Clofarabine (Clolar)

Number: 0867

Policy

Aetna considers clofarabine injection (Clolar) medically necessary for the following indications:

  • Acute myeloid leukemia (AML) – therapy for relapsed or refractory disease
     
    • With cytarabine and/or idarubicin; or
    • As a component of repeating the initial successful induction regimen if late relapse (≥12 months)
       
  • Acute lymphoblastic leukemia (ALL) – relapsed / refractory Philadelphia chromosome-negative B-ALL or for relapsed/refractory Philadelphia chromosome-positive B-ALL refractory to tyrosine kinase inhibitors (TKIs)
  • Refractory or recurrent childhood (18 years of age or younger) Langerhans cell histiocytosis.

Aetna considers clofarabine not medically necessary for persons who exhibit significant disease progression on clofarabine.

Aetna considers clofarabine experimental and investigational for all other indications including the following (not an all-inclusive list):

  • B-cell lymphoma
  • Breast cancer
  • Central nervous system tumors (e.g., ependymoma)
  • Chronic myelomonocytic leukemia (CMML)
  • Ewing sarcoma
  • Mesothelioma
  • Myelodysplastic syndrome
  • Non-Hodgkin lymphomas (e.g., diffuse large B-cell lymphoma, indolent B-cell lymphomas, and mantle cell lymphoma)
  • Rosai-Dorfman disease
  • T-cell lymphoma.

Dosing Recommendations

Dosing Information for Pediatric ALL

Clolar is supplied as a 20 mg/20 ml single-use vial.

  • Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days of a 28-day cycle.  Repeat cycles every 2 to 6 weeks.
  • Provide supportive care, such as intravenous infusion fluids, anti-hyperuricemic treatment, and alkalinization of urine throughout the 5 days of Clolar administration to reduce the risk of tumor lysis and other adverse events.
  • Discontinue Clolar if hypotension develops during the 5 days of administration.
  • Reduce the dose in patients with renal impairment.
  • Use dose modification for toxicity.

Background

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. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with clofarabine." 

Guidelines from the National Comprehensive Cancer Network (2019) indicate clofarabine for the following:

  • Acute Lymphoblastic Leukemia (ALL)

    Therapy for relapsed/refractory Philadelphia chromosone-negative B-cell ALL or for Philadelphia chromosome-positive B-cell ALL refractory to tyrosine kinase inhibitor therapy [2A]
     
    • as a single agent
    • as a component of clofarabine-containing regimens (e.g. clofarabine, cyclophosphamide, and etoposide)
       
  • Acute Myeloid Leukemia (AML)

    Therapy for relapse or refractory disease [2A]
     
    • as a component of repeating the initial successful induction regimen if late relapse (≥12 months since induction regimen) 
    • in combination with cytarabine and granulocyte colony-stimulating factor (G-CSF) or in combination with idarubicin
    • in combination with cytarabine, G-CSF, and idarubicin

  • Acute Myeloid Leukemia (AML)

    For treatment induction in patients age ≥ 60 years as part of an alternative non-anthracycline-containing regimen (eg, clofarabine-based regimen) in candidates for intensive remission induction therapy who exceed anthracycline dose or have cardiac issues but are still able to receive aggressive therapy [Category 3 recommendation]
  • Pediatric Acute Lymphoblastic Leukemia

    Therapy for relapsed/refractory Ph-negative B-ALL, or in combination with dasatinib or imatinib for relapsed/refractory Ph-positive B-ALL as a component of clofarabine-containing regimens (e.g. clofarabine, cyclophosphamide, and etoposide) [2A]

Most common adverse reactions (greater than or equal to 10 %) with Clolar were nausea (73 %), vomiting (78 %), diarrhea (56 %), febrile neutropenia (55 %), headache (43 %), rash (38 %), pruritus (43 %), pyrexia (39 %), fatigue (34 %), palmar-plantar erythrodysesthesia syndrome (16 %), anxiety (21 %), flushing (19 %), and mucosal inflammation (16 %).

