Hodgkin’s disease-worldwide incidence of 2-3 per 100,000 people.
About 9000 people a year in the US get Hodgkin’s disease.
One-fifth the incidence of non-Hodgkin’s lymphoma.
WHO classification divides HL into two main types: classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma.
Accounts for .5% of all malignancies.
More than 65,000 new cases worldwide annually.
Accounts for 11.7% of all lymphomas in US.
In 2022, an estimated 8540 people will be diagnosed with HL in the US, and 920 people will die.
HD is among the most curable of malignancies with modern treatments.
Cure rates for HD have increased so markedly that the overriding treatment considerations often relate to long-term toxicity.
Incidence has been steadily increasing over the last four decades.
Slight male predominance.
The incidence in children age 5-14 years is estimated to be about 380 each year.
First-degree relatives have a 3-9 fold increase in risk compared to the general population.
Monozygotic twins siblings have a greatly increased risk for developing the disease up to 100 fold compared to normal cohorts.
The incidence is highest among Causasians, African-Americans, and Histpanics, and lower in Asians and American Indians.
Characterized by neoplastic Reed-Sternberg cells occurring with inflammatory changes.
Estimated five-year overall survival rate is more than 86%.
Affected lymph nodes consist of lymphocytes, histiocytes, plasma cells, fibroblasts and other cells.
Mononucleated Hodgkin’s cells and polynucleated Reed-Sternberg cells comprise only 0.1-1.0% of the entire population of lymph node cells in the various types of Hodgkin’s disease.
Reed-Sternberg cells induce the accumulation of non-malignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes which then constitute the majority of tumor cellular infiltrate.
Reed-Sternberg cells are monoclonal germinal center derived B cells.
Reed-Sternberg cells lack immunoglobulin due to a defect in transcription regulation.
The cellular infiltrate in HD plays a role in allowing the Reed-Sternberg cells to survive by providing an environment that supresses cytotoxic immune responses, as well as providing cellular interactions and cytokines that support growth and survival.
HD infiltrate in classical disease is composed of T helper 2 and regulatory T cells and lacks T helper 1 cells, CD8 cytotoxic T cells and natural killer cells.
Effacement of lymph node can range from partial involvement with a few atypical cells to total involvement with a complete alteration of lymph node architecture.
Reed-Stemberg cells escape apoptosis by several mechanisms include latent EBV infection in nuclear factor pathways as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen1 proteins, EBV latent infection membrane protein1, and LMP2.
Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present classical Hodgkin’s lymphoma.
Mononuclear variant, Hodgkin’s cells, or multinuclear variant Reed-Sternberg cells are indispensable for diagnosis, but their mere presence is not enough for diagnosis, as a growth pattern of Hodgkin’s disease is needed.
Small percentage of neoplastic cells secrete multiple cytokines, including IL-5, IL-4, tumor necrosis factor, and granulocyte macrophage colony stimulating factor which created an inflammatory reaction.
Immunologic abnormalities reported include: ITP, auto-immune hemolytic anemia immune neutropenia, and antibodies to insulin.
It is suggested that an abnormal immune response to infection may play a role in pathogenesis.
Incidence of AIHA 1.5-2.7%.
Substantial proportion of patients with classical and lymphocyte predominant disease are B cell derived monoclonal disorders.
Classified largely in 2 entities: nodular lymphocyte predominant and classical Hodgkin’s disease, with the latter subtype as nodular sclerosing, lymphocyte rich, mixed cellularity, and lymphocyte depleted subtypes.
Classical HD accounts or 95% of cases and noduular-lymphocyte predominant occurs in approximately 5% of cases.
Classical Hodgkin’s lymphoma visually presents with asymptomatic mediastinal or cervical lymphadenopathy.
At least 50% of patients with classical Hodgkin’s disease with have stage I or II disease.
Most cases of childhood Hodgkin’s disease are classical type.
Approximately 40% of patients present with stage III or IV at presentation.
Rarely classical HD associated with T cell derived lymphocytes.
Two risk factors include infectious mononucleosis and immunocompromised state.
Elevated levels of VEGF associated with Hodgkin’s lymphoma and the elevation persists after treatment and long into suined remission.
Median age at presentation is the mid-30’s.
Bimodal distribution with a large peak occurring between ages 15-35 and a lesser peak in patients older than 50 years.
Male:female ratio 1.4:1.
Not increased in patients treated with chronic immunosuppressive agents.
In economically advanced societies associated with younger age, higher educational tus of mother, decreased exposure to playmates, fewer siblings, suggesting a lowered exposure to infectious agents at an early age.
Incidence of Hodgkin’s disease by age varies with different histologic types.
Increased incidence in Jews and among first degree relatives of persons with the disease.
Siblings have a 2-5-fold increased risk and siblings of the same sex there is as high as 9-fold increase.
Increased risk among parent-child relationships but not among spouses.
Monozygotic twin of a patient with disease has an increased risk compared to dizygotic twin sibling of a patient with HD.
Incidence of Hodgkin’s lymphoma is 1.8 times higher among smokers, and increases with the duration of smoking.
Epstein-Barr virus implicated in etiology by epidemic, serologic and by detection of viral genome in tissue specimens of patients with HD.
Epstein-Barr virus infection is present in up to 40% of Hodgkin’s lymphoma cases, suggesting a role in pathogenesis.
Epstein-Barr virus implicated in etiology of the disease in multiple epidemiological and serological studies and the Epstein-Barr virus genome has been detected in tumor specimens in trials.
HIV infection patients are at increased risk of HD compared with the general population.
The incidence of HD is 5-14 times higher in HIV infected patients then in noninfected patients.
HIV patients with HD have a higher stage disease, in unusual sites and have a poor prognosis.
Patients with HIV typically have CD4!lymphocyte counts greater than 200 cells per microliter, with the incidence of Hodgkin’s lymphomaa declining with lower CD4 lymphocyte counts.
HIV-related HD tends to have an aggressive course with high rates of EBV virus positivity.
Infections with chickenpox, measles, mumps, rubella, and pertussis in childhood may be inversely associated with the risk of Hodgkin’s disease and may be protective.
Significantly increased risk to develop in HIV positive patients and is associated with advanced disease with unusual sites of presentation and poorer outcome.
WHO classification divides Hodgkin’s disease into two main types: classical and lymphocyte predominant.
Classical Hodgkin’s disease is divided into four subtypes: nodular sclerosis, mixed cellularity, lymphocyte depleted and lymphocyte rich.
Bulk of the tumor in classical Hodgkin’s disease is not malignant B cells, but an immune infiltrate dominated by CD4 positive T cells and macrophages.
CD30 is a cell proteins expressed on Reed-Sternberg cells.
CD30 expressed in high levels on Reed-Sternberg cells, and is found only rarely on cells and healthy tissue.
Approximately 20-30% of classical Hodgkin’s lymphoma patients have Epstein-Barr virus.
Lymphocyte predominant Hodgkin’s disease lacks Reed Sternberg cells, but has lymphocyte predominant cells, sometimes referred to as popcorn cells.
High-risk disease associated with very high sedimentation rate, systemic symptoms, multiple sites of disease, male gender, and low lymphocyte counts.
Lymphocyte predominant Hodgkin’s disease can have nodular or diffuse forms.
Lymphocyte predominant nodular subtype has predominantly B lymphocytes, whereas the diffuse subtype has mainly T cells in the background.
Nodular sclerosing Hodgkin’s disease-most common type accounting for 50-60% of cases in developed countries.
Nodular sclerosis classical Hodgkin’s lymphoma affects young adults more often than the, is seen more frequently in developed countries and accounts for an early peak in Western populations.
Nodular sclerosing Hodgkin’s disease more common in women then men and less frequently associated and Epstein Barr virus.
The histological hallmark of nodular sclerosing Hodgkin’s disease is the presence of bands of birefringent collagen, would increased production of interleukin-13.
Nodular sclerosing Hodgkin’s disease has a relatively preserved nodular structure in contrast with mixed cell HD and lymphocyte depleted HD.
After the epidemiologic risk patterns of the nodular sclerosing Hodgkin’s disease differs from mixed cell Hodgkin’s disease, suggesting the lesions might not share a common etiology.
The incidence of nodular sclerosing Hodgkin’s disease continues to rise and its incidence decreases as the CD4 count decreases in patients with HIV, suggesting an intact immune system is needed for the development of this lesion.
The incidence of mediastinal involvement is more common in the sclerosing than other types of classical Hodgkin’s disease.
Both nodular sclerosing Hodgkin’s disease and primary mediastinal large B-cell lymphoma lack immunoglobulin expression and functional expression of HLA class one antigens and share cytogenetic abnormalities.
In nodular sclerosing HD there are abundant lymphocytes, and variable numbers of neutrophils and eosinophils noted histologically.Nodular sclerosing HD with a high proportion of Reed-Sternberg cells and appearance of a lymphocyte depleted-like process, with necrosis and prominent fibrohistiocystic stroma are features of grade 2 nodular sclerosing HD, associated with a higher relapse rate and poorer response to therapy.
Mixed cell Hodgkin’s disease accounts for approximately 30% of cases.
Mixed cell HD and lymphocyte depleted HD associated with lower socioeconomic tus, increased prevalence in men, frequent Epstein-Barr viral infections, and a different pattern of spread with sparing of the mediastinum and thymus gland compared to nodular sclerosing HD.
Mixed cell HD and lymphocyte depleted HD share clinical, epidemiologic, and biologic features.
Mixed cell HD and lymphocyte depleted HD differ by the extent of deletion of lymphocytes and degree of immunosuppression in the host.
Mixed cell HD and lymphocyte depleted HD both occur in the setting of HIV infection.
Mixed cell HD and lymphocyte depleted HD are associated with poor prognosis than are other types of HD.
Mixed cell HD associated with a bimodal age-incidents and accounts for most cases of classical HD in children.
