Hodgkin ENHODGKIN LYMPHOMA, NODULAR SCLEROSIS]. Nodular sclerosis Hodgkin lymphoma is the most classical Hodgkin lymphoma and most common Hodgkin lymphoma overall. This tumor generally occurs in young adults, usually women, and generally involve cervical or supraclavicular lymph nodes. As the name implies the lymphoma is characterized by a nodular configuration created by sclerotic/fibrotic bands surrounding cellular clusters of cells (arrows) containing Reed-Sternberg cells.
HODGKIN LYMPHOMA, MIXED CELLULARITY]. Classical Hodgkin lymphoma of mixed cellularity type is the 2nd most common type of Hodgkin lymphoma in general population and the most common variety in HIV+ patients. Most patients present with peripheral and/or abdominal adenopathy and B-symptoms (fever, night sweats, and weight-loss). The lymph node architecture is diffusely effaced by a polymorphous population of small lymphocytes, histiocytes, plasma cells, and eosinophils in varying proportions. Among this mixed inflammatory cell infiltrate are present scattered mononucleate and multinucleate large Reed-Sternberg cells (arrow).
HODGKIN LYMPHOMA, LYMPHOCYTE DEPLETED]. Classical Hodgkin lymphoma of the lymphocyte-depleted subtype is the rarest form of Hodgkin lymphoma (<1%) and shows distinctive morphologic features including depletion of lymphocytes and an abundance of Reed-Sternberg cells. Most of the patients are adults with a median age of 35 years and present with stage III or stage IV disease. Note a lack of small lymphocytes and abundance of larger RS cells in a fibrotic stroma.
HODGKIN LYMPHOMA, NODULAR LYMPHOCYTE PREDOMINANT TYPE]. Nodular lymphocyte predominant Hodgkin lymphoma (nLP-HL) is a rare lymphoid malignancy usually seen in cervical, axillary, or inguinal lymph nodes in adults. The lymph node usually shows a nodular architecture with or without partially diffuse areas. Cases with completely diffuse effacement of nodes are most likely not examples of nLP-HL but may be examples of T-cell/Histiocyte-rich B-cell non-Hodgkin lymphoma or lymphocyte-rich classical Hodgkin lymphoma. Note nodular architecture (arrow) of this involved node.
SMALL LYMPHOCYTIC LYMPHOMA]. Small lymphocytic lymphoma (SLL) is the tissue manifestation of B-cell chronic lymphocytic leukemia (CLL). Although CLL is the most common chronic leukemia, SLL is NOT the most common lymphoma. This is because not all patients with CLL present with lymphomatous involvement of nodes or other solid tissues. Morphologically, involvement of nodes shows diffuse effacement by a proliferation of small lymphocytes. The node also shows poorly-defined pale areas called pseudo-follicles or proliferation centers (three arrows) that are composed of a mixture of small to medium and larger lymphocytes, prolymphocytes and paraimmunoblasts. These pseudofollicles/proliferation centers are not identified in any other lymphoma and are the morphologic hallmark of small lymphocytic lymphoma.
MANTLE CELL LYMPHOMA]. Mantle cell lymphoma, a type of mature B-cell non-Hodgkin lymphoma, is thought to arise from or differentiate toward a CD5+ subpopulation of mantle zone B-cells of lymphoid follicles. The lymphoma can take one of three morphologic growth patterns, mantle-zone, nodular, and diffuse, possibly reflecting the histologic stages of development. This example shows a diffuse growth pattern, which is the most common histologic pattern seen at the time of clinical presentation.
FOLLICULAR LYMPHOMA]. Follicular lymphoma is the 2nd most common B-cell non-Hodgkin lymphoma after diffuse large B-cell lymphoma. It comprises up to 20% of lymphoma in adults in the USA and in Western Europe. As the name implies the lymphoma takes a “follicular” or nodular pattern of growth with or without diffuse areas. This form of lymphoma is almost always a disease of adults with very rare examples documented in the pediatric age group.
DIFFUSE LARGE B-CELL LYMPHOMA]. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) in adults worldwide. It is not a single entity but a group of B-cell lymphomas that share two morphologic elements, a diffuse growth pattern (as shown in the photomicrograph) and large lymphocytes (defined as >2 times larger than a small mature lymphocyte). If all distinct categories of DLBCL can be excluded the lymphoma by default is characterized as DLBCL, NOS (not otherwise categorized).
[T-CELL RICH B-CELL LYMPHOMA]. T-cell/histiocyte-rich B-cell lymphoma is a form of diffuse large B-cell lymphoma that shows only scattered larger neoplastic B-cells amongst a vast majority of small non-neoplastic T-cells and histiocytes. The lymphoma usually presents in stage III or stage IV. Because of the unusual histology this lymphoma is often confused with lymphocyte-rich classical Hodgkin lymphoma and the rare diffuse form of lymphocyte-predominant Hodgkin lymphoma.
NODAL MARGINAL ZONE B-CELL LYMPHOMA]. Primary nodal marginal zone lymphoma is a rare B-cell neoplasm usually seen in adults. In initial stages expansion of the follicular marginal zone is seen with or without attenuated follicular mantle zones. In later stages expansion of neoplastic marginal zone B-cells causes colonization of follicles with diffuse effacement of nodal architecture. In this example a few residual germinal cells can be identified (long arrow) but most of the cortex shows a diffuse architecture (big arrow).
ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA]. Angioimmunoblastic T-cell lymphoma is a systemic T-cell lymphoproliferative disorder with characteristic clinical and histopathologic findings. The lymph node shows diffuse effacement of the architecture but some residual follicles may remain in partially involved nodes. Patients present with constitutional symptoms and generalized lymphadenopathy. Skin rash with pruritis may be present. Immune dysregulation with antinuclear and anti-smooth muscle antibodies may be identified and patients often have polyclonal hypergammaglobulinemia.
TANAPLASTIC LARGE CELL LYMPHOMA]. Anaplastic large cell lymphoma is a distinct T-cell lymphoma type which shows heterogeneity in clinical presentation, morphology and immunophenotype. The disease can be primarily nodal, cutaneous, and non-cutaneous extranodal. In lymph node the growth pattern is primarily sinusoidal (arrowheads) with large tumor cells percolating through sinuses at least early in nodal involvement.
Célula de Reed Sternberg doctorsgates.blogspot.com
Work up• The workup in a patient with suspected non-Hodgkin lymphoma (NHL) should include the following:• Complete blood cell (CBC) count• Serum chemistry studies, including lactate dehydrogenase (LDH)• Serum beta2-microglobulin level• HIV serology• Chest radiography• Computed tomography (CT) scan of the neck, chest, abdomen, and pelvis• Positron emission tomography (PET) scan• Excisional lymph node biopsy• Bone marrow aspirate and biopsy• Hepatitis B testing in patients in whom rituximab therapy is planned because reactivation has been reported• Other studies may be indicated, depending on the clinical presentation.
Hemograma• In the early stage of disease, patients with NHL may have blood counts within the reference range. As the disease progresses, a CBC count with differential and platelet count in patients with NHL may show the following:• Anemia secondary to bone marrow infiltration, autoimmune hemolysis (particularly associated with small lymphocytic lymphoma [SLL]/chronic lymphocytic leukemia [CLL]), bleeding, anemia of chronic disease• Thrombocytopenia, leukopenia, or pancytopenia secondary to bone marrow infiltration or autoimmune cytopenias• Lymphocytosis with circulating malignant cells (common in patients with low-grade lymphomas)• Thrombocytosis (paraneoplastic syndrome associated with lymphomas or reactive secondary to blood loss)
Bioquimica• Elevated lactate dehydrogenase (LDH): indicates poor prognosis; correlates with increased tumor burden• Abnormal liver function test (LFT) results: secondary to hepatic involvement, hypermetabolic tumor growth, chronic inflammation• Hypercalcemia: in patients with acute form of adult T-cell lymphoma- leukemia (ATLL) n elevated beta2-microglobulin level may be seen. Elevated levels correlate with a poor prognosis.• Occasionally, NHL is associated with monoclonal gammopathy. A Coombs test may be positive result (especially in SLL/CLL). Hypogammaglobulinemia may be present.• HIV serology should be obtained, especially in patients with diffuse large cell immunoblastic or small noncleaved histologies. HTLV-1 serology should be obtained in patients with ATLL.