Warnings and Precautions

  • Myelosuppression

    Clolar causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. Myelosuppression is usually reversible with interruption of Clolar treatment and appears to be dose-dependent. Monitor complete blood counts.
  • Hemorrhage

    Serious and fatal hemorrhage, including cerebral, gastrointestinal and pulmonary hemorrhage, has occurred. The majority of the cases were associated with thrombocytopenia. Monitor platelets and coagulation parameters and treat accordingly.
  • Infections

    Clolar increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. A total of 83% of patients experienced at least one infection after Clolar treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue Clolar, and treat promptly.
  • Hyperuricemia (Tumor Lysis)

    Administration of Clolar may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid.
  • Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome

    Clolar may cause a cytokine release syndrome (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and organ impairment which may be fatal. Monitor patients frequently for these conditions. In clinical trials, SIRS was reported in two patients (2%); capillary leak syndrome was reported in four patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multi-organ failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue Clolar and provide appropriate supportive measures. The use of prophylactic steroids may be of benefit in preventing signs or symptoms of SIRS or capillary leak. Consider use of diuretics and/or albumin.
  • Venous Occlusive Disease of the Liver

    Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in a combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia. Two cases (2%) of VOD in the mono-therapy studies were considered related to study drug. Monitor for and discontinue Clolar if VOD is suspected.
  • Hepatotoxicity

    Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of Clolar. In clinical studies, Grade 3-4 liver enzyme elevations were observed in pediatric patients during treatment with Clolar at the following rates: elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 44% of patients. Monitor hepatic function and for signs and symptoms of hepatitis and hepatic failure. Discontinue Clolar for Grade 3 or greater liver enzyme and/or bilirubin elevations.
  • Renal Toxicity

    In clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients; acute renal failure was reported as Grade 3 in three patients (3%) and Grade 4 in two patients (2%). Hematuria was observed in 13% of patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clolar as necessary.
  • Enterocolitis

    Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation, hemorrhage or sepsis complications. Monitor patients for signs and symptoms of enterocolitis and treat promptly.
  • Skin Reactions

    Serious and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Discontinue Clofarabine for exfoliative or bullous rash, or if SJS or TEN is suspected.
  • Embryo-fetal Toxicity

    Clolar can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Clolar.
  • Nursing Mothers

    Female patients should be advised to avoid breast-feeding during treatment with Clolar.

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 and colleagues (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 first and second 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 (2015) 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.

Zoellner and colleagues (2015) noted that prognosis is poor for patients with biologically aggressive non-Hodgkin lymphoma (NHL), refractory to chemotherapy or relapsed after autologous transplantation, especially when no disease control before allogeneic transplantation is achieved. In 16 patients (median age of 53 years, median prior regimens of 5) with relapsed or refractory non-remission NHL, these researchers analyzed retrospectively the effectiveness of a sequential therapy comprising clofarabine re-induction followed by a reduced-intensity conditioning with fludarabine, cyclophosphamide (CY), and melphalan, and T-cell-replete HLA-haploidentical transplantation. High-dose CY was utilized post-transplantation. All patients engrafted. Early response (day +30) was achieved in 94 %. Treatment-related grade III to IV toxicity occurred in 56 %, most commonly transient elevation of transaminases (36 %), while there was a low incidence of infections (19 % cytomegalovirus (CMV) re-activation, 19 % invasive fungal infection) and GVHD (GVHD: acute III to IV: 6 %; mild chronic: 25 %). One-year non-relapse mortality was 19 %. After a median follow-up of 21 months, estimated 1- and 2-year progression-free survival (PFS) was 56 % and 50 %, respectively, with 11 patients (69 %) still alive after 2 years. The authors concluded that sequential therapy is feasible and effective and provided an acceptable toxicity profile in high-risk non-remission NHL. Presumably, cytotoxic re-induction with clofarabine provided enough remission time for the graft-versus lymphoma effect of HLA-haploidentical transplantation to kick in, even in lymphomas that are otherwise chemo-refractory. These preliminary findings need to be validated by well-designed studies.