Mixed cell HD is relatively uncommon in young adults and increases incidence after the age of 50 years.
Mixed cell HD incidents, patterns that of Epstein-Barr viral infections as seen in the very young and elderly.
Lymphocyte rich classic Hodgkin’s disease represent 4-5% of cases.
Lymphocyte depleted Hodgkin’s disease occurs in less than 1% of cases.
Classical HD comprises 95% of cases.
Classical HD is a lymphocyte rich process, previously confused with nodular lymphocyte predominant HD.
Classical HD usually presents with e I or II disease.
Classical HD has a rich background of normal lymphocytes, the Reed Sternberg cells are smaller than those in other subtypes, and immunohistologic studies are needed to distinguish it from lymphocyte predominant HD.
Classical HD has an older age at presentation and usually lacks mediastinal involvement.
Classical HD has a high event free and overall survival of 97% at 30 months.
Lymphocyte predominant disease has atypical Reed-Sternberg cells called histiocytic and lymphocytic cell, popcorn cell, as its nucleus resembles the explosion of a popcorn kernel.
Classical Reed-Sternberg cells in positively for CD15 and but lack CD20, a B cell marker.
Histiocytic and lymphocytic cells in positively for leukocyte common antigen CD45 and express B cell antigens CD19, CD20, CD22 and lack CD15 and rarely express .
Lymphocytic predominant disease usually presents as an asymptomatic adenopathy, progresses slowly and frequently relapses after treatment.
Lymphocyte predominant disease is rarely fatal.
Lymphocyte predominant disease has a 5-year survival of patients with early e disease and without treatment of 93% and 80% survival at 10 years.
Lymphocyte predominant disease responds to chemotherapy, but less toxic treatments such as Rituximab may be used alone.
Hodgkin’s disease staging helps classify patients into three groups: early-e favorable-e I-II with no unfavorable factors, early-e unfavorable-e 1-II with any unfavorable factors such as large mediastinal disease or B symptoms or numerous sites of disease or elevated ESR, and advanced e disease-es III-IV.
Posterior-anterior and lateral chest x-rays are encouraged in patients with large mediastinal masses.
75% present as early e I or II disease.
Less than 25% of patients with have primary refractory disease and up to 1/3 of those patients who achieve a complete remission after first line therapy will relapse.
Unfavorable prognostic factors include mediastinal bulk disease in early-e disease.
Mediastinal bulk on chest x-ray measures the mediastinal mass ratio-the MMR ratio refers to the maximum width of the mass to the maximum intrathoracic diameter, and an MMR greater than 0.33 is defined as bulky disease.
Mediastinal bulk of disease also defined as that exceeding one third of the internal transverse diameter of the thorax at T5-T6 interspace on a PA x-ray.
Bulky lymphadenopathy also refers to any node or nodal mass 10 cm or greater.
Unfavorable prognostic factors in e I-II disease includes the presence of B symptoms, involvement of more than three nodal sites, and sedimentation rate greater than 50.
The following seven adverse prognostic factors reduce survival rates by 7-8% per year: age 45 years or older, male gender, e for disease, albumin level less than 4 g/dL, hemoglobin less than 10.5 g/dL, leukocytosis with a white count of 15,000/millimeter3 and lymphocyte leukemia with lymphocyte count of less than 8% (Hasenclever D et al).
Use of extended field radiotherapy and combination chemotherapy has led to 80% to 90% cure of e I and II patients.
More than 80% of all patients younger than age 60 years with a new diagnosis likely to be cured.
Approximately 15-30% of patients experience refractory or recurrent disease.
10-20% of patients with favorable features an early stage disease in up to 30% with advanced stage disease experience relapse.
Lymphocyte-predominant disease makes up 3-5% of cases, nodular sclerosing type makes up 60-70% of cases and mixed cell subtype makes up 20-30% of cases.
Newly diagnosed patients present with enlarged cervical or supraclavicular lymph nodes in 60-70% of cases, radiographic evidence of thoracic involvement in 50-60% of cases and 40% present with B symptoms.
More than 80% of patients present with enlarged lymph nodes above the diaphragm and commonly involves the anterior mediastinum.
Involvement of cervical, supraclavicular and axillary areas are commonly involve, while the inguinal areas is less frequently involved.
Progression free survivals of 85-95% at 5 years in patients with early e disease, but recurrent HD is the leading cause of death in these patients for the first 15 years after diagnosis and treatment.
After 15 years death due to intercurrent illness/diseases exceeds the deaths due to Hodgkin’s disease.
TREATMENT:
Initial treatment is based on hitologic characteristics, stage presentation, and presence or absence of prognostic factors associated with poor outcome.
With early disease, patients commonly receive combined modality with abbreviated chemotherapy courses, followed by involved field radiation.
Consideration of fertility preservation with semen cryopreservation for male patients and ovarian tissue cryopreservation and female patients before the start of chemotherapy with alkylating agents or pelvic RT.
With advanced stage disease patients commonly receive a prolonged course of combination chemotherapy, radiation therapy used only in select cases.
In patients with a relapsed/refractory disease, salvage chemotherapy followed by high dose autologous stem cell transplant is the standard of care.
The goal of second line therapy is to attain a PET-negative complete remission before high dose therapy/autologous cell transplant.
Deauville five point scale scores are based on the uptake of F – fluorodeoxyglucose with the score is 1-3 being considered negative and scores 4-5 considered positive.
Positive Deauville 5 point scores are recognized as a significant risk factor for a relapse and decreased progressive free survival.
Prognostic factors to predict outcomes for patients undergoing high dose chemo therapy/autologous stem cell transplant are end of treatment to relapse interval of less than 12 months and extra nodal disease at relapse.
Brentuximab is available also for refractory or relapsed patients.
A CD30 directed Ab-directed conjugate, as CD30 is expressed on malignant Hodgkin’s Reed Sternberg cells.
Combination chemotherapy yields cure rate of 60-80% in advanced-e and bulky disease.
Control of early-e and overall survival is approximately 90% at 10 years.
Treatment for early e unfavorable disease is combined modality treatment with 4-6 courses of chemotherapy, typically ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by 30 Gy of involved-field radiotherapy.
In a random study of 405 patients with previously untreated e IA or IIA non-bulky I Hodgkin’s disease treated with a ABVD alone or subtotal nodal irradiation with or without ABVD for 4 to 6 months: at 12 years the overall survival was 94% among those with a DVD alone, compared to 87% among those receiving subtotal nodal irradiation, with the rates of freedom from disease progression 87 and 92%, respectively, and the rate of event free survival 85% and 80% respectively- the higher rate of overall survival from ABVD is due to a lower rate of death from other causes (Meyer RM et al).
For many, four cycles of ABVD followed by 30 Gy of involved field radiation is the n treatment for early-e Hodgkin’s disease (Engert A, Ferme, C).
Treatment with two cycles of ABVD followed by 20 Gy of involved field radiation therapy is as effective and less toxic than four cycles of ABVD followed by 30 Gy of involved field radiation in a random up up up up clinical study involving 1370 patients (Engert A).
BEACOPP (Bleomycin, Etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, and prednisone) vs ABVD randomly assigned to previously untreated and unfavorable Hodgkin’s disease patients with e IIB, III, or IV, or an international prognostic score of three or greater on a scale of 0 to 7, followed by local radiotherapy when indicated: median follow-up 61 months and the seven year rate of freedom from first progression was 85% for
BEACOPP and 73% for ABVD, and the seven year rate of event free survival 78% and 71%, respectively (Viviani, S et al).
In the above study after completion of the planned treatment, including salvage therapy, this seven year rate of freedom from a second progression was 88% for the BEACOPP group and 82% in the ABVD group, and the seven year rate of overall survival was 89% and 84%, respectively with more frequent adverse events in the BEACOPP group.
The conclusion from the above study is that the initial choice of chemotherapy of BEACOPP or ABVD significantly influence long-term survival.
BEACOPP treatment had a freedom from treatment failure rate of 85.5% at five years, which is significantly higher than the rate of 73% in the ABVD group, but is associated with increased hemorrhagic and non-hematologic toxic effects, in fertility and secondary neoplasias.
BEACOPP associated with a death rate due to acute toxic effects of 3%, and the rate of secondary cancers of 4.9%, azoospermia rate of 90% in males and greater than 50% of infertility rate in women: ABVD is rarely associated with severe myelosuppression, death from acute toxic effects, secondary leukemias and infertility.
eBEACOP-escalated does reduces the five-year aggression free survival rate of greater than 90%.
In a randomized trial of chemotherapy in advanced HD, no significant difference in response rate, FFS or overall survival, or 5 year toxicity for ABVD (plus RT for bulky mediastinal disease), compared with nford C (with RT for nodal sites >5cm)(Gordon L et al).In the above study complete remission and clinical complete remission rates of 73% for ABVD and 69% for nford V.
About 15% of early ed patients with unfavorable disease relapse within 5 years and 5% have primarily progressive disease.
About 1300 deaths from refractory disease in the US.
Of patients with advanced disease, almost 30% will have disease progression, with one third of these patients experiencing chemotherapy induction failure and two thirds of these patients will relapse after achieving complete remission.
Of patients with advanced disease that relapse 40-45% will relapse within 12 months of completing initial therapy, and outcome with conventional salvage therapy is poor.
The goal of second-line therapy is to attain a PET-negative complete remission before autologous or allogeneic hemmatopoetic transplantation.
ASCT in patients failing chemotherapy for advanced HD is better than n salvage chemotherapy with an improved long-term disease free survival (Schmitz N et al).
Event-free, progression-free and overall survival is significantly better for patients responding to second-line chemotherapy compared to those undergoing a poor response and then undergoing autologous or allogeneic bone marrow transplant.
Two randomized studies showed a significant improvement in freedom from treatment failure for patients receiving ASCT in comparison with those who received conventional chemotherapy for relapsed disease.
