non-hodgkin's%20lymphoma
NON-HODGKIN'S LYMPHOMA

Non-Hodgkin's lymphoma is a heterogeneous group of lymphoproliferative malignancies.
It is the most common hematologic cancer.
The most common subtypes are the diffuse large B-cell and follicular lymphoma. The subtypes are based on the malignant cell's morphology, genetic features, immunohistological characteristics, and stage of maturation.

Principles of Therapy

Indications for initiation of treatment in follicular lymphoma (FL):

  • 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
    • Eastern Cooperative Oncology Group (ECOG) performance status >1
    • Serum LDH/β2-microglobulin level > upper limit of normal
    • Hemoglobin level <12 g/dL
    • >60 years old
    • Ann Arbor Stage III-IV
    • >5 nodal sites involved

Pharmacotherapy

Alkylating Agents
  • Eg Bendamustine, Chlorambucil, Cyclophosphamide, Ifosfamide
  • May be used in combination with Vincristine, Prednisone, Dexamethasone, Rituximab, Procarbazine, Doxorubicin, or Fludarabine for patients with indolent noncontiguous stage II/III/IV NHL
  • Recommended as 1st line treatment for elderly patients with FL with or without Rituximab
  • Bendamustine (± Rituximab) & Chlorambucil are recommended as 1st line treatment for CLL patients without deletions 11q/17p or TP53 mutation aged >70 year & younger with significant comorbidities
    • Chlorambucil is also recommended for CLL patients intolerant to purine analogs, & as 2nd-line alternative therapy for PTCL patients
    • Bendamustine/Rituximab combination may be used as 2nd-line & subsequent therapy in patients with DLBCL
  • May be given with or without corticosteroids
Anti-CD20 Monoclonal Antibodies
Alemtuzumab
  • Studies have shown increased overall response rate in CLL patients as compared to Chlorambucil
    • Should not be used as first-line treatment for CLL
  • Second-line & subsequent treatment option for PTCL patients who are against organ & transplant, & for symptomatic management of T-PLL patients (IV route with or without Pentostatin)
Brentuximab vedotin
  • Second-line & subsequent treatment option for PTCL & DLBCL patients, & systemic 1st-line therapy for patients with MF/SS
Obinutuzumab
  • Recommended 1st line treatment for CLL patients without deletions 11q/17p or TP53 mutation aged >70 years & younger with significant comorbidities & for FL patients as 2nd-line consolidation or extended dosing therapy in patients with Rituximab-refractory disease
  • Also recommended for CLL patients intolerant to purine analogs & CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged <70 years without significant comorbidities & >70 years & younger with comorbidities
  • Approved for treatment-naive CLL patients in combination with Chlorambucil
Ofatumumab
  • Recommended for CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged <70 year without significant comorbidities & >70 year & younger with comorbidities, & for CLL patients with del (17p)/TP53 mutation with relapsed/refractory disease
  • Also recommended as 2nd-line extended-dosing maintenance therapy for patients with complete or partial response after relapsed or refractory CLL/SLL therapy
  • Needs further studies to be proven effective for patients with indolent noncontiguous stage II/III/IV NHL
Radio-labeled Anti-CD20 Monoclonal Antibodies
  • Eg Yttrium-90-Labeled Ibritumomab tiuxetan
  • Suggested for indolent noncontiguous stage II/III/IV NHL & indolent/aggressive recurrent
  • NHL patients, without prior treatment, with or without bone marrow involvement
    Studies have shown 60-80% response rate in relapsed/refractory NHL patients
Rituximab
  • First-line therapy for patients with indolent noncontiguous stage II/III/IV NHL
    • May be combined with other chemotherapeutic drugs (Bendamustine, Cladribine, Fludarabine, Cyclophosphamide, Vincristine, Prednisone, Doxorubicin, Mitoxantrone)
