CC BY-NC-ND
0ASBMI
American Society for Blood and Marrow Transplantation
Fludarabine and Pharmacokinetic-Targeted Busulfan before Allografting for Adults with Acute
Lymphoid Leukemia
12 12 2 Stella Santarone, Joseph Pidala, Marta Di Nicola, Teresa Field, Melissa Alsina,
2 2 2 2 2 Ernesto Ayala, William Janssen, Mohamed A. Kharfan-Dabaja, LeonelOchoa, Lia Perez, 2 2 2 2 Janelle Perkins, Jyoti Raychaudhuri, Hugo Fernandez, Claudio Anasetti
We aimed to evaluate the safety and efficacy of fludarabine (FLU) and pharmacokinetic-targeted busulfan (BU) as conditioning regimen for hematopoietic cell transplantation (HCT) in adult patients with acute lymphoid leukemia (ALL). Forty-four patients with ALL (27 in first complete remission [CRI] and 17 in more advanced disease stage: 4 with primary induction failure [PIF], 12 in CR2, and I in CR3) received FLU and pharmacokinetic-targeted BU as preparative therapy for HCT. Grafts were T-replete, filgrastim-mobilized peripheral blood stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (TAC) and short-course methotrexate in 36 patients, TAC and sirolimus in 3, and TAC and mycophenolate mofetil in 5. Primary engraftment was achieved in all 44 patients. The cumulative incidence of transplant-related mortality (TRM) was 2% (95% confidence interval [CI] 0%-I6%) at 100 days and 18% (95% CI I0%-34%) at 2 years. The 2-year cumulative incidence of relapse was 19% (95% CI 8%-4I%) for those transplanted in CRI, and 48% (29%-80%) for those with more advanced disease. After a median follow-up of 32 months (range: I5-69 months), the 2-year overall survival (OS) was 54% (95% CI 39%-69%). Relapse-free survival (RFS) at 2 years was 63% (95% CI 45%-8I%) for patients transplanted in CRI and 34% (95% CI II%-57%) for patients transplanted in more advanced disease. When compared to irradiation-containing regimens, FLU and PK-targeted BU appear safer and similarly effective in controlling ALL, providing a treatment option for adult patients with ALL.
Biol Blood Marrow Transplant 17: 1505-1511 (2011) © 2011 American Society for Blood and Marrow Transplantation KEY WORDS: HCT, ALL, Busulfan, Fludarabine
INTRODUCTION
Advances in the intensified chemotherapeutic regimens of adult acute lymphoblastic leukemia (ALL) have greatly improved patient outcome and survival in the last decades. Over 90% of adults with ALL achieve complete remission (CR), but most experience relapse, and the 5-year survival is only 25% to 40% [1] Allogeneic hematopoietic cell transplantation (HCT) is an effective postremission therapy when compared
From the 'Department of Biomedical Sciences, Chieti-Pescara University, Chieti, Italy; and Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, Florida. Financial disclosure: See Acknowledgments on page 1510. Correspondence and reprint requests: Joseph Pidala, MD, MS, Blood and Marrow Transplantation, Moffitt Cancer Center, University of South Florida, Tampa, FL 33612 (e-mail: joseph.pidala@ moffitt.org).
Received January 25, 2011; accepted February 26, 2011
© 2011 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
doi:10.1016/j.bbmt.2011.02.011
to chemotherapy for patients with ALL [2], but in adults over 35 years the benefits from HCT antileuke-mia effects are offset from the high transplant-related mortality (TRM) [3]. Reduced-intensity conditioning (RIC) regimens offer the opportunity for safer transplantation in older adults, but dose intensity remains important to prevent leukemia relapse after HCT [4]. For example, with a very low-intensity regimen of fludarabine (FLU) plus 200 cGy total body irradiation (TBI), the relapse rate was 24% per year in adults transplanted in first remission [5]. Busulfan (BU) is as potent in inducing apoptosis of primary ALL cells as it is in acute myeloid leukemia (AML) cells [6]. Marrow ablative doses of BU combined with FLU have been extremely well tolerated in older adults [7-10]. However, a randomized trial in children with ALL found that conditioning with BU administered based on weight or body surface area leads to lower survival compared to TBI [11]. As there is broad variation in BU clearance in children and adults, individualized BU dosing based on pharmacokinetic (PK) parameters is expected to decrease rejection, relapse,
and toxicity [12-15]. Based on these considerations, we have adopted a FLU/BU regimen with PK-guided dose adjustments as conditioning regimen for ALL patients undergoing HCT. Here, we report the results in 44 adult patients.
