Number: 0740

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


  1. Criteria for Initial Approval

    Aetna considers pralatrexate (Folotyn or generic pralatrexate) medically necessary for persons with the following conditions:

    1. Adult T-cell leukemia/lymphoma (ATLL)

      For treatment of ATLL when both of the following criteria are met:

      1. The requested medication is used as a single agent; and
      2. The requested medication is used as subsequent therapy; or
    2. Breast implant-associated anaplastic large cell lymphoma (ALCL)

      For treatment of breast implant associated ALCL when both of the following criteria are met:

      1. The requested medication will be used as a single agent; and
      2. The requested medication will be used as subsequent therapy; or
    3. Cutaneous anaplastic large cell lymphoma

      For treatment of cutaneous anaplastic large cell lymphoma (ALCL) when the requested medication is used as a single agent; or

    4. Extranodal NK/T-cell lymphoma

      For treatment of extranodal NK/T-cell lymphoma when all of the following criteria are met:

      1. The requested medication will be used as a single agent; and
      2. The member has relapsed or refractory disease; and
      3. The member has had an inadequate response or contraindication to asparaginase-based therapy (e.g., pegaspargase); or
    5. Hepatosplenic T-cell lymphoma

      For treatment of hepatosplenic T-cell lymphoma when both of the following criteria are met:

      1. The requested medication will be used as a single agent; and
      2. The member has had two or more previous lines of chemotherapy; or
    6. Mycosis fungoides or Sezary syndrome (MF/SS)

      For treatment of MF or SS; or

    7. Peripheral T-cell lymphoma (PTCL)

      For treatment of PTCL (including the following subtypes: anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell lymphoma with TFH phenotype, or follicular T-cell lymphoma) when both of the following criteria are met:

      1. The requested medication will be used as a single agent; and
      2. The requested medication will be used to treat relapsed or refractory disease or for initial palliative therapy.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. Continuation of Therapy

    Aetna considers continuation of pralatrexate (Folotyn or generic pralatrexate) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Note: Vitamin B-12 supplementation is considered medically necessary for members taking pralatrexate. See CPB 0536 - Vitamin B-12 Therapy.

Dosage and Administration

Pralatrexate (Folotyn) is available as a 20 mg/1 mL or 40 mg/2 mL in a single-dose vial for injection.

Peripheral T-cell lymphoma

The recommended dose of pralatrexate for peripheral T-cell lymphoma is 30 mg/m2 administered intravenously over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity.

Prior to initiating pralatrexate, individuals should be supplemented with vitamin B12 1 mg intramuscularly within 10 weeks prior to treatment and every eight‐to‐10 weeks thereafter (after initial dose, vitamin B12 may be administered on the same day as pralatrexate) and folic acid 1.0-1.25 mg orally on a daily basis beginning within 10 days prior to initiating pralatrexate (continue during treatment and for 30 days after last pralatrexate dose).

Source: Acrotech Biopharma, 2020

Note: Pralatrexate is also available as a generic formulation.

Experimental and Investigational

Aetna considers pralatrexate (Folotyn) experimental and investigational for all other indications, including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

  • Esophagogastric cancer
  • Head and neck squamous cell cancer
  • Multiple myeloma
  • Non-small cell lung carcinoma
  • Pleural mesothelioma
  • Solid tumors (e.g., bladder cancer, colorectal cancer, esophageal and gastroesophageal cancer, fallopian tube cancer, ovarian cancer, pancreatic cancer, and primary peritoneal cancer, not an all-inclusive list).


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:

38206 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous
38232 Bone marrow harvesting for transplantation; autologous
38241 Hematopoietic progenitor cell (HPC); autologous transplantation
96374 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug
96375 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); each additional sequential intravenous push of a new substance/drug (List separately in addition to code for primary procedure) medicine
96379 Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion

HCPCS codes covered if selections criteria are met:

J9307 Injection, pralatrexate, 1 mg

ICD-10 codes covered if selection criteria are met:

