Clolar was approved by the Food and Drug Adminstration (FDA) for acute lymphoblastic leukemia (ALL): "Clolar (clofarabine) Injection is a purine nucleoside metabolic inhibitor indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted".
Guidelines from the National Comprehensive Cancer Network (2013) indicate Clolar for the following:
In a phase I study, Abramson et al (2013) evaluated the effects of clofarabine in patients with relapsed/refractory non-Hodgkin lymphoma (NHL). Patients were treated once-daily on days 1 through 21 of a 28-day cycle for a maximum of 6 cycles. The study was conducted with a 3 + 3 design with 10 additional patients treated at the recommended phase II dose. A total of 30 patients were enrolled including indolent B-cell lymphomas (n = 21), mantle cell lymphoma (n = 6) and diffuse large B-cell lymphoma (n = 3). The primary toxicities were hematologic including grade 3 to 4 neutropenia (53 %) and thrombocytopenia (27 %); 3 mg was determined to be the recommended phase II dose. Tumor volume was reduced in 70 % of patients, and the overall response rate (ORR) was 47 % including 27 % complete remissions (CRs). Responses were seen in indolent B-cell lymphomas and mantle cell lymphoma. At a median follow-up of 17 months, 68 % of responding patients remain in ongoing remission. The authors concluded that oral clofarabine was well-tolerated with encouraging efficacy in indolent B-cell lymphomas and mantle cell lymphomas, warranting further investigation.
Lubecka-Pietruszewska et al (2014) stated that clofarabine (2-chloro-2'-fluoro-2'-deoxyarabinosyladenine, ClF) is a second-generation 2'-deoxyadenosine analog that is structurally related to cladribine (2-chloro-2'-deoxyadenosine, 2CdA) and fludarabine (9-beta-d-arabinosyl-2-fluoroadenine, F-ara-A). It demonstrates potent anti-tumor activity at much lower doses than parent compounds with high therapeutic efficacy in pediatric blood cancers. Previous studies from these researchers in breast cancer cells indicated that 2CdA and F-ara-A are involved in epigenetic regulation of gene transcription. These investigators therefore examined if ClF influences methylation and expression of selected tumor suppressor genes, such as adenomatous polyposis coli (APC), phosphatase and tensin homolog (PTEN), and retinoic acid receptor beta 2 (RARbeta2), as well as expression of p53, p21 and DNA methyltransferase 1 (DNMT1) in MCF-7 and MDA-MB-231 breast cancer cell lines with different invasive potential. Promoter methylation and gene expression were estimated using methylation-sensitive restriction analysis (MSRA) and real-time PCR, respectively. Clofarabine demonstrated potent growth inhibitory activity in MCF-7 and MDA-MB-231 cells after 96 hours of treatment with IC50 determined as equal to 640 nM and 50 nM, respectively. In both breast cancer cell lines, ClF led to hypo-methylation and up-regulation of APC, PTEN and RARbeta2 as well as increase in p21 expression. Only in non-invasive MCF-7 cells, these changes were associated with down-regulation of DNMT1. The authors concluded that these results provided first evidence of ClF implications in epigenetic regulation of transcriptional activity of selected tumor suppressor genes in breast cancer. It seems to be a new important element of ClF anti-cancer activity and may indicate its potential efficacy in epigenetic therapy of solid tumors, especially at early stages of carcinogenesis.
Simko et al (2014) noted that existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. These researchers reported their experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (n = 11), systemic JXG (n = 4), and RDD (n = 3). Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children's Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity. Patients were treated with a median of 3 chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m(2)/day for 5 days. Cycles were administered every 28 days for a median of 6 cycles (range of 2 to 8 cycles); 17 of 18 patients are alive. All surviving patients showed demonstrable improvement after 2 to 4 cycles of therapy, with 11 (61 %) complete responses, 4 (22 %) partial responses, and 2 patients still receiving therapy. Five patients experienced disease recurrence, but 3 of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections. The authors concluded that clofarabine has activity against LCH, JXG, and RDD in heavily pre-treated patients, but prospective multi-center trials are needed to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population.