Central Nervous System Tumors

To characterize the clofarabine disposition in mice for further pre-clinical efficacy studies, Patel et al (2015) evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, intra-peritoneal [IP] injection) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extra-cellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a non-linear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/ml) for ependymoma neurospheres. The authors concluded that these findings showed the clofarabine exposure reached in the tumor ECF was below that associated with an anti-tumor effect in in-vitro washout study. Thus, clofarabine was de-prioritized as an agent to treat ependymoma, and further pre-clinical studies were not pursued.

Myelodysplastic Syndrome

In a phase II clinical trial, Jabbour and colleagues (2017) evaluated the safety and activity of a combination of low-dose clofarabine and cytarabine for patients with higher-risk myelodysplastic syndromes (MDS) after hypo-methylating agent (HMA) failure.  A total of 70 patients with higher-risk MDS who had no response, progressed, or relapsed after at least 4 cycles of HMA therapy were treated.  The median age was 72 years; 39 % of the patients had high-risk disease according to the International Prognostic Scoring System (IPSS), and 50 % of the patients had poor-risk cytogenetics; 23 % of the patients had therapy-related MDS.  The median number of prior cycles of HMA was 6 (range of 4 to 45). The ORR was 44 %.  The 6-week mortality rate was 9 %.  Grade-III and higher non-hematologic toxicities were rare, but infections occurred in 52 % of patients, and fever of unknown origin occurred in 33 %.  The median OS was 10 months (95 % confidence interval [CI]: 1 to 37 months); 13 % of the patients underwent ASCT.  The responding patients had a median OS of 22 months, whereas the non-responding patients had a median OS of 4 months.  A complex karyotype was associated with worse response rates and OS.  The authors concluded that the combination of low-dose clofarabine and cytarabine is clinically active in these patients with few therapeutic options.

B-Cell Lymphoma and T-Cell Lymphoma

Foss and Parker (2018) stated that clofarabine is a second-generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory ALL.  In adults, clofarabine has been investigated in several phase-I and phase-II clinical trials as a single agent and in combination for relapsed or refractory acute leukemia.  These studies have shown that clofarabine has activity and an acceptable safety profile in patients with hematological malignancies.  In this phase-I dose escalation trial, clofarabine was evaluated in patients with relapsed or refractory, low-grade or intermediate-grade, B-cell or T-cell lymphoma.  The starting dose of 10 mg/m2 per week was administered intravenously (IV) for 3 consecutive weeks every 28 days, and doses were escalated in cohorts of 3.  The study objectives were to determine the maximum tolerated dose (MTD), characterize and quantify the toxicity profile, and determine the ORR of clofarabine administered once-weekly for 3 weeks and repeated every 4 weeks.  Eligible patients were over the age of 18, had a histologically confirmed low-grade or intermediate-grade B-cell or T-cell lymphoma, and must have previously been treated with 1 standard chemotherapy regimen, excluding single-agent rituximab.  The primary objectives included in statistical analyses were MTD, toxicity, and ORR; 4 patients were enrolled in cohort 1 (clofarabine 10 mg/m2), 4 in cohort 2 (clofarabine 15 mg/m2), 3 in cohort 3 (clofarabine 20 mg/m2), 2 in cohort 4 (clofarabine 30 mg/m2), and 1 in cohort 5 (clofarabine 40 mg/m2); MTD was not reached in the study.  The most common toxicity observed was myelosuppression.  A total of 4 (29 %) patients experienced grade 3 leukopenia, with 3 (21 %) patients experiencing grade 4 neutropenia.  The myelosuppression was not considered to be a dose-limiting toxicity (DLT), as it resolved within 7 days.  A total of 14 patients were enrolled: 10 patients with T-cell non-Hodgkin lymphoma (NHL) and 4 patients with B-cell NHL.  All 14 patients received at least 1 dose of clofarabine and were evaluable for response; 1 patient with cutaneous T-cell lymphoma (CTCL) had a partial response (PR); 5 (36 %) had stable disease (SD), and 8 patients (57 %) had no response.  The 1 patient with a response had stage III erythroderma and was treated in the 10 mg/m2 cohort; a nodal complete response by positron emission tomography (PET) scan was observed with a PR of the skin.  The authors concluded that in this study, weekly administration of clofarabine was demonstrated to be safe and associated with minimal hematologic toxicity at doses ranging from 10 to 40 mg/m2.  In prior studies when dosed daily for 5 consecutive days, the MTD was shown to be 4 mg/m2.  Weekly dosing within this dose range did not result in dose modifications, and the MTD was not reached.  They stated that clinical efficacy was observed in 1 patient with CTCL who was treated in the lowest-dose cohort.  Moreover, these investigators noted that there was no dose response relationship observed in these studies, although conclusions regarding efficacy were limited by small numbers in each cohort.  The mechanism of action of clofarabine to block DNA synthesis via inhibition of ribonucleotide reductase and DNA polymerases could potentially overcome drug resistance to conventional cytotoxic agents in patients with relapsed lymphoma.  They stated that further studies could explore combinations of clofarabine with other novel agents in relapsed T‐ and B‐cell lymphomas.

