Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG.

The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.

A Molecular Recognition Approach To Synthesize Nucleoside Analogue Based Multifunctional Nanoparticles for Targeted Cancer Therapy.

Tumor-targeted drug delivery with simultaneous cancer imaging is highly desirable for personalized medicine. Herein, we report a supramolecular approach to design a promising class of multifunctional nanoparticles based on molecular recognition of nucleobases, which combine excellent tumor-targeting capability via aptamer, controlled drug release, and efficient fluorescent imaging for cancer-specific therapy. First, an amphiphilic prodrug dioleoyl clofarabine was self-assembled into micellar nanoparticles with hydrophilic nucleoside analogue clofarabine on their surface. Thereafter, two types of single-stranded DNAs that contain the aptamer motif and fluorescent probe Cy5.5, respectively, were introduced onto the surface of the nanoparticles via molecular recognition between the clofarabine and the thymine on DNA. These drug-containing multifunctional nanoparticles exhibit good capabilities of targeted clofarabine delivery to the tumor site and intracellular controlled drug release, leading to a robust and effective antitumor effect in vivo.

Long-Term Follow-Up and Impact of Comorbidity before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia-Lessons Learned from the Prospective BRIDGE Trial.

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be the only treatment providing long-term disease control. The BRIDGE trial studied the safety and efficacy of a clofarabine-based salvage therapy before HSCT in patients with r/r AML. Here, we report the long-term follow-up of this phase II multicenter trial and exploratory analyses on the impact of comorbidity on outcome. Eighty-four patients with a median age of 61 years (range, 40 to 75) were enrolled. Patients were scheduled for at least 1 cycle of salvage therapy with CLARA (clofarabine 30 mg/m2; cytarabine 1 g/m2, days 1 to 5). Chemo-responsive patients with a donor received HSCT after first CLARA. The conditioning regimen consisted of clofarabine 30 mg/m2, day -6 to -3, and melphalan 140 mg/m2 day -2. The Eastern Cooperative Oncology Group (ECOG) score, the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), and the Cumulative Illness Rating Scale were obtained at study enrollment as well as before HSCT. Sixty-seven percent of the patients received HSCT within the trial. After a median follow up of 40 months, the estimated 3-year overall survival (OS) for all enrolled patients and those with HSCT within the trial was 40% and 55%, respectively. Relapse-free survival for patients who underwent transplantation with a complete remission afterwards (n = 50) was 48%, calculated from the day of transplantation. In multivariate analysis, both the HCT-CI and ECOG score had a statistically significant impact on OS with a hazard ratio of 1.22 (P = .025)and 1.72 (P = .001), respectively. Using a clofarabine-based salvage therapy combined with early allogeneic HSCT, we were able to achieve good long-term results for patients with r/r AML. In this cohort, both the HCT-CI and the ECOG scores gave prognostic information on OS, showing the feasibility and clinical relevance of comorbidity evaluation at the time of diagnosis of r/r AML patients.

Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study.

Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m2. All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m2 in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m2 of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM.

Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML.

Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS, 35% ± 3 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ± 2 vs 22% ± 3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic risk AML (EFS, 26% ± 4 vs 40% ± 5 at 4 years; Cox P = .002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% ± 5 vs 40% ± 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.

Treating adults with acute lymphocytic leukemia: new pharmacotherapy options.

INTRODUCTION: Advances in acute lymphocytic leukemia (ALL) therapy has led to long-term survival rates in children. However, only 30%-40% of adults achieve long-term disease-free survival. After relapse, the outcome of salvage chemotherapy is very disappointing with less than 10% of long survival. Novel agents are therefore desperately required to improve response rates and survival, but also the quality of life of patients. Areas covered: The following review is a comprehensive summary of various novel options reported over the past few years in the therapeutic area of adult ALL. Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches. In a near future, the incorporation of monoclonal antibodies and T-cell directed approaches including blinatumomab and chimeric antigen receptor T cells may increase the cure rates and may reduce the need for intensive therapy.

Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome.

Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu. In a preliminary report, we previously showed the safety and efficacy of Clo ± Flu with i.v. Bu in 51 patients with high-risk AML, CML, and MDS. The study has now been completed, and we present long-term follow-up data on the entire 70-patient population, which included 49 (70%), 8 (11%), and 13 (19%) patients with AML, MDS, and CML, respectively. Thirteen patients (19%) were in complete remission, and 41 patients (59%) received matched unrelated donor grafts. Engraftment was achieved in all patients. Sixty-three patients (90%) achieved complete remission. There were no deaths reported at day +30, and the 100-day nonrelapse mortality rate was 4% (n = 3). Thirty-one percent of patients (n = 22) developed grades II to IV acute graft-versus-host disease, and the median overall survival and progression-free survival times were 2.4 years and .9 years, respectively. Our results confirm the safety and overall and progression-free survival advantage of the arms with higher Clo doses and lower Flu doses, which was most prominent in the AML/MDS group.

