Peripheral T-Cell Lymphoma: Pharmacologic Management

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of cancers that affect mature T cells. They fall under the umbrella of non-Hodgkin lymphoma, which is anticipated to account for 4.1% of new cancer cases in 2023.¹ PTCLs are rare at less than 1 case per 100,000 people in the United States; therefore, there is an unmet need for improved treatments.² 

According to the National Cancer Institute (NCI) Physician Data Query (PDQ®) treatment guidelines, patients with PTCL often have poorer outcomes or worse treatment response and survival compared with those with aggressive B-cell lymphomas.³ The majority of patients with PTCL present with stage IV disease at multiple extranodal sites, which complicates treatment and reduces overall survival. 

This article will outline current PTCL treatment guidelines from NCI³ and the National Comprehensive Cancer Network (NCCN).⁴ For information on all other T-cell lymphomas, please reference “Adult T-Cell Lymphomas: Pharmacologic Management.” 

Pharmacologic recommendations will be provided for the following PTCL subtypes:

• Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) positive and negative
• Hepatosplenic T-cell lymphoma
• Breast implant-associated ALCL
• Other subtypes
  • Peripheral T-cell lymphomas not otherwise specified (NOS)
  • Angioimmunoblastic T-cell lymphoma (AITL)
  • Enteropathy-associated T-cell lymphoma (EATL)
  • Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
  • Nodal peripheral T-cell lymphoma 
  • Follicular T-cell lymphoma 

Anaplastic Large Cell Lymphoma

ALCL is a form of CD30-positive PTCL that often harbors anaplastic lymphoma kinase (ALK) mutations.⁴ Patients with ALK-positive ALCL tend to have better outcomes compared with patients who are ALK-negative or those with other PTCL subtypes. Children and young adults are more likely to have ALK-positive ALCL compared with older adults. 

First-Line Treatments for Anaplastic Large Cell Lymphoma

Since ALCL expresses CD30, NCCN recommends first-line treatment with brentuximab vedotin and combination chemotherapy with cyclophosphamide, doxorubicin, and prednisone (CHP).⁴ NCI also recommends brentuximab vedotin with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).³ Both recommendations are based on results from the ECHELON-2 clinical trial.⁵ Table 1 highlights first-line chemotherapy regimens (preferred and other recommended) for ALCL from NCCN. 

Table 1. First-Line Chemotherapy Regimens for Anaplastic Large Cell Lymphoma

Regimen	Dosing	Treatment Duration	Indication
Brentuximab vedotin + CHP	Brentuximab vedotin 1.8 mg/kg IV, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, prednisone 100 mg oral	21-day cycle for 6-8 cycles: Cyclophosphamide, doxorubicin, and brentuximab vedotin IV on day 1, prednisone oral on days 1-5	Preferred first-line therapy
CHOP	Cyclophosphamide 750 mg/m2 IV + doxorubicin 50 mg/m2 IV + vincristine 2 mg IV, prednisone 100 mg oral	21-day cycle for 6 cycles (ALCL, ALK+): Cyclophosphamide, doxorubicin, and vincristine IV on day 1, prednisone oral on days 1-5	Other recommended first-line therapy
CHOEP	Cyclophosphamide 750 mg/m2 IV + doxorubicin 50 mg/m2 IV + vincristine 2 mg IV, etoposide 100 mg/m2 IV, prednisone 100 mg oral	21-day cycle for 6 cycles: Cyclophosphamide, doxorubicin, and vincristine IV on day 1, etoposide IV on days 1-3, prednisone on days 1-5	Other recommended first-line therapy
Dose-adjusted EPOCH	Etoposide 50 mg/m2 IV + 0.4 mg/m2 continuous IV infusion + doxorubicin 10 mg/m2 IV, prednisone 60 mg oral, cyclophosphamide 750 mg/m2 IV	21-day cycle until complete response:  Etoposide, vincristine, and doxorubicin continuous IV infusion for 96 hours on days 1-4, prednisone oral on days 1-6, cyclophosphamide on day 6	Other recommended first-line therapy

ALK = anaplastic lymphoma kinase; CHP = cyclophosphamide, doxorubicin, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CHOEP = cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; IV = intravenous.

From NCI guidelines,³ NCCN guidelines,⁴ Horwitz et al,⁵ Cederleuf et al,⁶ and Maeda et al.⁷

Second-Line Treatments for Anaplastic Large Cell Lymphoma

NCCN supports patients enrolling in clinical trials as part of standard second-line therapy whether they are eligible to undergo autologous hematopoietic stem cell transplantation or not.⁴ The benefits of enrolling in a clinical trial include better access to individualized care and experimental treatments, and increased monitoring from clinical trial clinicians and staff. 

Patients eligible to undergo stem cell transplantation are recommended to receive single-agent brentuximab vedotin administered as 1.8 mg/kg on day 1 of a 21-day cycle for up to 16 cycles.⁸ Other recommended consolidation chemotherapy regimens are detailed in Table 2.