C82.50 - C82.59 Diffuse follicle center lymphoma
C84.00 - C84.09 Mycosis fungoides
C84.10 - C84.19 Sezary disease
C84.40 - C84.49 Peripheral T-cell lymphoma, not classified [adult]
C84.60 - C84.7A Anaplastic large cell lymphoma
C84.A0 - C86.6 Cutaneous T-cell lymphoma unspecified, other mature T/NK-cell lymphomas, mature T/NK-cell lymphomas, other specified and unspecified types of non-Hodgkin lymphoma and other specified types of T/NK-cell lymphoma [relapsed or refractory monomorphic epitheliotropic]
C91.50 Adult T-cell lymphoma/leukemia (HTLV-1-associated) not having achieved remission
C91.51 Adult T-cell lymphoma/leukemia (HTLV-1-associated), in remission
C91.52 Adult T-cell lymphoma/leukemia (HTLV-1-associated), in relapse
C91.Z0 Other lymphoid leukemia not having achieved remission [adult T-cell lymphoma]
C91.Z2 Other lymphoid leukemia, in relapse [adult T-cell lymphoma]

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

C11.0 - C11.9 Malignant neoplasm of nasopharynx
C15.3 - C15.9 Malignant neoplasm of esophagus
C16.0 - C16.9 Malignant neoplasm of stomach
C18.0 - C21.8 Malignant neoplasm of colon, rectum, rectosigmoid junction, and anus
C22.1 Intrahepatic bile duct carcinoma
C23 - C24.9 Malignant neoplasm of gallbladder and other and unspecified parts of biliary tract
C25.0 - C25.9 Malignant neoplasm of pancreas
C31.0 - C31.9 Malignant neoplasm of accessory sinuses (paranasal)
C33 - C34.92 Malignant neoplasm of trachea, bronchus and lung [non-small-cell lung cancer (NSCLC)]
C37 Malignant neoplasm of thymus
C38.4 Malignant neoplasm of pleura
C43.0 - C44.99 Melanoma and other malignant neoplasms of skin
C45.0 Mesothelioma of pleura
C46.1 Kaposi's sarcoma of soft tissue
C48.1 Malignant neoplasm of specified parts of peritoneum [primary]
C48.2 Malignant neoplasm of peritoneum, unspecified [primary]
C49.0 - C49.9 Malignant neoplasm of other connective and soft tissue
C50.011 - C50.929 Malignant neoplasm of breast
C53.0 - C55 Malignant neoplasm of cervix uteri and corpus uteri
C56.1 - C56.9 Malignant neoplasm of ovary
C57.00 - C57.02 Malignant neoplasm of fallopian tube
C61 Malignant neoplasm of prostate
C64.1 - C68.9 Malignant neoplasm of kidney and other and unspecified urinary organs
C67.0 - C67.9 Malignant neoplasm of bladder
C73 Malignant neoplasm of thyroid gland
C90.00 - C90.02 Multiple myeloma
D00.0 - D09.9 In situ neoplasms


U.S. Food and Drug Administration (FDA)-Approved Indications

  • Treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)

Compendial Uses

  • Adult T-cell leukemia/lymphoma (ATLL)
  • Mycosis fungoides/Sezary syndrome (MF/SS)
  • Cutaneous anaplastic large cell lymphoma (ALCL)
  • Extranodal NK/T-cell lymphoma
  • Hepatosplenic T-cell lymphoma
  • Anaplastic large cell lymphoma
  • Peripheral T-cell lymphoma not otherwise specified
  • Angioimmunoblastic T-cell lymphoma
  • Enteropathy associated T-cell lymphoma
  • Monomorphic epitheliotropic intestinal T-cell lymphoma
  • Nodal peripheral T-cell lymphoma with TFH phenotype
  • Follicular T-cell lymphoma
  • Breast implant associated anaplastic large cell lymphoma (ALCL)

Pralatrexate is available as Folotyn (Acrotech Biopharma LLC) and is a 10-deazaaminopterin derivative, is a novel anti-folate designed to have high affinity for the reduced folate carrier type 1; inhibiting dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.

Per the prescribing information, pralatrexate (Folotyn) carries the following warnings and precautions:

  • Myelosuppression
  • Mucositis
  • Dermatologic reactions
  • Tumor lysis syndrome
  • Hepatic toxicity
  • Risk of increased toxicity with renal impairment
  • Embryo-fetal toxicity.