Ewing Sarcoma

Celik and colleagues (2018) noted that Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy that predominantly affects children and adolescents.  CD99 is a cell surface protein that is highly expressed on ES cells and is required to maintain their malignancy.  These researchers screened small molecule libraries for binding to extracellular domain of recombinant CD99 and subsequent inhibition of ES cell growth.  They identified 2 structurally similar FDA-approved compounds, clofarabine and cladribine that selectively inhibited the growth of ES cells in a panel of 14 ES versus 28 non-ES cell lines.  Both drugs inhibited CD99 dimerization and its interaction with down-stream signaling components.  A membrane-impermeable analog of clofarabine showed similar cytotoxicity in culture, suggesting that it could function through inhibiting CD99 independent of DNA metabolism.  Both drugs drastically inhibited anchorage-independent growth of ES cells, but clofarabine was more effective in inhibiting growth of 3 different ES xenografts.  The authors concluded that these findings provided a novel molecular mechanism for clofarabine that involves direct binding to a cell surface receptor CD99 and inhibiting its biological activities.

Rosai-Dorfman Disease

Averitt and co-workers (2018) stated that Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy is a rare non-Langerhans' cell histiocytic disease resulting from the proliferation and accumulation of sinus histiocytes within lymph nodes.  Extra-nodal involvement frequently occurs, which increases the morbidity and mortality of the disease.  There is no clear consensus with regard to the most effective diagnostic and treatment modalities.  This report focused on the diagnostic imaging, treatment, and outcomes for 3 cases of Rosai-Dorfman disease.  Imaging has typically utilized computed tomography (CT)/magnetic resonance imaging (MRI) to detect extra-nodal involvement.  However, the addition of fluorodeoxyglucose positron emission tomography (PET)/CT scans has shown value in identifying lesions unidentified or ambiguous on other modalities.  Fluorodeoxyglucose PET/CT detected disease involvement in 2 instances either not reported or not felt to be significant on correlative CT imaging.  Areas of involvement included the stomach/liver in case 1, and the paranasal sinus in case 3.  In addition, previously utilized chemotherapy regimens have not consistently displayed regression of the disease, which gave credence to the pursuit of more successful treatment.  The authors stated that clofarabine has shown promise in its use against histiocytic disorders; they noted that clofarabine demonstrated the ability to decrease lesion size and should be considered as an effective chemotherapeutic therapy.

Combination Therapy with Clofarabine, Donor Lymphocyte Infusion with Concurrent Blinatumomab in Relapsed/Refractory Acute Precursor B-Lymphoblastic Leukemia

Choi and colleagues (2020) noted that the therapeutic approach for relapsed/refractory (R/R) ALL remains to be a challenge.  In this case-study, the patient was diagnosed as B-cell ALL at 6 months of age and relapsed for the second time following repeat allogeneic HSCT (allo-HSCT; one after first complete remission [CR1] and the other after CR2).  During blinatumomab monotherapy, he developed an extra-medullary relapse.  Finally, the combined therapy with clofarabine, donor lymphocyte infusion (DLI), and blinatumomab induced CR of the bone marrow and extra-medullary relapse.  Unfortunately, the patient developed central nervous system (CNS) relapse, however, this case showed a promising potential for combination therapy with clofarabine, DLI, and blinatumomab in relapsed/refractory B-cell ALL.