Table 2. Second-Line Chemotherapy Recommendations for Transplant-Eligible Patients With Anaplastic Large Cell Lymphoma

Regimen	Dosing	Treatment Schedule
DHA	Cisplatin 100 mg/m2 IV, cytarabine 2 g/m2 pulse, dexamethasone 40 mg IV or oral	21- or 28-day cycles for 6-10 cycles: Cisplatin on day 1 as 24-hour continuous IV infusion, cytarabine on day 2 as 2 pulses 12 hours apart, dexamethasone IV or oral on days 1-4
ESHAP	Etoposide 40 mg/m2 IV, cisplatin 25 mg/m2 IV, methylprednisolone 500 mg IV, cytarabine 2 g/m2 IV	21- or 28-day cycles for 6-8 cycles: Etoposide and cisplatin 24-hour continuous IV infusion on days 1-4, methylprednisolone IV on days 1-5, cytarabine IV infusion over 2-3 hours on day 5
GDP	Cisplatin 75 mg/m2 IV, gemcitabine 100 mg/m2 IV, dexamethasone 40 mg oral	21-day cycle for 6 cycles: Cisplatin IV over 1 hour on day 1, gemcitabine IV over 30 minutes on days 1 and 8, dexamethasone oral on days 1-4
GemOx	Gemcitabine 1000 mg/m2 IV, oxaliplatin 100 mg/m2 IV	21-day cycle for 6-8 cycles: Gemcitabine IV and oxaliplatin IV on day 1 OR 15-day cycle for 6-8 cycles: Gemcitabine IV and oxaliplatin IV with G-CSF
GVD	Liposomal doxorubicin 20 mg/m2 IV, gemcitabine 800-1000 mg/m2 IV, vinorelbine 25 mg/m2 IV	21-day cycle for 2-6 cycles: Liposomal doxorubicin IV on day 1, gemcitabine IV and vinorelbine IV on days 1 and 8
ICE	Ifosfamide 5 g/m2 IV. etoposide 100 mg/m2 IV, carboplatin at target AUC of 5 mg·min/mL IV	14-day cycle for 3 cycles:  Ifosfamide 24-hour continuous IV on day 1, etoposide IV bolus on days 1-3, carboplatin IV on day 2

AUC = area under the curve; DHA = dexamethasone, cytarabine, and platinum (carboplatin, cisplatin, or oxaliplatin); ESHAP = etoposide, methylprednisolone, cytarabine, and platinum (cisplatin or oxaliplatin); G-CSF = granulocyte colony-stimulating factor; GDP = gemcitabine, dexamethasone, and cisplatin; GemOx = gemcitabine and oxaliplatin; GVD = gemcitabine, vinorelbine, and liposomal doxorubicin; ICE = ifosfamide, carboplatin, and etoposide; IV = intravenous.

From NCCN treatment guidelines.⁴

Patients who are not undergoing transplantation should receive single-agent brentuximab vedotin. NCCN has provided additional second-line therapies indicated for patients who are undergoing transplantation and those who are not. Table 3 lists these therapies with their appropriate indications.⁴ 

Table 3. Second-Line Treatments for Anaplastic Large Cell Lymphoma

Drug	Dosing	Treatment Schedule	Indication
Alectinib	600 mg oral	21-day cycle for 16 cycles: 300 mg twice daily oral for total of 600 mg	Transplant/no transplant; for ALK+ disease only
Belinostat	1000 mg/m2 IV	21-day cycle: 30-minute IV infusion on days 1-5	Transplant/no transplant
Bendamustine	120 mg/m2 IV	21-day cycle for 6 cycles: IV infusion on days 1-2	Transplant/no transplant
Bortezomib	1.3 mg/m2 IV	21-day cycle for 6 cycles: IV infusion on days 1, 4, 8, and 11 followed by 7 days of rest	No transplant
Crizotinib	500 mg oral	250 mg twice daily until disease progresses or unacceptable toxicity occurs	Transplant/no transplant; ALK+ disease only
Duvelisib	50 mg oral	2 cycles (treatment length not specified)	Transplant/no transplant
Gemcitabine	1200 mg/m2 IV	28-day cycles for 3 cycles: IV infusion on days 1, 8, and 15	Transplant/no transplant
Pralatrexate	30 mg/m2/wk IV	Weekly for 6 weeks followed by 1 week of rest; repeat treatment every 7 weeks until disease progresses or unacceptable toxicity occurs	Transplant/no transplant
Romidepsin	14 mg/m2 IV	28-day cycle for 6 cycles: 4-hour IV infusion on days 1, 8, and 15	Transplant/no transplant

ALK = anaplastic lymphoma kinase; IV = intravenous.

From NCCN treatment guidelines,⁴ Fukano et al,⁹ O’Connor et al,¹⁰ Damaj et al,¹¹ Zinzani et al,12 Bossi et al,¹³ and Brammer et al.¹⁴

The US Food and Drug Administration (FDA) approved crizotinib for treating ALCL in pediatric and young adult patients. This approval came after a multicenter, open-label trial of 26 patients revealed that crizotinib treatment resulted in an 88% overall response rate. Additionally, response was maintained for at least 1 year following treatment in 22% of patients.¹⁵ 

Hepatosplenic T-Cell Lymphoma

Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell lymphoma involving the liver, spleen, and bone marrow. It is an aggressive PTCL subtype often associated with poor treatment response and prognosis.⁴ Approximately 20% of cases of HSTCL are associated with chronic immune suppression or immune-mediated disease, including organ transplantation and inflammatory bowel disease; concomitant use of immunomodulators and tumor necrosis factor-α (TNF-α) inhibitors can also give rise to HSTCL.⁴ 

