Non-Hodgkin's Lymphoma Management

Evaluation

The following provides useful prognostic information that may be used to guide therapeutic decisions:  

International Prognostic Index (IPI)  

The risk factors are:

• Age >60 years old
• Elevated serum LDH
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2-4
• Ann Arbor stage III-IV
• >1 nodal sites involved

The risk group (all patients) are:

• 0-1 risk factor: Low
• 2 risk factors: Low-intermediate
• 3 risk factors: High-intermediate
• 4 or 5 risk factors: High

The risk group for patients ≤60 years old (risk factors: Ann Arbor stage III-IV, elevated serum LDH, ECOG PS 2-4) are:

• 0 risk factor: Low
• 1 risk factor: Low-intermediate
• 2 risk factors: High-intermediate
• 3 risk factors: High

The risk group for patients with stage I or II DLBCL are:

• 0 or 1 risk factor: Low
• 2-4 risk factors: High

National Comprehensive Cancer Network (NCCN) - International Prognostic Index (IPI)  

Risk factors:

• 1 point:
  • >40-≤60 years old
  • >1 to ≤3 serum LDH
  • ECOG PS ≥2
  • Ann Arbor stage III-IV
  • Positive for extranodal disease
• 2 points
  • >60-<75 years old
  • >3 serum LDH
• 3 points: ≥75 years old

Risk group:

• 0-1 risk factor: Low
• 2-3 risk factors: Low-intermediate
• 4-5 risk factors: High-intermediate
• ≥6 risk factors: High

Groupe d’Etude des Lymphomes Folliculaires (GELF) Criteria

• ≥3 nodal sites involved, each measuring ≥3 cm in diameter
• Any nodal/extranodal tumor mass ≥7 cm
• Cytopenias (leukocytes <1.0 x 10⁹/L, platelets <100 x 10⁹/L)
• Presence of systemic symptoms
• Splenomegaly
• Pleural effusion/peritoneal ascites
• Leukemia (>5.0 x 10⁹/L malignant cells)

Follicular Lymphoma International Prognostic Index (FLIPI) Criteria

• ECOG PS >1
• Serum LDH/β2-microglobulin level > upper limit of normal (ULN)
• Hemoglobin level <12 g/dL
• ≥60 years old
• Ann Arbor stage III-IV
• ≥5 nodal sites involved

Prognostic Group  

Indolent

• Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)
• Primary cutaneous anaplastic large cell lymphoma
• FL
• HCL
• MZL (extranodal, nodal, splenic)
• MF/SS
• T-LGLL

Aggressive

• DLBCL
• Follicular large cell lymphoma
• ALCL
• ENKL
• Lymphomatoid granulomatosis
• Lymphoblastic lymphoma
• ATLL
• MCL
• True histiocytic lymphoma
• Primary effusion lymphoma
• Angioimmunoblastic T-cell lymphoma
• PTCL
• AIDS-related lymphoma
• BL/diffuse small noncleaved-cell lymphoma
• EATL
• Polymorphic post-transplantation lymphoproliferative disorder
• Mediastinal large B-cell lymphoma (primary mediastinal large B-cell lymphoma)
• Intravascular large B-cell lymphoma (intravascular lymphomatosis)

Pharmacological therapy

Standard Chemotherapeutic Regimens  

CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone)  

CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) is recommended in the first-line treatment of ALCL, PTCL not otherwise specified (NOS), nodal PTCL, EATL, MEITL, AITL, FTCL and ATLL in patients not able to tolerate intensive regimens or those with non-CD30 expressing ATLL, and in the primary treatment of patients with primary cutaneous ALCL with regional node involvement. In combination with Etoposide (CHOEP), CHOP is used in the first-line treatment of ALCL, PTCL-NOS, nodal PTCL, EATL, MEITL, AITL, FTCL and ATLL, as first-line or additional therapy in patients with HSTCL, as primary treatment of patients with primary cutaneous ALCL with regional node involvement; and as first-line therapy of patients with SPTCL with hemophagocytic lymphohistiocytosis (HLH), systemic disease or high tumor burden. In combination with Obinutuzumab or Rituximab is recommended as one of the preferred regimens in the first- and second-line treatment of FL. In combination with Rituximab is recommended as one of the preferred regimens in the first-, second-line and subsequent therapy of MZL.  

RCHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone)  

RCHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) is recommended in the first- and second-line treatment of patients with FL, MZL, in the first-line treatment of primary mediastinal large B-cell lymphoma (PMBL) and DLBCL, and for concurrent chemoimmunotherapy of monomorphic and polymorphic PTLD. R-mini-CHOP may be used in DLBCL patients who are very frail and >80 years old with comorbidities and in frail or older patients with high-grade B-cell lymphomas (HGBL) with MYC and BCL2 rearrangements with or without BCL6 rearrangements. This is recommended for aggressive induction therapy, alternating with RDHAP and for less aggressive induction of MCL. A dose-intensified CHOP (maxi-CHOP) alternating with Rituximab and high-dose Cytarabine (NORDIC regimen) is recommended for aggressive induction of MCL.  

Treatment option for HGBL with MYC and BCL2 rearrangements with or without BCL6 rearrangements. A combination with liposomal Doxorubicin (RCDOP) may be used as first-line treatment in DLBCL patients with poor LV function, frail or aged >80 years old with comorbidities. This is one of the preferred treatment options if not previously given in patients with DLBCL arising from FL and MZL with no response to treatment or with disease progression after ≥2 chemoimmunotherapy regimens. This is used for patients with aggressive stage I/contiguous stage II (4-6 cycles), indolent noncontiguous stage II/III/IV, and aggressive noncontiguous stage II/III/IV NHL. Studies recommend a regimen of 3-6 cycles in patients with aggressive stage I and contiguous stage II NHL when given with IF-XRT. Studies have shown better treatment response (increased event-free survival and overall survival) to R-CHOP as compared to CHOP in advanced-stage DLBCL >60 years.

Non-Hodgkins Lymphoma_Management 1

• First-line treatment for patients with PMBL, DLBCL, PTCL and BL
• Induction therapy of patients with BL in combination with intrathecal Methotrexate

EPOCH-R may also be used as first-line treatment in patients with DLBCL with poor LV function and in patients with SPTCL with HLH, systemic disease or high tumor burden, for second-line treatment of patients with DLBCL without intention to proceed to transplant and for HGBL with translocations of MYC and BCL2 and/or BCL6 or NOS. This may be used as second-line therapy for patients with BL with relapse >6-18 months after appropriate first-line therapy and if not previously given.  

SMILE (steroid [Dexamethasone], Methotrexate, Ifosfamide, Pegaspargase, Etoposide) (modified)  

SMILE (steroid [Dexamethasone], Methotrexate, Ifosfamide, Pegaspargase, Etoposide) is recommended in the induction therapy of advanced-stage ENKL.  

Other Chemotherapeutic Combinations  

AspaMetDex (Pegaspargase, Methotrexate, Dexamethasone)  

AspaMetDex (Pegaspargase, Methotrexate, Dexamethasone) is an induction therapy option of ENKL.

Non-Hodgkins Lymphoma_Management 2

Non-Hodgkins Lymphoma_Management 3

Non-Hodgkins Lymphoma_Management 4

• Second-line treatment of patients with FL where anti-CD20 monoclonal antibody treatment is not appropriate
• First- and second-line treatment of FL and MZL given in combination with Rituximab. A combination with Obinutuzumab may also be used. A combination with Tafasitamab is one of the preferred treatment options in patients with histologic transformation to DLBCL with contraindication to transplant
• First-line therapy of MZL and in the second-line treatment of patients with non-germinal center B-cell (GCB) DLBCL given in combination with Rituximab
• Second-line and subsequent treatment of MZL particularly in elderly and infirm patients who are intolerant of other treatment regimens given in combination with Rituximab
• In combination with Obinutuzumab, this may be used in the second-line and subsequent therapy of MZL

Liposomal Doxorubicin  

Liposomal Doxorubicin is a systemic therapy option for stage IB-IV MF and stage IVA1-IVA2 SS.