Cutaneous manifestations in leukemia patients.

Cutaneous complications are common in patients with leukemia. However, the cause is not always immediately clear, as there are often numerous potential etiologies. Thrombocytopenia or coagulopathy can result in ecchymoses or petechiae, whereas extramedullary (EM) involvement by leukemia can present as a rash. Leukemia can also result in skin manifestations via indirect means, including several types of paraneoplastic phenomena. Moreover, various agents routinely used to treat leukemia-most notably cytarabine (cytosine arabinoside)-can precipitate quite profound skin eruptions. Finally, infections, including fungal invasion of the skin, can be responsible for rashes, as can the vast array of antimicrobials that are administered to leukemia patients.

The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.

ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators.

Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial.

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.

Haploidentical Bone Marrow Transplantation With Clofarabine and Busulfan Conditioning for a Child With Multiple Recurrent Acute Lymphoblastic Leukemia.

Outcome of children with acute lymphoblastic leukemia (ALL) has improved over the years, but not for those with multiple recurrences because of high therapy resistance and heavily pretreated history that potentially cause physical damages. We describe the case of an 11-year-old boy with a third relapse of ALL and a history of 2 allogeneic bone marrow transplantations. He was successfully treated with clofarabine combination chemotherapy and achieved a fourth remission at 16 months following haploidentical bone marrow transplantation with conditioning regimen of clofarabine and busulfan. Clofarabine/busulfan conditioning might be a preferable option for children with multiple recurrent ALL, and warrants further investigation.

Control of relapsed or refractory acute myeloid leukemia by clofarabine in preparation for allogeneic stem cell transplant.

Allogeneic stem cell transplant is indicated for patients with refractory or relapsed acute myeloid leukemia (AML). Since elimination of the leukemic load is thought to be a prerequisite for treatment success, we here investigate toxicity and anti-leukemic activity of a clofarabine-AraC salvage protocol preceding transplant. In this retrospective analysis, we observed induction of objective remissions in 86% of patients receiving clofarabine-AraC as compared to 83% with sequential high dose AraC/mitoxantrone (S-HAM) and 50% after mitoxantrone/topotecane/AraC (MTC) salvage strategies. In addition, clofarabine conferred anti-leukemic activity to some patients who failed initial MTC or S-HAM therapy. For overall and leukemia-free survival, we identified cytogenetically defined adverse risk markers but not response to therapy to be a strong predictor. In summary, the clofarabine-AraC salvage strategy combines pronounced anti-leukemic activity with an acceptable toxicity profile and allows the majority of patients with relapsed or refractory AML to proceed to allo-SCT, even in cytogenetically defined high risk situations.

How I treat Langerhans cell histiocytosis.

"Langerhans cell histiocytosis" (LCH) describes a spectrum of clinical presentations ranging from a single bone lesion or trivial skin rash to an explosive disseminated disease. Regardless of clinical severity, LCH lesions share the common histology of CD1a(+)/CD207(+) dendritic cells with characteristic morphology among an inflammatory infiltrate. Despite historical uncertainty defining LCH as inflammatory vs neoplastic and incomplete understanding of mechanisms of pathogenesis, clinical outcomes have improved markedly over the past decades through cooperative randomized clinical trials based on empiric therapeutic strategies. Significant advances include recognition of high- and low-risk clinical groups defined by hematopoietic and/or hepatic involvement, and of the importance of optimal intensity and of duration of chemotherapy. Nevertheless, mortality of high-risk patients, disease recurrence, lack of robustly tested salvage strategies, and significant disease morbidity of both high- and low-risk patients remain challenges. Recent discovery of recurrent somatic mutations in mitogen-activated protein kinase pathway genes at critical stages of myeloid hematopoietic differentiation in LCH patients supports redefinition of the disease as a myeloproliferative disorder and provides opportunities to develop novel approaches to diagnosis and therapy.

A case of frosted branch angiitis in an immunocompromised child.

Frosted branch angiitis is a rare vascular reaction believed to be a nonspecific immune response to an infective, neoplastic, or idiopathic insult. The clinical presentation is characteristic and typically affects children and younger adults, and the prognosis is good. We report a case of frosted branch angiitis during immune recovery in a 2-year-old boy with Langerhans cell histiocytosis on systemic immunosuppressive therapy.