Guidelines on LCH in children from the National Cancer Institute (PDQ) (NCI, 2015) state that some LCH patients with high-risk multisystem disease develop a “macrophage activation” of their marrow. The guidelines state that this may be confusing to clinicians who may think the patient has hemophagocytic lymphohistiocytosis and LCH. The best therapy for this life-threatening manifestation is not clear, because it tends not to respond well to standard hemophagocytic lymphohistiocytosis therapy. The guidelines state that clofarabine is one option to consider in this situation. A Euro-Histio-Net guideline on LCH in adults (Girshikofsky, et al., 2013) states that clofarabine has been successfully used as salvage therapy for refractory childhood LCH (citing Rodriguez-Galindo, 2008).
By contrast guidelines on LCH from the Histiocyte Society (Minkov, et al., 2009), on adult LCH from NCI (2015), and a separate guideline on childhood LCH from members of the Euro Histio Net (Haupt, et al., 2013) have no recommendation for clofarabine. These guidelines have recommendations for steroids, vinblastine, cladribine and cytarabine for multisystem LCH.
Tischer et al (2013) stated that clofarabine is a novel purine nucleoside analog with immunosuppressive and anti-leukemic activity in AML and ALL. This retrospective study was performed to evaluate the feasibility and anti-leukemic activity of a sequential therapy using clofarabine for cytoreduction followed by conditioning for haploidentical hematopoietic stem cell transplantation (HSCT) in patients with non-remission acute leukemia. Patients received clofarabine (5 × 30 mg/m² IV) followed by a T cell replete haploidentical transplantation for AML (n = 15) or ALL (n = 3). Conditioning consisted of fludarabine, cyclophosphamide plus either melphalan, total body irradiation (TBI) or treosulfan/etoposide. High-dose cyclophosphamide was administered for post-grafting immunosuppression. Neutrophil engraftment was achieved in 83 % and complete remission in 78 % at day +30. The rate of acute graft versus host disease (GvHD) grade II to IV was 22 %, while chronic GvHD occurred in 5 patients (28 %). Non-relapse mortality (NRM) after 1 year was 23 %. At a median follow-up of 19 months, estimated overall survival (OS) and relapse-free survival at 1 year from haploidentical HSCT were 56 and 39 %, respectively. Non-hematological regimen-related grade III to IV toxicity was observed in 10 patients (56 %) and included most commonly transient elevation of liver enzymes (44 %), mucositis (40 %), and skin reactions including hand-foot syndrome (17 %), creatinine elevation (17 %), and nausea/vomiting (17 %). The concept of a sequential therapy using clofarabine for cytoreduction followed by haploidentical HSCT proved to be feasible and allowed successful engraftment, while providing an acceptable toxicity profile and anti-leukemic efficacy in patients with advanced acute leukemia. NRM and rate of GvHD were comparable to results after HSCT from HLA-matched donors.
Rabitsch et al (2014) stated that allogeneic HSCT is the only curative rescue therapy for patients with chemotherapy-refractory acute leukemia. Disease control prior to HSCT is essential for long-term disease-free survival (DFS) after HSCT. These investigators retrospectively analyzed the outcome of 20 patients aged 21 to 64 years with refractory leukemia (AML, n = 16; ALL, n = 4) who received debulking therapy with clofarabine (10 mg/m², days 1 to 4) and cyclophosphamide (200 mg/m², days 1 to 4; ClofCy) prior to HSCT. Clofarabine/cyclophosphamide (1 to 4 cycles) was well-tolerated and resulted in a substantial reduction of leukemic cells in all patients. Hematopoietic stem cell transplantation was performed in 15 of 20 patients. After HSCT (myeloablative, n = 9; dose-reduced, n = 6), all patients showed engraftment and full donor chimerism (related donors, n = 4 or unrelated donors, n = 11) and all patients achieved complete hematologic remission (CR). The median survival after HSCT was 531 days (range of 48 to 1,462 days), and 6 patients were still alive after a median of 1,245 days. Seven patients died after they had relapsed between days +152 and +1,496. One patient died from acute graft-versus-host disease (day +48) and 1 from systemic fungal infection (day +87). The authors concluded that clofarabine/cyclophosphamide is a novel effective treatment approach for patients with chemotherapy-refractory acute leukemia prior to HSCT. Moreover, they stated that whether this novel debulking protocol leads to improved long-term outcome in patients with refractory leukemias remains to be determined in forthcoming clinical studies.