Monoclonal Antibodies  

Alemtuzumab  

Alemtuzumab is a systemic therapy option for stage IB-IIA, III MF, stage IVA1-IVA2 SS and relapsed/refractory MF/SS. This may be used as one of the alternative regimens for initial palliative-intent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL. This is a second-line and subsequent treatment option for PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL patients who are against organ transplant, ATLL, for first- or second-line therapy of symptomatic management of T-PLL patients (IV route with or without Pentostatin), first-line/additional treatment option for patients with HSTCL (with Pentostatin), and as additional or second-line therapy (if not previously used) in patients with T-LGLL unresponsive to first-line therapy.  

Avelumab  

Avelumab is one of the preferred treatment options for patients with relapsed/refractory EKNL.  

Brentuximab vedotin  

Brentuximab vedotin is a second-line and subsequent treatment option for CD30+ PTCL, CD30+ AITL, ALCL, CD30+ ATLL, CD30+ ENKL and AITL patients, systemic first-line therapy for patients with MF/SS, and preferred primary treatment of patients with primary cutaneous ALCL. This is a second-line treatment option in DLBCL patients with CD30+ disease without intention to proceed to transplant. In combination with CHP (Cyclophosphamide, Doxorubicin, Prednisone), Brentuximab vedotin is recommended as first-line therapy of ALCL, PTCL, as initial therapy of CD30+ ATLL, primary treatment of patients with primary cutaneous ALCL with regional node involvement and as a first-line/additional treatment option for patients with CD30+ HSTCL. This may be used as one of the preferred regimens for initial palliative-intent therapy in patients with CD30+ PTCL, CD30+ AITL and ALCL. In combination with Bendamustine, Brentuximab vedotin is an alternative second-line and subsequent therapy for patients with CD30+ PTCL and ALCL.  

Loncastuximab tesirine  

Loncastuximab tesirine is an alternative third-line and subsequent therapy option for patients with relapsed/refractory DLBCL previously given ≥2 lines of systemic therapy. This is used in the treatment of DLBCL arising from FL and nodal MZL, after ≥2 previous chemoimmunotherapy regimens.  

Mogamulizumab  

Mogamulizumab is recommended in the second-line and subsequent therapy of patients with ATLL and systemic first-line therapy of MF/SS.  

Nivolumab  

Nivolumab monotherapy or in combination with Brentuximab vedotin is a treatment option for relapsed/refractory PMBL and ENKL.  

Obinutuzumab  

Obinutuzumab is recommended for FL patients in the first- and second-line consolidation or extended dosing therapy and in the second line and subsequent treatment in combination with Bendamustine, CHOP or CVP, of patients with Rituximab-refractory disease. This is recommended as second-line extended therapy in patients with MZL who were treated with Bendamustine + Obinutuzumab and with Rituximab-refractory disease.

Pembrolizumab  

Pembrolizumab is indicated for patients with relapsed/refractory PMBL, ENKL and stage IB-IV MF/stage IVA1-IVA2 SS, as an alternative option for first-line therapy of MF/SS and refractory/relapsed MF/SS requiring systemic therapy.  

Polatuzumab-vedotin  

Polatuzumab-vedotin may be used alone or in combination with Bendamustine with or without Rituximab as a bridging therapy option until CAR T-cell therapy product is available or as second-line therapy if transplant is contraindicated in patients with DLBCL. This may be used alone or in combination with Bendamustine with or without Rituximab in the treatment of DLBCL arising from FL and MZL when transplant is contraindicated and without response to treatment or with disease progression after ≥2 chemoimmunotherapy regimens.  

Rituximab  

Rituximab is a first-line therapy for patients with indolent noncontiguous stage II/III/IV CD20-positive NHL.  May be combined with other chemotherapeutic drugs (Bendamustine, Cladribine, Fludarabine, Cyclophosphamide, Vincristine, Prednisone, Doxorubicin, Mitoxantrone).  

