nhl Presenting by FMalek MD Assistant Professor Ped Hematologist amp Oncologist Mofid Childrens Hospital Introduction The nonHodgkin lymphomas NHLs occurring in children and adolescents and young adults AYA are characterized by various agerelated differences in tumor biology ID: 930362
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Slide1
In the name of godbrief review on nhl
Presenting by
F.Malek
M.D
Assistant Professor Ped Hematologist & Oncologist
Mofid
Children’s Hospital
Slide2Slide3Introduction
The non-Hodgkin lymphomas (NHLs) occurring in children and adolescents and young adults (AYA) are characterized by various age-related differences in tumor biology and survival.
Children
generally present with high-grade lymphomas, such as
Burkitt
lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and anaplastic large cell lymphoma, whereas low-grade histologic subtypes, such as follicular lymphoma, occur more frequently with increasing age
.
Slide4Introduction
Treatment outcome for children with NHL is generally superior to that observed in adults.
Factors
contributing to this discrepancy include psychosocial factors, patient factors, and differences in tumor biology and therapy.
Patient factors. There are certain age-associated patient/host factors that can influence treatment
outcome
Components
of the IPI, such as lactate
dehydrogenase
(LDH), may have prognostic significance in
children
Slide5However, there are some inherited immunodeficiency conditions, such as ataxia-telangiectasia and X-linked lymphoproliferative syndrome, where specific treatment modifications need to be incorporated.
Age-related pharmacokinetic challenges must be considered in treatment planning
.
In this regard, drug clearance may vary with age and the maximum tolerated dose for many cancer agents is higher in younger
patients.
Slide6Diffuse large B-cell lymphoma
The
DLBCLs are mature B-cell neoplasms characterized by the expression of surface immunoglobulin (
sIg
) and B cell– associated
surface
markers (CD19, CD20, CD22, and CD79a
).
Over the past15 to 20 years, most children with DLBCL have
been treated with regimens designed for BL, resulting in what appear to be superior outcomes compared with CHOP-based
approaches
used in earlier treatment eras.
Slide7Diffuse large B-cell lymphomaEfforts to
improved
outcomes for those with DLBCL have featured the incorporation of rituximab into frontline therapy.
The
COG performed a pilot study in which
6 doses of rituximab
were incorporated into an LMB-96 backbone
.
The
feasibility results of this study led to an international B-NHL protocol for children with high-grade mature B-cell lymphomas
The BFM reported preliminary results on a trial that incorporated a rituximab window into a BFM back- bone designed for children with high-grade mature B-cell NHL
Slide8Burkitt lymphoma
Burkitt
lymphoma is a mature B-cell lymphoma expressing surface immunoglobulin (
sIg
) and a spectrum of surface B-cell markers (CD19, CD20, CD22): CD10, BCL6, CD38, CD77, and CD43
The t(8;14) is considered the classical translocation and involves the heavy-chain Ig gene on chromosome 14, and the t(8;22) and t(2;8) translocations are
considered
the variant translocations involving the light-chain
immunoglobulin
genes.
Slide9Burkitt lymphoma
One of the most widely used regimens was the LMB-89 regimen, which featured 3 arms
of
therapy based on
risk and
by
intensification of therapy including the addition of HDMTX
(
cytarabine
, etoposide, and
CNS
prophylaxis/treatment.
Slide10. The current criteria for these group designations are as follows:.
Group A comprises those with completely resected limited- stage disease,
Group
C includes those with CNS involvement
and or more than 25
% lymphoma blasts in the bone marrow,
and
Group B includes those not meeting the criteria for either Group A or C
.
Outcomes with this regimen were excellent
Slide11The BFM designed a study featuring
a rituximab window and BFM backbone designed for children with BL and DLBCL; the outcome results for this trial are pending
A current international COG/SFOP (French Society of Pediatric Oncology) trial for children with BL and DLBCL
demon-
strated
a survival advantage for those
higher-risk (stage III with LDH . 2X ULN, stage IV and
Burkitt
leukemia) patients
(all ,18 years of age) who were randomly selected to receive rituximab
Slide12Anaplastic large-cell lymphoma
The ALCLs are primarily of T-cell
immunophenotype
, although null-type and B-lineage cases have rarely been reported.