  • Monotherapy is recommended as 1st line treatment for patients with FL
    • Also used as 2nd-line & subsequent therapy for patients with FL
  • Recommended for patients with indolent stage I & contiguous stage II NHL
    • Considered in patients with contraindications for radiotherapy, & for those unresponsive to other chemotherapeutic agents & interventions
  • Recommended 1st-line treatment for CLL patients without deletions 11q/17p or TP53 mutation aged >70 year & younger with significant comorbidities & when combined with Methylprednisone in patients with 17p deletion/TP53 mutation with relapsed/refractory disease
  • Also recommended for frail CLL/SLL patients with significant comorbidities intolerant to purine analogs, CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged >70 year & younger with comorbidities (dose-dense)
    • Treatment option for patients with refractory/relapsed CLL aged <70 year without significant comorbidities without del (11q/17p)/TP53 mutation when given in combination with high-dose Methylprednisone
  • Used in combination with high-dose autologous stem cell rescue as 1st line consolidation therapy for MCL patients
  • Also recommended for patients with indolent NHL in relapse
    • Studies show a response rate of 40-50% in patients with indolent NHL
    • May also be combined with other chemotherapeutic drugs
  • Several studies have shown that maintenance therapy with Rituximab improves overall survival in FL patients
Antimetabolites (Folic Acid/Purine/Pyrimidine Analogs)
  • Eg 2-Chlorodeoxyadenosine, Fludarabine, Gemcitabine, Methotrexate, Pralatrexate
  • Recommended for patients with indolent noncontiguous stage II/III/IV NHL
  • Studies have shown that treatment with Fludarabine improves complete response rate, partial response rate & progression-free survival in CLL patients
    • Fludarabine may also be combined with Chlorambucil
  • Pralatrexate (preferred) & Gemcitabine are 2nd-line & subsequent therapies for patients with PTCL, & systemic 1st-line therapy for patients with MF/SS
  • Methotrexate may be used as 2nd-line systemic therapy for patients with MF/SS
Denileukin diftitox
  • Recombinant interleukin fusion toxin combination of interleukin-2 and diphtheria toxin
  • Recommended for the treatment of cutaneous T-cell lymphoma especially MF
  • Studies have shown 25% objective response rate in aggressive B-cell NHL patients
Lenalidomide
  • Recommended as an alternative 2nd-line & subsequent therapy for patients with PTCL
Other Antineoplastic Agents
  • Eg Belinostat, Bortezomib, Ibrutinib, Idelalisib, Pentostatin, Romidepsin
  • Belinostat has been approved for the treatment of relapsed/refractory PTCL
  • Patients with relapsed/refractory CLL may be given Idelalisib or Ibrutinib
    • Idelalisib may also be used for relapsed Fl & SLL with previous history of ≥2 treatments
    • Ibrutinib may also be given as 2nd-line systemic therapy to patients with MCL
  • Pentostatin in combination with Cyclophosphamide & Rituximab showed significant clinical activity against CLL & may be used as 2nd-line therapy for patients with MF/SS
  • Romidepsin is indicated for patients with cutaneous T-cell lymphoma & PTCL who have undergone >1 previous therapy for PTCL & is an alternative systemic therapy for patients with MF/SS
  • Bortezomib may be used alone or in combination with Rituximab as 2nd-line therapy of patients with MCL or MF/SS, as 2nd-line & subsequent therapy for PTCL patients who are against organ transplant
  • There are ongoing studies investigating the use of these drugs for other types of cancer
Ibrutinib
  • May be used in patients with relapsed/refractory CLL, & as 2nd-line systemic therapy for patients with MCL
  • Also recommended for frail CLL/SLL patients with significant comorbidities intolerant to purine analogs, & as 1st-line therapy for the following CLL patients:
    • With or without del(11q/17p)/TP53 mutation with relapsed/refractory disease aged >70 year & younger with significant comorbidities & <70 year without significant comorbidities
    • With del(17p)/TP53 mutation with relapsed/refractory disease
    • With del(11q) with relapsed/refractory disease aged >70 year & younger with significant comorbidities & <70 year without significant comorbidities
  • Associated with transient increase in lymphocyte count, grade 2 bleeding & hypertension
Idelalisib
  • Treatment option for patients with relapsed/refractory CLL, relapsed FL & SLL with previous history of >2 treatments, & MCL
Venetoclax
  • May be used for CLL patients with del(17p)/TP53 mutation with relapsed/refractory disease
Chemotherapeutic Combinations
  • ACVBP (Cyclophosphamide, Doxorubicin, Vindesine, Bleomycin, & Prednisone)
    • Recommended for patients with aggressive noncontiguous stage II/III/IV NHL
  • Alemtuzumab + Rituximab or Fludarabine
    • Rituximab & Fludarabine combinations are recommended for CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged <70 year without significant comorbidities
    • Rituximab combination may be used for patients >70 year & younger with comorbidities, & for CLL patients with del (17p)/TP53 mutation with relapsed/refractory disease
  • CALGB (Cancer and Leukemia Group B) regimens
    • CALGB 10002 (Cyclophosphamide & Prednisone followed by Ifosfamide or Cyclophosphamide; high-dose Methotrexate, Leucovorin, Vincristine, Dexamethasone, & Doxorubicin/Etoposide/Cytarabine; or intrathecal Methotrexate, Cytarabine & Hydrocortisone; + Rituximab) may be used as induction therapy in patients with BL
    • CALGB 59909 (Rituximab + Methotrexate + CHOP; EAR [Etoposide, Cytarabine, Rituximab]; CBV auto SCT [Carmustine, Etoposide, Cyclophosphamide, autologous stem cell]; Rituximab) may be used as induction therapy in patients with MCL
  • CHOP (Cyclophosphamide, Doxorubicin, Vincristine, & Prednisone)
    • Recommended for patients with indolent noncontiguous stage II/III/IV NHL & aggressive noncontiguous stage II/III/IV NHL; 1st-line treatment for PTCL, & ATLL
  • CNOP (Cyclophosphamide, Mitoxantrone, Vincristine, & Prednisone)
    • Recommended for patients with aggressive noncontiguous stage II/III/IV NHL
  • COP-Bleomycin (Cyclophosphamide, Vincristine, Bleomycin & Prednisone)
    • Recommended for patients with FL
  • CVP (Cyclophosphamide, Vincristine & Prednisone)
    • Recommended for patients with indolent noncontiguous stage II/III/IV NHL
    • Patients may be given Rituximab as maintenance therapy after treatment
  • C-MOPP (Cyclophosphamide, Vincristine, Procarbazine & Prednisone/Prednisolone)
    • Recommended for patients with indolent noncontiguous stage II/III/IV NHL
  • EPOCH-R (Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin) + Rituximab (dose-adjusted)
    • Recommended 1st-line treatment for patients with DLBCL, PTCL, & patients with ATLL excluding Rituximab
      • May also be used as 1st-line treatment in patients with DLBCL with poor LV function
    • May be used as induction & 2nd-line therapy for patients with BL
  • ESHAP-R (Etoposide, Methylprednisolone, Cytarabine, Cisplatin) + Rituximab
    • Recommended 1st-line, 2nd-line & subsequent treatment of patients with DLBCL & 2nd-line therapy for PTCL with Rituximab excluded
  • FCR (Fludarabine, Cyclophosphamide & Rituximab)
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation aged <70 years or older patients without significant comorbidities & those with refractory/relapsed disease >70 years & younger with comorbidities (reduced-dose) & <70 years old without comorbidities
    • Recommended 2nd-line treatment for patients with MCL
  • FMD (Fludarabine, Mitoxantrone +/- Dexamethasone)
    • May be used in patients with indolent noncontiguous stage II/III/IV NHL & T-PLL (with subsequent IV Alemtuzumab)
  • GemOx (Gemcitabine, Oxaliplatin) ± Rituximab