Failure of or relapse from autologous SCT is associated with a dismal prognosis.
Autologous stem cell transplant is potentially curative treatment for some patients with progressive or recurrent HD after failing initial combination: effective in approximately 50% of such patients.
Allogeneic SCT is the standard treatment for patients relapsing post ASCT, provided they respond to salvage therapy and have a donor.
Reduced intensity conditioning allogeneic SCT is associated with decreased transplant related mortality, better survival, and the development of GVHD is associated with a lower relapse rate.
Relapse of HD after autologous stem cell transplant associated with 55% survival at 2 years and 32% at 5 years (Martinez C et al).
Most common secondary malignancies are solid tumors and acute leukemia.
Secondary malignancies most commonly involve the lung, breast, and digestive tract, organs that lie adjacent to radiation fields.
Radiation toxicity include secondar malignancies , cardiovascular disease, hypothyroidism, cerebrovascular accidents, and muscle atrophy.
Cumulative incidence of grade 3-5 chronic toxicity to chemotherapy and radiation theray among 25 year survivors following treatment (Oeffinger KC et al).
Oberved secondary cancers in 30,000 patients treated for HD associated with a 2.3 risk compared to expected risk.
Secondary malignancies are now the leading cause of death in the long term Hodgkin’s disease, survivors(Aleman BM et al).
Among the female Hodgkin’s disease survivors breast cancer is the most commonly diagnosed solid tumor (Dores GM e al)
For women treated for Hodgkin’s disease before age 30, the risk of developing breast cancer is six times greater than the general population with an excess risk of 20-40 occurrences per 10,000 patients annually.
The incidence of NHL range from 1- 5.9% following treatment for Hodgkin’s disease.
ABVD (doxirubicin, bleomycin, vinblastine, dacarbazine) results in a 5-year event-free-survival rates of 70-75%, overall survival rates of 85-90% with considerable risk of cardiotoxicity and secondary tumors when the mediastinum is treated with mantle field irradiation.
15 year tumor free survival rate after ABVD is 45% and overall survival is 60%.
ABVD as effective as ABVD plus radiation in early disease, suggesting the majority of patients are curable without being exposed to the risks of therapeutic radiation.
HD6 study indicated ABVD alone is associated with a lower 12 year mortality compared to the use of radiation based treatment in patients with limited e Hodgkin’s lymphoma, mainly due to fewer deaths from other causes-for e IA or IIa non-bulky disease.
In the HD6 study the 12 year overall survival rate for patients receiving ABVD alone was 94% versus 87% for patients receiving subtotal nodal radiation, and the rates of freedom from disease progression was 87% among patients with ABVD alone versus 92% among patients receiving subtotal nodal radiation, and event free survival was 85% and 80%, respectively.
HD6 trial of patients with non-bulky e IA or IIA Hodgkin’s disease randomly assigned 4-6 cycles of ABVD therapy alone or to subtotal nodal radiation therapy alone or in combination with 2 cycles of ABVD we: at a median follow-up time of 11.3 years the rate of overall survival WAS lower with sub total nodal radiation therapy with or without 2 cycles of a DVD, then would he be be be alone due to the number of deaths from causes other than Hodgkin’s lymphoma, you including secondary cancers(Meyer RM et al).
HD7 study of 650 patients in a randomized trial comparing combination chemotherapy with ABVD for two cycles followed by extended field radiotherapy vs extended radiotherapy alone in patients with newly diagnosed favorable disease: results at a median observation time of 87 months no difference in complete response rates (95 vs 94%), overall survival (92 vs 94%), but freedom from treatment failure was significantly better in the combination arm of 22% vs 3%.
HD10 trial of the German Hodgkin Study Group demonstrated that among patients with very favorable e I or II Hodgkin’s lymphoma outcome in those who received only 2 cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus involved field radiation therapy in reduced doses was similar to the outcome in those who received 4 cycles of chemotherapy and involved field radiation therapy at n doses (Engert A et al).
HD10 trial five-year relapse rate was less than 10%.
MAL, 18 involved in T-cell activation is expressed in primary mediastinal large B-cell lymphomas and in nodular sclerosing Hodgkin’s disease.
75% present as early e I or II disease.
Use of extended field radiotherapy and combination chemotherapy has led to 80% to 90% cure of e I and II patients.
More than 80% of all patients younger than age 60 years with a new diagnosis likely to be cured.
Patients with stage IV disease have a cure rate of only about 66%, whereas those with stage I disease have a cure rate of 90%.
Lymphocyte-predominant disease makes up 3-5% of cases, nodular sclerosing type makes up 60-70% of cases and mixed cell subtype makes up 20-30% of cases.
Newly diagnosed patients present with enlarged cervical or supraclavicular lymph nodes in 60-70% of cases, radiographic evidence of thoracic involvement in 50-60% of cases and 40% present with B symptoms.
More than 80% of patients present with enlarged lymph nodes above the diaphragm and commonly involves the anterior mediastinum.
Involvement of cervical, supraclavicular and axillary areas are commonly involve, while the inguinal areas is less frequently involved.
Progression free survivals of 85-95% at 5 years in patients with early e disease, but recurrent HD is the leading cause of death in these patients for the first 15 years after diagnosis and treatment.
After 15 years death due to intercurrent illness/diseases exceeds the deaths due to Hodgkin’s disease.
Combination chemotherapy yields cure rate of 60-80% in advanced-e and bulky disease.
Control of early-e and overall survival is approximately 90% at 10 years.
Treatment for early e unfavorable disease is combined modality treatment with 4-6 courses of chemotherapy, typically ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by 30 Gy of involved-field radiotherapy.
BEACOPP (Bleomycin, Etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, and prednisone) vs ABVD randomly assigned to previously untreated and unfavorable Hodgkin’s disease patients with e IIB, III, or IV, or an international prognostic score of three or greater on a scale of 0 to 7, followed by local radiotherapy when indicated: median follow-up 61 months and the seven year rate of freedom from first progression was 85% forBEACOPP and 73% for ABVD, and the seven year rate of event free survival 78% and 71%, respectively (Viviani, S et al).
In the above study after completion of the planned treatment, including salvage therapy, this seven year rate of freedom from a second progression was 88% for the BEACOPP group and 82% in the ABVD group, and the seven year rate of overall survival was 89% and 84%, respectively waived more frequent adverse events in the BEACOPP group.
About 15% of early ed patients with unfavorable disease relapse within 5 years and 5% have primarily progressive disease.
About 1300 deaths from refractory disease in the US.
Of patients with advanced disease, almost 30% will have disease progression, with one third of these patients experiencing chemotherapy induction failure and two thirds of these patients will relapse after achieving complete remission.
Of patients with advanced disease that relapse 40-45% will relapse within 12 months of completing initial therapy, and outcome with conventional salvage therapy is poor.
ASCT in patients failing chemotherapy for advanced HD is better than n salvage chemotherapy with an improved long-term disease free survival (Schmitz N et al).
Failure of or relapse from autologous SCT is associated with a dismal prognosis.
Autologous Hodgkin’s disease-worldwide incidence of 2-3 per 100,000 people.
Monozygotic twin of a patient with disease has an increased risk compared to dizygotic twin sibling of a patient with HD.
Epstein-Barr virus implicated in etiology by epidemic, serologic and by detection of viral genome in tissue specimens of patients with HD.
Significantly increased risk to develop in HIV positive patients and is associated with advanced disease with unusual sites of presentation and poorer outcome.
WHO classification divides Hodgkin’s disease into two main types: classical and lymphocyte predominant.
Classical Hodgkin’s disease is divided into four subtypes: nodular sclerosis, mixed cellularity, lymphocyte depleted and lymphocyte rich.
Bulk of the tumor in classical Hodgkin’s disease is not malignant B cells, but an immune infiltrate dominated by CD4 positive T cells and macrophages.
CD30 is a cell proteins expressed on Reed-Sternberg cells.
Approximately 20-30% of classical Hodgkin’s lymphoma patients have Epstein-Barr virus.
Nodular sclerosing Hodgkin’s disease-most common type accounting for 50-60% of cases in developed countries.
Bulky lymphadenopathy also refers to any node or nodal mass 10 cm or greater.
Unfavorable prognostic factors in e I-II disease includes the presence of B symptoms, involvement of more than three nodal sites, and sedimentation rate greater than 50.
The following seven adverse prognostic factors reduce survival rates by 7-8% per year: age 45 years or older, male gender, e for disease, albumin level less than 4 g/dL, hemoglobin less than 10.5 g/dL, leukocytosis with a white count of 15,000/millimeter3 and lymphocyte leukemia with lymphocyte count of less than 8% (Hasenclever D et al).
Use of extended field radiotherapy and combination chemotherapy has led to 80% to 90% cure of e I and II patients.
More than 80% of all patients younger than age 60 years with a new diagnosis likely to be cured.
Approximately 15-30% of patients experience refractory or recurrent disease.
Lymphocyte-predominant disease makes up 3-5% of cases, nodular sclerosing type makes up 60-70% of cases and mixed cell subtype makes up 20-30% of cases.
Newly diagnosed patients present with enlarged cervical or supraclavicular lymph nodes in 60-70% of cases, radiographic evidence of thoracic involvement in 50-60% of cases and 40% present with B symptoms.
More than 80% of patients present with enlarged lymph nodes above the diaphragm and commonly involves the anterior mediastinum.
Involvement of cervical, supraclavicular and axillary areas are commonly involve, while the inguinal areas is less frequently involved.
Progression free survivals of 85-95% at 5 years in patients with early e disease, but recurrent HD is the leading cause of death in these patients for the first 15 years after diagnosis and treatment.
After 15 years death due to intercurrent illness/diseases exceeds the deaths due to Hodgkin’s disease.
Combination chemotherapy yields cure rate of 60-80% in advanced-e and bulky disease.
Control of early-Hodgkin’s disease-worldwide incidence of 2-3 per 100,000 people.
