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Types of Lymphoma > Hodgkins Lymphoma

Last update: 09/04/2014

Adult Hodgkins:
Overview | In the News | Types | Staging | Symptoms | Difference with NHL | Treatment | Long Term Effects
| Risk Factors | Clinical Trials | Prognosis & Survival | Research News  |
Pediatric Hodgkins | Nodular Predominant

TOPIC SEARCHES to help you to keep current: 
PubMed: Diagnosis | Review | Therapies | Prognosis | Refractory
 
Clinical Trials: 
Newly diagnosed or untreated HL | Relapsed HL

Google Scholar: Hodgkin treatments

Overview of 
Lymphoma

What is lymphoma?
Lymphoma simplified

Lymphatic System
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Hodgkin's lymphoma is a cancer of lymphocytes - a type of blood cell that protects against infection as part of the immune system.  In Hodgkin's disease, the abnormal lymphocyte is the Reed-Sternberg cell (a B lymphocyte).

Lymphoma develops from an acquired (not inherited) injury to the DNA in the genes of a single cell - the cell of origin.  The defects in the cell are passed on with each cell division, giving the defective lymphocytes a growth and survival advantages over normal cells.  So when a lymphoma develops cell division is not balanced by cell death. The abnormal cells eventually accumulate to form tumors most commonly in the lymph glands.  

More than 75% of all newly diagnosed patients with adult Hodgkin lymphoma (HL) can be cured with combination chemotherapy and/or radiation therapy.  The cure rate is even higher for early stage HL with standard therapy.   The present focus of clinical research is to reduce the toxicity of treatment without compromising the cure rate. 

About Hodgkin Lymphoma

bullet Definition and etiology - GHSG -
German Hodgkin Study Group http://bit.ly/15DCvMo 

Symptoms of Hodgkin's Lymphoma  
 

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painless swelling in the neck, armpits or groin 

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night sweats

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unexplained fever

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unexplained weight loss

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unexplained fatigue

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cough or difficulty in breathing

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persistent itch all over the body (pruritus)

NOTE: These symptoms are common to many conditions other than Hodgkin's disease. A definite diagnosis can only be made by removing an enlarged lymph node or part of it and examining the cells. This test is known as a biopsy. It is a very small operation and is commonly done under local anesthesia.


Staging

Staging describes how wide spread the disease is. Hodgkin's disease is characterized by contiguous (side-by-side) spread. Metastasis - dissemination to all areas - is a late event. 

Staging and other clinical factors (A/B, Favorable / Unfavorable) determine which protocols are used as therapy- often combined modality therapy (chemotherapy and involved field radiation). 

NOTE: Treatment protocols are still being evaluated in clinical trials, such as to see if the toxicity of the treatment can be reduced without decreasing the effectiveness by leaving out radiation therapy based on response (as detected by CT/PET imaging) following the first or second cycle of chemotherapy. 

(Therapy for all stages of Hodgkins Lymphoma is very effective - has a high cure rate, but late toxicity remains a concern.)

hodgclinic.gif (6487 bytes) 

Anne Arbor staging for Hodgkin's Lymphoma - Virginia.edu
click to enlarge illustration

Stage I  (A/B)
or (Favorable/Unfavorable)
Single node region (or extranodal) site
Stage II (A/B)
or (Favorable/Unfavorable)
Two or more lymph nodes on same side of diaphragm
Stage III (A/B)
Lymph Nodes (sites) on both sides of the diaphragm
Stage IV (A/B)
Multiple or disseminated spread


A / B Staging Designation

"Each stage of Hodgkin's disease is designated (A or B) based on
Absence (A)
or presence of B-symptoms (B).

"The B stage always indicates the presence of certain symptoms: loss of more than 10 percent of body weight in the previous 6 months, fever without any known cause other than Hodgkin's disease, and night sweats that leave the body soaked."  Source: umgcc.org
 

Favorable / Unfavorable Staging Designation

"Patients are designated as having early unfavorable Hodgkin lymphoma (HL) if they have clinical stage I or stage II disease and one or more of the following risk factors:
 

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B symptoms
(fever ≥38°C, soaking night sweats, weight loss ≥10% within 6 months).

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Extranodal disease (beyond lymph node system).

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Bulky disease (≥10 cm or >33% of the chest diameter on chest x-ray).

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Three or more sites of nodal involvement.

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Sedimentation rate of 50 or more.

Source: Cancer.gov


Incidence of Hodgkin's Lymphoma

"The American Cancer Society estimates that 7,350 men and women (3,980 men and 3,370 women) will be diagnosed with Hodgkin's lymphoma.

"The age-adjusted incidence rate was 2.8 per 100,000 men and women per year. These rates are based on cases diagnosed in 2004-2008 from 17 SEER geographic areas."

* SEER Incidence:

"From 2004-2008, the median age at diagnosis for Hodgkin lymphoma was 38 years of age"

Approximately
   12.3% were diagnosed under age 20;
   31.5% between 20 and 34;
   15.8% between 35 and 44;
   12.5% between 45 and 54;
   9.7% between 55 and 64;
   8.5% between 65 and 74;
   7.2% between 75 and 84; and
   2.3% 85+ years of age.