PATIENTS AND METHODS
Forty-four consecutive patients with ALL who received conditioning with FLU/BU before an allogeneic HCT at the Moffitt Cancer Center, Tampa, Florida, between February 2005 and March 2009 were included in this report. All patients provided informed consent for follow-up, and were part of a retrospective study of the FLU/BU regimen approved by the University of South Florida institutional review board. Table 1 shows the patients' characteristics. CR was defined by standard morphological criteria. Twenty-seven patients with predominantly high-risk disease received HCT in CR1, and 17 received transplants for more advanced disease including CR2, CR3, and primary induction failure. High-risk categorization for those in CR1 was based on the following definitions: age $35 years; presenting white blood cell count > 100,000 for B cell ALL and >30,000 for T cell phenotype ALL; and high-risk cytogenetic abnormalities including t(9:22), t(4:11), 11q23, and t(1:19). Of these 27 CR1 patients, 2 did not meet any of these criteria and were therefore considered standard risk. Of the remainder, 13 were age $35 years, 12 total (9 for B phenotype and 3 for T cell phe-notype) met criteria for elevated presenting white blood cell count, 13 had t(9:22), 1 had t(4:11), and 1 had 11q23; none had t(1:19). Sixteen of the 17 patients with the Philadelphia (Ph) chromosome received imati-nib (n = 14) or dasatinib (n =2) during induction and maintenance prior to transplant. The median duration of tyrosine kinase inhibitor (TKI) therapy prior to HCT for those treated was 5.8 months (range: 2.811.8). Of these 16 patients, 14 were treated with TKI following HCT with a median duration of post-HCT therapy of 11.6 months (range: 2.4-45.3). In 2 of these 14 cases, TKI therapy was discontinued (after 16 and 8 months of TKI therapy, respectively) because of mye-losuppression, which could not be managed with dose reduction and supportive transfusion and growth factor therapy.
Transplantation Procedures
Thirty-one patients received FLU/BU as standard treatment (target BU AUC 5300 mM*min/L) and 13 patients (target BU AUC 6,000 mM*min/L in 8 cases and 7500 mM*min/L in 5 cases) were enrolled on an ongoing trial to assess the maximum tolerated BU area under the concentration curve (AUC). Day 0 was the day of transplantation. The treatment consisted of FLU, 40 mg/m2 infused over 30 minutes daily on days —6 to —3, each dose immediately followed by
intravenous BU, 130-180 mg/m2 over 4 hours daily on the same days. BU PK samples were obtained on day —6 and assayed by mass spectrometry. On days — 4 and —3, the BU dose was adjusted to target the desired average AUC. The median BU AUC level following the first 2 doses in the target AUC 5300 group was 6105 mM*min/L (range: 3952-8524); for the target AUC 6000 group, this was 6693 mM*min/L (range: 1046-11,313); finally, for the target AUC 7500 group, this was 7856 mM*min/L (range: 7083-8904). The median (range) total BU dose administered was 510 mg/m2 (360-704) for the AUC 5300 group, 564 mg/m2 (361-688) for the AUC 6000 group, and 720 mg/m2 (606-720) for the AUC 7500 group. Seizure prophylaxis consisted of lorazepam 0.5 mg orally every 6 hours from day — 7 to day 0.
Donors were HLA-genotypically identical siblings (n = 22) or unrelated volunteers (UV) (n = 22) selected on the basis of HLA-A, -B, -C, DRB1, and DQB1 compatibility by high-resolution DNA typing. Twelve UV donors were HLA-identical, 6 were mismatched for 1 antigen and 4 for 2 antigens. Twenty-two donors were males and 22 females. Donors and patients were sex mismatched in 23 cases (52%), with a female donor for a male recipient in 14 cases (32%).