Substantial proportion of patients with classical and lymphocyte predominant disease are B cell derived monoclonal disorders.
Classified largely in 2 entities: nodular lymphocyte predominant and classical Hodgkin’s disease, with the latter subtype as nodular sclerosing, lymphocyte rich, mixed cellularity, and lymphocyte depleted subtypes.
Rarely classic HD associated with T cell derived lymphocytes.
Two risk factors include infectious mononucleosis and immunocompromised state.
Elevated levels of VEGF associated with Hodgkin’s lymphoma and the elevation persists after treatment and long into sustained remission.
Median age at presentation is the mid-30’s.
Bimodal distribution with a large peak occurring between ages 15-35 and a lesser peak in patients older than 50 years.
Male:female ratio 1.4:1.
Not increased in patients treated with chronic immunosuppressive agents.
In economically advanced societies associated with younger age, higher educational status of mother, decreased exposure to playmates, fewer siblings, suggesting a lowered exposure to infectious agents at an early age.
Incidence of Hodgkin’s disease by age varies with different histologic types.
Increased incidence in Jews and among first degree relatives of persons with the disease.
Siblings have a 2-5-fold increased risk and siblings of the same sex there is as high as 9-fold increase.
Increased risk among parent-child relationships but not among spouses.
Monozygotic twin of a patient with disease has an increased risk compared to dizygotic twin sibling of a patient with HD.
Epstein-Barr virus implicated in etiology by epidemic, serologic and by detection of viral genome in tissue specimens of patients with HD.
Significantly increased risk to develop in HIV positive patients and is associated with advanced disease with unusual sites of presentation and poorer outcome.
WHO classification divides Hodgkin’s disease into two main types: classical and lymphocyte predominant.
Classical Hodgkin’s disease is divided into four subtypes: nodular sclerosis, mixed cellularity, lymphocyte depleted and lymphocyte rich.
Bulk of the tumor in classical Hodgkin’s disease is not malignant B cells, but an immune infiltrate dominated by CD4 positive T cells and macrophages.
Approximately 20-30% of classical Hodgkin’s lymphoma patients have Epstein-Barr virus.
Lymphocyte predominant Hodgkin’s disease lacks Reed Sternberg cells, but has lymphocyte predominant cells, sometimes referred to as popcorn cells.
Lymphocyte predominant Hodgkin’s disease can have nodular or diffuse forms.
Lymphocyte predominant nodular subtype has predominantly B lymphocytes, whereas the diffuse subtype has mainly T cells in the background.
Nodular sclerosing Hodgkin’s disease-most common type accounting for 50-60% of cases in developed countries.
Nodular sclerosis classical Hodgkin’s lymphoma affects young adults more often than the elderly, is seen more frequently in developed countries and accounts for an early peak in Western populations.
Nodular sclerosing Hodgkin’s disease more common in women then men and less frequently associated and Epstein Barr virus.
The histological hallmark of nodular sclerosing Hodgkin’s disease is the presence of bands of birefringent collagen, would increased production of interleukin-13.
Nodular sclerosing Hodgkin’s disease has a relatively preserved nodular structure in contrast with mixed cell HD and lymphocyte depleted HD.
After the epidemiologic risk patterns of the nodular sclerosing Hodgkin’s disease differs from mixed cell Hodgkin’s disease, suggesting the lesions might not share a common etiology.
The incidence of nodular sclerosing Hodgkin’s disease continues to rise and its incidence decreases as the CD4 count decreases in patients with HIV, suggesting an intact immune system is needed for the development of this lesion.
The incidence of mediastinal involvement is more common in the sclerosing than other types of classical Hodgkin’s disease.
Both nodular sclerosing Hodgkin’s disease and primary mediastinal large B-cell lymphoma lack immunoglobulin expression and functional expression of HLA class one antigens and share cytogenetic abnormalities.
In nodular sclerosing HD there are abundant lymphocytes, and variable numbers of neutrophils and eosinophils noted histologically.
Nodular sclerosing HD with a high proportion of Reed-Sternberg cells and appearance of a lymphocyte depleted-like process, with necrosis and prominent fibrohistiocystic stroma are features of grade 2 nodular sclerosing HD, associated with a higher relapse rate and poorer response to therapy.
Mixed cell Hodgkin’s disease accounts for approximately 30% of cases.
Mixed cell HD and lymphocyte depleted HD associated with lower socioeconomic status, increased prevalence in men, frequent Epstein-Barr viral infections, and a different pattern of spread with sparing of the mediastinum and thymus gland compared to nodular sclerosing HD.
Mixed cell HD and lymphocyte depleted HD share clinical, epidemiologic, and biologic features.
Mixed cell HD and lymphocyte depleted HD differ by the extent of deletion of lymphocytes and degree of immunosuppression in the host.
Mixed cell HD and lymphocyte depleted HD both occur in the setting of HIV infection.
Mixed cell HD and lymphocyte depleted HD are associated with poor prognosis than are other types of HD.
Mixed cell HD associated with a bimodal age-incidents and accounts for most cases of classical HD in children.
Mixed cell HD is relatively uncommon in young adults and increases incidence after the age of 50 years.
Mixed cell HD incidents, patterns that of Epstein-Barr viral infections as seen in the very young and elderly.
Lymphocyte rich classic Hodgkin’s disease represent 4-5% of cases.
Lymphocyte depleted Hodgkin’s disease occurs in less than 1% of cases.
Classical HD comprises 95% of cases.
Classical HD is a lymphocyte rich process, previously confused with nodular lymphocyte predominant HD.
Classical HD usually presents with e I or II disease.
Classical HD has a rich background of normal lymphocytes, the Reed Sternberg cells are smaller than those in other subtypes, and immunohistologic studies are needed to distinguish it from lymphocyte predominant HD.
Classical HD has an older age at presentation and usually lacks mediastinal involvement.
Classical HD has a high event free and overall survival of 97% at 30 months.
Lymphocyte predominant disease has atypical Reed-Sternberg cells called histiocytic and lymphocytic cell, popcorn cell, as its nucleus resembles the explosion of a popcorn kernel.
Classical Reed-Sternberg cells stain positively for CD15 and but lack CD20, a B cell marker.
Histiocytic and lymphocytic cells stain positively for leukocyte common antigen CD45 and express B cell antigens CD19, CD20, CD22 and lack CD15 and rarely express .
Lymphocytic predominant disease usually presents as an asymptomatic adenopathy, progresses slowly and frequently relapses after treatment.
Lymphocyte predominant disease is rarely fatal.
Lymphocyte predominant disease has a 5-year survival of patients with early e disease and without treatment of 93% and 80% survival at 10 years.
Lymphocyte predominant disease responds to chemotherapy, but less toxic treatments such as Rituximab may be used alone.
Hodgkin’s disease ing helps classify patients into three groups: early-e favorable-e I-II with no unfavorable factors, early-e unfavorable-e 1-II with any unfavorable factors such as large mediastinal disease or B symptoms or numerous sites of disease or elevated ESR, and advanced e disease-es III-IV.
75% present as early e I or II disease.
Unfavorable prognostic factors include mediastinal bulk disease in early-e disease.
Mediastinal bulk on chest x-ray measures the mediastinal mass ratio-the MMR ratio refers to the maximum width of the mass to the maximum intrathoracic diameter, and an MMR greater than 0.33 is defined as bulky disease.
Mediastinal bulk of disease also defined as that exceeding one third of the internal transverse diameter of the thorax at T5-T6 interspace on a PA x-ray.
Bulky lymphadenopathy also refers to any node or nodal mass 10 cm or greater.
Unfavorable prognostic factors in e I-II disease includes the presence of B symptoms, involvement of more than three nodal sites, and sedimentation rate greater than 50.
The following seven adverse prognostic factors reduce survival rates by 7-8% per year: age 45 years or older, male gender, e for disease, albumin level less than 4 g/dL, hemoglobin less than 10.5 g/dL, leukocytosis with a white count of 15,000/millimeter3 and lymphocyte leukemia with lymphocyte count of less than 8% (Hasenclever D et al).
Use of extended field radiotherapy and combination chemotherapy has led to 80% to 90% cure of e I and II patients.
More than 80% of all patients younger than age 60 years with a new diagnosis likely to be cured.
Approximately 15-30% of patients experience refractory or recurrent disease.
Lymphocyte-predominant disease makes up 3-5% of cases, nodular sclerosing type makes up 60-70% of cases and mixed cell subtype makes up 20-30% of cases.
Newly diagnosed patients present with enlarged cervical or supraclavicular lymph nodes in 60-70% of cases, radiographic evidence of thoracic involvement in 50-60% of cases and 40% present with B symptoms.
More than 80% of patients present with enlarged lymph nodes above the diaphragm and commonly involves the anterior mediastinum.
Involvement of cervical, supraclavicular and axillary areas are commonly involve, while the inguinal areas is less frequently involved.
Progression free survivals of 85-95% at 5 years in patients with early e disease, but recurrent HD is the leading cause of death in these patients for the first 15 years after diagnosis and treatment.
After 15 years death due to intercurrent illness/diseases exceeds the deaths due to Hodgkin’s disease.
Combination chemotherapy yields cure rate of 60-80% in advanced-e and bulky disease.
Control of early-e and overall survival is approximately 90% at 10 years.
Treatment for early e unfavorable disease is combined modality treatment with 4-6 courses of chemotherapy, typically ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by 30 Gy of involved-field radiotherapy.
In a random study of 405 patients with previously untreated Hodgkin’s disease-worldwide incidence of 2-3 per 100,000 people.
One-fifth the incidence of non-Hodgkin’s lymphoma.
Approximately 8490 cases diagnosed annually in the U.S., with about 1320 deaths.
Characterized by neoplastic Reed-Sternberg cells occurring with inflammatory changes.