Since HSTCL is a rare cancer, NCCN treatment recommendations are largely based on case reports and single-center retrospective studies. The most appropriate first-line recommendation is enrollment in a clinical trial or induction therapy to prime for successful hematopoietic stem cell transplantation.⁴ 

CHOP-based regimens are ineffective for HSTCL and are not recommended by NCCN. Instead, the preferred first-line regimen is ifosfamide, carboplatin, and etoposide (ICE). Other cytotoxic chemotherapy and targeted therapy regimens for treating HSTCL include⁴:

• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and cytarabine
• Alemtuzumab + pentostatin
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)
• CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone)
• DHA (dexamethasone, cytarabine, platinum-based agent)

Patients with CD30-positive HSTCL may be treated with brentuximab + CHP, described in Table 1. Table 4 outlines the dosing recommendation for alemtuzumab + pentostatin. All other treatment regimens are outlined in Tables 1 and 2. 

Table 4. Other First-Line Treatment Recommendations for Hepatosplenic T-Cell Lymphoma

Regimen	Dosing	Treatment Schedule
Alemtuzumab + pentostatin	Alemtuzumab 30 mg IV and pentostatin 4 mg/m2 IV	14 doses total or until complete response:  Pentostatin IV every week for 4 weeks, then every 2 weeks until complete response or best response is achieved 3 months or until complete response: Alemtuzumab IV administered 1 hour after first pentostatin dose using dose escalation (3 mg, 10 mg, 30 mg) in first 3 days, then treat 3 times a week until complete response or best response is achieved

DHA = dexamethasone, cytarabine, platinum (carboplatin, cisplatin, or oxaliplatin); IV = intravenous.

From Ravandi et al.¹⁶

Breast Implant-Associated Anaplastic Large Cell Lymphoma

Breast implant-associated ALCL is a type of PTCL first reported in 1997. It affects individuals who have received a breast implant with a textured surface; there are no documented cases of breast implant-associated ALCL in individuals with smooth-surfaced implants. Breast implant-associated ALCL is a distinct subtype from other systemic and cutaneous T-cell lymphomas and breast cancers.⁴

Patients with breast implant-associated ALCL are first treated with surgery to remove the implant and excise any tumors. A total capsulectomy is recommended over partial capsulectomy and systemic therapy and/or radiation therapy. Clinicians are advised to have a biopsy performed on any suspicious lymph nodes.⁴ 

If a total capsulectomy is not possible or if patients have residual disease, additional therapy may be required. NCCN notes that breast implant-associated ALCL is rare, and there are few studies demonstrating the efficacy of one regimen over another.⁴

Anthracycline-based regimens for ALCL may be used for breast implant-associated disease. Recommended first-line treatments include⁴:

• Brentuximab vedotin ± CHP
• CHOP
• CHOEP
• Dose-adjusted EPOCH

Regimens and dosing for these agents are outlined in Table 1. 

Other Peripheral T-Cell Lymphoma Subtypes

NCCN treatment guidelines divide the remaining PTCL subtypes into different treatment groups depending on the treatment round. This section will outline treatments for⁴: 

• PTCL not otherwise specified (NOS)
• Angioimmunoblastic T-cell lymphoma (AITL)
• Enteropathy-associated T-cell lymphoma (EATL)
• Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
• Nodal peripheral T-cell lymphoma with follicular helper T cells, (nodal PTCL, TFH)
• Follicular T-cell lymphoma (FTCL)

First-Line Treatments

The recommended first-line treatments for these remaining subtypes are similar to those for ALCL. For patients with CD30-negative disease, CHOP is the preferred treatment regimen.⁴ NCCN makes this recommendation based on the efficacy seen in treating non-Hodgkin B-cell lymphomas. However, most patients with PTCL treated with CHOP eventually experience relapse and/or develop refractory disease. 

There is an unmet need for large studies to determine the best treatment for CD30-negative PTCL, driven by the rarity of this malignancy. As such, NCCN recommends that all patients with these CD30-negative PTCL subtypes enroll in clinical trials as first-line therapy.⁴ This may provide an added benefit over the anthracycline-based regimens used today. 

Recommended first-line chemotherapy regimens of brentuximab vedotin, CHOP, CHOEP, and dose-adjusted EPOCH follow those for treating ALCL. Regimens and dosing are outlined in Table 1. 

Table 5 outlines other recommended regimens along with the dosing information and schedule from NCCN. 