Rituximab is recommended in the following:

• For patients with indolent stage I and contiguous stage II NHL, this is considered in patients with contraindications for radiotherapy, and for those unresponsive to other chemotherapeutic agents and interventions
• First- and second-line treatment of patients with FL and for elderly or infirm patients who cannot tolerate other treatment regimens for FL and MZL
• First- and second-line consolidation or extended dosing therapy of patients with FL and as first-line extended therapy for MZL
• First-line therapy of patients with splenic, extranodal (MALT) and nodal MZL and for the sequential chemoimmunotherapy of monomorphic (B-cell type) and polymorphic PTLD
• Initial therapy option for patients with PCBCL with generalized disease
• Maintenance therapy of MCL patients after less aggressive therapy with R-CHOP or Bendamustine + Rituximab
• Maintenance therapy of MCL patients after less aggressive therapy with R-CHOP or Bendamustine + Rituximab

Treatment options in the following:

• First-line therapy of patients with extranodal MALT and nodal MZL
• Second-line/subsequent therapy of patients with MZL with longer duration of remission and second-line treatment for DLBCL patients without intention to proceed to transplant
• Refractory/relapsed HCL in patients unable to receive purine analogs

Rituximab is also recommended for patients with indolent NHL in relapse. Studies show a response rate of 40-50% in patients with indolent NHL. This may also be combined with other chemotherapeutic drugs. Several studies have shown that maintenance therapy with Rituximab improves overall survival in FL patients.

Tafasitamab  

Tafasitamab is used as second-line therapy for patients with relapsed/refractory DLBCL with contraindication to transplant, in combination with Lenalidomide. This is also used in the treatment of DLBCL arising from FL and MZL when transplant is contraindicated and there is no response to treatment or with disease progression after ≥2 chemoimmunotherapy regimens.  

Bispecific Antibody Therapy Agents  

Epcoritamab-bysp  

Epcoritamab-bysp is one of the preferred agents used as third-line and subsequent therapy in patients with FL after ≥2 previous lines of therapy, patients with DLBCL with previous treatment of ≥2 systemic therapies including those with progressive disease after transplant or CAR T-cell therapy and as a treatment option of DLBCL arising from FL and MZL with previous treatment of ≥2 systemic therapies including those with progressive disease after transplant or CAR T-cell therapy.  

Glofitamab-gxbm  

Glofitamab-gxbm is one of the preferred agents used as third-line and subsequent therapy in patients with DLBCL with previous treatment of ≥2 systemic therapies including those with progressive disease after transplant or CAR T-cell therapy and as a treatment option of DLBCL arising from FL with previous treatment of ≥2 systemic therapies including those with progressive disease after transplant or CAR T-cell therapy.  

Mosunetuzumab-axgb  

Mosunetuzumab-axgb is one of the preferred agents used as third-line and subsequent therapy in patients with FL after ≥2 previous lines of therapy.  

Other Antineoplastic Agents  

Example drugs:  Acalabrutinib, Alectinib, Azacitidine, Belinostat, Bortezomib, Brigatinib, Ceritinib, Crizotinib, Dabrafenib, Denileukin diftitox, Duvelisib, Ibrutinib, Lorlatinib, Pirtobrutinib, Romidepsin, Ruxolitinib, Selinexor, Trametinib, Umbralisib, Vemurafenib, Venetoclax, Vorinostat, Zanubrutinib 

There are ongoing studies investigating the use of these drugs for other types of cancer.  

Acalabrutinib  

Acalabrutinib is recommended in the second-line and subsequent treatment of patients with MZL and MCL. In combination with Rituximab, Acalabrutinib is a treatment option for less aggressive induction therapy in patients with MCL and as maintenance therapy after high-dose therapy (HDT) or autologous stem cell rescue therapy (ASCRT) or aggressive induction therapy in patients with MCL.