RX• A chest radiograph yields positive information in approximately one fourth of patients with NHLs. It may identify hilar or mediastinal adenopathy, pleural or pericardial effusions, and parenchymal involvement. The chest radiograph may demonstrate a bulky mediastinal mass, which is associated with primary mediastinal large B-cell lymphoma or lymphoblastic lymphoma.• Obtain an upper GI series with small bowel follow-through in patients with head and neck involvement (eg, tonsil, base of tongue, nasopharynx, Waldeyer ring) and those with a GI primary lesion.
TC, cintigrafia óssea e de gálio• A CT scan of the neck, chest, abdomen, and pelvis is used to detect enlarged lymph nodes, hepatosplenomegaly, or filling defects in the liver and spleen. Currently, it is the most widely used test for initial staging, assessing treatment response, and conducting follow-up care.• A bone scan is ordered only in patients with bone pain, elevated alkaline phosphatase, or both. Bone lesions are particularly associated with the acute form of ATLL and diffuse large B-cell lymphomas.• Gallium scans are an option in selected cases of NHL. These scans can detect initial sites of disease, reflect therapy response, and detect early recurrences. This scan is positive in nearly all patients with aggressive and highly aggressive lymphomas and in approximately 50% of patients with indolent lymphomas at diagnosis.
PET e USG• Whole body F-18 2-deoxyglucose (FDG) positron emission tomography (PET) scan can be used for the initial evaluation of patients with NHL; however, this scan is more useful for posttreatment evaluation to differentiate early recurrences or residual disease from fibrosis or necrosis. This PET scan has a higher predictive value for relapse than classic CT scan imaging. A study by Zinzani et al determined that midtreatment scanning using PET allowed physicians to better make crucial decisions on further treatment.• A study by Terezakis found that incorporating FDG-PET into CT-based treatement planning in patients with lymphoma resulted in beneficial changes in management, volume definition, and normal tissue dosimetry for a significant amount of patients.• Obtain an ultrasound of opposite testis in male patients with a testicular primary lesion.
Coração• A multiple gated acquisition (MUGA) scan should be performed to measure the left ventricular ejection fraction (LVEF) of patients who are being considered for treatment with anthracyclines.• In general, anthracyclines should not be administered to those patients with LVEF of less than 50%.
RNM• Obtain an MRI of the brain and spinal cord of patients who are suspected of having primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma. An MRI scan can also be performed to identify focal areas of marrow involvement in those patients suspected to have bone marrow involvement but in whom random bone marrow biopsy findings have been negative.
BX• A well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph node is the mainstay of pathologic diagnosis. Excisional lymph node biopsy is required because lymphoma diagnosis relies heavily on careful assessment of altered nodal architecture accompanying lymphomatous infiltrates. Fine-needle aspiration (FNA) is insufficient for establishing a diagnosis; needle-core biopsies have a limited role in establishing a diagnosis of NHL.• Bone marrow aspirate and biopsy• Perform this procedure for staging rather than diagnostic purposes. Bilateral bone marrow aspirate and biopsy should be performed because bone marrow involvement is usually patchy. In bone marrow sections, the neoplastic cells may infiltrate in a focal (ie, paratrabecular or nonparatrabecular, depending on the type of lymphoma), interstitial, or diffuse pattern.• Biopsy of extranodal sites• In approximately 30-35% of adult patients with NHL, the extranodal sites are the primary presenting sites. The most common site is the GI tract.• Processing extranodal biopsy material for lymphoma protocol studies is important whenever suspicion of a hematolymphoid neoplasm exists.
PL• Lumbar puncture for cerebrospinal fluid (CSF) examination should be performed in patients with the following conditions:• Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, or nasopharyngeal involvement, or two or more extranodal sites of disease• High-grade lymphoblastic lymphoma• High-grade small noncleaved cell lymphomas (eg, Burkitt and non-Burkitt types)• HIV-related lymphoma• Primary CNS lymphoma• Neurologic signs and symptoms
BX ganglio• NHLs are a heterogeneous group of lymphoproliferative malignancies, with varying morphologic features depending on the specific subtype. The abnormal lymphocytes in the lymph node, bone marrow, or extranodal sites can be small cleaved or noncleaved, intermediate, or large cell and can have a follicular or diffuse pattern. In contrast with reactive follicular hyperplasia, lymphomas usually alter the lymph node architecture, and the capsule is usually involved.
Imunofenotipo• Immunophenotypic analysis of lymph node, bone marrow, peripheral blood (if positive for neoplastic cells), or a combination of these complements and confirms the results of routine tissue section and may be useful in resolving a diagnostic dilemma in patients with an atypical morphology.• This analysis provides information about lineage and clonality, which are complementary to the histology of a given case. Analysis is also useful for subclassifying certain lymphoma subtypes, which has therapeutic and prognostic importance.• Immunophenotypic analysis helps to distinguish reactive from neoplastic lymphoid infiltrates, lymphoid from nonlymphoid malignancies, and specific lymphoid neoplasms. Although bcl -• expression distinguishes follicular lymphoma from reactive follicular hyperplasia, bcl -1 expression strongly favors a diagnosis of mantle cell lymphoma. CD30 expression is important for the recognition of anaplastic large cell lymphoma, and it can also be found in the majority of Hodgkin lymphomas.
Jasinowodolinski D; Meirelles GSP ; Müller NLJ. bras. pneumol. vol.32 no.1 São Paulo Jan./Feb. 2006
Translocations• The t(14;18)(q32;q21) translocation is the most common chromosomal abnormality associated with NHL. This translocation occurs in 85% of follicular lymphomas and 28% of higher-grade NHLs. This translocation results in the juxtaposition of the bcl -2 apoptotic inhibitor oncogene at chromosome band 18q21 to the heavy chain region of the immunoglobulin (Ig) locus within chromosome band 14q32.• The t(11;14)(q13;q32 translocation has a diagnostic nonrandom association with mantle cell lymphoma. This translocation results in the overexpression ofbcl -1 (cyclin D1/PRAD 1), a cell-cycle regulator on chromosome band 11q13.• The 8q24 translocations lead to c-myc dysregulation. This is frequently observed in high-grade small noncleaved lymphomas (Burkitt and non- Burkitt types), including those associated with HIV infection.
Translocations• The t(2;5)(p23;q35) translocation occurs between the nucleophosmin (NPM) gene and the anaplastic lymphoma kinase (ALK1) gene. It results in the expression of an aberrant fusion protein found in a majority of anaplastic large cell lymphomas.• Two chromosomal translocations, t(11;18)(q21;q21) and t(1;14)(p22;132), are associated with mucosa-associated lymphoid tissue (MALT) lymphomas. The more common (ie, t[11;18][q21;q21]) translocates the apoptosis inhibitorAP12 gene with the MALT1 gene, resulting in the expression of an aberrant fusion protein. The other translocation, t(1;14)(p22;132), involves the translocation of the bcl -10 gene to the immunoglobulin gene enhancer region.
Infections• Some viruses are implicated in the pathogenesis of NHL, probably because of their ability to induce chronic antigenic stimulation and cytokine dysregulation, which leads to uncontrolled B- or T-cell stimulation, proliferation, and lymphomagenesis. Epstein-Barr virus (EBV) is a DNA virus that is associated with Burkitt lymphoma (especially the endemic form in Africa), Hodgkin disease, lymphomas in immunocompromised patients (eg, from HIV infection, organ transplantation), and sinonasal lymphoma.• Human T-cell leukemia virus type 1 (HTLV-1) causes a latent infection via reverse transcription in activated T-helper cells. This virus is endemic in certain areas of Japan and the Caribbean islands, and approximately 5% of carriers develop adult T-cell leukemia or lymphoma.
Infections• Hepatitis C virus (HCV) is associated with the development of clonal B-cell expansions and certain subtypes of NHL (ie, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia), especially in the setting of essential (type II) mixed cryoglobulinemia.• Kaposi sarcoma–associated herpesvirus (KSHV) is associated with body cavity–based lymphomas in patients with HIV infection and in patients with multicentric Castleman disease.• Helicobacter pylori infection is associated with the development of primary gastrointestinal (GI) lymphomas, particularly gastric mucosa-associated lymphoid tissue (MALT) lymphomas.
IPI• Age - Younger than 60 years versus older than 60 years• LDH level - Within the reference range versus elevated• Performance status - Eastern Cooperative Oncology Group (ECOG) grade 0-1 versus 2-4• Ann Arbor stage - Stage I-II versus III-IV• Number of extranodal sites - Zero to 1 versus more than 1
FLIPI• For patients with follicular lymphoma—the second most common subtype of NHL—the Follicular Lymphoma International Prognostic Index (FLIPI) score appears to be more discriminating than the IPI. The FLIPI score is calculated on the basis of 5 adverse prognostic factors, as follows:• Age (>60 y)• Ann Arbor stage (III-IV)• Hemoglobin level (< 12 g/dL)• Number of nodal areas (>4)• Serum LDH level (above normal)• Three risk groups are defined: low risk (0-1 adverse factor), intermediate risk (2 factors), and poor risk (3 or more adverse factors).