The frequency of genetic abnormalities varies with age in ALCL.
Most
pediatric cases of ALCL are ALK-positive.
The prognosis for children with
ALCL is superior
to that observed in adults, which may be driven by the differences in biology described here before.
Slide13Anaplastic large-cell lymphomaVaried approaches have been used in the management of pediatric ALCL and range from CHOP-based approaches to those designed for the treatment of BL, with fairly comparable treatment results.
Factors
associated with adverse risk include ALK antibody status, minimal disseminated disease (MDD), and minimal residual disease (MRD), and may be used to risk stratify-therapy.
Slide14Anaplastic large-cell lymphomaTargeted therapeutic approaches have been shown to be active in adults and children with relapsed ALCL
The antibody drug
conjugate
,
brentuximab
vedotin
, which targets CD30, has demonstrated safety and activity in phase 1 and 2 trials.
Crizotinib
, a small- molecule inhibitor of ALK, has also been shown to be active and well tolerated in both children and adults
.
In
this regard, both
brentuximab
vedotin
and
crizotinib
have both been incorporated into the current frontline COG trial for children with newly diagnosed ALCL
Slide15Lymphoblastic lymphoma
Lymphoblastic lymphomas (LLs) comprise both precursor-T and precursor-B phenotypes
.
Among the pediatric age group, the majority have a precursor-T
immunophenotype
Current strategies for the treatment of LL have largely been derived from successful approaches to the treatment of T-ALL
.
Two randomized trials in the United States demonstrated that HDMTX can be safely eliminated for most children with LL, as long as sufficient intrathecal chemotherapy is administered.
Slide16Lymphoblastic lymphomaSeveral trials have demonstrated that
prophylactic cranial irradiation can be safely eliminated without compromising outcome
.
The
measurement of minimal disseminated disease
(MDD) in the bone marrow at diagnosis
has been shown to have prognostic significance.
Current trials are including this risk factor in trial design with some form of intensification for those with increased MDD
Slide17follicular lymphomas
The follicular lymphomas (FLs) are mature low-grade B-cell neoplasms
Historically, most children with FL have received some type of conservative management approach, which generally
includes
surgical resection and chemotherapy, although some have been treated successfully with surgery alone
In this regard, most
children with completely resected “pediatric” FL (BCL-2– and lacking the t(14;18)) are currently treated with close observation without chemotherapy or radiotherapy. Additional data for this “watchful waiting” approach are needed.
Slide18Slide19Risk factors and treatment of childhood and adolescent Burkitt lymphoma/
leukaemia
Burkitt
lymphoma/
leukaemia
is the most common (40%) form of non-Hodgkin lymphoma that occurs in children and adolescents.
Currently, the
prognosis
for the
advanced
stage has a 5-year EFS of 85– 90% with <6 months of chemotherapy only.
Radiation
therapy has been eliminated for children and adolescents with
Burkitt
lymphoma/
leukaemia
except in emergencies, such as superior vena cava syndrome and acute
neurological
impairment or in patients with relapse/progression.
Slide20Current risk factors in the prognosis of childhood and adolescent
Burkitt
lymphoma/
leukaemia
include
:
lactate dehydrogenase level
bone
marrow
central
nervous system
involvement
,
poor
response to cyclophosphamide, vincristine and prednisone reduction therapy
poor
risk cytogenetics
Slide21Immunotherapy
Rituximab was safe and well-tolerated when combined with FAB B4 therapy in children with stage III/IV BL resulting in a 95% 3 year EFS (Cairo et al, 2010b).
Also
, the addition of rituximab to FAB Group C therapy for children and adolescents with CNS disease was associated with a 93% 3-year EFS and OS
These studies demonstrated the safety of this agent in children and adolescents with CD20-positive NHL.
Slide22Slide23Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD201 malignancies: An international retrospective study
Primary or recurrent B cell lymphoid malignancies involving the central nervous system (CNS) remain a therapeutic challenge, irrespective of the subtype.