    • Recommended 2nd-line & subsequent treatment for patients with DLBCL, & 2nd-line therapy for PTCL
  • GDP (Gemcitabine, Dexamethasone, Cisplatin/Carboplatin) ± Rituximab
    • Recommended 2nd-line & subsequent treatment for patients with DLBCL, & 2nd-line therapy for PTCL
  • HyperCVAD (hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone) + Rituximab
    • May be used as induction therapy for patients with MCL & BL, alternating with high-dose Methotrexate & Cytarabine + Rituximab, 1st-line alternative therapy for PTCL patients, & for patients with ATLL alternating with high-dose Methotrexate & Cytarabine
  • Idelalisib + Rituximab
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged <70 years without significant comorbidities & >70 years & younger with comorbidities, & for CLL patients with del (17p)/TP53 mutation with relapsed/refractory disease
  • M-BACOD (Methotrexate, Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone, Dexamethasone, & Leucovorin)
    • Recommended for patients with aggressive noncontiguous stage II/III/IV NHL
    • Studies have shown improvements in long-term disease-free survival by 35-45% with Doxorubicin-based chemotherapeutic combinations
  • MACOP-B (Methotrexate, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin, & Leucovorin)
    • Recommended for patients with aggressive noncontiguous stage II/III/IV NHL
    • May be used in patients with indolent noncontiguous stage II/III/IV NHL
  • MINE (Mesna, Ifosfamide, Mitoxantrone, Etoposide) ± Rituximab
    • Recommended 2nd-line & subsequent treatment for patients with DLBCL
  • Obinutuzumab + Chlorambucil
    • Recommended for frail CLL/SLL patients with significant comorbidities & as 1st line therapy for CLL patients without del (11q/17p)/TP53 mutation >70 years or younger patients with significant comorbidities & those intolerant of purine analogs
  • OFAR (Oxaliplatin, Fludarabine, Cytarabine & Rituximab)
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged <70 years without significant comorbidities & for CLL patients with del (17p)/TP53 mutation with relapsed/refractory disease
  • Ofatumumab + Chlorambucil
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation aged >70 years or younger patients with significant comorbidities & those intolerant of purine analogs
  • PCR (Pentostatin, Cyclophosphamide & Rituximab)
    • Recommended for CLL patients without 11q/17p del/TP53 mutation aged <70 years or older patients without significant comorbidities & those with refractory/ relapsed disease >70 years & younger with comorbidities (reduced-dose) & <70 years old without comorbidities; as 2nd-line treatment for MCL patients
  • PEPC (Prednisone, Etoposide, Procarbazine, Cyclophosphamide) ± Rituximab
    • May be used as 2nd-line therapy in patients with MCL & as 1st-line, 2nd-line & subsequent therapy in patients with DLBCL & those with poor LV function
  • ProMACE CytaBOM (Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Vincristine, Methotrexate, & Leucovorin)
    • Recommended for patients with aggressive noncontiguous stage II/III/IV NHL
  • R-ACVBP (Rituximab, Cyclophosphamide, Doxorubicin, Vindesine, Bleomycin & Prednisone)
    • May be used for patients with aggressive stage I/contiguous stage II NHL
  • R-Bendamustine (Rituximab + Bendamustine)
    • Used for patients with indolent noncontiguous stage II/III/IV NHL
    • Recommended as 1st line treatment for patients with FL, H. pylori-positive gastric MALT lymphoma
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation aged <70 years or older patients without significant comorbidities & those with refractory/ relapsed disease >70 years & younger with comorbidities & <70 years old without comorbidities
  • RCHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, & Prednisone)
    • Used for patients with aggressive stage I/contiguous stage II (4-6 cycles), indolent noncontiguous stage II/III/IV, & aggressive noncontiguous stage II/III/IV NHL