In a prospective, phase II clinical trial, Chevallier et al (2014) evaluated the safety and effectiveness of a clofarabine, intravenous busulfan and anti-thymocyte globulin-based reduced-toxicity conditioning (CloB2A2) regimen before allogeneic stem cell transplantation. A total of 30 high-risk patients (median age of 59 years; AML, n = 11, ALL, n =13; myelodysplastic syndrome [MDS] n = 5, bi-phenotypic leukemia n = 1) were included in this study. At time of their transplant, 20 and 7 patients were in 1st and 2nd CR, respectively, while 3 patients with MDS were responding to chemotherapy or who had not been previously treated. The CloB2A2 regimen consisted of clofarabine 30 mg/m(2)/day for 4 days, busulfan 3.2 mg/kg/day for 2 days and anti-thymocyte globulin 2.5 mg/kg/day for 2 days. The median follow-up was 23 months. Engraftment occurred in all patients. The 1-year OS, leukemia-free survival, relapse incidence and non-relapse mortality rates were 63 ± 9 %, 57 ± 9 %, 40 ± 9 %, and 3.3 ± 3 %, respectively. Comparing patients with AML/MDS versus those with ALL/bi-phenotypic leukemia, the 1-year OS and leukemia-free survival rates were 75 ± 10 % versus 50 ± 13%, respectively (p = 0.07) and 69 ± 12 % versus 43 ± 13 %, respectively (p = 0.08), while the 1-year relapse incidence was 25 ± 11 % versus 57 ± 14 %, respectively (p = 0.05). The authors concluded that the CloB2A2 regimen prior to allogeneic stem cell transplantation is feasible, allowing for full engraftment and low toxicity. Disease control appears to be satisfactory, especially in patients with AML/MDS.
Ghanem et al (2014) noted that the outcome of patients with MDS and chronic myelomonocytic leukemia (CMML) post-clofarabine is unknown. These researchers reviewed 109 patients with MDS or CMML with a median age of 67 years, treated with a clofarabine-based chemotherapy as frontline (n = 38) or salvage (n = 71) therapy. A total of 58 (53 %) patients received salvage therapy after clofarabine failure: 13 allogeneic stem cell transplant (ASCT), 18 high-dose cytarabine-containing regimen, 10 hypomethylating agents and 17 investigational treatments. A total of 8 patients achieved CR and 3 had stable disease for an overall response rate of 19 %. With a median follow-up of 3 months from clofarabine failure, 12 patients (11 %) remained alive, 5 remain in CR, 4 of them after ASCT. The median OS post-clofarabine failure was 4 months with a 1-year survival rate of 23 %. The authors stated that this outcome is predictable, with patients with high-risk disease at the time of clofarabine failure having the worse survival. To-date, patients with MDS continue to have a short survival after failure of all available therapies. Ultimately, patients who are candidates for additional treatments should be offered novel approaches. They concluded that the outcome of patients with MDS and CMML post-clofarabine failure is poor. The pattern is similar to patients with MDS post-hypomethylating agent failure and predictable using University of Texas M. D. Anderson Cancer Center global scoring system.
Lee et al (2014) previously demonstrated that resveratrol and clofarabine elicited a marked cytotoxicity on malignant mesothelioma (MM) MSTO-211H cells but not on the corresponding normal mesothelial MeT-5A cells. Little is known of the possible molecules that could be used to predict preferential chemosensitivity on MSTO-211H cells. Resveratrol and clofarabine induced down-regulation of Mcl-1 protein level in MSTO-211H cells. Treatment of cells with cycloheximide in the presence of proteasome inhibitor MG132 suggested that Mcl-1 protein levels were regulated at the post-translational step. The siRNA-based knockdown of Mcl-1 in MSTO-211H cells triggered more growth-inhibiting and apoptosis-inducing effects with the resultant cleavages of procaspase-3 and its substrate PARP, increased caspase-3/7 activity, and increased percentage of apoptotic propensities. However, the majority of the observed changes were not shown in MeT-5A cells. The authors concluded that these studies indicated that the preferential activation of caspase cascade in malignant cells might have important applications as a therapeutic target for MM.