Lymphoma

Lymphoma

Fontes
Medscape, eMedicine, Pathpedia,
http://chemoregimen.com

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.[13]
• 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.[14] A study by Zinzani et al determined that
midtreatment scanning using PET allowed physicians to better make
crucial decisions on further treatment.[15]
• 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.[16]
• 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 NL
J. 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,[2] 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

IPI
• 0-1 risk factors - 75%

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.[6] 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).

Treatment depends on
• Tumor stage
• Phenotype (B-cell, T-cell or natural killer (NK)
cell/null-cell)
• Histology (ie, low-, intermediate-, or high-grade)
• Symptoms
• Performance status
• Patient age
• Comorbidities

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.[17] 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.[18]
• 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.[22] 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.[23]

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.[24] 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.[25]
• 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.[26] 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.[27]

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[28] :
• 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.[29]
• Bendamustine and rituximab combination has been successfully used in
patients with mantle cell lymphoma in the first and second-line setting.
[30] 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.[31]

LNH agressivo
• Bortezomib has also been used in patients with relapsed or
refractory mantle cell lymphoma.[32]
• 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 d'Etude des Lymphomes de l'Adulte) 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.[33] 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.[34] 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.[34]

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[35]
• 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.[36] 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.[39]

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.[35]
• A study by Witzig et al concluded that lenalidomide is
well tolerated and produces durable responses in
patients with relapsed or refractory aggressive NHL.
[42]

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).[43]
• 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.[44]
• 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.[45]

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.[46] 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.[46]

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 Hodgkin's 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 Hodgkin's
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 Hodgkin's 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 Hodgkin's 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
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
Vincristine 1.4 mg/m2 (max 2 mg) iv d8
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 Hodgkin's 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

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 Hodgkin's lymphoma: CALGB 59804. Ann Oncol 2007; 18:1071 (
• 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
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
• Czuczman, MS et al. Prolonged clinical and molecular remission in patients with
low-grade or follicular non-Hodgkin's 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-Hodgkin's 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-Hodgkin's 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-
Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol 2008; 26:204 (

• 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
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-hodgkin's
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
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 (
• Goy, A et al. Phase II study of proteasome inhibitor bortezomib in
relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 2005;
• O'Connor, OA et al. Phase II clinical experience with the novel proteasome
inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma
and mantle cell lymphoma. J Clin Oncol 2005; 23:676 (link to the article).

Linfoma do Manto recaída
• R-GemOx
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
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
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
•

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

• 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
• Regimen 3
Temsirolimus (Torisel) 175 mg iv qw x 3, followed by 75 mg iv qw
• Hess G et al. Phase III study of patients with relapsed, refractory mantle cell lymphoma
treated with temsirolimus compared with investigator's choice therapy. 2008 ASCO annual

Difuso de Gdes células em idosos
• CHOP
Cyclophophamide (Cytoxan) 750 mg/m2 iv d1
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

Agressivos de alto risco
• CEPP (non-anthracycline-containing regimen)
Cyclophosphamide (Cytoxan) 600 mg/m2 iv d1 and 8
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-Hodgkin's
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
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-Hodgkin's

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

Burkitt
• CODOX-M/IVAC (for high risk patients: do not meet low risk below)
• Cycle 1 and 3 ( CODOX-M )
Cyclophosphamide (Cytoxan) 200 mg/m2/d iv d2-5
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
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)
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;

• CALGB 9251
Burkitt
• Cycle 1
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
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
Doxorubicin (Adriamycin) 25 mg/m2/d iv bolus d 4 and 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;

•
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 (
• Abrey LE et al. Treatment of primary CNS lymphoma: the next step. J Clin Oncol 2000; 18:3144 (

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

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
Ifosfamide 800 mg/m2/d iv over 1 h 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
Cyclophosphamide (Cytoxan) 200 mg/m2/d iv over 1 h d2-5
• Cycle C (3 wks)
Cytarabine (Ara-C) 3 g/m2/d iv over 3 hrs d1-2
Vindesine 5 mg iv d1
• 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

•

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