Source: SEER - Stat Fact Sheet 2006

Type
New Cases 
Deaths per year 
Survival 5/10/15 year
Hodgkin's 7,000 1,400 83% &  74% & 66%



Types of Hodgkin's Lymphoma

Hodgkin's lymphoma: the pathologist's viewpoint http://www.ncbi.nlm.nih.gov

"Presently, HL is classified into two largely distinct entities, namely nodular lymphocyte predominance HL (NLPHL) and  classical HL (CHL), ... the latter being further subtyped as nodular sclerosis (NSCHL), lymphocyte rich (LRCHL), mixed cellularity (MCCHL), and lymphocyte depletion (LDCHL) subtypes . " 

    Source:
 HODGKIN LYMPHOMA: AN UPDATE ON ITS BIOLOGY and CLASSIFICATION

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Nodular Sclerosis
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Mixed Cellularity
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Nodular Lymphocyte Depleted (LD)  (uncommon - grey zone)

The pathologic and clinical heterogeneity (variation)
of lymphocyte-depleted Hodgkin's disease  http://bit.ly/40Jh7F 
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Nodular Lymphocyte Predominant (NLPHL) see below
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Infradiaphragmatic versus supradiaphragmatic Hodgkin lymphoma:
a retrospective review of 1114 patients. Leuk Lymphoma.
2005 Dec;46(12):1715-20. PMID: 16263573

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CD20 expression in Hodgkin's Lymphoma

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CD20 Expression in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin’s Disease: Associations With Presenting Features and Clinical Outcome jco.org 

 


What is the difference between Hodgkin's and non-Hodgkin's lymphoma?

The difference is in the type of lymphocytes involved - the cell of origin.

In Hodgkin's disease, the abnormal lymphocyte is the Reed-Sternberg cell (a B lymphocyte). This particular lymphocyte isn't found in other types of lymphomas.  All other types of lymphomas are called non-Hodgkin's (NHL).  

Important clinical differences are the very high cure rate of Hodgkin's; that it tends to affect younger people* ; and that the incidence rate of Hodgkin's is lower - compared to NHL.

Identifying the correct type of lymphoma is important because treatment for Hodgkin's and non-Hodgkin's can be very different. Pathologists can distinguish between Hodgkin's and non-Hodgkin's by examining the cell sample from a biopsy under a microscope.

In the United States, an estimated 8,490 new cases were diagnosed with HL while HL was accountable for 1,320 deaths in 2010 .

Progress:  In the 1960s, the 5-year survival rate for HL was less than 10%. With breakthroughs in combination chemotherapy regimens, the reported 5-year survival for patients with HL during the years 2000–2004 was 85.2%. 

Incidence Patterns and Outcomes for Hodgkin Lymphoma Patients in the United States http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010617/

 

Prognostic indicators (risk factors) in  Hodgkin's Lymphoma

According to Cancer.gov, 2012:

"Estimated new cases and deaths from Hodgkin lymphoma in the United States in 2012:  New cases: 9,060 | Deaths: 1,190.

More than 75% of all newly diagnosed patients with adult Hodgkin lymphoma (HL) can be cured with combination chemotherapy and/or radiation therapy.

National mortality has fallen more rapidly for adult HL than for any other malignancy over the last 5 decades.

Prognosis for a given patient depends on several factors. The most important factors are the presence or absence of

systemic symptoms,
the stage of disease,
presence of large masses, and
the quality and suitability of the treatment administered.

Other important factors are age (therapy for very young children requires special attention), sex, erythrocyte sedimentation rate, extent of abdominal involvement, hematocrit, and absolute number of nodal sites of involvement.

See Cancer.gov for more and for references.
 

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HODGKIN’S LYMPHOMA — FAVORABLE PROGNOSIS STAGE I AND II
Summary of Literature Review, 2012

Expert Panel on Radiation Oncology — Hodgkin’s Lymphoma: Prajnan Das, MD, MPH1; Andrea Ng, MD2; Louis S. Constine, MD3; Ranjana Advani, MD4; Christopher Flowers, MD, MS5; Jonathan W. Friedberg, MD6; David C. Hodgson, MD7; Cindy L. Schwartz, MD8; Richard B. Wilder, MD9; Lynn D. Wilson, MD, MPH10; Michael J. Yunes MD.11

Prognostic Factors

The definition of favorable prognosis for stage I and II Hodgkin’s lymphoma varies among major cooperative groups.

The German Hodgkin’s Study Group (GHSG) defines favorable disease as no large mediastinal adenopathy (one-third of the maximum thoracic diameter), an erythrocyte sedimentation rate (ESR) of less than 50 and no “B” symptoms or an ESR of <30 with “B” symptoms, no extranodal disease and one to two sites of nodal involvement.

In contrast, the European Organisation for Research and Treatment of Cancer (EORTC) criteria for favorable prognostic features include age 50 or younger, no large mediastinal adenopathy, an ESR of <50 and no “B” symptoms or an ESR of <30 with “B” symptoms, and lymphoma limited to one to three regions of involvement [1,2]. In interpreting trial results, it is important to pay attention to the risk group definition, as the results are applicable only to patients who fit the specific inclusion criteria.

full text:  http://www.acr.org pdf 

 
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Incidence Patterns and Outcomes for Hodgkin Lymphoma Patients in the United States http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010617/
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Better Prognosis for Patients with Lymphocyte-predominant Hodgkin’s Lymphoma patient.cancerconsultants.com 

"In order to better understand characteristics of LPHL [Lymphocyte-predominant HL], researchers from Germany conducted an analysis of 8,298 HL patients treated within a German medical trial to compare patient characteristics and treatment outcomes among cHL [classical HL) patients and others diagnosed with LPHD . "
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2009: Disparities in survival after Hodgkin lymphoma: a population-based study http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888633/

Young-adult patients of black race/ethnicity had worse survival in all stages of disease: in this group, risk of death from all causes was 52% to over two-fold greater and risk of death from HL 65% to over four-fold greater than that in white patients (Table 4).

Older-adult black patients had a suggestively higher risk of death from HL, with the risk 46% greater (stages III/IV) than that in white patients.