Intensive conventional chemotherapy, intravenous rituximab and hematopoietic stem cell transplantation (HSCT) are limited in efficacy in the treatment of CNS disease, partly because of the drug/antibody penetration of the blood brain barrier
In contrast, regional delivery of drugs directly into the CSF is pharmacologically advantageous, with small doses producing high CSF concentrations with minimal systemic exposure
Slide24Rituximab is a chimeric murine/human monoclonal anti CD20 antibody, with a human IgG1-antibody and a variable region isolated from a murine anti-CD20 monoclonal antibody
The
mechanism of action of rituximab
comprises complement-mediated lyses of B cells and involves antibody-dependent cellular cytotoxicity
Results in patients with B cell lymphoid malignancies with
leptomeningeal
infiltration suggest that IT or intraventricular rituximab may have a therapeutic
possibly
could
be considered for prophylaxis for malignancies with risks of CNS recurrence.
Slide25We report 25 children with CNS involvement of CD201 B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses.
The
median number of doses received by each patient was 6, with a median dose of 25 mg.
The
most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients.
Slide26These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr.
Three
patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure.
Eighteen
patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission
.
This case series suggests that IT/ intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/ intraventricular rituximab for patients with CNS involvement of CD201B lymphoid malignancies are warranted.
Slide27Slide28Advances in therapies for non-Hodgkin lymphoma in children
Pediatric patients with newly diagnosed, non-Hodgkin Lymphoma (NHL) have an excellent overall survival.
However
, therapy regimens are associated with acute toxicity and late effects. Furthermore, patients with relapsed or refractory disease have relatively few options with proven clinical benefit
Slide29Brentuximab vedotin
ALCL tumor cells strongly express CD30 on their surface, making this receptor an attractive target for antibody therapy.
Initial
trials with an anti-CD30 monoclonal antibody showed tolerability, but only 17% response rate in patients with relapsed disease
.
The toxin is delivered to the surface of the CD30 –positive cell and internalized which allows for the interruption of the
microtubular
network
A phase II study that included pediatric and adult patients with relapsed or refractory ALCL showed that BV had an 86% overall response rate , with tumor reductions seen within 6 weeks of therapy initiation and mean duration of response of 12.6 month
Slide30Although fairly well tolerated, many patients experience low-grade neuropathy, with only rare events of high-grade neuropathy re- ported. Additionally, severe pulmonary toxicity has been reported when BV is combined with bleomycin
Slide31Crizotinib
Approximately 25 years ago, the chromosomal rearrangement involving the anaplastic lymphoma kinase (
ALK
) gene was
identfied
in the majority of ALCL in pediatric patients.
ALK is a transmembrane receptor tyrosine kinase. Approximately 85% of these rearrangements are t(2;5)(p23;q35) leading to the expression of the fusion protein NPM-ALK, which is thought to play a role in lymphomagenesis via aberrant phosphorylation of intracellular
substrates
and activation of the RAS-ERK
pathway
Slide32Based on these promising results with targeted therapies for relapsed, refractory ALCL, the Children’s Oncology Group (COG) has initiated a study to evaluate each of these in frontline
therapy
newly diagnosed patients will receive standard
therapyI
,
patients will be randomized to concurrently receive either BV or
crizotinib
.
The study opened for accrual in 2013 and has exceeded expected recruitment.
No
efficacy data are available, and whether these targeted agents will actually improve the survival in this disease is still unknown.
Slide33An earlier attempt to increase the EFS in newly diagnosed ALCL patients involved the incorporation of vinblastine.
As
a single agent, vinblastine had an 83% CR rate in relapsed ALCL but when added to the treatment regimens of newly diagnosed patients, it failed to improve the long-term EFS
Slide34Rituximab therapy in newly diagnosed pediatric NHL
Given the histologic and molecular differences between adult and pediatric tumors, and inconclusive evidence from small pediatric trials, this larger scale pediatric trial is necessary to determine the significance of incorporating rituximab into the therapy for newly diagnosed pediatric patients with B-NHL
Rituximab therapy is not without side effects. In safety studies, it was shown that B cell numbers and function typically return within 1 year of completion of rituximab therapy.
