lymphoma.types treatment management clinical features

Medical students

1. lymphoma

2. NHL Non-Hodgkin lymphoma arises either from B cells, T cells, or natural killer cells due to chromosomal translocation or mutation/deletion. Proto-oncogenes are activated by chromosomal translocation, and tumor suppressor genes are inactivated by chromosomal deletion or mutation. The t (14;18) translocation is the most common chromosomal abnormality in Non-Hodgkin lymphoma. This translocation is most common in follicular lymphoma. The t (11;14) translocation is associated with mantle cell lymphoma. This results in the overexpression of cyclin D1, a cell cycle regulator. The t (8;14) translocation of c- myc and heavy chain Ig is associated with Burkitt lymphoma. Alteration in BCL-2 and BCL-6 is associated with diffuse large B-cell lymphoma. Primary CNS lymphoma is mostly associated with HIV/AIDS Incidence increase with age Median age is 65 years old Male > female B cell 70% T cell 30%

3. Types of NHL

4.  Immune Modulation Congenital and acquired states of immunosuppression are the strongest factor known to increase NHL risk. These conditions include ataxia-telangiectasia, Wiskott -Aldrich syndrome, common variable hypogammaglobulinemia, X-linked lymphoproliferative syndrome, and severe combined immunodeficiency . Viruses Epstein-Barr virus (EBV) appears to be an important cofactor, and host defects in immune regulation resulting in uncontrolled infection and proliferation of B-lymphocytes likely contribute to the development of NHL. Acquired immunodeficiency states such as HIV infection are associated with 75- to 100-fold increased risk of NHL compared with the general population . These NHLs are usually high-grade and often present with extranodal disease. Increased risk varied by NHL subtypes, ranging from 30-fold, 50-fold, and 1020-fold for DLBCL, Burkitt lymphoma, and central nervous system lymphoma, respectively. The occurrence of NHL in HIV-infected persons has been attributed to deficient immune surveillance of oncogenic herpesviruses, such as EBV and human herpesvirus 8 , as well as defective immune regulation and chronic antigenic stimulation due to other infections .

5. Kaposi Sarcoma-associated Herpesvirus (KSHV) KSHV-like DNA sequences are frequently detected in primary effusion lymphomas, in patients with Kaposi sarcoma, and in those with multicentric Castleman disease- plasmablastic lymphoma . These herpesvirus 8 (HHV-8)-related NHL subtypes are associated almost exclusively with HIV infection in settings of profound immunosuppression, particularly primary effusion lymphomas.   Hepatitis C Virus (HCV) Several studies have linked HCV to NHL, but results are not entirely consistent. A positive association between HCV and B-cell NHL was found in some studies. A study in Southern Italy showed a higher incidence of HCV infection in high-grade NHL than in low-grade NHL , whereas other studies report a higher incidence in low-grade NHL

6. Bacterial Infections Chronic gastric infection with  H. pylori   has been linked to the development of low-grade, gastric mucosa-associated lymphoid tissue (MALT) lymphoma . A pooled analysis of 1,052 marginal zone lymphoma cases and 13,766 controls in 12 case–control studies from the InterLymph found a positive association between self-reported peptic ulcers and risk of extranodal marginal zone lymphoma, but not nodal or splenic marginal zone lymphoma. Eradication of  Helicobacter pylori  has been shown to result in the regression of MALT lymphoma . Infection with  B. burgdorferi,   the causative agent in Lyme disease, has been detected in about 35 % of patients with primary cutaneous B-cell lymphoma. A near-complete remission of a primary marginal zone B-cell lymphoma was observed after eradication of  Borrelia burgdorferi  with antibiotic treatment .

7. Transplantation Patients who are treated with immunosuppressive drugs following solid organ transplant or hematopoietic stem cell transplant are at substantially increased risk (30–50 times) for NHL , particularly during the first year after transplant . The risk varied widely across subtypes and appeared markedly elevated for DLBCL, marginal zone lymphoma, lymphoplasmacytic lymphoma, and NK/T-cell lymphoma . Chronic antigenic stimulation induced by the graft and significant immunosuppression associated with EBV infection are the probable mechanisms. Polyclonal or monoclonal B-cell proliferations are seen in transplant patients, but these often regress when immunosuppressive therapy is stopped. However, the proliferation may persist and evolve into an aggressive NHL. Loss of control of persistent EBV infection caused by the immunosuppressive therapy appears to be important to this process.

8. Chemo/Radiotherapy Patients who receive chemotherapy and/or radiation are also at increased risk for developing subsequent secondary NHL . In the SEER database, NHL risk was increased after initial radiotherapy for all solid cancers combined, non-small cell lung cancer, and prostate cancer. Risk increased with longer latency after radiotherapy, but there was no clear pattern by NHL subtype or age. Autoimmune diseases An increased incidence of gastrointestinal lymphomas is seen in patients with celiac (nontropical) sprue and inflammatory bowel disease, particularly Crohn’s disease . Sjogren’s syndrome has been associated with NHL overall, particularly follicular lymphoma , DLBCL , marginal zone lymphoma , and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LPL/WM) . Systemic lupus erythematosus and rheumatoid arthritis have also been associated with B-cell lymphoma . It remains unclear whether the excess risk is due to immunosuppressive drugs to treat these autoimmune conditions or the condition itself.