Hispanic patients with later-stage disease similarly had worse survival than white patients.
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Hodgkin's lymphoma in the elderly: The results of 10 years of follow-up.
Leuk Lymphoma. 2006 Aug;47(8):1518-22. PMID: 16966262
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Hodgkin disease survival in Europe and the U.S.: prognostic significance of morphologic groups. Cancer. 2006 Jul 15;107(2):352-60. PMID: 16770772 

Morphology distribution varied markedly across Europe and much less in the U.S., with nodular sclerosis less common in Europe (45.9%) than the U.S. (61.7%). The RER data showed that patients who had lymphocyte depletion, NOS, and mixed cellularity had a significantly worse prognoses compared with patients who had nodular sclerosis, whereas patients who had lymphocyte predominance had the best prognosis.
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MAL [a gene also expressed in mediastinal (thymic) large B-cell lymphoma] is expressed in a subset of Hodgkin lymphoma and identifies a population of patients with poor prognosis. Am J Clin Pathol. 2006 May;125(5):776-82. PMID: 16707382 

"Expression correlated with nodular sclerosis subtype, and within this subtype, with grade 2 histology."
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Prognostic impact of bone involvement in Hodgkin lymphoma.
Neoplasma. 2008;55(2):96-100. PMID: 18237246 Medscape

...  bone involvement is a relatively common finding in HL and is not an independent adverse prognostic factor. Key words: Hodgkin lymphoma - bone involvement - prognostic factors.

Resources

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Adv Hematol. 2011:

The Management of Classical Hodgkin's Lymphoma: Past, Present, and Future http://1.usa.gov/ZaTenx
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About  cancerbacup.org.uk | nci.nih.gov | Cancer.gov
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Hodgkin’s Lymphoma: Evolving Concepts 
with Implications for Practice  asheducationbook.org
Ralph M. Meyer, Richard F. Ambinder and Sigrid Stroobants
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An overview of HD: pleiad.umdnj.edu
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Online support forum: forums.webmagic.com 
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Foundations  KDH Hodgkin's Disease Foundation.org 

New and Noteworthy:

* Investigational PD-1 Immune Checkpoint Inhibitor Nivolumab Receives U.S. FDA Breakthrough Therapy Designation for Hodgkin Lymphoma  http://bit.ly/1rE0OL6 
* Br J Haematol 2013:  Surveillance after treatment
Hodgkin lymphoma patients in first remission: routine positron emission tomography/computerized tomography imaging is not superior to clinical follow-up for patients with no residual mass. http://1.usa.gov/1jIvDIf
* ASH Educ Prg 2013:
Novel therapy for Hodgkin lymphoma. http://1.usa.gov/1btkxyX

"the challenge will be to address the needs of high-risk groups, reduce long-term therapy-related morbidity, position current established treatments with novel therapies, and concurrently develop biomarkers to aid in patient selection. Brentuximab vedotin, which was approved in 2011, is already shifting the treatment paradigm of HL."
* ASH Educ Prg 2013:
Management of early-stage Hodgkin lymphoma: is there still a role for radiation? http://1.usa.gov/1hKr0Ox
* ASH Educ Prg 2013:
Lymphocyte-predominant Hodgkin lymphoma: what is the optimal treatment? http://1.usa.gov/1buDCEs
* ASH Paper: 3-Year Follow-Up Of Long-Term Remissions From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Relapsed Or Refractory Hodgkin Lymphoma http://bit.ly/1hyZXpf

* ASH Paper: 3-Year Follow-Up - Brentuximab Vedotin In Relapsed Or Refractory Hodgkin Lymphoma http://bit.ly/1hyZXpf

* ASH Paper: Single-Agent Brentuximab Vedotin For First Therapy Of Hodgkin Lymphoma In Patients Age 60 Yrs and Above: http://bit.ly/18mG3VW
* Hematol Oncol Clin North Am. 2013
Relapsed/Refractory Hodgkin Lymphoma: What Is the Best Salvage Therapy and Do We Need RIC-Allo SCT? http://1.usa.gov/1jULu3E
* Helio 2013:
Prognostic score predicted outcomes in older patients with Hodgkin’s lymphoma http://bit.ly/Igi30h
* ASH Paper:  
Myeloablative cd-45 Radioimmunotherapy then Auto transplant for High-Risk T/B-cell and Hodgkin lymphoma http://bit.ly/1jprN3H

Early but interesting phase I study with goal of addressing urgent unmet need - relapse in high risk lymphomas.
* ASH Paper:
Brentuximab Vedotin In Pediatric Relapsed Or Refractory Hodgkin Lymphoma (HL) Or Anaplastic Large-Cell http://bit.ly/1axwojx
* Medscape Medical News > Oncology, 2013
 BEACOPP Beats ADVD for Survival in Hodgkin's Lymphoma http://bit.ly/16hi347 
(free registration and login required)

The finding comes from a network meta-analysis reported by Nicole Skoetz, MD, and colleagues from the Cochrane Hematological Malignancies Group, working with German researchers who originally developed the BEACOPP regimen, including Peter Borchmann, MD, Volker Diehl, MD, and Andreas Engert, MD, from the German Hodgkin Study Group.

== snip:

"To our knowledge, we show for the first time that the already known positive effect of BEACOPP regimens on PFS translates into a significant overall survival advantage," the researchers comment.

In an editorial, Dr. Longo writes that the escalated BEACOPP regimen "has not gained traction outside of Germany for several reasons," which include substantially greater acute haematologic toxicity and a much higher rate of secondary acute leukemia and myelodysplasia than ABDV. In addition, BEACOPP induces infertility in nearly all men and women who receive it, he pointed out.

... Dan Longo, MD, professor of medicine at Harvard Medical School in Boston, who was not involved with the study, recently commented that using escalated BEACOPP as the primary treatment results in "overtreating the majority of patients."
COMMENT: It should be noted that imaging with PET after two cycles of therapy appears to reliably predict who will have disease progression - which could potentially help to avoid "over treating the majority of patients."

See FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma http://bloodjournal.hematologylibrary.org/content/107/1/52.long 


This finding of an improved survival for BEACOPP increases the significance of the CALGB 50604 study - which will take a few years to mature. This study is evaluating risk-adapted treatment following 2 cycles of ABVD. In this study, patients  with PET negative scans received a total of 4 cycles of ABVD, and patients with PET positive scans switched to 2 cycles of escalated BEACOPP followed by involved field radiotherapy.