Slide3520% of patients who receive rituximab therapy will have prolonged
hypogammaglobulinemia
and impaired immune function, with some becoming dependent on intravenous immunoglobulin therapy due to persistent
infection
Currently, several second- and third-generation anti-CD20 monoclonal antibodies are in development and undergoing trials in adult patients with NHL but with no pediatric experience.
It
is uncertain if they will have improved efficacy or fewer long-term effects.
Slide36Targeting CD19
CD19 became an attractive protein to target in attempts to treat B-cell malignancies because of its ubiquitous expression on B cells at most stages of maturation. CD19 is located on the surface of all B cells except plasma cells
The majority of BL, DLBCL, and
B-lymphoblastic
lymphoma (B-LL) will express CD19 on their
surface
Many therapies directed against CD19 were first studied in the context of acute lymphoblastic leukemia (B-ALL) but indications are now being expanded to explore their role in B cell lymphomas
Slide37SGN-CD19ASGN-CD19A is an antibody-drug conjugate (ADC) similar to BV. It contains a humanized anti-CD19 monoclonal antibody that is joined to a tubulin inhibitor, monomethyl
auristatin
F (MMAF).
A current open phase 1 trial is investigating the role of SGN-CD19A in B-ALL, B-LL and
Burkitt
lymphoma in adults and pediatric patients as young as 1 year of age
A unique toxicity that has been observed in both trials is corneal complications described as superficial
microcystic
keratopathy. This toxicity has been managed with steroid eye drops.
Slide38Blinatumomab
Blinatumomab
is a bispecific T-cell engager (
BiTE
) used in B-cell malignancies.
BiTE
therapies are a novel approach to
immuno
therapy where monoclonal antibodies to 2 separate proteins are joined together and force an interaction between a cytotoxic T cell, via CD3 binding, and cells that express the second
protein
in
the case of
blinatumomab
this is any cell that expresses CD19
.
This therapy relies on the patient’s endogenous T cells to destroy the target B cells that express CD19 through cell lysis
.
Slide39Data are maturing regarding
blinatumomab
use in children. An international phase 1 pediatric trial was recently completed
evaluat
-
ing
blinatumomab
as a single agent in relapsed or refractory B-ALL.
An important limitation in
blinatumomab
use is toxicity. In both adults and pediatric patients, common toxicities of leukemia therapy are observed
Including
decrease in peripheral blood cell counts and infections; however, unique side effects observed are cytokine release syndrome (CRS) and neurotoxicity ranging from mild confusion to overt encephalopathy.
Steroid
pretreatment and slow dose-escalation has diminished the incidence of CRS and
neurotoxicity
during
blinatumomab
therapy
Slide40CD19 –specific CAR T cells
In addition to
blinatumomab
, chimeric antigen receptor T cells (CAR T cells) have also been developed to target CD19 – expressing malignancies. The primary focus of CD19 –specific CAR T cells has been relapsed/refractory B-ALL and CLL.
tumor-specific
T cells that bind the target antigen mandated by the antigen-binding domain of a monoclonal antibody fragment cloned into a
construct
hat also includes a T cell-receptor-derived CD3 signaling chain
A major difference between
BiTE
therapy and CAR T cells, is that
BiTE
therapy relies on endogenous T cells in the patient at the time of therapy, and their function may be limited if the patient is heavily pretreated.
Slide41Radiotherapy for Non-Hodgkin’s lymphoma: still standard practice and not an outdated treatment option
NHLs exhibit both high
chemosensitivity
and
radiosensitivity
.
The
excellent response rates achieved over the last 15 years with R-CHOP treatments in aggressive
lymphomas
, and with rituximab alone or in combination with chemotherapy in indolent
lympomas
have lead to the premise that RT might be obsolete, causing unnecessary toxicities without impacting favorably on outcome.
Omitting RT in the treatment of NHLs should not be con-
sidered
outside of well conducted prospective studies.
Slide42Two large observational studies in FL and DLBCL demonstrate a clear trend towards RT-free regimens in the most recent years. However, abandonment of RT in favor of (chemo-) immunotherapy alone might negatively affect patient OS. Omitting RT in the treatment of NHLs should not be con-
sidered
outside of well conducted prospective studies.