Alectinib  

Alectinib is an alternative regimen as initial palliative-intent therapy in patients with ALK-positive ALCL. This is a treatment option in the second-line and subsequent treatment of patients with ALK-positive ALCL.  

Azacitidine  

Azacitidine may be used as one of the alternative regimens for initial palliative-intent therapy in patients with AITL, nodal PTCL and FTCL. This is an alternative second-line and subsequent therapy for patients with AITL, nodal PTCL and FTCL.  

Belinostat  

Belinostat is one of the preferred treatment options for second-line and subsequent therapy of PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL and as alternative second-line and subsequent therapy of ALCL, ATLL and ENKL. This may be used as one of the preferred regimens for initial palliative-intent therapy of PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL and as an alternative regimen for initial palliative-intent therapy of ALCL.  

Bexarotene  

Bexarotene is a systemic therapy option for stage IB-III MF. Bexarotene with or without Prednisone may be used as first-line therapy for patients with SPTCL without HLH and with low tumor burden and as maintenance therapy in patients with SPTCL.  

Bortezomib  

Bortezomib may be used alone or in combination with Rituximab as second-line therapy of patients with MCL, treatment option for relapsed/refractory MF/SS, as second-line and subsequent therapy for patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL, FTCL and ALCL who are against organ transplant, and for ATLL. This may be used as one of the alternative regimens for initial palliative-intent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL, FTCL and ALCL.  

Brigatinib  

Brigatinib is an alternative regimen as initial palliative-intent therapy in patients with ALK-positive ALCL. This is a treatment option in the second-line and subsequent treatment of patients with ALK-positive ALCL.  

Ceritinib  

Ceritinib is an alternative regimen as initial palliative-intent therapy in patients with ALK-positive ALCL. This is a treatment option in the second-line and subsequent treatment of patients with ALK-positive ALCL.

Crizotinib  

Crizotinib is an alternative regimen as initial palliative-intent therapy in patients with ALK-positive ALCL. This is a treatment option in the second-line and subsequent treatment of patients with ALK-positive ALCL.  

Dabrafenib  

In combination with Trametinib, Dabrafenib is one of the preferred treatment options in patients with relapsed/refractory HCL with relapse <2 years or with incomplete hematologic recovery with indications for treatment present after initial therapy if not previously treated with BRAF inhibitor and in patients with progressive HCL after relapsed/refractory therapy if not previously treated with BRAF inhibitor.  

Denileukin diftitox  

Denileukin diftitox is a systemic therapy option for stage IB-III MF.  

Duvelisib  

Duvelisib may be used as one of the preferred regimens for initial palliative-intent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL and as an alternative regimen for initial palliative-intent therapy in patients with ALCL. This is one of the preferred treatment options for second-line and subsequent therapy of PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL. In combination with Romidepsin, Duvelisib is an alternative second-line and subsequent therapy for PTCL-NOS, EATL, MEITL with the intention to proceed to transplant and second-line and subsequent therapy for patients with AITL, nodal PTCL, FTCL and ALCL.

Non-Hodgkins Lymphoma_Management 5

• Second-line and subsequent treatment of patients with MCL with short response duration to previous chemoimmunotherapy. This may be combined with Rituximab or Venetoclax
• Second-line treatment of MZL

Ibrutinib is a treatment option in the second-line treatment of non-GCB DLBCL with no intention to proceed to transplant and in the treatment of progressive HCL after relapsed/refractory therapy. In combination with Rituximab, Ibrutinib is a treatment option as maintenance therapy after HDT or ASCRT or aggressive induction therapy in patients with MCL. This is associated with a transient increase in lymphocyte count, grade 2 bleeding and hypertension.  

Lorlatinib  

Lorlatinib is a treatment option in the second-line and subsequent treatment of patients with ALK-positive ALCL.  