9. Staging The Lugano classification is the current staging used for patients with NHL. The Lugano classification is based on the Ann Arbor staging system, originally developed for Hodgkin lymphoma in 1974 and modified in 1988. This staging system is based on the number of tumor sites (nodal and extranodal ) and their location. Stage I refers to NHL involving a single lymph node region (stage I) or a single extra lymphatic organ or site (stage IE) without nodal involvement. A single lymph node region can involve one node or a group of adjacent nodes.  Stage II refers to two or more involved lymph node regions on the same side of the diaphragm (stage II) or localized involvement of an extra lymphatic organ or site (stage IIE).  Stage III refers to lymph node involvement on both sides of the diaphragm (stage III).  Stage IV refers to the widespread involvement of one or more extra lymphatic organs like the liver, bone marrow, and lung, with or without associated lymph node involvement. The subscript "E" is used if the limited extranodal extension is noted; the more extensive extranodal disease is categorized as stage IV. Spleen involvement is considered nodal rather than extranodal . 

10. Grading non-Hodgkin lymphoma low-grade or indolent non-Hodgkin lymphoma is where the cancer grows slowly, and patient may not experience any symptoms for many years high-grade or aggressive non-Hodgkin lymphoma is where the cancer grows quickly and aggressively Low-grade tumours don't necessarily need immediate medical treatment, but are sometimes harder to completely cure. High-grade lymphomas need to be treated immediately, but tend to respond much better to treatment and can often be cured. In some cases, low-grade lymphomas can develop into high-grade lymphomas over time.

11. Patients present with complaints of fever, weight loss, or night sweats, also known as B symptoms. Systemic B symptoms are more common in patients with a high-grade variant of non-Hodgkin lymphoma. More than two-thirds of the patient present with painless peripheral lymphadenopathy. Patients have different presentations and vary according to the site involved. Clinical features of the patients, according to the subtypes, are: Burkitt Lymphoma:  Patients often have rapidly increasing tumor masses. This type of lymphoma may present with tumor lysis syndrome. Endemic (African)  forms may have jaw or facial bone tumors in 50 to 60 percent of cases. The primary involvement of the abdomen is less common. The primary tumor can spread to extranodal sites like the mesentery, ovary, testis, kidney, breast, and meninges.

12. The  non-endemic (sporadic)  form involves the abdomen and presents most often with massive ascites involving the distal ileum, stomach cecum, and/or mesentery, bone marrow. Symptoms related to bowel obstruction or gastrointestinal bleeding, often having features of acute appendicitis or intussusception, can be seen. Approximately 25 percent of cases have involvement of the jaw or facial bones. If Lymphadenopathy is present, it is usually localized. Bone marrow and CNS involvement are seen in 30 and 15 percent of cases, respectively, at the time of initial presentation but are more common in recurrent or treatment-resistant diseases. The kidney, testis, ovary, and breast can also be involved. The patients with  immunodeficiency-related  Burkitt Lymphoma have presentation according to the signs or symptoms related to the underlying immunodeficiency (e.g., AIDS, congenital immunodeficiency, acquired immunodeficiency due to hematopoietic or solid organ transplantation). Immunodeficiency-related cases most often involve lymph nodes, bone marrow, and CNS.

13. Mantle cell Lymphoma:  Most patients with mantle cell lymphoma have advanced-stage disease at diagnosis (70 percent). Approximately 75 percent of patients initially present with lymphadenopathy; the extranodal disease is the primary presentation in the remaining 25 percent. Common sites of involvement include the lymph nodes, spleen (45 to 60 percent), Waldeyer's ring, bone marrow (>60 percent), blood (13 to 77 percent), and extranodal sites, such as the gastrointestinal tract, breast, pleura, and orbit. Up to one-third of patients have systemic B symptoms, such as fever, night sweats, and unintentional weight loss, at presentation.  Gastrointestinal Lymphoma:  Usually presents with nonspecific symptoms such as epigastric pain or discomfort, anorexia, weight loss, nausea and/or vomiting, occult GI bleeding, and/or early satiety. Primary central nervous system (CNS) lymphoma:  Patients with primary central nervous system (CNS) lymphoma may present with headache, lethargy, focal neurologic deficits, seizures, paralysis, spinal cord compression, or lymphomatous meningitis. Involved lymphoid sites should be carefully examined. These include Waldeyer's ring (tonsils, the base of the tongue, nasopharynx), cervical, supraclavicular, axillary, inguinal, femoral, mesenteric, and retroperitoneal nodal sites should be examined. The liver and spleen should be examined.

14. A Head and neck examination should be done. Enlargement of preauricular nodes and tonsillar asymmetry suggests nodal and extranodal involvement of the head and neck, including Waldeyer's ring. Orbital structures like the eyelid, extraocular muscles, lacrimal apparatus, and conjunctivae can be involved in the marginal zone, mantle cell lymphoma, and primary central nervous lymphoma (primary CNS lymphoma). Therefore, these structures should be examined. Mediastinal involvement can be seen in primary mediastinal large B cell lymphoma or due to secondary spread. Patients with mediastinal involvement can present with a persistent cough, chest discomfort, or without any clinical symptoms, but patients usually have an abnormal chest X-ray. Superior vena cava syndrome can be part of the clinical presentation.  The involvement of retroperitoneal, mesenteric, and pelvic nodes is common in most histologic subtypes of NHL. Ascites may be present due to lymphatic obstruction, which is usually chylous.