Table 5. First-Line Chemotherapy Regimens for Other Peripheral T-Cell Lymphoma Subtypes

Regimen	Dosing	Treatment Schedule
CHOP followed by IVE, alternating with intermediate-dose methotrexate (Newcastle regimen)	Cyclophosphamide 750 mg/m2 IV + doxorubicin 50 mg/m2 IV + vincristine 1.4 mg IV, prednisone 100 mg oral, followed byifosfamide 3000 mg/m2 IV, etoposide mg/m2 IV, epirubicin 50 mg/m2 IV, methotrexate 1500 mg/m2 IV	21-day cycle for 3 cycles: Cyclophosphamide, doxorubicin, and vincristine IV on day 1, prednisone oral on days 1-5, followed by ifosfamide, etoposide, epirubicin, and methotrexate on days 1-3
HyperCVAD alternating with high-dose methotrexate and cytarabine	Methotrexate 200 or 800 mg/m2 IV, cyclophosphamide 300 mg/m2 IV, dexamethasone 40 mg oral, cytarabine 1000 mg/m2 IV, doxorubicin 25 mg/m2 IV, vincristine 2 mg/m2 IV	21-day cycle for 4 cycles:  Methotrexate regimen:Methotrexate 200 mg/m2 IV bolus followed by 800 mg/m2 IV infusion over 24 hours on days 1-2, cyclophosphamide IV every 12 hours with mesna 600 mg/m2/d IV, dexamethasone oral on days 1-4 and 11-14 OR Cytarabine regimen:Cytarabine IV on day 3 with folic acid 50 mg oral 24 hours after the last methotrexate dose (continue folic acid 15 mg oral every 6 hours for 8 doses), doxorubicin continuous IV infusion on day 4 with G-CSF 5 µg/kg starting 24 hours after doxorubicin, vincristine IV on days 4 and 11 given 12 hours after last cyclophosphamide dose

CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; hyperCVAD = cyclophosphamide, vincristine, doxorubicin, dexamethasone; G-CSF = granulocyte colony-stimulating factor; IV = intravenous; IVE = ifosfamide, epirubicin, and etoposide.

From NCCN non-Hodgkin lymphoma treatment guidelines.⁴

Second-Line Treatments

Clinicians treating patients with relapsed PTCL should determine the appropriate second-line therapy based on their intent to proceed to transplantation. NCCN treatment recommendations are further divided by subtype based on small case reports and clinical trials. 

Patients Intended for Stem Cell Transplant

Table 6 details NCCN treatment recommendations for patients intended to undergo hematopoietic stem cell transplantation.⁴ 

Table 6. Second-Line Therapy for Patients Intended to Undergo Hematopoietic Stem Cell Transplantation

Regimen	Indication	Preferred or Other Recommended Treatment?
Belinostat	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred
Bendamustine	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Brentuximab vedotin	CD30-positive PTCL, AITL	Preferred regimen for CD30-positive PTCL; preferred regimen for CD30-positive AITL
DHA	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred
Duvelisib	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
ESHAP	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred
GDP	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred
Gemcitabine	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
GemOx	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred
GVD	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
ICE	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred
Lenalidomide	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Pralatrexate	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred for PTCL-NOS, EATL, MEITL; other recommendation for AITL, nodal PTCL (TFH), and FTCL
Romidepsin	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred

AITL = angioimmunoblastic T-cell lymphoma; DHA = dexamethasone, cytarabine, and platinum (carboplatin, cisplatin, or oxaliplatin); EATL = enteropathy-associated T-cell lymphoma; ESHAP = etoposide, methylprednisolone, cytarabine, and platinum (cisplatin or oxaliplatin); FTCL = follicular T-cell lymphoma; GDP = gemcitabine, dexamethasone, and cisplatin; GemOx = gemcitabine and oxaliplatin; GVD = gemcitabine, vinorelbine, and liposomal doxorubicin; ICE = ifosfamide, carboplatin, etoposide; MEITL = monomorphic epitheliotropic intestinal T-cell lymphoma; nodal PTCL (TFH) = nodal peripheral T-cell lymphoma with follicular helper T cells; NOS = not otherwise specified; PTCL = peripheral T-cell lymphoma.

From NCCN treatment guidelines.⁴

Patients Not Intended for Stem Cell Transplant

Patients who are not intended to undergo hematopoietic stem cell transplantation may receive the treatment regimens outlined in Table 7.

Table 7. Second-Line Therapies for Patients Not Intended to Receive a Hematopoietic Stem Cell Transplant

Regimen	Indication	Preferred or Other Recommended Treatment?
Alemtuzumab	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Belinostat	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred
Bendamustine	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Brentuximab vedotin	CD30-positive PTCL, AITL	Preferred regimen for CD30-positive PTCL; preferred regimen for CD30+ AITL
Bortezomib	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Duvelisib	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Gemcitabine	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Lenalidomide	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Other
Pralatrexate	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred regimen for PTCL-NOS, EATL, MEITL; other recommendation for AITL, nodal PTCL (TFH), and FTCL
Romidepsin	PTCL-NOS, EATL, MEITL, AITL, nodal PTCL (TFH), FTCL	Preferred

AITL = Angioimmunoblastic T-cell lymphoma; EATL = enteropathy-associated T-cell lymphoma; FTCL = follicular T-cell lymphoma; MEITL = monomorphic epitheliotropic intestinal T-cell lymphoma; nodal PTCL (TFH) = nodal peripheral T-cell lymphoma with follicular helper T cells; NOS = not otherwise specified; PTCL = peripheral T-cell lymphoma.

From NCCN treatment guidelines.⁴

Monitoring and Managing Side Effects, Adverse Events, and Drug-Drug Interactions

The following sections outline the side effects and adverse events that may occur when treating patients with recommended chemotherapy agents, monoclonal antibody drugs, and small molecule inhibitors for PTCL. There are also considerations for using these therapies in special populations, including elderly patients, pregnant or breastfeeding patients, and patients with impaired organ function. 