QT• Most of the chemotherapy for NHL, whether combination or single-drug, can be administered in an outpatient setting, at an infusion clinic. In the infusion clinic, specially trained oncology nurses, who are supervised by oncologists, administer the chemotherapy. Growth factor support (eg, GCSF, GM-CSF, erythropoietin) is also administered in an outpatient treatment setting.• Infusional chemotherapy (eg, infusional cyclophosphamide, doxorubicin, and etoposide [CDE], which should be administered continuously for 4 days) should be administered as inpatient treatment. High-dose chemotherapy and bone marrow and/or stem cell transplantation are administered in an inpatient setting of a tertiary hospital with an approved transplant center.
QT• For the initial treatment of patients with intermediate- or high-grade lymphoma and patients with bulky disease, an inpatient setting is recommended in order to monitor for tumor lysis syndrome and to manage appropriately.• Admit patients with NHL for complications of disease progression (eg, pain control for intractable pain) or adverse effects from chemotherapy (eg, dehydration secondary to diarrhea, vomiting requiring IV hydration, severe mucositis). Patients with fever during neutropenia should be admitted for broad-spectrum antibiotic therapy.
LNH indolente• Follicular lymphoma (grade I-IIIa) comprises 70% of this group. Other entities in this group include small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, and marginal zone lymphomas (MZL, nodal or extranodal).• Indolent stage I and contiguous stage II NHL• Standard management consists of radiotherapy alone. Forty percent of patients with limited-stage disease remained disease-free at 10 years after radiation in a study done by Mac Manus and Hoppe. No randomized study has shown combined chemotherapy and radiation to be better than radiation alone.
LNH Indolente• A study by Rossier et al found that low-dose involved-field radiotherapy is effective in treating patients with recurrent low-grade lymphoma.• Radiation therapy (2500-4000 cGy) produces a 10-year failure-free survival (FFS) rate of 50-60%, with an overall survival (OS) rate of 60-80%. Offering adjuvant chemotherapy to selected patients with stage I-II NHL who have unfavorable prognostic factors (eg, B symptoms, >2 nodal sites), and to those with follicular mixed histology is not unreasonable. Early treatment in asymptomatic patients has not been shown to improve survival.
LNH Indolente• Indolent noncontiguous stage II, III, and IV NHL• The treatment of indolent B-cell lymphomas continues to evolve as new therapies with potent antitumor activity and limited toxicity are becoming available. Monoclonal antibodies are changing the treatment paradigm of patients with B-cell lymphomas. However, controversies persist regarding the best treatment strategy and the best time to initiate treatment.• The disease course of indolent lymphomas is characterized by a continuous decrease in the quality and the duration of response with each subsequent treatment or treatments. This effect is primarily due to the acquisition of chemotherapy resistance.
LNH Indolente II, III e IV• sustained complete remissions can be achieved with various treatment modalities.• The use of rituximab, a monoclonal antibody targeting CD20 antigen present in benign and malignant B-cells, in combination with systemic chemotherapy, has resulted in an improved duration of remission and survival for patients with indolent B-cell lymphomas when compared to chemotherapy. Prospective studies and 2 meta-analyses suggest that the rituximab-chemotherapy, also known as chemo-immunotherapy, may be changing the natural progression of indolent lymphomas.• Asymptomatic patients, especially older patients and patients with concomitant medical problems, deferred therapy with careful observation is an option. Early intervention in asymptomatic patients does not appear to prolong survival. The median time to progression is 4-6 years, and OS is 6-10 years.
LNH Indolente II, III e IV• The treatment of symptomatic patients with indolent lymphomas should be focused on achieving the best possible quality of response without producing excessive toxicity. Single-agent treatment with chlorambucil or cyclophosphamide (with or without prednisone) is useful in elderly patients with significant comorbidities. However, only a few achieve remission; most achieve palliation.• Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Frequently used combination regimens are CHOP (cyclophosphamide, hydroxydaunomycin [Adriamycin], vincristine [Oncovin], and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and fludarabine alone or in combination (eg, with cyclophosphamide or mitoxantrone). Combination agents are useful in bulky and rapidly progressive disease and have higher response rates than single agents, but there is no improvement in overall survival.[19, 20, 21]
New approach - Indolent LNH II, III, IV• Czuczman and Rummel - new treatment options for NHL are comparing traditional chemotherapy with high-dose regimens. The efficacy of bendamustine plus rituximab for the first-line treatment of advanced follicular, indolent, and mantle cell lymphomas is the most important recent development. In 2011, the NCCN upgraded the combination of rituximab and bendamustine to a category 1 recommendation for suggested first-line therapy of follicular lymphoma. Other important results include the lack of superiority of high-dose chemotherapy plus rituximab compared with traditional chemotherapy plus rituximab for high-risk patients with aggressive B-cell lymphomas. Promising outcomes have been seen with the combination of lenalidomide plus rituximab for both rituximab-refractory and non–rituximab-refractory indolent NHL.
New approach – II, III, IV indolent LNH• Randomized trials have shown that adding rituximab to chemotherapy regimens results in higher response rates, longer time to progression, and longer survival than chemotherapy. For example, Czuczman et al reported a 95% overall response rate and increase in time to progression with addition of rituximab to CHOP chemotherapy. Rituximab as a single agent is also useful in patients who are unable to tolerate chemotherapy or those patients who elect to undergo treatment in the absence of high tumor burden.
New approach II, III, IV indolent LNH• A study by Gaulard et al : rituximab plus low-dose CHOP (R-miniCHOP) offered a good compromise between efficacy and safety in patients older than 80 years. The authors concluded that R-miniCHOP should be considered the new standard of treatment in these patients.• Bone marrow transplantation may have a role in patients with relapsed high-risk disease. Allogeneic transplants have lower relapse rates but higher transplant-related mortality than autologous transplants. The precise role of transplantation in indolent lymphomas is still being investigated.• A study by Watanabe et al : denser dose R-CHOP strategy was not associated with improved progression-free survival in patients with untreated indolent B-cell lymphoma.
LNH Agressivo• Diffuse large B-cell lymphoma is the most common type of NHL. Other distinct entities in this group include immunoblastic, anaplastic, lymphoblastic, large-cell, Burkitt, and Burkitt-like lymphomas (high-grade lymphomas). Mantle cell lymphomas also behave aggressively.• Aggressive stage I and contiguous stage II (nonbulky or < 10 cm) NHL• Based on 2 large randomized trials (ie, Southwest Oncology Group [SWOG], Eastern Cooperative Oncology Group [ECOG]), the preferred treatment option for patients with intermediate-grade NHL is combination chemotherapy (3 cycles of CHOP) plus involved-field radiation therapy.
LNH Agressivo• According to SWOG data, patients who are treated with chemotherapy and involved-field radiation therapy have significantly better progression- free survival rates (ie, 77% versus 66%) and 5-year overall survival (OS) rates (ie, 82% versus 72%) compared with patients surviving 8 cycles of chemotherapy (ie, CHOP) alone. Patients with high-grade disease should be strongly considered for treatment with more aggressive regimens beyond CHOP.• Aggressive noncontiguous stage II, III, and IV NHL• Approximately 40-50% of these patients are cured with standard therapy, approximately 35-40% will respond but ultimately progress or relapse, and the remainder will be have disease that is refractory to primary treatment. Scoring systems such the IPI score have been developed and validated to estimate the response rate or survival rate of a given patient with aggressive lymphomas.
LNH agressivo• A prospective randomized trial in patients with diffuse large-cell lymphoma showed no difference in response rate (RR), OS, or time to treatment failure (TTF) at 3 years with any of the following regimens :• CHOP• Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM)• Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD)• Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B)
LNH agressivo• Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine) plus rituximab has been shown to achieve a high rate of durable remission in patients with mantle cell lymphoma. It is a toxic regimen and is typically used in patients with good performance status, who can tolerate it; otherwise, R-CHOP is used.• Bendamustine and rituximab combination has been successfully used in patients with mantle cell lymphoma in the first and second-line setting.  A study by Weidmann et al found that bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in elderly patients who are not eligible for R-CHOP because of its efficacy and low toxicity.