Grafts were T-replete, filgrastim-mobilized peripheral blood stem cells (PBSCs). PBSCs were obtained following the Moffitt institutional program in case of sibling donors or through the National Marrow Donor program in case of UV. The PBSC dose was targeted to approximately 5.0 x 106 CD34+ cells/kg patient body weight. PBSCs were infused on day 0 without further manipulation. The median dose of CD34+ and CD3 + cells infused was 7.7 x 106/kg (range: 3-10.0) and 3.14 x 108/kg (range: 1.26-9.04), respectively.
All patients received tacrolimus (TAC) as graft-versus-host disease (GVHD) prophylaxis for a minimum of 6 months posttransplant. The TAC doses were adjusted to maintain whole-blood trough levels of 5 to 15 ng/mL. As additional posttransplant immunosup-pressive therapy, 36 patients received methotrexate at 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11, 5 patients received mycophenolate mofetil 1 g twice daily for 1 year, and 3 received sirolimus targeted to 4 to 12 ng/mL in serum for 1 year. Patients transplanted from mismatched UV donors received either rabbit anti-thymocyte globulin 7.5 mg/kg on days —3 to —1 (n = 4), or visilizumab 3 mg/m2 on day 0 (n = 1) under an ongoing investigational protocol.
Outcome Assessment
Neutrophil engraftment was defined as the first of the 3 consecutive days with neutrophils more than 0.5 x 109/L and platelet engraftment as the first of 3 consecutive days with platelets more than 20 x 109/L. Chimerism was documented by single tandem repeat
Table 1. Demographics and Clinical Data
No. of Patients*
No. of patients 44
Patient sex
Male 27
Female 17
Median age, years (range) 40 (20-57)
Age <35 18
Age $35 26
Median WBC count at diagnosis x I09/L (range) 19 (2-674)
T cell immunophenotype II
B cell immunophenotype 33
Karyotype abnormalities at diagnosis
t(9;22) 8
t(9;22) + other chromosomal abnormalities 9
Complex karyotype 4
Other abnormalities 7
None I6
Disease status at HCT
CRI 27
CR2 I2
Patients with previous CNS involvement 5
Median time diagnosis to HCT, months (range) 7 (3-99)
Median time CRI to HCT (CRI only), months (range) 6 (3-46)
WBC indicates white blood cells; CR, complete remission; PIF, resistant to initial remission induction; HCT, hematopoietic cell transplant; CNS, central nervous system. *No. of patients, except where indicated.
polymorphism analysis of marrow or peripheral blood samples. Acute GVHD and chronic GVHD (cGVHD) were graded according to standard criteria [16,17]. Toxicity was scored using the Common Toxicity Criteria version 3.0 (NCI, Bethesda, MD). TRM was defined as death because of any cause other than leukemia relapse. Event-related data were measured from the date of transplantation to that of death from any cause in the case of overall survival
(OS) and from the date of transplantation to that of disease relapse or death from any cause in the case of relapse-free survival (RFS).
Statistical Analysis
All qualitative factors were summarized as frequency and percentage, and all quantitative factors as median and range. Data were analyzed as of January 24, 2011. The Kaplan-Meier method was used to analyze OS and RFS. Stratified survival curves were compared using the log-rank test. The probability of nonrelapse mortality (NRM) and leukemia relapse were evaluated applying the cumulative incidence (CI) method taking into account competing risks. Similarly, the cumulative incidence of grade 2 to 4 acute GVHD (aGVHD) and NIH consensus criteria determined moderate-to-severe chronic GVHD (cGVHD) were estimated [16,17], accounting for primary disease relapse and nonrelapse death as competing risk events. Statistical analyses were performed utilizing NCSS 2007 software version 7.1.20. Gray's method was applied for comparing CI between groups using R software [18].