Chemotherapy

Cytotoxic chemotherapies induce apoptosis by inhibiting DNA synthesis or interfering with repair mechanisms to target rapidly dividing cells. Although they are appropriate treatments for PTCL, they often have unintended effects resulting in adverse events. Patients should be monitored regularly while undergoing treatment with a chemotherapy regimen; if an adverse event occurs, then a decision should be made to treat it and reduce the dose or discontinue treatment. 

Antihistamine therapy, corticosteroids, and epinephrine are recommended to treat infusion-related reactions, anaphylaxis, skin reactions, and other signs of hypersensitivity. Antiemetic agents and fluids are recommended to treat nausea and vomiting. Patients should undergo regular laboratory assessment to monitor for any changes in liver function or blood cell counts. Appropriate antibiotics, antivirals, and antifungals should be administered as needed to prevent infections from myelosuppressive and immunosuppressive effects. 

Many chemotherapy drugs are associated with embryo-fetal toxicity. Patients should be counseled on the drugs’ effects on a developing embryo or fetus and provided with recommendations for contraception. Breastfeeding individuals who are undergoing chemotherapy treatment should also be made aware of the risk to a breastfeeding infant or child. 

Table 8 outlines common adverse events, drug interactions, and considerations for special populations for chemotherapy drugs. 

Table 8. Side Effect Profiles of Chemotherapy Drugs

Drug	Adverse Events	Drug Interactions	Use In Special Populations
Bendamustine	Diarrhea, fatigue, pyrexia, nausea, vomiting Warnings: Hepatotoxicity, secondary malignancies, infections, extravasation injury, TLS, infusion-related reaction, myelosuppression, PML, skin reactions	CYP1A2 inhibitors and inducers	May be harmful to fetus; avoid using in breastfeeding patients
Bortezomib	Neutropenia, sensory neuropathy, thrombocytopenia Warnings: Cardiotoxicity, thrombocytopenia, thrombotic microangiopathy, peripheral neuropathy, GI toxicity, hepatotoxicity, hypotension, neutropenia, PRES, pulmonary toxicity, TLS	Strong CYP3A4 inhibitors and inducers	May be harmful to fetus; avoid using in breastfeeding patients
Carboplatin	Abdominal pain, decreased appetite, back pain, constipation, upper respiratory infection, cough, diarrhea, fatigue and weakness, vomiting, pyrexia, headache, joint pain, musculoskeletal pain, nausea, rash Warnings: Infusion-related reactions	None indicated	May be harmful to fetus; avoid using in breastfeeding patients; do not use in patients with severe renal or hepatic impairment
Cyclophosphamide	Alopecia, diarrhea, febrile neutropenia, nausea, neutropenia, pyrexia, vomiting Warnings: Cardiotoxicity, veno-occlusive liver disease, immunosuppression, myelosuppression, pulmonary toxicity, renal toxicity, urinary tract toxicity, increased risk of serious infections	ACE inhibitors, trastuzumab, G-CSF/GM-CSF, protease inhibitors, amiodarone, anthracyclines, zidovudine, azathioprine, busulfan, cytarabine, natalizumab, pentostatin, thiazide diuretics, indomethacin	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in patients with hepatic and renal impairment
Cytarabine	Abnormal gait, back pain, confusion, vomiting, weakness, constipation, fatigue, headache, nausea, pyrexia Warnings: Chemical arachnoiditis, convulsions, neurotoxicity	Use caution when administering other cytotoxic agents intrathecally	May be harmful to fetus; avoid using in breastfeeding patients
Doxorubicin	Anorexia, diarrhea, constipation, cytopenias, hand-foot syndrome, nausea, pyrexia, rash, stomatitis, vomiting, fatigue and weakness Warnings: Cardiomyopathy, thrombocytopenia, neutropenia	None indicated	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in patients with hepatic impairment
Etoposide	Pyrexia, abdominal pain, neutropenia, constipation, dysphagia, nausea, vomiting Warnings: Anaphylaxis, myelosuppression, leukemias, optic neuritis	Warfarin	May be harmful to fetus; avoid using in breastfeeding patients
Gemcitabine	Cytopenias, proteinuria,  dyspnea, nausea, rash, vomiting, elevated liver enzymes Warnings: Hepatotoxicity, infusion-related reactions, radiation toxicity, renal toxicity, pulmonary toxicity	None indicated	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in patients with renal or hepatic impairment
Ifosfamide	Infection, alopecia, cytopenias, vomiting, hematuria, nausea Warnings: CNS toxicity, secondary malignancies, cardiotoxicity, myelosuppression, veno-occlusive liver disease, neurotoxicity, pulmonary toxicity, urotoxicity, serious infections	CYP3A4 inhibitors and inducers	May be harmful to fetus; avoid using in breastfeeding patients; adjust dosing and monitor with geriatric patients; use with caution in patients with renal or hepatic impairment
Lenalidomide	Constipation, peripheral edema, cough, cytopenias, diarrhea, fatigue, nausea, pyrexia, rash Warnings: Hepatotoxicity, infusion-related reactions, myelosuppression, secondary malignancies, serious infections, TLS, tumor flare reactions, venous thromboembolism	Digoxin, erythropoiesis-stimulating agents, estrogen therapies	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in geriatric patients; use with caution in patients with renal impairment
Liposomal doxorubicin	Alopecia, anorexia, asthenia, back pain, vomiting, cough, pharyngitis, diarrhea, dyspepsia, rash, hand-foot syndrome, headache, infection, mucositis, dyspnea, nausea, pyrexia, stomatitis Warnings: Cardiomyopathy, secondary oral neoplasms, hand-foot syndrome, infusion-related reactions	None indicated	May be harmful to fetus; avoid using in breastfeeding patients; reduce dosing in patients with hepatic impairment
Methotrexate	Abdominal distress, fatigue, chills, dizziness, infection, leukopenia, ulcerative stomatitis, nausea, pyrexia Warnings: Toxicities (GI, renal, neurologic, pulmonary, and hepatic), myelosuppression, serious infections, hypersensitivity, infertility, skin reactions, secondary malignancies, TLS	Anticoagulants, sulfa drugs, antifolate drugs,  NSAIDs, aspirin, protein-bound drugs, folic acid, hepatotoxic drugs, oral antibiotics (neomycin, penicillin, sulfonamide), nephrotoxic products, nitrous oxide, probenecid, proton pump inhibitors, weak acids	May be harmful to fetus; avoid using in breastfeeding patients; monitor patients with renal or hepatic impairment
Oxaliplatin	Cytopenias, emesis, diarrhea, nausea, elevated liver enzymes, fatigue, stomatitis Warnings: Hemorrhage, severe myelosuppression, hypersensitivity, pulmonary and hepatic toxicity, peripheral sensory neuropathy, PRES, rhabdomyolysis	Anticoagulants, drugs that prolong the QT interval, nephrotoxic drugs	May be harmful to fetus; avoid using in breastfeeding patients; reduce dosing in patients with renal impairment
Pralatrexate	Anemia, constipation, cough, edema, epistaxis,  fatigue, nausea, mucositis, pyrexia, thrombocytopenia, vomiting Warnings: Hepatotoxicity, mucositis, myelosuppression, skin reactions, TLS	Probenecid, NSAIDs	May be harmful to fetus; avoid using in breastfeeding patients
Romidepsin	Anemia, constipation, fatigue, hypomagnesemia, thrombocytopenia, dysgeusia, infections, anorexia, nausea, neutropenia, pyrexia, diarrhea, vomiting Warnings: Electrocardiographic changes, infections, myelosuppression, TLS	Warfarin, strong CYP3A4 inhibitors and inducers (such as rifampin)	May be harmful to fetus; avoid using in breastfeeding patients; reduce dosing in patients with hepatic impairment
Vincristine	Anemia, decreased appetite, constipation, diarrhea, fatigue, insomnia, nausea, peripheral neuropathy, pyrexia, febrile neutropenia Warnings: Myelosuppression, extravasation tissue injury, severe constipation and bowel obstruction,  hepatic toxicity, myelosuppression, neurotoxicity, TLS	P-gp inhibitors or inducers, strong CYP3A inhibitors or inducers	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in patients with hepatic impairment
Vinorelbine	Asthenia, injection site reaction, cytopenias, elevated liver enzymes, nausea, peripheral neuropathy, constipation,  vomiting Warnings: Neurotoxicity, extravasation tissue injury, pulmonary toxicity, renal failure, hepatotoxicity, myelosuppression, severe constipation and bowel obstruction	CYP3A inhibitors	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in patients with hepatic impairment