The most common adverse reactions (>35%) included mucositis, thrombocytopenia, nausea, and fatigue (Acrotech Biopharma, 2020).

Pre-clinical and clinical studies have demonstrated that pralatrexate has significant activity against peripheral T-cell lymphoma (PTCL), an often aggressive type of non-Hodgkin's lymphoma (NHL).  The dose-limiting toxicity (DLT) for pralatrexate is mucositis, which could be abrogated with folic acid and vitamin B-12 supplementation.  Because of the relative rarity of this group of diseases, large-scale prospective clinical trials are difficult to implement (Rosenstein and Link, 2008; Rueda et al, 2009).

Molina (2008) stated that pralatrexate was developed to overcome the limitations of the folate analog, methotrexate.  Compared with methotrexate in pre-clinical studies, pralatrexate demonstrated superior intra-cellular transport via the reduced folate carrier, and increased accumulation within cells by enhanced polyglutamylation.  Pre-clinical studies in-vitro and in models of B-cell lymphomas, T-cell lymphomas and non-small cell lung carcinoma (NSCLC) indicated that pralatrexate exhibited anti-tumor activity that was superior to the activity of other anti-folates.  The administration of pralatrexate to patients with T-cell lymphomas and NSCLC resulted in significant tumor remissions.  At the time of publication, pralatrexate was in phase II clinical trials for the treatment of PTCL, a phase I/II trial in combination with gemcitabine for the treatment of NHL, and a phase IIb trial in comparison with erlotinib in patients with NSCLC.  Because of the limited therapies available for PTCL, pralatrexate could have a secure niche for the treatment of this indication, if ongoing clinical trials and future phase III trials confirm the efficacy of the drug.  The authors noted that, in contrast, for pralatrexate to be incorporated into the accepted treatment options for NSCLC, the drug will need to prove clear superiority to established agents.

In a phase II study, Krug et al (2007) examined the response rate of malignant pleural mesothelioma to pralatrexate at an intravenous dose of 135 mg/m2 every 2 weeks.  After a protocol amendment, patients were supplemented with vitamin B-12 and folic acid at the time of starting therapy.  A total of 16 patients were enrolled.  No complete or partial responses were observed.  Two patients with epithelioid histology had minor responses; 3 other patients remained on study with stable disease for 9, 9, and 48 months.  The median time to progression was 3 months.  The overall median survival time was 7 months (95 % confidence interval [CI]: 3.2 to 16.2 months) and the 1-year survival was 31 % (95 % CI: 15 % to 65 %).  Three patients (19 %) had grade 2 stomatitis, 8 (50 %) had grade 3, and 1 (6 %) had grade 4.  The authors concluded that with this particular dose and schedule, pralatrexate as a single agent had no activity in malignant pleural mesothelioma.

In phase I study, Azzoli et al (2007) determined the maximum tolerated dose (MTD) and toxicity of pralatrexate plus paclitaxel or docetaxel in patients with advanced cancer.  Pralatrexate was administered intravenously every 2 weeks (days 1 and 15) in a 4-week cycle.  Depending on the taxane used and dose being tested, the taxane was administered on days 1 and 15; days 2 and 16; or days 1, 8, and 15.  In the latter part of the study, patients in the docetaxel arm were treated with vitamin B-12 and folic acid supplementation to mitigate toxicity and allow pralatrexate dose escalation.  For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested.  For pralatrexate plus docetaxel plus vitamin supplementation, pralatrexate 120 mg/m(2) plus docetaxel 35 mg/m(2) administered on the same day every other week was defined as the MTD and schedule, with DLT at higher dose combinations including stomatitis and asthenia.  Significant anti-tumor activity was observed for this combination in patients with NSCLC.  The authors concluded that pralatrexate (120 mg/m(2)) plus docetaxel (35 mg/m(2)) plus vitamin supplementation is well-tolerated with signs of efficacy against NSCLC that merit phase II testing.