LNH agressivo• Bortezomib has also been used in patients with relapsed or refractory mantle cell lymphoma.• ProMACE-CytaBOM, m-BACOD, and MACOP-B all proved more toxic than CHOP. However, non-CHOP regimens such as MACOP-B are used as first-line therapies in some subtypes of NHL such as primary mediastinal large B-cell NHL.• After more than 2 decades of scientific investigations, the treatment of aggressive lymphomas was changed by the clinical development of rituximab. Currently, 6-8 cycles of CHOP chemotherapy in combination with rituximab is the standard of care in patients with advanced disease.
Rituximab- CHOP• The GELA (Groupe dEtude des Lymphomes de lAdulte) study was the first phase III trial to demonstrate the efficacy of combining rituximab with standard doses of CHOP chemotherapy for elderly (older than 60 y) patients with diffuse large B-cell lymphoma. At 5-year follow-up, OS was 58% with rituximab and CHOP versus 46% with CHOP alone. The results of this study were further validated by other international randomized studies favoring the use of rituximab and chemotherapy in elderly patients with aggressive B-cell lymphomas.• Studies in younger patients also showed the benefit of combining rituximab and CHOP chemotherapy. A large international study, the MabThera International Trial (MInT,) supported the role of rituximab-chemotherapy in young patients with aggressive B-cell lymphomas. The study, which has been presented only in an abstract form, was a phase III trial in which 823 patients (ages 18-60 y) with diffuse large B-cell, CD20+ NHL (DLBCL). They were randomized to receive either rituximab plus a standard anthracycline-containing chemotherapy regimen (standard chemotherapy) or standard chemotherapy alone as induction therapy. The rituximab plus standard chemotherapy regimens increased 2-year overall survival (OS) from 86% to 95% compared with standard chemotherapy alone and resulted in significant improvement in time to treatment failure and projected overall survival.
Resgate, falha de tratamento• Ongoing research is being focused on identifying patients at risk for treatment failure and developing tailored treatment for patients with aggressive lymphoma based on clinical scores (IPI score) or gene profiles. Patients at high risk of relapse (IPI intermediate or poor risk groups) might have an improved 5-year event-free survival/overall survival from autologous and allogeneic bone marrow or peripheral stem cell transplantation following chemotherapy.
Profilaxia SNC• CNS prophylaxis, usually with 4-6 injections of methotrexate intrathecally, is recommended for patients with paranasal sinus or testicular involvement, diffuse small noncleaved cell or Burkitt lymphoma, or lymphoblastic lymphoma. CNS prophylaxis for bone marrow involvement is controversial.
Linfoma Linfoblástico• Treatment of acute lymphoblastic lymphoma, a very aggressive form of NHL, is usually patterned after acute lymphoblastic leukemia (ALL) therapy. Other subtypes of high-grade lymphomas are usually treated with more aggressive variations of CHOP chemotherapy, including the addition of high-dose methotrexate or other chemotherapy drugs and higher doses of cyclophosphamide.
LNH Indolente Recaída• In general, treatment with standard agents rarely produces a cure in patients who have relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse usually ensues. Favorable survival after relapse has been associated with age younger than 60 years, prior complete remission rather than partial remission, and duration of response longer than 1 year.
LNH Indolente recaída• For relapse that remains low grade, the following are possible treatment options:• Single alkylating agents (chlorambucil or bendamustine)• Novel biological agents and small molecule inhibitors showing promising results in patients with indolent lymphomas include ofatumumab, lenalidomide, and temsirolimus• Combination chemotherapy - CVP, CHOP, and others• Purine analogues - Fludarabine, 2-CDA• Rituximab (results in a 40-50% RR in patients with relapsed/refractory indolent B-cell lymphomas) in standard or extended schedules of administration• Radioimmunotherapy
Imuno RT e RT• 131 Iodine-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high overall response rates and complete response rates with minimal toxicity. Tositumomab (a murine IgG2a lambda monoclonal antibody directed against CD20 antigen) plus131 I (Bexxar) has been approved by the US Food and Drug Administration for relapsed or refractory, low-grade, follicular, or transformed NHL.[37, 38]• Ibritumomab tiuxetan plus90 Yttrium (Zevalin) also has been approved for use in relapsed indolent lymphoma. These radioimmunotherapy agents typically are used only in patients with less than 25% bone marrow involvement with lymphoma and in patients refractory to rituximab.• Local relapse can be treated with radiotherapy. High-dose chemotherapy plus stem cell transplantation is being investigated to determine whether it can produce significantly better survival rates compared with conventional chemotherapy.
LNH Agressivo Recaída• High-dose chemotherapy plus stem-cell transplantation is the treatment of choice for patients who have recurrent aggressive lymphomas. Preliminary studies indicate that approximately 20-40% of patients have a long-term disease-free status, but the precise percentage depends on patient selection and specific treatment used.• Second-line chemotherapy regimens such as ICE (ifosfamide, carboplatin, etoposide), DHAP (dexamethasone, high-dose cytarabine, cisplatin), or EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone) are usually used with rituximab if the tumor is CD20 positive.• Gemcitabine and navelbine are also being attempted in these relapsed patients. Chemotherapy is usually followed by stem-cell transplantation.
LNH Agressivo Recaída• In the PARMA trial, patients with relapsed NHL who were randomized to autologous bone marrow transplantation followed by involved-field radiation therapy did better than those randomized to conventional chemotherapy and involved-field radiation therapy.[40, 41] After a 5-year median follow-up study, the event-free survival (EFS) rate was significantly better with transplantation (46% versus 12%), and the OS rate was also better (53% versus 32%).• In general, patients who respond to initial therapy and who respond to conventional salvage therapy prior to bone marrow transplantation have better survival outcomes. Patients who relapse late (>12 mo after diagnosis) have better OS than patients who relapse earlier. Patients who are not candidates for transplantation can be treated with chemotherapy with or without monoclonal antibodies. If possible, these patients should be enrolled into clinical trials.
LNH Agressivo recaída• Tumor vaccines are still being investigated for use in patients with lymphoma. Novel biological and small agents showing promising results in ongoing clinical trials include CMC-544, lenalidomide, bortezomib, and temsirolimus.• A study by Witzig et al concluded that lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive NHL. 
Linfoma T• The treatment of T-cell lymphomas continues to be challenging. T-cell lymphomas are divided into 2 subgroups: cutaneous or systemic T-cell disorders. Typically, cutaneous T-cell lymphomas (CTCL) are managed with topical agents and oral disease modifiers during the early stage of the disease. Systemic chemotherapy is usually incorporated late in the course of the disease with modest activity. Systemic T-cell lymphomas represent a challenge to the practicing oncologist.
Linfoma T• The complexity of each subtype of T-cell lymphomas, the low incidence, and poor response to standard therapies are important factors that contribute to the poor clinical outcomes of this group of neoplasms. Most patients with T-cell lymphomas are better served by participating in clinical trials exploring dose-intense regimens, early bone marrow transplantation, and/or novel chemotherapeutic agents. Treatment options for T-cell lymphoma can be categorized as follows:• Combination chemotherapy regimens - CHOP, CHOP plus etoposide, gemcitabine based-regimens• Single chemotherapy agents - Pralatrexate• Monoclonal antibodies - Alemtuzumab (effective in prolymphocytic T-cell leukemia and hepatosplenic gamma-delta T-cell lymphoma)• Immunotoxin - Denileukin diftitox• Novel biological agents and small molecule inhibitors - Histone deacetylase inhibitors (vorinostat, panobinostat, romidepsin), lenalidomide, and bortezomib
Linfoma T• The US Food and Drug Administration (FDA) granted accelerated approval for pralatrexate injection (Folotyn) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).• In June 2011, the FDA granted accelerated approval for romidepsin (Istodax) for treatment of PTCL in patients who have received at least 1 prior therapy.• Jacobsen et al concluded that hematopoietic stem cell transplantation (HSCT) can result in long-term remissions in patients with relapsed or refractory T-cell lymphoma, especially those with nodal histologies.