Affected lymph nodes consist of lymphocytes, histiocytes, plasma cells, fibroblasts and other cells.
Mononucleated Hodgkin’s cells and polynucleated Reed-Sternberg cells comprise only 0.1-1.0% of the entire population of lymph node cells in the various types of Hodgkin’s disease.
Effacement of lymph node can range from partial involvement with a few atypical cells to total involvement with a complete alteration of lymph node architecture.
Mononuclear variant, Hodgkin’s cells, or multinuclear variant Reed-Sternberg cells are indispensable for diagnosis, but their mere presence is not enough for diagnosis, as a growth pattern of Hodgkin’s disease is needed.
Small percentage of neoplastic cells secrete multiple cytokines, including IL-5, IL-4, tumor necrosis factor, and granulocyte macrophage colony stimulating factor which created an inflammatory reaction.
Immunologic abnormalities reported include: ITP, auto-immune hemolytic anemia immune neutropenia, and antibodies to insulin.
Incidence of AIHA 1.5-2.7%.
Substantial proportion of patients with classical and lymphocyte predominant disease are B cell derived monoclonal disorders.
Classified largely in 2 entities: nodular lymphocyte predominant and classical Hodgkin’s disease, with the latter subtype as nodular sclerosing, lymphocyte rich, mixed cellularity, and lymphocyte depleted subtypes.
Rarely classic HD associated with T cell derived lymphocytes.
Two risk factors include infectious mononucleosis and immunocompromised state.
Elevated levels of VEGF associated with Hodgkin’s lymphoma and the elevation persists after treatment and long into sustained remission.
Median age at presentation is the mid-30’s.
Bimodal distribution with a large peak occurring between ages 15-35 and a lesser peak in patients older than 50 years.
Male:female ratio 1.4:1.
Not increased in patients treated with chronic immunosuppressive agents.
In economically advanced societies associated with younger age, higher educational status of mother, decreased exposure to playmates, fewer siblings, suggesting a lowered exposure to infectious agents at an early age.
Incidence of Hodgkin’s disease by age varies with different histologic types.
Elderly Hodgkin patients, usually defined as 60 years or older, have inferior outcomes compared with younger patients.
5 year failure free survival 74% in patients younger than 60 years and 48% in those 60 or older, and overall survival 90% versus 58%, respectively.
Older age at presentation strongly negative risk factor and is associated with a greater likelihood of more advanced stage presentation and more aggressive histology, have more comorbidities, and are less tolerant of therapy, and experience more toxicity.
Increased incidence in Jews and among first degree relatives of persons with the disease.
Siblings have a 2-5-fold increased risk and siblings of the same sex there is as high as 9-fold increase.
Increased risk among parent-child relationships but not among spouses.
Monozygotic twin of a patient with disease has an increased risk compared to dizygotic twin sibling of a patient with HD.
Epstein-Barr virus implicated in etiology by epidemic, serologic and by detection of viral genome in tissue specimens of patients with HD.
Significantly increased risk to develop in HIV positive patients and is associated with advanced disease with unusual sites of presentation and poorer outcome.
WHO classification divides Hodgkin’s disease into two main types: classical and lymphocyte predominant.
Classical Hodgkin’s disease is divided into four subtypes: nodular sclerosis, mixed cellularity, lymphocyte depleted and lymphocyte rich.
Bulk of the tumor in classical Hodgkin’s disease is not malignant B cells, but an immune infiltrate dominated by CD4 positive T cells and macrophages.
CD30 is a cell proteins expressed on Reed-Sternberg cells.
Approximately 20-30% of classical Hodgkin’s lymphoma patients have Epstein-Barr virus.
The histological hallmark of nodular sclerosing Hodgkin’s disease is the presence of bands of birefringent collagen, would increased production of interleukin-13.
Nodular sclerosing Hodgkin’s disease has a relatively preserved nodular structure in contrast with mixed cell HD and lymphocyte depleted HD.
After the epidemiologic risk patterns of the nodular sclerosing Hodgkin’s disease differs from mixed cell Hodgkin’s disease, suggesting the lesions might not share a common etiology.
The incidence of nodular sclerosing Hodgkin’s disease continues to rise and its incidence decreases as the CD4 count decreases in patients with HIV, suggesting an intact immune system is needed for the development of this lesion.
The incidence of mediastinal involvement is more common in the sclerosing than other types of classical Hodgkin’s disease.
Both nodular sclerosing Hodgkin’s disease and primary mediastinal large B-cell lymphoma lack immunoglobulin expression and functional expression of HLA class one antigens and share cytogenetic abnormalities.
In nodular sclerosing HD there are abundant lymphocytes, and variable numbers of neutrophils and eosinophils noted histologically.
The following seven adverse prognostic factors reduce survival rates by 7-8% per year: age 45 years or older, male gender, Hodgkin’s disease-worldwide of 2-3 per 100,000 people.
One-fifth the incidence of non-Hodgkin’s lymphoma.
Approximately 8490 cases diagnosed annually in the U.S., with about 1320 deaths.
Characterized by neoplastic Reed-Sternberg cells occurring with inflammatory changes.
Affected lymph nodes consist of lymphocytes, histiocytes, plasma cells, fibroblasts and other cells.
Mononucleated Hodgkin’s cells and polynucleated Reed-Sternberg cells comprise only 0.1-1.0% of the entire population of lymph node cells in the various types of Hodgkin’s disease.
Effacement of lymph node can range from partial involvement with a few atypical cells to total involvement with a complete alteration of lymph node architecture.
Mononuclear variant, Hodgkin’s cells, or multinuclear variant Reed-Sternberg cells are indispensable for diagnosis, but their mere presence is not enough for diagnosis, as a growth pattern of Hodgkin’s disease is needed.
Small percentage of neoplastic cells secrete multiple cytokines, including IL-5, IL-4, tumor necrosis factor, and granulocyte macrophage colony stimulating factor which created an inflammatory reaction.
Immunologic abnormalities reported include: ITP, auto-immune hemolytic anemia immune neutropenia, and antibodies to insulin.
Incidence of AIHA 1.5-2.7%.
Substantial proportion of patients with classical and lymphocyte predominant disease are B cell derived monoclonal disorders.
Classified largely in 2 entities: nodular lymphocyte predominant and classical Hodgkin’s disease, with the latter subtype as nodular sclerosing, lymphocyte rich, mixed cellularity, and lymphocyte depleted subtypes.
Rarely classic HD associated with T cell derived lymphocytes.
Two risk factors include infectious mononucleosis and immunocompromised state.
Elevated levels of VEGF associated with Hodgkin’s lymphoma and the elevation persists after treatment and long into sustained remission.
Median age at presentation is the mid-30’s.
Bimodal distribution with a large peak occurring between ages 15-35 and a lesser peak in patients older than 50 years.
Male:female ratio 1.4:1.
Not increased in patients treated with chronic immunosuppressive agents.
In economically advanced societies associated with younger age, higher educational status of mother, decreased exposure to playmates, fewer siblings, suggesting a lowered exposure to infectious agents at an early age.
Incidence of Hodgkin’s disease by age varies with different histologic types.
Increased incidence in Jews and among first degree relatives of persons with the disease.
Siblings have a 2-5-fold increased risk and siblings of the same sex there is as high as 9-fold increase.
Increased risk among parent-child relationships but not among spouses.
Monozygotic twin of a patient with disease has an increased risk compared to dizygotic twin sibling of a patient with HD.
Epstein-Barr virus implicated in etiology by epidemic, serologic and by detection of viral genome in tissue specimens of patients with HD.
Significantly increased risk to develop in HIV positive patients and is associated with advanced disease with unusual sites of presentation and poorer outcome.
WHO classification divides Hodgkin’s disease into two main types: classical and lymphocyte predominant.
Classical Hodgkin’s disease is divided into four subtypes: nodular sclerosis, mixed cellularity, lymphocyte depleted and lymphocyte rich.
Bulk of the tumor in classical Hodgkin’s disease is not malignant B cells, but an immune infiltrate dominated by CD4 positive T cells and macrophages.
Most patients with classical HD are CD3 and CD 45 negative, and CD 20 may be detectable in fewer within 40% of patients.
Approximately 20-30% of classical Hodgkin’s lymphoma patients have Epstein-Barr virus.
Lymphocyte predominant Hodgkin’s disease lacks Reed Sternberg cells, but has lymphocyte predominant cells, sometimes referred to as popcorn cells.
Lymphocyte predominant Hodgkin’s disease can have nodular or diffuse forms.
Lymphocyte predominant nodular subtype has predominantly B lymphocytes, whereas the diffuse subtype has mainly T cells in the background.
Nodular sclerosing Hodgkin’s disease-most common type accounting for 50-60% of cases in developed countries.
Nodular sclerosis classical Hodgkin’s lymphoma affects young adults more often than the elderly, is seen more frequently in developed countries and accounts for an early peak in Western populations.
Nodular sclerosing Hodgkin’s disease more common in women then men and less frequently associated and Epstein Barr virus.
The histological hallmark of nodular sclerosing Hodgkin’s disease is the presence of bands of birefringent collagen, would increased production of interleukin-13.
Nodular sclerosing Hodgkin’s disease has a relatively preserved nodular structure in contrast with mixed cell HD and lymphocyte depleted HD.
After the epidemiologic risk patterns of the nodular sclerosing Hodgkin’s disease differs from mixed cell Hodgkin’s disease, suggesting the lesions might not share a common etiology.
The incidence of nodular sclerosing Hodgkin’s disease continues to rise and its incidence decreases as the CD4 count decreases in patients with HIV, suggesting an intact immune system is needed for the development of this lesion.
The incidence of mediastinal involvement is more common in the sclerosing than other types of classical Hodgkin’s disease.
Both nodular sclerosing Hodgkin’s disease and primary mediastinal large B-cell lymphoma lack immunoglobulin expression and functional expression of HLA class one antigens and share cytogenetic abnormalities.