Combination Therapy with Clofarabine, Cytarabine, and Mitoxantrone in Relapsed/Refractory Acute Myeloid Leukemia

Gill and colleagues (2020) noted that clofarabine is active in R/R AML.  In a phase-II clinical trial, these researchers treated 18- to 65-year-old AML patients refractory to first-line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high-dose cytarabine consolidation, with clofarabine (30 mg/m2/day, Days 1 to 5), cytarabine (750 mg/m2/day, Days 1 to 5), and mitoxantrone (12 mg/m2/day, Days 3 to 5) (CLAM).  Patients achieving remission received up to 2 consolidation cycles of 50 % CLAM, with eligible cases bridged to allo-HSCT.  The mutational profile of a 69-gene panel was evaluated.  A total of 26 men and 26 women at a median age of 46 (22 to 65) years were treated.  The ORR after the first cycle of CLAM was 90.4 % (CR: 69.2 %; CR with incomplete hematologic recovery, CRi: 21.2 %); 22 CR/CRi patients underwent allo-HSCT.  The 2-year OS, relapse-free survival (RFS), and event-free survival (EFS) were 65.8 %, 45.7 %, and 40.2 %, respectively.  Multi-variate analyses showed that superior OS was associated with CR after CLAM (p = 0.005) and allo-HSCT (p = 0.005), and superior RFS and EFS were associated with allo-HSCT (p < 0.001).  CR after CLAM and allo-HSCT resulted in 2-year OS of 84.3 % and 90 %, respectively.  Karyotypic aberrations and genetic mutations did not influence responses or survivals.  Grade-3/4 neutropenia/thrombocytopenia and grade-3 febrile neutropenia occurred in all cases.  Other non-hematologic toxicities were mild and uncommon.  There was no treatment-related mortality (TRM) and the performance of allo-HSCT was not compromised.  The authors concluded that clofarabine, cytarabine, and mitoxantrone was highly safe and effective in refractory/relapsed AML.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

96413 Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
+96415     each additional hour (List separately in addition to code for primary

HCPCS codes covered if selection criteria are met:

J9027 Injection, clofarabine, 1 mg

Other HCPCS codes related to the CPB:

J9100 Injection, cytarabine, 100 mg
J9211 Injection, idarubicin hydrochloride, 5 mg

ICD-10 codes covered if selection criteria are met:

C91.00 - C91.02 Acute lymphoid leukemia
C92.00, C92.02
C92.40, C92.42
C92.50, C92.52
C92.60, C92.62
C92.A0, C92.A2
Acute myeloid leukemia
C93.00, C93.02 Acute monoblastic/monocytic leukemia
C94.00, C94.02
C94.20, C94.22
Acute erythroid and megakaryoblastic leukemia
E88.89 - E88.9 Other and unspecified metabolic disorders [Recurrent or refractory childhood Langerhans cell histiocytosis]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C34.00 - C34.92, C38.4 Malignant neoplasm of bronchus, lung, and pleura [mesothelioma]
C40.00 - C40.92 Malignant neoplasm of bone and articular cartilage of limbs
C41.0 - C41.9 Malignant neoplasm of bone and articular cartilage of other and unspecified sites.
C50.011 - C50.929 Malignant neoplasm of breast
C83.00 - C83.09 Small cell B-cell lymphoma
C83.10 - C83.19 Mantle cell lymphoma
C83.30 - C83.39 Diffuse large B-cell lymphoma.
C83.80 - C83.89 Other non-follicular lymphoma
C84.40 - C84.49 Peripheral T-cell lymphoma, not classified
C84.90 - C84.99 Mature T/NK-cell lymphomas, unspecified
C84.A0 - C84.A9 Cutaneous T-cell lymphoma, unspecified
C84.Z0 - C84.Z9 Other mature T/NK-cell lymphomas
C85.80 - C85.89 Other specified types on non-Hodgkin lymphoma
C93.10 Chronic myelomonocytic leukemia not having achieved remission
C96.5 - C96.6 Multifocal, unisystemic and unifocal Langerhans-cell histiocytosis
D46.0 - D46.9 Myelodysplastic syndromes
D76.3 Other histiocytosis syndromes[Rosai-Dorfman disease]
E71.39 Other disorders of fatty-acid metabolism
E75.21 - E75.22,
E75.240 - E75.249, E75.3
Other sphingolipidosis
E80.3 Defects of catalase and peroxidase
J84.82 Adult pulmonary Langerhans cell histiocytosis