ACE = angiotensin-converting enzyme; CNS = central nervous system; G-CSF = granulocyte colony-stimulating factor; GI = gastrointestinal; GM-CSF = granulocyte-macrophage colony-stimulating factor; NSAID = nonsteroidal anti-inflammatory drug; P-gp = P-glycoprotein; PML = progressive multifocal leukoencephalopathy; PRES = posterior reversible encephalopathy syndrome; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^17-33

Monoclonal Antibody Drugs

Monoclonal antibody drugs for PTCL interact with various proteins found on the surface of T cells to induce antibody-dependent cellular cytotoxicity. Since these therapies interact with and hamper the immune system, patients should be closely monitored for signs of infection. Monoclonal antibody drugs are also associated with an increased risk of infusion-related and hypersensitivity reactions, including:

• Signs of serious infection;
• Sudden tachycardia, chills, fever, chills, nausea, and/or vomiting; 
• Toxic epidermal necrolysis;
• Autoimmune complications affecting the heart, liver, lungs, and kidneys; and
• Stevens-Johnson syndrome.

Clinicians may pretreat patients with acetaminophen and antihistamines prior to infusion to minimize the side effects.

It is important to note that alemtuzumab is no longer commercially available in the United States due to the increased risk of severe adverse events (stroke, malignancies, autoimmunity, and infusion-related reactions). After administration, patients should be monitored closely for 2 hours for any signs of an adverse reaction. Serious and fatal viral and bacterial infections with Epstein-Barr virus, cytomegalovirus, and Pneumocystis jirovecii have also been reported in patients undergoing treatment with monoclonal antibodies. Clinicians should continue to monitor patients closely for any signs of infection. 