Some patients may wish to avoid the risks associated with BEACOPP cited in the Medscape coverage of this report, however it seems to be important for patients to fully consider any proven survival advantage -- which accounts for all risk factors known and unknown.
... The issue of the impact of upfront BEACOPP on outcomes for patients needing subsequent salvage therapy also raised by Dr. Longo seems to be addressed by the improvement in overall survival - assuming that the meta analysis accounts for these outcomes as well.
Adding:  I think the controversy shows the importance of shared decision-making. Assuming that the more aggressive approach is better in terms of survival, the well-informed patient might still choose the less effective but lower toxic protocol ... because it has a lower risk of infertility ... or some other risk that is of concern to that patient.

It will be important to know the magnitude of the improvement in survival for BEACOPP and how do the treatment compare in terms of toxicities short and long term.

Looking ahead, the response-adapted approach with PET could help people to decide after 2 cycles - helping to identify patients who needs the more aggressive dose-escalated BEACOPP and who can remain with ABVD ... and who can also prudently avoid radiation.
~ KarlS.
 
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haematol June 1, 2012

PET/CT surveillance for Hodgkin lymphoma in first remission has low positive predictive value and high costs http://bit.ly/1dmFaEi

SNIP:  This study adds to the existing evidence in showing that PET/CT surveillance, both routine and clinically indicated, is associated with low PPV and that routine PET/CT surveillance has unacceptably high costs. However, the results do indicate that routine PET/CT surveillance could be more effective in diagnosing early relapse compared to previously used surveillance imaging. Indiscriminate use of routine PET/CT surveillance is not efficacious and, if used at all, it should be reserved for high-risk patients for a limited follow-up period. Finally, the use of expensive surveillance imaging can only be justified if an early, preclinical relapse diagnosis actually improves a patient’s outcome. This issue remains to be resolved in prospective trials.
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J Natl Compr Canc Netw 2013:
Targeted therapy in relapsed classical Hodgkin lymphoma.  Full Text

KarlS: This technical article highlights some of the agents either approved or in development for relapsed/refractory Hodgkin lymphoma, such as cd30 antibodies and much more.
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Leuk Lymph 2013:

Loss of utility of bone marrow biopsy as a staging evaluation for Hodgkin lymphoma in the PET era: a West of Scotland study. http://1.usa.gov/1bktnSo

KarlS:  This report appears to be good news for patients - reducing the need to have worrisome procedures to stage at diagnosis and monitor for response to treatment. 
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J Nucl Med 2013:

Interim 18F-FDG PET in Hodgkin Lymphoma: Would PET-Adapted Clinical Trials Lead to a Paradigm Shift? http://1.usa.gov/17zw6n0
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Experts on Novel Treatment Approaches in Hodgkin Lymphoma - with video

KarlS:  Direct link to excellent and important interviews video
 

See also Research News below

 

 

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Pediatric Hodgkins lymphoma

In the News

bullet How A Drug Shortage Hiked Relapse Risks For Lymphoma Patients npr.org

Medscape Topics:

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Background
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Pathophysiology (biology - technical)
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Etiology (risk factors)
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Epidemiology (incidence by country, race, etc)
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Prognosis
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Patient Education
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History (how it present)
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Physical Examination
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Differential Diagnoses (What else it might be)
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Staging
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Workup: Approach Considerations
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Workup: CBC, Chemistry Panel, and Other Tests
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Imaging: Radiography and Other Imaging Studies
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Imaging: Positron Emission Tomography
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Biopsy (examining the cells)
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Histologic Findings (classification by biological features)
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Treatment: Approach Considerations
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Treatment: Radiation Therapy
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Treatment: Chemotherapy Regimens
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Supportive Medications
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Long Term Monitoring
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Medication Summary
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Antineoplastic Agents (types of treatment agents)
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Antineoplastics, Antimetabolite (Gemcitabine (Gemzar)
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Monoclonal antibodies (Brentuximab vedotin (Adcetris)
PubMed Search: 
Pediatric Hodgkin lymphoma second malignancy radiotherapy ncbi.nlm.nih.gov
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Pediatric Hodgkin lymphoma: trade-offs between short- and long-term mortality risks http://1.usa.gov/IK2VZn
Risk Factors

 

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Risk Factors for Acquiring HL

What causes Hodgkin's disease is not known.  Risk factors associated with contracting this kind of blood cancer include:

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Inborn immune deficiency diseases

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Acquired immunodeficiency from AIDS or immunosuppressive drugs

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Living in Western countries, being of higher social class, more educated

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Genetic pre-disposition, clusters are noted in siblings with similar HLA genotypes

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Infection with Epstein-Barr Virus (EBV) history is noted in up to 40% of patients developing Hodgkin's. 
 
Elevated levels of the IgG and IgA immunoglobulins against the EBV capsid antigen are noted 3 months to 12 years prior to clinical Hodgkin's development.
 
Components of the EBV genome have been noted in the cellular DNA of the Reed-Stemberg cell (Ref. Weiss NEJM 320: 502 1989). 

However, the EBV is not noted in all patients and may be merely a marker of the poorer cellular immunity (but intact humoral immunity) seen in Hodgkin's patients. 1

"The most important risk factors are: 1) genetic; 2) Epstein-Barr virus (infectious mononucleosis); 3) congenital and acquired immunodeficiency; 4) occupational exposure (the wood industry).

"Epstein Barr virus (EBV) is associated with around one-third of Hodgkin's lymphoma (HL) cases and this association is believed to be causal."

"The increased risk of NHL and HL among individuals with a family history of hematopoietic malignancy was approximately twofold for both lymphoma types."