Complicação da terapia• Cytopenias (ie, neutropenia, anemia, thrombocytopenia)• Nausea or vomiting• Infection• Fatigue• Neuropathy• Dehydration after diarrhea or vomiting• Cardiac toxicity from doxorubicin• Catheter-related sepsis• Catheter-related thrombosis• Secondary malignancies• Tumor lysis syndrome• Atherosclerosis
Complicação da Terapia• Tumor lysis syndrome• This syndrome commonly occurs after treatment of high-grade bulky NHLs because of their exquisite sensitivity to therapy, which is caused by their high proliferative capacity. Tumor lysis syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and renal failure. Death from cardiac asystole can occur from hyperkalemia.• Measures to prevent this complication include aggressive hydration, allopurinol administration, and urine alkalinization. Frequent monitoring of input and output, electrolytes, uric acid, and creatinine is necessary. Dialysis is sometimes required.• Atherosclerosis• In a 3-year study, Bilora et al found evidence that patients receiving radiotherapy and chemotherapy for lymphoma (either NHL or Hodgkin lymphoma) are predisposed to early development of atherosclerosis. In 96 patients, the investigators found increased intima-media thickness at 1-year follow-up; thickness had decreased at 3-year follow-up, but reduction in flow-mediated dilatation measured in the patients at 1 year had not improved by the 3-year examination.
Long Term Monitoring• Treatment and follow-up care of patients with NHL are usually performed on an outpatient basis. Monitoring patients’ blood cell counts while they are receiving chemotherapy (eg, prior to each treatment cycle and 10-14 d after each treatment cycle) is important.• Monitor adverse effects of chemotherapy with a detailed patient history, an examination, a CBC, and serum chemistries (especially liver function tests, electrolytes, lactate dehydrogenase, and blood urea nitrogen [BUN]/creatinine).• Treat symptomatic adverse effects such as nausea, vomiting, diarrhea, mucositis, anorexia, pain, and fatigue. Administer packed red blood cell (PRBC) transfusions for patients with symptomatic anemia and provide platelet transfusions for patients with a platelet count less than 10,000- 20,000/mm3. Provide growth factor (eg, granulocyte colony-stimulating factor [GCSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], erythropoietin) support as necessary.• Perform a disease and response to treatment evaluation by obtaining patient history, physical examination (at intervals q2-3mo), and imaging studies (eg, CT scans at intervals q4-12mo).• Provide psychosocial support for the patient and family.
LH• Hodgkin’s disease• ABVD Doxorubicin (Adriamycin) 25 mg/m2 iv d1 and 15 Bleomycin 10 U/m2 iv d1 and 15 Vinblastine 6 mg/m2 iv d1 and 15 Dacarbazine (DTIC) 375 mg/m2 iv d1 and 15 Q4w
LH ABVD - Artigos• Gianni AM et al. Comparable 3-year outcome following ABVD or BEACOPP first-line chemotherapy, plus pre-planned high-dose salvage, in advanced Hodgkins lymphoma (HL): a randomized trial of the Michelangelo, GITIL and IIL cooperative groups. 2008 ASCO annual meeting. Abstract 8506 (link to the abstract).• Engert A et al. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkins lymphoma: Final results of the GHSG HD7 trial. J Clin Oncol 2007; 25:3495 (link to the article).• Bonadonna G et al. ABVD plus subtotal nodal versus involved-field radiotherapy in early- stage Hodgkins disease: long-term results. J Clin Oncol 2004; 22:2835 (link to the article).• Carde, P et al. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkins disease: The H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 1993; 11:2258 (link to the article).• Canellos GP et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Eng J Med 1992; 327:1478 (link to the article).
LH• MOPP Nitrogen mustard 6 mg/m2 iv d1 and 8 Vincristine 1.4 mg/m2 iv d1 and 8 Procarbazine 100 mg/m2 po qd d1-14 Prednisone 40 mg/m2 po qd d1-14 Q4w x 6 cycles• Canellos GP et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Eng J Med 1992; 327:1478 ( link to the article).
LH• BEACOPP Bleomycin 10 IU/m2 iv d8 Etoposide (VP-16) 100 mg/m2/d iv d1-3 Doxorubicin (Adriamycin) 25 mg/m2 iv d1 Cyclophosphamide (Cytoxan) 650 mg/m2 iv d1 Vincristine 1.4 mg/m2 (max 2 mg) iv d8 Procarbazine 100 mg/m2 po qd d1-7 Prednisone 40 mg/m2 po qd d1-7 Q3w• Dann EJ et al. Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 2007; 109:905 (link to the article).
LH• Increased-dose BEACOPP Bleomycin 10 IU/m2 iv d8 Etoposide (VP-16) 200 mg/m2/d iv d1-3 Doxorubicin (Adriamycin) 35 mg/m2 iv d1 Cyclophosphamide (Cytoxan) 1250 mg/m2 iv d1 Vincristine 1.4 mg/m2 (max 2 mg) iv d8 Procarbazine 100 mg/m2 po qd d1-7 Prednisone 40 mg/m2 po qd d1-14 Filgrastim (Neupogen) support Q3w• Diehl V et al. Ten-year results of a German Hodgkin Study Group randomized trial of standard and increased dose BEACOPP chemotherapy for advanced Hodgkins lymphoma (HD9). 2007 ASCO annual meeting. Abstract LBA 8015 (link to the abstract).• Diehl V et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Eng J Med 2003; 348:2386 (link to the article).
LH• Stanford V Nitrogen mustard 6 mg/m2 iv d1 Doxorubicin (Adriamycin) 25 mg/m2 iv d1 and 15 Vinblastine 6 mg/m2 iv d1 and 15 Vincristine 1.4 mg/m2 iv d8 and 22 Bleomycin 5 U/m2 iv d8 and 22 Etoposide (VP-16) 60 mg/m2 iv d15 and 16 Prednisone 40 mg po qod x 10 weeks, then taper by 10 mg every other day between weeks 10 and 12 Q4w x 3 cycles (12 weeks) For patients older than 50, reduce Vinblastine to 4 mg/m2 amd Vincristine to 1 mg/m2 in cycle 3. Bactrim DS po bid Acyclovir 200 mg po tid Ketoconazole 200 mg po qd 2-4 weeks after chemotherapy, consolidation radiotherapy to 36 Gy for lymph nodes > or equal to 5 cm and/or macroscopic nodules in spleen• Horning SJ et al. Assessment of the Stanfod V regimen consolidative radiotherapy for bulky and advanced Hodgkin’s disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol 2000; 18:972 (link to the article).
LH recaída ou indicação de TX• GVD For transplant-naive patients: Gemcitabine (Gemzar) 1000 mg/m2 iv d1, 8 Vinorelbine (Navelbine) 20 mg/m2 iv d1, 8 Pegylated liposomal doxorubicin (Doxil) 15 mg/m2 iv d1, 8 Q3w For post-transplant patients: Gemcitabine (Gemzar) 800 mg/m2 iv d1, 8 Vinorelbine (Navelbine) 15 mg/m2 iv d1, 8 Pegylated liposomal doxorubicin (Doxil) 10 mg/m2 iv d1, 8 Q3w• Bartlett NL et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkins lymphoma: CALGB 59804. Ann Oncol 2007; 18:1071 ( link to the article).• Rituximab (for relapsed lymphocyte-predominant Hodgkin lymphoma) Rituximab (Rituxan) 375 mg/m2 iv qw x 4• Schulz H et al. Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long- term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group. Blood 2008; 111:109 (link to the article).
LNH Indolente e Linfoma Agressivo• R-CHOP Rituximab (Rituxan) 375 mg/m2 iv d1 Cyclophophamide (Cytoxan) 750 mg/m2 iv d1 Doxorubicin (Adriamycin) 50 mg/m2 iv d1 Vincristine 1.4 mg/m2 ( max 2 mg ) iv d1 Prednisone 100 mg po qd d1-5 Q3w x 6-8 cycles• Buske C et al. Front-line combined immuno-chemotherapy (R-CHOP) significantly improves the time to treatment failure and overall survival in elderly patients with advanced stage follicular lymphoma-results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). 2006 ASH annual meeting. Abstract 482 (link to the abstract).• Czuczman, MS et al. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkins lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 2004; 23:4711 (link to the article).
LNH Indolente• Chlorambucil Chlorambucil (Leukeran) 10 mg po qd• Ardeshna, KM et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 2003; 362:516 (link to the article).• Cyclophosphamide Cyclophosphamide (Cytoxan) 100 mg/m2 po qd• Peterson, BA et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 2003; 21:5 (link to the article).• Fludarabine Fludarabine 25 mg/m2 iv qd d1-5 q4w• Klasa, RJ et al. Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low- grade non-Hodgkins lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol 2002; 20:4649 (link to the article).