RESULTS
Regimen-Related Toxicity
Significant toxicity was limited only to oral mucositis. Twenty-six patients (59%) experienced grade III to IV oral mucositis, which was transient and completely reversible in all cases. No other significant toxicity occurred. In particular, no patient was affected by central nervous system (CNS) toxicity, veno-occlusive disease of the liver, or idiopathic pneumonia syndrome. The median duration of hospitalization was 25 days (range: 9-41).
Engraftment
All patients achieved primary sustained engraft-ment, with a median time of 15 (range: 11-20) days to 0.5 x 109/L neutrophils and 15 (range: 9-22) days to 20 x 109/L platelets. There was no early or late graft failure. At a median of 37 (range: 23-114) days post-transplant, engraftment studies showed that 14 of 35 (40%) evaluable patients were complete (100%) donor chimeras and 21 were mixed chimeras with a median of 100% (range: 97%-100%%) donor granulocytes and 98.5% (range: 68%-100%) donor T-lymphocytes. Median granulocyte and T-lymphocyte donor engraft-ment was 100% at 6 months posttransplant.
Accounting for primary disease relapse and nonre-lapse deaths as competing risk events, the 100-day cumulative incidence of grade 2 to 4 aGVHD was 64% (95% CI 51%-80%). The cumulative incidence of grade 3 to 4 aGVHD was 14% (95% CI 7%-29%). The cumulative incidence of NIH consensus criteria determined moderate-to-severe chronic GVHD was 21% (95% CI 12%-38%).
There was no early mortality resultant from conditioning regimen-related toxicity. Nine nonrelapse deaths occurred. Three died (days +227, +161, and +255, respectively) of pneumonia and respiratory failure. One died of disseminated fungal infection on day + 113. Two died from aGVHD (1 on day +53, and the other of late aGVHD on day +275). Three (days + 143, +312, and +1084, respectively) diedofunknown etiology. The cumulative incidence estimate of NRM at 100 days was 2% (95% CI 0%-16%), 18% (95% CI 10%-34%) at 1 year, and 18% (95% CI 10%-34%) at 2 years. Two-year TRM (Figure 1) was 17% (95% CI 6%-47%) for those age <35, and 19% (95% CI 9%-42%) for those age 35 and greater (P = .73). Given the potential toxicity associated with escalating BU target AUC among the patients in this series, we examined NRM stratified by AUC: the 2-year NRM for AUC 5300 was 13% (95% CI 5%-32%), AUC 6000 was
1.000 n
a) 0.750 ^ o c <D "O O C
eu 0.500 ->
" 0.250 -
12.0 24.0
time (months)
Figure 1. Cumulative incidence of nonrelapse mortality according to age <35 (solid line) vs. age $35 (dashed line), P = .73.
25% (95% CI 8%-83%), and AUC 7500 was40% (95% CI 14%-100%), P = .32 for comparison. This finding is supported by the results of prospective trial of BU dose escalation, which demonstrates significantly increased NRM in the AUC 7500 group [19]. These findings suggest that optimal BU AUC utilizing this approach is 5300 to 6000 mM*min/L.
Leukemia Relapse
Leukemia relapse occurred in 13 patients (30%) at a median of 122 days after transplant (range: 7-681). The cumulative incidence estimate ofleukemia relapse at 2 years was 19% (95% CI 8%-41%) for patients transplanted in CR1, and 48% (95% CI 29%-80%) for those with more advanced disease (P = .036) at time of transplant (Figure 2). Among the 17 patients with Ph(+) disease, the 2-year relapse incidence was 24% (95% CI 10%-57%), and was 34% (95% CI 20%-58%) in the remaining 27 patients with Ph(—) disease, P = .5 for comparison. Importantly, the majority of those with Ph(+) disease were treated with both pre- and post-HCT TKI therapy, which contributed to disease control. Twelve patients were refractory to subsequent chemotherapy and died, whereas 1 patient was reinduced back into CR with salvage systemic chemotherapy, and has sustained this remission for 15 months with ongoing nilotinib therapy. Donor lymphocyte infusion was not utilized.