  1. [Risk factors for Hodgkin's lymphomas] An Esp Pediatr. 2001 Sep;55(3):239-43. Review. Spanish. PMID: 11676899
  2. Leuk Lymphoma. 2003  Risk factors for Hodgkin's lymphoma by EBV status and significance of detection of EBV genomes in serum of patients with EBV-associated Hodgkin's lymphoma. Review. PMID: 15202522 | Related articles
  3. Characteristics of Hodgkin's lymphoma after infectious mononucleosis.
    N Engl J Med. 2003 Oct 2;349(14):1324-32. PMID: 14523140


    snips:

    "We estimated that the median incubation period for Hodgkin's lymphoma attributable to infectious mononucleosis–related EBV infection was 4.1 years, with a peak in risk 2.4 years after infection.

    These estimates are in accordance with those of a large case–control study of Hodgkin's lymphoma in which the median interval between infectious mononucleosis and Hodgkin's lymphoma was five years.17

    ...

    We emphasize that in absolute terms, the risk of Hodgkin's lymphoma after infectious mononucleosis is only on the order of 1 case per 1000 persons.5  Consequently, other cofactors acting in concert with infectious mononucleosis–related EBV infection presumably must be present for the infection to give rise to Hodgkin's lymphoma.16
  4. Family history of hematopoietic malignancy and risk of lymphoma.
    J Natl Cancer Inst. 2005 Oct 5;97(19):1466-74.

    PMID: 16204696 | Related articles

Resources

  1. About risk factors  cancergroup.com   
  2. Epstein-Barr virus (EBV) associated lymphomas  Related abstracts

    The three main types of EBV-associated B-cell lymphoma are Burkitt lymphoma, Hodgkin lymphoma and post-transplant lymphomas
Treatments &
Long Term Side Effects
Questions for your doctor
  Patients Against Lymphoma
General, Treatment & Side Effects, and Tests

Treatment Overview
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Treatments & Long Term Side Effects

Generally, Hodgkins disease is treated with chemotherapy or radiotherapy. Sometimes, both are given.  Treatment depends on the stage of the disease, it's location in the body, symptoms, and the age and general health of the patient. 

Google Scholar: Hodgkin treatments

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TREATMENT - Standard of care
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Early Favorable Hodgkin's Lymphoma  Cancer.gov
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Early Unfavorable Hodgkin's Lymphoma  Cancer.gov
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Advanced Favorable Hodgkin's Lymphoma  Cancer.gov
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Advanced Unfavorable Hodgkin's Lymphoma  Cancer.gov
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Recurrent Adult Hodgkin’s Lymphoma  Cancer.gov
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Overview  NCI.gov  
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NCCN Treatment Guidelines http://www.nccn.org  pdf (req. free registration)
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Hodgkin's Lymphoma: Basing the Treatment on the Evidence (2001)  asheducationbook.org
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Evidence-Based Management of Hodgkin's Disease 
from Cancer Control: Journal of the Moffitt Cancer Center
For Parents:
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Guidance for Parents on Childhood cancers by NCI PDF
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A parent's guide to children's cancer  CancerBACUP

Long Term Side Effects

TOPIC SEARCH: PubMed

       Fertility and Hodgkin lymphoma ncbi.nlm.nih.gov

"Successfully treated children and adolescents with Hodgkin's disease have a substantial risk for the occurrence of subsequent neoplasms. The most frequent SMNs (skin, thyroid, and breast) are readily detected by physical examination and available screening procedures." 1
 
  1. Second Malignant Neoplasms After Treatment for Hodgkin's Disease  Medscape free login req.
  2. A systematic overview of radiation therapy effects in Hodgkin's lymphoma. Acta Oncol. 2003;42(5-6):589-604. Review. PMID: 14596517
  3. Late cardiotoxicity after treatment for Hodgkin's lymphoma. 
    Blood. 2006 Nov 21; PMID: 17119114 
  4. Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin lymphoma.
    Cancer. 2007 Oct 16; PMID: 17941006 

    Contemporary IFRT is predicted to substantially reduce risk of secondary breast and lung cancer compared with mantle RT, with considerable variation in risk among individuals. Individualized prospective risk estimates could facilitate patient-specific counseling and the development of more effective RT techniques.

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Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL)

Also see PubMed   and  Find Clinical trials

This is a rare subtype of Hodgkin lymphoma, sometimes referred to as gray zone lymphoma.

Nodular Lymphocyte Predominant Hodgkin's Disease (NLPHD) 

"B-cell lymphoproliferative disorder distinct from classical HD. Uncommon, accounting for approximately 5-7% of all cases of HD;  Most cases are clinically indolent; not associated with systemic B symptoms
 
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Biology, clinical course and management of nodular lymphocyte-predominant Hodgkin lymphoma   asheducationbook
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Nodular lymphocyte predominant Hodgkin lymphoma Review

Technical background on diagnostic

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Origin and pathogenesis of nodular lymphocyte–predominant Hodgkin lymphoma as revealed by global gene expression analysis
http://www.ncbi.nlm.nih.gov
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Hodgkin's disease, lymphocyte predominance type, nodular--further evidence for a B cell derivation. L & H variants of Reed-Sternberg cells express L26, a pan B cell marker http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1880773/

Clinical Reports

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NEW J Clin Onc 2014:
Mature Results of a Phase II Study of Rituximab Therapy for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. http://1.usa.gov/1aUPT8d
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ASH 2011 - Frontline Therapy of Nodular Lymphocyte Predominant Hodgkin Lymphoma with Rituximab: The Stanford University Experience
http://ash.confex.com/ash/2011/webprogram/Paper41254.html
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ASH 2011 - Phase II Study of Rituximab in Newly Diagnosed Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): A Report From the German Hodgkin Study Group (GHSG) http://ash.confex.com/ash/2011/webprogram/Paper42713.html
Clinical Trials
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Hodgkin Lymphoma (HL) Clinical Trials: ClinicalTrials.gov

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Newly diagnosed or untreated HL
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Relapsed HL
Prognostic Factors and Survival
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Prognostic Factors

Prognostic factors:  Not to be confused with predictive!