In nodular sclerosing HD there are abundant lymphocytes, and variable numbers of neutrophils and eosinophils noted histologically.
Nodular sclerosing HD with a high proportion of Reed-Sternberg cells and appearance of a lymphocyte depleted-like process, with necrosis and prominent fibrohistiocystic stroma are features of grade 2 nodular sclerosing HD, associated with a higher relapse rate and poorer response to therapy.
Mixed cell Hodgkin’s disease accounts for approximately 30% of cases.
Mixed cell HD and lymphocyte depleted HD associated with lower socioeconomic status, increased prevalence in men, frequent Epstein-Barr viral infections, and a different pattern of spread with sparing of the mediastinum and thymus gland compared to nodular sclerosing HD.
Classical Reed-Sternberg cells stain positively for CD15 and but lack CD20, a B cell marker.
Histiocytic and lymphocytic cells stain positively for leukocyte common antigen CD45 and express B cell antigens CD19, CD20, CD22 and lack CD15 and rarely express .
Lymphocytic predominant disease usually presents as an asymptomatic adenopathy, progresses slowly and frequently relapses after treatment.
Lymphocyte predominant disease is rarely fatal.
Lymphocyte predominant disease has a 5-year survival of patients with early disease and without treatment of 93% and 80% survival at 10 years.
Lymphocyte predominant disease responds to chemotherapy, but less toxic treatments such as Rituximab may be used alone.
Hodgkin’s disease staging helps classify patients into three groups: early- favorable- I-II with no unfavorable factors, early- unfavorable- 1-II with any unfavorable factors such as large mediastinal disease or B symptoms or numerous sites of disease or elevated ESR, and advanced disease-s III-IV.
75% present as early I or II disease.
Unfavorable prognostic factors include mediastinal bulk disease in early- disease.
Mediastinal bulk on chest x-ray measures the mediastinal mass ratio-the MMR ratio refers to the maximum width of the mass to the maximum intrathoracic diameter, and an MMR greater than 0.33 is defined as bulky disease.
Mediastinal bulk of disease also defined as that exceeding one third of the internal transverse diameter of the thorax at T5-T6 interspace on a PA x-ray.
Bulky lymphadenopathy also refers to any node or nodal mass 10 cm or greater.
Unfavorable prognostic factors in I-II disease includes the presence of B symptoms, involvement of more than three nodal sites, and sedimentation rate greater than 50.
The following seven adverse prognostic factors reduce survival rates by 7-8% per year: age 45 years or older, male gender, for disease, albumin level less than 4 g/dL, hemoglobin less than 10.5 g/dL, leukocytosis with a white count of 15,000/millimeter3 and lymphocyte leukemia with lymphocyte count of less than 8% (Hasenclever D et al).
Use of extended field radiotherapy and combination chemotherapy has led to 80% to 90% cure of I and II patients.
More than 80% of all patients younger than age 60 years with a new diagnosis likely to be cured.
Approximately 15-30% of patients experience refractory or recurrent disease.
Lymphocyte-predominant disease makes up 3-5% of cases, nodular sclerosing type makes up 60-70% of cases and mixed cell subtype makes up 20-30% of cases.
Newly diagnosed patients present with enlarged cervical or supraclavicular lymph nodes in 60-70% of cases, radiographic evidence of thoracic involvement in 50-60% of cases and 40% present with B symptoms.
More than 80% of patients present with enlarged lymph nodes above the diaphragm and commonly involves the anterior mediastinum.
Involvement of cervical, supraclavicular and axillary areas are commonly involve, while the inguinal areas is less frequently involved.
Progression free survivals of 85-95% at 5 years in patients with early disease, but recurrent HD is the leading cause of death in these patients for the first 15 years after diagnosis and treatment.
After 15 years death due to intercurrent illness/diseases exceeds the deaths due to Hodgkin’s disease.
Some patients have intolerance to alcohol and may experience pain at the site of disease.
Patients may develop fever that lasts days and then resolves and retruns, a process known as PEL-Ebstein fever.
Combination chemotherapy yields cure rate of 60-80% in advanced- and bulky disease.
Control of early- and overall survival is approximately 90% at 10 years.
Treatment for early unfavorable disease is combined modality treatment with 4-6 courses of chemotherapy, typically ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by 30 Gy of involved-field radiotherapy.
In a random study of 405 patients with previously untreated IA or IIA non-bulky I Hodgkin’s disease treated with a ABVD alone or subtotal nodal irradiation with or without ABVD for 4 to 6 months: at 12 years the overall survival was 94% among those with a DVD alone, compared to 87% among those receiving subtotal nodal irradiation, with the rates of freedom from disease progression 87 and 92%, respectively, and the rate of event free survival 85% and 80% respectively- the higher rate of overall survival from ABVD is due to a lower rate of death from other causes (Meyer RM et al).
For many, four cycles of ABVD followed by 30 Gy of involved field radiation is the stan treatment for early- Hodgkin’s disease (Engert A, Ferme, C).
Treatment with two cycles of ABVD followed by 20 Gy of involved field radiation therapy is as effective and less toxic than four cycles of ABVD followed by 30 Gy of involved field radiation in a random up up up up clinical study involving 1370 patients (Engert A).
BEACOPP (Bleomycin, Etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, and prednisone) vs ABVD randomly assigned to previously untreated and unfavorable Hodgkin’s disease patients with IIB, III, or IV, or an international prognostic score of three or greater on a scale of 0 to 7, followed by local radiotherapy when indicated: median follow-up 61 months and the seven year rate of freedom from first progression was 85% for
BEACOPP and 73% for ABVD, and the seven year rate of event free survival 78% and 71%, respectively (Viviani, S et al).
In the above study after completion of the planned treatment, including salvage therapy, this seven year rate of freedom from a second progression was 88% for the BEACOPP group and 82% in the ABVD group, and the seven year rate of overall survival was 89% and 84%, respectively withmore frequent adverse events in the BEACOPP group.
The conclusion from the above study is that the initial choice of chemotherapy of BEACOPP or ABVD significantly influence long-term survival.
BEACOPP treatment had a freedom from treatment failure rate of 85.5% at five years, which is significantly higher than the rate of 73% in the ABVD group, but is associated with increased hemorrhagic and non-hematologic toxic effects, in fertility and secondary neoplasias.
BEACOPP associated with a death rate due to acute toxic effects of 3%, and the rate of secondary cancers of 4.9%, azoospermia rate of 90% in males and greater than 50% of infertility rate in women: ABVD is rarely associated with severe myelosuppression, death from acute toxic effects, secondary leukemias and infertility.
In a randomized trial of chemotherapy in advanced HD, no significant difference in response rate, FFS or overall survival, or 5 year toxicity for ABVD (plus RT for bulky mediastinal disease), compared with Stanford C (with RT for nodal sites >5cm)(Gordon L et al).
In the above study complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V.
About 15% of early d patients with unfavorable disease relapse within 5 years and 5% have primarily progressive disease.
About 1300 deaths from refractory disease in the US.
Of patients with advanced disease, almost 30% will have disease progression, with one third of these patients experiencing chemotherapy induction failure and two thirds of these patients will relapse after achieving complete remission.
Of patients with advanced disease that relapse 40-45% will relapse within 12 months of completing initial therapy, and outcome with conventional salvage therapy is poor.
ASCT in patients failing chemotherapy for advanced HD is better than stan salvage chemotherapy with an improved long-term disease free survival (Schmitz N et al).
Failure of or relapse from autologous SCT is associated with a dismal prognosis.
Autologous stem cell transplant is potentially curative treatment for some patients with progressive or recurrent HD after failing initial combination: effective in approximately 50% of such patients.
Relapse of HD after autologous stem cell transplant associated with 55% survival at 2 years and 32% at 5 years (Martinez C et al).
Most common secondary malignancies are solid tumors and acute leukemia.
Secondary malignancies most commonly involve the lung, breast, and digestive tract, organs that lie adjacent to radiation fields.
Radiation toxicity include secondar malignancies , cardiovascular disease, hypothyroidism, cerebrovascular accidents, and muscle atrophy.
Cumulative incidence of grade 3-5 chronic toxicity to chemotherapy and radiation theray among 25 year survivors following treatment (Oeffinger KC et al).
Oberved secondary cancers in 30,000 patients treated for HD associated with a 2.3 risk compared to expected risk.
Secondary malignancies are now the leading cause of death in the long term Hodgkin’s disease, survivors(Aleman BM et al).
Among the female Hodgkin’s disease survivors breast cancer is the most commonly diagnosed solid tumor (Dores GM e al)
For women treated for Hodgkin’s disease before age 30, the risk of developing breast cancer is six times greater than the general population with an excess risk of 20-40 occurrences per 10,000 patients annually.
The incidence of NHL range from 1- 5.9% following treatment for Hodgkin’s disease.
ABVD (doxirubicin, bleomycin, vinblastine, dacarbazine) results in a 5-year event-free-survival rates of 70-75%, overall survival rates of 85-90% with considerable risk of cardiotoxicity and secondary tumors when the mediastinum is treated with mantle field irradiation.
15 year tumor free survival rate after ABVD is 45% and overall survival is 60%.
ABVD as effective as ABVD plus radiation in early disease, suggesting the majority of patients are curable without being exposed to the risks of therapeutic radiation.
HD6 study indicated ABVD alone is associated with a lower 12 year mortality compared to the use of radiation baseD treatment in patients with limited Hodgkin’s lymphoma, mainly due to fewer deaths from other causes-for IA or IIa non-bulky disease.
In the HD6 study the 12 year overall survival rate for patients receiving ABVD alone was 94% versus 87% for patients receiving subtotal nodal radiation, and the rates of freedom from disease progression was 87% among patients with ABVD alone versus 92% among patients receiving subtotal nodal radiation, and event free survival was 85% and 80%, respectively.