15. About 50 percent of patients may develop extranodal disease (secondary extranodal disease), while between 10 and 35 percent of patients will have primary extranodal lymphoma at the time of diagnosis. The most common site of primary extranodal disease is the gastrointestinal tract, followed by the skin. Other sites involved with aggressive NHLs at presentation include the testis, bone, and kidney. Rare sites include the ovary, bladder, heart, adrenal glands, salivary glands, prostate, and thyroid.  Extra lymphatic disease symptoms are usually seen associated with aggressive NHL and are not common in indolent lymphomas. Testicular NHL is the most common malignancy involving the testis in men over age 60. It usually presents as a mass and comprises 1 percent of all NHL and 2 percent of all extranodal lymphomas . Epidural spinal cord compression (ESCC) can cause irreversible loss of motor, sensory, and/or autonomic function. NHL is thought to first involve the paraspinal soft tissues and then invade the cord via the vertebral foramen without first causing bony destruction.

16. Biopsy Excisional or incisional biopsy:  This is the most common type of biopsy if lymphoma is suspected, because it almost always provides enough of a sample to diagnose the exact type of NHL. If the doctor removes the entire lymph node, it is called an  excisional biopsy . If a small part of a larger tumor or node is removed, it is called an  incisional biopsy . Needle biopsy:  Needle biopsies are less invasive than excisional or incisional biopsies, but the drawback is that they might not remove enough of a sample to diagnose lymphoma (or to determine which type it is). Most doctors don’t use needle biopsies to diagnose lymphoma. But if they suspect that a lymph node is enlarged because of an infection or by the spread of cancer from another organ (such as the breast, lungs, or thyroid), a needle biopsy may be the first type of biopsy done. An excisional biopsy might still be needed even after a needle biopsy has been done, to diagnose and classify lymphoma.

17.   There are 2 main types of needle biopsies: In a  fine needle aspiration (FNA) biopsy, a very thin, hollow needle attached to a syringe to withdraw (aspirate) a small amount of tissue from an enlarged lymph node or a tumor. For a  core needle biopsy, a larger needle to remove a slightly larger piece of tissue. Lumbar puncture:  usually reserved in those with a high risk of CNS involvement, i.e., highly aggressive NHL (Burkitt lymphoma, DLBCL, peripheral T cell lymphoma, grade 3b FL, mantle cell lymphoma, precursor T or B lymphoblastic leukemia/lymphoma, human immunodeficiency virus (HIV)-positive NHL), who have epidural, bone marrow, testicular, or paranasal sinus involvement, or at least two extranodal disease sites.  CSF should be sent for both cytology and flow cytometry. Bone marrow aspiration and biopsy:  sometimes needed for the staging of the NHL. However, with the widespread use of PET scans, their utility is decreasing.

18. Immunophenotypic analysis of lymph node: p an-B cell antigens ( CD19, CD20), T cells (CD5, CD 3) The tumor cells in Burkitt lymphoma express surface immunoglobulin (Ig) of the IgM type and immunoglobulin light chains (kappa more often than lambda), B cell-associated antigens (CD19, CD20, CD22, CD79a), germinal center-associated markers (CD10 and BCL6), as well as HLA-DR and CD43Expression of CD21, the Epstein-Barr virus (EBV)/C3d receptor, is dependent on EBV status of the tumors. Essentially, all endemic BL cases are EBV positive and express CD21, whereas the vast majority of non-endemic BL in non-immunosuppressed patients are EBV negative and lack CD21 expression.  Mantle cell tumor cells express high levels of surface membrane immunoglobulin M (IgM) and IgD ( sIgM±IgD ), which is more often of lambda light chain type. They also demonstrate pan-B cell antigens (e.g., CD19, CD20), CD5, and FMC7. Nuclear staining for cyclin D1 (BCL1) is present in >90 percent of cases, including those that are CD5 negative.

19. Cytogenetic testing (karyotyping):  In this lab test, the cells are checked for any abnormalities in the chromosomes. The cells need to be grown in the lab first, so the results can take a week or more. Fluorescent in situ hybridization (FISH):  This test looks more closely at lymphoma cell DNA using special fluorescent dyes that only attach to specific genes or parts of chromosomes. FISH can find most chromosome changes that can be seen in standard cytogenetic tests, as well as some gene changes too small to be seen with cytogenetic testing. FISH is very accurate and can usually provide results within a couple of days. Polymerase chain reaction (PCR):  PCR is a very sensitive DNA test that can find gene changes and certain chromosome changes too small to be seen with a microscope, even if there are very few lymphoma cells in a sample. Other molecular/genetic tests:  Other, newer types of lab tests might also be done on the lymphoma cells to learn more about the gene and protein changes in the cells.

20. Computed tomography (CT) scan When looking for lymphoma in the body, CT scans are often combined with a PET scan Magnetic resonance imaging (MRI) is concerned about spread to the spinal cord or brain, MRI can be very useful for looking at these areas.