TOPIC SEARCH:  Google Scholar

About survival statistics:  Statistics cannot predict what will happen to you or a loved one.  Each patient and case is unique, and treatment outcomes can vary from one person to another.  Indeed, not even your doctor can tell you for sure what will happen.  The term '5 year survival' is used often.  It relates to the proportion of people in research studies who were still alive 5 years after diagnosis. Patients who live 6,  10,  or 30 years after diagnosis are also in this group. Also see Jay Gould's encouraging essay: The Median isn't the Message
 

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Incidence Patterns and Outcomes for Hodgkin Lymphoma Patients in the United States http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010617/

In the United States (US), an estimated 8,490 new cases were diagnosed with HL while HL was accountable for 1,320 deaths in 2010 [3]. In the 1960s, the 5-year survival rate for HL was less than 10% [4]. With breakthroughs in combination chemotherapy regimens, the reported 5-year survival for patients with HL during the years 2000–2004 was 85.2% [5].

Age distribution of HL by race. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010617/figure/fig2/

Predictors mortality among Hodgkin lymphoma patients
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010617/table/tab3/

age > 45, disease stage, extranodal disease, b-symptoms, LD HL
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Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study http://www.ncbi.nlm.nih.gov
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Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classical Hodgkin lymphoma.
Blood. 2006 Mar 21; PMID: 16551964 
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Prognosis of bulky Hodgkin's disease treated with chemotherapy alone or combined with radiotherapy.
Cancer Surv. 1985;4(2):439-58. PMID: 2430700 
Research News
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Research News

TOPIC SEARCHES to help you to keep current: 

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Allogeneic Transplantation in Hodgkin Lymphoma
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Cancer patients who receive chest radiation should screen for heart disease every 5-10 years  

He added: "Survivors of Hodgkin's lymphoma and breast cancer received high doses of radiation on their chest under the old treatment regimes.
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FDG-PET/CT for assessment of response to Brentuximab Vedotin treatment in relapsed and refractory Hodgkins
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ASCO 2013:  Clinical or survival benefit to routine surveillance
imaging for classical Hodgkin lymphoma patients in
first complete remission.


Routine surveillance imaging (RSI) versus
clinical surveillance (CS)
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HemOnc Today: Optimized fertility advice needed for
Hodgkin's lymphoma survivors
http://bit.ly/U2KmjV
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ASCO 2013:
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Nodular lymphocyte-predominant and classical Hodgkin lymphoma subtypes: Differences in biology, survival, and impact of radiotherapy.
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Single institution experience of brentuximab vedotin (SGN-35) impact on allogeneic transplant in patients with relapsed/refractory CD 30 positive lymphoma.
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Four-cycle ABVD unsuitable for older patients with Hodgkin’s lymphoma http://bit.ly/11un1Kd 
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Abexinostat (S78454 / PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients

https://ash.confex.com/ash/2012/webprogram/Paper48044.html
 
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ASH 2012 - Hodgkin Lymphoma abstracts PAL
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Abexinostat (S78454 / PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients

https://ash.confex.com/ash/2012/webprogram/Paper48044.html

Lymphoma subtypes were Hodgkin's lymphoma (HL) (n=11),
At the time of data cut off, all but 1 (HL) responses were ongoing between cycle 6 and cycle 22 (median 13.5 cycles).


Studies recruiting: lymphomation.org
 
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ASCO 2012 - Hodgkin Lymphoma (HL) abstracts PAL
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Medscape: CT Overused in Monitoring Pediatric Hodgkin's Lymphoma
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 J Clin Onc: Long-Term Results of CCG 5942:  Randomized Comparison of Chemotherapy With and Without Radiotherapy for Children With Hodgkin's Lymphoma 
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Oncology Times: ONLINE FIRST: Hodgkin Lymphoma: Novel Agents Can Act as Bridge to Allogeneic Transplant for Selected Patients
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Interim FDG-PET Scan in Hodgkin's Lymphoma: Hopes and Caveats  
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Onclive: Chemotherapy Alone With No Radiation Superior for Limited-Stage Hodgkin Lymphoma
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JCO: Early-Stage Hodgkin's Lymphoma: In Pursuit of Perfection
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JCO: Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial
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Rev. Bras. Hematol. Hemoter: Fertility in female survivors of Hodgkin's lymphoma
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FDA Briefing Document
Oncologic Drugs Advisory Committee Meeting
July 14, 2011 | BLA 125388 (Adcetris) brentuximab vedotin
Proposed Indication:
Treatment of Relapsed or Refractory Hodgkin Lymphoma
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NEJM, 2012: ABVD Alone versus Radiation-Based Therapy in Limited-Stage Hodgkin's Lymphoma

We randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin's lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy.

The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy

Among patients with Hodgkin's lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes.
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ASH 2011 - Frontline Therapy of Nodular Lymphocyte Predominant Hodgkin Lymphoma with Rituximab: The Stanford University Experience
http://ash.confex.com/ash/2011/webprogram/Paper41254.html
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ASH 2012 - Hodgkin Lymphoma abstracts PAL
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ASCO 2012 - Hodgkin Lymphoma (HL) abstracts PAL
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Medscape: CT Overused in Monitoring Pediatric Hodgkin's Lymphoma
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 J Clin Onc: Long-Term Results of CCG 5942:  Randomized Comparison of Chemotherapy With and Without Radiotherapy for Children With Hodgkin's Lymphoma 
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Oncology Times: ONLINE FIRST: Hodgkin Lymphoma: Novel Agents Can Act as Bridge to Allogeneic Transplant for Selected Patients
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Interim FDG-PET Scan in Hodgkin's Lymphoma: Hopes and Caveats  
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Onclive: Chemotherapy Alone With No Radiation Superior for Limited-Stage Hodgkin Lymphoma
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JCO: Early-Stage Hodgkin's Lymphoma: In Pursuit of Perfection
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JCO: Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial
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Rev. Bras. Hematol. Hemoter: Fertility in female survivors of Hodgkin's lymphoma
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FDA Briefing Document
Oncologic Drugs Advisory Committee Meeting
July 14, 2011 | BLA 125388 (Adcetris) brentuximab vedotin
Proposed Indication:
Treatment of Relapsed or Refractory Hodgkin Lymphoma
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NEJM, 2012: ABVD Alone versus Radiation-Based Therapy in Limited-Stage Hodgkin's Lymphoma

We randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin's lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy.