Table 9. Side Effect Profiles of Monoclonal Antibody Drugs

Drug	Adverse Events	Drug Interactions	Use in Special Populations
Alemtuzumab Note: This medication is no longer available commercially in the United States; it can be obtained through a restricted program for clinical use	Cytopenias, anxiety, chills, CMV infection and viremia, urticaria, dyspnea, emesis, insomnia, nausea, abdominal pain, pyrexia, rash, tachycardia Warnings: Infusion-related reactions, immunosuppression and increased risk of infection, cytopenias	None indicated	May be harmful to fetus; avoid using in breastfeeding patients
Brentuximab vedotin	Diarrhea, upper respiratory infection, nausea, neutropenia, peripheral neuropathy, pyrexia, fatigue Warnings: Pulmonary toxicity, anaphylaxis, hyperglycemia, gastrointestinal complications, infusion-related reactions, hematologic toxicities, TLS, hepatotoxicity, increased risk of infection, peripheral neuropathy, PML, serious dermatologic reactions	Contraindicated for use with bleomycin due to pulmonary toxicity, P-gp inhibitors, strong CYP3A4 inducers or inhibitors	May be harmful to fetus; avoid using in breastfeeding patients; not recommended in patients with moderate to severe hepatic impairment or severe renal impairment

CMV = cytomegalovirus; P-gp = P-glycoprotein; PML = progressive multifocal leukoencephalopathy; TLS = tumor lysis syndrome. 

From FDA-approved prescribing information.^34,35

Small Molecule Inhibitors

Small molecule inhibitors are targeted specifically toward an overactive pathway, enzyme, or protein in PTCL. Kinase and histone deacetylase inhibitors tend to exhibit fewer off-target effects compared with cytotoxic chemotherapy agents. Patients should still be monitored for signs of adverse events, and doses should be adjusted accordingly. A number of medications require dose adjustment in patients with renal or hepatic impairment. 

Table #. Side Effect Profiles of Small Molecule Inhibitors

Drug	Adverse Events	Drug Interactions	Use In Special Populations
Alectinib	Elevated alkaline phosphatase level, rash, constipation, diarrhea, headache, upper respiratory infection, oral mucositis Warnings: Bradycardia, severe myalgia, hemolytic anemia, hepatotoxicity, ILD, renal impairment	None indicated	May be harmful to fetus; avoid using in breastfeeding patients; reduce dosing in patients with severe hepatic impairment
Belinostat	Pyrexia, anemia, vomiting, fatigue, nausea Warnings: GI toxicity, hematologic toxicity, hepatotoxicity, infections, TLS	UGT1A1 inhibitors	May be harmful to fetus; avoid using in breastfeeding patients; use with caution in patients with moderate to severe hepatic impairment
Crizotinib	Abdominal pain, vision disorder, pruritus, cough, diarrhea, fatigue, headache, musculoskeletal pain, nausea, pyrexia, stomatitis, vomiting, decreased appetite Warnings: Bradycardia, GI toxicity, hepatotoxicity, ILD, pneumonitis, prolonged QT interval, severe vision loss	Moderate or strong CYP3A inhibitors, strong CYP3A inducers, CYP3A substrates, drugs that cause bradycardia or prolong the QT interval (calcium channel blockers, β-blockers, clonidine, digoxin)	May be harmful to fetus; avoid using in breastfeeding patients; reduce dosing in patients with moderate to severe hepatic impairment
Duvelisib	Abdominal pain, pneumonia, vomiting, rash, arthralgia, constipation, cough, decreased appetite, dyspnea, elevated liver enzymes, fatigue, mucositis, musculoskeletal pain, nausea, pyrexia, respiratory infections, cytopenias, edema Warnings: Colitis, diarrhea, hepatotoxicity, skin reactions, infections, neutropenia, pneumonitis	Moderate or strong CYP3A4 inhibitors and inducers, CYP3A4 substrates	May be harmful to fetus; avoid using in breastfeeding patients

GI = gastrointestinal; ILD = interstitial lung disease; TLS = tumor lysis syndrome; UGT1A1 = UDP-glucuronosyltransferase 1A1. 