Pirtobrutinib  

Pirtobrutinib is a treatment option in the second-line therapy of patients with relapsed/refractory MZL after previous treatment with covalent BTK inhibitors and in patients with MCL with progressive disease after prior covalent BTK inhibitor therapy. This is one of the preferred regimens for elderly or infirm patients who cannot tolerate other treatment regimens.  

Romidepsin  

Romidepsin may be used as one of the preferred regimens for initial palliative-intent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL and as an alternative regimen for initial palliative-intent therapy in patients with ALCL. This is indicated for patients with cutaneous T-cell lymphoma, second-line and subsequent therapy of PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL, and first-line systemic therapy for patients with MF/SS or in relapsed/refractory EKNL. In combination with Duvelisib, Romidepsin is an alternative second-line and subsequent therapy for PTCL-NOS, EATL, MEITL with the intention to proceed to transplant and second-line and subsequent therapy for AITL, nodal PTCL, FTCL and ALCL. Romidepsin with or without Prednisone may be used as first-line and maintenance therapy of patients with SPTCL with HLH, systemic disease or high tumor burden and as additional therapy of patients with SPTCL without HLH and with low tumor burden with inadequate response to first-line therapy.  

Ruxolitinib  

Ruxolitinib may be used as one of the alternative regimens for initial palliative-intent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL, FTCL and ALCL. This is an alternative second-line and subsequent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL, FTCL, ALCL and T-PLL. This may be used as additional or second-line therapy (if not previously given) in patients with T-LGLL who did not respond to first-line therapy.  

Selinexor  

Selinexor is a third-line and subsequent therapy option for patients with DLBCL after ≥2 previous systemic treatments including those with progressive disease after transplant or CAR T-cell therapy. This is a treatment option of DLBCL arising from FL when transplant is contraindicated and without response to treatment or with disease progression after ≥2 chemoimmunotherapy regimens including patients with disease progression after transplant or CAR T-cell therapy.

Trametinib  

In combination with Dabrafenib, Trametinib is one of the preferred treatment options in patients with relapsed/refractory HCL with relapse <2 years or with incomplete hematologic recovery with indications for treatment present after initial therapy if not previously treated with BRAF inhibitor and in patients with progressive HCL after relapsed/refractory therapy if not previously treated with BRAF inhibitor.  

Vemurafenib  

Vemurafenib with or without monoclonal antibody may be used as initial therapy of HCL in patients who are not candidates for purine analogs including those who are frail and those with active infection. Vemurafenib with or without Rituximab may be used in the treatment of relapsed/refractory HCL with relapse ≥2 years in patients who are not candidates for purine analogs including those who are frail and with active infection or with relapse <2 years or with incomplete hematologic recovery with indications for treatment after initial therapy and for treatment of progressive disease after relapsed/refractory therapy.  

Venetoclax  

Venetoclax is a treatment option in the second-line treatment of MCL with or without Rituximab or Ibrutinub. Venetoclax with or without Rituximab is a treatment option in patients with progressive HCL after relapsed/refractory therapy and with resistance to BRAF inhibitor therapy.  

Vorinostat  

Vorinostat is recommended in the systemic first-line therapy of MF/SS.  

Zanubrutinib  

Zanubrutinib is recommended in the second-line and subsequent treatment of patients with MCL and relapsed/refractory MZL after at least one prior anti-CD20-mAB-based regimen. In combination with Obinutuzumab, Zanubrutinib is recommended in the third-line and subsequent therapy in patients with relapsed/refractory FL as Bruton tyrosinkinase inhibitor after ≥2 previous systemic therapies. In combination with Rituximab, Zanubrutinib is a treatment option as maintenance therapy after HDT or ASCRT or aggressive induction therapy in patients with MCL. This is a treatment option in patients with progressive HCL after relapsed/refractory therapy.

Skin-Directed Therapeutic Agents  

Skin-directed therapeutic agents are used for primary cutaneous B-cell and T-cell lymphomas. Recommended topical agents include Carmustine, corticosteroids, Imiquimod, Mechlorethamine, and retinoids (eg Acitretin, Bexarotene, Isotretinoin, Tazarotene). For generalized skin involvement: Corticosteroids, Mechlorethamine. Topical calcineurin inhibitor (eg Pimecrolimus) may be used in patients with MF/SS for perioral and periorbital affected areas of skin as a steroid-sparing treatment.  