LNH Indolente• Rituximab Rituximab (Rituxan) Regimen 1 375 mg/m2 iv qw x 4 followed by 375 mg/m2 iv q2m x 4• Ghielmini, M et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004; 103:4416 (link to the article).• Regimen 2 375 mg/m2 iv qw x 4 followed by 375 mg/m2 iv qw x 4 every 6 months• Hainsworth, JD et al. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re- treatment at progression in patients with indolent non-Hodgkins lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2005; 23:1088 (link to the article).• Bendamustine Bendamustine (Treanda) 120 mg/m2 iv over 30-60 min d1 and 2 Q3w x 12 cycles• Friedberg JW et al. Bendamustine in patients with rituximab-refractory indolent and transformed non- Hodgkins lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol 2008; 26:204 ( link to the article).• Oxaliplatin (for MALT lymphoma) Oxaliplatin (Eloxatin) 130 mg/m2 iv over 2 hours Q3w x 6 cycles• Raderer M et al. Phase II study of oxaliplatin for treatment of patients with mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005; 23:8442 (link to the article).
LNH Indolente• R-CVP Rituximab (Rituxan) 375 mg/m2 iv d1 Cyclophosphamide (Cytoxan) 750 mg/m2 iv d1 Vincristine 1.4 mg/m2 ( max 2 mg ) iv d1 Prednisone 40 mg/m2 po qd d1-5 Q3w x 8 cycles• Marcus RE et al. MabTher (rituximab) plus cyclophosphamide, vincristine and prednisone (CVP) chemotherapy improves survival in previously untreated patients with advanced follicular non-hodgkins lymphoma (NHL). 2006 ASH annual meeting. Abstract 481 (link to the abstract).• Marcus RE et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105:1417 (link to the article).• CVP + maintenance R Cyclophosphamide (Cytoxan) 1000 mg/m2 iv d1 Vincristine 1.4 mg/m2 ( max 2 mg ) iv d1 Prednisone 100 mg po qd d1-5 Q3w x 6-8 cycles Followed by Rituximab (Rituxan) 375 mg/m2 iv qw x 4, q6m x 4 (2 years)• Hochster HS et al. Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B. 2005 ASH annual meeting. Abstract 349 (link to the abstract).
LNH Indolente• Bortezomib Bortezomib (Velcade) 1.3-1.5 mg/m2 iv d1, 4, 8 and 11 Q3w• Approved by FDA on 12/8/06 (link to FDA file).• Strauss SJ et al. Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity. J Clin Oncol 2006; 24:2105 ( link to the article).• Goy, A et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkins lymphoma. J Clin Oncol 2005; 23:667 (link to the article).• OConnor, OA et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkins lymphoma and mantle cell lymphoma. J Clin Oncol 2005; 23:676 (link to the article).
Linfoma do Manto recaída• R-GemOx Rituximab (Rituxan) 375 mg/m2 iv d1 Gemcitabine (Gemzar) 1000 mg/m2 (in 500 ml normal saline) iv d1 Oxaliplatin (Eloxatin) 100 mg/m2 iv over 2 hrs d1 Q2-3w x 8 cycles• Rodriguez J et al. Rituximab, gemcitabine and oxaliplatin: an effective regimen in patients with refractory and relapsing mantle cell lymphoma. Leuk Lymphoma 2007; 48:2172 (link to the article).• Gnaoui TE et al. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol 2007; Advanced access published May 11, 2007 (link to the article).• Rituximab + Thalidomide Rituximab (Rituxan) 375 mg/m2 iv qw x 4 Thalidomide ((Thalomid) 200 mg po qd x 2 weeks, then 400 mg po qd until disease progression• Kaufmann H et al. Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood 2004; 104:2269 (link to the article).• Rituximab + Lenalidomide Rituximab (Rituxan) 375 mg/m2 iv qw x 4 Lenalidomide (Revlimid) 20 mg po qd d1-21 q4w until disease progression• Wang M et al. A phase I/II study of lenalidomide (Len) in combination with rituximab (R) in relapsed/refractory mantel cell lymphoma (MCL) with early evidence of efficacy. 2007 ASCO annual meeting. Abstract 8030 (link to the abstract).•
Linfoma do Manto recaída• Temsirolimus Regimen 1 Temsirolimus (Torisel) 250 mg iv over 30 min qw for a total of 12 months or 2 months after CR Premedication Diphenhydramine (Benadryl) 25-50 mg iv• Witzig TE et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005; 23:5347 (link to the article).• Regimen 2 Temsirolimus (Torisel) 25 mg iv qw for a total of 12 months or 2 months after CR Premedication Diphenhydramine (Benadryl) 25-50 mg iv• Ansell SM et al. Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: a phase II trial in the North Central Cancer Treatment Group. 2006 ASCO annual meeting. Abstract 7532 (link to the abstract).• Regimen 3 Temsirolimus (Torisel) 175 mg iv qw x 3, followed by 75 mg iv qw Premedication Diphenhydramine (Benadryl) 25-50 mg iv• Hess G et al. Phase III study of patients with relapsed, refractory mantle cell lymphoma treated with temsirolimus compared with investigators choice therapy. 2008 ASCO annual meeting. Abstract 8513 (link to the abstract).
Difuso de Gdes células em idosos• CHOP Cyclophophamide (Cytoxan) 750 mg/m2 iv d1 Doxorubicin (Adriamycin) 50 mg/m2 iv d1 Vincristine 1.4 mg/m2 ( max 2 mg ) iv d1 Prednisone 100 mg po qd d1-5 Q3w x 6-8 cycles• Feugier P et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de I’Adulte. J Clin Oncol 2005; 23:4117 (link to the article).
Agressivos de alto risco• CEPP (non-anthracycline-containing regimen) Cyclophosphamide (Cytoxan) 600 mg/m2 iv d1 and 8 Etoposide (VP-16) 70 mg/m2/d iv d1-3 Procarbazine 60 mg/m2/d po d1-10 Prednisone 60 mg/m2/d po d1-10 Q4w x 6 cycles• Chao NJ et al. CEPP: an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkins lymphoma. Blood 1990; 76:1293 (link to the article).• ICE regimen 1 Ifosfamide 1000 mg/m2/d iv over 1 h d1-2 (hours 0 and 1) Etoposide (VP-16) 150 mg/m2/d iv over 11 hrs after ifosfamide d1-2 (hours 1-11) Carboplatin (Paraplatin) 200 mg/m2/d iv over 1 h after etoposide d1-2 (hours 11-12) Etoposide (VP-16) 150 mg/m2/d iv over 11 hrs after carboplatin d1-2 (hours 12-24) Mesna 333 mg/m2 iv 30 minutes before ifosfamide, repeat 4 and 8 hrs after ifosfamide Q4w x 2 cycles• Fields KK et al. Ifosfamide, carboplatin and etoposide: a new regimen with a broad spectrum of activity. J Clin Oncol 1994; 12:544 (link to the article).• regimen 2 Ifosfamide 5000 mg/m2 mixed with Mesna 5000 mg/m2 iv over 24 hrs d2 Carboplatin (Paraplatin) AUC 5 (max 800mg) iv d2 Etoposide (VP-16) 100 mg/m2/d iv d1-3 Filgrastim (Neupogen) 5 ug/kg sc qd d5-12 Q2w x 3 cycles• Moskowitz, CH et al. Ifosfamide, carboplatin, and etoposide: A highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkins lymphoma. J Clin Oncol 1999; 17:3776 (link to the article).
Agressivos recaída• RICE Rituximab (Rituxan) 375 mg/m2 iv d1 q2w x 3 cycles ICE regimen 2 as above• Kewalramani, T et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 2004; 103:3684 (link to the article).• ESHAP Etoposide (VP-16) 40 mg/m2/d iv over 1 hr d1-4 Methylprednisolone 500 mg/d iv over 15 min d1-5 Cisplatin (CDDP) 25 mg/m2/d civi d1-4 Cytarabine (Ara-C) 2000 mg/m2 iv over 2 hr d5 Q3-4w x 6-8 cycles• Velasquez, WS et al. ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994; 12:1169 (link to the article).