From FDA-approved prescribing information.^36-39

References

1. Cancer stat facts: non-Hodgkin lymphoma. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed June 15, 2023. https://seer.cancer.gov/statfacts/html/nhl.html 
2. Foss FM, Zinzani PL, Vose JM, Gascoyne RD, Rosen ST, Tobinai K. Peripheral T-cell lymphoma. Blood. 2011;117(25):6756-6767. doi:10.1182/blood-2010-05-231548
3. Non-Hodgkin Lymphoma Treatment (PDQ ®)–Health Professional Version. National Cancer Institute. Updated May 18, 2023. Accessed June 24, 2023. https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq#_113
4. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®): T-Cell Lymphomas. National Comprehensive Cancer Network. Published January 5, 2023. Accessed June 15, 2023. https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf
5. Horwitz S, O’Connor OA, Pro B, et al; ECHELON-2 Study Group. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240. doi:10.1016%2FS0140-6736(18)32984-2
6. Cederleuf H, Pedersen MB, Jerkeman M, Relander T, d’Amore F, Ellin F. The addition of etoposide to CHOP is associated with improved outcome in ALK+ adult anaplastic large cell lymphoma: a Nordic Lymphoma Group study. Br J Haematol. 2017;178(5):739-746. doi:10.1111/bjh.14740
7. Maeda Y, Nishimori H, Yoshida I, et al. Dose-adjusted EPOCH chemotherapy for untreated peripheral T-cell lymphomas: a multicenter phase II trial of West-JHOG PTCL0707. Haematologica. 2017;102(12):2097-2103. doi:10.3324%2Fhaematol.2017.167742
8. Pro B, Advani R, Brice P, et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2017;130(25):2709-2717. doi:10.1182%2Fblood-2017-05-780049
9. Fukano R, Mori T, Sekimizu M, et al. Alectinib for relapsed or refractory anaplastic lymphoma kinase‐positive anaplastic large cell lymphoma: an open‐label phase II trial. Cancer Sci. 2020;111(12):4540-4547. Doi:10.1111%2Fcas.14671
10. O’Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492-2499. doi:10.1200%2FJCO.2014.59.2782
11. Damaj G, Gressin R, Bouabdallah K, et al. Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol. 2013;31(1):104-110. doi:10.1200/JCO.2012.43.7285
12. Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(27):4293-4297. doi:10.1200/JCO.2007.11.4207
13. Bossi E, Aroldi A, Brioschi FA, et al. Phase two study of crizotinib in patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma relapsed/refractory to chemotherapy. Am J Hematol. 2020;95(12):E319-E321. doi:10.1002/ajh.25967
14. Brammer JE, Zinzani PL, Zain J, et al. Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma from the phase 2 Primo trial: results of an interim analysis. Blood. 2021;138(suppl 1):2456. doi:10.1182/blood-2021-148939
15. FDA approves crizotinib for children and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma. US Food & Drug Administration. Updated January 15, 2021. Accessed June 24, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large
16. Ravandi F, Aribi A, O’Brien S, et al. Phase II study of alemtuzumab in combination with pentostatin in patients with T-cell neoplasms. J Clin Oncol. 2009;27(32):5425-5430. Doi:10.1200%2FJCO.2009.22.6688
17. Bendamustine. Prescribing Information. DailyMed. Updated June 5, 2023. Accessed June 24, 2023. 
18. Bortezomib. Prescribing Information. DailyMed. Updated October 15, 2019. Accessed June 24, 2023. 
19. Carboplatin. Prescribing Information. DailyMed. Updated July 7, 2021. Accessed June 24, 2023. 
20. Cyclophosphamide. Prescribing Information. DailyMed. Updated February 17, 2023. Accessed June 24, 2023. 
21. Cytarabine. Prescribing Information. DailyMed. Updated June 3, 2021. Accessed June 24, 2023. 
22. Doxorubicin hydrochloride. DailyMed. Updated December 31, 2019. Accessed June 24, 2023. 
23. Etoposide. Prescribing Information. DailyMed. Updated June 2, 2022. Accessed June 24, 2023. 
24. Gemcitabine. Prescribing Information. DailyMed. Updated January 4, 2020. Accessed June 24, 2023. 
25. Ifosfamide. DailyMed. Updated April 19, 2023. Accessed June 24, 2023. 
26. Lenalidomide. Prescribing Information. DailyMed. Updated March 6, 2023. Accessed June 24, 2023. 
27. Doxil. Prescribing Information. DailyMed. Updated May 31, 2022. Accessed June 24, 2023. 
28. Methotrexate. Prescribing Information. DailyMed. Updated June 4, 2021. Accessed June 24, 2023. 
29. Oxaliplatin. Prescribing Information. DailyMed. Updated July 12, 2022. Accessed June 24, 2023. 
30. Pralatrexate. Prescribing Information. DailyMed. Updated November 15, 2022. Accessed June 24, 2023. 
31. Romidepsin. Prescribing Information. DailyMed. Updated December 31, 2021. Accessed June 24, 2023. 
32. Vincristine sulfate. Prescribing Information. DailyMed. Updated February 3, 2023. Accessed June 24, 2023. 
33. Vinorelbine. Prescribing Information. DailyMed. Updated May 31, 2022. Accessed June 24, 2023. 
34. Campath. Prescribing Information. DailyMed. Updated May 3, 2023. Accessed June 24, 2023. 
35. Adcetris. Prescribing Information. DailyMed. Updated June 21, 2023. Accessed June 24, 2023. 
36. Alecensa. Prescribing Information. DailyMed. Updated June 16, 2022. Accessed June 24, 2023. 
37. Beleodaq. Prescribing Information. DailyMed. Updated May 15, 2023. Accessed June 24, 2023. 
38. Xalkori. Prescribing Information. DailyMed. Updated October 3, 2022. Accessed June 24, 2023. 
39. Copiktra. Prescribing Information. DailyMed. Updated December 28, 2021. Accessed June 24, 2023. 

Author Bio

Emily Wagner, MS, earned a bachelor of science degree in biotechnology from the Rochester Institute of Technology in 2018 and a master of science degree in biomedical sciences with a focus in pharmacology from the University of Colorado Anschutz Medical Campus in 2020. During her thesis work, she studied non-small cell lung cancer and how the immune system plays a role in response to different treatments. Emily currently lives in Colorado where she enjoys the mountains, spending time with her dog, baking, and reading a good book.