Other Therapeutic Agents  

Zidovudine may be used as initial/first-line therapy for acute, chronic or smoldering ATLL, as additional therapy for acute, chronic or smoldering ATLL if with response after initial treatments and as second-line or subsequent therapy of acute, chronic or smoldering ATLL. Arsenic trioxide may be used as second-line and subsequent therapy for ATLL.  

Interferon alfa/gamma-1b is a systemic therapy option of patients with MF/SS and primary treatment of patients with primary cutaneous ALCL and initial/first-line therapy for acute, chronic or smoldering ATLL, as additional therapy for acute, chronic or smoldering ATLL if with response after initial treatments and as second-line or subsequent therapy of acute, chronic or smoldering ATLL. Peginterferon-alfa 2a may be used in relapsed/refractory HCL in patients with relapse <2 years or with incomplete hematologic recovery with indications for treatment present after initial therapy. This may be used as initial/first-, second-line or subsequent therapy for acute, chronic or smoldering ATLL.  

Ciclopsorin may be used as an alternative regimen for initial palliative-intent therapy in patients with AITL, nodal PTCL and FTCL. This is an alternative second-line and subsequent therapy in patients with AITL, nodal PTCL and FTCL without intention to proceed to transplant. Ciclopsorin with or without corticosteroids may be used as first- or second-line therapy in patients with T-LGLL with anemia. Ciclopsorin with or without Prednisone may be used as first-line and maintenance therapy of patients with SPTCL.

Supportive Therapy  

Autoimmune Cytopenias  

Most common forms in NHL patients include autoimmune hemolytic anemia, immune thrombocytopenic purpura and pure red blood cell aplasia. Treatment includes administration of corticosteroids; Rituximab, IVIg, or Cyclosporin may be given for patients unresponsive to corticosteroid therapy and Eltrombopag or Romiplostim may be used for the treatment of thrombocytopenia in patients with ITP refractory to steroids, IVIg or splenectomy. Splenectomy may also be considered for steroid-refractory patients.  

Infection/Reactivation  

Cytomegalovirus (CMV) Reactivation  

Cytomegalovirus (CMV) reactivation occurs in 25% of patients undergoing treatment with Alemtuzumab. There is increased risk of reactivation in patients receiving phosphoinositide 3-kinase (PI3K) inhibitors (eg Duvelisib ± Romidepsin) or anti-CD52 antibody (eg Alemtuzumab). Prophylaxis with Ganciclovir may be considered in patients with increasing viral load during treatment.

Non-Hodgkins Lymphoma_Management 6

• First-line: Antihistamines, Gabapentin, Pregabalin
• Second-line: Aprepitant, Mirtazapine, selective serotonin reuptake inhibitors (SSRIs)
• Third-line: Naltrexone, systemic corticosteroids

Non-Hodgkins Lymphoma_Management 7

Nonpharmacological

Observation  

A “watch and wait” approach should be offered to patients who are asymptomatic, with clinically non-progressive localized disease, or with residual disease after treatment. Observation may be considered when the potential toxicity of ISRT or systemic therapy outweighs the potential clinical benefit. A referral to a radiation oncologist is preferred.  

Phototherapy  

Example:  Ultraviolet B (UVB), narrowband UVB (NB-UVB), Psoralen plus ultraviolet A (PUVA), ultraviolet A1 (UVA1)  

Phototherapy is a skin-directed treatment option for patients with MF/SS. Ultraviolet B or narrowband UVB is recommended for limited/localized skin involvement. UVB, NB-UVB, PUVA, or UVA1 may be used for generalized skin involvement.

Non-Hodgkins Lymphoma_Management 8

Surgery

Transplantation  

Further studies are needed to support the use of bone marrow transplant (BMT) in high-risk NHL patients. This is a treatment of choice for patients with aggressive recurrent NHL. Studies show improved survival (20-40% long-term disease-free rate) in high-risk patients.

