Pharmacokinetically-targeted BU and fludarabine as conditioning before allogeneic hematopoietic cell transplantation for adults with ALL in first remission

Kunter, Ghada M; Perkins, Janelle; Pidala, Joseph; Nishihori, Taiga; Kharfan‐Dabaja, Mohamed A.; Field, Teresa; Perez, Lia; Locke, Frederick L.; Ayala, Ernesto; Tomblyn, Marcie; Ochoa-Bayona, José L.; Betts, Brian C.; Nieder, Michael L.; Anasetti, Claudio

doi:10.1038/bmt.2013.121

Cited by 10 publications

(9 citation statements)

References 37 publications

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“…Transient transaminitis was common, as was also reported by Magenau and colleagues(39). Six patients developed VOD, with one patient having fatal VOD, and this was also comparable to the Flu-Bu experience reported by others (8, 11, 14). All of these patients had extensive therapy prior to HCT with median time from diagnosis to HCT of 17.5 months.…”

Section: Discussionsupporting

confidence: 89%

“…Inotuzumab is a CD22 monoclonal antibody conjugated to the toxin calecheamicin that is very effective in relapsed ALL(40) but associated with hepatic toxicity, and has been noted to be associated with increased VOD rates across our various transplant regimens(41). The 100-day NRM rate of 6% was comparable to what was reported for Flu-Bu(14), and markedly lower than the 19% reported by Doney and colleagues using TBI-based regimens(42). …”

Section: Discussionsupporting

confidence: 63%

“…Flu-Bu with an 2-year OS rate of 63% for patients transplanted in first complete remission (CR1)(12); importantly long-term NRM was only 18% at 2 years(12). In an updated report on their series, with 65 patients transplanted with Flu-Bu in CR1 for ALL, the 2-year OS was 65%, and NRM remained low at 14%(14). Based on the single agent activity of clofarabine in refractory or relapsed ALL, we hypothesized that a combination of clofarabine and i.v.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in the study by Kunter et al, patients with daily Bu AUC targeting 5300 microMol-min had a better OS compared to those targeting >6000 microMol-min (p=.04)(14). Thus, we targeted a (median) daily AUC of 5500 microMol-min for our younger patients for maximum disease control, and 4000 microMol-min for our patients greater than 59 years in efforts to minimize toxicity.…”

Section: Discussionmentioning

confidence: 99%

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Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

Kebriaei

Bassett

Lyons

et al. 2017

Biology of Blood and Marrow Transplantation

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We investigated the long-term safety and disease-control data obtained with intravenous busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (SCT). 107 patients with median age 38 years (range 19–64 years) received a matched sibling (n=52), or matched unrelated donor transplant (n=55) for ALL in first complete remission (n=62), second complete remission (n=28), or more advanced disease (n=17). Nearly half of the patients had high-risk cytogenetic profiles as defined by the presence of t(9;22) (n=34), t(4;11) (n=4), or complex cytogenetics (n=7). Clo 40 mg/m2 was given once daily, each dose followed by pharmacokinetically-dosed Bu infused over three hours daily for 4 days, followed by hematopoietic cell infusion after two rest days. The Bu dose was based upon the drug clearance determined by a test Bu dose, 32 mg/m2, given 48 hours prior to the high dose regimen. The target daily area under the curve (AUC) was 5,500 microMol-min for patients less than 60 years of age and 4000 microMol-min for patients older than 59 years of age. With a median follow-up of 3.3 years among surviving patients (1–5.8 years), the 2-year progression-free survival (PFS) rates for patients transplanted in CR1, CR2, or more advanced disease were 62%, 34%, and 35%, respectively. The regimen was well tolerated with non-relapse mortality (NRM) rates of 10% and 31% and at 100 days and 2 years, respectively. The incidence of grades II–IV and III–IV acute graft versus host disease (GVHD) were 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) rates for patients transplanted in CR1, CR2, or more advanced disease were 70%, 57%, and 35%, respectively. Among 11 patients older than 59 years treated with reduced dose Bu in CR1 (n=7) or CR2 (n=4), 4 remain alive and disease-free with a median follow up of 2.6 years (2–4.7 years). Only the presence of MRD at time of transplant was associated with significantly worse PFS and OS on multivariate analysis. The Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. Overall survival and NRM rates compare favorably with traditional myeloablative TBI-based conditioning regimens.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

Kebriaei

Bassett

Lyons

et al. 2017

Biology of Blood and Marrow Transplantation

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“…In another phase II study for ALL patients in first CR, the combination of fludarabine with PK-directed i.v. busulfan yielded 2-year RFS and OS rates of 61% and 65%, respectively, in 65 ALL patients (median age of 42 years) in first CR [85].…”

Section: Advances In Transplantation In Allmentioning

confidence: 98%

Advances in adult acute lymphoblastic leukemia therapy

Aldoss

Stein

2017

Leukemia & Lymphoma

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Progress in adult acute lymphoblastic leukemia (ALL) treatment has been met with challenge until recently. A steady improvement in outcomes is being witnessed among adults with ALL, and it will be enhanced further with early referral of newly diagnosed ALL patients to specialized centers, enrolling more ALL adults in clinical trials, adopting pediatric-inspired ALL regimens in younger adults, tailoring treatments according to minimal residual disease response and disease genetics, incorporating novel therapies and tyrosine kinase inhibitors in frontline regimens, early referral to transplant when indicated, expanding the donor pool, and developing more effective salvage therapies for relapsed/refractory ALL. In this review, we will discuss the most significant advances in treating adult ALL observed in the last five years that have the potential to enhance adult ALL treatment and outcome.

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Pediatric‐inspired therapy compared to allografting for Philadelphia chromosome‐negative adult ALL in first complete remission

et al. 2016

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For adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric-inspired chemotherapy may also offer durable leukemia free survival in the absence of HCT. We compared 422 HCT recipients aged 18-50 years with Ph-ALL in CR1 reported to the CIBMTR with an age-matched concurrent cohort of 108 Ph- ALL CR1 patients who received a Dana-Farber Consortium pediatric-inspired non-HCT regimen. At four years follow-up, incidence of relapse after HCT was 24% [95% C.I. 19-28] vs. 23% [95% C.I. 15-32] for the non-HCT (“chemo”) cohort (p=0.97). Treatment-related mortality (TRM) was higher in the HCT cohort (HCT 37% [95% C.I. 31-42] vs. chemo 6% [95% C.I. 3 – 12], p<0.0001). DFS in the HCT cohort was 40% [95% C.I. 35-45] vs. 71% [95% C.I. 60-79] for chemo, p<0.0001. Similarly, OS favored chemo (HCT 45% [95% C.I. 40-50]) vs. chemo 73% [95% C.I. 63-81], p<0.0001). In multivariable analysis, the sole factor predictive of shorter OS was the administration of HCT (HR 3.12 [1.99 – 4.90], p<0.0001). For younger adults with Ph- ALL, pediatric-inspired chemotherapy had lower TRM, no increase in relapse, and superior overall survival compared to HCT.

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Pharmacokinetically-targeted BU and fludarabine as conditioning before allogeneic hematopoietic cell transplantation for adults with ALL in first remission

Abstract: The NCI Common Terminology Criteria for Adverse Events v3.0 is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term.

Cited by 10 publications

References 37 publications

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results

Advances in adult acute lymphoblastic leukemia therapy

Pediatric‐inspired therapy compared to allografting for Philadelphia chromosome‐negative adult ALL in first complete remission

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