulfan efficiently, thus avoiding the requirement of PK studies during the conditioning regimen.

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High Rate of Engraftment and Low Regimen-Related Toxicity Using Fludarabine, Melphalan and Thiotepa Conditioning for Unrelated Donor Cord Blood Transplantation

Blood ◽

10.1182/blood.v112.11.4414.4414 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4414-4414

Author(s):

Stefan O Ciurea ◽

Partow Kebriaei ◽

Issa F Khouri ◽

Muzaffar H. Qazilbash ◽

Roy B Jones ◽

...

Keyword(s):

Acute Leukemia ◽

Cord Blood ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Adult Patients ◽

High Rate ◽

Unrelated Donor ◽

Platelet Recovery ◽

Blood Transplantation

Abstract BACKGROUND: Cord blood transplantation (CBT) represents an alternative source of stem cells for adult patients who lack a matched sibling or unrelated donor. However, the optimal type and intensity of the preparative regimen for patients receiving a CBT is not clear. We hypothesized that a conditioning regimen consisting of fludarabine, melphalan and thiotepa will be associated with an acceptable rate of engraftment and treatmentrelated mortality in patients receiving a CBT. METHODS: 37 patients, median age 31 years (2–57) and a median weight of 73kg, were treated between 8/2003 and 5/2008. All had advanced hematologic malignancies (24 with acute leukemia, 12 with lymphoma and one with CLL) At the time of transplant, 21 pts (57%) were in complete remission (CR) (first CR=20%) and 16 had relapsed/refractory disease. Grafts consisted of double (29 pts) or single (8 pts) CB units. Cytogenetics for patients with acute leukemia were poor in 11, intermediate in 9, good in 1 and unknown in 3 pts. Donor recipient HLA matching was (intermediate resolution class I HLA A and B and high-resolution DRB1): 3/6 (n=1, 1.5%), 4/6 (n=47, 71.2%) and 5/6 (n=18, 27.3%) alleles (n=66 units). Median total nucleated cell count was 1.8×107/kg (range 1–5.8). Nineteen patients received ex-vivo expanded units. The conditioning regimen consisted of melphalan 140 mg/m2 on day -8, thiotepa 10 mg/m2 on day -7, fludarabine 160 mg/m2 over 4 days on days -6, -5, -4, -3, and rabbit ATG 1.25 mg/kg on day -4 and 1.75 mg/kg on day -3 (FMT). Patients with CD 20+ lymphoid malignancies also received rituximab 375mg/m2 on day -9 (n=8, 22%). GVHD prophylaxis was tacrolimus and mini-methotrexate in 23 (62%) and tacrolimus and mycophenolate in 14 pts (38%). RESULTS: 36 patients (97%) were evaluable for engraftment. 1 patient died within 30 days due to progressive leukemia. 34/36 patients (95%) engrafted neutrophils and had hematopoietic recovery with 100% cord blood-derived cells. At day 30, of the 29 patients who received a double CBT, 75% had chimerism derived entirely from one donor while 25% had mixed donors chimerism. Neutrophil recovery to ANC >0.5 × 10e9/l occurred after a median of 21 days (range 6–45) and platelet recovery to >20 × 10e9/l after a median of 37 days (range 26–134, N=24; 67%). 32/37 pts (87%) were in CR after transplant with 16 surviving after a median follow-up of 12.1 months. Thirteen patients (36%) developed gr II–IV aGVHD (gr III–IV aGVHD in 5 patients, 14%), and 13 of 32 patients had cGVHD (40%), with the majority experiencing extensive GVHD. 11 patients (29.7%) relapsed after a median of 7 months post transplant and 12 died of nonrelapse causes. Day-100 treatment-related mortality in this heavily pre-treated population was 10%. Overall, causes of death included disease relapse (n=9), infections (n=6), organ failure (n=3), pulmonary hemorrhage (n=1) and GVHD (n=2). CONCLUSIONS: The FMT regimen was sufficiently immunosuppressive to support high rate of engraftment with acceptable TRM in heavily pre-treated adult patients with advanced hematologic malignancies undergoing CBT. These results support further evaluation of this regimen in CBT.