21. Positron emission tomography (PET) scan For a  PET scan , you are injected with a slightly radioactive form of glucose which collects mainly in cancer cells. A special camera is then used to create a picture of areas of radioactivity in the body. The picture is not detailed like a CT scan or MRI, but it can provide helpful information about whole body. See if an enlarged lymph node contains lymphoma. Find small areas that might be lymphoma, even if the area looks normal on a CT scan. Check if a lymphoma is responding to treatment.

22. A  complete blood count (CBC)  measures the levels of different cells in the blood. For a person already known to have lymphoma, low blood cell counts might mean that the lymphoma is growing in the bone marrow and affecting new blood cell formation. Blood chemistry tests  are often done to look at how well the kidneys and liver are. If lymphoma has been diagnosed, the  lactate dehydrogenase (LDH)  level may be checked. LDH levels are often increased in people with lymphomas. hepatitis B virus (HBV), hepatitis C virus (HCV),  or  human immunodeficiency virus (HIV).  Infections with these viruses may affect your treatment. Tests of heart and lung function   echocardiogram  (an ultrasound of the heart) or a  MUGA scan.   pulmonary function tests .

23. Treatment Diffuse Large B cell lymphoma (DLBCL):  In Stage I or II, the R-CHOP regimen is often given for 3 to 6 cycles, with/without radiation therapy to the lymph node that is affected. In stage III or IV, six cycles of R-CHOP is the preferred treatment. Imaging tests such as PET/CT scans are done to evaluate treatment response after 2-4 cycles. Intrathecal chemotherapy or high doses of methotrexate intravenously is given to patients in the presence or at high risk of central nervous system involvement. For "Double-hit" lymphomas, that is, with translocations of MYC and BCL2 and/or BCL6 as detected by FISH or standard cytogenetics, DA-EPOCH-R is preferred.  Refractory or relapsed DLBCL can be treated with a salvage regimen followed by bone marrow transplant for eligible patients or Chimeric antigen receptor T cell (CAR-T) cell therapy.CAR -T therapy is a form of immunotherapy in which the patient's own T lymphocytes are genetically modified with a gene that encodes a CAR that targets the patient's cancer. CAR-T therapy has shown effectiveness against refractory CD19-expressing B lymphoid malignancies.

24. Follicular lymphoma:  This type of lymphoma has indolent nature, and it shows a good response to treatment, but it is quite difficult to cure. Relapse is usually common after several years. Patients with low-burden disease can be observed, and treatment deferred unless symptomatic. The preferred treatment in stage I and stage II in the early stage is radiotherapy. Chemotherapy, along with a monoclonal antibody, is another option. Treatment in stage III, IV, and bulky stage II lymphoma is a monoclonal antibody (rituximab or obinutuzumab ) along with chemotherapy. Among the chemotherapy options, bendamustine or a combination regimen such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) are commonly used. After the response to initial treatment, the role of maintenance therapy is conflicting.

25. Mantle cell lymphoma (MCL):  MCL with multiple areas of involvement is commonly treated with aggressive chemotherapy plus rituximab in eligible patients. Intense chemotherapy regimens such as R-Hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone, alternately given with high-dose methotrexate plus cytarabine) + rituximab, alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cytarabine, cisplatin),  NORDIC regimen (dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with rituximab + high-dose cytarabine, or RDHAP (Rituximab, dexamethasone, cytarabine, cisplatin). After the response to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation is undertaken in eligible patients. This is typically followed by maintenance rituximab for three years. 

26. Burkitt lymphoma:  This is a very fast-growing lymphoma. Some examples of chemo regimens used for this lymphoma include Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) alternating with high dose methotrexate and cytarabine ( ara -C) + rituximab, CODOX-M (cyclophosphamide, vincristine [Oncovin], doxorubicin, and high-dose methotrexate) alternating with IVAC ( ifosfamide , etoposide [VP-16], and cytarabine [ ara -C]) + rituximab, or Dose adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and doxorubicin) + rituximab. Intrathecal methotrexate is given when there is evidence of involvement of the brain and spinal cord. Tumor lysis syndrome is common in Burkitt lymphoma. Therefore, tumor lysis syndrome prophylaxis and monitoring are required.  Primary CNS lymphoma:  High dose methotrexate-based chemotherapy regimen has been shown to be the most effective treatment. If the patient achieves a complete response to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation should be considered for eligible patients.

27. HIV-associated lymphoma:  Patients with HIV tend to have more aggressive forms of lymphoma, such as diffuse large B-cell lymphoma, primary CNS lymphoma, or Burkitt lymphoma. The use of highly active antiretroviral therapy (HAART) to treat HIV in addition to  chemotherapy±immunotherapy is usually employed.  Some exceptions in the treatment of lymphomas can be found here: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach:  If infection with  Helicobacter pylori  is present and the lymphoma is confined to the stomach, and peri-gastric lymph nodes, treatment with antibiotics and Histaminic (H2) blockers can eliminate the organism-related antigenic stimulus, and the lymphoma may regress permanently. Mycosis fungoides:  This type of T-cell lymphoma of the skin usually has a very indolent course and is best treated with skin-directed treatments, including topical steroids, topical retinoids, skin irradiation, psoralen-associated ultraviolet exposure, topical chemotherapy. If the patient experiences failure with skin-directed therapies can then use systemic biologic therapies.