HD6 trial of patients with non-bulky IA or IIA Hodgkin’s disease randomly assigned 4-6 cycles of ABVD therapy alone or to subtotal nodal radiation therapy alone or in combination with 2 cycles of ABVD we: at a median follow-up time of 11.3 years the rate of overall survival WAS lower with sub total nodal radiation therapy with or without 2 cycles of a DVD, then would he be be be alone due to the number of deaths from causes other than Hodgkin’s lymphoma, you including secondary cancers(Meyer RM et al).
HD7 study of 650 patients in a randomized trial comparing combination chemotherapy with ABVD for two cycles followed by extended field radiotherapy vs extended radiotherapy alone in patients with newly diagnosed favorable disease: results at a median observation time of 87 months no difference in complete response rates (95 vs 94%), overall survival (92 vs 94%), but freedom from treatment failure was significantly better in the combination arm of 22% vs 3%.
HD10 trial of the German Hodgkin Study Group demonstrated that among patients with very favorable I or II Hodgkin’s lymphoma outcome in those who received only 2 cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus involved field radiation therapy in reduced doses was similar to the outcome in those who received 4 cycles of chemotherapy and involved field radiation therapy at stan doses (Engert A et al).
HD10 trial five-year relapse rate was less than 10%.
Mononucleated Hodgkin’s cells and polynucleated Reed-Sternberg cells comprise only 0.1-1.0% of the entire population of lymph node cells in the various types of Hodgkin’s disease.
Effacement of lymph node can range from partial involvement with a few atypical cells to total involvement with a complete alteration of lymph node architecture.
Mononuclear variant, Hodgkin’s cells, or multinuclear variant Reed-Sternberg cells are indispensable for diagnosis, but their mere presence is not enough for diagnosis, as a growth pattern of Hodgkin’s disease is needed.
Small percentage of neoplastic cells secrete multiple cytokines, including IL-5, IL-4, tumor necrosis factor, and granulocyte macrophage colony stimulating factor which created an inflammatory reaction.
Immunologic abnormalities reported include: ITP, auto-immune hemolytic anemia immune neutropenia, and antibodies to insulin.
Incidence of AIHA 1.5-2.7%.
Substantial proportion of patients with classical and lymphocyte predominant disease are B cell derived monoclonal disorders.
Classified largely in 2 entities: nodular lymphocyte predominant and classical Hodgkin’s disease, with the latter subtype as nodular sclerosing, lymphocyte rich, mixed cellularity, and lymphocyte depleted subtypes.
Rarely classic HD associated with T cell derived lymphocytes.
Two risk factors include infectious mononucleosis and immunocompromised state.
Elevated levels of VEGF associated with Hodgkin’s lymphoma and the elevation persists after treatment and long into sustained remission.
Median age at presentation is the mid-30’s.
Bimodal distribution with a large peak occurring between ages 15-35 and a lesser peak in patients older than 50 years.
Male:female ratio 1.4:1.
Not increased in patients treated with chronic immunosuppressive agents.
In economically advanced societies associated with younger age, higher educational status of mother, decreased exposure to playmates, fewer siblings, suggesting a lowered exposure to infectious agents at an early age.
Incidence of Hodgkin’s disease by age varies with different histologic types.
Increased incidence in Jews and among first degree relatives of persons with the disease.
Siblings have a 2-5-fold increased risk and siblings of the same sex there is as high as 9-fold increase.
Increased risk among parent-child relationships but not among spouses.
Monozygotic twin of a patient with disease has an increased risk compared to dizygotic twin sibling of a patient with HD.
Epstein-Barr virus implicated in etiology by epidemic, serologic and by detection of viral genome in tissue specimens of patients with HD.
Significantly increased risk to develop in HIV positive patients and is associated with advanced disease with unusual sites of presentation and poorer outcome.
Nodular sclerosing Hodgkin’s disease-most common type accounting for 50-60% of cases in developed countries.
Nodular sclerosis classical Hodgkin’s lymphoma affects young adults more often than the elderly, is seen more frequently in developed countries and accounts for an early peak in Western populations.
Nodular sclerosing Hodgkin’s disease more common in women then men and less frequently associated and Epstein Barr virus.
The histological hallmark of nodular sclerosing Hodgkin’s disease is the presence of bands of birefringent collagen, would increased production of interleukin-13.
Nodular sclerosing Hodgkin’s disease has a relatively preserved nodular structure in contrast with mixed cell HD and lymphocyte depleted HD.
After the epidemiologic risk patterns of the nodular sclerosing Hodgkin’s disease differs from mixed cell Hodgkin’s disease, suggesting the lesions might not share a common etiology.
The incidence of nodular sclerosing Hodgkin’s disease continues to rise and its incidence decreases as the CD4 count decreases in patients with HIV, suggesting an intact immune system is needed for the development of this lesion.
Both nodular sclerosing Hodgkin’s disease and primary mediastinal large B-cell lymphoma lack immunoglobulin expression and functional expression of HLA class one antigens and share her cytogenetic abnormalities.
In nodular sclerosing HD there are abundant lymphocytes, and variable numbers of neutrophils and eosinophils noted histologically.
Nodular sclerosing HD with a high proportion of Reed-Sternberg cells and appearance of a lymphocyte depleted-like process, with necrosis and prominent fibrohistiocystic stroma are features of grade 2 nodular sclerosing HD, associated with a higher relapse rate and poorer response to therapy.
MAL, 18 involved in T-cell activation is expressed in primary mediastinal large B-cell lymphomas and in nodular sclerosing Hodgkin’s disease.
Mixed cell Hodgkin’s disease accounts for approximately 30% of cases.
Mixed cell HD and lymphocyte depleted HD associated with lower socioeconomic status, increased prevalence in men, frequent Epstein-Barr viral infections, and a different pattern of spread with sparing of the mediastinum and thymus gland compared to nodular sclerosing HD.
Mixed cell HD and lymphocyte depleted HD share clinical, epidemiologic, and biologic features.
Mixed cell HD and lymphocyte depleted HD differ by the extent of deletion of lymphocytes and degree of immunosuppression in the host.
Mixed cell HD and lymphocyte depleted HD both occur in the setting of HIV infection.
Mixed cell HD and lymphocyte depleted HD are associated with poor prognosis than are other types of HD.
Mixed cell HD associated with a bimodal age-incidents and accounts for most cases of classical HD in children.
Mixed cell HD is relatively uncommon in young adults and increases incidence after the age of 50 years.
Mixed cell HD incidents, patterns that of Epstein-Barr viral infections as seen in the very young and elderly.
Lymphocyte rich classic Hodgkin’s disease represent 4-5% of cases.
Lymphocyte depleted Hodgkin’s disease occurs in less than 1% of cases.
Classical HD comprises 95% of cases.
Classical HD is a lymphocyte rich process, previously confused with nodular lymphocyte predominant HD.
Classical HD usually presents with I or II disease.
Classical HD has a rich background of normal lymphocytes, the Reed Sternberg cells are smaller than those in other subtypes, and immunohistologic studies are needed to distinguish it from lymphocyte predominant HD.
Classical HD has an older age at presentation and usually lacks mediastinal involvement.
Classical HD has a high event free and overall survival of 97% at 30 months.
Lymphocyte predominant disease has atypical Reed-Sternberg cells called histiocytic and lymphocytic cell, popcorn cell, as its nucleus resembles the explosion of a popcorn kernel.
Classical Reed-Sternberg cells stain positively for CD15 and but lack CD20, a B cell marker.
Histiocytic and lymphocytic cells stain positively for leukocyte common antigen CD45 and express B cell antigens CD19, CD20, CD22 and lack CD15 and rarely express .
Lymphocytic predominant disease usually presents as an asymptomatic adenopathy, progresses slowly and frequently relapses after treatment.
Lymphocyte predominant disease is rarely fatal.
Lymphocyte predominant disease has a 5-year survival of patients with early disease and without treatment of 93% and 80% survival at 10 years.
Lymphocyte predominant disease responds to chemotherapy, but less toxic treatments such as Rituximab may be used alone.
75% present as early I or II disease.
Use of extended field radiotherapy and combination chemotherapy has led to 80% to 90% cure of I and II patients.
More than 80% of all patients younger than age 60 years with a new diagnosis likely to be cured.
Lymphocyte-predominant disease makes up 3-5% of cases, nodular sclerosing type makes up 60-70% of cases and mixed cell subtype makes up 20-30% of cases.
Newly diagnosed patients present with enlarged cervical or supraclavicular lymph nodes in 60-70% of cases, radiographic evidence of thoracic involvement in 50-60% of cases and 40% present with B symptoms.
More than 80% of patients present with enlarged lymph nodes above the diaphragm and commonly involves the anterior mediastinum.
Involvement of cervical, supraclavicular and axillary areas are commonly involve, while the inguinal areas is less frequently involved.
Progression free survivals of 85-95% at 5 years in patients with early disease, but recurrent HD is the leading cause of death in these patients for the first 15 years after diagnosis and treatment.
After 15 years death due to intercurrent illness/diseases exceeds the deaths due to Hodgkin’s disease.
Combination chemotherapy yields cure rate of 60-80% in advanced- and bulky disease.
Control of early- and overall survival is approximately 90% at 10 years.
Treatment for early unfavorable disease is combined modality treatment with 4-6 courses of chemotherapy, typically ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by 30 Gy of involved-field radiotherapy.
BEACOPP (Bleomycin, Etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, and prednisone) vs ABVD randomly assigned to previously untreated and unfavorable Hodgkin’s disease patients with IIB, III, or IV, or an international prognostic score of three or greater on a scale of 0 to 7, followed by local radiotherapy when indicated: median follow-up 61 months and the seven year rate of freedom from first progression was 85% forBEACOPP and 73% for ABVD, and the seven year rate of event free survival 78% and 71%, respectively (Viviani, S et al).