The above policy is based on the following references:

  1. Abraham A, Alsultan A, Jeng M, et al. Clofarabine salvage therapy for refractory high-risk Langerhans cell histiocytosis. Pediatr Blood Cancer. 2013;60(6):E19-E22.
  2. Abramson JS, Takvorian RW, Fisher DC, et al. Oral clofarabine for relapsed/refractory non-Hodgkin lymphomas: Results of a phase 1 study. Leuk Lymphoma. 2013;54(9):1915-1920.
  3. Averitt AW, Heym K, Akers L, et al. Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman disease): Diagnostic and treatment modalities for this rare entity revisited. J Pediatr Hematol Oncol. 2018;40(4):e198-e202.
  4. Bell JA, Galaznik A, Huelin R, et al. Systematic literature review of treatment options and clinical outcomes for patients with higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia. Clin Lymphoma Myeloma Leuk. 2018;18(4):e157-e166.
  5. Celik H, Sciandra M, Flashner B, et al. Clofarabine inhibits Ewing sarcoma growth through a novel molecular mechanism involving direct binding to CD99. Oncogene. 2018;37(16):2181-2196.
  6. Chevallier P, Labopin M, Socie G, et al. Results from a clofarabine-busulfan-containing, reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: The phase 2 prospective CLORIC trial. Haematologica. 2014;99(9):1486-1491.
  7. Choi HJ, Choi JY, Kim BK, et al. Combination therapy with chemotherapy, donor lymphocyte infusion with concurrent blinatumomab in relapsed/refractory acute precursor B-lymphoblastic leukemia. J Pediatr Hematol Oncol. 2020 Apr 2 [Online ahead of print].
  8. DRUGDEX System [Internet database]. Ann Arbor, MI: Truven Health Analytics Micromedex; updated periodically.
  9. Fadrel S, Gandhi V, O’Brien S, et.al. Results of a phase I - II study of clofarabine in combination with cytarabine (Ara-C) in relapsed and refractory acute leukemia. Blood. 2005;105(3):940-947.
  10. Foss FM, Parker T. A phase I dose-escalation study of clofarabine in patients with relapsed or refractory low-grade or intermediate-grade B-cell or T-cell lymphoma. Oncologist. 2018;23(4):397-e30.
  11. Genzyme Corporation. Clolar (clofarabine) injection for intravenous use. Prescribing Information. Cambridge, MA: Genzyme Corporation; revised October 2016.
  12. Ghanem H, Garcia-Manero G, Faderl S, et al. Outcomes of patients with myelodysplatic syndrome and chronic myelomonocytic leukemia post clofarabine failure. Ther Adv Hematol. 2014;5(2):29-34.
  13. Gill H, Yim R, Pang HH, et al. Clofarabine, cytarabine, and mitoxantrone in refractory/relapsed acute myeloid leukemia: High response rates and effective bridge to allogeneic hematopoietic stem cell transplantation. Cancer Med. 2020;9(10):3371-3382.
  14. Girschikofsky M, Arico M, Castillo D, et al. Management of adult patients with Langerhans cell histiocytosis: Recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013;8:72.
  15. Haupt R, Minkov M, Astigarraga I, et al.; Euro Histio Network. Langerhans cell histiocytosis (LCH): Guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer. 2013;60(2):175-184.
  16. Jabbour E, Faderl S, Sasaki K, et al. Phase 2 study of low-dose clofarabine plus cytarabine for patients with higher-risk myelodysplastic syndrome who have relapsed or are refractory to hypomethylating agents. Cancer. 2017;123(4):629-637.