28. Radiation Oncology Radiation therapy is recommended in the following situations:  Early-stage (stage I or II): Radiation therapy is given alone or in combination with chemotherapy.  Advanced and aggressive lymphomas: Usually, chemotherapy is the mainstay of treatment. However, radiation can be employed for palliation purposes, e.g., pain and lymphadenopathy causing urinary/gastrointestinal tract obstruction. Radiation therapies are given for several weeks and are mostly given five days a week if given for treatment. Palliative radiation is usually shorter.

29. Toxicity and Adverse Effect Management Common adverse events of chemotherapy include :myelosuppression, neutropenic fever, and immunosuppression. Myelosuppression is treated with transfusions (red cells and platelets) or the administration of colony-stimulating factors (e.g., granulocyte colony-stimulating factor). Neutropenia leads to an increased risk of infections from bacteria, viruses, and fungi. Management is dependent on the degree of neutropenia and if febrile. Patients are also susceptible to infections like Varicella and herpes zoster. Post-exposure prophylaxis is given against varicella-zoster infection. Multiple chemotherapeutic agents induce nausea and vomiting. Usually, anti-emetic serotonin receptor antagonists and/or benzodiazepines, among other agents, are used for treatment and prophylaxis. Anthracycline can cause cardiotoxicity, especially doxorubicin. Dexrazoxane has shown significant benefits in anthracycline-induced cardiotoxicity.  Radiotherapy can also cause heart failure, but the mechanism is different from that of chemotherapy. It causes diffuse fibrosis in the interstitium of the myocardium and progressive fibrosis of pericardial layers, cells in the conduction system, and the cusps or leaflets of the valves. The left ventricular ejection fraction is usually preserved. Vincristine can cause neurotoxicity.

30. Long-term fatigue is a common symptom present in two-thirds of survivors of NHL. Fatigue usually improves in the year after treatment completion. The risk of developing a second malignancy is increased in long-term survivors of NHL. The risk of developing myelodysplastic syndrome and acute myeloid leukemia is high. The risk of developing lung cancer and cutaneous melanoma was increased among survivors of follicular lymphoma. Depending on the area of radiation, patients can develop squamous cell carcinoma of the head and neck and breast cancer.  Radiation to the neck and mediastinum can result in hypothyroidism. Patients undergoing hematopoietic cell transplantation with total body irradiation (TBI) conditioning were documented to suffer from growth hormone deficiency, hypogonadism, insulin resistance, and dyslipidemia. NHL survivors are at risk for developing endocrine abnormalities such as gonadal dysfunction and hypothyroidism.  Cytotoxic agents and radiation therapy can produce gonadal dysfunction in both males and females. Fertility preservation should be offered to all. Options include freezing (cryopreservation) of embryos, oocytes, and spermatozoa. Cranial irradiation, a history of intrathecal chemotherapy, older age at the time of treatment, and hematopoietic cell transplantation can lead to neurologic and psychiatric complications like post-traumatic stress disorder.  Patients treated with an anti-CD20 monoclonal antibody (rituximab) are at risk of developing progressive multifocal leukoencephalopathy (PML). All patients at increased risk should undergo screening for neurocognitive impairment so that appropriate occupational therapy and social services referrals may be made.

31. Prognosis The prognosis of non-Hodgkin lymphoma mainly depends on histopathology, the extent of involvement, and patient factors. International Prognostic Index (IPI) and its variant are used as the main prognostic tools in patients with non-Hodgkin lymphoma. It helps to determine overall survival after standard-of-care treatment. IPI is assessed by factors including :  age>60 years, Serum LDH more than normal, Eastern Cooperative oncology group(ECOG) performance status more than or equal to 2, clinical stage III or IV, and >1 extranodal involvement. One point is given for each factor, a total score from (0 to 5), which determines the degree of risk. These are classified as low risk (0-1 adverse factor), Intermediate risk (2 adverse factors), and poor risk (three or more adverse factors).  IPI has been modified for most of the NHL for better assessment of prognosis, e.g., FLIPI for follicular lymphoma, MIPI for mantle cell lymphoma, and so on. Patients with aggressive T- or NK cell lymphomas usually have a worse prognosis. Patients with low-grade lymphomas have increased survival, which is usually 6 to 10 years. However, they can have the transformation into high-grade lymphomas.