Survival
Twenty-three patients survive disease free after a median follow-up of 32 months (range: 15-69 months) posttransplant. The performance status of surviving patients at last visit was excellent with a Karnofsky score of 90% to 100%. The 2-year estimate for OS of
1.000-,
0.750 -
0.500 -
O 0.250 -
8.0 16.0 time (months)
Figure 2. Cumulative incidence of relapse, stratified according to remission status at time of transplant (solid line = CRI, dashed line = more advanced disease, including CR2 and -3, and primary induction failure), P = .036 for comparison.
all patients was 54% (95% CI 39%-69%), which differed according to remission status at the time of transplantation (Figure 3). The 2-year estimate of RFS for the overall sample was 52% (95% CI 37%-67%). RFS at 2 years was 63% (95% CI 45%-81%) for patients transplanted in CR1 and 34% (95% CI 11%-57%) for patients transplanted in more advanced disease (Figure 4). Among the 17 patients with Ph(+) ALL, 10 (59%) survive disease free and 7 died (1 for aGVHD, 2 pneumonia/respiratory failure, 1 unknown, and 3 after leukemia relapse). Patient age, remission status, Ph positivity, and donor type did not demonstrate significant association with OS, and therefore were not considered in a multivariable analysis.
DISCUSSION
The majority of adults with ALL will achieve complete remission after intensive induction chemotherapy. However, most will fail on account of disease relapse during or after consolidation and maintenance chemotherapy. Conversely, allogeneic HCT in first CR can provide sustained disease-free survival (DFS) of 40% to 60%. Major randomized trials and systematic review and meta-analyses demonstrate the superiority of HCT over non-HCT therapy in adult ALL in first complete remission (CR1) [2,20]. As well, HCT offers the only curative therapy in those beyond CR1. Therefore, HCT plays an integral role in the therapy of adult ALL.
However, the optimal conditioning regimen before HCT for adult patients with ALL remains unknown. TBI in combination with cyclophosphamide (CY) or etoposide is considered standard preparative therapy by many centers [21]. However, TBI-containing
A 1000
_ 0.750
_ 0.750 >
0 2 4 7 9 11 13 15 17 20 22 24 months
Figure 3. Overall survival, stratified by remission status at time of transplant (dashed line = CR1, solid line = more advanced disease), log-rank P = .06.
regimens are associated with important toxicity and late adverse effects. Beyond shared late effects of allogeneic transplantation, data indicate that TBI is associated with increased risk for cataract formation, whereas busulfan is associated with greater risk for irreversible alopecia [22]. Importantly, the largest randomized trial of HCT in ALL to date has demonstrated prohibitive TRM in those with high-risk disease, which undermined the beneficial reduction in disease relapse [3]. Busulfan has been utilized in conjunction with cyclophosphamide as an alternative to TBI-containing conditioning prior to HCT for ALL. Several retrospective comparisons of registry data have examined outcomes after busulfan versus TBI-based conditioning. These are heterogeneous in several important disease risk and transplantation variables. As well, these exclusively report the results of oral busulfan administration without pharma-cokinetic monitoring. Although most suggest superior event-free survival (EFS) and lower relapse after TBI-based conditioning [23-25], another demonstrates comparable outcomes [26]. The only randomized prospective trial conducted to date that comprised 43 pediatric ALL patients demonstrated superior EFS after TBI-based conditioning, but comparable relapse risk and OS [11]. In total, no high-quality evidence demonstrates the superiority of TBI-based conditioning prior to HCT for adult ALL, and the toxicity associated with this historical myeloablative approach undermines the success of HCT.
In the last decade, much effort has been made to reduce BU regimen-related toxicity and mortality without compromising efficacy. The use of pharmacokinetic targeting of intravenous (i.v.) BU has allowed for more precise busulfan delivery, which has resulted in increased efficacy and reduced regimen related toxicity. Once-daily i.v. BU in combination with FLU has been shown to be convenient, allow consistent dose-to-dose BU levels in the same patient and
0 2 4 7 9 11 13 15 17 20 22 24 months
B 1.000
_ 0.750 >
^ 0.500
0 2 4 7 9 11 13 15 17 20 22 24 months
Figure 4. (A) Relapse-free survival from date of transplantation, stratified by remission status (dashed line = CR1, solid line = more advanced disease), log-rank P = .09. (B) Relapse-free survival from date of transplantation, stratified by age (solid line = age <35, dashed line = age $35), log-rank P = .79.
complete drug clearance between doses, and minimize toxicities [9,10,27,28]. Although the majority of this work has been performed in myeloid malignancies, Russell et al. [29] have reported in a series including 28 adult ALL patients low treatment-related mortality of 3% and encouraging 3-year projected DFS of 65% following myeloablative daily i.v. BU, FLU, 400 CGY TBI, and thymoglobulin.