  17. Lee YJ, Lee YJ, Lee SH. Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation. BMB Rep. 2015;48(3):166-171.
  18. Lubecka K, Kaufman-Szymczyk A, Cebula-Obrzut B, et al. Novel clofarabine-based combinations with polyphenols epigenetically reactivate retinoic acid receptor beta, inhibit cell growth, and induce apoptosis of breast cancer cells. Int J Mol Sci. 2018;19(12).
  19. Lubecka K, Kaufman-Szymczyk A, Fabianowska-Majewska K. Inhibition of breast cancer cell growth by the combination of clofarabine and sulforaphane involves epigenetically mediated CDKN2A upregulation. Nucleosides Nucleotides Nucleic Acids. 2018;37(5):280-289.
  20. Lubecka-Pietruszewska K, Kaufman-Szymczyk A, Stefanska B, et al. Clofarabine, a novel adenosine analogue, reactivates DNA methylation-silenced tumour suppressor genes and inhibits cell growth in breast cancer cells. Eur J Pharmacol. 2014;723:276-287.
  21. Minkov M., Grois N, McClain K, et al. Langerhans cell histiocytosis. Histiocytosis Society Evaluation and Treatment Guidelines. Pitman, NJ: Histiocytosis Association; April 2009.
  22. Montalban-Bravo G, Garcia-Manero G, Jabbour E. Therapeutic choices after hypomethylating agent resistance for myelodysplastic syndromes. Curr Opin Hematol. 2018;25(2):146-153.
  23. National Cancer Institute (NCI). Childhood acute lymphoblastic leukemia (PDQ): Treatment (Health Professional Version). Bethesda, MD: National Cancer Institute (NCI); 2015.
  24. National Cancer Institute (NCI). Treatment of adult LCH. Langerhans Cell Histiocytosis Treatment (PDQ). Health Professional. Bethesda, MD: NCI; updated January 30, 2015.
  25. National Cancer Institute (NCI). Treatment of childhood LCH. Langerhans Cell Histiocytosis Treatment (PDQ). Health Professional. Bethesda, MD: NCI; updated January 30, 2015.
  26. National Comprehensive Cancer Network (NCCN). Clofarabine. NCCN Drug & Biologics Compendium. Fort Washington, PA: NCCN; 2019.
  27. Patel YT, Jacus MO, Boulos N, et al. Preclinical examination of clofarabine in pediatric ependymoma: Intratumoral concentrations insufficient to warrant further study. Cancer Chemother Pharmacol. 2015;75(5):897-906
  28. Rabitsch W, Böhm A, Bojic M, et al. Clofarabine/cyclophosphamide for debulking before stem cell transplantation. Eur J Clin Invest. 2014;44(8):775-783.
  29. Rodriguez-Galindo C, Jeng M, Khuu P, et al. Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer. 2008;51(5):703-706.
  30. Rudrapatna VK, Morley K, Boucher KM, et al. Phase I trial of low-dose oral clofarabine in myelodysplastic syndromes patients who have failed frontline therapy. Leuk Res. 2015;39(8):835-839
  31. Simko SJ, Tran HD, Jones J, et al. Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer. 2014;61(3):479-487.
  32. Tischer J, Stemmler HJ, Engel N, et al. Feasibility of clofarabine cytoreduction followed by haploidentical hematopoietic stem cell transplantation in patients with relapsed or refractory advanced acute leukemia. Ann Hematol. 2013;92(10):1379-1388.
  33. Zoellner AK, Fritsch S, Prevalsek D, et al. Sequential therapy combining clofarabine and T-cell-replete HLA-haploidentical haematopoietic SCT is feasible and shows efficacy in the treatment of refractory or relapsed aggressive lymphoma. Bone Marrow Transplant. 2015;50(5):679-684