32. Complications Life-threatening emergent complications of NHL should be considered during the initial workup and evaluation. Early recognition and prompt therapy are critical for these situations, which may interfere with and delay treatment of the underlying NHL. These can include: Febrile neutropenia Hyperuricemia and tumor lysis syndrome - Presents with fatigue, nausea, vomiting, decreased urination, numbness, tingling of legs, and joint pain. Laboratory findings include an increase in uric acid, potassium, creatinine, and phosphate and a decrease in calcium levels. This can be prevented with vigorous hydration and allopurinol. Spinal cord or brain compression Focal compression depending on the location and type of NHL - airway obstruction (mediastinal lymphoma), intestinal obstruction and intussusception, ureteral obstruction

33. Superior or inferior vena cava obstruction Hyperleukocytosis Adult T-cell leukemia-lymphoma can cause hypercalcemia. Pericardial tamponade Lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia can cause hyperviscosity syndrome. Hepatic dysfunction Venous thromboembolic disease Autoimmune hemolytic anemia and thrombocytopenia - can be observed with small lymphocytic lymphoma

34. HD

35. In general, the management of Hodgkin lymphoma depends on the subtype. Most clinicians divide classic Hodgkin lymphoma into the following three general groups: Early-stage favorable Early-stage unfavorable Advanced-stage disease However, favorable disease is defined differently by different groups. The two most commonly used definitions are that of the European Organization for the Research and Treatment of Cancer (EORTC) and the German Hodgkin Study Group (GHSG). The EORTC definition uses the following patient criteria   Limited-stage disease Age younger than 50 years No bulky mediastinal adenopathy Erythrocyte sedimentation rate (ESR) less than 50 mm/h No B symptoms (or an ESR < 30 mm/h with B symptoms) Three or fewer sites of involvement

36. The GHSG definition uses the following criteria   : No more than two sites of disease No extranodal extension No bulky mediastinal disease ESR < 50 mm/h (or < 30 mm/h if B symptoms present) With either definition, any patient with early-stage disease who does not meet the above criteria is considered to have early-stage unfavorable disease. In general, patients with early-stage favorable disease are treated with less intense chemotherapy and radiation regimens than those that are used for early-stage unfavorable disease. Advanced-stage disease is generally treated with chemotherapy alone, with radiation therapy reserved for selected patients.

37. Treatment toxicity Short-term toxicity varies based on the regimen and modalities used (chemotherapy, radiation, combination of both, and stem cell transplantation) and include: Hematologic toxicity: Anemia (need for transfusion), thrombocytopenia, increased risk of infection (febrile neutropenia) Pulmonary toxicity, particularly if bleomycin or thoracic radiation are used Cardiac toxicity from anthracycline therapy Treatment-related toxicity that can lead to death

38. Long-term toxicities vary based on patient age and treatment regimen. In general, the older the patient, the less the concern for long-term toxicity. Hematologic: Development of treatment-related myelodyplasia or acute leukemia Pulmonary: Increased risk of lung cancer or fibrotic lung disease, particularly in smokers Cardiac: Congestive heart failure from treatment, increased risk of coronary artery disease Infectious: Long-term increased risk of infection from splenectomy (rarely done in current practice), long-term immunodeficiency from treatment effects Cancer: Increased risk of secondary cancers, particularly breast cancer in young women treated with mediastinal radiation; increased risk of sarcomas in radiation fields; increased risk of lung cancer in smokers Neurologic: Chemotherapy-induced neuropathy, muscular atrophy Psychiatric: Depression and anxiety related to diagnosis and complications from treatment

39. Management of patients with early-stage favorable HL Stages IA-IIA : Regimens that combine chemotherapy and radiation therapy (RT) have replaced RT alone for treatment of early-stage, favorable disease. Involved-site radiation therapy (ISRT) is typically recommended, because high-dose, large-field radiation therapy (LFRT) increases risk for heart disease, pulmonary dysfunction, and secondary cancers. Stage IA-IIA disease can be treated with the ABVD regimen for up to six cycles, or with the Stanford regimen for two cycles ( ie , 8 weeks). ABVD regimen The ABVD regimen includes doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine   Combined modality consisting of  doxorubicin  25 mg/m 2  IV plus  bleomycin  10 units/m 2  IV plus  vinblastine  6 mg/m 2  IV plus  dacarbazine  375 mg/m 2  IV on days 1 and 15; every 28 d generally for two to four cycles; followed by ISRT at a dose of 20-30 Gy (depending on German Hodgkin Study Group [GHSG] criteria) Patients with fewer than two disease sites can be safely treated with two cycles of ABVD followed by ISRT; other patients with early-stage favorable HL should receive four cycles  

40. In selected patients with limited-stage, nonbulky HL with early response confirmed by functional imaging, ABVD for six cycles without RT has proved effective and safe. Imaging studies demonstrating response should be performed before proceeding with radiation therapy Changes in therapy due to lack of efficacy must be supported by biopsy results documenting refractory/relapsed disease Stanford V regimen The Stanford V regimen includes doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone given in a 28-day cycle, as follows: Day 1:  mechlorethamine  6 mg/m 2  IV on day 1 plus Days 1 and 15: doxorubicin 25 mg/m 2  IV and vinblastine 6 mg/m 2  IV plus Days 8 and 22: bleomycin 5 units/m 2  IV and  vincristine  1.4 mg/m 2  IV (not to exceed 2 mg/dose) plus Days 15 and 16:  etoposide  60 mg/m 2  IV plus Prednisone 40 mg/m 2  PO every other day during weeks 1-6 (taper during weeks 7 and 8) Follow with ISRT 30 Gy within 3 weeks of chemotherapy completion

41. Stages I-II unfavorable, bulky disease   : ABVD regimen for four cycles followed by ISRT or Stanford V regimen for three cycles (12 weeks) plus ISRT or Escalated BEACOPP for two cycles then ABVD for two cycles plus ISRT Stages I-II unfavorable, nonbulky disease   : ABVD regimen for two cycles (initially with staging and additional ABVD cycles as warranted) or Stanford V regimen for two cycles then ABVD for two cycles + ISRT or Escalated BEACOPP for two cycles then ABVD for two cycles + ISRT