O'Connor et al (2009) determined the MTD and efficacy of pralatrexate in patients with lymphoma.  Pralatrexate, initially given at a dose of 135 mg/m(2) on an every-other-week basis, was associated with stomatitis.  A re-designed, weekly phase I/II study established an MTD of 30 mg/m(2) weekly for 6 weeks every 7 weeks.  Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/microL, and a platelet count greater than 50,000/microL for the first dose of any cycle.  The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity.  On a weekly schedule, the MTD was 30 mg/m(2) weekly for 6 weeks every 7 weeks.  This schedule modification resulted in a 50 % reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis.  Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B-12 supplementation.  Of 48 assessable patients, the overall response rate was 31 % (26 % by intention-to-treat), including 17 % who experienced complete remission (CR).  When analyzed by lineage, the overall response rates were 10 % and 54 % in patients with B-cell and T-cell lymphomas, respectively.  All 8 patients who experienced CR had T-cell lymphoma, and 4 of the 6 patients with a partial remission were positron emission tomography negative.  The duration of responses ranged from 3 to 26 months.  The authors concluded that pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.

In September 2009, the Food and Drug Administration (FDA) approved pralatrexate (Folotyn), designated as an orphan drug, for the treatment of PTCL, which is a relatively rare disease occurring in less than 9,500 patients each year in the United States.  Folotyn was approved under the FDA's accelerated approval process.  It is indicated for patients who have relapsed, or have not responded well to other forms of chemotherapy.  The FDA approved Folotyn based on evidence that it reduces tumor size, because tumor shrinkage is considered reasonably likely to predict a clinical benefit such as extending the survival of cancer patients.  Tumor shrinkage was seen on imaging scans in 1 study.  Of 109 patients with PTCL in the trial, 27 % had reduction in tumor size.  The most common adverse reactions associated with the use of Folotyn were irritation or sores of the mucous membranes such as the lips, the mouth, and the digestive tract, low platelet cell counts, low white blood cell counts, fever, nausea, and fatigue.  Patients treated with Folotyn should take folate and vitamin B-12 supplements to reduce mucous membrane irritation.

Marchi and colleagues (2010) examined the in-vitro and in-vivo activities of pralatrexate alone and in combination with bortezomib in PTCL.  In-vitro, pralatrexate and bortezomib exhibited concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines.  Pralatrexate showed synergism when combined with bortezomib in all cell lines studied.  Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel.  Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents.  In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone.  The authors concluded that collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of PTCL.

Zain and O'connor (2010) described how pralatrexate is being combined with other agents in both the pre-clinical and clinical arenas.  The authors stated that pralatrexate is a unique anti-folate that has been rationally designed to have a high affinity for the reduced folate receptor and the enzyme folylpolyglutamy synthetase.  It is active in PTCL and NSCLC.  It is now being studied in combination with other chemotherapeutic and targeted agents for the treatment of hematological malignancies.

In a phase II b clinical trial, Kelly and colleagues (2012) evaluated pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease.  In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day.  The primary objective was to estimate OS in all patients and pre-specified subgroups using relative comparisons of hazard ratios (HRs).  Secondary endpoints included progression-free survival, response rate, and safety.  Key eligibility criteria included
  1. greater than or equal to 1 prior platinum-based therapy,
  2. Eastern Cooperative Oncology Group performance status of 0 to 1, and
  3. a smoking history of 100 cigarettes or more.  
A total of 201 patients were randomized.  A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95 % CI: 0.61 to 1.14) in the intent-to-treat population.  This favorable survival result was seen in most prespecified subgroups for pralatrexate.  The largest reduction in the risk of death was observed in patients with non-squamous cell carcinoma (n = 107; HR = 0.65; 95 % CI: 0.42 to 1.0).  The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23 %).  Discontinuation of pralatrexate for any grade of mucositis was 21 %.  The authors concluded that pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC.  They stated that future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.