We here report the safety and efficacy of PK-BU in combination with FLU as conditioning regimen for HCT in adult patients with ALL. Our results indicate that the combination of FLU with PK-targeted BU is well tolerated. Oral mucositis was the only significant toxicity with a profile of incidence not different from that observed with other conditioning regimens. It was invariably self-limiting with no long-term sequelae. No cases of veno-occlusive disease, CNS toxicity, or idiopathic pneumonia syndrome were observed, and no deaths resulted from regimen-related complications. An indirect confirmation of the low toxicity profile of our regimen is the short duration of hospitalization (25 days ranging from 9-41 days). All patients included in our study achieved sustained
engraftment with no evidence of early or late graft failure. The speed of engraftment was comparable to that observed with other preparative regimens. We observed that by day 180 after HCT our patients had a median T-lymphocyte and myeloid cell chimerism of 100%. TRM at 100 days and at 1 and 2 years was 2% and 18%, respectively, lower than observed in CR1 patients with an allogeneic sibling donor reported in the largest ALL trial ever performed [3], and lower than in other published series [21,30]. Our patients were adults, half were older than 40 years and half had donors other than matched siblings.
Acknowledging the limitations inherent in the small sample size and moderate follow-up period, the preliminary results indicate encouraging disease control, and support the importance of regimen intensity in conditioning therapy for ALL. The cumulative incidence of ALL relapse post-HCT compares favorably to that reported after the nonmyeloablative regimen of fludarabine/200 cGY TBI [5], and RIC regimens [31-34]. As well, the incidence of leukemia relapse seems no higher than that observed for patients transplanted with TBI-containing regimens; the cumulative incidence of relapse reported by Goldstone et al. [3] for ALL in CR1 was 24% in standard risk and 37% in Ph(—) high-risk ALL. Importantly, the majority of Ph(+) patients in this series received a tyrosine kinase inhibitor (imatinib or dasatinib) both prior to and after HCT, which would be expected to contribute to disease control. Importantly, imatinib has been safely administered as preemptive therapy or as treatment for minimal residual disease for Ph(+) leukemia after HCT [35]. As well, retrospective data has demonstrated significantly reduced relapse and improved DFS after HCT in Ph(+) ALL patients who have received imatinib prior to HCT [36]. The use of this therapy in the majority of Ph(+) patients in our series limits comparison to historical literature on HCT outcomes for Ph(+) ALL. Importantly, allied literature on transplantation outcomes for ALL demonstrate ongoing relapse and death events beyond the follow-up period for surviving patients in our series. Therefore, further follow-up of this cohort is needed to discern the success of our reported conditioning and transplantation approach on ALL disease control.
When compared to TBI-containing regimens, FLU and PK-targeted BU demonstrate reduced NRM, but provide comparable disease control. Ultimately, prospective trials are needed to elucidate the optimal conditioning regimen in adult ALL.
ACKNOWLEDGMENTS
Financial disclosure: This work was supported in part from an unrestricted grant from PDL BioPharma,
Redwood City, CA, and grant 3 P30-CA7692 from the NCI, Bethesda, MD.
AUTHORSHIP STATEMENT
S.S. collected data, and wrote the paper; J.P. contributed to data collection, statistical analysis, and writing the paper; H.F. and L.P. contributed to analyzed data and also provided editorial comments in writing the paper; M.A., L.O., E.A., M.A.K., T.F., and J.R. contributed to analyze data; M.D.N. performed statistical analysis; W.J. and J.P. collection data; C.A. wrote the paper.
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