42. ABVD regimen: Combined modality consisting of doxorubicin 25 mg/m  2  IV plus   bleomycin 10 IU/m  2  IV plus   vinblastine 6 mg/m  2  IV plus  dacarbazine 375 mg/m  2  IV on days 1 and 15; every 28 d for two cycles (for nonbulky disease) or four cycles (bulky) +/- ISRT 30 Gy or systemic chemotherapy with ABVD for six cycles  ISRT at 30 Gy should be strongly considered for patients with bulky disease or those exhibiting a slow response to therapy, as confirmed by functional imaging with PET ( ie , patients with PET scan–avid disease after four cycles of ABVD) Changes in therapy due to lack of efficacy must be supported by biopsy results documenting proven refractory/relapsed disease          

43. Stanford V regimen The Stanford V regimen includes doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone given in a 28-day cycle, as follows  [ 5 ]  : Day 1: mechlorethamine 6 mg/m 2  IV on day 1 plus Days 1 and 15: doxorubicin 25 mg/m 2  IV and vinblastine 6 mg/m 2  IV plus Days 8 and 22: bleomycin 5 units/m 2  IV and vincristine 1.4 mg/m 2  IV (not to exceed 2 mg/dose) plus Days 15 and 16: etoposide 60 mg/m 2  IV plus Prednisone 40 mg/m 2  PO every other day during weeks 1-10 (taper during weeks 11 and 12) Follow within 3 weeks with ISRT 36 Gy in patients with stage 1-2 bulky mediastinal disease or bulky disease >10 cm; for nonbulky disease, use ISRT 30-36 Gy based upon presence of B symptoms

44. Escalated BEACOPP: follow byTwo 28-day cycles of ABVD and then ISRT Escalated BEACOPP comprises bleomycin, etoposide, doxorubicin,  cyclophosphamide , vincristine [Oncovin],  procarbazine , and  prednisone  in a combined-modality 21-day cycle consisting of the following: Day 1: Cyclophosphamide 1,200 mg/m 2  PO plus doxorubicin 35 mg/m 2  IV plus Days 1-3: etoposide 200 mg/m 2  IV plus Days 1-7: procarbazine 100 mg/m 2  PO plus Days 1-14: prednisone 40 mg PO plus Day 8: vincristine 1.4 mg/m 2  IV (not to exceed 2 mg/dose) plus bleomycin 10 mg/m 2  IV, 

45. Stages III-IV: ABVD for up to six cycles +/- ISRT  [ 7 ]   or Stanford V for three cycles (12 weeks) if International Prognostic Score (IPS) < 3, +/- ISRT Patients with advanced HL and IPS ≥4 should be treated with dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for four cycles, followed by either four standard doses of BEACOPP (bleomycin 10 units/m 2  IV on day 8 plus  etoposide 100 mg/m 2  IV on days 1-3 plus  doxorubicin 25 mg/m 2  IV on day 1 plus  cyclophosphamide  650 mg/m 2  IV on day 1 plus  vincristine 1.4 mg/m 2  IV [not to exceed 2 mg/dose] on day 8 plus  procarbazine  100 mg/m 2  PO on days 1-7 plus  prednisone 40 mg/m 2  PO on days 1-14; every 21 d) if early responders  [ 8 ]  OR

46. For slow responders, administer four additional dose-escalated BEACOPP (bleomycin 10 units/m 2  IV on day 8 plus  etoposide 200 mg/m 2  IV on days 1-3 plus  doxorubicin 35 mg/m 2  IV on day 1 plus  cyclophosphamide 1200 mg/m 2  IV on day 1 plus  vincristine 1.4 mg/m 2  IV [not to exceed 2 mg/dose] on day 8 plus  procarbazine 100 mg/m 2  PO on days 1-7 plus  prednisone 40 mg/m 2  PO on days 1-14; every 21d)  [ 8 ] ISRT should be strongly considered following any of the above chemotherapy regimens for patients with bulky disease or those exhibiting a slow response to therapy by functional imaging (PET scan) Changes in therapy due to lack of efficacy must be supported by biopsy results documenting refractory/relapsed disease

47. Previously untreated stage III-IV classical HL : Brentuximab vedotin  plus AVD is indicated as first-line therapy for previously untreated stage III-IV classical HL  [ 9 ] Brentuximab 1.2 mg/kg IV (not to exceed 120 mg/dose) plus doxorubicin 25 mg/m  2  IV plus vinblastine 6 mg/m  2  IV plus dacarbazine 375 mg/m  2  IV on days 1 and 15 of each 28-day cycle for up to 6 cycles Treatment recommendations for relapsed/refractory HL It has been estimated that approximately 20-30% of patients with HL do not achieve a long-term remission with front-line chemotherapy Salvage therapy followed by high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) can cure approximately 50% of patients Based on the British Columbia data, the best timing for HDC-ASCT is after the first relapse   Regimens for patients eligible for HDC-ASCT (treatment goal = cure): Many regimens are used in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL); these are primarily based on chemotherapy agents non–cross-resistant to those used in the front-line setting, with or without  rituximab

