In the name of god brief review on - PowerPoint Presentation

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In the name of godbrief review on nhl

Presenting by

F.Malek

M.D

Assistant Professor Ped Hematologist & Oncologist

Mofid

Children’s Hospital

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Slide3

Introduction

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

.

Slide4

Introduction

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

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However, 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.

Slide6

Diffuse 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.

Slide7

Diffuse 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

Slide8

Burkitt 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.

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Burkitt 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.

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. 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

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The 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

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Anaplastic 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.

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Anaplastic 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.

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Anaplastic 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

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Lymphoblastic 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.

Slide16

Lymphoblastic 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

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follicular 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.

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Risk 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.

Slide20

Current 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

Slide21

Immunotherapy

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.

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Safety 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

Slide24

Rituximab 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.

Slide25

We 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.

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These 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.

Slide27

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Advances 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

Slide29

Brentuximab 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

Slide30

Although 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

Slide31

Crizotinib

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

Slide32

Based 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.

Slide33

An 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

Slide34

Rituximab 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.

Slide35

20% 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.

Slide36

Targeting 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

Slide37

SGN-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.

Slide38

Blinatumomab

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

.

Slide39

Data 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

Slide40

CD19 –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.

Slide41

Radiotherapy 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.

Slide42

Two 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.