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Unrelated Cord Blood Transplantation: Comparison After Single Unit Cord Blood Intrabone Injection and Double Unit Cord Blood Transplantation In Patients with Hematological Malignant Disorders. A Eurocord-EBMT Analysis

Blood ◽

10.1182/blood.v116.21.223.223 ◽

2010 ◽

Vol 116 (21) ◽

pp. 223-223 ◽

Cited By ~ 4

Author(s):

Vanderson Rocha ◽

Myriam Labopin ◽

Annalisa Ruggeri ◽

Marina Podestà ◽

Dolores Caballero ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Adult Patients ◽

Myeloablative Conditioning ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

The Impact

Abstract Abstract 223 The use of single cord blood unit for transplantation in adult patients is limited due to the high risk of graft failure and delayed neutrophil and platelet recoveries. The limited hematopoietic progenitors in UCB grafts and their homing after IV injection, have prompted investigators to study the design of delivering CB grafts directly into the bone marrow (BM) space (IBCBT) or to use double cord blood transplantation (dUCBT) to improve engraftment. To evaluate the impact of IBCBT, we made a retrospective based registry comparison with dUCBT performed in the same time period (2006-2010) and reported to Eurocord-EBMT. We included 87 and 149 patients who received either IBCBT or dUCBT, respectively, after a myeloablative conditioning regimen for malignant disorders. IBCBT was performed in 8 EBMT centers whereas dUCBT was performed in 56 EBMT centers. Majority of patients in both groups had acute leukemia. IBCBT patients were older (p<0.001), more frequently received an autologous graft (p<0.001) and had positive CMV serology (p<0.001), and importantly had more advanced disease at transplantation (p=0.04). Median number of infused (after thawing) nucleated cells injected intrabone was 2.5×107/kg and it was 3.9×107/kg in dUCBT (p<0.001). In 72% of both groups, CB grafts were HLA 4/6 (the highest HLA disparity was taken into consideration in dUCBT). Other differences were regarding GVHD prophylaxis that was based on CSA+MMF in 100% of IBCBT and in 62% of dUCBT cases; ATG was used in all IBCBT and 40% of dUCBT. Median follow-up time was 18 months in IBCBT and 17 months in dUCBT. At day 30, cumulative incidence (CI) of neutrophil recovery (ANC >500) was 83% after IBCBT and 63% after dUCBT, and at day 60, it was 90% in both groups; the median time to reach ANC>500 was 23 and 28 days after IBCBT and after dUCBT (p=0.001) respectively. At Day-180 CI of platelets recovery was 81% after IBCBT and 65% after dUCBT (p<0.001) with a median time of 36 days and 49 respectively (p=0.002). At day 100, CI of acute GVHD (II-IV) was 19% and 47% (p<0.001) and chronic GVHD 34% and 37% respectively (p=NS) respectively. Unadjusted 2 years-CI of NRM and RI were 31% and 23% after IBCBT and 35% and 28% after dUCBT, respectively (p=NS). Unadjusted 2 y-DFS estimation was 47% after IBCBT and 37% after dUCBT (p=NS). In multivariate analysis adjusting for statistical differences between 2 groups (such as status of the disease at transplant, age, CMV, previous transplants, GVHD prophylaxis), recipients of IBCBT had improved DFS (HR: 1.64, p=0.035), faster platelet recovery (HR:2.13, p<0.001) and decreased acute GVHD (HR:0.31; p<0.001) compared to dUCBT recipients. We did not find a cut-off value of number of nucleated cells after IBCBT or dUCBT that could be associated with outcomes after both approaches. In conclusion, both strategies have extended the use of CB transplants to adults in need of cord blood transplantation. Therefore, IBCBT is an option to transplant adult patients with single CB units after myeloablative conditioning regimen and may impact the total costs of cord blood transplantation. Based on these results, intra-bone technique may disclose new transplant potentialities also with other HSC sources. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Stem Cell Tranplantation (allo-SCT) for Adult Patients with Active Refractory/Relapsed Hematological Malignancies: a Survey From the Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).