The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy

Among patients with Hodgkin's lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes.
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ASH 2011 - Frontline Therapy of Nodular Lymphocyte Predominant Hodgkin Lymphoma with Rituximab: The Stanford University Experience
http://ash.confex.com/ash/2011/webprogram/Paper41254.html
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ASH 2011 - Phase II Study of Rituximab in Newly Diagnosed Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): A Report From the German Hodgkin Study Group (GHSG) http://ash.confex.com/ash/2011/webprogram/Paper42713.html
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HL - Blood: Progress in Hodgkin lymphoma: a population-based study on patients diagnosed in Sweden 1973-2009
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JCO: More Is Not Necessarily Better When Treating Hodgkin's Lymphoma, Joseph M. Connors
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JCO: Long-Term Follow-Up Analysis of ABVD versus Stanford V versus MOPP/EBV/CAD in Newly Diagnosed Advanced-Stage Hodgkin's
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JCO: Eight Cycles of Escalated-Dose BEACOPP Compared With Four Cycles of Escalated-Dose BEACOPP Followed by Four Cycles of Baseline-Dose BEACOPP With or Without Radiotherapy
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Lymphocyte-Depleted Classical Hodgkin's Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group
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ASCO: Meta-Analysis of the Association between Smoking and Incidence of Hodgkin's Lymphoma
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Oncology Stat: PET Scans Key to Less Radiation for Hodgkin's Lymphoma?  Also:
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Cohort study evaluates risk of secondary malignancy following chemotherapy treatment for Hodgkin's lymphoma - Highlights the need for regular follow-up care.
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J Clin Oncol: Lymphocyte-Depleted Classical Hodgkin's Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group.
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Blood: Phase II study of PVAG in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma
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FDA Approves Brentuximab Vedotin for Hodgkin and Anaplastic Large-Cell Lymphoma
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ABVD versus BEACOPP for Hodgkin's Lymphoma When High-Dose Salvage Is Planned http://bit.ly/pwq2Ej
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ABVD VS BEACOPP summary from medscape-- requires registration: Chemo Toxicity May Tip Scales in Advanced Hodgkin's Lymphoma http://bit.ly/mUveA8
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Is routine G-CSF support needed for treatment with ABVD of Hodgkin lymphoma?  http://1.usa.gov/rv01AP
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BEACOPP regimen associated with 97% OS in young patients with high-risk Hodgkin’s lymphoma http://bit.ly/hl8w38
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Do Patients with Limited-stage Hodgkin Lymphoma Require Radiotherapy?

PRO:  Less Is More: Less ABVD with Mini-RT Is a Clear Winner in Hodgkin Lymphoma

By Joachim Yahalom, MD  http://ascopost.com

CON: Most Patients with Limited-stage Hodgkin Lymphoma Do Not Require Radiotherapy

By Joseph M. Connors, MD, FRCPC  http://www.ascopost.com

ASH 2010:

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Locally Extensive and Advanced Stage Hodgkin's Lymphoma: ABVD Vs. Stanford V +/- Radiation Therapy ash.confex.com
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Relapsed or Refractory Hodgkin Lymphoma -- Brentuximab Vedotin (SGN-35)  ash.confex.com
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Relapsed/Refractory Hodgkin Lymphoma Patients Following Autologous Hematopoietic Stem Cell Transplant Final Analysis: Phase II Study of Oral Panobinostat  ash.confex.com
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HIV-associated Hodgkin's lymphoma (HIV-HL): Results of a prospective multicenter trial http://bit.ly/bpJmKE

"Conclusions:
In pts with HIV-HL risk-adapted CT and concomitant HAART is feasible and effective. However, pts must closely be monitored for neutropenic infections. These data suggest that the prognosis of HIV-HD may approach results achieved in the HIV-negative population with HL."  (Which is very good indeed.)
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March 2009: Developments in the management of Hodgkin's lymphoma, The Lancet, March 2010

Lisa Lowry a, Peter Hoskin b, David Linch

Biggest take-aways:

1) PET & CT/PET scans used pre-treatment result in a change in staging in 4 out of 10 patients, with a change in the treatment plan for 2 of those patients but more care & scrutiny over all.

2) PET & CT/PET scans given mid-course in treatment can predict outcome and treatment plans can be modified earlier. How treatment modification on the basis of such scans affects outcome is still being studied, for example http://clinicaltrials.gov/ct2/show/NCT00433433 .

3) Nodular lymphocyte-predominant Hodgkin's lymphoma pts (a rare and somewhat indolent subtype) respond well to Rituxan and for many of these patients, surgery to remove affected nodes and low dose IFRT (involved-field radiotherapy) may be sufficient treatment resulting in 80% achieving long-term progression free survival (PFS). For those NL-P HL patients, chemo may only be necessary in relapse.

4) Current controversy over treatment recommendations for first timers: Treat with ABDV and accept 20% relapse and then treat the relapsers with heavier chemo vs. offer more aggressive treatment at the outset to all and reduce relapse rates?

5) Small field radiation (IFRT) targeted to specific nodes and immediate area (with complex planning and delivery techniques) controls disease as well as other forms of higher-dose and wider field radiation, but with fewer side effects.

6) Combined modalities (chemo + radiation) enable a reduction of the number of cycles of chemo, which can reduce long term side effects such as heart damage (cardio-toxicity).

7) Patients with clinical stage I or IIA disease without bulk or other adverse risk factors who achieve complete remission from chemo do not derive additional benefit from radiation according to findings. Progression Free Survival is not increased.