Burkitt• CODOX-M/IVAC (for high risk patients: do not meet low risk below)• Cycle 1 and 3 ( CODOX-M ) Cyclophosphamide (Cytoxan) 800 mg/m2 iv d1 Cyclophosphamide (Cytoxan) 200 mg/m2/d iv d2-5 Doxorubicin (Adriamycin) 40 mg/m2 iv d1 Vincristine 1.5 mg/m2 iv d1, 8 for cycle 1 and d1, 8, 15 for cycle 3 Methotrexate (MTX) 1200 mg/m2 iv over 1 h d10, then 240 mg/m2 per hour civi for the next 23 hrs Leucovorin 50 mg iv q6h begins 36 hrs from the start of MTX till MTX level < 0.05 uM Filgrastim (Neupogen) begins 24 hrs from the start of Leucovorin till ANC > 1000/mL CNS prophylaxis: Intrathecal Cytarabine (Ara-C) 70 mg d1 and 3, Methotrexate (MTX) 12 mg d15 CNS treatment: Cycle 1: Intrathecal Cytarabine (Ara-C) 70 mg d1, 3 and 5, Methotrexate (MTX) 12 mg d15 and 17 Cycle 3: Intrathecal Cytarabine (Ara-C) 70 mg d1 and 3, Methotrexate (MTX) 12 mg d15• Cycle 2 and 4 ( IVAC ) Ifosfamide 1500 mg/m2/d iv d1-5 Etoposide (VP-16) 60 mg/m2/d iv d1-5 Cytarabine (Ara-C) 2000 mg/m2 iv q12h d1 and 2 (total 4 doses) Filgrastim (Neupogen) begins 24 hrs after completion of chemotherapy till ANC > 1000/mL CNS prophylaxis: Intrathecal Methotrexate (MTX) 12 mg d5 CNS treatment: Cycle 2: Intrathecal Methotrexate (MTX) 12 mg d5, Cytarabine (Ara-C) 70 mg d7 and 9 Cycle 4: Intrathecal Methotrexate (MTX) 12 mg d5 Radiotherapy for CNS disease and testicular involvement
Peqs não clivadas com baixo risco• Modified CODOX-M (for low risk patients: single extraabdominal mass or completely resected abdominal mass and normal serum LDH) Cyclophosphamide (Cytoxan) 800 mg/m2 iv d1 Cyclophosphamide (Cytoxan) 200 mg/m2/d iv d2-5 Doxorubicin (Adriamycin) 40 mg/m2 iv d1 Vincristine 1.5 mg/m2 iv d1, 8 Methotrexate (MTX) 1200 mg/m2 iv over 1 h d10, then 240 mg/m2 per hour civi for the next 23 hrs Leucovorin 50 mg iv q6h begins 36 hrs from the start of MTX till MTX level < 0.05 uM Filgrastim (Neupogen) begins 24 hrs from the start of Leucovorin till ANC > 1000/mL CNS prophylaxis: Intrathecal Cytarabine (Ara-C) 70 mg d1, Methotrexate (MTX) 12 mg d3 Total of 3 cycles• Magrath, I et al. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 1996; 14:925 (link to the article).
• CALGB 9251 Burkitt• Cycle 1 Cyclophosphamide (Cytoxan) 200 mg/m2/d iv d1-5 Prednisone 60 mg/m2/d po d1-7• Cycle 2, 4, 6 Ifosfamide 800 mg/m2/d iv over 1 hr d1-5 Mesna 200 mg/m2 iv at 0, 4 and 8 hrs after ifosfamide d1-5 Methotrexate (MTX) 150 mg/m2 iv over 30 minutes d1, followed by 1350 mg/m2 civi over 23.5 hrs Leucovorin 50 mg/m2 iv 36 hrs after start of MTX, followed by 15 mg/m2 iv q6h till MTX level < 0.05 uM Vincristine 2 mg iv d1 Cytarabine (Ara-c) 150 mg/m2/d civi d 4 and 5 Etoposide (VP-16) 80 mg/m2/d iv over 1 hr d 4 and 5 Dexamethasone (Decadron) 10 mg/m2/d po d1-5• Cycle 3, 5, 7 Cyclophosphamide (Cytoxan) 200 mg/m2/d iv d1-5 Methotrexate (MTX) 150 mg/m2 iv over 30 minutes d1, followed by 1350 mg/m2 civi over 23.5 hrs Leucovorin 50 mg/m2 iv 36 hrs after start of MTX, followed by 15 mg/m2 iv q6h till MTX level < 0.05 uM Vincristine 2 mg iv d1 Doxorubicin (Adriamycin) 25 mg/m2/d iv bolus d 4 and 5 Dexamethasone (Decadron) 10 mg/m2/d po d1-5 Intrathecal (cycle 2-7) Methotrexate (MTX) 15 mg d1 Cytarabine (Ara-c) 40 mg d1 Hydrocortisone 50 mg d1 Brain radiation 24 Gy post chemotherapy if bone marrow involvement Start cycle 2 right after cycle 1, cycle 2-7 are given q3w• Rizzieri, DA et al. Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer 2004; 100:1438 (link to the article). Lee EJ et al. Brief-duration high-intensity chemotherapy for patients with small noncleaved -cell lymphoma or FAB L3 acute lymphocytic leukemia: results of Cancer and Leukemia Group B Study 9251. J Clin Oncol 2001; 19:4014 (link to the article).
Pre B ou T linfoblástico• Hyper-CVAD/MTX-Ara-C• Cycle 1,3,5,7 (3-4 wks/cycle) Cyclophosphamide (Cytoxan) 300 mg/m2 iv over 2 hrs q12 hrs x 6 doses d1-3 Mesna 600 mg/m2/d civi d1-3 to start 1 h before cyclophosphamide till 12 hrs after completion of cyclophosphamide Vincristine 2 mg iv d4, 11 Doxorubicin (Adriamycin) 50 mg/m2 iv over 24 hrs (over 48 hrs if LVEF < 50%) d4 Dexamethasone (Decadron) 40 mg po or iv qd d1-4 and d11-14• Cycle 2,4,6,8 (3-4 wks/cycle) Methotrexate (MTX) 200 mg/m2 iv over 2 hrs followed by 800 mg/m2 civi over 22 hrs d1 Cytarabine (Ara-C) 3 g/m2 (1 g/m2 for patients over 60 years old) iv over 2 hrs q12 hrs x 4 doses d2-3 Leucovorin 50 mg iv q6 hrs starting 12 hrs after completion of MTX till MTX level < 0.05 uM• Intrathecal chemotherapy Prophylaxis Methotrexate (MTX) 12 mg d2 of each cycle for a total of 3-4 treatments Cytarabine (Ara-C) 100 mg d8 of each cycle for a total of 3-4 treatments Therapeutic Intrathecal chemotherapy twice a week (Methotrexate (MTX) 12 mg and Cytarabine (Ara-C) 100 mg respectively) till no more cancer cells in CSF, then decrease intrathecal chemotherapy to once a week x 4, followed by Methotrexate (MTX) 12 mg d2, Cytarabine (Ara-C) 100 mg d8 for the remaining chemotherapy cycles Cranial radiotherapy 24-30 Gy if cranial nerve palsies• Thomas, DA et al. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood 2004; 104:1624 (link to the article).