In the above study after completion of the planned treatment, including salvage therapy, this seven year rate of freedom from a second progression was 88% for the BEACOPP group and 82% in the ABVD group, and the seven year rate of overall survival was 89% and 84%, respectively waived more frequent adverse events in the BEACOPP group.
About 15% of early d patients with unfavorable disease relapse within 5 years and 5% have primarily progressive disease.
About 1300 deaths from refractory disease in the US.
Of patients with advanced disease, almost 30% will have disease progression, with one third of these patients experiencing chemotherapy induction failure and two thirds of these patients will relapse after achieving complete remission.
Of patients with advanced disease that relapse 40-45% will relapse within 12 months of completing initial therapy, and outcome with conventional salvage therapy is poor.
ASCT in patients failing chemotherapy for advanced HD is better than stan salvage chemotherapy with an improved long-term disease free survival (Schmitz N et al).
Failure of or relapse from autologous SCT is associated with a dismal prognosis.
Autologous stem cell transplant is potentially curative treatment for some patients with progressive or recurrent HD after failing initial combination: effective in approximately 50% of such patients.
Relapse of HD after autologous stem cell transplant associated with 55% survival at 2 years and 32% at 5 years (Martinez C et al).
Most common secondary malignancies are solid tumors and acute leukemia.
Secondary malignancies most commonly involve the lung, breast, and digestive tract, organs that lie adjacent to radiation fields.
Oberved secondary cancers in 30,000 patients treated for HD associated with a 2.3 risk compared to expected risk.
Secondary malignancies are now the leading cause of death in the long term Hodgkin’s disease, survivors(Aleman BM et al).
Among the female Hodgkin’s disease survivors breast cancer is the most commonly diagnosed solid tumor (Dores GM e al)
For women treated for Hodgkin’s disease before age 30, the risk of developing breast cancer is six times greater than the general population with an excess risk of 20-40 occurrences per 10,000 patients annually.
The incidence of NHL range from 1- 5.9% following treatment for Hodgkin’s disease.
ABVD (doxirubicin, bleomycin, vinblastine, dacarbazine) results in a 5-year event-free-survival rates of 70-75%, overall survival rates of 85-90% with considerable risk of cardiotoxicity and secondary tumors when the mediastinum is treated with mantle field irradiation.
15 year tumor free survival rate after ABVD is 45% and overall survival is 60%.
ABVD as effective as ABVD plus radiation in early disease, suggesting the majority of patients are curable without being exposed to the risks of therapeutic radiation.
HD7 study of 650 patients in a randomized trial comparing combination chemotherapy with ABVD for two cycles followed by extended field radiotherapy vs extended radiotherapy alone in patients with newly diagnosed favorable disease: results at a median observation time of 87 months no difference in complete response rates (95 vs 94%), overall survival (92 vs 94%), but freedom from treatment failure was significantly better in the combination arm of 22% vs 3%.
Brentuximab is directed antibody drug-conjugate for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma, after other treatments have failed.
Brentuximab in Hodgkin’s disease indicated after failure of autologous stem cell transplant or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not autologous stem cell transplant candidates.
Research has demonstrated that brentuximab vedotin has helped improve the prognosis and survival of patients with Hodgkin lymphoma who had relapsed after stem cell transplantation or had refractory disease.
Overall response rate was 60.9%.
Stable disease was in 10.9% and progression was observed in 28.1% .
Progression-free survival (PFS) for the patient population was 14 months.
For patients with a complete or partial response to therapy, the median PFS was not reached by the end of the analysis, but patients with stable disease or progression had an event-free survival of 7 months.
It is most effective in patients with chemotherapy-sensitive disease and when used as a consolidation therapy immediately after ASCT.
Brentuximab Is an antibody conjugate directed against CD30.
In refractory HD patients the response rate to Brentuximab is 75% and complete remission rate of 34%.
Frontline Brentuximab plus ABVD has a response rate of 95%.
AETHERA trial tested the use of Brentuximab in patients that have undergone an autologous stem cell transplant and received maintenance Brentuximab-progression free survival was 61% at 3 years compared to 43% for placebo.
ECHELON-1 compared ABVD to AVD plus brentuximab in untreated Classic HD stage III/IV for up to 6 cycles: At 2 years the brentuximab group had PFS of 82.1% vs 77.2%, with a 23% lower risk of progression,and death.
In the he ECHELON-1 trial, investigators compared Adcentris plus AVD to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for stage III or IV Hodgkin lymphoma:The 3-year progression-free survival (PFS) was superior in patients who received A+AVD, and this benefit was seen across most subgroups.
in the above study in the non-bleomycin containing regimen, lower rates of pulmonary toxicity was seen with grade 3+ pulmonary toxicity, only seen in 1% of patients versus 3% in the ABVD group.
In children with recurrent disease the 5-year survival generally less than 35%.
Disease-free survival approximately 45% with combination chemotherapy for patients with poor prognostic features.
For women treated at a young age the increased risk of breast cancer is the main long-term concern.
Substantial amounts of radiation exposure to breast tissue in women treated with radiotherapy for Hodgkin’s disease.
Highest risk for increased risk of breast cancer after radiation occur in female patients treated between 10 and 20 years of age.
Most studies have not shown overall survival benefit for the addition of radiotherapy after a complete remission is induced by multiagent chemotherapy.
Some trials suggest the addition of radiation to polychemotherapy for advanced Hodgkin’s disease can increase progression free survival for patients with bulky disease, B-symptoms, nodular sclerosis histology and in young patients.
Long-term follow-up of patients treated with radiation revealed more deaths from radiation than from recurrent Hodgkin’s disease.
Mediastinal radiation for Hodgkin’s disease associated with 3 times increase in risk of myocardial infarction.
In a population of 5 year survivors there is a 3-5 fold increase in cardiovascular disease, even after a follow-up of 25 years.
Studies reveal a 2-7 fold increase risk of cardiotoxicity after radiation when the heart is included in part of the radiation field.
Radiation induce cardiotoxicity usually seen 5-10 years following radiotherapy.
In patients treated with anthracycline chemotherapy there is a 2 fold increased risk of CHF and valvular disorders, added to the effects of mediastinal radiation.
25 year cumulative incidence of CHF and cardiomyopathy is 7.9% after mediastinal radiation and anthracycline based chemotherapy.
Patients treated with radiation have a 25% risk at 25 years of having a second malignancy.
Hodgkin’s disease in children has a greater than 90% long-term survival in patients with favorable risk disease.
Studies demonstrate excess mortality among patients followed beyond 10 years from their childhood Hodgkin’s lymphoma diagnosis as a result of late toxic effects of therapy including the development of secondary neoplasms and nonneoplastic treatment complication.
Late complications of radiation therapy include secondary malignancies, particularly breast cancer, valvular heart disease, and premature coronary artery disease.
In a study evaluating efficacy of four cycles of vinblastine, Adriamycin, methotrexate, and prednisone (VAMP) in patients with favorable risk Hodgkin lymphoma of childhood who achieve a complete response after two cycles and did not receive radiotherapy vs. those with less than a complete response given involved field radiotherapy:both groups had about a 90% 2 year event free survival ( Metzger ML et al).
Ligand activation of programmed cell death 1 (PD-!) is common in HD and nivolumab induced an 87% response rate in heavily pretreated patients with refractory or relapsed disease.
PD-1 inhibitors have a high overall response rates and durable responses.
Nivolumab has been approved to treat patients with classic HL that has relapsed or progressed after autologous hematopoietic cell transplant and post-transplant brentuximab vedotin.
Pembrolizumab had a 86% respone rate in patients with HD that failed brentuximab.
In classic Hodgkin’s disease pembrolizumab treatment among relapsed and refractory patients associated with an overall response rate of 69% and a complete remission rate of 22.4% (Chen R).
In the S 1826 brentuximab was compared with nivolumab when combined with the active chemotherapy AVD (No bleomycin):the two year progression free survival was 92% with nivolumab plus AVD as compared with 83% with brentuximab plus AVD.
NivolumabABD Was also more effective in older patients.
Newer regimens of gemcitabine, vinorelbine, pehylated liposomal doxorubicin (GVD), ifosphamide, gemcitabine, vinorelbine (IGEV), gemcitabine,carboplatin,dexamethqsone (GCD) have demonstrated efficacy in relapsed/recurrent disease, as has bendamustine, lenalididomide and everolimus.
Bendamustine is highly active in heavily pretreated patients with refractory and relapsed HD with an overall response rate of 56% among evaluable patients.
Bendamustine plus gemcitabine and vinorelbine used as an induction therapy for AMBT in patients with relapsed or refractory disease had an overall response rte of 83%.
Positron emission tomography (PET) scanning is used to assess the stage of disease and for follow-up with a negative scan after treatment the best indicator of a durable remisssion.
A negative PET scan after treatment indicates the patient is likely to have a long term remission and potentially cure rate of about 90%.
PET scan after two cycles of induction with BEACOPP chemotherapy can guide treatment in patients with advanced Hodgkin’s lymphphoma to allow the use of ABVD the less toxic regimen in early responders without impairing disease control and reducing toxicities.
Brentuximab plus AVD (doxorubicin, Vinblastine, and dacarbazine:A+AVD compared with ABVD in advanced Hodgkin’s disease showed improvement in overall survival of 4.5 percentage points.
Some patients treated with checkpoint inhibitors and other immunotherapies experience a flare reaction, and suggest reassessment to therapy should not be too early.
The addition of brentuximab to standard chemotherapy result in a superior efficacy rate with a 59% lower risk of an event or death and no increase in incidence of toxic effects at three years, in pediatric patients with high risk Hodgkin’s lymphoma.
Adding the immune checkpoint inhibitor nivolumab to chemotherapy significantly improves progression-free survival in advanced stage Hodgkin lymphoma while also reducing toxicities, making it a new standard of care, compared with the CD30-targeting drug brentuximab vedotin.
The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab to AVD.