Abramovits et al (2012) stated that T-cell lymphoma accounts for 10 to 15 % of all cases of NHL in the United States (approximately 5,000 to 6,000 cases a year).  Peripheral T-cell lymphoma comprises a subgroup of rare and aggressive NHL that develops from T cells in different stages of maturity outside of the thymus.  Cutaneous T-cell lymphoma (CTCL) is a subgroup that falls within the T-cell lymphoma population but is classified differently than other PTCLs.  Most cases of CTCL are considered indolent and can often be treated with less aggressive therapies.  Eight percent to 55 % of CTCL cases undergo transformation, and once this transformation occurs, the disease acts similarly to other PTCLs and its classification changes to that of a PTCL.  Transformed CTCL requires aggressive systemic therapy.  Pralatrexate (PDX) is the first FDA-approved drug for relapsed and refractory PTCL and has also gained compendia approval for treatment of CTCL.  Pralatrexate is an anti-folate chemotherapeutic inhibitor of dihydrofolate reductase.  It has a high affinity for the one carbon-reduced folate carrier, which leads to better cellular internalization of the drug and has a greater anti-tumor effect than methotrexate.  Several clinical trials have been conducted to evaluate the use of this drug in PTCL and other malignancies such as NSCLC.

Hui and colleagues (2012) reviewed the pharmacology, pharmacokinetics, clinical trials, adverse effects, dosage, and economic considerations of PDX.  Peripheral T-cell lymphoma comprises approximately 15 to 20 % of all aggressive lymphomas and 5 to 10 % of all NHL.  Advanced PTCL is often refractory to traditional first-line chemotherapy regimens.  Pralatrexate has a higher potency than methotrexate and edatrexate.  The safety and effectiveness of PDX have been demonstrated in the PROPEL trial, a prospective phase II trial in patients with relapsed or refractory PTCL.  Patients with prior stem cell transplantation receiving PDX also had similar response rates.  Pralatrexate was investigated on the treatment of relapsed or refractory cutaneous T-cell lymphoma, previously treated advanced NSCLC, and other solid malignancies.  Pralatrexate has similar side effects to other DHFR inhibitors.  The most common side effect of PDX is mucositis.  The recommended dose of PDX is 30 mg/m(2) once-weekly for 6 weeks in 7-week cycle until disease progresses or unacceptable toxicity for PTCL and may require dose reduction or discontinuation.  Patients should be supplemented with oral folic acid and intramuscular vitamin B-12 injections.  The authors concluded that PDX provides clinical benefit to patients with relapsed or refractory PTCL with durable complete and partial responses in patients who had not responded to multiple prior treatment regimens.

Koch et al (2013) noted that balancing the safety and effectiveness of drugs is important for successful cancer therapy, as adverse reactions can prohibit the use of effective treatments.  Pralatrexate is a novel anti-folate with a higher affinity for tumor cells than methotrexate, FDA-approved for use in relapsed and refractory PTCL and transformed mycosis fungoides (T-MF).  Patients with T-MF have a higher incidence of adverse events than patients with other lymphomas, necessitating a lower recommended dose of 15 mg/m2 (versus 30 mg/m2 for PTCL).  Dose-limiting toxicity mucositis occurs in about 25 % of patients with T-MF, but milder mucositis is observed in almost all patients with T-MF, frequently leading to therapy discontinuation despite clinical response.  Leucovorin rescue is the standard of care for high-dose methotrexate therapy, but has not been studied or recommended for use with PDX.  These investigators reported their clinical experience using leucovorin with PDX (30 mg/m2) with good clinical response and no DLTs.  The authors concluded that prophylactic leucovorin deserves further investigation in prospective clinical trials to allow patients with cutaneous lymphomas to receive the full benefit of PDX therapy without intolerable toxicity.

The British Committee for Standards in Haematology’s guidelines on “The management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma)” (Dearden et al, 2013) noted that “There are insufficient data to recommend novel agents such as gemcitabine, bendamustine, pralatrexate, and romidepsin”.

In a phase II clinical trial, Ho and colleagues (2014) examined the effects of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC).  This was a single-arm, Simon optimal 2-stage study.  Patients with R/M HNSCC previously treated with chemotherapy were eligible.  The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) bi-weekly on a 4-week cycle with vitamin supplementation.  Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation.  Radiologic imaging was to be obtained about every 2 cycles.  A total of 13 subjects were enrolled; 12 were treated; 7 of the 12 patients had previously received greater than or equal to 2 lines of chemotherapy.  The most common grade 3 toxicity was mucositis (3 patients).  Seven patients did not complete 2 cycles of therapy due to progression of disease (n = 4), toxicity (n = 1), death (n = 1), and withdrawal of consent (n = 1).  Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate.  No clinical activity was observed.  The median OS was 3.1 months.  The study was closed early due to lack of efficacy.  The authors concluded that pralatrexate does not possess clinical activity against previously treated R/M HNSCC.  Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.