8) Patents who are still PET positive after salvage treatment chemo are predicted to do poorly with an autologous stem cell transplant & may wish to consider a reduced-intensity-conditioning allograft (allogeneic BMT or SCT). More research & further studies are needed.

9) As the cure rate for Hodgkin's lymphoma has increased, keeping late effects to a minimum (without decreasing cure rate) has become an important factor in initial management decisions.

10) In one notable trial, escalated BEACOPP showed significant improvement in freedom from treatment failure and overall survival versus a hybrid regimen of COPP-ABVD.

~ PAL editors (Lay summary - as always, discuss with your doctors.)
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Gemcitabine in the treatment of Hodgkin lymphoma Abstract 2008
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A systematic overview of radiation therapy effects in Hodgkin's lymphoma.
Acta Oncol. 2003;42(5-6):589-604. Review. PMID: 14596517 
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Articles on Refractory HD  PubMed
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Allogeneic stem cell transplantation in children and adolescents with recurrent and refractory Hodgkin's lymphoma 
Blood. 2009 Jun PMID: 19498021
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outcomes: min-SCT: Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following  autologous stem cell transplantation

This study compares outcome of reduced-intensity conditioned transplant (RIT) with outcome of conventional non-transplant therapy in patients with Hodgkin's lymphoma relapsing following autograft.

There were 72 patients in two groups who had relapsed, and received salvage therapy with chemotherapy radiotherapy. 

One group (n=38) then underwent alemtuzumab-containing RIT. The second group-historical controls (n=34), relapsing before the advent of RIT-had no further high-dose therapy.

This group was required to respond to salvage therapy and live for over 12 months post-relapse, demonstrating potential eligibility for RIT, had this been available.

Overall survival (OS) from diagnosis was superior following RIT
(48% at 10 years versus 15% ; P=0.0014),

as was survival from autograft
(65% at 5 years versus 15% ; P0.0001).

For the RIT group, OS at 5 years from allograft was 51% , and in chemo-responsive patients was 58% , with current progression-free survival of 42% .

Responses were seen in 8 of 15 patients receiving donor lymphocyte infusions (DLI) for relapse/progression, with durable remission in five patients at median follow-up from DLI of 45 months (28-55).

These data demonstrate the potential efficacy of RIT in heavily pre-treated patients whose outlook with conventional therapy is dismal, and provide evidence of a clinically relevant graft-versus-lymphoma effect.


full text: http://www.nature.com/bmt/journal/v41/n9/full/1705977a.html 
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Outcomes: Rituxan in relapsed lymphocyte-predominant Hodgkin Lymphoma: Long-term results of a phase-II trial of the German Hodgkin Lymphoma Study Group (GHSG). Blood. 2007 Oct 15; PMID: 17938252 

Thus, rituximab is highly effective in relapsed and refractory NLPHL. This study is registered at /www.klinisches-studienzentrum.de/trial/285 
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Outcome of Patients Experiencing Progression or Relapse After Primary Treatment With Two Cycles of Chemotherapy and Radiotherapy for Early-Stage Favorable Hodgkin's Lymphoma.
 J Clin Oncol. 2007 Apr 9;  PMID: 17420510 

Relapse after primary treatment with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine followed by RT is rare. In our analysis, results were influenced by a high treatment-related mortality rate.
Additional studies are needed to define the optimal salvage therapy.
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Long-term events in adult patients with clinical stage IA-IIA nonbulky Hodgkin's lymphoma treated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine and adjuvant radiotherapy: a single-institution 15-year follow-up. PMID: 17085663  

"Long-term events were mostly related to radiotherapy; the role of short ABVD chemotherapy was very limited, as documented by fertility preservation and lack of secondary myelodysplasia/leukemia."
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Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma. Cancer. 2005 Aug 10; PMID: 16094666 
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Vanishing Bile Duct Syndrome in Hodgkin's Disease:
case report ~ Department of Internal Medicine and Hematology and Blood Transfusion Center, Universidade Estadual de Campinas, Campinas, Brazil  full text | Related PubMed articles
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Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood. 2004 Dec 1;104(12):3483-9. Epub 2004 Dec 1. PMID: 15315964 | Related articles
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Baseline Tumor Burden Predicts Clinical Outcome in Hodgkin Lymphoma  leukemia-lymphoma.org
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Long Term Outcome in Adolescents with Hodgkin's Lymphoma: Poor Results using Regimens Designed for Adults. Leuk Lymphoma. 2004;45(8):1579-1585. PMID: 15370209
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The clinical value of tumor burden at diagnosis in Hodgkin lymphoma.
Cancer. 2004 Sep 15 PMID: 15372482 
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Strong impact of highly active antiretroviral therapy on survival in patients with human immunodeficiency virus-associated Hodgkin's disease. Br J Haematol. 2004 May;125(4):455-62. PMID: 15142115 | Related articles
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Investigational EBV-based T-cell therapy   Related PubMed abstracts 
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Efficacy of vinblastine, bleomycin, methotrexate (VBM) combination chemotherapy with involved field radiotherapy in early stage (I-IIA) Hodgkin disease patients. Leuk Lymphoma. 2003 Nov;44(11):1919-23. Review. PMID: 14738143 | Related articles
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Involved-field radiotherapy for advanced Hodgkin's lymphoma.
N Engl J Med. 2003 Jun 12;348(24):2396-406. PMID: 12802025  PubMed
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Epstein-Barr virus and other candidate viruses in the pathogenesis of Hodgkin's disease. Semin Hematol. 1999 Jul;36(3):260-9. Review.
PMID: 10462326  PubMed | Related Abstracts
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Severe Pruritus should be a B-symptom in Hodgkin's disease.
Cancer. 1983 May 15;51(10):1934-6. PMID: 6831358  PubMed
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Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol. 2003 Feb 15;21(4):607-14.
PMID: 12586796  PubMed
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Treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood 2003; 101: 420-424..  PubMed
 
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professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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