• Linfoma linfoblástico ou Pré B CALGB 9111 • Cycel 4 (8 wks)• Cycle 1 (4 wks) Doxorubicin (Adriamycin) 30 mg/m2/d iv d1, 8, 15 Cyclophosphamide (Cytoxan) 1200 mg/m2 iv d1 Vincristine 2 mg iv d1, 8, 15 Doxorubicin (Adriamycin) 45 mg/m2/d iv d1, 2, 3 Dexamethasone (Decadron) 10 mg/m2/d po d1-14 Vincristine 2 mg iv d1, 8, 15, 22 Cyclophosphamide (Cytoxan) 1000 mg/m2 iv d29 Prednisone 60 mg/m2 po or iv qd d1-21 6-Thioguanine 60 mg/m2/d po d29-42 L-Asparaginase 6000 IU/m2 sc or im d5, 8, 11, 15, 18, 22 Cytarabine (Ara-C) 75 mg/m2/d sc d29-32 and 36-39 Reduce doses if patients older than 60: • Cycle 5 (16 months) Cyclophosphamide (Cytoxan) 800 mg/m2 iv d1 Vincristine 2 mg iv d1 qm Doxorubicin (Adriamycin) 30 mg/m2/d iv d1, 2, 3 Prednisone 60 mg/m2/d d1-5 qm Prednisone 60 mg/m2 po qd d1-7 Methotrexate (MTX) 20 mg/m2/d po d1, 8, 15, 22 Filgrastim (Neupogen) 5 mcg/kg sc qd d4 till ANC > 6-Mercaptopurine (6-MP) 60 mg/m2/d po d1-28 1000/uL • Larson RA et al. A randomized controlled trial of• Cycle 2 (4 wks,repeat once) filgramstim during remission induction and Cyclophosphamide (Cytoxan) 1000 mg/m2 iv d1 consolidation chemotherapy for adults with acute 6-Mercaptopurine (6-MP) 60 mg/m2/d po d1-14 lymphoblastic lymphoma: CALGB study 9111. Blood Cytarabine (Ara-C) 75 mg/m2/d sc d1-4 and 8-11 1998; 92:1556 (link to the article). Vincristine 2 mg iv d15, 22 L-Asparaginase 6000 IU/m2 sc or im d15, 18, 22, 25 Intrathecal Methotrexate (MTX) 15 mg d1 Filgrastim (Neupogen) 5 mcg/kg sc qd d2 till ANC > 5000/uL• Cycle 3 (12 wks) 6-Mercaptopurine (6-MP) 60 mg/m2/d po d1-70 Methotrexate (MTX) 20 mg/m2 po d36, 43, 50, 57, 64 Intrathecal Methotrexate (MTX) 15 mg d1, 8, 15, 22, 29 Brain radiation 24 Gy d1-12
Primário do SNC• High dose Methotrexate Methotrexate (MTX) 8 g/m2 iv over 4 hrs q2w till CR or up to 8 cycles, followed by 8 g/m2 iv qm x 11 months• Batchelor, T et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: A report of NABTT 96-07. J Clin Oncol 2003; 21:1044 (link to the article).• MPV + RT + Ara-C Methotrexate (MTX) 3.5 g/m2 iv over 2 hours d1 Leucovorin 10 mg q6h x 12 doses starting 24 hours after MTX infusion Vincristine 1.4 mg/m2 (max 2.8 mg) iv d1 Procarbazine 100 mg/m2 po qd d1-7 cycles 1, 3, 5 only Q2w x 5 cycles Intra-ommaya Methotrexate (MTX) 12 mg on alternate weeks after systemic MTX Leucovorin 10 mg q6h x 8 doses starting 24 hours after intra-ommaya MTX 3-5 weeks after MPV, whole-brain radiotherapy (WBRT) 1.8 Gy/d x 25 days to a total of 45 Gy for patients younger than 60 years 3 weeks after WBRT, consolidation Cytarabine (Ara-C) 3 g/m2/d iv over 3 hours for 2 days. A second cycle of Cytarabine (Ara-C) is given 1 month later• Garvrilovic IT et al. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 2006; 24:4570 ( link to the article).• Abrey LE et al. Treatment of primary CNS lymphoma: the next step. J Clin Oncol 2000; 18:3144 ( link to the article).
Primário do SNC• R-MPV + RT + Ara-C Rituximab (Rituxan) 500 mg/m2 iv over 5 hours d1 of each cycle Methotrexate (MTX) 3.5 g/m2 iv over 2 hours d2 of each cycle Leucovorin 20-25 mg q6h starting 24 hours after MTX infusion for 72 hours or until serum MTX level < 1 x 10-8 mg/dL. Increase leucovorin to 40 mg q4h if MTX level > 1 x 10-5 mg/dL at 48 hours or > 1 x 10-8 mg/dL at 72 hours Vincristine 1.4 mg/m2 (max 2.8 mg) iv d2 of each cycle Procarbazine 100 mg/m2 po qd d1-7 of odd-numbered cycles only Filgrastim (Neupogen) 5 mcg/kg/d sc for 3 to 5 days starting 24 hours after the last dose of procarbazine during odd- numbered cycles, and starting 96 hours after MTX infusion or when MTX levels < 1 x 10-8 mg/dL during even-numbered cycles If positive CSF cytology: intra-ommaya Methotrexate (MTX) 12 mg between days 5 and 12 of each cycle Q2w x 5 cycles After 5 cycles of R-MPV: If CR, whole-brain radiotherapy (WBRT) 1.8 Gy/d for 13 days to a total of 23.4 Gy beginning 3-5 weeks after the completion of R-MPV If PR, 2 more additional cycles of R-MPV. If CR after 7 cycles of R-MPV, WBRT 1.8 Gy/d x 13 days to a total of 23.4 Gy beginning 3-5 weeks after the completion of R-MPV. If persistent disease after 7 cycles of R-MPV, WBRT 1.8 Gy/d x 25 days to a total of 45 Gy beginning 3-5 weeks after the completion of R-MPV If stable disease or progressive disease after 5 cycles of R-MPV, WBRT 1.8 Gy/d x 25 days to a total of 45 Gy beginning 3-5 weeks after the completion of R-MPV 3 weeks after completion of WBRT, consolidation Cytarabine (Ara-C) 3 g/m2/d (max 6 g) iv over 3 hours for 2 days Filgrastim (Neupogen) 5 mcg/kg/d sc for 10 days starting 48 hours after completion of Ara-C A second cycle of Cytarabine (Ara-C) is given 1 month later• Shah GD et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007; 25:4730 (link to the article).
Primário do SNC• Bonn protocol Cycle A (3 wks) Methotrexate (MTX) 5 g/m2 (3 g/m2 for patients over 65 years old) civi over 24 hrs d1 Vincristine 2 mg iv d1 Ifosfamide 800 mg/m2/d iv over 1 h d2-5 Dexamethasone (Decadron) 10 mg/m2/d po d2-5 Prednisone 2.5 mg intraventricularly qd d2-4 Methotrexate (MTX) 3 mg intraventricularly qd d2-4 Cytarabine (Ara-C) 30 mg intraventricularly d5• Cycle B (3 wks) Methotrexate (MTX) 5 g/m2 (3 g/m2 for patients over 65 years old) civi over 24 hrs d1 Vincristine 2 mg iv d1 Cyclophosphamide (Cytoxan) 200 mg/m2/d iv over 1 h d2-5 Dexamethasone (Decadron) 10 mg/m2/d po d2-5 Prednisone 2.5 mg intraventricularly qd d2-4 Methotrexate (MTX) 3 mg intraventricularly qd d2-4 Cytarabine (Ara-C) 30 mg intraventricularly d5• Cycle C (3 wks) Cytarabine (Ara-C) 3 g/m2/d iv over 3 hrs d1-2 Vindesine 5 mg iv d1 Dexamethasone (Decadron) 20 mg/m2/d po d3-7 Prednisone 2.5 mg intraventricularly qd d3-6 Methotrexate (MTX) 3 mg intraventricularly qd d3-6 Cytarabine (Ara-C) 30 mg intraventricularly d7• Sequence of cycles: A (d1-5), B (d22-26), C (d43-49). Repeat cycles A, B and C once for a total of 6 cycles. Pels, H et al. Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy. J Clin Oncol 2003; 21:4489 (link to the article).
Primário do SNC• MTX + Ara-C + ASCT + RT Methotrexate (MTX) 8 g/m2 iv over 4 hours d1, 10, 20 Leucovorine rescue 15 mg/m2 q6h until MTX clearance Cytarabine (Ara-C) 3 g/m2 iv over 3 hours d 30 and 31 Thiotepa 40 mg/m2 iv d 31 Carmustine (BCNU) 400 mg/m2 iv d 50 Thiotepa 5 mg/kg iv d 51, 52 Autologous stem-cell transplantation (ASCT) d56 Hyperfractionated whole brain radiation 2 cycles of 1 Gy/d to 45 Gy for patients with CR or 50 Gy for patients with PR starting d90• Illerhaus G et al. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 2006; 24:3865 (link to the article).• Temozolomide Temozolomide (Temodar) 150 mg/m2/d po d1-5 q4w• Reni M et al. Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer 2007; 96:864 (link to the article).
Primário do SNC• CYVE + ASCT Cytarabine (Ara-C) 2 g/m2/d iv over 3 hours d2-5 (if 60 years of age and older, reduce to 2 g/ m2/d d2-4) Cytarabine (Ara-C) 50 mg/m2/d iv over 12 hours d1-5 Etoposide (VP-16) 200 mg/m2/d iv over 2 hours d2-5 (if 60 years of age and older, reduce to 150 mg/m2/d d2-5) Q4w x 2 cycles Thiotepa 250 mg/m2/d iv d9-7 Busulfan (Myleran) total dose 10 mg/kg po or 8 mg/kg iv d6-4 (if 60 years of age and older, reduce dose by 40%) Cyclophosphamide (Cytoxan) 60 mg/kg/d d3-2 Autologous stem cell transplantation (ASCT) on d0 Soussain C et al. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: societe Francaise de Greffe de Moelle Osseuse-Therapie Cellulaire. J Clin Oncol 2008; 26:2512 (link to the article).• Soussain C et al. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol 2001; 19:742 (link to the article).•