    • Studies recommend a regimen of 3-6 cycles in patients with aggressive stage I & contiguous stage II NHL when given with IF-XRT
    • Studies have shown better treatment response (increased event-free survival & overall survival) to R-CHOP as compared to CHOP in advanced-stage DLBCL >60 year
    • Recommended as 1st line treatment for patients with FL, H. pylori-positive gastric MALT lymphoma, DLBCL
    • Combination with liposomal Doxorubicin may be used as 1st-line treatment in DLBCL patients with poor LV function
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged <70 years without significant comorbidities
    • May be used for aggressive induction therapy of patients with MCL, alternating with RDHAP or sequentially with RICE
    • Treatment option for advanced-stage symptomatic FL
  • R-CVP (Rituximab, Cyclophosphamide, Vincristine, & Prednisone)
    • Recommended for patients with indolent noncontiguous stage II/III/IV NHL
    • Recommended as 1st line treatment for patients with FL, H. pylori-positive gastric MALT lymphoma
    • Addition of Gemcitabine (RGCVP) or Etoposide (RCEOP) to this combination may be used in patients as 1st-line treatment in DLBCL patients with poor LV function
      • RGCVP may also be used in patients >80 years old with comorbidities
      • RCEOP may be used as 2nd-line & subsequent therapy for patients with DLBCL
  • RDHAP (Rituximab, Dexamethasone, Cisplatin, Cytarabine)
    • May be used for aggressive induction therapy of patients with MCL, alternating with RCHOP, as 2nd-line & subsequent therapy for patients with DLBCL, & 2nd-line therapy for PTCL with Rituximab excluded (DHAP)
  • R-F (Rituximab + Fludarabine)
    • Recommended for patients with indolent noncontiguous stage II/III/IV NHL
    • Recommended as 2nd line treatment for patients with FL
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation aged <70 years or older patients without significant comorbidities & >70 years & younger with comorbidities
    • Recommended 1st line therapy for frail CLL/SLL patients with significant comorbidities
  • R-FCM (Rituximab, Fludarabine, Cyclophosphamide & Mitoxantrone)
    • Recommended for patients with indolent noncontiguous stage II/III/IV NHL
    • Recommended as 2nd line treatment for patients with FL & as 2nd-line treatment for patients with MCL
  • R-FM (Rituximab, Fludarabine & Mitoxantrone)◦
    • Used for patients with indolent noncontiguous stage II/III/IV NHL & as 2nd-line treatment for patients with MCL>
  • R-FND (Rituximab, Fludarabine, Mitoxantrone, & Dexamethasone)
    • Recommended as 2nd line treatment for patients with FL
  • RICE (Rituximab, Ifosfamide, Carboplatin, Etoposide)
    • May be used for aggressive induction therapy of patients with MCL, given sequentially with RCHOP, as 2nd-line & subsequent therapy for patients with DLBCL, as 2nd-line therapy for patients with BL, & 2nd-line therapy for PTCL with Rituximab excluded (ICE)
  • R-Lenalidomide (Rituximab + Lenalidomide)
    • Recommended 1st line treatment for patients with FL & 2nd-line & subsequent therapy for patients with FL, MCL, & DLBCL
    • Recommended for CLL patients without del (11q/17p)/TP53 mutation with relapsed/refractory disease aged <70 years without significant comorbidities & >70 years & younger with comorbidities, & for CLL patients with del (17p)/TP53 mutation with relapsed/refractory disease
  • Rituximab + Chlorambucil
    • Recommended for CLL patients without 11q/17p del/TP53 mutation >70 years or younger patients with significant comorbidities & those intolerant of purine analogs & those with refractory/ relapsed disease >70 years & younger with comorbidities, & as 1st line therapy for frail CLL/SLL patients with significant comorbidities
    •  Also used as 1st-line therapy for elderly or infirm patients who cannot tolerate any 1st-line treatments
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