Blood ◽

10.1182/blood.v116.21.3456.3456 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3456-3456

Author(s):

Patrice Chevallier ◽

Noel Milpied ◽

Karin Bilger ◽

Gérard Socié ◽

Ibrahim Yakoub-Agha ◽

...

Keyword(s):

Stem Cell ◽

Conflicts Of Interest ◽

Phase 1 ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Best Supportive Care ◽

Adult Patients ◽

Peripheral Blood Stem Cells ◽

Hematological Diseases

Abstract Abstract 3456 Patients with active refractory/relapsed hematological diseases have a very poor outcome. Best supportive care or investigational therapies in phase 1 trials are usually proposed to these patients. However, some previous data suggested that allo-SCT might be an efficient therapy even in the setting of chemorefractory disease, because long-term immune-mediated disease control can be achieved in some patients after allo-SCT. The aim of this study was to evaluate on a large series the outcome of adult patients with active refractory/relapsed hematological diseases at time of allo-SCT and to determine which sub-group would most benefit from such approach. Between 2005 and 2009, 861 patients with various hematological diseases (AML, n=323; ALL, n=43; MDS, n=129, CMML, n=12; MPS, n=110; CML, n=28; NHL, n=100; HL, n=40; myeloma, n=36; CLL, n=24; and other, n=16) were treated with allo-SCT, and reported to the SFGM-TC Registry. Per study criteria, all patients presented with active refractory or relapsed disease at time of transplant. This series included 517 males (60%) and 344 females (40%). The median age at transplant was 50 (range, 16–71) years. The median interval between diagnosis and transplant was 17 (range, 1–99) months. 32% of patients failed at least one prior SCT (Autologous or allogeneic prior to allo-SCT). 350 (41%) patients received allo-SCT from an HLA-matched sibling donor, while the remaining 59% received an allogeneic graft from a matched unrelated or mismatched donor. The stem cell source was mainly peripheral blood stem cells (n=617; 72%). Bone marrow was used in 139 patients (16%), and cord blood in 107 patients (12%). Myeloablative conditioning regimen was used in 328 patients (38%), and various reduced-intensity regimens were used in other cases (62%). With a median follow-up of 290 (range, 1–1854) days after allo-SCT, engraftment was observed in 88% of cases. Grade II-IV and grade III-IV acute GVHD occurred in 35% (n=301) and 17% (n=144) of patients, respectively. Chronic GVHD was observed in 185 patients (21%; limited: n=77; extensive: n=82; missing data: n=24). At last follow-up, 347 patients (40%) were still alive (of whom 297 were in CR; 86%). 246 patients (28.5%) died of disease progression, and 232 patients died of transplant-related causes (NRM: 27%). The Kaplan-Meier (KM) estimates of overall survival (OS) at one and 2 years were 39% (95%CI, 36–43%) and 31% (95%CI, 28–35%), respectively. Of note, in patients with lymphoma (n=140), OS at 1 and 2 years were 57% (95%CI, 48–66%) and 49% (95%CI, 40–58%) versus 36% (95%CI, 32–40%) and 27% (95%CI, 23–31%), respectively, in all other diagnoses (P=0.00004). In a Cox multivariate analysis accounting for relevant factors, a diagnosis of lymphoma (NHL or Hodgkin) was the most significant factor associated with improved survival (RR=1.68; 95%CI, 1.3–2.2; P=0.0001). Despite its retrospective nature and the inherent selection biases, in case of availability of suitable donor, this data support the use of allo-SCT in adult patients with active refractory/relapsed hematological diseases, especially in patients with lymphomas. Results are expected to be further improved with the advent of novel conditioning regimens and maintenance therapies after transplant that are currently tested as part of prospective studies. Disclosures: No relevant conflicts of interest to declare.

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