48. The goal of salvage regimens is to achieve maximum tumor burden cytoreduction in preparation for HDC-ASCT   ICE regimen ( ifosfamide , carboplatin, and etoposide)   :  Ifosfamide  5 g/m 2  IV on day 2 plus  carboplatin  area under the curve (AUC) 5 (not to exceed 800 mg/dose) on day 1 plus  etoposide 100 mg/m 2  IV daily on days 1-3; every 14 d for two cycles (see the  Carboplatin AUC Dose Calculation [Calvert formula]  calculator) DHAP regimen (high-dose cytarabine [Ara-C], cisplatin, and dexamethasone)   : Dexamethasone 40 mg on days 1-4 plus  cytarabine  at 2 g/m 2  IV every 12 h for two doses on day 2, plus  cisplatin  100 mg/m 2  IV on day 1; every 21 days for two cycles ESHAP regimen (etoposide, methylprednisolone, Ara-C, and cisplatin)    : Etoposide 40 mg/m 2 /day IV plus  methylprednisolone  500 mg/day IV plus  cisplatin at 25 mg/m 2 /day continuous IV infusion for 4 d plus  cytarabine 2 g/m 2  on day 5; every 21-28 d for three cycles (transplant candidate)

49. Regimens for patients who are not eligible for HDC-ASCT or patients who have relapsed/refractory disease after HDC-ASCT Unfortunately, patients who are not eligible for HDC-ASCT or in whom HDC-ASCT has failed remain a challenge for the treating oncologist, pointing to the need for novel therapeutic strategies. Second-line therapies include the following  [ 16 ]  : Brentuximab vedotin   : 1.8 mg/kg IV infused over 30 min q3wk; continue treatment, not to exceed 16 cycles, or until disease progression or unacceptable toxicity Nivolumab  is indicated for classical HL that has relapsed or progressed after ASCT and post-transplantation brentuximab vedotin   Nivolumab dosage is 240 mg IV q2wk or 480 mg q4wk over 30 min until disease progression or unacceptable toxicity Pembrolizumab  is indicated for adult and pediatric patients with refractory classical HL or who have relapsed after 3 or more prior lines of therapy Pembrolizumab dosage is 200 mg IV q3wk or 400 mg IV q6wk until disease progression or unacceptable toxicity (for up to 24 months)  

50. Everolimus  10 mg PO once daily C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone): cyclophosphamide 650 mg/m 2  plus vincristine 1.4 mg/m 2  (not to exceed 2 mg/dose) on day 1 plus procarbazine 100 mg/m 2 /day PO on days 1-7 plus prednisone 40 mg/m 2 /day PO on days 1-14; every 28 d ESHAP (etoposide, methylprednisolone, Ara-C, and cisplatin)  [ 15 ]  : Etoposide 40 mg/m 2 /day IV plus methylprednisolone 500 mg/day IV plus cisplatin 25 mg/m 2 /day continuous IV infusion on days 1-4 plus cytarabine 2 g/m 2  on day 5; every 21-28 d for six cycles (nontransplant candidate) GCD (gemcitabine, carboplatin, dexamethasone): gemcitabine 1000 mg/m 2  IV on days 1 and 8 plus carboplatin AUC 5 IV on day 1 plus dexamethasone 40 mg/day PO on days 1-4 GVD (gemcitabine, vinorelbine, liposomal doxorubicin):  vinorelbine  20 mg/m 2  IV plus  gemcitabine  1000 mg/m 2  IV plus  doxorubicin liposomal  15 mg/m 2  IV on days 1 and 8; every 21d for 2-6 cycles

51. IGEV ( ifosfamide , gemcitabine, vinorelbine): 2000 mg/m 2  IV plus  mesna  2600 mg/m 2  IV plus gemcitabine 800 mg/m 2  on days 1-4 plus vinorelbine 20 mg/m 2  on day 1 Mini-BEAM ( carmustine , cytarabine, etoposide, melphalan):  carmustine  60 mg/m 2  on day 1 plus etoposide 75 mg/m 2 /day IV plus cytarabine 100 mg/m 2  q12h on days 2-5 plus  melphalan  30 mg/m 2  IV on day 6; every 4-6 weeks MINE (etoposide, ifosfamide , mesna , mitoxantrone):  ifosfamide  1.33 g/m 2 /day IV plus mesna 1.33 g/m 2 /day IV (with ifosfamide ), then mesna 500 mg PO 4 hr after each ifosfamide dose plus etoposide 65 mg/m 2 /day IV on days 1-3 plus  mitoxantrone  8 mg/m 2  IV on day 1 Histone deacetylase inhibitors,   immunomodulatory drugs, and adoptive cell transfer are therapeutic strategies with promising antitumor activity in heavily pretreated patients with HL Referral of patients with relapsed/refractory HL is mandatory to further improve the clinical outcome of such patients. Third-line therapies   Bendamustine  in patients who have failed HDT/ASCR or at least 2 prior multiagent chemotherapy regimens: 120 mg/m2 on days 1-2; every 28d for up to 6 cycles Lenalidomide : 25 mg PO once daily on days 1-21; every 28d

52. Thank you