Petullo et al (2015) stated that the appropriate second-line therapy for patients with advanced gastro-esophageal (GE) or esophageal cancer after failure of first-line platinum-based therapy is unclear. Pralatrexate and docetaxel have independently been shown to have efficacy in the treatment of these cancers. In a phase II clinical trial, these researchers examined the effectiveness of the combination of these agents in the treatment of GE and E cancer. A Fleming phase II design with a single stage of 32 patients was planned. Pralatrexate 120 mg/m(2) and docetaxel 35 mg/m(2) were administered on day 1 of 14-day cycles. The primary end-point was to evaluate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and secondary end-points were to evaluate for progression-free survival (PFS) and overall survival (OS). The study was halted prematurely due to loss of funding after the accrual of 6 patients. Two patients had stable disease (SD) and 4 patients had disease progression per RECIST. When applying PERCIST criteria in 4 evaluable patients, 2 had a partial response (PR) and 2 had SD. Median PFS was 1.9 months (95 % CI: 0.8 to 7.2) and median OS was 5.5 (0.8 to 11.7) months. The authors concluded that pralatrexate and docetaxel as therapy in refractory esophageal and GE adenocarcinoma did not demonstrate meaningful preliminary activity.

Grem and colleagues (2015) noted that PDX is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Pre-clinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). In a phase I clinical trial, a total of 27 patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m2 on day 1 followed 24 hours later by 5-FU at a dose of 3,000 mg/m2 /48 hours every 2 weeks with folic acid and vitamin B-12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8 %, 14.8 %, and 0 % of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6 %), dehydration (33.3 %), fatigue (25.9 %), and diarrhea (22.2 %). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities. The median PFS was 112 days (range of 28 to 588 days). Seven patients (26 %) had a PFS of greater than 180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. The authors concluded that the recommended dose of PDX was 148 mg/m2. A subset of heavily pre-treated patients had PFS durations of greater than or equal to 6 months with this regimen.

Bladder Cancer

In a retrospective study, Wang and colleagues (2019) examined the clinical efficacy and mechanism of pralatrexate (PTX) combined with palbociclib isethionate (PAL) in the treatment of bladder cancer patients.  Medical records of 82 bladder cancer patients admitted to Shengjing Hospital of China Medical University from February 2015 to February 2018 were reviewed.  Patients treated with PTX combined with PAL served as study group (42 cases) and patients with conventional GC (gemcitabine plus cisplatin) chemotherapy regimen were the control group (40 cases).  Changes in liver function indexes before and after treatment were observed, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil).  Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used for detection of relative expression levels of serum dihydrofolate reductase (DHFR) and vascular endothelial growth factor (VEGF) before and after treatment in the 2 groups.  The clinical efficacy after treatment and adverse reactions during treatment were observed in the 2 groups.  There was no significant difference in the clinical remission rate (RR) nor in the serum ALT, AST, ALP and TBil levels between the study and the control groups (p > 0.05).  Concentrations of serum ALT, AST, ALP and TBil were significantly higher than those before treatment in both groups (p < 0.05). Serum ALT, AST, ALP and TBil concentrations in study group were significantly lower than those in control group (p < 0.05).  There was no significant difference in the incidence of thrombocytopenia and leukopenia between the 2 groups (p > 0.05).  There was no significant difference in relative expression levels of serum DHFR mRNA and VEGF mRNA before treatment between the study and control groups (p > 0.05).  Those after treatment were significantly lower than those before treatment in both groups (p < 0.05), and those after treatment in study group were significantly lower than those in control group (p < 0.05).  PTX combined with PAL could reduce adverse reactions of nausea and vomiting and liver function impairment during treatment and suppress tumor neovascularization.  This was achieved possibly by inhibiting expression levels of DHFR and VEGF, thereby killing cancer cells.  The authors concluded that PTX combined with PAL may become a new method for the treatment of bladder cancer patients; DHFR and VEGF are expected to become novel therapeutic targets for the treatment of bladder cancer.