Non-Hodgkins Lymphoma_Management 9

• Consolidation after aggressive treatment of MCL
• Consolidation/additional treatment of DLBCL and BL with partial or complete response after second-line therapy
• Second-line or extended dosing of FL and MZL

Autologous HCT may be considered in the first-line consolidation therapy of PTCL. Allogeneic HCT may be used in the second-line consolidation treatment of BL, DLBCL and MCL, as third-line consolidation therapy of FL and MZL as additional therapy in patients with acute and chronic ATLL, as consolidation or additional therapy in patients with HSTCL and as additional therapy in patients with SPTCL with HLH, systemic disease or high tumor burden or relapsed/refractory SPTCL. This may be considered in patients with indolent recurrent NHL, and aggressive noncontiguous stage II/III/IV NHL. Studies show an increase in the progression-free survival rate of patients given SCT as compared to those given chemotherapy alone.

Radiation Therapy

Local radiotherapy is a recommended initial therapy for patients with limited-stage disease as it increases survival rates in these patients. Studies have shown that the addition of radiation therapy to chemotherapy in patients with bulky disease resulted in improved treatment outcomes. Advanced RT delivery techniques such as intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), breath hold or respiratory gating, image-guided RT (IGRT) and/or proton therapy should be considered in special cases where radiation exposure of specific organs is reduced while achieving the primary goal of local tumor control.  

Involved-site radiation therapy (ISRT) is the recommended appropriate field for NHL as it is aimed directly at the lymph nodes containing the involved structure and site of skin involvement on cutaneous lymphomas. This is concentrated on the involved node and extranodal extensions, reducing the field exposed to radiation, thereby sparing other organs from unnecessary radiation exposure. Local ISRT may be used as initial therapy in patients with PCBCL.  

The recommended doses are:  

• FL, MZL: 24-30 Gy
• MCL: 24-36 Gy
• DLBCL: 40-55 Gy (as primary treatment); 20-36 Gy (in combination with hematopoietic cell transplant [HCT]); 30-36 (after complete response to chemotherapy); 36-50 Gy (after partial response to chemotherapy); 40-55 Gy (refractory disease)
• PTCL: 30-36 Gy (consolidation); 40-50 Gy (complementary with partial response to chemotherapy); 40-55 Gy (as primary treatment); 20-36 Gy (in combination with HCT)
• ENKL: 50-55 Gy (as primary treatment); 45-56 Gy (in combination therapy)
• MF/SS with limited or localized skin involvement: 8-12 Gy; 24-30 Gy for unilesional presentation
• Palliative RT: 20-26 Gy in 15-18 fractions
• Primary cutaneous ALCL: 24-30 Gy (curative treatment); 2 Gy (palliative)
• SPTCL: 36-45 Gy (curative treatment)

Involved-site radiation therapy (ISRT) is a treatment option as bridging therapy until CAR T-cell product is available in patients with DLBCL. This may be used as one of the alternative regimens for initial palliative-intent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL, FTCL and ALCL. This is a treatment option as second-line and subsequent therapy in patients with PTCL-NOS, EATL, MEITL, AITL, nodal PTCL and FTCL without intention to proceed to transplant, ATLL with localized symptomatic disease and ENKL. External beam radiation therapy (EBRT) is an option for the initial management of patients with cutaneous lymphomas with solitary or regional disease.

Non-Hodgkins Lymphoma_Management 10

• Primary cutaneous MZL and primary cutaneous follicle center lymphoma: 24-30 Gy
• MF/SS: 8-12 Gy (individual plaque and tumor lesions); 24-30 Gy (unilesional presentation)

Total skin electron beam therapy (TSEBT), either alone or in combination with adjuvant therapy, may be considered for early-stage MF. The recommended dose range is 12-36 Gy (4-6 Gy/week) and in individual tumors, it is 4-12 Gy.