Esophagogastric Cancer

In a phase-II clinical trial, Malhotra and colleagues (2020) examined the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophago-gastric cancer (EGC), analyzed the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and assessed microRNA profile of tumor epithelium as a predictive biomarker.  This was a 2-stage trial with a safety lead in cohort and a primary end-point of overall response rate (ORR).  Patients received bi-weekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2).  Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed; ORR was 26 %; DLTs were observed in 2 of 4 patients at D1 and 0 at D-1.  The T>C polymorphism in DHFR rs11951910 was significantly associated with lower PFS (p ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS (p = 0.02).  Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better OS (p = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS (p = 0.04).  There was no correlation between epithelial microRNA expression profile with disease progression or response.  The authors concluded that the combination of oxaliplatin and pralatrexate did not meet the primary end-point of improved ORR in advanced EGC in the current study.  SNP analysis revealed associations of variants in DHFR, GGH, and SLC19A1 with clinical outcome; thus, pharmacogenomic analysis may be relevant to the clinical use of pralatrexate in other malignancies.

Fallopian Tube, Ovarian, and Primary Peritoneal Cancers

In a phase I and II clinical trial, Del Carmen and colleagues (2016) identified the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer.  In phase I, patients received carboplatin (at an area under the curve of 5) and increasing doses of pralatrexate until the MTD of pralatrexate was achieved.  The primary end-point was the response rate.  Additional end-points were safety, response duration, PFS, OS, and pharmacokinetics.  A total of 30 patients were enrolled in phase I, and 20 patients were enrolled in phase II. Of all 50 patients, 49 completed the study.  The mean patient age was 59 years, and patients completed a median of 6 cycles.  The MTD for pralatrexate was 105 mg/m2 .  The clinical benefit rate (CRs plus PRs plus SD) was 86 %.  Of 26 patients who received the MTD, 12 had a PR, 11 had SD, and 2 had disease progression.  The PFS rate at 3 and 6 months was 87 % and 79 %, respectively; and the OS rate was 98 % at 6 and 12 months and 66 % at 24 months.  Of 30 patients, 18 (60 %) in phase I experienced an adverse event (AE) of any grade; and, of those, 4 patients (13 %) had a grade-3 or greater AE.  In phase II, 12 patients (60 %) had an AE of any grade, and 4 (20 %) had grade-3 or greater toxicity.  There was a significant reduction in the total body clearance of pralatrexate when it was received concurrently with carboplatin.  The authors concluded that most patients responded to carboplatin-pralatrexate combination; this regimen was well-tolerated and effective in this patient population.  These preliminary findings need to be further investigated in phase III clinical trials.

Multiple Myeloma

In a phase I clinical trial, Dunn and colleagues (2016) examined the safety and effectiveness of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma (MM).  A standard 3 + 3 design was employed.  Patients received intravenous (iv) pralatrexate at doses ranging from 10 to 30 mg/m(2) and bortezomib (iv) at a dose of 1.3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle.  A total of 11 participants were enrolled and completed a median of 2 cycles.  The MTD was 20 mg/m(2); 2 patients experienced DLT of mucositis.  The most frequent non-hematological toxicities were fatigue (55 %) and mucositis (45 %).  There were 3 serious AEs in 3 patients: rash, sepsis and hypotension; 1 patient (9 %) had a very good PR, 1 (9 %) had a PR, 1 (9 %) had minimal response, and 2 (18 %) had progressive disease.  The median duration of response was 4 months, the median time to next treatment was 3.4 months and the median time to progression was 4 months.  The authors concluded that pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory MM.  these preliminary findings need to be further investigated.

Pancreatic Cancer

Weng et al (2022) stated that gemcitabine is the 1st-line chemotherapeutic agent for pancreatic cancer; however, gemcitabine-resistance frequently leads to poor prognosis.  Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer.  These researchers established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3.  They found that pralatrexate significantly inhibited the growth of BxPC-GEM-20.  The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM.  Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell.  Furthermore, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92 % in-vivo.  This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice.  Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy.  Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate.  Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway.  Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer.  The authors concluded that pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer.  This may result in the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.


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